Doctoral Thesis Effectiveness of Tumor Necrosis Factor Inhibitors in Patients

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Bente Glintborg 2018 Effectiveness of tumor necrosis factor inhibitors in patients with psoriatic arthritis and axial spondyloarthritis 5 - 0 - 970989 - 87 - ISBN 978 ISBN Doctoral thesis Doctoral 2018 Glintborg, Bente

Doctoral thesis

Effectiveness of tumor necrosis factor inhibitors in patients with psoriatic arthritis and axial spondyloarthritis – treatment response, drug retention and predictors thereof

Results from the nationwide DANBIO registry

Bente Glintborg, MD, PhD 2018

The DANBIO registry and Copenhagen Center for Arthritis Research, COPECARE Center for Rheumatology and Spine Diseases Centre of Head and Orthopedics Rigshospitalet

ISBN 978-87-970989-0-5

The Faculty of Health and Medical Sciences at the University of Copenhagen has accepted this dissertation, which consists of the already published dissertations listed below, for public defence for the doctoral degree in Medicine. Copenhagen, 17 October 2018. Ulla Wewer, Head of Faculty

The defence will take place at Rigshospitalet, Glostrup, Auditorium C, 23 November 2018

List of contents

List of contents ...... 3

Preface ...... 6

Abbreviations...... 8

Publications ...... 10

1. Introduction ...... 13

2. Aims ...... 14

2.1. Overall aim ...... 14

2.2. Specific aims ...... 14

3. Background ...... 15

3.1. Spondyloarthritis ...... 15

3.1.1. PsA, disease manifestations and classification criteria ...... 16

3.1.2. PsA, outcome measures and response criteria ...... 16

3.1.3. AxSpA, classification criteria and disease manifestations ...... 17

3.1.4. AxSpA, outcome measures and response criteria ...... 17

3.1.5. Treatment strategies in PsA and AxSpA ...... 18

3.2. How to study bDMARD treatment outcomes, efficacy versus effectiveness ...... 19

3.3. Predictors of treatment effectiveness in PsA and axSpA ...... 20

3.4. Real world registries ...... 21

4. Patients and methods ...... 23

4.1. Cohorts and study design ...... 23

4.1.1. Patient inclusion ...... 23

4.1.2. Patient exclusion ...... 26

4.2. Validation of data in DANBIO ...... 26

4.3. Baseline characteristics, measures of disease activity and outcomes ...... 27

4.4. Comorbidities ...... 29

4.5. Ethics...... 30

4.6. Statistical analysis ...... 30

5. Summary of results ...... 33

5.1. Baseline demographics of study cohorts ...... 33

5.2. Summary of results and discussion according to specific aims ...... 35

5.2.1. Treatment response, treatment retention, and predictors thereof during the first TNFi treatment course in PsA (Specific aim 1, Paper 1) ...... 35

5.2.2. Treatment response, treatment retention, and predictors thereof among PsA patients switching to a subsequent bDMARD (Specific aim 2, Paper 2)...... 37

5.2.3. Impact of different infliximab dose regimens on treatment response and treatment retention during the first TNFi treatment course in PsA (Specific aim 3, Paper 3) ...... 38

5.2.4. The impact of smoking on baseline disease activity and outcomes during the first TNFi treatment course in PsA (Specific aim 4, Paper 4) ...... 41

5.2.5. Treatment response, treatment retention, and predictors thereof during the first TNFi treatment course in patients with AS (Specific aim 5, paper 5) ...... 42

5.2.6. Treatment response, treatment retention, and predictors thereof among AS patients switching to a subsequent bDMARD (Specific aim 6, paper 6) ...... 43

5.2.7. The impact of smoking on baseline disease activity and outcomes during the first TNFi treatment course in patients with AS (Specific aim 7, paper 7) ...... 45

5.2.9. The impact of switch from originator to biosimilar infliximab on disease activity and one-year treatment retention (Specific aim 9, paper 9) ...... 49

6. Methodological considerations ...... 51

6.1. Data quality and interpretation ...... 51

6.2. Confounders included in multivariable analyses ...... 54

6.3. Other methodological considerations ...... 58

7. Discussion of future perspectives ...... 59

7.1. Data enrichment ...... 59

7.2. Collaboration across countries ...... 60

7.3. Important research questions for future registry research ...... 61

7.3.1. The biosimilar drugs ...... 61

7.3.2. Treatment strategy, switching and prediction of response ...... 62

8. Conclusion ...... 64

9. Danish summary ...... 65

10. English summary ...... 66

11. References ...... 68

12. Papers 1-9 ...... 89

Preface The writing of this doctoral thesis is the result of several years of hard work and research. Dedicated stubbornness and a wish to prove that it is possible are obligatory elements. But first and foremost, the thesis is the result of a fruitful and positive collaboration with colleagues and experienced researchers. There is no doubt that this doctoral thesis would not have happened if it was not for professor Merete Lund Hetland and professor Mikkel Østergaard. We first met when I was in the beginning of my rheumatology specialist training in 2008. I was totally inexperienced within the field of rheumatology, but they guided me patiently and introduced me to the epidemiological research methodology, outcome measures and of course the DANBIO registry. They trusted me to analyze the first DANBIO data on patients with ankylosing spondylitis – until then the registry had mainly published within rheumatoid arthritis. Since then Merete has continuously been my guide and mentor, she has willingly shared her time, her experience, ideas and network, and she has encouraged and inspired me to do research for more than a decade. She was the main initiator behind the Danish Rheumatologic Biobank and she facilitated my employment as a national clinical project leader. This gave me the opportunity to do research during the daytime in parallel with the implementation of the biobank and my employment as a senior consultant at department of rheumatology at Gentofte University Hospital. Thanks to Head of Department, Henrik Røgind and Senior Nurse, Tine Lundbak, Center for Rheumatology and Spine Diseases for their support and willingness to provide time for my research. Without their flexibility it would not have been possible to combine research with my employment at Gentofte. Furthermore, I would like to thank senior consultant Annette Hansen who I first met at Herlev Hospital in 2008 where she taught me how to treat and diagnose within the field of rheumatology. She encouraged me to apply for the job as senior consultant at department of rheumatology at Gentofte when I reached the last year of my specialist training. Since then she has patiently accepted my requests to get more time for research and less time to see patients in the clinic. It has not been easy to get a functioning work schedule with me as an employee, but she has always been supportive. Thanks to senior consultant Lene Dreyer, who has excellent knowledge within epidemiological research and who has been my colleague for several years. She has always been there for advice and scientific discussions. And thank you to all my other good friends and colleagues at the departments of rheumatology at Gentofte and Glostrup (none mentioned none forgotten). It is a major privilege to have continuous clinical work and research anchored at two such inspiring departments. Thank you to all the co-authors from the local departments of rheumatology who willingly have agreed to validate their data in DANBIO. More and more departments have been interested to participate in the research

6 process during the later years, and I take this as a sign that you find the research projects (nearly) as interesting as I do. Thank you to all the other collaborators, professor Björn Guðbjörnsson from Iceland, and the DANBIO secretariat – Dorte Vendelbo Jensen, Sandra Zbinden Pedersen and Rikke Hodal Meincke. There would be no DANBIO and there would be no thesis if it was not for Niels Steen Krogh, Zitelab. I have not fully understood his time-optimistic approach to deadlines and data delivery dates. But Niels never rejects an idea or says that something is impossible – and we have always somehow succeeded to comply with the deadlines in the end. My deepest appreciation for my mother, Sonja – who brought two ambitious twin daughters into this world so many years ago, and my father, Meiner who although he died before I finished medical school would have been ever so proud if he could have experienced this. The best and most important of all is saved for last: My ever-understanding husband Henrik who has encouraged and accepted that I spend time in front of the computer during yet another evening and who has supported me repeatedly during the writing of this thesis. Without you this would not have been possible. And to the two sweet blondes, Mille and Kalle – you are more important than any registry and any research in the world.

Bente Glintborg Winter 2017

Post scriptum, Fall 2018 I would like to thank the assessment committee, Professor Axel Finckh, University of Geneva, Switzerland, Professor Oliver Fitzgerald, University College Dublin, Ireland and Professor Søren Jacobsen, University of Copenhagen, Denmark.

Abbreviations ACR: American College of Rheumatology ADA: Anti-drug antibodies AE: Adverse Event Anti-CCP: anti-cyclic citrullinated peptide AS: Ankylosing Spondylitis ASAS: Assessment of SpondyloArthritis ASDAS: Ankylosing Spondylitis Disease Activity Score AxSpA: Axial Spondyloarthritis BAS: Bath Ankylosing Spondylitis BASDAI: Bath Ankylosing Spondylitis Disease Activity Index BASFI: Bath Ankylosing Spondylitis Function Index BASMI: Bath Ankylosing Spondylitis Metrology Index bDMARDs: biologic Disease Modifying Antirheumatic Drugs BMI: Body Mass Index CRP: C-reactive protein csDMARD: conventional synthetic Disease Modifying Antirheumatic Drugs DAPSI: Disease activity in Psoriatic Arthritis DAS28: Disease Activity Score (28 joints) EULAR: European League of Rheumatology HAQ: Health Assessment Questionnaire HLA-B27: Human Leukocyte Antigen – B27 HR: Hazard Ratio IBD: Inflammatory Bowel Disease IgM-RF: Immunoglobin M-Rheumatoid Factor IL: Interleukin IQR: Inter-Quartile Ranges LOE: Lack Of Effect MDA: Minimal Disease Activity MOA: Mode Of Action MRI: Magnetic Resonance Imaging MTX: Methotrexate NNT: Numbers Needed to Treat

Nr-axSpA: Non radiographic axial Spondyloarthritis NSAIDs: Non Steroid Anti-Inflammatory Drugs PsA: Psoriatic Arthritis PsO: Psoriasis RADS: Rådet for Anvendelsen af Dyr Sygehusmedicin RCT: Randomized Controlled Trial SI-joints: Sacroiliac joints SpA: Spondyloarthritis TNF: Tumor Necrosis Factor TNFi: Tumor Necrosis Factor Inhibitor US: Ultrasound VAS: Visual Analogue Scale

Publications The present doctoral thesis is based on the following 9 publications which in the following are cited as Paper 1, Paper 2 etc. The papers are available as appendices.

Paper 1 Bente Glintborg, Mikkel Østergaard, Lene Dreyer, Niels Steen Krogh, Ulrik Tarp, Michael Sejer Hansen, Signe Rifbjerg-Madsen, Tove Lorenzen, Merete Lund Hetland Treatment response, drug survival, and predictors thereof in 764 patients with psoriatic arthritis treated with anti-tumor necrosis factor α therapy: results from the nationwide Danish DANBIO registry. Arthritis & Rheumatology 2011 Feb;63(2):382-901

Paper 2 Bente Glintborg, Mikkel Østergaard, Niels Steen Krogh, Martin Dehn Andersen, Ulrik Tarp, Anne Gitte Loft, Hanne M. Lindegaard, Mette Holland-Fischer, Henrik Nordin, Dorte Vendelbo Jensen, Christian Holkmann Olsen, Merete Lund Hetland Clinical response, drug survival, and predictors thereof among 548 patients with psoriatic arthritis who switched tumor necrosis factor α inhibitor therapy: results from the Danish Nationwide DANBIO Registry Arthritis & Rheumatology 2013 May;65(5):1213-232

Paper 3 Bente Glintborg, Bjorn Gudbjörnsson, Niels Steen Krogh, Emina Omerovic, Natalia Manilo, Mette Holland- Fischer, Hanne M. Lindegaard, Anne Gitte Loft, Henrik Nordin, Laura Johnsen, Sussi Flejsborg Oeftiger, Annette Hansen, Claus Rasmussen, Gerdur Grondal, Arni Jon Geirsson, Merete Lund Hetland Impact of different infliximab dose regimens on treatment response and drug survival in 462 patients with psoriatic arthritis: results from the nationwide registries DANBIO and ICEBIO Rheumatology (Oxford) 2014 Nov;53(11):2100-93

Paper 4 Pil Højgaard/Bente Glintborg, Merete Lund Hetland, Torben Højland Hansen, Philip Rask Lage-Hansen, Martin H. Petersen, Mette Holland-Fischer, Christine Nilsson, Anne Gitte Loft, Bjarne Nesgaard Andersen, Thomas Adelsten, Jørgen Jensen, Emina Omerovic, Regitse Christensen, Ulrik Tarp, René Østgård, Lene Dreyer Association between tobacco smoking and response to tumour necrosis factor α inhibitor treatment in psoriatic arthritis: results from the DANBIO registry

Annals of the Rheumatic Diseases 2015 Dec;74(12):2130-64

Paper 5 Bente Glintborg, Mikkel Østergaard, Niels Steen Krogh, Lene Dreyer, Hanne Lene Kristensen, Merete Lund Hetland Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years' surveillance in the Danish nationwide DANBIO registry Annals of the Rheumatic Diseases 2010, Nov;69(11):2002-85

Paper 6 Bente Glintborg, Mikkel Østergaard, Niels Steen Krogh, Ulrik Tarp, Natalia Manilo, Anne Gitte Loft, Annette Hansen, Annette Schlemmer, Victoria Fana, Hanne M. Lindegaard, Henrik Nordin, Claus Rasmussen, Leif Ejstrup, Dorte Vendelbo Jensen, Peter Mosborg Petersen, Merete Lund Hetland Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor α inhibitor therapy: results from the Danish nationwide DANBIO registry Annals of the Rheumatic Diseases 2013 Jul;72(7):1149-556

Paper 7 Bente Glintborg, Pil Højgaard, Merete Lund Hetland, Niels Steen Krogh, Gina Kollerup, Jørgen Jensen, Stavros Chrysidis, Inger Marie Jensen Hansen, Mette Holland-Fischer, Torben Højland Hansen, Christine Nilsson, Jakob Espesen, Henrik Nordin, Anne Gitte Loft Rasmussen, Randi Pelck, Tove Lorenzen, Sussi Flejsborg Oeftiger, Barbara Unger, Frank Jaeger, Peter Mosborg Petersen, Claus Rasmussen, Lene Dreyer Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry Rheumatology (Oxford) 2016 Apr;55(4):659-687

Paper 8 Bente Glintborg, Inge Juul Sørensen, Mikkel Ostergaard, Lene Dreyer, Abdiweli Awil Mahamoud, Niels Steen Krogh, Oliver Hendricks, Lis Smedegaard Andersen, Johnny Lillelund Raun, Marcin R. Kowalski, Laura Danielsen, Randi Pelck, Henrik Nordin, Jens Kristian Pedersen, Dorte Gunver Adsersen Kraus, Susan Ringskær Christensen, Inge Marie Jensen Hansen, Jakob Esbesen, Annette Schlemmer, Anne Gitte Loft, Nabil al Chaer, Lone Salomonsen, Merete Lund Hetland

Ankylosing Spondylitis versus Nonradiographic Axial Spondyloarthritis: Comparison of Tumor Necrosis Factor Inhibitor Effectiveness and Effect of HLA-B27 Status. An Observational Cohort Study from the Nationwide DANBIO Registry J Rheumatol 2017 Jan;44(1):59-698

Paper 9 Bente Glintborg, Inge Juul Sørensen, Anne Gitte Loft, Hanne Lindegaard, Asta Linauskas, Oliver Hendricks, Inger Marie Jensen Hansen, Dorte Vendelbo Jensen, Natalia Manilo, Jakob Espesen, Mette Klarlund, Jolanta Grydehøj, Sabine Sparre Dieperink, Salome Kristensen, Jimmi Sloth Olsen, Henrik Nordin, Stavros Chrysidis, Dorte Dalsgaard Pedersen, Michael Veedfald Sørensen, Lis Smedegaard Andersen, Kathrine Lederballe Grøn, Niels Steen Krogh, Lars Pedersen, Merete Lund Hetland A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis - one year clinical outcomes from the DANBIO registry Annals of the Rheumatic Diseases, 2017;76(8):1426-1439

1. Introduction The disease spectrum of spondyloarthritis (SpA) includes heterogeneous diseases such as psoriatic arthritis (PsA), axial spondyloarthritis (axSpA) and ankylosing spondylitis (AS). During the last 1-2 decades, treatment with tumor necrosis factor inhibitors (TNFi) has substantially improved patient outcomes in these diseases. The frequency of SpA in Europe is estimated to be 1.2% 10;11 and the diseases within the spectrum are associated with chronic pain, poorer quality of life and decreased work productivity.12;13 When a drug is marketed, treatment effects and safety have been studied in randomized clinical trials (RCTs). The strict inclusion and exclusion criteria and the focus on short term outcomes applied in RCTs is different from the routine care situation where heterogeneous patient groups are treated for long periods of time and the monitoring is less tight. This gap between the RCT and routine care is increasingly acknowledged and emphasizes the need for studies of treatment effectiveness: how does the drug perform when applied in daily routine care? Thus, real world evidence through post-marketing monitoring of safety and long-term outcomes in nationwide registries with prospective follow-up in routine care is increasingly acknowledged as a valuable supplement to RCTs.14-17 In clinical settings, TNFi treatment failure due to insufficient treatment response or adverse events is frequent and occurs in up to 30-40% of patients.18-20 Valid tools to predict outcomes and pin-point the patients most likely to benefit from treatment are still very limited and personalized treatment strategies addressing specific patient characteristics are practically non-existing. Treatment strategies follow a schematic algorithm where all patients are approached similarly and treated according to disease severity.21;22 Whenever one treatment fails, the clinician has very limited options to predict whether the next treatment will be successful, and treatments are administered according to a trial-and-error rationale. The introduction of the expensive biological treatments has facilitated the need for clinical registries that could be used for monitoring of treatment outcomes within the rheumatologic diseases. In addition to being a tool on the individual patient level, these registries may also provide research data regarding e.g. treatment effectiveness and long term safety. Lately, marketing of the biosimiar biological drugs has highlighted the need for post-marketing observational research.23 In Denmark, patients with inflammatory arthritis are followed prospectively in the DANBIO registry, which enables research on real- life effectiveness, switching and predictors of response.

2. Aims

2.1. Overall aim The aim of the present thesis was to investigate long-term TNFi treatment effectiveness in patients with axSpA and PsA based on data from the nationwide DANBIO registry, and to identify clinical characteristics and other factors associated with outcomes. Paper 9 also included patients with RA, but it is beyond the scope of this thesis to describe this patient subgroup in further details.

The overall aim involved the following specific aims (with corresponding paper in parentheses):

2.2. Specific aims To investigate treatment response and drug retention rate in patients with PsA who: 1. Initiated first TNFi treatment course (Paper 1) 2. Switched from the first to a subsequent bDMARD (Paper 2) In patients with PsA initiating their first TNFi treatment course to investigate the impact of 3. Infliximab dose regimens (Paper 3) 4. Tobacco smoking (Paper 4)

To investigate treatment response and retention in patients with AS who: 5. Initiated first TNFi treatment course (Paper 5) 6. Switched from the first to a subsequent bDMARD (Paper 6) In patients with AS initiating their first TNFi treatment course 7. To investigate the impact of tobacco smoking (Paper 7)

In patients with axSpA initiating their first TNFi treatment course in routine care to investigate: 8. The impact of axSpA sub-diagnosis (AS versus non-radiographic axial SpA (nr-axSpA)) on treatment response and treatment retention (Paper 8)

In patients with inflammatory arthritis who switched from originator to biosimilar infliximab (CT-P13) to investigate 9. The impact of the switch on disease activity and one-year treatment retention (Paper 9)

3. Background

3.1. Spondyloarthritis The disease spectrum of spondyloarthritis (SpA) consists of a group of diseases with common clinical and genetic characteristics. The main disease entities are PsA, AS, reactive arthritis and arthritis related to inflammatory bowel disease.24 Since the concept of related seronegative spondyloarthritides was initially suggested several decades ago,25 the nomenclature of these diseases has evolved. Depending on the clinical disease presentation, SpA can be sub-divided into axial SpA (axSpA) and peripheral SpA (Figure 1).26;27 Clinical features include inflammatory back pain and sacroiliitis, peripheral arthritis, enthesitis, dactylitis, anterior uveitis, psoriasis, inflammatory bowel disease and presence of the HLA-B27 antigen.24;27 In the following, focus will be on the disease entities PsA and axSpA (including AS).

Figure 1. The disease spectrum of SpA, adapted from reference 27 Schematic diagram showing the main diagnoses within the SpA spectrum

3.1.1. PsA, disease manifestations and classification criteria PsA is a heterogeneous disease with various disease manifestations such as involvement of skin, peripheral joints, entheses, nails and axial joints. Various classification criteria have been suggested28 of which the criteria by Moll and Wright (1973)29 and the CASPAR classification criteria (2006)30 are most widely used. Where the Moll and Wright criteria are very simple (inflammatory arthritis, psoriasis and IgM rheumatoid factor sero-negativity), the CASPAR criteria include both dermatologic, rheumatologic and radiographic features.31 Current RCTs mainly use the CASPAR criteria due to their high sensitivity and specificity. It has been attempted to group the patients according to classical disease presentations. Moll and Wright suggested 5 subgroups: predominant distal interphalangeal joint disease, asymmetric oligoarthritis, polyarthritis, spondylitis and arthritis mutilans.29 Some classical disease features may be seen in PsA: Enthesitis is characterized by inflammation at the site of attachments of tendons, ligaments and joint capsule fibers. Enthesitis is frequent in PsA but only rarely seen in RA and may affect e.g. the Achilles tendon and fascia plantaris.32 Dactylitis – inflammation of an entire digit due to tenosynovitis, synovitis and subcutaneous swelling is another classical feature.33 However, it remains a challenge to correctly establish the PsA diagnosis in routine care due to overlapping patterns to other SpA related diseases, to RA, fibromyalgia and osteoarthritis.31;34

3.1.2. PsA, outcome measures and response criteria PsA may cause arthritis, enthesitis, dactylitis, spondylitis, psoriasis and nail disease, and measures for each of these clinical domains have been developed (reviewed in 35). Measures of peripheral arthritis are reported as 28 swollen/tender joint count similar to what is done in patients with RA36 – or the 68/66 tender/swollen joint count.37 Patient reported outcomes are patient’s global score measured on an visual analog scale, fatigue and pain, whereas the Health Assessment Questionnaire (HAQ) may be applied as a measurement of functional status.33 The composite tool DAS28 includes the 28 joint count (swollen/tender), CRP and patient’s global score,36 whereas the disease score DAPSA (Disease activity in PsA) includes a 66/68 joint count, patient’s scores of pain and global and the CRP value. In routine care, the DAS28 score is the composite disease activity score most frequently applied. DAS28 was initially developed and validated for RA, but studies have reported DAS28 to be an acceptable measure of disease activity in PsA.38 Similarly, the ACR20/50/70 response and the EULAR good/moderate response may be applied for changes in disease activity, although these measures are also adapted from RA.39;40 A major disadvantage is that these measures only include the 28 joint-count and thus e.g. the distal interphalangeal joints, which are often affected in PsA, are not included. It is increasingly acknowledged that PsA in some ways is a more complex disease than RA. Several efforts have been made to construct multidimensional scores able to further capture disease

16 manifestations of the skin, enthesitis, dactylitis and spinal disease (e.g. the composite psoriatic disease activity index (CPDAI), Minimal Disease Activity (MDA), the PsA Disease Activity Score (PASDAS))(reviewed in 41). These efforts are mainly driven by the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) and the Outcome Measures in Rheumatology (OMERACT).35;42;43

3.1.3. AxSpA, classification criteria and disease manifestations The classical disease within axSpA is AS, which is characterized by back pain, stiffness and limited range of movement combined with radiographic changes in the sacroiliac joints according to the modified New York criteria (1984).44 However, acknowledging that early inflammatory disease is not captured by the New York criteria, the Amor criteria (1990) and the European Spondylarthropathy Study Group (ESSG) criteria (1991)45 were developed.46;47 In year 2009, the ASAS (Assessment of Spondyloarthritis International Society) classification criteria for axSpA were published.47;48 The ASAS criteria illustrate an emphasis on diagnosing disease early before the development of radiographic changes. The criteria may be applied to patients with back pain (≥3 months) and age ≤45 years at onset. Sacroiliitis on imaging (MRI or radiographs) or HLA-B27 positivity combined with ≥1 or ≥2 SpA features, respectively, are necessary to fulfil the criteria.47 SpA features are arthritis, enthesitis, uveitis, dactylitis, psoriasis, inflammatory bowel disease, response to NSAIDs, SpA family history, HLA-B27 positivity and elevated CRP.47;49 Thus, the disease spectrum of axSpA includes patients with radiographic axSpA, who fulfil the modified New York criteria for AS, and patients with nonradiographic axial SpA (nr-axSpA) who have either sacroiliitis on MRI with one additional SpA feature or who are HLA-B27 positives with two additional features.

3.1.4. AxSpA, outcome measures and response criteria The Bath Ankylosing Spondylitis Disease Activity score (BASDAI) was introduced in year 1994 and is the most widely used measure of patient reported disease activity in axSpA.50 The BASDAI consists of six 10 cm horizontal VAS scales that measures fatigue, spinal and peripheral joint pain, tenderness and morning stiffness. The final score ranges from 0-10 cm (best-worst).50 The BAS Function Index (BASFI) constitutes a patient self-reported measurement of function (0-10, best-worst),51 and the BAS Metrology Index (BASMI) is five clinical measures that reflect axial mobility (final score 0-10, best-worst).52 The ASAS group has suggested core sets on how to monitor axSpA patients in routine care (reviewed in 47) – and besides the three BAS scores, routine monitoring of CRP, evaluation of joints and entheses (44-joint count and validated enthesitis scores) and patient’s VAS global, pain and fatigue are included.53 The ASAS group has endorsed response criteria based on relative changes in the BASDAI score:

ASAS20 and ASAS40 improvement and ASAS 5/6 improvement criteria or achievement of a low absolute score (ASAS partial remission criteria).54;55 In year 2009, the ASDAS score was developed56 which is calculated based on measures of CRP (alternatively erythrocyte sedimentation reaction), back pain, peripheral pain, patient’s global score, and morning stiffness. The cut off values are suggested to be 1.3, 2.1 and 3.5 units for inactive, moderate, high and very high disease activity, respectively.57 In routine care, it is convenient to apply the BASDAI50%/20mm response criteria (a 50% relative or 20 mm absolute reduction in the BASDAI score), which solely relies on the change in the BASDAI score.58;59

3.1.5. Treatment strategies in PsA and AxSpA In 2003, treatment with bDMARDs was approved for the treatment of PsA and AS. Until the 1990’es and the beginning of the 2000’s, the main treatment option in PsA had been conventional synthetic disease modifying antirheumatic drugs (csDMARDs) whereas it was physiotherapy and non-steroid anti- inflammatory drugs (NSAIDs) in axSpA. The first bDMARD available was infliximab followed by etanercept and adalimumab, later came golimumab and certolizumab pegol. These drugs are all inhibitors of the tumor necrosis factor (TNF) pathway.20;60-63 Lately, drugs with other modes of action (MOA) have been introduced e.g. secukinumab (Interleukin (IL)17A blocker), ustekinumab (IL12/23 inhibition), apremilast (phosphodiesterase 4 inhibition) – and several treatments targeting other immune-pathways are expected.64 As patents on the originator bDMARDs expire, the cheaper biosimilars are developed.65 A biosimilar may be defined as a ‘biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference product’.65 Due to the complexity of the molecules, a biosimilar is never completely identical to the originator product. Extensive regulations have evolved to ensure comparable efficacy and safety of the biosimilar and the reference product.66 In year 2015, the first biosimilar bDMARD was marketed in Denmark, namely CT-P13 (biosimilar infliximab) which was followed by biosimilar etanercept, SB4, in 2015. Numerous biosimilars are expected in the coming years.66 Treatment algorithms and guidelines for bDMARD treatment (including biosimilars) in PsA and axSpA are available from ASAS/EULAR and the Danish Society of Rheumatology. Within both disease entities, bDMARDs are administered in patients with progressive inflammatory disease and insufficient response to conventional treatment. Several treatment options are available and new treatments are emerging, and the guidelines are thus updated regularly.58;59;67-72 There is no doubt that the availability of bDMARDs differs between countries and that political and health economic factors have an impact on the penetration of these expensive drugs.73 In Denmark, bDMARDs for rheumatic diseases can only be prescribed and administered at hospital

18 departments of rheumatology and not by private practitioners. The drugs are fully reimbursed and of no cost to the individual patient. Thus, social factors and economic status should have minimal impact on which patients receive treatment. Until year 2012, it was the responsibility of the treating physician to choose between the bDMARDs. Since 2012, the council for the use of expensive hospital medicines (Rådet For Anvendelse af Dyr Sygehusmedicin, RADS – now Medicinerrådet) has provided treatment guidelines regarding first and second line bDMARD treatment.74 This has had a major impact on the bDMARD prescription patterns in Danish routine care.75;76

3.2. How to study bDMARD treatment outcomes, efficacy versus effectiveness When a drug is marketed, experience mainly stems from randomized controlled clinical trials (RCTs) which study the safety and efficacy of the drug under controlled conditions.77 Thus, these trials are characterized by strict inclusion criteria, exclusion of patients with comorbidities or disease complications resulting in a homogeneous and motivated patient group, use of many resources and expert staff, and close adherence to a study protocol. Due to this strict standardization of the setting combined with randomization and blinding of treatment, any positive or negative result is attributed to the intervention. The therapeutic benefits of bDMARDs in AS and PsA have been documented in RCTs. (reviewed in 19;78) However, when the drug subsequently is used in routine care, the patient group is large and heterogeneous with higher age and various comorbidities, risk of non-adherence to treatment, less stringent administration of drug (dose, interval) and use of routine care staff which may influence outcomes. It has previously been demonstrated that the majority of patients treated in routine care would not comply with RCT inclusion criteria.17;79 The extent to which a drug achieves its intended effect and tolerability in the usual clinical setting may be defined as treatment effectiveness.77 Treatment retention is the extent to which the patients remain on treatment. Retention is a proxy outcome parameter expressing both effectiveness and safety and may be perceived as a combination of benefits and risks of the treatment.80 Observational studies and RCTs are thus complementary methods with each their strengths and weaknesses.81;82 An obvious advantage of the observational study design is that patients treated in routine care irrespective of disease severity, age and comorbid disease are included. Furthermore, observational data allows longer follow up periods of a large number of patients and research questions not addressed in RCTs may be investigated e.g. switching and comparison of treatment effects according to drug type. Disadvantages include lack of randomization and risks of bias or confounding. A bias is ‘a systematic error in the design, recruitment, data collection or analysis that results in mistaken estimation of the true effect of exposure on outcome’.83 Examples of bias include selection bias

(systematic error in the selection and retention of patients) and misclassification/information bias (inaccurate classification of disease or exposure or other variables e.g. misdiagnosis and missing data). A confounder is a variable, which distorts the measure of the association between exposure and outcome.83 Thus, a confounder wholly or partially accounts for the observed effect of a risk factor on disease status. The following applies to a confounder: It is an independent risk factor for the outcome, it is associated with the risk factor, and it is not on the causal pathway between exposure and disease.83 Examples of bias and confounding in the papers included in the present thesis are further discussed below (results Section 5.2. and methodological considerations Section 6.2.).

3.3. Predictors of treatment effectiveness in PsA and axSpA Although treatment with bDMARDs has revolutionized the treatment of PsA and axSpA, many patients do not benefit from treatment due to adverse events or insufficient treatment response. The treatments are expensive and patients may potentially be harmed due to risk of adverse events. Therefore, it is important to correctly identify the patients most likely to benefit from treatment early during the treatment course or even before the treatment commences. As discussed above, the extrapolation from RCTs to routine care is a challenge as the patients who actually receive treatment with a specific drug may differ from the patients who were included in the original trials. Various factors are potentially associated with treatment effectiveness. Some factors apply to patient demographics or biological factors that could influence drug pharmacokinetics, dynamics and/or immunogenecity (e.g. body mass index, gender, age, co-medication with csDMARDs, comorbidities). Others relate to disease status and potential for reversibility (disease duration, radiographic changes) whereas some factors are of a strategic (or political) character. For example, the marketing of more bDMARDs might encourage faster bDMARD switching in case of lack of effect. Similarly, introduction of biosimilars might potentially facilitate treatment initiation at an earlier time point during the disease course due to lower price. Treatment guidelines and time trends (patient/physician demands of a certain treatment, pricing, availability of drug) are other factors that might have an impact on disease duration and disease status at the time of treatment initiation and thereby affect effectiveness.82 Clinical factors potentially associated with treatment effectiveness are shown in Table 1.84;85

Table 1 Baseline factors potentially associated with treatment outcomes

Demographic features Gender Age Disease duration Smoking Body mass index Comorbidities Socioeconomic status Disease characteristics Classification criteria (e.g. HLA-B27 in ax-SpA) Disease activity (e.g. CRP, patient reported outcomes) Disease status (functional status, radiographic changes, early/late disease) Disease phenotype (e.g. peripheral/axial) Treatment strategy bDMARD drug type Originator bDMARD versus biosimilar bDMARD dose regimen Co-medication with csDMARDs Number of previous bDMARD treatment courses Reason for stop of previous bDMARD Other* Biomarkers measured in biological material (blood) Imaging results (MRI, US etc.) * It is beyond the scope of the present theses to discuss biomarkers measured in blood/biological material in further detail. Furthermore, imaging will not be addressed.

3.4. Real world registries Registries may be defined as ‘longitudinal observational cohorts, typically prospective, which enroll patients with a specific purpose; it could either be drug- or disease-based or both’.86 Registries represent an excellent source of information regarding medication use and treatment effectiveness in routine care. Furthermore, several of the factors potentially associated with treatment outcomes mentioned above may be identified in registries. In order to ensure external validity and generalizability, the registry should have high completeness and should include and follow patients who are representative of the typical patient. Thus regarding bDMARDs, (almost) all users of the drug should be included in the registry – or at least a random patient sample in order to avoid selection during recruitment of patients.87 Furthermore, the patients should be monitored with close intervals in order to capture changes in disease activity, concomitant treatment with csDMARD or other signs of bDMARD failure/response.87 The marketing of the bDMARDs has encouraged the establishing of registries within rheumatology in several European countries, including the Danish DANBIO registry, in the Unites States and across the world.14;88;89 Whereas several focus on RA, others include patients with axSpA and PsA, e.g. the SCQM of Switzerland, the BIOBADASER of Spain, the LORHEN of Italy, the BSRBR-AS of UK, the SRQ, ARTIS and SwePsA of Sweden, just to mention examples from Eurpean countries.88-91 The registries are often

21 initiated in collaboration with the national societies of rheumatology aiming to improve pharmacovigilance and knowledge on treatment effectiveness and long term safety.14 Pharmacovigilance is by the World Health Organization defined as ‘the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem’.92 However, it also lies within the responsibilities of the registries to investigate long term disease outcomes, quality of life and to perform independent research.14 DANBIO is a Danish nationwide rheumatologic registry that was initiated in year 2000.93;94 The registry is approved by the Danish Board of Health and the Danish Data Protection Agency. In the early years, data were submitted to DANBIO by paper formulas. Since 2006, all data entry has occurred prospectively by an online system (www.danbio-online.dk). Patient report outcomes and data regarding comorbidities, smoking and lifestyle by touch screens in the waiting area.95 It is mandatory to include the following patient groups in DANBIO: 1) all rheumatic patients treated with bDMARDs (irrespective of diagnosis) and 2) all newly referred RA patients irrespective of treatment.94 DANBIO includes data on (reviewed in 94): • patient characteristics: social security number, age, gender, disease duration, symptom duration, BMI • disease characteristics: serology (antiCCP, IgM-RF), which classification criteria the patient fulfills upon diagnosis (voluntary and not uniformly available, e.g. HLAB27 status), year of diagnosis, year of symptom start, radiographic data (MRI in axSpA, X-ray status hand/feet) • disease activity, patient reported outcomes: VAS global/fatigue/pain, BASDAI and BASFI-scores (axSpA), HAQ • disease activity, objective measures: tender and swollen 28-joint count (68 joint count only available in a minority of patients), enthesitis count (only available in a minority of patients), BASMI, CRP • composite measures of disease activity: DAS28, ASDAS (since year 2010) • current and previous treatment with csDMARDS and bDMARDs (name, administration route, dose regimen, start/stop date, reason for withdrawal) • health behavioral factors: smoking, alcohol consumption, physical activity, EQ-5D DANBIO coverage is audited yearly by the DANBIO secretariat and coverage is >90% for patients treated with bDMARDs in routine care.76;93 It is recommended that clinical data are registered at least 1-2 times yearly and whenever the patient starts or stops treatment with a DMARD. The ICEBIO registry was established in year 2008 and includes data regarding Icelandic patients with inflammatory arthritis. Data are collected prospectively on the same IT-platform as DANBIO.3;96

4. Patients and methods The current thesis is based on data retrieved from the DANBIO registry. In paper 3, ICEBIO data from Iceland were also included (Icelandic data will not be explored further in the thesis).

4.1. Cohorts and study design All cohorts were identified in the DANBIO registry. The criteria for patient inclusion and –exclusion, the patient cohorts and methods for data validation are briefly described below. For more details please see enclosed papers (Appendix 1-9).

4.1.1. Patient inclusion The time periods for patient inclusion into the cohorts were in most papers from the start of DANBIO (year 2000) until specific censoring dates. All Danish departments of rheumatology were invited to participate in the studies. Table 2 shows participating departments and inclusion time intervals for the 9 papers/cohorts.

Table 2 Participating departments and inclusion intervals according to publication year

Publication Paper Participating departments Inclusion time interval year no. Number Departments of rheumatology 2010 5 4 Gentofte, Hvidovre/Glostrup, Rigshospitalet, Slagelse 2000 – 2008 (Nov) 2011 1 6 Gentofte, Glostrup, Rigshospitalet, Aarhus, 2000 – 2009 (Nov) Frederiksberg, Vejle 2013 6 13 Gentofte, Glostrup, Aarhus, Frederiksberg, Vejle, 2000 – 2011 (Jan) Aalborg, Køge, Odense, Rigshospitalet, Hjørring, Esbjerg, Helsingør, Randers 2013 2 9 Gentofte, Glostrup, Frederiksberg, Aarhus, Vejle, 2000 – 2012 (Jan) Odense, Aalborg, Rigshospitalet, Helsingør 2014 3 11 Glostrup, Reykjavik Iceland, Frederiksberg, Aalborg, 2000 – 2013 (March) Odense, Vejle, Rigshospitalet, Helsingør/Hillerød, Køge, Gentofte, Hjørring 2015 4 14 Gentofte, Frederiksberg, Glostrup, Holbæk, Esbjerg, 2000 – 2012 (Jan) Svendborg, Aalborg, Odense, Vejle, Rigshospitalet, Helsingør/Hillerød, Køge, Aarhus, Silkeborg 2015 7 17 Gentofte, Rigshospitalet/Glostrup, Frederiksberg, 2000 – 2014 (Jan) Esbjerg, Svendborg, Aalborg, Holbæk, Odense, Vejle, Aarhus, Køge, Silkeborg, Slagelse, Horsens, Holstebro, Randers, Hjørring 2016 8 16 Gentofte/Herlev, Rigshospitalet/Glostrup, Gråsten, 2005 – 2014 (July) Rønne, Fredericia, Hjørring, Horsens, Køge, Rigshospitalet/Blegdamsvej, Odense, Silkeborg, Svendborg, Vejle, Aalborg, Aarhus, Slagelse 2017 9 18 Gentofte/Herlev, Rigshospitalet/Glostrup, Switch May 2015-Jan Frederiksberg, Gråsten, Rønne, Esbjerg, Hillerød, 2016* Hjørring, Holstebro, Horsens, Køge, Odense, Silkeborg, Svendborg, Vejle, Viborg, Aalborg, Aarhus * For details, see Paper 9.

Patients were included in the cohorts according to the diagnosis registered in DANBIO i.e. the diagnosis according to the expert opinion of the treating rheumatologist. The main inclusion criteria and the number of patients included in the 9 cohorts are shown in Table 3.

Table 3 Inclusion criteria and number of patients included in the different cohorts

Paper no. Diagnosis Main inclusion criteria Patients included, n 1 PsA ≥1 TNFi treatment courses 764 2 PsA ≥2 bDMARD treatment courses 548 3 PsA Infliximab the first TNFi treatment course 462 4 PsA ≥1 TNFi treatment course 1388 5 AS ≥1 TNFi treatment courses 842 6 AS ≥2 bDMARD treatment courses 432 7 AS ≥1 TNFi treatment course 1576 8 AxSpA ≥1 TNFi treatment course 1250 Available classification criteria 9 PsA, AxSpA, RA Switch from originator to biosimilar infliximab 802

The cohorts were partly overlapping (Figure 2A and B). The patients included in paper 9 were not characterized by TNFi treatment start year but according to biosimilar switching and are hence not included in the figures. Further data regarding the RA patients included in paper 9 will not be presented in this thesis. In the following, tables and figures refer to data from the original papers except Figure 5B and Figure 8 which are based on an update of the data originally presented (DANBIO per May 1st 2017).

Figure 2 Number of patients (y-axis) in DANBIO starting first and second TNFi according to year of treatment start (x-axis). Arrows along x-axis indicate time intervals for patient inclusion according to paper number. A: patients with PsA, B: patients with AS. (Data-source: Paper 8 and Paper 3 dataset)

4.1.2. Patient exclusion In all papers, patients were excluded if they • had not been followed in DANBIO since commencement of the first TNFi • received their bDMARD treatment from non-rheumatologic departments and hence were not systematically registered in DANBIO (e.g. departments of dermatology or gastroenterology) • received a first bDMARD that was not a TNFi - or that was a TNFi not indicated for the relevant rheumatologic disease in the given time period (e.g. certolizumab pegol for AS before year 2014, golimumab for PsA before year 2013) • participated in clinical studies/trials and e.g. received blinded project bDMARD treatment • had contra-intuitive registrations (e.g. negative bDMARD treatment duration etc.)

4.2. Validation of data in DANBIO The data in DANBIO are entered prospectively by an online system. The IT solution minimizes the risk of errors compared to paper formats and uses a standardized format for the collection of variables. Examples of prospective data validation are: 1) min-max boundaries of patient reported outcomes e.g. VAS, and 2) that a new bDMARD cannot be prescribed before the previous bDMARD has been withdrawn - including registration of the reason for withdrawal. These solutions have however been implemented gradually and were not available in the earlier years. Retrospective data validation occurs annually when the local departments of rheumatology are requested to assess coverage of bDMARD treated patients. Furthermore, hospital patient records may be used to update missing data (e.g. CRP) before the evaluation of quality indicators that are reported in the DANBIO Annual Clinical Quality Report.94 As part of research projects, further retrospective data validation may lead to even higher data completeness regarding specific covariates or outcomes. Thus, as part of the data collection process of the 9 papers included in this thesis, all Danish department of rheumatology were invited to participate and to verify the data entered in DANBIO specifically regarding: • Treatment duration of bDMARDs including exact date for starting the drug and the date of the first missed dose/stop date • In case of withdrawal to enter reason for withdrawal • If bDMARD treated patients with lack of follow-up for >6 months were still treated or had withdrawn Furthermore, in specific papers, focus was on entering data regarding:

• Infliximab treated patients’ body height/weight/BMI (including Landspitali University Hospital, Reykjavik) (Paper 3) • Which classification criteria individual patients fulfilled upon start of the first TNFi (Paper 8). These data were only available in a limited number of patients treated in routine care. Thus, patients were only included in study 8 if their local department of rheumatology entered the required information • The exact switch date from originator to biosimilar infliximab. If the biosimilar treatment had stopped to enter the reason for withdrawal (Paper 9)

4.3. Baseline characteristics, measures of disease activity and outcomes An overview of the included baseline patient characteristics, measures of disease activity, function and clinical response to treatment is shown in Table 4 for PsA and Table 5 for axSpA. It is beyond the scope of this thesis to report further data on RA (Paper 9). All the reported variables were identified in DANBIO except comorbidities (Paper 9, see next Section 4.4.). Disease activity was evaluated according to the available clinical data in DANBIO (‘visits’) and captured according to the following time windows: The baseline visit was defined as the time of TNFi treatment start. The time window applied for the baseline visit (bDMARD start date) varied across the papers. Thus, the baseline visit included data from 5 days before until 6 days after treatment start (Paper 1, 2, 4, 5, 6), or from 30 days before until 6 days after treatment (Paper 3), or from 60 days before until 6 days after treatment start (Paper 7, 8). In Paper 9, which included patients on long-time treatment with infliximab, a longer time interval of 90 days before baseline was defined. The time windows for the visits after 2 weeks (1-4 weeks), 6 weeks (5-9 weeks), 6 months (18-32 weeks), 2 years (91-117 weeks), 3 years (143-182 weeks), 4 years (183-233 weeks) and 5 years (234-285 weeks) was identical in all papers. In Paper 9, additional time windows covering before the baseline visit were applied: 3 months’ window: 0-25 weeks, 6 months’ window: 25-32 weeks before start of CT-P13. Treatment retention was defined as the number of days during which individual patients maintained treatment with the bDMARD. Stop date was the date of the first missed treatment dose. Temporary treatment interruptions of < 3months durations were allowed. Reasons for stopping treatment were categorized as LOE, AE (side effects, infection, death, cancer) or other (pregnancy, surgery, loss to follow-up, remission, several reasons for discontinuation). Patients were classified as having achieved a clinical response according to the 3 and 6 months’ visits. Definition of response varied across papers: In Paper 1 and 5, patients with at least one registration of clinical response at either of the two time points were considered a responder. In Paper 2, 3, 4, 6, 7, 8,

27 patients were required to have a clinical response at both visits in order to be considered a responder. In case of missing data, one registration of response was sufficient to categorize the patient as responder. No response measures were applied in Paper 9.

Table 4 Overview of reported baseline characteristics, measures of disease activity, function and clinical response in PsA according to paper number PsA Paper no. 1 2 3 4 9 Baseline Gender, age + + + + + characteristics Disease/symptom duration + + + + Concomitant MTX + + + + + Concomitant oral prednisolone + Height/weight/BMI + + Smoking status + TNFi type + + + + + TNFi dose regimen + + TNFi start year + + + + + Previous csDMARDs + Number of comorbidities (10 years back)** + Disease activity CRP + + + + + and function DAS28 + + + + + 28 swollen and tender joint count + + + + VAS pain/global/fatigue + + + + +* VAS physician + + + BASDAI/BASMI/BASMI + HAQ + + + + + Outcome bDMARD treatment duration + + + + + measures Reason for treatment withdrawal + + + + + EULAR good response + + + + ACR20/50/70 + + + + DAS28 remission + Changes in disease activity (baseline vs. 3-6 + + + mths) NNT + *Only VAS fatigue, ** identified in the Danish National Patient Registry

Table 5 Overview of reported baseline characteristics, measures of disease activity, function and clinical response in axSpA according to paper number AxSpA Paper no. 5 6 7 8 9 Baseline Gender, age + + + + + characteristics Disease/symptom duration + + + + Concomitant MTX + + + + + Concomitant prednisolone + Height/weight/BMI + + Smoking status + + TNFi type + + + + + TNFi start year + + + + HLA B27 status + Classification criteria + Number of comorbidities (10 years back)** + Disease CRP + + + + + activity, VAS pain/global/fatigue + + + + +* function VAS physician + + BASDAI + + + + + BASMI/BASFI + + + + Thorax excursion range + ASDAS + + + Outcome bDMARD treatment duration + + + + + measures Reason for treatment withdrawal + + + + + BASDAI50%/20mm response + + + + BASDAI<40mm + + ASAS40, ASAS remission + ASDAS inactive disease + + ASDAS clinically important improvement + Changes in disease activity (baseline vs. 3-6 + + + + mths) NNT + *Only VAS fatigue, **Identified in the Danish National Patient Registry

4.4. Comorbidities

Comorbidities (previous cancer, infections, cardiovascular disease etc.) may have an impact on bDMARD prescription patterns and are suspected to affect treatment outcomes.14;97 Thus it is of interest to include comorbidities as a potential confounder in analyses of treatment effectiveness. In DANBIO, comorbidities may be included through patient self-report on the touch screen (= ‘yearly visit’). However, this is not done routinely and data are not uniformly available. In paper 9, number of comorbidities according to the Charlson comorbidity index98 was identified in the National Patient Register.99 This was done by cross linkage by social security numbers. The National Patient Register contains diagnoses from hospitalization-discharges and from in- and out-patient

29 care and has high completeness.100 The possibilities of enrichment of DANBIO data with information from national registries are further discussed in Section 7.1. regarding future perspectives.

4.5. Ethics DANBIO has been approved by the Data Protection Agency since year 2000 (j. nr. 2207-58-0014 and j. nr. 2007-58-0006), and since year 2006 as a national quality registry by the National Board of Health (j. nr. 7- 201-03-12/1). Patient registration in DANBIO does not require patient consent. According to Danish Law, publication of registry data does not require approval by Ethics committees.

4.6. Statistical analysis In all papers, demographics and descriptive data are mainly presented by medians (IQR), and groups are compared by non-parametric testing (Unpaired: Chi square test, Mann-Whitney test. Paired: Wilcoxon’s signed rank test). Treatment retention and factors associated with retention were investigated with Kaplan- Meier plots, log rank tests and uni- and multivariate Cox regression analyses (hazard ratios). Stratified analyses according to reason for stop of treatment (AE/LOE) were done in paper no 1-6. In paper 1-8 the response rates were calculated as the proportion of patients who achieved a clinical response at the 3-6 months visits by the algorithm described above. Factors associated with response were investigated with multivariable logistic regression analyses (odds ratios). Further details on statistical analyses are described in the papers. Table 6A and Table 6B show which baseline characteristics that were included in the multivariable statistical analyses in each paper, and if they were included as categorical or continuous variables. Variables that were not included in the multivariable analyses were either 1) available but rendered irrelevant for that paper or 2) of relevance but unavailable. The reason for unavailable data could be poor quality in DANBIO and hence need for validation before publication (e.g. smoking status or diagnostic criteria for axSpA in the early publications).

Table 6A Baseline DANBIO characteristics included in multivariable analyses in PsA patients according to paper number Paper 1 Paper 2 Paper 3 Paper 4 Paper 9 Main outcome Effectiveness Effectiveness Impact of Impact of Infliximab non- of 1st TNFi of 2nd infliximab dose smoking on medical switch bDMARD regimens on effectiveness effectiveness of 1st TNFi Gender K K K K K TNFi type K K K CRP K C Methotrexate K K K K K Age C C C K C Disease duration C C C K Swollen joint count C C Tender joint count C VAS global C C C VAS pain C C VAS fatigue C C HAQ C C C DAS28 C C C C Start year K K K Stop reason first TNFi K Time interval between C C infliximab infusions Infliximab dose K, C C Smoking status K No. of comorbidities* C K=categorical, C=continuous, *Identified in the Danish National Patient Registry

Table 6B Baseline characteristics included in multivariable analyses in AS or axSpA patients according to paper number Paper 5 Paper 6 Paper 7 Paper 8 Paper 9 Main outcome Effectiveness of Effectiveness Impact of Impact of diagnosis Infliximab non- 1st TNFi of 2nd smoking on on effectiveness 1st medical switch bDMARD effectiveness of TNFi 1st TNFi Gender K K K C C TNFi type K K K K CRP K C K C Methotrexate K K K K K Age C C K C C Disease duration K C VAS global C C VAS pain C VAS fatigue C C BASDAI C C C C BASFI C C BASMI C C ASDAS C Start year K K K Stop reason first TNFi K Smoking status K K HLA-B27 K axSpA subdiagnosis K No. of comorbidities* C K=categorical, C=continuous, *identified in the Danish National Patient Registry

5. Summary of results

5.1. Baseline demographics of study cohorts Table 7A and Table 7B show the main baseline characteristics of patients with PsA and AS (axSpA for paper 8 and 9), respectively. For paper 3, only demographics for Danish and not Icelandic patients are shown. For paper 9, characteristics of patients with RA are not reported. As shown in Figure 1A and Figure 1B, the cohorts are partly overlapping.

Table 7A Baseline demographics in PsA according to paper number Paper 1 2 3* 4 9 Non-switchers Switchers N=874 N=548 Patient number, n 764 1422 376 1388 120 Women, n (%) 396 (52) 699 (49) 204 (54) 679 (48) 58 (48) Age, years 47 (38-56) 48 (39-56) 48 (40-56) 48 (38-56) 52 (44-61) Type of TNFi, n (%) Adalimumab 320 (42) 636 (45) - 634 (46) - Etanercept 184 (24) 318 (22) - 322 (23) - Infliximab 260 (34) 429 (30) 376 (100) 432 (31) 120 (100) Golimumab - 39 (3) - - - Concomitant MTX, n (%) 410 (54) 482 (55) 283 (52) 260 (69) 746 (53) 84 (69) Disease duration, years 5 (2-11) 4 (1-10) 3 (1-9) 7 (3-13) 4 (1-10) 12 (9-20) CRP, mg/l 10 (4-22) 9 (3-19) 9 (3-23) 10 (4-25) 9 (3-20) 4 (1-6) DAS28 4.8 (3.9-5.5) 4.4 (3.6-5.2) 4.8 (4.0-5.7) 4.7 (3.8-5.5) 4.6 (3.7-5.4) 2.3 (1.7-3.1) Patient’s global score, 69 (50-81) 68 (48-83) 70 (53-85) 69 (51-84) 68 (50-83) 34 (10-67) mm HAQ 1.0 (0.6-1.5) 0.9 (0.5-1.4) 1.1 (0.6-1.6) 1.1 (0.8-1.6) 1.0 (0.5-1.5) 0.6 (0.1-1.1) Numbers are medians (IQR) unless otherwise stated. Not all numbers are shown in original papers * Only patients in DANBIO are shown (ICEBIO patients excluded)

Table 7B Baseline demographics in AS (axSpA for paper 8 and 9) according to publication number Paper 5 6 7 8 9 Non-switchers Switchers N=1004 N=432 Patient number, n 842 1436 1576 1250 279 Diagnosis AS AS AS AxSpA AxSpA Women, n (%) 239 (28) 360 (25) 442 (28) 458 (37) 73 (26) Type of TNFi, n (%) Adalimumab 247 (29) 532 (37) 625 (40) 519 (41) - Etanercept 150 (18) 231 (16) 274 (17) 183 (15) - Infliximab 445 (53) 653 (45) 547 (34) 294 (24) 279 (100) Golimumab - 20 (1) 130 (8) 246 (20) - Concomitant MTX, n 343 (41) 262 (26) 157 (36) 407 (26) 222 (18) 89 (32) (%) Age, years 41 (32-50) 41 (33-51) 41 (32-49) 41 (32-51) 40 (31-49) 47 (39-55) Disease duration, 5 (1-3) 5 (1-4) 3 (1-11) 3 (1-13) 1 (0-6) 13 (7-20) years CRP, mg/l 14 (7-27) 13 (5-27) 13 (5-26) 12 (4-24) 9 (3-20) 4 (1-8) BASDAI, mm 59 (44-72) 56 (43-69) 62 (52-76) 59 (45-71) 61 (49-73) 24 (10-40) BASMI, mm 40 (20-50) 40 (20-60) 40 (20-60) 40 (20-50) 30 (10-40) 20 (10-40) BASFI, mm 50 (34-67) 47 (31-65) 54 (39-71) 50 (33-67) 50 (34-68) 28 (13-47) Patient’s global score, 67 (48-81) 66 (46-79) 72 (57-85) 69 (50-82) 72 (53-85) 31 (14-56) mm Numbers are medians (IQR) unless otherwise stated. Not all numbers are shown in original papers

The baseline demographics for paper 1-8 reflect that the patients have high disease activity at start of TNFi therapy illustrated by high patient’s global score, DAS28 (for PsA), BASDAI (for axSpA) and a high level of functional impairment (HAQ for PsA, BASMI and BASFI for axSpA). In contrast, baseline demographics for paper 9 reflect that the cohort included patients on long-lasting stable treatment with infliximab and thus lower disease activity, longer disease duration and higher age. The disease characteristics and patient demographics that were reported in the papers reflected information that was available from DANBIO. In Paper 9, data were enriched with data from the National Patient Registry regarding number of comorbidities. DANBIO was developed for use in routine care and the collection of data should be feasible in a busy routine care setting. Thus, some disease characteristics are not routinely registered e.g. which classification criteria for the patient fulfills or specifics regarding disease phenotype. For example, in PsA, information regarding enthesitis, dactylitis, psoriatic skin manifestations or disease phenotype (arthritis mutilans, erosive disease, axial disease, etc.) is not available. Thus, all patients are considered as having the same type of disease, and common measures of disease activity and outcome are applied in all patients. In PsA these outcome measures focus on peripheral 28- joint involvement combined with patient reported outcomes and functional status. It is however possible that certain disease characteristics e.g. degree of psoriatic skin involvement might have had an impact on

34 when to start which drug in which patient – and when to render the treatment effective or ineffective. Similarly in axSpA, the treatment might be driven by mainly peripheral joint involvement, uveitis or other inflammation outside the spine.

5.2. Summary of results and discussion according to specific aims The main results presented in this section refer to the specific aims stated in Section 2.2. The main focus will be on significant/positive results, for additional results please see the original papers 1-9. Issues of relevance for the specific aim are discussed and should be perceived as a supplement to the discussion available in the original papers. The term Baseline refers to the time point for start of the first TNFi unless otherwise stated.

5.2.1. Treatment response, treatment retention, and predictors thereof during the first TNFi treatment course in PsA (Specific aim 1, Paper 1) At baseline, women had higher subjective measures of disease activity, higher tender joint count and HAQ score compared to men, whereas swollen joint count was lower. Concomitant use of methotrexate was more frequent among patients treated with infliximab. The median TNFi treatment retention was 2.9 years and 70% of the patients maintained treatment after 1 year and 57% after 2 years. The main reason for stopping treatment was lack of treatment effect (52% of withdrawals) followed by adverse events (28%). Baseline factors associated with longer retention in multivariable analyses were male gender, increased CRP, use of methotrexate and low patient’s global score. Lower HAQ was only significant in univariate analysis. There was a significant improvement in disease activity and patient reported outcomes and - function during TNFi treatment (2 weeks to 5 years after initiation of treatment). After 6 months’ treatment, the EULAR good response rate was 54% and the ACR20/50/70 rates were 59%/45%/24%, respectively. No adjustments for non-completers were conducted in these analyses. The baseline factors associated with response were CRP>10mg/L (significant for EULAR good response, ACR20, ACR50 and ACR70 response), male gender (EULAR good response), younger age (EULAR good response), use of methotrexate (ACR20) and higher patient’s global (ACR20). In crude univariable analyses, the NNT in order to achieve an ACR70 response were 7 if the CRP ≤10 mg/L and 3 if CRP >10 mg/L. When the paper was published in year 2011, only few observational studies regarding TNFi treatment outcomes in routine care were available.97;101-105 Afterwards, several studies have been published which are either prospective registry based e.g. from Italy,106 Norway107;108 and Canada109 whereas others report single-center studies or retrospective evaluations (reviewed in 84;85). Similarly to our study, these

35 papers found that treatment with TNFi was well tolerated with one-year retention rates ranging between 76-94%, and in case the patient stopped it was mainly due to lack of effect.97;101;104;107;110;111 The proportion of patients with response varies across studies partly due to the application of various response measures. Some previous studies applied ACR and EULAR response rates as in our study whereas others calculated disease state e.g. clinical remission or minimal disease activity. Minimal disease activity was achieved in 61-64% of patients110;112, DAS28 remission in 58%103, ACR20 response in 76- 79%104 and EULAR good or moderate response in 70-75%.97;102 One study found that the response rate doubled from 4 to 8 months therapy110 and another that a subgroup of patients had delayed response not apparent until after one year.109 This indicated that efficacy should be evaluated at late time-points and not as early as 3-6 months as recommended in guidelines.70 We did not specifically address this issue in our data, but as shown in table 2 of the paper, there seemed to be a further improvement in measures of disease activity between 6-12 months, however patients withdrawn from treatment early and hence not contributing data might bias these results. A systematic review and meta-analysis regarding predictors of TNFi treatment response in PsA concluded that no uniform predictors could be identified.85 However, similar to our study, several publications have found elevated CRP102;110;113;114 and male gender97;103;106;110;112;114 to be associated with TNFi treatment response. The role of co-medication with methotrexate has been addressed in several publications115 (reviewed in 85) as it is of high clinical relevance to establish if combination therapy is superior to monotherapy. Indeed, 54% of the patients in our study received concomitant methotrexate. In randomized trials there does not seem to be any additional effect of adding methotrexate to TNFi treatment.116;117 Although some studies have indicated positive impact of co-medication with methotrexate on treatment retention and outcome, the meta-analysis did not find any additional effects of adding methotrexate.85 A similar conclusion was made in a GRAPPA treatment guideline.22 However differences across TNFi drug types cannot be ruled out.118;119 In epidemiological research, confounding by indication is an important consideration and is discussed in Section 6.2. below. The heterogeneity of studies and the various outcome measures applied across studies might potentially explain the lack of significance of the individual potential predictors in meta-analysis. Within AS it has been attempted to construct matrix models that combine numerous baseline predictors into a model with a maximum capture of which patients respond to treatment, 120 see discussion for paper 5 below. Similar attempts have not been done in PsA. Thus, in routine care it remains a challenge to correctly identify clinical predictors of bDMARD response in individual patients.

5.2.2. Treatment response, treatment retention, and predictors thereof among PsA patients switching to a subsequent bDMARD (Specific aim 2, Paper 2) The main baseline demographics according to switch status are summarized in Table 7A. During follow-up (median 2.3 years (IQR 1.0-4.3)) 39% of patients switched treatment to a second bDMARD, 44% maintained treatment and 17% stopped treatment without starting a new bDMARD. Upon start of the first TNFi, the patients who subsequently switched to another bDMARD (= switchers) were more frequently women, had shorter disease duration, had higher HAQ, DAS28, VAS pain, VAS fatigue, swollen and tender joint count compared to the patients who maintained treatment (=non-switchers). The main reason for switching was lack of treatment effect. The treatment retention decreased after switching and the proportion of patients who maintained treatment after 2 years during the first, second and third treatment course was 52%, 42% and 40 %, respectively. The factors associated with longer treatment retention during the second bDMARD treatment course were lower VAS fatigue upon start of therapy (multivariable Cox regression analysis). Male gender, fewer tender joints and treatment start during the earlier years were only significant factors in univariable regression analyses. The disease activity decreased significantly during both the first, second and third bDMARD treatment course. The proportion of patients who achieved a clinical response decreased significantly after switching exemplified by a NNT to achieve an ACR20 response during the first and second and third treatment course of 2 and 5 and 6, respectively. The factors associated with response to the second TNFi were fewer tender joints (for ACR20 and ACR50, EULAR good response), lower HAQ (ACR50, EULAR good response), higher DAS28 (ACR20, ACR50, ACR70, EULAR good response), no use of methotrexate (ACR20, ACR50) and reasons for stopping the previous TNFi (ACR20, ACR50). Inhibition of the TNFi pathway was until recently the only available mechanism of action (MOA) for biological treatment in PsA.72 Thus, if a patient failed treatment with the first TNFi, switching to a second became routine care.22 The availability of therapies with other MOAs (e.g. secukinumab: Interleukin (IL)17A blocker, ustekinumab: IL12/23 inhibition, apremilast: phosphodiesterase 4 inhibition) has further intensified the debate on effective switch patterns in PsA. The subject is to some degree addressed in RCTs where TNFi failures are subsequently treated with e.g ustekinumab121, secukinumab122 or certolizumab pegol.123 However, no RCTs have systematically addressed switching in PsA, and the main experience still comes from observational studies (reviewed in 124). Our study illustrated that switching in routine care was a frequent event and occurred in nearly 40% of the patients and that switching was mainly due to lack of effect. Lower switch rates have

37 been found in other countries (South-Sweden 34%,125 Great Britain 17%,126 Norway 15%,127 Spain 5%128), perhaps illustrating differences in the availability of bDMARDs across countries. Overall, lack of effect was the most frequent reason for stopping and switching treatment.124 Our results that patients benefitted from switching to a second TNFi although effectiveness was attenuated compared to first line was in agreement with other observational studies.129 Similarly, available guidelines recommend TNFi switching in PsA.22;72 We saw a tendency toward effects of even a third TNFi. There are very limited data regarding switching beyond a second TNFi and available studies include very few patients (<60).125;126 Why one TNFi is efficient when another one is not is unclear and might be due to the formation of anti-drug antibodies (ADA) or other drug specific factors overcome by switching.130 A recent Swedish study recommended that switching to a third TNFi should not be performed due to poor chances of response. 125 The availability of DMARDs with other MOA available during the recent years is likely to change the patterns of switching in routine care.131 We were not able to identify uniform predictors of outcome after switching, and the subject has only been addressed in few previous studies124;125 which also found lower HAQ and higher DAS28 to be associated with better response.125 However, it must be concluded that when it comes to predicting effectiveness of TNFi treatment after the first and second treatment course, options are still very limited.131

5.2.3. Impact of different infliximab dose regimens on treatment response and treatment retention during the first TNFi treatment course in PsA (Specific aim 3, Paper 3) This paper was the result of collaboration between Denmark and Iceland and included data from both DANBIO and ICEBIO. In Denmark and Iceland, there are different guidelines on how to dose infliximab: Danish patients are dosed according to body weight whereas Icelandic patients start treatment with 200 mg (corresponding to 3.3 mg per kilo for a person with weight 60 kg) irrespective of body weight followed by dose up-titration if necessary. According to the Remicade summary of products characteristics, the recommended dose for treatment of PsA is 5 mg/kg bodyweight.132 Since 2012, guidelines from the Danish Council for the Use of Expensive Hospital Medicines became available recommending a similar dose.74 The main aims of this paper were to describe the infliximab dose regimens used in routine care in the two countries and to investigate if the lower start doses used in Iceland affected infliximab effectiveness. The Danish patients received higher infliximab doses compared to the Icelandic patients (3.1 mg/kg versus 2.3 mg/kg) and they had lower BMI, higher DAS28 and higher tender joint count at baseline. The Danish patients who received infliximab >5 mg/kg were more frequently women, started treatment during the later years and had higher VAS physician and lower swollen joint count compared to patients starting lower doses.

During a median follow-up time of 550 days, the majority of patients received sustained doses <5 mg/kg (77% Danish patients, 96% Icelandic patients). Retention rate was significantly shorter among Danish than Icelandic patients (1-year: 58% vs.66 %). Treatment retention was shorter among patients who started treatment during the later years or who did not receive concomitant methotrexate (Kaplan-Meier). Baseline infliximab dose did not influence treatment retention when it was included as a categorical variable in Kaplan-Meier or multivariable Cox regression analysis, but as a continuous variable, Danish patients on lower start doses had poorer treatment retention. After 1 year’s treatment, Danish and Icelandic patients had similar disease activity, and the baseline infliximab dose had no impact on the disease activity. Similarly, 6 month’s response rates (EULAR good response, ACR20, ACR50 and ACR70 response rates) were not associated with infliximab dose (Danish patients, logistic regression analyses) and the response rates were similar in Danish and Icelandic patients. The paper showed that treatment guidelines regarding recommended infliximab dose were implemented slowly in Denmark. As illustrated in Figure 3 (based on data from DANBIO used in Paper 9 including year 2016), the average start infliximab dose has steadily increased during the years, but in year 2015 the baseline dose was still below the recommended 5 mg/kg. This probably reflects wide use of the initially recommended RA dose regimen of 3 mg/kg for PsA patients.

The fact that originator infliximab upon marketing had mainly been tested in 5mg/kg doses illustrates the need for observational post-marketing research to investigate the use of other doses in routine care. The use of bDMARDs in lower doses than recommended in the summary of products characteristics may occur as a part of a step-down strategy among patients in clinical remission or may be due to use of low start doses.133;134 On the other hand, if a patient has insufficient response to infliximab, the dose per infusion may be increased - or the interval between infusions reduced in order to maximize effect.135 Doses as high as 10 mg/kg might be considered in RA.136 Our study indicated that lower infliximab doses were as effective as the higher doses – both within the Danish patient population but also when Danish patients were compared to Icelandic patients. However, confounding by indication is an important issue to consider in the interpretation of the results (see Section 6.2. below). Although we tried to eliminate such potential confounding in the multivariable analyses, it cannot be ruled out that residual confounding affected the results. For instance the start infliximab dose might be influenced by the patients’ disease presentation (e.g. spinal disease favoring higher doses and which could explain low joint counts), or prescription related factors (e.g. calendar year with start of treatment during earlier years favoring lower doses). These factors might have influenced patient characteristics or treatment effectiveness. Currently, the adjustment of the infliximab dose regimen or the decision to stop treatment due to LOE in Danish routine care is done according to a clinical evaluation. Several studies have demonstrated an association between higher drug levels, lack of ADA and better treatment effect indicating a benefit of therapeutic drug monitoring.137-139 Co-medication with csDMARDs seems to reduce the formation of ADA in a dose dependent manner.119;140;141 However, the usefulness of measurements of drug levels and ADA in routine care is still debated142 and would require a definition of an optimal therapeutic drug concentration and awareness of the complexity of therapeutic drug monitoring.143-145 It is also unclear whether higher infliximab induction dose reduces immunogenicity141 – an issue of high relevance e.g. considering the low initial doses used in Iceland. In conclusion, lower infliximab doses and subsequent dose escalation according to response seems feasible in many patients with PsA. The use of lower doses might potentially reduce medication costs for society. However, RCTs addressing different baseline doses, exploring the occurrence and impact of ADA and appropriate therapeutic drug monitoring algorithms are still lacking. Thus, it seems appropriate for the time being to use infliximab according to available guidelines to ensure uniform treatment of all patients across Denmark.

5.2.4. The impact of smoking on baseline disease activity and outcomes during the first TNFi treatment course in PsA (Specific aim 4, Paper 4) The main baseline demographics for all included patients are summarized in Table 7A. Among the 1388 included patients, 83% had known smoking status. Of these, 33% were current, 41% were never and 26% were previous smokers. Current smokers had shorter disease duration, lower BMI, higher HAQ, higher VAS fatigue and global score compared to never smokers. Current smokers had poorer treatment retention than never smokers - but only in univariable and not multivariable analysis. In analyses stratified by TNFi type, current smokers had poorer retention for etanercept and infliximab (multivariable Cox regression analysis). Previous smokers who had stopped smoking >4 years ago had similar treatment retention as never smokers. Reduction in disease activity after 3 and 6 months’ treatment was similar among current and never smokers. Current smokers had poorer EULAR good response rates, ACR20 and ACR50 response rates than never smokers but mainly in univariable analyses. In multivariable analyses results were only significant for EULAR good response among men. Our study illustrated that smoking was a very common exposure in patients with PsA and that more than half of the TNFi treated patients were either current or previous smokers. A similar number (62%) was found in a recent cross sectional questionnaire-based survey among Swedish patients with PsA (concurrent DMARD treatment was not reported).146 The Swedish survey found smokers to report worse health status than non-smokers in accordance with our findings. Thus, it seems important to bear in mind that those PsA patients who smoke might have a different disease presentation than non-smokers although the underlying mechanism is unknown. Several studies have investigated the impact of smoking on TNFi treatment effects in RA,147- 150 however data are still sparse in PsA18;97;108 where studies are often small, single-center and/or retrospective with only unadjusted analyses.111;112;151-153 Five observational studies18;97;108;111;153 of baseline predictors associated with TNFi effectiveness in PsA reported smoking to be a negative predictor of treatment retention (univariate analyses)97;108;153 or unassociated111 whereas the impact on smoking on response was either insignificant18;111 or not described.97;108;153 Thus although there is no doubt that smoking is poor for overall health, data on the impact on TNFi treatment effects are vague and mainly apparent in univariable analysis. Furthermore, our study suggests that smoking cessation improves chances of a better treatment outcome since we found previous smokers who stopped treatment >4 years before start of TNFi to have retention rates similar to never smokers.

5.2.5. Treatment response, treatment retention, and predictors thereof during the first TNFi treatment course in patients with AS (Specific aim 5, paper 5) Upon start of the first TNFi, women had higher subjective measures of disease activity (BASDAI, BASFI, VAS scores) but lower BASMI and CRP compared to men. Concomitant use of methotrexate was more frequent among patients treated with infliximab. The median TNFi treatment retention was 4.3 years, and the proportions of patients who remained on treatment after one and two years were 74% and 63%, respectively. The main reason for stopping treatment was lack of treatment effect (48% of withdrawals) followed by adverse events (29%). The baseline factors associated with longer retention were male gender, increased CRP (>14 mg/L) and low VAS fatigue. There was a significant improvement in disease activity after 2 weeks. After 6 months’ treatment, the BASDAI50%/20mm response rate was 63%. No adjustment for withdrawal was done in this analysis. The baseline factors associated with BASDAI50%/20mm response were CRP>14mg/l, lower BASFI and younger age. When these results were published, only few observational studies on TNFi treatment effects in AS in routine care were available and none of them had studied factors associated with outcome. Several publications have addressed these aspects during the later years (reviewed in 85;154). There is an overall tendency across RCTs and observational studies towards better response among patients characterized by younger age, male gender and higher CRP. Furthermore, HLAB-27 positivity seems to be associated with better response, however this factor was not included in our analyses due to incomplete data in DANBIO at the time of publication. Similar to PsA, it is debated whether co-medication with methotrexate improves TNFi effectiveness in AS.80;155 Indeed, use of methotrexate in routine care is highly prevalent (20-41% of TNFi treated patients).5;155-157 One RCT adding MTX to infliximab therapy found negative results,158 and a Cochrane review based on 3 RCTs concluded that there was no added benefit of MTX in AS.159 In observational studies some find a positive impact on treatment retention155;156 others find none107;157;160 or even a negative impact of methotrexate co-medication.161 Confounding by indication is very likely to affect these results – methotrexate might be prescribed more frequently to patients with peripheral arthritis, patients treated with infliximab, or patients with higher disease activity which are all factors potentially linked to outcome. In two recent studies the authors aimed to address this by propensity score adjusted analyses.155;157 The study by Sepriano et al157 found no impact of MTX co-medication on treatment retention whereas response rates were not reported. The study by Ciurea et al155 found improved drug retention among axSpA patients treated with combination therapy, mainly in non-smokers and patients

42 treated with infliximab, but response rates were similar. The authors included data on TNFi switch patients along with non-switchers, which might have affected the results. It is a challenge to apply these observational data obtained on a group level to the individual patient level. Nearly half of the patients treated with TNFi in routine care have normal levels of CRP and 20- 25% of the patients are women. And although the chance of response is poorer for a woman with normal CRP, some of these patients respond to treatment – similar to the discussion for PsA above. In year 2011, Vastesaeger et al. proposed an algorithm including several predictive factors in one common model based on data from two RCTs in AS.120 The authors suggested that in the lack of good alternatives, expert opinion combined with objective markers of inflammation despite attempted treatment with NSAIDs should warrant treatment with TNFi in AS during a defined trial period. This latter ‘defined trial period’ is perhaps important to bear in mind – that treatment effects should always be re-evaluated after a specific time period and the treatment should be stopped in case of lack of effect. The use of clinical quality registries such as DANBIO provides optimal conditions for the evaluation of treatment effects because the disease activity upon start of treatment is uniformly available. Implementation of this principle may, however, represent a challenge. Thus, according to Paper 9, a substantial fraction (79%) of axSpA patients treated with originator infliximab for median 6 years were not in remission (ASDAS<1.3) when they switched to the biosimilar CT-P13. In conclusion, there are still no uniform baseline clinical factors that are able to distinguish a future TNFi responder from a non-responder upon start of therapy in AS or in PsA for that matter. It is possible that addition of imaging results (e.g. active inflammation on MRI of SI joints) or specific biomarkers measured in blood in the future might lead to more precise prediction models in the future.162-164

5.2.6. Treatment response, treatment retention, and predictors thereof among AS patients switching to a subsequent bDMARD (Specific aim 6, paper 6) The main baseline demographics according to switch status are summarized in Table 7B. During follow-up (median 2.4 years (IQR 1.0-4.8)) 32% of patients switched treatment to a second bDMARD, 53% maintained treatment and 29% stopped treatment without starting a new bDMARD. Upon start of the first TNFi, the patients who later switched to a second bDMARD were more frequently women, treated with methotrexate, had shorter disease duration, higher VAS scores, BASFI and BASDAI compared to non- switchers. The main reason for switching was insufficient treatment response. The treatment retention decreased after switching and the proportion of patients who maintained treatment after 2 years during the first, second and third treatment course was 58%, 47% and 49 % respectively. The factors associated

43 with longer treatment retention of the second bDMARD were male gender and low BASFI (upon start of the second bDMARD, multivariable Cox regression analysis) whereas treatment with adalimumab and previous treatment with infliximab were significant factors in univariable regression analyses. The disease activity decreased significantly during both the first, second and third bDMARD treatment course. However, fewer patients achieved a clinical response after switching, and the NNT to achieve a BASDAI50%/20mm response during the first and second and third treatment course was 2 and 3 and 4, respectively. The factors associated with BASDAI50%/20mm response during the second TNFi treatment course were higher CRP, lower VAS fatigue and lower BASFI (upon start of the second TNFi). Our study illustrates that switching occurs in nearly 1 of 3 TNFi treated patients in routine care, which is largely similar to the results from other countries.127;165-167 TNFi’s are still the main MOA for bDMARD treatment in axSpA although secukinumab, an IL17A inhibitor, was recently marketed.168;169 Experience on switching mainly stem from observational studies. These studies have often been retrospective or minor with inclusion of <200 switchers.127;165-167;170-172 It is however agreed across these studies, than whenever treatment with the first TNFi fails in AS – which most often occurs due to lack of effect, switching to a second TNFi should be recommended regardless of the reason for withdrawal of the first (reviewed in 173). A phase 3 study, Rhapsody, studied treatment with adalimumab among patients who were either bDMARD naïve or had failed treatment with infliximab, etanercept or both.174 The study found that patients were more likely to achieve response if they were biologics naïve or if they had failed the previous TNFi treatment due to secondary lack of effect (and not primary lack of effect). Regarding switching, it seemed more effective to switch infliximab -> adalimumab compared to etanercept ->adalimumab.174 Only few studies have been powered to compare differences in baseline characteristics among switchers versus non-switchers. In a Spanish study including 131 switch patients with mixed spondylopathies, switching occurred mainly among women and patients with higher VAS scores167 – similar to the results found in our study. In a Korean study, 70 switchers more frequently had ankylosis of the SI –joints and were less frequently treated with adalimumab.165 The predictors of treatment effects of the second TNFi treatment course have only been investigated in few studies.170;175;176 It has been speculated that if a patient stops treatment with a TNFi due to secondary LOE this indicates TNFi driven disease. Thus, beneficial effects of a second TNFi should be expected as discussed in the Rhapsody trial.174;176 DANBIO data do not allow a distinction between primary and secondary lack of effect, and several other observational studies have not included these data either.127;171;177 In a recent Swiss study, the authors perceived stop after >6 months due to LOE to be

44 indicative of secondary LOE.178 The 12-months ASDAS response after switching among these patients were significantly higher than among patients who had failed the previous TNFi treatment course due to primary LOE.178 The authors included patients with axSpA according to the ASAS criteria. Patients who stopped due to primary LOE were more often HLAB-27 negative, had normal CRP and did not have radiographic axSpA. This could indicate potential misclassification that might have affected the results.178 In conclusion, the current knowledge regarding bDMARD switching is widely similar for axSpA and PsA. As discussed for Paper 2 above, switching is a very frequent event in routine care, but little is still known regarding the most effective TNFi switch patterns and when to switch to a bDMARD with another MOA. The second TNFi treatment course is effective, although not as effective as the first, but no uniform predictive factors exist regarding effectiveness after switching. The reason for stopping the previous TNFi may be of relevance. Among switchers, it may be important to apply predefined schedules for re-evaluation of treatment effects – just as it was discussed for the first bDMARD treatment course above. It must be kept in mind that some patients have e.g. concomitant fibromyalgia, irreversible damage or other comorbid disease causing pain, which is not modifiable to bDMARD treatment.179;180

5.2.7. The impact of smoking on baseline disease activity and outcomes during the first TNFi treatment course in patients with AS (Specific aim 7, paper 7) The main baseline demographics for all included patients are summarized in Table 7B. Among the 1576 patients, 90% had known smoking status. Among these, 43% were current, 41% were never and 16% were previous smokers. Current smokers were more frequently male, had longer disease duration and had higher BAS scores compared to never smokers. Current smokers had poorer treatment retention than never smokers both overall and stratified according to gender and TNFi type. Previous smokers who had stopped smoking ≥6 years ago had similar treatment retention as never smokers. The decline in disease activity after 3 months’ treatment was smaller among current smokers. Current smokers had poorer BASDAI50%/20mm response rates after 6 months than never smokers. These results mimic those seen for TNFi treated PsA patients: that smoking is common in these patient groups and that smoking is associated with poorer outcomes i.e. higher disease activity at start of therapy, poorer response rates and shorter treatment retention. Interestingly, a similar trend is seen among previous smokers, mainly if smoking cessation occurs in the recent years, indicating a time- dependent positive impact of smoking cessation.

Although some studies fail to demonstrate any negative impact of smoking,181;182 the common knowledge across studies in axSpA is that smokers have earlier disease onset, higher disease activity, increased radiographic progression and poorer treatment outcomes.183-189 Among the studies that have investigated how smoking influences TNFi treatment outcomes, an observational study performed in the Swiss SCQM registry demonstrated similar negative impact of current smoking among 698 patients with axSpA, especially in patients with elevated CRP at baseline.190 The authors found no negative impact of previous smoking, however information regarding years since smoking cessation was not available. A recent study by the same main authors155 demonstrated that current smoking ameliorated the effect of csDMARD co-medication on TNFi retention rates. This illustrates the importance of including smoking status as a potential confounder in multivariable analyses, as it seems to interact with other covariates. The causality between smoking and outcomes remains to be established.191 Apart from any impact on biochemical and inflammatory markers, smoking status is associated to potential confounders such as more comorbidities, depression, decreased physical activity, lower educational level and socioeconomic status.7;188 It has been argued that mechanical stress and blue-collar work/occupational activity might be the true causative factor whereas smoking is the confounder of such a relationship.192 In conclusion, our study supports the growing evidence of a negative impact of smoking in AS. It also stresses the importance of including smoking status in observational study research – further methodological considerations are discussed below. It is obvious that smoking cessation must be recommended to patients consulting their rheumatologist for health beneficial reasons,191;193 but the exact relationship between smoking cessation and reversion of the negative smoking effects remains to be established.

5.2.8. The impact of axSpA sub-diagnosis (AS versus non-radiographic axial SpA (nr-axSpA)) on treatment response and treatment retention during the first TNFi treatment course in patients with AxSpA (Specific aim 8, paper 8) The main baseline demographics for all included patients are summarized in Table 7B. Among 1250 included patients, 29% had nr-axSpA, 50% had AS and 21% lacked X-rays of the sacroiliac joints at the start of the first TNFi. In the paper, patients with lacking X-rays were defined as having ‘unspecified axSpA’ because the exact sub-diagnosis could not be established. Patients with nr-axSpA were more frequently women, HLA-B27 negative, had shorter disease duration, higher VAS scores and BASDAI, but lower CRP and BASMI than patients with AS. Patients with nr- axSpA had shorter TNFi treatment duration but only in univariable and multivariable analyses. Response

46 rates (after 3-6 months) and changes in disease activity (after 3 months) were similar in AS and nr-axSpA. Patients that were HLA-B27 positive had longer treatment retention and better response rates compared to HLA-B27 negative, both overall and stratified by axSpA sub-diagnosis. HLA-B27 status was available in DANBIO for 84% of the patients. As shown in Figure 4, more HLA-B27 negative patients started TNFi treatment during the later years. The same tendency was seen across sub-diagnoses (not shown). This might be due to a higher emphasis on radiographic imaging and MRI’s during the later years. Thus, it should be kept in mind that the positive impact of HLA-B27 on treatment outcomes at least in part may be due to changes in the case mix over time.

Figure 5A shows the number of patients who started the first TNFi treatment course stratified by diagnosis in DANBIO (AS or nr-axSpA, raw data from DANBIO with no further validation) between year 2000 and 2016. Figure 5B shows the number of patients starting their first TNFi treatment per year according to sub-diagnosis including unclassified patients (lack of radiographic imaging). Please notice that Figure 5A only includes the subgroup of axSpA patients where data have been validated by the local departments of rheumatology (=patients included in Paper 8), and this is also the reason why only data between year 2005 and 2013 are shown. Two points can be made: 1) A substantial number of patients had unspecified ax-SpA due to lacking radiographic imaging of SI joints upon start of TNFi treatment, and the number increased during the later years. This illustrates that MRI is increasingly preferred as the

47 diagnostic imaging procedure instead of X-rays in routine care, 2) The overall number of patients with nr- axSpA increased during the period whereas the number of TNFi treated AS patients remained stable.

According to the data presented in Paper 8, there seems to be a time trend towards more patients having nr-axSpA upon start of TNFi treatment. Furthermore, imaging in the form of MRI rather than X-rays is being used for disease classification. This strategy is not in accordance with Danish guidelines, where MRI is recommended as the primary imaging procedure but should be followed by X-rays in cases with positive MRI findings – especially among patients >30 years old. X-rays should be used for classification purposes (AS versus nr-axSpA), but also to correctly rule out differential diagnoses (degenerative disease etc). X-rays could be the primary imaging modality in patients with long standing disease and clinical suspicion of AS.59 Therefore, there is a potential risk that some patients were incorrectly diagnosed as having nr-axSpA due to lacking X-rays. It is debated how the ASAS classification criteria should be applied in routine care. Indeed, it is difficult to distinguish between AS versus nr-axSpA due to the challenge of correct interpretation of radiographs and MRIs - and misclassification of radiographs may occur in 20-40% of cases.194 TNFi’s were initially marketed to treat AS, but have in RCTs been shown to be effective in nr-axSpA as well.195-197 However, in USA, TNFi treatment is only recommended in AS and not nr-axSpA according to guidelines from the US Food and Drug Administration (FDA).194 Similarly, in Denmark, physiotherapy free of charge is only available in AS and not nr-axSpA.198 For these reasons, classification into AS or nr-axSpA has a major impact for individual patients in some countries. On the other hand, several studies have similarly to our findings shown that patients with nr-axSpA have pain and disability levels similar to patients with AS199 and that the two patient groups respond equally well to treatment.19;200-202 Recent ACR guidelines suggest that patients with nr-axSpA should be treated with TNFi if they are nonresponsive to NSAIDs and particularly in case of sacroiliitis with bone marrow oedema on MRI and/or elevated CRP.194;203 It should also be kept in mind that the ASAS criteria have been developed for classification and not for routine care diagnostic purposes, thus the criteria should always be accompanied by an expert opinion of the rheumatologist including the patient’s symptoms and relevant test results.48;194 In conclusion, the therapeutic and practical implications of a sub-classification within the axial spondyloarthritis disease spectrum in routine care are a matter of debate. It is undoubtedly a challenge to interpret and use treatment guidelines and radiographic findings in routine care. HLA-B27 positivity seems to be an important factor associated with TNFi treatment outcomes.

5.2.9. The impact of switch from originator to biosimilar infliximab on disease activity and one- year treatment retention (Specific aim 9, paper 9) This paper included 802 patients treated with originator infliximab who switched to the biosimilar drug CT- P13 according to a national Danish treatment guideline that dictated a non-medical switch for economic

49 reasons. Thus at the time of marketing, biosimilar infliximab costed less than half the price of the originator. The baseline patient demographics are shown in Table 7A and 7B for PsA and axSpA, respectively. For details regarding the sub-group of patients with RA, please see Paper 9. At time of the switch, the previous treatment duration of originator infliximab was >6 years. This is also reflected in the baseline disease activities shown in Tables 7A and B, which were markedly lower than in the other papers illustrating that a large proportion of the patients was in remission at the time of the switch. Three-months’ disease activity and flare rates were largely unaffected by the switch. The one-year crude retention rate of CT-P13 of 84% was not statistically different from that of originator infliximab in a comparison cohort, and just reached statistical significance in adjusted analysis. The withdrawal rates were similar across diagnoses. Among the 16% of patients who withdrew from CT-P13 treatment during one year follow-up, withdrawal was mainly due to lack of effect or adverse events. Higher VAS patient global and higher DAS28 (among RA patients) was associated with withdrawal. This illustrated that outcomes might not only be attributable to the drug per se – but might also be due to poor disease control or due to the so called ‘nocebo’ effect. Thus, it has been demonstrated that negative anticipations toward a drug e.g. due to lower price or that it is a generic substitution of the originator drug might facilitate a negative outcome.204 Due to the observational setting and the non-blinded study design, it was not possible to explore these issues further. In Denmark, all patients treated with originator infliximab was switched to the biosimilar drug in accordance with the national guideline. This increases the generalizability of the results and minimizes confounding by indication - compared to a situation where only a subgroup was switched.205 Only few studies have previously explored non-medical infliximab switching.206;207 The NOR-Switch RCT was performed in patients with inflammatory diseases, mainly inflammatory bowel disease, but 198 patients had arthritis. In this RCT, long term infliximab treated patients in routine care were switched from the originator to the biosimilar and main outcome was disease worsening within 52 weeks’ treatment. The study was designed as a non-inferiority trial, and the authors found that the flare rate was higher in the biosimilar vs. originator group (26.2 vs. 29.6) but was within the non-inferiority margin. The main conclusion was that treatment with CT-P13 was not inferior to the originator,208 which is in agreement with our results. Below in Section 7.3.1 regarding future perspectives, biosimilars are discussed in more detail.

6. Methodological considerations The 9 studies presented in this thesis were all based on observational data from the DANBIO registry. As discussed in the introduction, the use of observational data has methodological challenges that must be considered in the interpretation of data.82 In the following, some general methodological aspects are discussed including how missing data and misclassification was handled in the studies.

6.1. Data quality and interpretation

6.1.1. Missing data In all research there is a risk of missing data.209 In longitudinal observational studies and biologics registries, data are collected as part of routine care and missing data is an inherent challenge. Data may or may not be missing at random.210 In some cases it is easy to detect that data are incomplete (e.g. lacking registration of diagnosis or of baseline disease activity in a patient followed in the registry) whereas in other cases it is impossible to detect without additional sources of information (e.g. lacking inclusion of patients in the registry, or lacking registration of concomitant use of a csDMARD in bDMARD treated patients - which must be validated from e.g. hospital files). Data missing at random cause lack of power as some patients or variables are excluded from the statistical analysis. On the other hand, data that are missing not at random give a risk of selection bias. An example of the latter is incomplete data during follow-up caused by early treatment withdrawal due to lack of treatment effect or adverse events – or if patients systematically are included/excluded in DANBIO according to their disease status or disease activity (e.g. only the ill patients are monitored). Several efforts have been made to reduce missing data in DANBIO. In routine care, audits are performed yearly in order to ensure a continuously high registration percentage, and it has previously been shown that >90% of bDMARD treated patients are registered in DANBIO.76;94 This is important in order to ensure generalizability of the results.14 In the early years, a new bDMARD could be prescribed in DANBIO without necessarily stopping the previous bDMARD therapy, but during the later years this was prevented by the software thus facilitating fewer prescription errors in the system. Furthermore, in all papers an effort was made to enrich the data in DANBIO (e.g. CRP levels, concomitant use of csDMARDs) and to validate the registrations (treatment regimen, start and stop dates of bDMARD therapy, see methods Section 4.2.) based on co-authors’ access to the patient files. Thus, the Danish departments of rheumatology were invited to participate and to validate the registrations in DANBIO before data analysis. As is shown in Table 2, many departments participated and contributed to more complete data. Missing data may also be handled in the data analysis phase. In case of incomplete registration of disease activity upon start of bDMARD therapy, outcome measures regarding relative

51 changes in disease activity are not calculable. This results in loss of statistical power. In order to address this, larger time intervals were applied for the baseline visit in the later publications. As shown in Figure 7, approximately 85% of patients had available data if the time window for the baseline visit was defined as 60 days before until 5 days after start of therapy. The fact that more patients during the later years had a baseline visit 6-30 days before start of TNFi (year 2011-16 in Figure 7) might illustrate a lag time between the documentation of the disease status by the doctor preceding the decision to start biological treatment versus date of the first given dose.

In Paper 9, patients with long-lasting infliximab treatment (5-7 years) were included. These patients were followed with less frequent visits in DANBIO (according to the guideline to monitor patients in stable bDMARD treatment with ≥1 visit per year).211 We did several efforts to minimize missing data 1) As the patients were expected to have stable disease status a larger time interval of 120 days before until 6 days after switch to biosimilar infliximab was applied for the baseline visit, 2) overlapping time intervals

52 pre-baseline were applied in order to ensure flexibility in the selection of data for a specific time interval (data were only used once), 3) missing follow-up data upon the 3 months’ pre/post switch time intervals were imputed from the 6 months intervals. Patients withdrawn from therapy pose a problem in the analysis of treatment outcomes: patients who stop treatment early do not provide data regarding follow-up disease activity and may thus cause an overestimation of treatment effects. This was addressed by considering a patient who stopped therapy within the first three months as a non-responder (non responder imputation, Paper 3, 4, 7, 8, 9). Another possibility would have been to apply the Lundex correction where the estimates of treatment effects are adjusted for the proportion of patients withdrawn.212 The numbers of patients/observations that were available for each variable of interest were more rigorously reported in the later publications in order to comply with the STROBE guidelines.213;214 In paper 8 we furthermore applied supplementary statistical methods (multiple imputation of missing data) to test the robustness of the results. Furthermore, patients with unspecific axSpA (and lacking x-rays of the SI joints) were included as either AS or nr-axSpA in the statistical tests. Thus, several efforts are done prospectively and retrospectively in order to achieve as high data completes in DANBIO as possible in routine care as well as for research purposes. In the analytical phase and during the reporting of data, transparency regarding missing data and how these were handled increases the credibility of results.

6.1.2. Misclassification In all publications, diagnoses were according to the treating physician and misclassification cannot be ruled out. Furthermore, 21% of patients with axSpA in paper 8 had no available X-rays of the SI-joints upon start of TNFi therapy. Thus, it was not possible to conclude whether these patients fulfilled the classification criteria for AS or not. If patients with nr-axSpA were included in the AS group this might potentially have affected the results of Paper 5-7. Another potential misclassification error is use/no use of concomitant csDMARDs (including prednisolone, tablets and intraarticular injections). Lacking information on prednisolone use might explain why a small part of the patient group had low disease activity upon start of bDMARDs. The participating departments of rheumatology were asked to validate data regarding concomitant use of csDMARDs in order to minimize such misclassification.

6.1.3. Outcome data In all papers outcome measures were reported for certain time points as both 1) relative improvements compared to baseline (PsA: ACR20/50/70, EULAR good response, axSpA: BASDAI50%/20mm response,

ASAS40, ASDAS clinically important improvement) and 2) the current disease state (PsA: DAS28 remission. AxSpA: BASDAI<40mm, ASAS remission, ASDAS inactive disease) and disability (HAQ). Patients with high disease activity upon start of treatment have a higher chance of a relative improvement without necessarily having experienced a satisfactory end point. 82;215 It is therefore beneficial to use the outcome measures in combination. In DANBIO, DAS28 is frequently used as an outcome measure in PsA and only a minority of patients has available 66/68-joint counts. Due to the fact that the DAS28 score does not include the distal interphalangeal joints of the hand and feet it is ‘easier’ to achieve a low disease state. Thus, it has been demonstrated that use of the DAS28 in PsA results in higher response rates compared to other response measures e.g. minimal disease activity and other definitions of remission.84 Furthermore, entesitis, dactylitis and skin involvement are important disease domains not captured through routine care use of DANBIO. During the last decade, introduction of more sensitive CRP analyses has occurred stepwise in several departments. Details regarding the analytical method are not registered in DANBIO but might potentially have an impact on results. In all papers, a CRP value <10mg/L was interpreted as being within the normal range. If the CRP level was included as a continuous variable in a statistical analysis, it is of importance if a value of CRP ≤5 mg/l (the detection limit in many laboratories) was interpreted as ‘5 mg/L’ or ‘0 mg/L’. In publication 1, 5, 8, baseline CRP levels were included in the multivariable statistical models as a categorical value to address that it might be more important to consider above/below a certain threshold instead of expecting a linear effect.

6.2. Confounders included in multivariable analyses As mentioned in the introduction Section 3.2., one of the risks in observational studies is the inclusion of a heterogeneous mix of patients and an uneven distribution of confounders across treatment groups. A confounder may be defined as an extraneous variable that wholly or partially accounts for the observed effect of a risk factor on outcomes. Presence of confounders may cause incorrect assessment of the relationship between exposure (here: treatment with bDMARDs) and outcomes (treatment effectiveness).83 This may be exemplified by confounding by indication where e.g. concomitant use of csDMARDS or baseline dose of bDMARD may be linked to specific disease characteristics which again may be potentially linked to outcomes. For instance, concomitant use of csDMARD (methotrexate) may be associated with TNFi drug type (higher methotrexate use among patients treated with infliximab) or may be associated with certain disease characteristics (peripheral arthritis in axSpA). Similarly, a higher baseline

54 dose of infliximab could be linked to disease presentation (axial symptoms in axSpA thereby facilitating 5mg/kg bodyweight) or start year of treatment (higher doses in PsA and axSpA used during the later years due to national guidelines recommending use of 5 mg/kg). Confounding may be addressed by multivariable confounder adjusted analyses, but still the risk of residual confounding exists.80 As shown in Table 6A and 6B, the variables included in the multivariable models varied across papers. In the methods’ sections of the respective papers, the confounders included in the multivariable regression models are discussed. In general, when several factors were closely intercorrelated only one was included in the model (e.g. VAS scores). In the papers where the impact of a specific factor on outcomes was investigated (smoking in paper 4 and 7, axSpA sub-diagnosis in paper 8), it was important to thoroughly consider which variables should be included in the multivariable analyses as potential confounders due to the risk of over-correction. Thus, if smokers for instance were more frequently men and gender was included in the statistical model together with smoking, a potential effect of smoking might be overlooked. We found patients to have clinically important differences in disease activity at baseline according to the variables we were looking at (smoking status in paper 4 and 7, axSpA sub-diagnosis in paper 8). Thus in paper 4 and 7, we rendered measures of disease activity (DAS28 etc.) to be intermediate factors that were hence not included in the multivariable model. In paper 8, BASDAI was included in the multivariable model due to the consideration that it is important to correct for this variable because higher BASDAI at baseline increased the chance of a relative improvement.215 In the following, examples of specific confounders included (or not included) in the 9 papers are discussed. Start year of TNFi treatment: As shown in paper 3, year of starting treatment was strongly associated with treatment retention rates. In paper 3, start year was considered an intermediate variable (part of the causal pathway between exposure and outcome) and hence not included in multivariable analyses. In the earlier papers (no. 1, 5, 6), start year of treatment was not included in the multivariable model and this may have affected the results. Similarly, other previous studies within the subject have not included calendar year.160;216;217 The impact of calendar year on outcomes may be due to changes in the treatment paradigm of the rheumatic diseases.218 During the later years, early and aggressive medical treatment with treat to target strategies and adherence to international treatment algorithms68;69 has resulted in increased antirheumatic drug use,219;220 start of bDMARDS earlier in the disease course221 and more frequent switching.219;222 In other words, the perception of disease activity (and when it is considered intolerable) has changed over the years.82 This is illustrated in Figure 8A and Figure 8B which show the disease activity in DANBIO upon start of the first TNFi (exemplified with DAS28 in PsA and BASMI in axSpA). According to

56 the figures, disease activity tended to be lower during recent years compared to former years. This is in accordance with findings by others.220 Smoking: As shown in paper 4 and 7, current smokers had poorer outcomes. However smoking status was not included as a potential confounder in paper 1, 2, 3, 5, 6 due to limited data regarding smoking status in DANBIO during the earlier years. Diagnosis (nr-axSpa versus AS): During the later years, the disease spectrum of axial spondyloarthritis has changed and an increasing number of patients has been diagnosed according to the ASAS classification criteria (see section 5.2.8 above). These criteria include patients with nr-axSpA who does not fulfill the modified New York criteria for AS (see introduction Section 3.1.3.). In paper 8, we found patients with nr-axSpa versus AS to differ in baseline disease activity and also to some degree in treatment outcomes. Any erroneous classification of patients with nr-axSpA as having AS in the publications 5, 6, 7 might potentially have affected the results. HLA-B27: As shown in paper 8, HLA-B27 positivity was strongly associated with better outcomes in both AS and nr-axSpA. HLA-B27 was not included as a potential confounder in paper 5, 6, 7 due to limited data. Comorbidities: As mentioned in the introduction, information regarding comorbidities are not routinely available in DANBIO. However, through cross linkage by social security numbers to national patient registries, diagnosis from in-hospital and out-patient care may be identified (ICD-10 codes). According to paper 9, approximately 20% of the infliximab treated patients had at least one comorbidity. Furthermore, there was a tendency towards poorer treatment retention after switch from originator to biosimilar infliximab among patients with more comorbidities. Thus, the lack of correction for comorbidities in the former publications might have affected the results.82;97;223 There is also the possibility that patients with comorbid disease are prescribed other bDMARDs or are monitored more tightly – which might affect the outcomes. In conclusion, it is sometimes difficult to decide whether a specific factor is a confounder or an intermediate factor. There is no ultimate right and wrong in how data are analysed but careful consideration is needed and additional sensitivity analyses might explore the robustness of the data. Furthermore, when the study results are compared to those of other cohorts, it is important to consider methodological issues and how potential confounders were adjusted for. A variety of other potential confounders would have been of relevance but are not routinely available in DANBIO. Examples include concomitant use of NSAIDs in axSpA224;225 , disease phenotype in PsA (e.g. axial disease) and axSpA (peripheral joint involvement),160 socioeconomic status and the presence of fibromyalgia.179;180

6.3. Other methodological considerations In all publications the baseline variables potentially associated to outcomes were included in the statistical model (e.g. disease activity). However, in order to evaluate in details how a specific factor correlates to outcome, it might be of relevance to include the covariates as time-varying variables. For instance, covariates such as DAS28 or ASDAS change dynamically during treatment and this might influence the results.157 On the other hand, when we wish to identify factors associated to outcomes even before the treatment starts, it seems of higher relevance to include only the baseline value.

7. Discussion of future perspectives Prospectively collected data regarding bDMARD treated patients in routine care provides a unique possibility to explore research questions that are difficult to address in RCTs e.g. rare outcomes, rare exposures or patient groups not routinely included in randomized trials. In the following paragraphs, aspects regarding the future perspectives for biologics registries including DANBIO for research within bDMARD treatment effectiveness are discussed.

7.1. Data enrichment DANBIO contains extensive data on patient demographics, treatment and treatment outcomes. For research purposes, these data may be enriched by additional information regarding the patient’s history or outcomes identified through external sources i.e. other registries. The papers included in this thesis present results that are mainly based on data from DANBIO. However, paper 9 includes data on number of previous comorbidities identified in the National Patient Registry (NPR=Landspatientregisteret).99;100 Comorbidities have been demonstrated to have an impact on disease activity and bDMARD treatment duration in PsA,226 and cormorbidities (e.g. previous cancers) may influence bDMARD prescription patterns.227 Therefore, it may be of importance to include comorbidity as a potential confounder in multivariable analyses of treatment effectiveness and safety.228;229 It is possible for patients to enter information on comorbid disease history in DANBIO by the touch screens in the waiting area.94 However, these data are currently not uniformly available. Thus, another method to obtain information regarding comorbidites is through linkage by social security numbers to NPR. NPR contains data on previous hospital contacts (hospitalizations and outpatient care) coded according to the international classification of diseases (IC-8, ICD-10 from 1994 onward) including date of admission and discharge, type of admission, chemotherapy and surgical procedures.100 NPR may, according to the scientific question, also provide information regarding the outcome of interest e.g. rare safety signals.230-233 Upon marketing, a drug has only been tested in a limited number of highly selected patients during the trial phase. Thus, rare safety events may not be detected until post marketing. Although adverse events may be reported by the health care personnel or the patients themselves (in Denmark by www.laegemiddlestyrelsen.dk), underreporting is likely to occur. Through linkage to national registries it is possible to link exposure (treatment) to adverse outcome (hospital contact/ambulatory care). Apart from the NPR, information from other Danish national registries may also be retrieved through linkage. The Danish Prescription database contains information on prescribed drugs including package size, drug name, indication for use and dosing schedule.234 The civil registration system includes

59 civil status, place of residence and vital status, IDA (Integrerede Database for Arbejdsmarkedsforskning) information regarding education, occupation, sick leave and disability compensation (1980-), and DREAM contains occupational and socio-economic data (1991-). Several publications have already explored research questions regarding bDMARD safety,233 bDMARD effectiveness,226 rare outcomes235;236 and socioeconomics237 taking advantage of this methodology where detailed information from biologic registries is linked to national registries. These publications often originate from Scandinavian countries - which apart from a similar tradition of biologic registries share the opportunity of data linkage. The majority of publications have been within RA. In the coming years, research within PsA and axSpA will be a valuable supplement to knowledge from randomized clinical trials and for post marketing pharmcovigilance.14;229

7.2. Collaboration across countries Collaboration across countries may increase statistical power to answer scientific questions regarding rare outcomes, rare exposures or treatment strategies.14;238 A classic example of a rare outcome is cancer risk during bDMARD treatment.230;233 Furthermore, collaboration may provide knowledge regarding bDMARD prescription patterns – which has an interest in its own right, but is also of relevance in order to evaluate heterogeneity between treated patients in different countries. Different prescription patterns across countries may occur for several reasons. Although there are international guidelines regarding treatment strategies, these may be overruled by national guidelines. In Denmark, The Danish Society of Rheumatology (Dansk Reumatologisk Selskab) has issued guidelines regarding the diagnosis and treatment strategies59;71 whereas The Council for use of expensive Drugs (RADS) (now: Medicinerrådet) has published instructions on first line bDMARD drug and subsequent drug choice after failure.74 Examples of different treatment strategies according to national guidelines are: 1) use of biosimilars including non-medical switching as discussed below 2) in some countries patients with nr-axSpA are obliged to have elevated CRP or signs of active inflammation on MRI in order to be candidates for treatment with bDMARDs,202 3) differences in infliximab start dose and step up strategy exemplified by Denmark versus Iceland as discussed in Paper 3. Across European countries there are huge inequities in access to bDMARD treatment due to unaffordability in lower income countries.73;239 This results in differences in the baseline disease activity and patient characteristics upon treatment initiation - which might affect the generalizability of the results.73;240 Patients from high availability bDMARD areas potentially have other treatment outcomes than patients from low availability areas.229;241 Lower disease activity and less structural damage upon treatment initiation might facilitate better outcomes (=window of opportunity). Previous studies in RA have indicated

60 higher response rates if treatment is initiated early in the disease course218;242 whereas the concept is less acknowledged in PsA and axSpA.243-245 Denmark along with the other Nordic countries have high access to bDMARDs, and treatment is fully reimbursed and provided free of charge to the patient.73 However, even in these similar countries there are differences in patient demographics and baseline disease activity upon start of bDMARD treatment illustrating different treatment strategies and availability of treatment.246 This heterogeneity across countries provides opportunities and challenges. Differences in access to treatment, baseline disease activity, prescription pattern, use of biosimilars etc. may be an opportunity for research that explores the impact of these differences – but on the other hand illustrates that pooling of data across countries should be done with caution. A proper statistical approach depending on the data at hand and the scientific question is important.87 The impact of these differences should be explored by collaboration during the data-analysis phase – and not only by comparing the published response rates across papers. Initiatives within the Scandinavian and European countries are on the way regarding PsA and axSpA.247-249

7.3. Important research questions for future registry research

7.3.1. The biosimilar drugs The marketing of the cheaper biosimilar drugs is expected to have a major impact on access to bDMARDs – especially in countries with low availability of biologic treatment.66;73;240;250 The biosimilars have already affected the prescription and switch patterns in many countries. Denmark, Norway and Holland are among countries where large numbers of patients in remission on treatment with the originator drug have been switched to the biosimilar.251;252 In Sweden, for instance, the uptake of the biosimilars has been much slower.205;247 By 2017 in Denmark, two rounds of non-medical switching had occurred namely upon marketing of biosimilar infliximab (CT-P13)9 and etanercept (SB4).253 Several hundred biosimilars are expected in the coming years,66 and it will be of interest to explore how the availability of cheaper bDMARDs affect prescription patterns and if a tendency towards earlier prescription of bDMARDs in the disease course is seen. This is a question that may be addressed by use of observational registry data. The biosimilars are required to have comparable safety and efficacy and similar immunogenicity compared to the originator drug. This must be demonstrated in a pharmacokinetic and – dynamic study performed in humans and ≥1 RCT before approval by the regulatory authorities.66 It has been argued that the risk of adverse events of the biosimilar is similar to the risk associated with the small changes that have occurred during the years of the manufacturing of the originator drug.254 However, even minor differences in the formulation, purity or packaging of a drug may potentially affect the

61 immunogenicity and the formation of ADA 23 resulting in lower drug concentrations and poorer long-term efficacy and safety.255 Although the RCTs have found no relevant differences in the immunogenicity profiles, it might be speculated if the same results would be found in patients treated in routine care (higher age, comorbidity, co-medication). Upon marketing, the biosimilars have often only been tested in few indications – for CT-P13 in axSpA and RA.206;207;256;257 However, in routine care extrapolation across diagnoses is often performed and the biosimilars are used in e.g. PsA and inflammatory bowel disease. This may theoretically be of importance since age, genetics, co-medication with csDMARDs and drug dose differ across diseases and as these are all factors that might affect immunogenicity.258;259 This stresses the importance of prospective follow-up of patients treated with biosimilars in clinical registries such as DANBIO. Previous RCTs and observational studies have only investigated single-way transition from originator to biosimilar (= one switch episode).254 In the future, multiple switches may be seen in the same patient due to cheaper biosimilars/bDMARDs continuously becoming available. This will pose a challenge to the monitoring of pharmacovigilance - but must however be addressed by real world observational clinical data as this type of drug interchangeability is difficult to assess in RCT studies.241

7.3.2. Treatment strategy, switching and prediction of response As discussed for Paper 2 and 6 above, bDMARD treatment failure followed by switching to another bDMARD occurs often in routine care. However, little is known regarding the most effective switch patterns. More and more treatments are becoming available and the switching patterns are becoming increasingly complex. Until recently, TNFi were the only mode of action for biological treatment in PsA and AS. However, the introduction of IL17A and IL12/IL23 inhibitors has further raised the need to explore optimal treatment strategies and when to switch to a bDMARD with other mode of action. Currently, secukinumab is not recommended as first line treatment in Denmark, and only few patients have received treatment with the drug. In Sweden the prescription rate is higher – but mainly as second line treatment.247 In the placebo controlled RCT MEASURE 2, secukinumab treatment was given to AS patients with active disease despite treatment with NSAIDs.260 In a subgroup analysis, efficacy was investigated among patients with previous TNFi failure.169 Response rates were lower than in TNFi naïve patients, but still significant and sustained clinical response was observed. The study was not powered to subgroup according to reasons for failure of previous TNFi or by bDMARD treatment number.169 Issues regarding effectiveness of various switch strategies may be addressed through observational registry data.84 Collaboration across registries as discussed above will improve power and enable earlier post- marketing studies of newly introduced drugs.

The concept of tailored or personalized medicine has become increasingly acknowledged within treatment of certain diseases e.g. cancer– and a similar concept seem appealing within inflammatory rheumatic diseases. To predict bDMARD treatment effectiveness in routine care based on clinical and simple biochemical measures has been attempted within RA.261;262 In the future, it is possible that more advanced prediction models aiming at personalized medicine will include biomarker analyses, imaging results (MRI, ultrasound), etc.263 The Danish Rheumatologic Biobank was established in year 2015 and is funded by the Danish Regions and the Danish Rheumatism Association. The Biobank provides an infrastructure for nationwide collection of biologic material for research of diagnostic, predictive and prognostic biomarkers within inflammatory arthritis.264;265 In parallel to the collection of biologic material (mainly blood samples), high quality clinical data are registered in DANBIO. Standardized operating procedures ensure that the material is of high quality - this provides optimal conditions for collaboration across different departments. Currently, >2000 samples are collected each year in Danish patients with inflammatory arthritis. Hopefully, the prospectively collected clinical data combined with biological material will facilitate research within personalized medicine end treatment effectiveness among patients with inflammatory arthritis.

8. Conclusion The nine papers and the results presented in this thesis demonstrate that observational registry data from DANBIO may answer research questions regarding bDMARD effectiveness in patients with PsA and axSpA/AS which only to a limited degree have been addressed in previous RCT studies. Examples are long term treatment effectiveness, baseline variables associated with treatment response and withdrawal, switching outcomes - including impact of non-medical biosimilar switching. Also in the future, DANBIO and other clinical rheumatology registries will be important data sources that enable research within questions that are difficult or impossible to investigate in a randomized setting. Methodologies regarding confounder adjustment, inclusion of external data from national registries and international collaboration will refine the observational research method even further.

9. Danish summary De biologiske lægemidler har de seneste 10-20 år forbedret behandlingsmulighederne indenfor rygsøjlegigt og psoriasisgigt ganske betydeligt. I den kliniske hverdag må op mod halvdelen af patienterne dog afbryde behandlingen pga. bivirkninger eller manglende effekt. Dette er en uhensigtsmæssig situation for patienten og for samfundet. Der er således et stort ønske om forbedrede muligheder for at forudse behandlingseffekter og bivirkninger hos patienterne - og for i det hele taget at forstå, hvorledes disse potente lægemidler anvendes optimalt i klinikken. Når de biologiske lægemidler markedsføres, er deres effekt og bivirkningsprofil afprøvet i randomiserede kliniske studier. Det er dog tiltagende anerkendt, at praktiske kliniske erfaringer, hvor lægemidlerne anvendes hos for eksempel ældre patienter med konkurrerende sygdomme og en mindre klassisk sygdomspræsentation, er et vigtigt supplement til de randomiserede studier. Den landsdækkende danske kliniske kvalitetsdatabase, DANBIO, blev etableret parallelt med markedsføringen af de biologiske lægemidler og indeholder nu prospektive data vedrørende >40.000 voksne patienter med inflammatorisk ledsygdom i Danmark. I databasen registreres oplysninger om de enkelte patienters sygdomskarakteristika, hvilken gigtbehandling patienten får, og hvilken effekt behandlingen har – målt som patient rapporterede data, objektive mål som for eksempel antal hævede og ømme led, udvalgte radiografiske data samt eventuelle årsager til stop af behandlingen, bivirkninger og lignende. I denne doktorafhandling præsenteres 9 artikler inden for sygdomsgrupperne rygsøjlegigt og psoriasisgigt. Alle artikler er publicerede i internationale reumatologiske tidsskrifter og tager udgangspunkt i data fra DANBIO. Artiklerne undersøger hvilke faktorer, som har betydning for langtidseffekt og tolerabilitet af biologisk behandling. Inden for psoriasisartrit beskrives biologisk behandlingseffekt og - varighed blandt patienter, der 1) starter deres første biologiske behandlingsforløb, 2) skifter fra deres første til et efterfølgende biologisk behandlingsforløb, og 3) anvender forskellige startdoser af lægemidlet infliximab (i samarbejde med det islandske ICEBIO register). Derudover 4) undersøges effekten af tobaksrygning. På lignende måde beskrives ved rygsøjlegigt behandlingseffekt og –varighed blandt patienter, der 1) starter deres første biologiske behandlingsforløb, 2) skifter fra deres første til et efterfølgende behandlingsforløb, 3) har/har ikke radiografiske forandringer på røntgen optagelser af korsbensled, eller som 4) er rygere versus ikke-rygere. Sluttelig beskrives konsekvenser af det landsdækkende danske skift fra original til biosimilært infliximab på tværs af reumatologiske diagnoser. Afhandlingen indeholder en gennemgang og diskussion af de 9 artikler samt en generel beskrivelse af den epidemiologiske forskningsmetode, som ligger bag - inklusive en diskussion af metodemæssige styrker og svagheder. Derudover perspektiveres den fremtidige anvendelse af kliniske reumatologiske databaser til forskning.

10. English summary The introduction of the biologic disease modifying antirheumatic drugs (bDMARDs) has during the last 1-2 decades significantly improved treatment outcomes among patients with axial spondyloarthritis and psoriatic arthritis. However, in a routine care setting, up to 50% of patients experience treatment failure due to side effects or lack of effect – with a negative impact on patient and on society. There is still an unmet need to fully understand the optimal treatment algorithms for the use of biologics in the clinic, and the ability to select the right treatment for the right patient (personalized medicine) is practically non- existing. Upon marketing, the beneficial effect and the safety profile of the biological drugs have been investigated in randomized clinical trials (RCTs). The extrapolation from RCTs to routine care is, however, a challenge as the patients who actually receive treatment with a specific drug may differ from the patients who were included in the original trials. This is due to higher age, less classical disease presentations, comorbid disease and treatment with co-medications. Thus, knowledge from observational registries is increasingly acknowledged as a valuable supplement to the randomised studies. The nationwide Danish DANBIO registry was initially established with the aim to monitor use of biological therapies. DANBIO now includes >40.000 adult patients with inflammatory arthritis treated with conventional synthetic or biologic DMARDs. Data are collected prospectively in routine care by an online solution and includes information on patient reported outcomes, objective disease measures, radiographic data, treatment regimen, reason for withdrawal and adverse events. This doctoral thesis presents 9 papers within axial spondyloarthritis (including ankylosing spondylitis) and psoriatic arthritis which all have been published in peer-reviewed high-impact journals and present data from the DANBIO registry. The papers all aim to investigate treatment response and long-term drug retention rates and predictors thereof in biologically treated patients. Within psoriatic arthritis, treatment effectiveness is investigated in 1) patients who initiate first TNFi treatment course, 2) patients who switch from the first to a subsequent bDMARD, 3) patients treated with different infliximab dose regimens (collaboration with Icelandic ICEBIO registry), 4) smokers versus non-smokers. In ankylosing spondylitis, treatment response and –retention is investigated 1) during the first TNFi treatment course, 2) after switching to a subsequent bDMARD, 3) according to tobacco smoking. In patients with axSpA initiating their first TNFi treatment course the impact of axSpA sub-diagnosis on treatment effectiveness is investigated. Finally, the impact of a non-medical switch from originator to biosimilar infliximab is described across diagnoses.

The thesis contains a summary and discussion of the 9 papers and a general description of the epidemiologic methodology applied across all manuscripts. Furthermore, the future perspectives of research within DANBIO and other clinical registries within rheumatology are discussed.

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12. Papers 1-9

Treatment Response, Drug Survival, and Predictors Thereof in 764 Patients With Psoriatic Arthritis Treated With Anti–Tumor Necrosis Factor ␣ Therapy

Results From the Nationwide Danish DANBIO Registry

Bente Glintborg,1 Mikkel Østergaard,2 Lene Dreyer,3 Niels Steen Krogh,4 Ulrik Tarp,5 Michael Sejer Hansen,1 Signe Rifbjerg-Madsen,6 Tove Lorenzen,7 and Merete Lund Hetland8

Objective. To investigate disease activity, treat- patients’ clinical response to anti-TNF␣ treatment (de- ment response, and drug survival, and predictors fined as achievement of the American College of Rheu- thereof, among Danish patients with psoriatic arthritis matology 20% [ACR20], ACR50, and ACR70 improve- (PsA) receiving their first treatment series with a tumor ment criteria or a European League Against necrosis factor ␣ (TNF␣) inhibitor. Rheumatism [EULAR] good response at least once Methods. Patients with PsA were identified from a during the first 6 months of treatment) and duration prospective nationwide rheumatologic database, the and rate of drug adherence (referred to as drug sur- Danish biologics registry DANBIO, using data regis- vival), as well as predictors thereof. tered from 2000–2009. Information was obtained on the Results. Of 764 patients with PsA, 320 received adalimumab, 260 infliximab, and 184 etanercept. Me- dian drug survival was 2.9 years, and 1-year and 2-year 1 Bente Glintborg, MD, PhD, Michael Sejer Hansen, MD, drug survival rates were 70% and 57%, respectively. PhD: Gentofte University Hospital, Hellerup, Denmark; 2Mikkel Østergaard, MD, PhD, DMSc: Copenhagen University Hospital at Clinical parameters that showed improvement over 6 Glostrup, Denmark; 3Lene Dreyer, MD, PhD: Copenhagen University months were the C-reactive protein (CRP) level, Health 4 Hospital, Rigshospitalet, Copenhagen, Denmark; Niels Steen Krogh, Assessment Questionnaire score, and 28-joint Disease MSc: Zitelab Aps, Copenhagen, Denmark; 5Ulrik Tarp, MD, DMSc: Århus University Hospital, Århus, Denmark; 6Signe Rifbjerg-Madsen, Activity Score. Male sex, CRP level >10 mg/liter, MD: Frederiksberg Hospital, Frederiksberg, Denmark; 7Tove Loren- concomitant methotrexate use, and low patient health zen, MD: Vejle Hospital, Vejle, Denmark; 8Merete Lund Hetland, MD, PhD: Copenhagen University Hospital at Glostrup, and DAN- visual analog scale score at baseline were associated BIO Registry, Copenhagen, Denmark. with longer drug survival. Improvement was achieved by Dr. Østergaard has received consulting fees, speaking fees, 59%, 45%, 24%, and 54% of patients according to the and/or research grants from Abbott, Amgen, Bristol-Meyers Squibb, Centocor, Genmab, GlaxoSmithKline, Novo Nordisk, Wyeth/Pfizer, ACR20, ACR50, ACR70 response criteria and EULAR Roche, Schering-Plough/MSD, and UCB (less than $10,000 each). Dr. good response, respectively. A CRP level >10 mg/liter Hansen has received consulting fees, speaking fees, and/or research was predictive of the improvement responses (odds ratio grants from Abbott, Roche, and Schering-Plough/MSD (less than $10,000 each). Dr. Lorenzen serves on the Danish Advisory Board of [OR] 2.6 for ACR20, OR 3.0 for ACR50, OR 3.6 for Abatacept, Bristol-Myers Squibb and is a member of the Abbott ACR70, and OR 2.2 for EULAR good response). Scientific Committee. Dr. Hetland has received consulting fees, speak- Conclusion. In these patients with PsA treated ing fees, and/or research grants from Abbott, Centocor, Roche, Schering-Plough/MSD, UCB-Nordic, and Wyeth/Pfizer (less than with their first TNF␣ inhibitor in clinical practice, high $10,000 each) and, on behalf of DANBIO, she has received grants drug adherence and responder rates were observed. from Abbott, Bristol-Myers Squibb, Roche, Schering-Plough/MSD, UCB-Nordic, and Wyeth/Pfizer. Moreover, increased levels of CRP at baseline were Address correspondence to Bente Glintborg, MD, PhD, associated with both good treatment responses and Gentofte University Hospital, Niels Andersensvej 65, 2900 Hellerup, continued treatment, which may be of clinical value in Denmark. E-mail: [email protected]. Submitted for publication May 8, 2010; accepted in revised selecting the patients most likely to benefit from treat- form October 21, 2010. ment with TNF␣ inhibitors.

382 ANTI-TNF␣ RESPONSE AND DRUG SURVIVAL IN PsA 383

The prevalence of psoriatic arthritis (PsA) among reports, coverage was calculated to be 88% in 2008 and 93% in Caucasians is 0.1–0.2%, with an estimated incidence of 6 2009. By November 1, 2009, 1,237 patients with PsA, diagnosed according to specialists in rheumatology, had been registered per 100,000 person-years (1). PsA covers a wide spec- in DANBIO. Of these patients, 432 were not included in the trum of disease manifestations, including peripheral and present study, because they were only treated with DMARDs axial arthritis, enthesitis, and dactylitis (2,3). and had never received biologic treatment. Another 41 pa- The wide range of disease manifestations in PsA tients were treated with biologic agents but participated in warrants individualized treatment and presents a chal- clinical studies, and therefore were also excluded. Thus, 764 patients were included in the present study (Table 1). Patients lenge to the treating physician (4). Similar to rheuma- treated by dermatologists are not included in the database. toid arthritis (RA), disease-modifying antirheumatic In Denmark, biologic treatments of rheumatic diseases drugs (DMARDs) are often the first line of treatment in can only be prescribed and administered at hospital depart- PsA. However, the experience with DMARDs has ments of rheumatology and not by private practitioners. The mainly been obtained in RA patients, and only a few drugs are fully reimbursed by the health care system and are of no cost to the individual patient. Therefore, the selection of randomized clinical trials have been performed in patients with PsA (4). In the past decade, several placebo- controlled clinical trials have described the effect of Table 1. Characteristics of the 764 patients with psoriatic arthritis* tumor necrosis factor ␣ (TNF␣)–inhibiting therapy in ␣ Demographic variables at baseline PsA (2,4,5). Until recently, 3 TNF inhibitors, inflix- Women, no. (%) 396 (52) imab, adalimumab, and etanercept, were available for Age, median (IQR) years 47 (38–56) the treatment of PsA (4,6). Disease duration, median (IQR) years 5 (2–11) Symptom duration, median (IQR) years 7 (4–14) National registries that include followup data on MTX use, no. (%) 410 (54) patients treated with biologic drugs have been estab- Previous DMARDs, no. (%)† lished in several countries (5,7–9). These real-life data Sulfasalazine 391 (51) MTX 288 (38) allow for the investigation of long-term drug effects Glucocorticoids 147 (19) among a heterogeneous group of patients, including Cyclosporine 67 (9) elderly patients who may experience comorbid diseases. Azathioprine 51 (7) Gold 47 (6) Such data provide a valuable supplement to results from Leflunomide 38 (5) randomized clinical trials, which often include a limited Not stated 97 (13) number of patients who fulfilled a strict set of inclusion TNF␣ inhibitor, no. (%) Adalimumab 320 (42) criteria and who were studied for a limited time span Etanercept 184 (24) (5,10,11). Infliximab 260 (34) The rheumatologic database of the Danish bio- Year of treatment initiation, no. (%) 2000 2 (0.3) logics registry DANBIO currently includes up to 8 years 2001 7 (1) of followup data. It is mandatory for the treating clini- 2002 8 (1) cians to prospectively report treatment and disease 2003 41 (5) 2004 65 (8) activity among patients being treated with biologic 2005 113 (15) agents for a rheumatic disease (12,13). Our aims, based 2006 118 (16) on the DANBIO data, were to report drug efficacy and 2007 128 (17) 2008 161 (21) drug survival (defined as duration and rate of adherence 2009 (January–November) 121 (16) to anti-TNF␣ treatment), as well as to identify predictors Reason for drug discontinuation, no. (%) thereof, among Danish patients with PsA who were Lack of efficacy 175 (23) ␣ Adverse effects 95 (12) receiving their first treatment course with a TNF Disease remission 9 (1) inhibitor in routine care. Psoriatic skin flare 7 (1) Planning pregnancy 6 (1) Cancer (suspected/verified) 5 (1) PATIENTS AND METHODS Lost to followup 4 (1) Other reasons 20 (3) Identification of patients. DANBIO is a nationwide Not stated 15 (2) Danish rheumatologic registry that was initiated in 2000 and Total discontinuations 336 (44) ϳ covers 90% of patients treated with a biologic drug in routine * IQR ϭ interquartile range; MTX ϭ methotrexate; TNF␣ ϭ tumor clinical care (12,13). Each year, all departments of rheumatol- necrosis factor ␣. ogy in Denmark (25 in total) are asked to report the personal † Some patients previously received Ͼ1 disease-modifying antirheu- identification code of all patients receiving biologic treatment. matic drug (DMARD), and therefore the percentages do not add up to When the codes in the registry were compared with these 100%. 384 GLINTBORG ET AL

Table 2. Disease activity in patients with psoriatic arthritis at baseline and during followup* Baseline 2 weeks 6 weeks 6 months 1 year 2 years 3 years 4 years 5 years CRP, mg/liter† 10 (4–22) 5 (1–9) 5 (1–10) 4 (1–9) 5 (1–10) 5 (1–10) 4 (2–9) 4 (1–9) 4 (1–8) No. of swollen 3 (1–7) 1 (0–4) 0 (0–1) 0 (0–1) 0 (0–1) 0 (0–1) 0 (0–1) 0 (0–1) 0 (0–1) joints† No. of tender 7 (3–13) 3 (1–8) 2 (0–6) 1 (0–5) 1 (0–3) 0 (0–2) 0 (0–3) 0 (0–2) 0 (0–2) joints† HAQ score† 1.0 (0.6–1.5) 0.75 (0.25–1.25) 0.6 (0.1–1.1) 0.6 (0.0–1.0) 0.4 (0.0–1.0) 0.4 (0.0–1.0) 0.3 (0.0–1.0) 0.3 (0.0–0.9) 0.5 (0.0–1.0) DAS28† 4.8 (3.9–5.5) 3.4 (2.6–4.3) 3.0 (2.1–4.0) 2.8 (1.9–3.9) 2.6 (1.8–3.6) 2.3 (1.7–3.1) 2.1 (1.7–3.2) 2.0 (1.5–2.9) 2.3 (1.7–2.9) VAS pain score, 63 (45–75) 36 (20–60) 27 (13–52) 21 (10–47) 20 (8–48) 20 (8–38) 21 (8–40) 24 (10–44) 22 (5–46) mm† VAS fatigue 65 (49–79) 51 (29–75) 44 (22–71) 35 (14–59) 37 (10–62) 31 (10–52) 19 (8–53) 29 (7–67) 22 (12–35) score, mm† VAS global 69 (50–81) 46 (21–68) 31 (15–58) 27 (10–52) 23 (9–51) 21 (10–45) 21 (8–48) 20 (7–43) 22 (9–39) score, mm† BASDAI, mm‡ 62 (46–75) 49 (28–68) 34 (22–52) 25 (11–47) 25 (9–49) 17 (10–47) 16 (7–47) 16 (6–26) 14 (1–42) BASFI, mm‡ 52 (35–68) 47 (26–62) 38 (21–55) 26 (6–47) 27 (7–46) 18 (6–57) 22 (5–57) 23 (5–48) 23 (6–64) BASMI, mm 20 (10–40) 20 (10–30)§ 10 (10–30)§ 10 (0–20)§ 20 (0–30)§ 10 (0–30) 20 (10–50) 15 (0–40) 40 (10–50) No. of patients 764 749 732 615 432 293 181 130 68 treated¶ No. of patients 658 275 366 406 318 229 127 104 45 with visit registered * Except where indicated otherwise, values are the median (interquartile range). The baseline visit was the time point at which the patient received his or her first dose of tumor necrosis factor ␣ inhibitor. Outcome data were reported according to the registrations in the DANBIO registry at the following time points: 2 weeks of treatment (time interval 1–4 weeks), 6 weeks (time interval 5–9 weeks), 6 months (time interval 18–32 weeks), 1 year (time interval 46–64 weeks), 2 years (time interval 91–117 weeks), 3 years (time interval 143–182 weeks), 4 years (time interval 183–233 weeks), 5 years (time interval 234–285 weeks), and 6 years (time interval 286–338 weeks). If more DANBIO registrations occurred within a given time interval, the one closest to the given time point was selected. If a patient had no registrations within a given time interval, data were registered as missing for the given time point. CRP ϭ C-reactive protein; HAQ ϭ Health Assessment Questionnaire; DAS28 ϭ Disease Activity Score in 28 joints; VAS ϭ visual analog scale; BASDAI ϭ Bath Ankylosing Spondylitis Disease Activity Index; BASFI ϭ Bath Ankylosing Spondylitis Functional Index; BASMI ϭ Bath Ankylosing Spondylitis Metrology Index. † P Ͻ 0.001 by paired comparison of followup data at all time points versus baseline. ‡ P Ͻ 0.05 by paired comparison of followup data at all time points versus baseline. § P Ͻ 0.05 at this time point versus baseline. ¶ Among patients with incomplete followup data, the followup time was estimated according to the latest visit registered in the DANBIO.

patients for treatment is not influenced by factors such as of health, and fatigue. In cases of clinical signs and/or symp- social status. According to national clinical guidelines, patients toms of axial involvement, the treating rheumatologist was who are considered for treatment should have continuously encouraged to additionally monitor axial disease activity, using active disease and must have experienced treatment failure the Bath Ankylosing Spondylitis Disease Activity Index with at least 1 DMARD. The decision to start and stop (BASDAI), Functional Index (BASFI), and Metrology Index treatment is made locally by a rheumatologist. (BASMI) (introduced in 2003) (17–19). In addition, disease Baseline demographic and clinical variables included activity and outcomes were evaluated using the C-reactive in the registry are age, sex, disease duration, and previous or protein (CRP) level and the swollen and tender joint counts. current treatment with methotrexate (MTX) or other All of these measures were determined at 0, 2, and 6 weeks, 6 DMARDs. In addition, disease activity parameters are pro- months, and 1, 2, 3, 4, and 5 years after initiation of the spectively reported to DANBIO through an online system anti-TNF␣ therapy (Table 2). (available at http://www.danbio-online.dk) (14). Data collec- The clinical response to anti-TNF␣ therapy was eval- tion occurs, at a minimum, biannually. uated as achievement of the American College of Rheumatol- The DANBIO database has been approved by the ogy 20% (ACR20), ACR50, and ACR70 improvement criteria Danish Board of Health and the Danish Data Registry. The (20) or a European League Against Rheumatism (EULAR) registration of data on patients treated with biologic agents good response (21). Arbitrarily, we classified patients as re- does not require patient consent. Publication of data does not sponders if they achieved a clinical response (determined as require approval by the Registry Ethics Committee. yes versus no) at least once during the first 6 months of Measures of disease activity and clinical response. treatment. Complete baseline and outcome data for the calcu- Levels of disease activity were monitored with the use of lations of the ACR and EULAR responses were available from Health Assessment Questionnaire (HAQ) scores (15), the 426 patients (56%) and 483 patients (63%), respectively. 28-joint Disease Activity Score (DAS28) (16), and visual Treatment duration. Duration of drug survival was analog scale (VAS) scores for pain, patient’s global assessment calculated as the number of days during which individual ANTI-TNF␣ RESPONSE AND DRUG SURVIVAL IN PsA 385

patients continued their treatment with the first TNF␣ inhib- RESULTS itor. The start date was the date at which the first dose was administered, and the stop date was the date of the first missed Patient characteristics. The number of patients dose. Temporary treatment interruptions (e.g., due to infec- with PsA who initiated their first treatment series with a tions or surgery) of Ͻ3 months’ duration were allowed. All TNF␣ inhibitor increased over the years of the registry. observations were censored at November 1, 2009. Reasons for The majority of patients received adalimumab (42%) drug discontinuation were registered. (Table 1). A total of 336 patients (44%) had withdrawn Queries were sent to the hospitals with regard to 133 ␣ patients for whom no followup data were available since July 1, from TNF inhibitor treatment by November 1, 2009. 2009 and for whom no treatment stop date was registered. As shown in Table 1, the most prevalent reasons for drug Subsequently, data on treatment duration were complete for discontinuation included lack of efficacy (in 175 of 336 741 (97%) of the 764 patients. For the remaining 23 patients patients; 52% of withdrawals) and adverse effects (in 95 whose followup data were incomplete, data were censored of 336 patients; 28% of withdrawals). Adverse effects according to the last visit registered in DANBIO. were infections in 33 patients, allergic reactions in 5 Statistical analysis. Analyses of the data were performed using SPSS software (version 16.0) and SAS software patients, infliximab infusion reactions in 5 patients, skin (version 9.0). Demographic and descriptive data are expressed rash in 12 patients, nausea/fatigue in 8 patients, neutro- as the median and interquartile range (IQR). Groups were penia in 3 patients, elevated liver enzyme levels in 2 compared by nonparametric testing (for unpaired data, chi- patients, chest pain in 2 patients, polyneuropathy in 2 square and Mann-Whitney tests; for paired data, Wilcoxon’s patients, and other/unspecified effects in 23 patients. signed rank test). Efficacy was analyzed as described above, One of the 5 patients who experienced infliximab infu- per protocol. In all statistical tests, P values less than 0.05 were considered statistically significant. sion reactions was receiving concomitant MTX at the Kaplan-Meier plots, log rank tests, and multivariate time of the reaction. Cox regression analyses were used for drug survival analyses. At baseline, 410 patients (54%) were receiving Logistic regression analysis was used for the identification of concomitant MTX. Baseline MTX use was more preva- factors associated with clinical response. In order to visualize lent among patients receiving infliximab (70%) com- stratified Kaplan-Meier drug survival curves, baseline VAS pared with those receiving adalimumab (49%) or etan- scores for global health status were converted into quartiles, P Ͻ and baseline CRP levels were converted into a binary variable ercept (39%) ( 0.001). After 3 months, 329 (80%) of (below versus above 10 mg/liter, according to the detection these patients continued to receive concomitant MTX, limit of the CRP level in most centers). For the analysis of time 44 patients (11%) had stopped receiving MTX but to discontinuation of treatment due to adverse events, discon- continued to receive TNF␣ inhibitor treatment, and 37 tinuations due to ineffectiveness were treated as censored patients (9%) had stopped receiving the TNF␣ inhibitor. observations. Similarly, discontinuations due to adverse events were handled as censored observations in the analysis of time When we compared the baseline data between to discontinuation due to ineffectiveness. women and men, we found that women had significantly In the Cox and logistic regression analyses, sex, type of higher HAQ scores (median 1.13 versus 0.88), VAS TNF␣ inhibitor, baseline CRP level (below or equal to 10 global health scores (median 72 mm versus 66 mm), mg/liter versus above 10 mg/liter), and baseline MTX use (yes VAS fatigue scores (median 70 mm versus 62 mm), VAS versus no) were included as categorical variables, whereas pain scores (median 65 mm versus 62 mm), and tender patient age, disease duration, swollen and tender joint counts, VAS scores, HAQ scores, and DAS28 scores were continuous joint counts (median 7 versus 6), whereas women had variables. The variables with least significance were excluded lower swollen joint counts (median 3 versus 4) (all P Ͻ stepwise (backward selection), leaving only statistically signif- 0.05 by Mann-Whitney test). Age (median 48 years icant variables in the model. The Bath Ankylosing Spondylitis versus 46 years), disease duration (median 4 years versus data were excluded from the analysis, because only a limited 6 years), DAS28 scores (median 4.8 for both), and number of patients had data on axial disease at baseline (for ϭ ϭ baseline CRP levels (median 10 mg/liter for both) were the BASDAI n 159, for the BASFI n 157, and for the P Ͼ BASMI n ϭ 122). Baseline MTX use was defined as any similar between women and men ( 0.05). concurrent use of MTX at baseline, irrespective of dose, and Therapeutic effect. All outcome parameters im- did not include former or later use of the drug. proved during followup (all P Ͻ 0.05 versus baseline, by In the logistic regression analysis, all interactions in- Wilcoxon’s signed rank test) (Table 2). Among the 483 volving sex, patient age, disease duration, MTX use, drug type, patients with available EULAR response data, 259 baseline HAQ scores, and DAS28 scores were tested. Each patients (54%) achieved a EULAR good response at interaction pair was included in the overall statistical model, and was thereafter excluded in the backward selection process least once during the first 6 months of treatment, 131 if the interaction was statistically nonsignificant. We found no (27%) achieved a moderate response, and 93 (19%) had statistically significant interactions. no response. ACR improvement responses were avail- 386 GLINTBORG ET AL

Figure 1. Crude drug survival curves of tumor necrosis factor ␣ (TNF␣) inhibitor use in patients with psoriatic arthritis, stratified according to sex, baseline C-reactive protein (CRP) level, and quartiles of visual analog scale (VAS) scores for patient’s global assessment of health. The x-axis shows treatment duration (in years), while the y-axis shows the cumulative survival rate. P values were determined by log rank test.

able for 426 patients, among whom 253 (59%) achieved swollen joint counts, and VAS fatigue score were not a response at the ACR20 level, 190 (45%) achieved associated with drug survival (Table 3). ACR50, and 104 (24%) achieved ACR70. In a stratified multivariate Cox regression analy- Drug survival. The total treatment period was sis that included only adverse effects as the event causing 2,135 person-years. The median duration of drug sur- drug termination, female sex (hazard ratio [HR] 1.8, vival was 2.9 years, and 1- and 2-year drug survival rates 95% confidence interval [95% CI] 1.3–1.9; P ϭ 0.01), were 70% and 57%, respectively. use of infliximab (HR versus adalimumab 0.49, 95% CI The crude retention rates were similar among 0.29–0.84 [P ϭ 0.01]; HR versus etanercept 0.46, 95% CI patients receiving infliximab, those receiving adali- 0.25–0.85 [P ϭ 0.01]), lack of concomitant use of MTX mumab, and those receiving etanercept (P Ͼ 0.05). As (HR 1.67, 95% CI 1.02–2.70; P ϭ 0.04), and a high shown in Figure 1, male sex (P Ͻ 0.001 by log rank test), number of tender joints (HR 1.03/joint, 95% CI 1.01– a CRP level Ͼ10 mg/liter at baseline (P ϭ 0.006), and a 1.06; P ϭ 0.02) at baseline were statistically significant low VAS score for global health at baseline (P ϭ 0.005) predictors of shorter drug survival. Similarly, including were associated with improved drug survival. Concomi- only lack of efficacy as the event causing drug termina- tant use of MTX at baseline did not affect drug survival tion, a CRP level Յ10 mg/liter (HR 2.11, 95% CI (P Ͼ 0.05). 1.49–3.00; P Ͻ 0.001) and a higher baseline VAS score Baseline disease parameters and patient charac- for global health (HR 1.18/cm, 95% CI 1.09–1.29; P Ͻ teristics were included in a Cox regression analysis in 0.001) were statistically significant factors associated order to identify the baseline factors associated with with shorter drug survival. subsequent discontinuation of TNF␣ inhibitor treat- Prediction of clinical response. In a multiple ment. In all patients, the VAS pain scores correlated logistic regression analysis (backward stepwise selection) strongly with VAS global health scores (Spearman’s with EULAR good response as the dependent variable, rho ϭ 0.81, P Ͻ 0.001). Therefore, the VAS pain score a CRP level of Ͼ10 mg/liter (odds ratio [OR] 2.2 for was excluded from the multivariate Cox regression ana- high versus low, 95% CI 1.5–3.2; P Ͻ 0.001), male sex lysis. In the final model, female sex, a high VAS global (OR 1.5 for male versus female, 95% CI 1.0–2.2; P ϭ health score at baseline, a low CRP level at baseline, and 0.04), and younger age (OR 0.98/year increase, 95% CI lack of concomitant MTX use were associated with 0.97–1.0; P ϭ 0.01) were associated with a EULAR good shorter drug survival, whereas patient age, type of clinical response, whereas type of biologic drug, disease biologic drug, DAS28 score, HAQ score, tender and duration, DAS28 scores, HAQ scores, VAS global ANTI-TNF␣ RESPONSE AND DRUG SURVIVAL IN PsA 387

Table 3. Baseline statistical predictors of discontinuing treatment with tumor necrosis factor ␣ inhibitors, as determined by multivariate Cox regression analysis* Final model after Unadjusted analysis backward selection

HR (95% CI) P HR (95% CI) P Sex Male 1 1 Female 1.65 (1.33–2.05) Ͻ0.001 1.42 (1.11–1.80) 0.005 No. of swollen joints 0.99 (0.97–1.02) 0.59 No. of tender joints 1.03 (1.02–1.05) Ͻ0.001 VAS fatigue score 1.03 (0.93–1.13) 0.62 VAS pain score 1.07 (1.01–1.13) 0.012 VAS global score 1.10 (1.04–1.16) 0.001 1.10 (1.04–1.17) 0.001 HAQ score 1.32 (1.10–1.58) 0.003 DAS28 1.09 (0.99–1.21) 0.093 CRP Յ10 mg/liter 1.39 (1.10–1.75) 1.40 (1.09–1.78) Ͼ10 mg/liter 1 0.006 1 0.008 MTX use Yes 1 1 No 1.21 (0.98–1.50) 0.082 1.37 (1.07–1.75) 0.013 Biologic drug Infliximab 1 Adalimumab 0.73 (0.58–0.95) 0.020 Etanercept 0.78 (0.60–1.03) 0.084 Age 1.00 (0.99–1.01) 0.61 * Values are the hazard ratio (HR) with 95% confidence interval (95% CI) determined in 764 patients with psoriatic arthritis. VAS ϭ visual analog scale; HAQ ϭ Health Assessment Questionnaire; DAS28 ϭ Disease Activity Score in 28 joints; CRP ϭ C-reactive protein; MTX ϭ methotrexate. health scores, and concomitant use of MTX at baseline liter), the percentages of patients achieving a clinical showed no statistically significant association with a response within 6 months of treatment were as follows: EULAR good clinical response (all P Ͼ 0.05). 51% versus 73% achieving ACR20, 33% versus 60% In a similar analysis using the ACR20 response as achieving ACR50, 14% versus 37% achieving ACR70, the dependent variable, concomitant use of MTX (OR and 47% versus 65% achieving a EULAR good re- 1.7 for use versus nonuse, 95% CI 1.1–2.6; P ϭ 0.03), a sponse. Thus, 1 in 7 patients achieved clinical improve- high VAS score for global health (OR 1.01/cm increase, ment according to the ACR70 if their CRP level was in 95% CI 1.00–1.02; P ϭ 0.01), and a CRP level Ͼ10 the normal range at treatment start, whereas 1 in 3 mg/liter (OR 2.4 for high versus low, 95% CI 1.7–3.9; patients whose CRP level was elevated at treatment start P Ͻ 0.001) were associated with clinical response. The achieved an ACR70 improvement response. unadjusted effect of a high CRP level was an OR of 2.6 (95% CI 1.7–3.9; P Ͻ 0.001). DISCUSSION In a multiple logistic regression analysis with ACR50 as the dependent variable, a CRP level Ͼ10 TNF␣ inhibitors are efficacious in the treatment mg/liter was the only variable associated with clinical of patients with PsA in randomized clinical trials (22– response (OR 3.0, 95% CI 2.0–4.5; P Ͻ 0.001). A similar 26). Data from clinical practice are needed to comple- result was found in the model using ACR70 as the ment the trials and to assess their external validity (27). measure of clinical response (for high CRP, OR 3.6, Published studies on patients with PsA treated with 95% CI 2.2–5.9; P Ͻ 0.001). Sex, age, type of biologic biologic drugs are, however, few (4,8,9,28,29). The drug, disease duration, DAS28 scores, HAQ scores, present nationwide study of 764 patients with PsA VAS global health scores, and concomitant MTX use followed up prospectively for up to 8 years in routine were not associated with ACR50 or ACR70 improve- care represents the largest cohort and the longest obser- ment responses. vation time published to date. Three findings of this When patients were stratified according to their study are of importance for clinical practice: approxi- baseline level of CRP (Յ10 mg/liter versus Ͼ10 mg/ mately half of the patients with PsA who received their 388 GLINTBORG ET AL

first treatment series with a TNF␣ inhibitor achieved a or ACR70 response. These discrepancies may be ex- clinical response (ACR50 or EULAR good response) plained, at least in part, by the concept of bias by within 6 months. The number needed to treat (NNT) to indication with regard to concomitant MTX treatment. achieve an ACR70 response was much higher in patients No data were available on the reasons for addition of whose baseline CRP level was in the normal range MTX to the biologic treatment regimen in some patients (NNT ϭ 7) than in patients whose baseline CRP level and not in others. Absence of concomitant MTX use was elevated (Ͼ10 mg/liter) (NNT ϭ 3). CRP was the might be associated with the presence of a comorbidity only baseline variable that was predictive of both longer of importance for drug continuation (9). MTX use was treatment continuation and good treatment response. linked to use of infliximab, but it is currently unknown Carmona et al reported a 1-year drug survival whether MTX has any effect on the formation of rate of 88% among 570 patients with PsA registered in immunopathogenic antibodies in PsA during anti-TNF␣ the Spanish national registry, although no efficacy data therapy (39). Randomized controlled trials of anti-TNF were reported (8). Similarly, 76% of British patients with medications in PsA have not shown any beneficial effect PsA followed up for more than 1 year were continuing to associated with the use of MTX as a concomitant receive treatment with their first TNF␣ inhibitor, ac- treatment in patients with PsA (23,24). cording to British registry data (5). A report based on In the present study, men had a longer treatment data from the South Swedish register did not explicitly duration and better EULAR response than did women present the drug survival rates, but a EULAR good (5,28,36,38). Shorter treatment duration and poorer response rate of 55% was reported among 261 patients treatment response among women treated with TNF␣ with PsA (9), a rate that was very similar to the 54% inhibitors have also been described in patients with RA found in our study. These findings are difficult to and in those with ankylosing spondylitis (37,38,40,41). compare with the results from randomized controlled Similarly, the tendency toward higher VAS and HAQ trials, as those trials have often focused on ACR20 scores in women has previously been observed (41,42). clinical responses or shorter observation periods, but the However, any linkage between musculoskeletal perfor- 6-month ACR50 response rate of 45% in our study is mance, sex hormones, or other sex-related factors and similar to the rates of 40–45% previously reported in anti-TNF␣ therapy has not been established (41). randomized trials (22–26). The main reason for drug discontinuation was An increased CRP level at baseline was the sole lack of treatment effect, whereas only a few patients factor most uniformly linked to clinical response and stopped treatment due to adverse events. Discontinua- treatment continuation. Similar results have been re- tion of infliximab use was related to adverse events. A ported by other authors among patients with PsA as well similar tendency has been described previously (5,43), as patients with RA and patients with spondylarthropa- but, due to the observational study design and lack of thies (9,30–37). The CRP level is probably linked to randomization of drug therapy, such data must be systemic inflammation in patients with rheumatic dis- interpreted with caution. ease, and thus it might be used to distinguish those The DANBIO data in our study can be consid- patients who mainly experience chronic irreversible ered of high quality. According to previous reports, damage from those with active inflammatory disease. In Ͼ90% of Danish patients treated with biologic agents contrast, some authors have found high baseline HAQ are registered in the DANBIO database, probably due or VAS scores to be predictive of drug discontinuation, to the fact that registration is mandatory irrespective of perhaps because of an association with chronic irrevers- patient’s consent (13). This is supported by the fact that ible disease (31). It would be of great value to select the coverage is much lower in databases using voluntary patients most likely to benefit from biologic treatment at registration and requiring patient consent (8). In the early stages of the decision process; in this aspect, CRP DANBIO registry, similar to that in most clinical trials, levels seem to be a promising candidate. the type of arthritis, peripheral or axial, is not registered. We found that MTX use was associated with Since the disease entities are treated differently (44), treatment continuation, a tendency that has been previ- this may have influenced the results. Similarly, smoking ously described by others (5,9,38) but only in analyses status and comorbid disease are other factors that might that were adjusted for other baseline variables. MTX use influence treatment outcomes (5). However, these data was not a uniform predictor of clinical response in our were only recently introduced in the registry and are still study, since it was only a predictor of the ACR20 not uniformly available. response and not the EULAR response or the ACR50 This analysis of 764 patients with PsA in a ANTI-TNF␣ RESPONSE AND DRUG SURVIVAL IN PsA 389

nationwide prospective registry documents that TNF␣ arthritis: 6 month results from a longitudinal, observational, inhibitors decrease the disease activity in patients with multicentre study. Ann Rheum Dis 2007;66:1038–42. 8. Carmona L, Gomez-Reino JJ. Survival of TNF antagonists in PsA in clinical practice. Overall, half of the patients spondylarthritis is better than in rheumatoid arthritis: data from achieved a good clinical response, but the response rate the Spanish registry BIOBADASER. Arthritis Res Ther 2006;8: and duration of drug survival were significantly higher in R72. 9. Kristensen LE, Gulfe A, Saxne T, Geborek P. Efficacy and patients with an elevated CRP level at baseline. Male sex tolerability of anti-tumour necrosis factor therapy in psoriatic was predictive of longer treatment continuation and a arthritis patients: results from the South Swedish Arthritis Treat- EULAR good response. The effect of concomitant ment Group register. Ann Rheum Dis 2008;67:364–9. 10. Aletaha D. Capturing real-life patient care in psoriatic arthritis MTX use was weak but seemed to have some beneficial and its risks: the challenge of analysing registry data. Arthritis Res effect on drug survival and achievement of the ACR20 Ther 2009;11:112. response. Other parameters, including the type of bio- 11. Pincus T, Yazici Y, van Vollenhoven R. Why are only 50% of courses of anti-tumor necrosis factor agents continued for only 2 logic drug, HAQ score, DAS28 score, VAS score, and years in some settings? Need for longterm observations in stan- disease duration, did not significantly affect drug sur- dard care to complement clinical trials. J Rheumatol 2006;33: vival or treatment efficacy. Among these Danish patients 2372–5. ␣ 12. Hetland ML, Unkerskov J, Ravn T, Friis M, Tarp U, Andersen LS, with PsA, the TNF -inhibiting treatments were well et al. Routine database registration of biological therapy increases tolerated, and only a few patients stopped treatment due the reporting of adverse events twentyfold in clinical practice: first to adverse effects. results from the Danish Database (DANBIO). Scand J Rheumatol 2005;34:40–4. 13. Hetland ML, Lindegaard HM, Hansen A, Podenphant J, Unker- ACKNOWLEDGMENTS skov J, Ringsdal VS, et al. Do changes in prescription practice in patients with rheumatoid arthritis treated with biological agents We thank all of the rheumatology departments in affect treatment response and adherence to therapy? Results from Denmark for reporting patient data to the DANBIO registry. the nationwide Danish DANBIO Registry. Ann Rheum Dis 2008;67:1023–6. 14. Schefte DB, Hetland ML. An open-source, self-explanatory touch AUTHOR CONTRIBUTIONS screen in routine care: validity of filling in the Bath measures on Ankylosing Spondylitis Disease Activity Index, Function Index, the All authors were involved in drafting the article or revising it Health Assessment Questionnaire and Visual Analogue Scales in critically for important intellectual content, and all authors approved comparison with paper versions. Rheumatology (Oxford) 2010;49: the final version to be published. Dr. Glintborg had full access to all of 99–104. the data in the study and takes responsibility for the integrity of the 15. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of data and the accuracy of the data analysis. patient outcome in arthritis. Arthritis Rheum 1980;23:137–45. Study conception and design. Glintborg, Østergaard, Tarp, Hetland. 16. Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Acquisition of data. Glintborg, Dreyer, Tarp, Rifbjerg-Madsen, Loren- Putte LB, van Riel PL. Modified disease activity scores that zen, Hetland. include twenty-eight–joint counts: development and validation in a Analysis and interpretation of data. Glintborg, Østergaard, Dreyer, prospective longitudinal study of patients with rheumatoid arthri- Krogh, Tarp, Hansen, Hetland. tis. Arthritis Rheum 1995;38:44–8. 17. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing REFERENCES spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994;21:2286–91. 1. Pedersen OB, Svendsen AJ, Ejstrup L, Skytthe A, Junker P. The 18. Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Mallorie occurrence of psoriatic arthritis in Denmark. Ann Rheum Dis P, et al. A new approach to defining functional ability in ankylos- 2008;67:1422–6. ing spondylitis: the development of the Bath Ankylosing Spondy- 2. Mease PJ. Psoriatic arthritis assessment and treatment update. Curr Opin Rheumatol 2009;21:348–55. litis Functional Index. J Rheumatol 1994;21:2281–5. 3. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic 19. Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett arthritis: epidemiology, clinical features, course, and outcome. SL, Calin A. Defining spinal mobility in ankylosing spondylitis Ann Rheum Dis 2005;64 Suppl II:ii14–7. (AS): the Bath AS Metrology Index. J Rheumatol 1994;21:1694–8. 4. Ritchlin CT, Kavanaugh A, Gladman DD, Mease PJ, Helliwell P, 20. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Boehncke WH, et al. Treatment recommendations for psoriatic Goldsmith C, et al. American College of Rheumatology prelimi- arthritis. Ann Rheum Dis 2009;68:1387–94. nary definition of improvement in rheumatoid arthritis. Arthritis 5. Saad AA, Ashcroft DM, Watson KD, Hyrich KL, Noyce PR, Rheum 1995;38:727–35. Symmons DP. Persistence with anti-tumour necrosis factor thera- 21. Van Gestel AM, Prevoo ML, van ’t Hof MA, van Rijswijk MH, van pies in patients with psoriatic arthritis: observational study from de Putte LB, van Riel PL. Development and validation of the the British Society of Rheumatology Biologics Register. Arthritis European League Against Rheumatism response criteria for rheu- Res Ther 2009;11:R52. matoid arthritis: comparison with the preliminary American Col- 6. Rozenblit M, Lebwohl M. New biologics for psoriasis and psoriatic lege of Rheumatology and the World Health Organization/ arthritis. Dermatol Ther 2009;22:56–60. International League Against Rheumatism criteria. Arthritis 7. Heiberg MS, Kaufmann C, Rodevand E, Mikkelsen K, Kolding- Rheum 1996;39:34–40. snes W, Mowinckel P, et al. The comparative effectiveness of 22. Saad AA, Symmons DP, Noyce PR, Ashcroft DM. Risks and anti-TNF therapy and methotrexate in patients with psoriatic benefits of tumor necrosis factor-␣ inhibitors in the management 390 GLINTBORG ET AL

of psoriatic arthritis: systematic review and metaanalysis of ran- activity in an observational psoriatic arthritis cohort. Arthritis Care domized controlled trials. J Rheumatol 2008;35:883–90. Res (Hoboken) 2010;62:970–6. 23. Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld 35. Gladman DD, Mease PJ, Choy EH, Ritchlin CT, Perdok RJ, Sasso SD, Choy EH, et al, for the Adalimumab Effectiveness in Psoriatic EH. Risk factors for radiographic progression in psoriatic arthritis: Arthritis Trial Study Group. Adalimumab for the treatment of subanalysis of the randomized controlled trial ADEPT. Arthritis patients with moderately to severely active psoriatic arthritis: Res Ther 2010;12:R113. results of a double-blind, randomized, placebo-controlled trial. 36. Van den Bosch F, Manger B, Goupille P, McHugh N, Rodevand Arthritis Rheum 2005;52:3279–89. E, Holck P, et al. Effectiveness of adalimumab in treating patients 24. Mease PJ, Kivitz AJ, Burch FX, Siegel EL, Cohen SB, Ory P, et al. with active psoriatic arthritis and predictors of good clinical Etanercept treatment of psoriatic arthritis: safety, efficacy, and responses for arthritis, skin and nail lesions. Ann Rheum Dis effect on disease progression. Arthritis Rheum 2004;50:2264–72. 2010;69:394–9. 25. Kavanaugh A, Krueger GG, Beutler A, Guzzo C, Zhou B, Dooley 37. Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL, LT, et al. Infliximab maintains a high degree of clinical response in Hetland ML. Predictors of treatment response and drug continu- patients with active psoriatic arthritis through 1 year of treatment: ation in 842 patients with ankylosing spondylitis treated with results from the IMPACT 2 trial. Ann Rheum Dis 2007;66: anti-tumour necrosis factor: results from 8 years’ surveillance in 498–505. the Danish nationwide DANBIO registry. Ann Rheum Dis 2010; 26. Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, 69:2002–8. 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Inefficacy of infliximab in ankylosing predicted? Arthritis Res Ther 2010;12:R94. spondylitis is correlated with antibody formation. Ann Rheum Dis 29. Virkki LM, Sumathikutty BC, Aarnio M, Valleala H, Heikkila R, 2007;66:133–4. Kauppi M, et al. Biological therapy for psoriatic arthritis in clinical 40. Hyrich KL, Watson KD, Silman AJ, Symmons DP. Predictors of practice: outcomes up to 2 years. J Rheumatol 2010. E-pub ahead response to anti-TNF-␣ therapy among patients with rheumatoid of print. arthritis: results from the British Society for Rheumatology Bio- 30. Davis JC Jr, van der Heijde DM, Dougados M, Braun J, Cush JJ, logics Register. Rheumatology (Oxford) 2006;45:1558–65. Clegg DO, et al. Baseline factors that influence ASAS 20 response 41. Sokka T, Toloza S, Cutolo M, Kautiainen H, Makinen H, Gogus F, in patients with ankylosing spondylitis treated with etanercept. et al. 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Rudwaleit M, Claudepierre P, Wordsworth P, Cortina EL, Sieper arthritis treated with adalimumab, etanercept, or infliximab: re- J, Kron M, et al. Effectiveness, safety, and predictors of good sults from eight years of surveillance of clinical practice in the clinical response in 1250 patients treated with adalimumab for nationwide Danish DANBIO registry. Arthritis Rheum 2010;62: active ankylosing spondylitis. J Rheumatol 2009;36:801–8. 22–32. 34. Coates LC, Cook R, Lee KA, Chandran V, Gladman DD. 44. Fernandez-Sueiro JL. The challenge and need of defining axial Frequency, predictors and prognosis of sustained minimal disease psoriatic arthritis. J Rheumatol 2009;36:2633–4.

Clinical Response, Drug Survival, and Predictors Thereof Among 548 Patients With Psoriatic Arthritis Who Switched Tumor Necrosis Factor ␣ Inhibitor Therapy

Results from the Danish Nationwide DANBIO Registry

Bente Glintborg,1 Mikkel Østergaard,2 Niels Steen Krogh,3 Martin Dehn Andersen,4 Ulrik Tarp,5 Anne Gitte Loft,6 Hanne M. Lindegaard,7 Mette Holland-Fischer,8 Henrik Nordin,9 Dorte Vendelbo Jensen,10 Christian Holkmann Olsen,4 and Merete Lund Hetland11

Objective. To describe the frequency of treatment Methods. We conducted an observational cohort switching and outcomes among patients with psoriatic study based on the Danish nationwide DANBIO regis- arthritis (PsA) who switched tumor necrosis factor ␣ try. Treatment outcomes were evaluated using the inhibitor (TNFi) agents in routine care. American College of Rheumatology criteria for 20% improvement (ACR20)/ACR50/ACR70, European 1Bente Glintborg, MD, PhD: Gentofte University Hospital League Against Rheumatism (EULAR) response crite- and DANBIO Registry, Copenhagen, Denmark: 2Mikkel Østergaard, ria for good response, and the 28-joint count Disease MD, PhD, DMSc: Copenhagen Center for Arthritis Research, Activity Score (DAS28) (remission). Kaplan-Meier and Glostrup Hospital, Glostrup, Denmark, and University of Copenha- gen, Copenhagen, Denmark; 3Niels Steen Krogh, MS: ZiteLab ApS, regression analyses were used for drug survival analyses Copenhagen, Denmark; 4Martin Dehn Andersen, MD, Christian and to identify predictors of outcome after treatment Holkmann Olsen, MD, PhD: Frederiksberg Hospital, Frederiksberg, switching. Denmark; 5Ulrik Tarp, MD, DMSc: Aarhus University Hospital, Aarhus, Denmark; 6Anne Gitte Loft, MD, DMSc: Vejle Hospital, Results. Of 1,422 patients starting TNFi agents, Vejle, Denmark; 7Hanne M. Lindegaard, MD, PhD: Odense Univer- 548 patients (39%) switched to a second biologic drug sity Hospital, Odense, Denmark; 8Mette Holland-Fischer, MD: Aalborg University Hospital, Aalborg, Denmark, and Aarhus Univer- during up to 10 years of followup. Median followup was sity Hospital, Aarhus, Denmark; 9Henrik Nordin, MD: Rigshospitalet 2.3 years (interquartile range [IQR] 1.0–4.3 years). and University of Copenhagen, Copenhagen, Denmark; 10Dorte Ven- Switchers were more frequently women (56% versus delbo Jensen, MD: Helsingør Hospital, Helsingør, Denmark; 11Merete Lund Hetland, MD, PhD, DMSc: Glostrup Hospital, Glostrup, Den- 45%), had a shorter disease duration (3 versus 4 years), mark, and University of Copenhagen and DANBIO Registry, Copen- a higher median Health Assessment Questionnaire hagen, Denmark. (HAQ) score (1.1 [IQR 0.6–1.6] versus 0.9 [IQR 0.5– Dr. Østergaard has received consulting fees, speaking fees, and/or honoraria from Abbott, Centocor/Janssen, Bristol-Myers 1.4]), DAS28 (4.8 [4.0–5.7] versus 4.4 [3.6–5.2]), pain Squibb, MSD, MorphoSys, Pfizer/Wyeth, Roche, and UCB (less than score on a visual analog scale (VAS) (65 mm [46–77] $10,000 each). Dr. Loft has received consulting fees, speaking fees, versus 62 mm [40–75]), and fatigue score on a VAS and/or honoraria from Abbott, MSD, Pfizer, and UCB (less than $10,000 each). Dr. Lindegaard has received consulting fees, speaking (69 mm [50–83] versus 64 mm [42–80] mm) (all P < fees, and/or honoraria from MSD and Roche (less than $10,000 each). 0.05 at start of first TNFi). During the first and second Dr. Holland-Fischer has received consulting fees, speaking fees, and/or honoraria from MSD, Roche, and UCB (less than $10,000 each). Dr. treatment, HAQ, DAS28, and VAS scores and C-reactive Hetland has received consulting fees, speaking fees, and/or honoraria protein levels had decreased after 6 months (all P < from Abbott, Bristol-Myers Squibb, MSD, Pfizer, Roche, and UCB 0.05), and median drug survival was 2.2 versus 1.3 years (less than $10,000 each). P Address correspondence to Bente Glintborg, MD, PhD, ( < 0.001). Lower fatigue score increased survival of Department of Rheumatology, Gentofte University Hospital, Niels the second TNFi. After switching, the proportions of Andersens Vej 65, 2900 Copenhagen, Denmark. E-mail: glintborg@ patients achieving a sustained ACR20, ACR50, ACR70, dadlnet.dk. Submitted for publication November 19, 2012; accepted in EULAR good response, and DAS28 remission after 3–6 revised form January 15, 2013. months were 22% (number needed to treat [NNT] 4.5),

1213 1214 GLINTBORG ET AL

13% (NNT 7.9), 5% (NNT 20), 19% (NNT 5.3), and 34% PATIENTS AND METHODS (NNT 2.9), respectively. Response rates were lower P DANBIO registry. The nationwide Danish DANBIO during the second treatment (all < 0.01 versus first registry was started in 2000 and was approved by the Danish TNFi). At the 2-year visit, 47% of switchers had achieved Health and Medicines Authority as a clinical quality registry in an ACR20 response. No differences between drug–drug 2006. DANBIO covers Ͼ90% of adults with rheumatic disease combinations were found. who are treated with biologic agents in routine care (21–23). Conclusion. Thirty-nine percent of the patients According to Danish legislation, the registration and publica- with PsA switched TNFi agents. Response rates and tion of data from clinical registries do not require patient consent or approval by ethics committees. drug survival were lower after switching; however, half In this observational cohort study based on data from of the switchers had an ACR20 response 2 years after the DANBIO registry, we included patients who were diag- starting the first TNFi. nosed as having PsA according to the treating rheumatologist. All treatment courses initiated before January 1, 2012 were Psoriatic arthritis (PsA) covers a wide spectrum evaluated. Patients were excluded if they received only DMARDs, if they received biologic agents as part of clinical of disease manifestations, including arthritis, enthesitis, trials, if they were not followed up in the registry since start of dactylitis, and axial spondylitis. This diversity in symp- their first TNFi, or if they did not receive a biologic drug toms warrants individualized treatment and presents a marketed to treat PsA as the first biologic agent. challenge to the treating physician. Methotrexate (MTX) In DANBIO, baseline data collected include age, sex, and other synthetic disease-modifying antirheumatic disease duration, and previous or current treatment with MTX or other DMARDs. Disease activity parameters are prospec- drugs (DMARDs) are often the first-line treatment in tively reported in an online system (www.danbio-online.dk) PsA (1–4). Upon treatment failure, tumor necrosis (24). Functional status is monitored using the Health Assess- factor ␣ inhibitors (TNFi) have proven effective in ment Questionnaire (HAQ) (25), and disease activity is eval- several randomized clinical trials, with 40–60% of pa- uated using the 28-joint count Disease Activity Score (DAS28) Յ tients achieving response according to the American (26), C-reactive protein (CRP) level (normal range 10 mg/ liter), and patient’s global, pain, and fatigue scores on a visual College of Rheumatology criteria for 20% improvement analog scale (VAS) and physician’s global score on a VAS. In (ACR20) (5–12). cases of clinical signs and/or symptoms of axial involvement, Currently, 4 TNFi agents with different chemical the treating rheumatologist monitors axial disease activity structures and pharmacokinetics are marketed to treat with the Bath Ankylosing Spondylitis Disease Activity Index PsA in Denmark: infliximab, adalimumab, etanercept, (27), Bath AS Functional Index (28), and Bath AS Metrology Index (29) (introduced in 2003). Bath AS data were not and golimumab. Among patients who experience TNFi included in this study since only a limited number of patients treatment failure due to insufficient response or adverse had baseline data recorded (20). events (AEs), switching to a second TNFi seems appeal- It is recommended that data on disease activity and ing. However, evidence on the effect of TNFi switching functional status be collected at least biannually or if the in PsA is scarce and mainly originates from smaller medical treatment is altered (19). Յ Data quality. Queries were sent to the hospitals re- observational studies that include 30 switch episodes garding treatment series with incomplete followup (20). All (13–17). The British Society for Rheumatology Biologics observations were censored as of April 20, 2012. All calcula- Register reported a 1-year drug survival rate of 74% tions were based on observed data, and no imputation of among 178 switchers with PsA. However, no outcome missing data was performed. Due to the observational clinical data or predictors among switchers were reported (18). study design, no specific monitoring or cross checking of data was performed as part of this study. However, all Danish No randomized trials on treatment switching in PsA departments of rheumatology that report to the DANBIO have been performed. registry regularly participate in audits in order to optimize data The Danish nationwide DANBIO registry now quality (19). includes Ͼ10 years of prospective followup of patients Drug survival. Drug survival was calculated as the with inflammatory arthritis treated with biologic agents number of days that individual patients continued treatment with the drug. The start date was the date the first dose was in routine care (19). We have previously described given, and the stop date was the date of the first missed dose. treatment response and predictors of TNFi treatment in Temporary treatment interruptions, e.g., due to infections or patients with PsA who had not received biologic agents surgery, of Յ3 months’ duration were allowed. If a patient (20). In the present study, we aimed to investigate frequen- restarted treatment with the same biologic drug after Ͼ3 cies and reasons for switching, treatment responses, months’ treatment interruption, the second treatment course with the drug was deleted from the data set (n ϭ 67 cases). duration and rates of drug adherence (referred to as The reasons for drug discontinuation are recorded in drug survival), and predictors thereof in patients with DANBIO in prespecified categories: lack of treatment effect, PsA who switched TNFi agents in routine clinical care. AEs, disease remission, pregnancy, surgery, cancer, death, SWITCHING OF TNFi IN PSORIATIC ARTHRITIS 1215

infections, loss to followup, and other reasons. The registration leflunomide use (20), and this variable was not included in the in DANBIO does not distinguish between primary and sec- analysis. The variables with the highest P values were excluded ondary lack of response. Thus, it was not possible to distinguish stepwise (backward selection), leaving only statistically signif- between these reasons for switching therapy. Below, icant variables in the final model. “switching-AE” denotes switching due to side effects, infection, death, or cancer. “Switching–lack of effect” denotes switching due to a lack or loss of effect. “Switching-other” RESULTS denotes switching due to any other cause (pregnancy, surgery, loss to followup, remission), or multiple reasons for drug DANBIO data and exclusion criteria. By January discontinuation. 1, 2012, 3,178 patients diagnosed as having PsA had Treatment response. At baseline, 3 months, and 6 been registered in DANBIO. We excluded 1,646 pa- months, disease activity was evaluated using the CRP level, tients who were treated with DMARDs only, 53 patients DAS28, patient’s pain, fatigue, and global scores on a VAS, treated with biologic agents as part of clinical trials, 42 and physician’s global score on a VAS, and physical function was evaluated using HAQ scores. patients not followed up in the registry since the start of Clinical response was evaluated as achievement of an their first TNFi, and 15 patients who did not receive a ACR20, ACR50, ACR70 response (30), or a European League biologic drug marketed to treat PsA as the first biologic Against Rheumatism (EULAR) good response (31). Arbi- agent. Thus, 1,422 patients who were naive for biologic trarily, we classified patients as “responders” if they achieved a clinical response (yes or no) at both the 3- and 6-month visits drugs and had been registered in DANBIO from the compared to the baseline registration data. Similarly, patients time of initiation of the first TNFi were included. Of were considered to be in DAS28 remission if they had a these, a subgroup of 548 patients (switchers) had re- Ͻ DAS28 of 2.6 at both the 3- and 6-month visits. In the case ceived treatment with Ն2 different biologic drugs (TNFi of missing data at either the 3- or 6-month visit, one record indicating clinical response was sufficient in order to classify or other) during followup. The total number of treat- the patient as a responder. Complete baseline and outcome ment courses was 2,241. data for the calculations of ACR and EULAR responses Baseline characteristics of the patients and pa- during the first treatment course were available for 530 (37%) tient disposition. Among the 1,422 patients included, and 624 (44%) of the 1,422 patients, respectively. 699 (49%) were women, and their median age was 48 The overall long-term treatment response was evaluated at the 2-year visit (the first visit Ͼ104 weeks after years (IQR 39–56 years). Median followup time was 2.3 initiating the first TNFi). A 2-year time period was chosen years (IQR 1.0–4.3 years). The patient flow is shown in arbitrarily to allow for an acceptable number of switch epi- Table 1. When data were censored, 548 patients (39%) sodes without excluding too many patients with insufficient had switched treatment, 632 patients (44%) were still followup time. Patients who switched treatment from the first TNFi after the 2-year visit were excluded from this analysis treated with the original TNFi, and 242 (17%) had (n ϭ 67). stopped treatment without starting a new TNFi. The Statistical analysis. Statistical analyses were per- main reasons for switching were lack of effect (57% of formed using SPSS version 16.0 and SAS version 9.0 software. switchers; n ϭ 311) or AE (28% of switchers; n ϭ 152). Demographic and descriptive data are presented as the median Among the 548 patients who started treatment with a and interquartile range (IQR). Groups were compared by nonparametric testing (using the chi-square and Mann- second biologic agent, 245 patients continued treatment, Whitney tests for unpaired data and Wilcoxon’s signed rank 189 (34%) switched to a third treatment, and 114 test for paired data). The proportion of patients in whom patients stopped without starting a new treatment. The treatment responses were achieved was expressed as the main reason for switching to a third biologic was lack of number needed to treat (NNT), calculated as the reciprocal ϭ value of response rates. In all statistical tests, P values less than effect (62% of switchers; n 118) (Table 1). Similarly, 0.05 were considered significant. 57 of the 189 patients (30%) switched to a fourth Kaplan-Meier plots and log rank tests were used to biologic drug, and 20 of those 57 patients (35%) assess drug survival. Unadjusted/univariate and multivariate switched to a fifth biologic drug. The median time Cox regression analyses with hazard ratios (HRs) were used interval between the first missed dose of the first TNFi for the identification of factors associated with drug survival in the second treatment course. Logistic regression analyses and and starting the second biologic drug was 15 days (IQR odds ratios (ORs) were used to identify factors associated with 1–62 days). clinical response. In the regression analyses, age, disease The most frequently used first-line drugs were duration, baseline CRP, DAS28, HAQ, and VAS scores were infliximab from 2001 to 2006 and adalimumab from 2007 included as continuous variables, and sex, type of TNFi to 2011. Etanercept was most frequently used as second- (current and previous treatment), concomitant MTX (yes/no), calendar year of starting TNFi, and reason for discontinuation line (49%) and third-line (30%) treatment. Frequent of the first TNFi (AE/lack of effect/other) were included as drug sequences were as follows: adalimumab then etan- categorical variables. Only a few patients had a history of ercept (n ϭ 155 patients), infliximab then etanercept 1216 GLINTBORG ET AL

Table 1. Patient flow through treatment courses, reasons for drug discontinuation, and biologic drugs used* First treatment Second treatment Third treatment Fourth, fifth, and course course course sixth treatment (n ϭ 1,422) (n ϭ 548) (n ϭ 189) courses (n ϭ 82) Continuous treatment 632 245 86 – Stopped and switched treatment 548 189 57 – Lack of effect 311 118 41 AE 152 43 12 Other 85 28 4 Stopped without starting new treatment 242 114 46 – Lack of effect 62 36 22 AE 79 39 15 Other 101 39 9 Biologic drug, no. (%) Adalimumab 636 (45) 188 (34) 42 (22) 15 (18) Etanercept 318 (22) 266 (49) 56 (30) 11 (13) Infliximab 429 (30) 59 (11) 37 (20) 10 (12) Golimumab 39 (3) 24 (4) 28 (15) 12 (15) Certolizumab pegol – 3 (1) 7 (4) 6 (7) Rituximab – 2 (0.4) 4 (2) 3 (4) Tocilizumab – 2 (0.4) 10 (5) 18 (22) Abatacept – 1 (0.2) 4 (2) 7 (9) Not stated – 3 (1) 1 (1) 0 (0) * Except where indicated otherwise, values are the number of patients. AE ϭ adverse event.

(n ϭ 107), infliximab then adalimumab (n ϭ 101), mg/kg, 4.5 mg/kg, and 4.3 mg/kg, respectively. The etanercept then adalimumab (n ϭ 84), adalimumab then average doses at the last registered visit were 3.8 mg/kg, infliximab (n ϭ 35), and etanercept then infliximab (n ϭ 5.0 mg/kg, and 5.3 mg/kg, respectively. At baseline, 765 24). Other combinations were used in Ͻ20 patients of 1,422 patients (54%) were receiving concomitant (Table 1). Biologic agents other than TNFi were initi- MTX. MTX was more frequently combined with inflix- ated in only 50 of 2,241 treatment series and will not be imab than with the other TNFi agents (P Ͻ 0.001). further addressed herein. Switchers were more frequently women, had a The average infliximab doses at the start of the shorter disease duration, had higher HAQ, DAS28, and first, second, and third treatment courses were 3.5 fatigue and pain scores (on a VAS), and had more

Table 2. Baseline demographics and disease activity at initiation of treatment with the first TNFi* Nonswitchers P, nonswitchers Continuous Stopped without receiving continuous P, switchers treatment starting new TNFi Overall Switchers treatment versus versus (n ϭ 632) (n ϭ 242) (n ϭ 874) (n ϭ 548) stopped† nonswitchers† Age 48 (39–56) 49 (38–55) 48 (39–56) 47 (38–56) 0.9 0.6 Women, no. (%) 259 (41) 134 (55) 393 (45) 306 (56) 0.0001 0.001 Disease duration, years 5 (1–10) 4 (1–10) 4 (1–10) 3 (1–9) 0.3 0.01 Symptom duration, years 7 (4–14) 7 (3–15) 7 (4–14) 7 (3–13) 0.9 0.04 Methotrexate use, no. (%) 347 (55) 135 (56) 482 (55) 283 (52) 0.8 0.12 DAS28 4.3 (3.6–5.1) 4.6 (3.7–5.4) 4.4 (3.6–5.2) 4.8 (4.0–5.7) 0.02 0.001 HAQ 0.9 (0.5–1.4) 1 (0.6–1.5) 0.9 (0.5–1.4) 1.1 (0.6–1.6) 0.008 0.0001 CRP, mg/liter 10 (3–20) 7 (3–16) 9 (3–19) 9 (3–23) 0.08 0.3 Fatigue score‡ 63 (39–78) 66 (50–83) 64 (42–80) 69 (50–83) 0.048 0.045 Global score‡ 66 (46–80) 72 (53–86) 68 (48–83) 70 (53–85) 0.004 0.08 Pain score‡ 61 (38–74) 63 (45–78) 62 (40–75) 65 (46–77) 0.06 0.03 Physician’s score‡ 32 (21–48) 34 (19–50) 33 (20–49) 40 (26–57) 0.9 0.0001 Tender joints (28-joint count) 4 (2–9) 7 (2–12) 5 (2–10) 7 (4–16) 0.008 0.0001 Swollen joints (28-joint count) 2 (0–5) 2 (0–5) 2 (0–5) 3 (0–7) 0.4 0.001 * Except where indicated otherwise, values are the median (interquartile range). TNFi ϭ tumor necrosis factor ␣ inhibitor; DAS28 ϭ Disease Activity Score 28 joints; HAQ ϭ Health Assessment Questionnaire; CRP ϭ C-reactive protein. † By Mann-Whitney and chi-square tests. ‡ Assessed on a 100-mm visual analog scale. SWITCHING OF TNFi IN PSORIATIC ARTHRITIS 1217

Figure 1. Kaplan-Meier drug survival curves showing drug survival by treatment course number. The table shows the number of patients who were still being treated at the corresponding time points. 95% CI ϭ 95% confidence interval. swollen and tender joints compared to nonswitchers 22% (NNT 4.5) and 18% (NNT 5.3), respectively. when they started the first TNFi (Table 2). Compared to Similarly, ACR50 response rates during the first, second, patients who continued the same treatment, nonswitch- and third treatment courses were 33% (NNT 3.1), 13% ers who stopped treatment without starting a new treat- (NNT 7.9), and 6% (NNT 16), respectively. ACR70 ment were more frequently women, had higher baseline response rates were 17% (NNT 5.9), 5% (NNT 20), and HAQ, DAS28, and global and fatigue scores (on a 2% (NNT 48). The proportions of patients in whom a VAS), and had more tender joints (Table 2). good response according to the EULAR criteria was Among the 548 switchers, baseline disease activ- achieved were 45% (NNT 2.3), 19% (NNT 5.3), and ity when they started the first treatment course was 17% (NNT 5.8), respectively, and the proportions of similar irrespective of the reason for switching (data not patients in DAS28 remission were 43% (NNT 2.3), 34% shown). (NNT 2.9), and 22% (NNT 4.4), respectively (Figure 2). Drug survival. The median overall drug survival Response rates were significantly lower during the sec- of the first TNFi was 2.2 years (95% confidence interval ond and third treatment courses compared to the first [95% CI] 1.9–2.5 years). Drug survival decreased after (all P Ͻ 0.05). switching (Figure 1). Median drug survival of the first Patient demographics (sex, age, and disease du- TNFi among switchers was 0.7 years (95% CI 0.6–0.8 ration) at baseline of the second and third treatment years). courses were similar among patients with missing and Treatment response. Disease activity was signifi- nonmissing data on ACR response rates (all P Ͼ 0.05; cantly reduced after 3 and 6 months’ treatment com- data not shown), whereas men (P ϭ 0.03) and patients pared to baseline during the first, second, and third with a longer disease duration (P ϭ 0.02) more often treatment courses (Table 3). had missing response data during the first treatment During the first treatment course, the proportion course. of patients in whom an ACR20 response was achieved At the 2-year visit, the proportions of nonswitch- within 3–6 months was 47% (NNT 2.2). Corresponding ers versus switchers who had an ACR20 response were rates during the second and third treatment course were 57% versus 47% (P ϭ 0.1), the proportions who had an 1218 GLINTBORG ET AL

Table 3. Disease activity during the first (n ϭ 1,422), second (n ϭ 548), and third (n ϭ 189) treatment courses* Treatment duration P, 0 versus P, 0 versus 0 months 3 months 6 months 3 months† 6 months† CRP, mg/liter First treatment course 9 (3–20) 4 (1–8) 4 (1–9) 0.0001 0.0001 Second treatment course 6 (2–15) 5 (2–9) 4 (1–9) 0.0001 0.001 Third treatment course 6 (2–17) 6 (2–10) 4 (2–9) 0.003 0.02 Fatigue score‡ First treatment course 65 (45–80) 42 (21–69) 38 (15–64) 0.0001 0.0001 Second treatment course 67 (49–81) 48 (25–68) 51 (25–72) 0.0001 0.01 Third treatment course 78 (68–88) 62 (33–79) 58 (33–74) 0.03 0.0001 Global score‡ First treatment course 69 (50–83) 32 (13–58) 29 (12–53) 0.0001 0.0001 Second treatment course 69 (46–81) 46 (22–75) 43 (20–70) 0.0001 0.0001 Third treatment course 77 (66–88) 53 (31–74) 59 (39–74) 0.0001 0.0001 Pain score‡ First treatment course 63 (43–76) 27 (12–53) 25 (11–49) 0.0001 0.0001 Second treatment course 65 (40–78) 38 (18–65) 40 (17–62) 0.0001 0.0001 Third treatment course 72 (60–82) 48 (26–71) 51 (31–67) 0.0001 0.0001 DAS28 First treatment course 4.6 (3.7–5.3) 2.7 (1.9–3.8) 2.7 (1.8–3.7) 0.0001 0.0001 Second treatment course 4.6 (3.7–5.4) 3.2 (2.2–4.0) 3.0 (2.2–4.1) 0.0001 0.0001 Third treatment course 5.0 (4.4–5.8) 3.7 (2.7–4.8) 3.2 (2.9–4.9) 0.0001 0.0001 HAQ First treatment course 1 (0.5–1.5) 0.6 (0.1–1.1) 0.6 (0.1–1.0) 0.0001 0.0001 Second treatment course 1.1 (0.6–1.6) 0.9 (0.4–1.5) 0.9 (0.4–1.4) 0.0001 0.0001 Third treatment course 1.4 (0.9–2.0) 1.0 (0.6–1.5) 1.3 (0.5–1.6) 0.02 0.003 * Outcome data were reported according to data recorded in the DANBIO registry at the following time points: 0 months (0–6 days after initiation of therapy), 3 months (10–17 weeks), and 6 months (18–32 weeks). If more than one data record was available for a given time interval, the one closest to the given time point was selected. If a patient had no data recorded within a given time interval, data were registered as missing for the given time point. Values are the median (interquartile range). CRP ϭ C-reactive protein; DAS28 ϭ Disease Activity Score in 28 joints; HAQ ϭ Health Assessment Questionnaire. † By Wilcoxon’s signed rank test. ‡ Assessed on a 100-mm visual analog scale.

ACR50 response were 45% versus 32% (P ϭ 0.02), the sus 17% (P ϭ 0.001), and the proportions with a EULAR proportions who had an ACR70 response were 35% ver- good response were 60% versus 41% (P Ͻ 0.001).

Figure 2. Proportion of patients in whom a clinical response was achieved within 3–6 months (A) and the number needed to treat (NNT) (B) during the first, second, and third treatment courses. ACR20 ϭ American College of Rheumatology criteria for 20% improvement; EULAR ϭ European League Against Rheumatism; DAS28 ϭ Disease Activity Score in 28 joints. SWITCHING OF TNFi IN PSORIATIC ARTHRITIS 1219

Table 4. Predictors of clinical response during the second treatment course, determined by multiple logistic regression analysis after backward selection* ACR20 ACR50 ACR70 EULAR good response

OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P Reason for stopping first TNFi – 0.006 – 0.04 – NS – 0.03 AE versus lack of effect 0.04 (0.004–0.3) 0.003 0.05 (0.03–0.7) 0.03 – NS 0.7 (0.2–2.3) NS Other versus lack of effect 2.1 (0.4–9.8) NS 2.7 (0.4–18) 0.3 – NS 4.9 (1.2–19) 0.02 Baseline HAQ, per unit – NS 0.08 (0.01–0.5) 0.005 – NS 0.4 (0.2–0.9) 0.02 Tender joint count, per joint 0.8 (0.7–0.9) 0.004 0.8 (0.7–0.9) 0.003 – NS 0.8 (0.7–0.9) 0.002 Baseline DAS28, per unit 7.6 (2.9–20.0) Ͻ0.001 31 (4.8–198) 0.0003 4.7 (1.5–14) 0.007 4.2 (1.9–9.2) 0.0003 No use of methotrexate 14.1 (3.4–59.5) 0.0003 10 (1.6–67) 0.02 – NS – NS * Sex, age, disease duration, swollen joint count, type of tumor necrosis factor ␣ inhibitor (TNFi; current or previous), year of starting TNFi, baseline C-reactive protein level, global, fatigue, pain, and physician’s global scores (on a visual analog scale) were not significant in any of the analyses. ACR20 ϭ American College of Rheumatology criteria for 20% improvement; OR ϭ odds ratio; 95% CI ϭ 95% confidence interval; EULAR ϭ European League Against Rheumatism; NS ϭ not significant; AE ϭ adverse event; HAQ ϭ Health Assessment Questionnaire; DAS28 ϭ Disease Activity in 28 joints.

Predictors of drug survival and response during switching of TNFi occurs frequently in clinical practice the second treatment course. In univariate Cox regres- and that nearly 40% of patients switched treatment sion analysis, drug survival of the second biologic agent during a median of 2.3 years of followup. Response rates was longer in men (P ϭ 0.02), in patients with fewer and drug survival times decreased after switching from tender joints (P ϭ 0.004), and in patients with lower the first to the second TNFi. However, significant de- fatigue score on a VAS (P ϭ 0.007). Patients who started creases in disease activity were observed during the first, the second TNFi in earlier years had longer drug survival second, and third treatment courses, and at the 2-year P ϭ ( 0.03). Differences in disease duration, baseline visit 47% of switchers had an ACR20 response and 41% CRP, HAQ, DAS28, swollen joint count, VAS global had a good response according to the EULAR criteria. score, VAS pain score, use of MTX, type of TNFi Only a few and mainly minor studies have previ- (current or previous), reason for withdrawal of the first ously addressed treatment switching in PsA patients TNFi, and age were not statistically significant. In mul- (13–17). We found that lack of treatment effect was the tivariate Cox regression analysis, the only predictor of main reason for switching and explained the switch in longer drug survival was lower fatigue score on a VAS the majority of cases, followed by AEs in 1 of 4 patients. (HR 1.1 cm [95% CI 1.04–1.3], P ϭ 0.007). An observational study from the British Society for The predictors of EULAR and ACR20/50/70 Rheumatology Biologics Register found switching in 178 responses after 3–6 months of treatment according to (31%) of 566 patients with PsA followed up for a mean multiple logistic regression analysis are shown in Table of 2.3 years (18). Gomez-Reino and Carmona reported 4. Fewer tender joints at baseline when the second TNFi switching in only 15 (5%) of 289 PsA patients followed was started predicted ACR20 response, ACR50 response, and a good response according to the EULAR up in the Spanish Base de Datos de Productos Biolo´gi- criteria. Lower HAQ score predicted ACR50 response cos de la Sociedad Espan˜ola de Reumatologı´a registry and a EULAR good response. Higher DAS28 predicted for up to 3.5 years (16). The authors did not explicitly ACR20, ACR50, and ACR70 responses and a EULAR state the reasons for switching, but discontinuation of good response, and no MTX use predicted ACR20 and the first TNFi was mainly due to AEs (16,18). In an ACR50 responses. Patients who stopped treatment with Austrian study switching occurred in 21 (33%) of 63 the previous TNFi due to an AE had a lower chance of patients with PsA followed up for up to 4 years, and ACR20 and ACR50 responses than patients who switching was mainly due to loss of effect (32). Other stopped due to lack of effect, and patients who stopped observational studies on switching in PsA have included for other reasons had a higher chance of response Ͻ15 switch episodes (13,14). Varying followup times, (Table 4). prescription guidelines, and access to treatment may, at least in part, explain the different switch rates. In this study, switchers had higher baseline dis- DISCUSSION ease activity and were more frequently women, which is This study based on the national DANBIO reg- consistent with previous reports (17). Higher baseline istry including 1,422 patients with PsA showed that disease activity among switchers has also been found in 1220 GLINTBORG ET AL

patients with rheumatoid arthritis (RA) (33,34) and clinical response after switching. We found that low those with ankylosing spondylitis (AS) (35), probably numbers of tender joints and low HAQ score at the reflecting more severe or refractory disease in these initiation of treatment with the second TNFi were patient groups. In RA, AS, and PsA, women have associated with clinical response. Lower fatigue score shorter drug survival (20,36–38) and experience poorer predicted both response and longer drug survival. This is effects of TNFi treatment than men (20,39,40), and consistent with previous studies of TNFi-naive patients women have higher switch rates in AS (20), but why and with PsA, AS, or RA, in which lower fatigue and HAQ how sex affects the response to TNFi is poorly under- scores were associated with response (20,39,43) and stood (40). longer drug survival (36) of the first TNFi. This might The response rates were significantly lower in the reflect a lower degree of chronic disability and impair- patients receiving the second or third treatment com- ment in these patient groups. pared to those who remained with the first TNFi, and The combination of TNFi therapy with synthetic the NNT to achieve ACR20 during the second treatment DMARDs in PsA is still debated, and several studies course was 4.5, compared to 2.2 during the first. Chakra- have shown no convincing additional effect of combining varty et al found a similar 6-month response rate among MTX and TNFi versus TNFi monotherapy (4,6,10,18). 30 switchers in the Consortium of Rheumatology Re- Due to the nonrandomized study design, the apparently searchers of North America registry (23%; NNT 4.3) negative or absent effect of concomitant MTX in the (17). Coates et al reported a reduction in DAS28 of 1.2 present study may be a proxy for comorbidities or other among 7 of 12 switchers at 12 weeks (NNT 1.7) com- patient-related factors. pared to 58 of 60 patients during the first treatment The infrequent use of etanercept in our cohort course (NNT 1) (14), whereas the other observational may reflect the perception that this drug is less effective studies of patients with PsA who switched treatment lack in psoriasis (4). A Danish registry study based on 742 response data (16,18). Similarly, drug survival decreased patients with psoriasis treated with TNFi showed adali- after switching, a tendency previously observed in other mumab to be the preferred first-line treatment in a observational studies (16–18,41). Compared to other dermatology setting (44). Thus, the activity and extent of populations with arthritis, switchers with PsA seem to psoriasis in skin and nails might affect treatment choice. have poorer drug survival rates than patients with AS This study has some limitations. In DANBIO, the (16,35) but better rates than patients with RA (16,32,42). 28-joint count and DAS28 score are used to monitor Recent EULAR guidelines recommend switch- disease activity. Only recently has it become possible to ing to a second TNFi in case of failure of the first (1). register a 68/66-joint count (45). Although the DAS28 This strategy is supported by our data showing that the has been validated in PsA patients (46), the lack of ACR20 response rates were similar among switchers and information regarding arthritis in, e.g., the distal joints nonswitchers at the 2-year visit, and an ACR20 response of hands and feet might have affected our results. and/or a good response according to the EULAR crite- We evaluated the clinical effect using the ACR ria was achieved in approximately half of the switchers. and EULAR responses. Although these response para- Furthermore, there were significant decreases in disease meters were developed to monitor relative changes in activity 3 months after starting the second TNFi com- disease activity among RA patients, they have been pared to the baseline visit. A similar tendency was even validated in patients with PsA (2,46,47) and are widely observed during the third treatment course. Thus, dis- used in clinical trials (5–12). However, a relative change ease activity decreased when a new TNFi was intro- in disease activity of, e.g., 20% and achievement of an duced, which supports the notion that switching has ACR20 response is not necessarily sufficient to consider some value in patients in whom initial TNFi treatment a patient well treated in a clinical setting (48). The has failed. Furthermore, since ACR20/50/70 and EU- impact of treatment on other disease manifestations, LAR responses are based on relative improvements such as skin psoriasis, enthesitis, and dactylitis, which compared to baseline disease activity, a carryover effect are not routinely registered in DANBIO, might affect from previous treatments may have caused underesti- whether the treatment was considered to be effective mates of the effects of switching. This might explain why (2,49,50). Furthermore, it is not explicitly registered in switching was more effective when evaluated by DAS28 DANBIO whether the PsA patient has axial spondylo- remission criteria. arthritis. Only a small percentage of patients had Bath To our knowledge, no previous reports on TNFi- AS scores recorded (20), and these data were therefore treated PsA patients have described the predictors of not included in the statistical analyses. The effect of SWITCHING OF TNFi IN PSORIATIC ARTHRITIS 1221

TNFi on axial disease manifestations might also have 3. Mease PJ. Psoriatic arthritis assessment and treatment update. affected the decision to continue or to switch therapy Curr Opin Rheumatol 2009;21:348–55. 4. Ash Z, Gaujoux-Viala C, Gossec L, Hensor EM, FitzGerald O, (20,51). Winthrop K, et al. A systematic literature review of drug therapies The nature of an observational registry study for the treatment of psoriatic arthritis: current evidence and confers some limitations regarding the reliability of the meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis 2012;71: results. Incompleteness of data is an inherent problem 319–26. within registry studies (52,53). In the present study, we 5. Mease PJ, Kivitz AJ, Burch FX, Siegel EL, Cohen SB, Ory P, et al. found no demographic differences among patients with Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:2264–72. missing/nonmissing response rate data during the sec- 6. Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld ond and third treatment courses, whereas there was a SD, Choy EH, et al, for the Adalimumab Effectiveness in Psoriatic tendency toward biased registration during the first Arthritis Trial Study Group. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: TNFi treatment course, with less missing data among results of a double-blind, randomized, placebo-controlled trial. women and patients with shorter disease duration. This Arthritis Rheum 2005;52:3279–89. may have affected our results. 7. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. In conclusion, nearly 40% of patients with PsA Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000;356:385–90. switched TNFi agents in routine care during up to 10 8. Antoni C, Krueger GG, de Vlam K, Birbara C, Beutler A, Guzzo years of followup, mainly due to lack of effect. The C, et al, for the IMPACT 2 Investigators. Infliximab improves signs response and remission rates and drug survival de- and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis 2005;64:1150–7. creased after switching. After 2 years, however, a clinical 9. Genovese MC, Mease PJ, Thomson GT, Kivitz AJ, Perdok RJ, response had been achieved in half of the switchers. Weinberg MA, et al. Safety and efficacy of adalimumab in Therefore, switching to another TNFi should be consid- treatment of patients with psoriatic arthritis who had failed disease modifying antirheumatic drug therapy. J Rheumatol 2007;34: ered in patients with PsA, irrespective of the reason for 1040–50. discontinuation of the first TNFi. 10. Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: ACKNOWLEDGMENTS results from the Infliximab Multinational Psoriatic Arthritis Con- trolled Trial (IMPACT). Arthritis Rheum 2005;52:1227–36. The authors thank the departments of rheumatology 11. Saad AA, Symmons DP, Noyce PR, Ashcroft DM. Risks and in Aalborg, Aarhus, Esbjerg, Fredericia, Frederiksberg, benefits of tumor necrosis factor-␣ inhibitors in the management Gentofte, Glostrup, Gråsten, Hjørring, Holbæk, Holstebro, of psoriatic arthritis: systematic review and metaanalysis of ran- Horsens, Helsingør, Kolding, Køge, Næstved/Nykøbing Fal- domized controlled trials. J Rheumatol 2008;35:883–90. ster, Odense, Randers, Rigshospitalet, Roskilde, Silkeborg, 12. Kavanaugh A, McInnes I, Mease P, Krueger GG, Gladman D, Slagelse, Svendborg, Vejle, and Viborg, Denmark for report- Gomez-Reino J, et al. Golimumab, a new human tumor necrosis factor ␣ antibody, administered every four weeks as a subcutane- ing to the DANBIO registry. ous injection in psoriatic arthritis: twenty-four–week efficacy and safety results of a randomized, placebo-controlled study [published erratum appears in Arthritis Rheum 2010;62:2555]. Arthri- AUTHOR CONTRIBUTIONS tis Rheum 2009;60:976–86. All authors were involved in drafting the article or revising it 13. Pitarch G, Sanchez-Carazo JL, Mahiques L, Oliver V. Efficacy of critically for important intellectual content, and all authors approved etanercept in psoriatic patients previously treated with infliximab. the final version to be published. Dr. Glintborg had full access to all of Dermatology 2008;216:312–6. the data in the study and takes responsibility for the integrity of the 14. Coates LC, Cawkwell LS, Ng NW, Bennett AN, Bryer DJ, Fraser data and the accuracy of the data analysis. AD, et al. 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Rheumatology 2014;53:21002109 RHEUMATOLOGY doi:10.1093/rheumatology/keu252 Advance Access publication 17 June 2014 Original article Impact of different infliximab dose regimens on treatment response and drug survival in 462 patients with psoriatic arthritis: results from the nationwide registries DANBIO and ICEBIO

Bente Glintborg1,2, Bjorn Gudbjornsson3,4, Niels Steen Krogh5, Emina Omerovic1, Natalia Manilo6, Mette Holland-Fischer7, Hanne M. Lindegaard8, Anne Gitte Loft9, Henrik Nordin10, Laura Johnsen11, 12 13 14

Sussi Flejsborg Oeftiger , Annette Hansen , Claus Rasmussen , Downloaded from Gerdur Grondal15, Arni Jon Geirsson15 and Merete Lund Hetland1,2,16

Abstract http://rheumatology.oxfordjournals.org/ Objective. The aim of this study was to describe dose regimens, dose escalation and clinical outcomes in TNF-a inhibitor (TNFi)naive patients with PsA treated with infliximab in routine rheumatology care. Methods. We conducted an observational cohort study based on the nationwide Danish Rheumatologic Database (DANBIO) and Center for Rheumatology Research (ICEBIO) registries. Stratified by country, characteristics of patients treated with 43 mg infliximab/kg body weight, 35 mg/kg or 55 mg/kg every 8 weeks were described. Outcomes were evaluated by ACR 20%, 50% and 70% (ACR20/50/70) responses and European League Against Rheumatism good response after 6 months, disease activity after 12 months, KaplanMeier plots and regression analyses. Results. Four hundred and sixty-two patients (376 Danish, 86 Icelandic) received treatment with infliximab. In Danish patients, the starting dose was 43 mg/kg in 110 patients (29%), 35 mg/kg in 157 (42%), 55mg/ by guest on February 17, 2016 kg in 38 (10%) and unregistered in 71 (19%). In Icelandic patients, corresponding numbers were 64 (74%), 17 (27%), 0 (0%) and 5 (6%). Patients with a higher body weight received lower doses per kilogram. Danish patients received higher doses than Icelandic patients at baseline [median 3.1 (interquartile range 3.03.8) vs 2.3 (2.12.9) mg/kg, P < 0.05] and after 12 months [3.3 (3.04.5) vs 2.9 (2.23.5) mg/kg, P < 0.0001]. After 12 SCIENCE CLINICAL months, 58% of Danish and 66% of Icelandic patients maintained treatment. Danish patients had shorter drug survival than Icelandic patients (1183 vs 483 days). In univariate analyses stratified by country, time until dose escalation, response rates, drug survival and 1-year’s disease activity were independent of starting dose. Drug survival was shorter among patients not receiving concomitant MTX. Conclusion. In clinical practice, > 70% of Icelandic and Danish PsA patients treated with infliximab received sustained doses below the 5 mg/kg every 8 weeks recommended in international guidelines. Lower starting doses did not affect drug survival or response. Key words: PsA, outcome, drug survival, biological treatment, infliximab, routine care, clinical registry.

1 Copenhagen Center for Arthritis Research, Center for Rheumatology Rheumatology, Køge Hospital, Køge, 13Department of Rheumatology, 2 and Spine Diseases, Danish Rheumatologic Database (DANBIO), Gentofte University Hospital, Copenhagen, 14Department of 3 Glostrup Hospital, Glostrup, Denmark, Center for Rheumatology Rheumatology, Vendsyssel Teaching Hospital, Hjørring, Denmark, 4 Research (ICEBIO), Landspitali University Hospital of Iceland, Faculty 15Department of Rheumatology, Landspitali University Hospital of 5 of Medicine, University of Iceland, Reykjavik, Iceland, Zitelab Aps, Iceland, Reykjavik, Iceland and 16Department of Clinical Medicine, 6 Department of Rheumatology, Frederiksberg Hospital, Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, 7 Department of Rheumatology, Aalborg University Hospital, Aalborg, Copenhagen, Denmark. 8Department of Rheumatology, Odense University Hospital, Odense, 9Department of Rheumatology, Vejle Sygehus, Sygehus Lillebælt, Submitted 31 December 2013; revised version accepted 25 April 2014. 10 Department of Infectious Diseases and Rheumatology, Correspondence to: Bente Glintborg, Department of Rheumatology, 11 Rigshospitalet, Copenhagen, Department of Rheumatology, Glostrup Hospital, 2600 Glostrup, Copenhagen, Denmark. 12 Helsingør and Hillerød Hospital, Hillerød, Department of E-mail: [email protected]

! The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected] Impact of infliximab dose regimens in PsA

Introduction golimumab and 19 received other biologic drugs. We excluded 82 patients treated with bDMARDs as part of Therapy with TNF-a inhibitors (TNFis) has improved treat- clinical trials and 39 patients with insufficient data on ment outcome in patients with PsA who have failed treat- their first TNFi treatment course. Only the 462 patients ment with conventional synthetic DMARDs (csDMARDs) who received infliximab as the first bDMARD were [18]. B included in the present study. By March 2013, four TNFis were marketed in Denmark DANBIO and ICEBIO use a common web-based system and Iceland to treat PsA: adalimumab, etanercept, goli- (www.danbio-online.dk) [31]. Baseline demographics in- mumab and infliximab [7, 912]. The recommended dose clude age, gender, body weight, height, disease duration, regimens for adalimumab, etanercept and golimumab in previous or current treatment with MTX or other PsA are equal to the regimens in RA, i.e. fixed dosage csDMARDs. Functional status and peripheral disease ac- independent of the patient’s body weight. For infliximab, tivity are monitored prospectively by the Health HAQ [32], patients with PsA are recommended higher doses than the 28-joint DAS (DAS28) [33], CRP level (normal range patients with RA, i.e. 5 vs 3 mg/kg body weight every 8 410 mg/l) and visual analogue scales (VASs) for pain, pa- weeks [1316]. This recommendation is based on data tient’s global assessment and fatigue. It is not explicitly from randomized placebo-controlled clinical trials [4, 6, registered whether a patient has spinal disease. Data 17, 18]. Data on the effectiveness of lower infliximab registration is recommended to occur at least biannually, doses in PsA are, however, scarce [1923]. or when the medical treatment is changed [24]. Downloaded from The Danish nationwide DANBIO registry now includes >10 years of prospective follow-up of patients with in- Infliximab dose regimens flammatory arthritis treated with biologics in routine care The infliximab dose per infusion was reported as (i) the [24, 25]. Similarly, Icelandic patients have been registered total dose per infusion (in mg) and (ii) the dose measured and followed in the ICEBIO registry since 2007 [26].

in milligrams per kilogram of body weight. The patients http://rheumatology.oxfordjournals.org/ Based on data from DANBIO and ICEBIO we aimed to were treated at weeks 0 (baseline), 2 and 6 and thereafter describe the following: (i) the infliximab dose regimens at regular intervals (typically every 8 weeks). Arbitrarily pa- used in clinical practice, (ii) dose escalation and (iii) tients were divided into three categories according to whether the starting dose regimen affected (a) treatment dose per kilogram of body weight at the baseline visit: response and (b) drug survival in TNFi-naive patients with 43,35,55 mg/kg. Dose escalation was defined as PsA receiving their first infliximab treatment course. increased dose and/or reduced time intervals between infusions compared with baseline. Patients and methods Data quality The nationwide Danish DANBIO registry commenced in Queries were sent to the departments regarding treatment 2000 and covers >90% of Danish adults treated with bio- series with incomplete data (infliximab dose regimens

logics due to rheumatic disease in routine care [2729]. by guest on February 17, 2016 and/or body weight) and the registries were corrected Prospective data registration in the Icelandic ICEBIO accordingly. registry started in 2007. Biologic treatment courses, which were started in Iceland before 2007, have been Treatment duration registered retrospectively. Currently ICEBIO covers >95% of all biologic treatment given in Iceland in patients Treatment duration was the number of days individual pa- with rheumatic disorders (B. Gudbjorsson, 2013, personal tients maintained infliximab treatment. The start date was communication). According to Danish legislation, the the date the first dose was given and the stop date was registration and publication of data from clinical registries the date of the first missed dose. Temporary treatment does not require patient consent or approval by an ethics interruptions of 43 months were allowed. All observations committee. In Iceland, this study was approved by the were censored by 15 March 2013. Among patients with no National Bioethics Committee (VSNb201310035/03.15) follow-up since 15 November 2012, data were censored and the Data Protection Authority (2012080907HGK). according to the last visit registered. In Iceland, local hospital guidelines in PsA recommend The reasons for drug discontinuation are registered in infliximab doses of 200 mg every 8 weeks, irrespective of DANBIO/ICEBIO in pre-specified categories: lack of treat- the patient’s body weight. In cases of insufficient re- ment effect (LOE), adverse events (AEs), disease remis- sponse, doses are increased stepwise to 300, 400 or sion, pregnancy, surgery, cancer, death, infections, loss 500 mg [26, 30]. In Denmark, no national treatment guide- to follow-up and other reasons. In the following, reasons lines existed during the study period. for discontinuation are divided into three categories: AEs By March 2013, 4966 patients with a diagnosis of PsA (including infection, death or cancer), LOE and other according to the treating physician had been registered (including pregnancy, surgery, loss to follow-up, remission (4742 patients in DANBIO, 224 in ICEBIO). Among these, or multiple reasons for discontinuation). 3237 patients were treated only with csDMARDs. The remaining 1729 patients were treated with biologic DMARDs Treatment response (bDMARDs): 462 patients received infliximab as the first Disease activity and physical function were evaluated at bDMARD, 705 adalimumab, 371 etanercept, 51 baseline and after 3, 6 and 12 months of therapy. The

www.rheumatology.oxfordjournals.org 2101 Bente Glintborg et al.

baseline visit was defined as the time window from 30 Calendar year of starting treatment and body weight days before until 6 days after the initiation of therapy. were considered intermediate variables potentially influ- For the 3-month visit the time window was 1017 enced by the starting dose of infliximab and were not weeks, for the 6-month visit it was 1832 weeks and for included. the 12-month visit it was 4664 weeks after initiation of treatment. If more than one registration occurred within a Results given time window, the one closest to the given time point was selected for analysis. If a patient had no registrations A total of 462 infliximab-treated patients (376 Danish, 86 within a given time window, data were registered as miss- Icelandic) were included. Baseline demographics for ing for the given visit. Danish and Icelandic patients are shown in Table 1 and In the analyses of the 12-month outcome, the last ob- Table 2, respectively. The median starting infliximab dose servation carried forward (LOCF) method was used was 3.1 mg/kg (IQR 3.03.8) for Danish patients and among patients with missing data at the 12-month visit 2.3 mg/kg (2.12.9) for Icelandic patients (P < 0.0001). and among patients who had stopped treatment within After up-titration, 94% of patients received infliximab at the first year. All other calculations were based on 8-week intervals. Danish patients had lower body weight observed data with no imputation of missing data. [80 kg (IQR 6894) vs 87 (7797), P = 0.001], lower BMI [27 2 Clinical response was evaluated as achievement of kg/m (IQR 2430) vs 29 (2632), P = 0.001], higher DAS28

ACR 20%, 50% or 70% response (ACR20/50/70) [34] or [4.7 (IQR 3.85.5) vs 4.2 (3.34.9), P = 0.009] and higher Downloaded from the European League Against Rheumatism (EULAR) good tender joint count (TJC) [6 (IQR 211) vs 4(26), P = 0.006] response [35]. We classified patients as responders if they compared with Icelandic patients upon initiation of ther- achieved clinical response (yes/no) at both the 3 - and 6- apy, whereas other baseline characteristics [age, gender month visits compared with baseline. In case of missing distribution, height, disease duration, MTX use, VAS data at either the 3 - or 6-month visit, one registration of score, swollen joint count (SJC) and CRP] were similar http://rheumatology.oxfordjournals.org/ clinical response was sufficient to characterize the patient (all P > 0.05). as a responder. Patients who had stopped treatment At baseline, Danish patients treated with 55 mg/kg within the first 10 weeks of therapy were considered infliximab had lower SJC and lower VAS physician score non-responders (non-responder imputation, n = 44). compared with Danish patients on lower doses, whereas other measures of disease activity were similar (Table 1). Doses >5 mg/kg were more often started in the later years Statistics and in women (Table 1). Among Icelandic patients there Statistical analyses were performed using SPSS version was a tendency towards higher VAS physician score and 16.0 (SPSS, Chicago, IL, USA) and SAS version 9.0 (SAS TJC among patients starting treatment with >3 mg/kg, Institute, Cary, NC, USA) software. Demographic and de- and no patients started on doses 55 mg/kg (Table 2). In scriptive data are presented as median [interquartile range both Denmark and Iceland, patients with higher body (IQR)]. Groups were compared by non-parametric tests weight and BMI received lower doses per kilogram by guest on February 17, 2016 (chi-squared, MannWhitney, Wilcoxon signed rank test). (Table 1 and Table 2). A P-value of < 0.05 was considered statistically At 12 months median infliximab doses for Danish and significant. Icelandic patients were 3.3 mg/kg (IQR 3.04.5) and 2.9 KaplanMeier plots and log-rank tests were performed (2.23.5) (P < 0.0001) every 8 (88) weeks, respectively. for infliximab drug survival analyses and to analyse time The median dose per infusion was 300 mg (IQR until dose escalation. Univariate and multivariate Cox re- 200300) and 200 (200300) (P < 0.01), respectively. gression analyses with hazard ratios (HRs) were used to Danish patients had similar disease activity irrespective identify the impact of baseline infliximab dose on drug of the baseline infliximab dose (LOCF, KruskalWallis survival. In the subanalysis of time to discontinuation test; Table 3). Similar results were found in Icelandic pa- due to AEs, discontinuations due to ineffectiveness were tients (data not shown, all P > 0.05). There were no differ- censored. Similarly, discontinuations due to AEs were ences in DAS28, VAS score, SJC, TJC or HAQ after 12 censored in the analysis of discontinuation due to ineffect- months between Danish and Icelandic patients iveness. Logistic regression analyses and odds ratios (MannWhitney, all P > 0.05, data not shown). were calculated to identify the impact of baseline inflixi- At the latest registered visit, 247 patients (53%) mab dose on clinical response. Baseline infliximab dose received infliximab in unaltered or reduced regimens, was included in all analyses as a categorical variable (43, whereas 145 patients (31%) (53% of Icelandic and 26% 35, 55 mg/kg). Additional sensitivity analyses were per- of Danish patients) had an increased dose due to either formed with the baseline dose (in mg/kg) as a continuous increased dose per infusion [65 patients, median dose variable. increase/kg 1.2 mg/kg (IQR 0.81.8)], shortening of the All multivariate analyses were performed stratified by time interval between infusions (32 patients) or both (48 country to avoid statistical interaction. The following base- patients). In 2% of patients the infliximab dose was line variables were considered a priori confounders and increased but the time intervals were prolonged or vice included in all multivariate analyses: gender, MTX use versa. Data were missing in 13% of patients. Danish pa- (yes/no), patient age, time interval between infusions tients on increased infliximab dose regimens had longer (weeks), disease duration (years), HAQ and DAS28. treatment duration [median 819 days (IQR 3211723)]

2102 www.rheumatology.oxfordjournals.org Impact of infliximab dose regimens in PsA

TABLE 1 Baseline demographics and disease activity for Danish patients registered in DANBIO according to infliximab dose at the baseline visit

Infliximab dose/kg (n = 305 a) P-valueb Total 43mg 35mg 5 5mg

Patients, n 376 110 157 38 Infliximab dose, mg 290 (200300) 200 (200293) 300 (200300) 403 (400500) <0.0001 Female, n (%) 204 (54) 50 (45) 96 (61) 23 (61) 0.03 Dosing interval, weeks 8 (88) 8 (88) 8 (88) 8 (88) 0.04 Year starting TNFi, n (%) 20002 20 (5) 6 (5) 5 (3) 0 (0) <0.001 20035 104 (28) 30 (27) 31 (18) 6 (15) 20068 145 (39) 54 (49) 69 (44) 4 (11) 200912 107 (28) 20 (18) 52 (33) 28 (74) Concomitant MTX, n (%) 260 (69) 82 (75) 111 22 0.2 Disease duration, years 7 (313) 9 (317) 7 (314) 6 (411) 0.6

Age, years 48 (4056) 46 (4055) 50 (4058) 47 (4154) 0.2 Downloaded from Body weight, kg 80 (6894) 82 (71100) 80 (6590) 80 (7090) 0.01 Body height, cm 172 (165178) 172 (166180) 172 (165178) 176 (167182) 0.2 BMI, kg/m2 27 (2430) 28 (2532) 26 (2330) 26 (2329) 0.006 HAQ 1.1 (0.81.6) 1.1 (0.61.6) 1.1 (0.81.6) 1.0 (0.61.8) 1.0 DAS28 4.7 (3.85.5) 4.9 (3.75.6) 4.7 (3.85.5) 4.0 (3.35.3) 0.1 CRP, mg/l 10 (425) 10 (524) 10 (426) 5 (212) 0.07 http://rheumatology.oxfordjournals.org/ SJC, n (range) 2 (16) 3 (07) 2 (15) 1 (02) 0.02 TJC, n (range) 6 (211) 6 (214) 6 (211) 4 (19) 0.3 VAS physician, score (range) 37 (2355) 38 (2657) 39 (2252) 25 (1739) 0.02 VAS global, mm 69 (5184) 67 (5084) 68 (4987) 72 (5290) 0.9 VAS fatigue, mm 68 (4783) 69 (4577) 70 (4986) 68 (4290) 0.4 VAS pain, mm 62 (4376) 65 (4578) 62 (3775) 58 (3481) 0.8

Data are presented as median (interquartile range) unless stated otherwise. aMissing data on baseline infliximab dose in 71 patients. bP-value in KruskalWallis test. TNFi: TNF-a inhibitor; DAS28: 28-joint DAS; SJC: swollen joint count; TJC: tender joint count; VAS: visual analogue scale. by guest on February 17, 2016 compared with the patients receiving unaltered/reduced The starting infliximab dose per kilogram was similar be- doses [371 days (1591249)] (P < 0.001). Similar results tween patients who continued treatment [median 3.0 mg/ were found in Icelandic patients [1207 days (4322139) kg (IQR 2.63.8)] and patients who stopped due to LOE vs 307 (120757), P < 0.001]. [3.1 mg/kg (2.73.6)] or AEs [3.1 mg/kg (2.93.5)] (P = 0.2). The numbers of Danish and Icelandic patients receiv- At the latest visit, patients who stopped treatment due to ing starting doses of 43, 35or55 mg/kg are shown in LOE received higher infliximab doses compared with pa- Fig. 1. Among patients with available data and who were tients who stopped due to AEs [median 3.5 mg/kg (IQR treated for >100 days, 77% (205/265) of Danish and 96% 3.04.7) vs 3.1 (2.93.7), P = 0.002]. (69/72) of Icelandic patients received sustained infliximab After 12 months, 58% of Danish and 66% of Icelandic doses <5 mg/kg (Fig. 1). patients were still on the drug. Drug survival was Data on baseline infliximab dose per kilogram were significantly shorter among Danish compared with missing in 71 Danish and 5 Icelandic patients. Danish pa- Icelandic patients [median 483 days (95% CI 372, 594) tients with missing data had similar gender, BMI and age vs 1183 (4701896), log rank 7.7, P = 0.005] (Fig. 2A). distribution to the 305 patients with available data (all The starting infliximab dose did not affect survival P > 0.05), whereas patients with missing data more often (Danish patients: Fig. 2B; Icelandic patients: Fig. 2C). started treatment during earlier years (P < 0.0001). In For Danish patients, drug survival was shorter in patients Icelandic patients, baseline demographics were similar not receiving concomitant MTX (Fig. 2D) and when treat- between patients with available and those with missing ment was started in later years (Fig. 2E). Similar results data on baseline dose (all P > 0.05). were found when KaplanMeier analyses were performed Cumulated follow-up time for Danish and Icelandic pa- among Icelandic patients (MTX use, P = 0.1; treatment tients was 1185 patient-years and the median follow-up start year, P = 0.003). The start dose did not affect the time was 550 days (95% CI 383, 317). Overall, 116 pa- time until dose escalation (P = 0.9). The median number tients (25%) stopped treatment due to LOE and 134 (29%) of days until dose escalation was similar for Danish and stopped due to AEs. The reasons for stopping treatment Icelandic patients [266 days (IQR 131560) vs 290 were similar for Danish and Icelandic patients (P = 0.4). (182559), P = 0.2].

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TABLE 2 Baseline demographics and disease activity for Icelandic patients registered in ICEBIO according to infliximab dose at the baseline visit

Infliximab dose/kg (n =81a) P-valueb Total 43mg 35mg 55mg

Patients, n 86 64 17 0 Infliximab dose, mg 200 (200200) 200 (200200) 200 (200350) — <0.0001 Female, n (%) 48 (56) 35 (54) 12 (71) — 0.2 Dosing interval, weeks 8 (88) 8 (88) 8 (88) — 1.0 Year starting TNFi, n (%) — 20002 5 (6) 5 (8) 0 (0) — 0.9 20035 15 (17) 10 (16) 2 (12) — 20068 25 (29) 16 (25) 8 (47) — 200912 41 (48) 33 (52) 7 (41) — Concomitant MTX, n (%) 53 (61) 40 (63) 10 (59) — 0.8 Disease duration, years 8 (317) 7 (317) 7 (235) — 0.8

Age, years 48 (3654) 49 (3755) 43 (3562) — 0.8 Downloaded from Body weight, kg 87 (7797) 92 (8099) 65 (6186) — <0.001 Body height, cm 172 (166182) 174 (167182) 167 (162169) — 0.002 BMI, kg/m2 29 (2632) 30 (2733) 24 (2130) — 0.006 HAQ 0.8 (0.31.1) 0.8 (0.31.0) 1.4 (0.22.1) — 0.3 DAS28 4.2 (3.34.9) 4.2 (3.34.9) 4.8 (4.46.0) — 0.1 CRP, mg/l 8 (519) 9 (419) 9 (639) — 0.7 http://rheumatology.oxfordjournals.org/ SJC, n (range) 3 (15) 3 (15) 5 (18) — 0.6 TJC, n (range) 4 (26) 4 (26) 6 (517) — 0.08 VAS physician, score (range) 55 (4267) 51 (4064) 72 (5689) — 0.05 VAS global, mm 35 (3781) 64 (3880) 89 (4797) — 0.1 VAS fatigue, mm 74 (4580) 72 (4980) 91 (47100) — 0.1 VAS pain, mm 65 (4281) 63 (4580) 88 (4797) — 0.2

Data are presented as median (interquartile range) unless stated otherwise. aMissing data on baseline infliximab dose in five patients. bP-value in KruskalWallis test. TNFi: TNF-a inhibitor; DAS28: 28-joint DAS; SJC: swollen joint count; TJC: tender joint count; VAS: visual analogue scale. by guest on February 17, 2016 TABLE 3 Disease activity at the 1-year visit for Danish patients according to the baseline infliximab dose

Baseline infliximab dose/kga

43mg 35mg 55mg P-value

Number still treated after 12 months, n (%) 70 (64) 89 (57) 24 (63) HAQ 0.8 (0.21.3) 0.6 (0.11.1) 0.9 (0.21.4) 0.8 DAS28 3.0 (2.33.9) 3.1 (2.14.2) 2.4 (2.14.1) 0.3 CRP, mg/l 5 (210) 5 (211) 4 (1.58.5) 0.4 SJC, n (range) 0 (03) 0 (02) 0 (01) 0.1 TJC, n (range) 1 (04) 2 (06) 0 (06) 0.5 VAS global, mm 33 (1362) 33 (1563) 37 (1984) 0.9 VAS fatigue, mm 47 (1668) 50 (2576) 63 (2583) 0.6 VAS pain, mm 27 (1359) 32 (1056) 36 (1677) 0.2

Data are presented as median (interquartile range), unless stated otherwise. aMissing data on baseline dose, n = 39 (16%). Last observation carried forward (LOCF) method. DAS28: 28-joint DAS; VAS: visual analogue scale; SJC: swollen joint count; TJC: tender joint count.

In multivariate Cox regression analysis among patients on a lower dose had shorter drug survival Danish patients, infliximab starting dose as a categorical [HR 0.7/mg/kg (95% CI 0.55, 0.95), P = 0.02]. The same value did not affect drug survival (P = 0.5). In a similar pattern was observed when looking only at patients analysis with starting dose as a continuous variable, who withdrew due to AEs [HR 0.7/mg/kg (95% CI

2104 www.rheumatology.oxfordjournals.org Impact of infliximab dose regimens in PsA

FIG.1Study flow chart of infliximab dose according to Discussion treatment duration, stratified by country In this observational study of 376 Danish and 86 Icelandic patients with PsA treated with infliximab in routine care, the majority of patients received continuous treatment with doses below the 5 mg/kg recommended in international guidelines. The starting infliximab dose did not affect the time until dose increase, drug effectiveness or drug survival. Icelandic patients received lower doses than Danish patients but had similar response rates and longer drug survival. In RA, treatment with infliximab doses at 3 mg/kg with gradual dose escalation according to clinical response is a well-known treatment strategy [3638]. The recommended infliximab dose regimen in PsA is 5 mg/kg every 8 weeks [13, 16] based on data from randomized controlled trials (RCTs) [4, 6, 17, 18]. Few data are available

on the effectiveness of lower doses [39] and originate Downloaded from mainly from small observational studies of 410 patients [19, 21] or case reports [20]. No randomized trials on dose escalation have been performed. Infliximab starting doses in patients with PsA treated in routine care vary across countries [4042]. In Sweden, patients with PsA routinely receive a starting dose of http://rheumatology.oxfordjournals.org/ 3 mg/kg [43, 44]. In the current study, Danish patients received a median starting dose of 3.1 mg/kg, which was independent of baseline disease activity. The more frequent use of a 5 mg/kg starting dose after year 2008 might reflect that RA dose regimens were copied in the earlier years and that adherence to international guidelines for PsA [13, 16] was higher in the later years. In Iceland, the treating physicians complied with national Icelandic treatment guidelines with a median starting 0.4, 1.1), P = 0.06] or LOE [HR 0.7 (95% CI 0.5, 1.0), dose of 2.3 mg/kg and no patients started treatment P = 0.07].

with doses 55 mg/kg. by guest on February 17, 2016 In multivariate Cox regression analysis of Icelandic pa- Despite dose escalation in 53% of Icelandic and 26% of tients, those who started treatment with doses 4 3 mg/kg Danish patients, the majority of patients received sus- had longer drug survival than patients starting on higher tained treatment with doses <5 mg/kg. This is in contrast doses [43 vs 35 mg/kg, HR 0.2 (95% CI 0.001, 0.5), to observational data on 32 patients with PsA followed for P = 0.02)]. In a similar analysis with infliximab starting 2 years by the South Swedish Arthritis Treatment Group dose as a continuous variable, the starting dose was not (SSATG). In the Swedish study, 72% of the patients statistically significant (P = 0.6). Stratified analyses ac- needed dose escalation [23]. The SSATG has previously cording to the cause of treatment termination were not reported the average infliximab dose among 114 patients performed in Icelandic patients due to few events. with PsA to be 5 mg/kg every 8 weeks after 6 months of In Danish patients, EULAR good response and ACR20/ treatment [43]. The Swedish patients apparently had simi- 50/70 response rates after 6 months were 33%, 38%, lar baseline disease activity and demographics as the 23% and 10%, respectively. EULAR and ACR response Danish and Icelandic populations [23]. The Swedish stu- data were available in 54% and 63% of patients, respect- dies provide no data on infliximab response rates and ively, with no systematic differences between patients survival [23, 43], so we do not know whether the different with complete and incomplete data, except for more pa- regimens affected outcome. tients with missing ACR response data during earlier Drug survival may be perceived as a measure of treat- years. The response rates were not associated with base- ment effectiveness [45]. In Danish patients, drug survival line dose (as categorical or continuous variable) in either was longer among patients who received higher baseline univariate or multivariate analyses. In Icelandic patients, infliximab doses, thus indicating a positive effect of higher EULAR good response and ACR20/50/70 response rates doses. However, the infliximab dose only affected drug after 6 months were 39%, 27%, 17% and 11%, respect- survival in multivariate and not univariate analyses. In ively. Response data were available in 38% of patients. Icelandic patients, the picture was less clear, perhaps There were no statistically significant differences in due to limited statistical power. The different treatment response rate between Danish and Icelandic patients strategies in Denmark vs Iceland might have an impact (all P > 0.05). on the results. In Iceland, patients had lower disease

www.rheumatology.oxfordjournals.org 2105 Bente Glintborg et al.

FIG.2KaplanMeier drug survival curves

A Survival according to country BCSurvival according to start dose, Denmark Survival according to start dose, Iceland

1,0 1,0 1,0

<= 3 mg/kg Denmark <= 3 mg/kg 3-5 mg/kg Iceland 3-5 mg/kg 0,8 0,8 >= 5 mg/kg 0,8 … p=0.005 p=0.2 p=0.4…

0,6 0,6 0,6

0,4 0,4 0,4

0,2 0,2 0,2

0,0 0,0 0,0

0 1 2 3 4 5 6 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Treatment duration, years Treatment duration, years Treatment duration, years

DESurvival according to concomitant methotrexate, Denmark Survival accoding to start year, Denmark Downloaded from

1,0 1,0 2000-2002 2003-2005 No use 2006-2008 2009-2012 0,8 Use 0,8 p=0.06 p=0.009

0,6 0,6 http://rheumatology.oxfordjournals.org/

0,4 0,4

0,2 0,2

0,0 0,0

0 1 2 3 4 5 6 6543210 Treatment duration, years Treatment duration, years

Infliximab drug survival (KaplanMeier) according to (A) country; (B) starting dose, Danish patients; (C) starting dose, Icelandic patients; (D) concomitant MTX, Danish patients and (E) start year, Danish patients. by guest on February 17, 2016

activity at treatment start and the majority of patients dose of infliximab. The current study demonstrated that received a fixed starting dose of 200 mg. In Denmark, the clinical use of infliximab and adherence to national and the starting dose was chosen according to the preference international guidelines varied between Denmark and of the treating physician. Thus confounding by indication Iceland. This illustrates that extrapolation of outcome or channelling bias cannot be ruled out and differences in data across countries must be done with caution and disease severity, co-morbidities or other psoriatic disease that publication of clinical data from various countries is manifestations might have affected drug effectiveness as of importance. judged by drug survival. We found that concomitant MTX improved infliximab Observational and registry studies provide a valuable drug survival. This is in accordance with previous studies supplement to RCTs regarding prescription practice and regarding TNFi treatment in PsA [25, 43, 4851]. The pos- treatment outcome when drugs are used in routine care sible beneficial effect of MTX combination therapy in PsA [29, 46]. In real life, with more liberal treatment criteria than might be reduced formation of anti-chimeric antibodies in RCTs, drug retention rates, and thus effectiveness, are [23, 51, 52]. often lower. In addition, patients who stopped treatment Drug survival was shorter among patients who started within 3 months were classified as non-responders in the treatment during the later years. This might illustrate a present study. As expected, we found the effectiveness of change in prescription practice with initiation of TNFi infliximab in routine care to be lower than drug efficacy in treatment among less ill patients with poorer treatment RCTs. Thus RCTs of infliximab in PsA have reported drug outcomes [53]. Also, the availability of more TNFis might efficacy (ACR20/50/70 response rates) to be approxi- lead to early switching [12]. This could also explain why mately 50%, 35% and 20%, respectively [6, 47]. We did many patients stopped infliximab treatment due to LOE not find effectiveness to be associated with the baseline although they only received a lower infliximab dose;

2106 www.rheumatology.oxfordjournals.org Impact of infliximab dose regimens in PsA

alternatively, economic considerations or fear of AEs speakers’ bureau for MSD and has provided consultancy might have affected this decision. services for MSD, AbbVie and UCB. M.H.-F. has received This study has limitations to consider. Few patients consulting fees from Roche, speaking fees from UCB and started treatment with infliximab 55 mg/kg and a lack of MSD and is an investigator for Roche. H.M.L. is an inves- power to detect potential beneficial effects of higher tigator for Lilly, MSD, Nordpharma and Roche and a con- doses cannot be excluded. Similarly, the patients who sultant to Roche and MSD. A.H. has served on speakers’ stopped treatment due to LOE while receiving doses bureaus for AbbVie, UCB and MSD and an advisory board <5 mg/kg might have experienced an effect on higher for AbbVie. All other authors have declared no conflicts of doses. Response data were only available in approxi- interest. mately half of the patients, and this might have affected our results. Although ACR and EULAR responses were originally developed to monitor treatment effect in RA, References they have been widely used in PsA [54, 55]. However, these measures do not include data on all joints poten- 1 Mease PJ, Kivitz AJ, Burch FX et al. Etanercept treatment tially affected in PsA, e.g. hips, DIP joints of the hand or of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:226472. ankles and joints of the feet. This may be of importance when these response measures are used in a clinical set- 2 Mease PJ, Gladman DD, Ritchlin CT et al. Adalimumab for ting and may cause an underestimation of disease activity the treatment of patients with moderately to severely Downloaded from active psoriatic arthritis: results of a double-blind, rando- [56]. This might perhaps explain the relatively low median mized, placebo-controlled trial. Arthritis Rheum 2005;52: SJC upon initiation of infliximab therapy seen in the pre- 327989. sent study. Spinal disease might affect the starting dose: perhaps patients with symptoms of spinal disease more 3 Mease PJ, Goffe BS, Metz J et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised frequently received higher doses in accordance with the trial. Lancet 2000;356:38590. http://rheumatology.oxfordjournals.org/ guidelines for AS. Furthermore, enthesitis, dactylitis or other psoriatic disease manifestations are potential con- 4 Antoni C, Krueger GG, de Vlam K et al. Infliximab improves founders, but we did not have data to investigate this. To signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis 2005;64:11507. address these issues further, a future randomized clinical trial comparing low vs traditional infliximab doses in PsA 5 Genovese MC, Mease PJ, Thomson GT et al. Safety and would be of relevance. Preferably such a trial should inefficacy of adalimumab in treatment of patients with psoriatic arthritis who had failed disease modifying anti- clude data on not only 68-joint disease activity, but also rheumatic drug therapy. J Rheumatol 2007;34:104050. skin and other psoriatic disease domains. In conclusion, this observational study from two coun- 6 Antoni CE, Kavanaugh A, Kirkham B et al. Sustained tries demonstrated that infliximab doses below the recom- benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the mended 5 mg/kg were widely used in PsA in routine care. infliximab multinational psoriatic arthritis controlled trial A low starting dose with subsequent step-up therapy (IMPACT). Arthritis Rheum 2005;52:122736. by guest on February 17, 2016 seemed an effective strategy. Concomitant use of MTX 7 Saad AA, Symmons DP, Noyce PR, Ashcroft DM. Risks was associated with improved drug survival. and benefits of tumor necrosis factor-alpha inhibitors in the management of psoriatic arthritis: systematic review Rheumatology key messages and metaanalysis of randomized controlled trials. J Rheumatol 2008;35:88390. . In Denmark and Iceland, infliximab doses < 5 mg/kg 8 Kavanaugh A, McInnes I, Mease P et al. Golimumab, a are widely used in routine treatment of PsA. new human tumor necrosis factor alpha antibody, ad- . A low infliximab starting dose with subsequent step ministered every four weeks as a subcutaneous injection up therapy seems effective in PsA. in psoriatic arthritis: twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum 2009;60:97686. Acknowledgements 9 Gossec L, Smolen JS, Gaujoux-Viala C et al. European League Against Rheumatism recommendations for the Thanks to the departments of rheumatology in Aalborg, management of psoriatic arthritis with pharmacological Aarhus, Esbjerg, Fredericia, Frederiksberg, Gentofte, therapies. Ann Rheum Dis 2012;71:412. Glostrup, Gra˚ sten, Hjørring, Holbæk, Holstebro, 10 Ash Z, Gaujoux-Viala C, Gossec L et al. A systematic lit- Horsens, Helsingør/Hillerød, Kolding, Køge, Odense, erature review of drug therapies for the treatment of Randers, Rigshospitalet, Roskilde, Rønne, Silkeborg, psoriatic arthritis: current evidence and meta-analysis in- Slagelse, Svendborg, Vejle and Viborg, Denmark for re- forming the EULAR recommendations for the manage- porting to the DANBIO registry and in Reykjavik, Akranes ment of psoriatic arthritis. Ann Rheum Dis 2012;71: 31926. and Akureyri, Iceland for reporting to the ICEBIO registry. 11 Rodgers M, Epstein D, Bojke L et al. Etanercept, infliximab Disclosure statement: C.R. has received research grants and adalimumab for the treatment of psoriatic arthritis: a from Pfizer, AbbVie and Vertex and speakers’ fees from systematic review and economic evaluation. Health AbbVie, Merck and Pfizer. A.G.L. has served on a Technol Assess 2011;15:i329.

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EXTENDED REPORT Association between tobacco smoking and response to tumour necrosis factor α inhibitor treatment in psoriatic arthritis: results from the DANBIO registry Pil Højgaard,1,2 Bente Glintborg,1,3,4 Merete Lund Hetland,3,4,5 Torben Højland Hansen,6 Philip Rask Lage-Hansen,7 Martin H Petersen,8 Mette Holland-Fischer,9 Christine Nilsson,10 Anne Gitte Loft,11 Bjarne Nesgaard Andersen,12 Thomas Adelsten,13 Jørgen Jensen,14 Emina Omerovic,3 Regitse Christensen,1 Ulrik Tarp,15 René Østgård,16 Lene Dreyer1,4

Handling editor Tore K Kvien ABSTRACT (PsA) who have insufficient response to synthetic 1 For numbered affiliations see Objectives To investigate the association between disease-modifying antirheumatic drugs (sDMARD). end of article. tobacco smoking and disease activity, treatment 2 However, only ∼60% of patients achieve ACR20 – adherence and treatment responses among patients with response.3 5 Thus, it is important to identify poten- Correspondence to psoriatic arthritis (PsA) initiating the first tumour necrosis tial response modifiers to facilitate a rational and Dr Bente Glintborg, α 56 Copenhagen Centre for factor inhibitor therapy (TNFi) in routine care. effective individualised treatment strategy. The Arthritis Research, Centre for Methods Observational cohort study based on the impact of tobacco smoking is of particular interest Rheumatology and Spine Danish nationwide DANBIO registry. Kaplan–Meier plots, since smoking is a potentially modifiable lifestyle Diseases, Copenhagen logistic and Cox regression analyses by smoking status factor. University Hospital Glostrup, (current/previous/never smoker) were calculated for Smoking is a possible risk factor for developing Copenhagen, Denmark; 78 [email protected] treatment adherence, ACR20/50/70-responses and PsA, but results are conflicting. However, little is EULAR-good-response. Additional stratified analyses known about the impact of smoking on disease – Bente Glintborg and were performed according to gender and TNFi-subtype activity and TNFi treatment response in PsA.9 13 In fi Pil Højgaard share rst (adalimumab/etanercept/infliximab). axial spondyloarthritis, smoking increases disease co-authorship. Results Among 1388 PsA patients included in the activity and radiographic progression and reduces – Received 11 February 2014 study, 1148 (83%) had known smoking status (33% quality of life.14 16 In rheumatoid arthritis (RA) – Revised 8 May 2014 current, 41% never and 26% previous smokers). Median smokers have higher disease activity,17 19 and TNFi – Accepted 11 July 2014 follow-up time was 1.22 years (IQR 0.44–2.96). At treatment is less efficacious.62023 Published Online First 25 July 2014 baseline, current smokers had lower Body Mass Index The nationwide DANBIO registry includes data (27 kg/m2 (23–30)/28 kg/m2 (24–31)) (median (IQR)), on patients with rheumatologic diseases treated shorter disease duration (3 years (1–8)/5 years (2–10)), with TNFi in Denmark. We have previously lower swollen joint count (2 (0–5)/3 (1–6)), higher visual- described demographics and outcomes in patients analogue-scale (VAS) patient global (72 mm (54–87)/ with PsA treated with TNFi.324The aim of the 68 mm (50–80)), VAS fatigue (72 mm (51–86)/63 mm present study was to investigate differences between (40–77)) and Health Assessment Questionnaire (HAQ) smokers and non-smokers regarding disease activity, score (1.1 (0.7 to 1.5)/1.0 (0.5 to 1.5)) than never smokers treatment responses and adherence rates in patients (all p<0.05). Current smokers had shorter treatment with PsA initiating their first TNFi therapy in adherence than never smokers (1.56 years (0.97 to routine care. Furthermore, to study if the impact of 2.15)/2.43 years (1.88 to 2.97), (median (95% CI)), log smoking was influenced by gender and TNFi drug rank p=0.02) and poorer 6 months’ EULAR-good-response type. rates (23%/34%), ACR20 (24%/33%) and ACR50 response rates (17%/24%) (all p<0.05), most pronounced PATIENTS AND METHODS in men. In current smokers, the treatment adherence was The DANBIO registry covers >90% of Danish poorer for infliximab (HR) 1.62, 95% CI 1.06 to 2.48) and adults treated in routine care with biologics due to – etanercept (HR 1.74, 1.14 to 2.66) compared to rheumatic disease.25 27 According to Danish legisla- never smokers, but not for adalimumab (HR 0.80, 0.52 to tion, the registration and publication of data from 1.23). clinical registries do not require patient consent or Conclusion In PsA, smokers had worse baseline approval by ethics committees. Physicians are patient-reported outcomes, shorter treatment adherence recommended to report data prospectively by an and poorer response to TNFi’s compared to non-smokers. online system at least biannually and when medica- This was most pronounced in men and in patients treated tion is changed (http://www.danbio-online.dk).28 with infliximab or etanercept. Baseline demographics include smoking habits, age, gender, Body Mass Index (BMI), disease dur- To cite: Højgaard P, ation, previous or current treatment with metho- Glintborg B, Hetland ML, INTRODUCTION trexate (MTX) or other sDMARD. Functional et al. Ann Rheum Dis Tumour necrosis factor α inhibitors (TNFi) are status and peripheral disease activity are monitored – 2015;74:2130 2136. effective therapies in patients with psoriatic arthritis by Health Assessment Questionnaire (HAQ),29 the

2130 Højgaard P, et al. Ann Rheum Dis 2015;74:2130–2136. doi:10.1136/annrheumdis-2014-205389 Downloaded from http://ard.bmj.com/ on February 17, 2016 - Published by group.bmj.com Clinical and epidemiological research

28-joint Disease Activity Score (DAS28),30 C-reactive protein Statistics (CRP) level (normal range ≤10 mg/L), and visual analogue Statistical analyses were performed by SPSS (V.20.0, SPSS, scales (VAS) for scores of pain, patient’s global and fatigue. It is Chicago, Illinois, USA). Demographic and descriptive data are not explicitly registered in DANBIO whether PsA patients have presented by medians/IQR. Groups were compared by non- axial disease. Due to a limited number of registrations of axial parametric tests (χ2, Kruskal–Wallis and Mann–Whitney tests). disease activity at baseline and follow-up, these data were not In all tests, p values <0.05 were considered statistically signifi- included in the present study. cant. Calculations were based on observed data and no imput- By 1 January 2012, 1536 patients with a diagnosis of PsA ation of missing data was performed. according to the treating rheumatologist had been registered Kaplan–Meier plots and log rank tests were performed for and treated with a biological drug (bDMARD). We excluded analyses of treatment adherence for current, never and previous patients treated with golimumab (n=19), bDMARDs other than smokers. By univariate and multivariate Cox regression analyses TNFi (n=42), patients participating in clinical trials (n=54) or we studied the impact of smoking on treatment adherence and not followed in DANBIO since start of their first TNFi (n=33), associated HRs. The assumption of proportional hazards in the leaving 1388 patients in the study. Cox regressions models was not fulfilled for previous smokers compared with current and never smokers and, therefore, only Tobacco smoking status the latter two smoking categories were included (figure 1A). In this study, patients were divided into three groups according Univariate and multivariate logistic regression analyses and ORs to smoking status: current (≥1 cigarette/day), previous and were calculated to identify the impact of smoking (current/ never smokers. In previous smokers, the number of years since never) on clinical responses. Previous smokers were included in smoking cessation was recorded. Smokers, who had stopped subanalyses. The following baseline factors were considered a smoking the same year as they started TNFi, were defined as priori confounders and included in all multivariate analyses: age previous smokers (n=24). (in quartiles), gender, disease duration (in tertiles), calendar year Queries were sent to the departments regarding patients with of starting TNFi (in tertiles). Age, disease duration and year of incomplete data on smoking status. Information was then treatment start were transformed into categorical variables to obtained from hospital files or by asking the patients. allow for possible non-linear effects. Baseline swollen joint count (SJC), MTX use (yes/no) and TNFi type (adalimumab/ Treatment adherence etanercept/infliximab) were considered potential confounders, Treatment adherence was calculated as the number of years indi- and were added one by one to the multivariate model, but were vidual patients maintained treatment. Start date was the date of only included if they altered the OR/HR of smoking by >10%. the first given dose, and stop date was the date of the first MTX use and TNFi type did not alter the OR/HR of smoking missed dose. Temporary treatment interruptions (eg, due to by >10% in any of the analyses (data not shown). Baseline VAS infections or surgery) of ≤3 months’ duration were allowed. All scores, CRP, BMI, tender joint count, HAQ, and DAS28 were observations were censored at April 20th 2012. Among patients considered intermediate variables between tobacco smoking and with no follow-up since December 2011, data were censored outcomes, and were hence excluded from multivariate analyses. according to the last visit registered. Additional stratified Kaplan–Meier plots, and multivariate Reasons for drug discontinuation are registered in DANBIO Cox and logistic regression analyses according to (1) gender and in pre-specified categories: lack of effect, adverse events, disease (2) TNFi type were performed. remission, pregnancy, surgery, cancer, death, infections, loss to In the subanalysis of time to discontinuation due to adverse follow-up and other reasons. In the following, reasons for dis- events, discontinuations due to ineffectiveness were treated as continuation are divided into three categories: ‘adverse events’ censored observations and vice versa. (including infection, death or cancer), ‘lack of effect’ and ‘other’ (including pregnancy, surgery, loss to follow-up, remission and other reasons for discontinuation). RESULTS A total of 1388 bDMARD-naive patients initiating treatment Treatment response with adalimumab, etanercept or infliximab as the first TNFi Disease activity was evaluated at baseline and after 3 and were included (table 1). Among 1148 patients (83%) with 6 months’ therapy. The baseline visit was defined as a visit known smoking status, 33% were current, 41% never and 26% within the time window that ranged from 5 days before until previous smokers. Patients with missing smoking information 6 days after initiation of therapy. For the 3 months’ visit, the had lower BMI, younger age, longer disease duration, higher time window was 10–17 weeks, and for the 6 months’ visit 18– CRP,higher SJC, lower VAS global and fatigue scores, compared 32 weeks after treatment start. If more than one registration to patients with available smoking information (table 1). occurred within a given time window for an individual patient, Thirty-four percent of women and 31% of men with known the registration closest to the given time-point was selected for smoking status were current smokers. analysis. If a patient had no registrations within a given time At baseline, current smokers had shorter disease duration, window, data were registered as missing for the given visit. lower BMI, higher HAQ, higher VAS fatigue and VAS global Clinical response was evaluated as achievement of ACR20/ compared to previous and never smokers (table 1). Previous 50/7031 or EULAR-good-response.32 Arbitrarily, we classified smokers were older than current and never smokers. The patients as ‘responders’ if they achieved clinical response reasons for stopping TNFi treatment were independent of (yes/no) at the 3-months’ and 6 months’ visits compared to smoking status (table 1). Male current smokers had higher HAQ baseline. In case of missing data at either the 3-months’ or (1 (0.6–1.4) vs 0.8 (0.4–1.3), (median (IQR)), p=0.03) and 6 months’ visit, one registration of clinical response was suffi- shorter disease duration (3 years (1–10) vs 6 years (2–13), cient to characterise the patient as responder. Patients who p=0.03) than male never smokers, whereas VAS scores, DAS28 stopped treatment within the first 3 months of therapy were and BMI were similar (all p>0.05). Female current smokers had considered non-responders (n=272). lower BMI (25 kg/m2 (23–29) vs 28 kg/m2 (24–32), p=0.001),

Højgaard P, et al. Ann Rheum Dis 2015;74:2130–2136. doi:10.1136/annrheumdis-2014-205389 2131 Downloaded from http://ard.bmj.com/ on February 17, 2016 - Published by group.bmj.com Clinical and epidemiological research

Table 1 Baseline demographics, disease activity and reasons for terminating TNFi treatment according to smoking status at the baseline visit Smoking status

Current Never Previous p Value* p Value† Smoking status unknown

Number, n (%) 380 (33) 466 (41) 302 (26) 240 (17) Age, years 47 (38–55) 47 (37–56) 52 (44–57) 0.9 <0.01 47 (37–55)¤ Disease duration, years 3 (1–8) 5 (2–10) 4 (1–10) <0.01 <0.01 6 (2–11)¤ Women, n (%) 197 (48) 204 (44) 156 (48) 0.02 0.06 122 (51) Body Mass Index, kg/m2 27 (23–30) 28 (24–31) 28 (25–32) 0.01 0.01 26 (23–31)¤ TNFi drug type, n (%) Adalimumab 182 (48) 208 (44) 152 (50) 0.1 0.01 92 (38) Etanercept 71 (19) 115 (25) 74 (25) 62 (26) Infliximab 127 (33) 143 (31) 76 (25) 86 (36) TNFi start year, n (%) 2000–2003 18 (5) 22 (5) 9 (3) 0.4 0.1 26 (10)¤ 2004–2007 112 (29) 165 (35) 99 (34) 134 (55) 2008–2011 250 (66) 279 (60) 194 (64) 80 (33) Methotrexate use, n (%) 205 (54) 247 (53) 155 (52) 0.8 0.5 139 (58) CRP, mg/L 8 (3–18) 9 (3–21) 8 (4–17) 0.2 0.4 12 (4–29)¤ Tender joint count (0–28) 6 (2–13) 6 (2–10) 6 (2–13) 0.4 0.5 8 (3–14) Swollen joint count (0–28) 2 (0–5) 3 (1–6) 2 (0–5) 0.1 0.1 4 (1–8)¤ HAQ 1.1 (0.7–1.5) 1.0 (0.5–1.5) 0.9 (0.5–1.5) 0.03 0.07 0.9 (0.5–1.4) DAS28 4.6 (3.7–5.4) 4.5 (3.6–5.3) 4.6 (3.6–5.3) 0.5 0.8 4.9 (3.9–5.6) Patient’s global (0–100), mm 72 (54–87) 68 (50–80) 66 (48–82) 0.01 0.01 65 (45–80)¤ Pain (0–100), mm 65 (45–80) 63 (42–75) 62 (38–75) 0.08 0.08 60 (40–73) Fatigue (0–100), mm 72 (51–86) 63 (40–77) 63 (46–78) <0.01 0.01 62 (38–76)¤ Doctor’s global (0–100), mm 35 (22–55) 30 (20–50) 37 (25–52) 0.8 0.09 33 (22–50) Stop reason, n (%)‡ Lack of efficacy 112 (47) 112 (47) 88 (53) 0.7 0.8 74 (48) Adverse events 87 (37) 85 (36) 55 (33) 46 (30) Other 30 (13) 36 (15) 18 (11) 23 (15) Unknown 8 (3) 4 (2) 4 (3) 10 (7) Numbers are medians (IQRs) unless otherwise stated. *Test of difference between current and never smokers (Mann–Whitney, χ2). †Test of difference between current, previous and never smokers (Kruskal–Wallis). ‡Percentages of patients according to smoking status who have terminated treatment. ¤Significantly different (p <0.05) compared to patients with known smoking status. TNFi, tumour necrosis factor alpha inhibitor; CRP, C reactive protein; DAS28, Disease Activity Score (28 joints, based on CRP); HAQ, Health Assessment Questionnaire; VAS, Visual Analogue Scale. higher VAS fatigue (77 mm (60–89) vs 61 mm (40–79), smokers). In multivariate Cox regression analyses adjusted for p=0.003) and shorter disease duration (2 years (1–6) vs 4 years gender, age, disease duration and start year of TNFi, we found (1–8), p=0.02) compared to female never smokers, whereas no significant difference in treatment adherence between VAS global, DAS28 score and HAQ scores were similar (all current smokers and never smokers, neither overall (HR 1.18 p >0.05). (0.97 to 1.44)) nor in males (HR 1.22 (0.97 to 1.67)) or The median follow-up time for all included patients was females (HR 1.14 (0.87 to 1.5). 1.22 years (IQR 0.44–2.96) (current smokers 1.05 years In Kaplan–Meier analyses stratifiedaccordingtoTNFidrug (0.41–2.69), never smokers 1.37 years (0.43–2.90), previous type, estimated median survival time was poorer among smokers 1.12 years (0.44–2.94)). The total follow-up time was current versus. never smokers in patients treated with etaner- 2790 patient years. Current smokers had poorer treatment cept (1.0 year (0.66 to 1.39) vs 3.5 years (2.6 to 4.4), adherence than never smokers and median time on TNFi treat- median (95% CI), log rank p=0.01), while smoking had no ment was 1.56 years (0.97–2.15) in current smokers vs impact on adherence in patients treated with infliximab 2.43 years (1.88–2.97) in never smokers (median (95% CI)) (1.2 years (0.69 to 1.61) vs 1.5 years (1.1 to 1.9), p=0.3) or (log rank p=0.02) (figure 1A). In men, current smokers had adalimumab (2.8 years (1.9 to 3.7) vs 2.4 years (1.5 to 3.4), poorer treatment adherence than never smokers (figure 1B), p=0.3). Similar results were found in univariate Cox regres- whereas, the association between smoking and treatment adher- sion analyses (data not shown). In multivariate Cox regres- ence was less pronounced among women (figure 1C). sion analysis, there was a statistically significant interaction In univariate Cox regression analysis, current smoking was between smoking and TNFi drug type (p=0.04). In stratified associated with poorer treatment adherence (HR 1.29, 95% CI analyses according to TNFi drug type, current smoking was (1.08 to 1.55) vs never smokers). In gender-stratified analyses, associated with poorer adherence to etanercept (HR 1.74 the same association was found for male current smokers (HR (1.14 to 2.66) vs never smokers) and infliximab (HR 1.62 1.41 (1.08 to 1.84) vs male never smokers) but not for female (1.06 to 2.48)), but not adalimumab (HR 0.80 (0.52 to current smokers (HR 1.14 (0.89 to 1.46) vs female never 1.23)) (table 2).

2132 Højgaard P, et al. Ann Rheum Dis 2015;74:2130–2136. doi:10.1136/annrheumdis-2014-205389 Downloaded from http://ard.bmj.com/ on February 17, 2016 - Published by group.bmj.com Clinical and epidemiological research

Figure 1 Kaplan–Meier drug adherence curves according to: (A) smoking status, all patients (log rank 7.7, p=0.02). (B) smoking status (current vs never), men (log rank 6.3, p=0.01). (C) smoking status (current vs never), women (log rank 1.1, p=0.3). (D) smoking stop year among previous smokers (log rank 1.0, p=0.053).

Univariate Cox regression analyses stratified according to stop EULAR-good-response: 24%/42% (p=0.002); ACR20: 25%/ reason showed a comparable effect of current smoking on drug 41% (p=0.01) and ACR50 response rates: 21%/32% (p=0.05) termination due to ‘adverse events’ and ‘lack of effect’ (HR (figure 2). In univariate logistic regression analysis, current 1.32 (0.98 to 1.78) and (HR 1.28 (0.98 to 1.67), respectively, smokers had lower odds of achieving EULAR-good-response both p=0.07 compared to never smokers). (OR=0.6 (95% CI 0.4 to 0.9) vs never smokers, p=0.01) and Changes between baseline and 3 months’ and 6 months’ ACR20 (OR=0.7 (0.4 to –0.9), p=0.04), ACR50 (OR=0.6 (0.4 disease activity were calculated for VAS patient’s global, VAS to 0.9) p=0.05) and ACR70 (OR=0.6 (0.4 to 1.16), p=0.14) fatigue, VAS pain, CRP, tender and SJC according to smoking responses. In multivariate analyses, the negative impact of status. There was a non-significant tendency towards a greater smoking on treatment responses (ACR20/50/70 and decline in CRP after 6 months among never compared to EULAR-good-response) only reached statistical significance in current smokers (4.5 mg/L (0.3–17) vs 3 mg/L (0–11), p=0.08), gender-stratified analyses, where smoking was associated with a whereas, data were insignificant at 3 months (p=0.6). No sig- lower EULAR-good-response rate in men (OR=0.5 (0.3 to 0.9), nificant differences were found for delta VAS scores or delta p=0.03 current vs never smokers). In logistic regression subana- joint counts among current versus never smokers at 3 months lyses stratified by type of TNFi, smoking status did not affect and 6 months (all p>0.05, data not shown). response rates (overall and by gender, all p>0.05). Current smokers had lower EULAR-good-response and In subanalyses, previous smokers were included as an add- ACR20/50 response rates than had never smokers, whereas, itional group. In Kaplan–Meier analysis, previous smokers ini- ACR70 response rates were similar (figure 2). Twenty-three tially had drug adherence similar to current smokers. Beyond percent of current smokers achieved a EULAR-good-response ∼6 months, the drug adherence for previous smokers was inter- after 6 months compared to 34% of never smokers (p=0.01). mediate to those for never smokers and current smokers The rates for ACR20 and ACR50 response were 24%/33% (figure 1A). When previous smokers were stratified according to (p=0.04) and 17%/24% (p=0.04), respectively. These differ- number of years since smoking cessation, the drug adherence ences were mainly present among men with improved with more years since smoking cessation (figure 1D).

Højgaard P, et al. Ann Rheum Dis 2015;74:2130–2136. doi:10.1136/annrheumdis-2014-205389 2133 Downloaded from http://ard.bmj.com/ on February 17, 2016 - Published by group.bmj.com Clinical and epidemiological research

Table 2 Impact of smoking on treatment adherence stratified by TNFi drug type Adalimumab Infliximab Etanercept HR (95% CI) p Value HR (95% CI) p Value HR (95% CI) p Value

Smoking status Never 1 0.22 1 0.04 1 0.01 Current 0.76 (0.49 to 1.18) 1.56 (1.01 to 2.41) 1.74 (1.13 to 2.68) Gender Men 1 0.02 1 0.78 1 0.7 Women 1.66 (1.10 to 2.56) 1.05 (0.69 to 1.6) 1.10 (0.71 to 1.69) Disease duration, years 0–21 1 1 3–7 0.91 (0.55 to 1.50) 0.72 1.02 (0.59 to 1.76) 0.94 0.93 (0.53 to 1.61) 0.80 >8 0.73 (0.43 to1.22) 0.23 0.71 (0.44 to 1.13) 0.15 1.04 (0.71 to 1.69) 0.88 Age, years ≤38 1 1 1 39–47 0.61 (0.32 to 1.2) 0.15 1.16 (0.67 to 2.01) 0.58 1.16 (0.63 to 2.11) 0.63 48–56 1.18 (0.71 to 2.0) 0.52 1.08 (0.58 to 2.03) 0.78 1.14 (0.61 to 2.11) 0.67 ≥57 1.02 (0.57 to 1.82) 0.95 1.05 (0.58 to 1.91) 0.86 1.16 (0.59 to 2.24) 0.66 TNFi start year 2000–2006 1 1 1 2007–2009 1.32 (0.76 to 2.28) 0.32 1.61 (0.98 to 2.64) 0.06 1.39 (0.83 to 2.32) 0.19 2010–2011 0.76 (0.37 to 1.55) 0.45 3.74 (1.83 to 7.61) 0.01 1.48 (0.77 to 2.8) 0.23 Baseline swollen joint count, 1.02 (0.97 to 1.07) 0.34 1.04 (0.98 to 1.09) 0.19 Not included* number per joint increase Multivariate Cox regression analyses including a priori confounders. *Swollen joint count did not alter the OR of smoking by >10% and was not included in the multivariate analysis. Baseline distribution of covariates according to TNFi drug type (adalimumab/infliximab/etanercept). Current smokers: 34%/37%/27%. Males: 50%/55%/47%. Age, median (IQR): 48 (38–56) years/48 (39–56) years/48 (39–56) years. Disease duration, median (IQR): 4 (1–9) years/4 (2–12) years/4 (1–10) years. HR, hazard ratio; TNFi, tumour necrosis factor alpha inhibitor.

In men, previous smokers tended to have higher disease perception or a poorer general health condition among EULAR-good-response and ACR20 response rates than current current smokers contributed to earlier TNFi treatment. smokers, and lower rates compared to never smokers (univariate Alternatively, sDMARD therapy may be less effective in smokers.19 logistic regression analyses, data not shown) (figure 2). The differences in baseline disease activity and demographics according to smoking status might explain, at least in part, why DISCUSSION current smokers had poorer treatment response and treatment In this observational study of 1388 PsA patients initiating their first adherence in univariate but not multivariate analyses. However, treatment with a TNFi, one-third of patients were current smokers. in multivariate subanalyses, smoking was associated with poorer Current smokers had higher HAQ and patient VAS scores, but treatment response in men and poorer treatment adherence shorter disease duration than never smokers upon initiation of among patients treated with etanercept or infliximab. The non- treatment. Current smokers had reduced response rates, most pro- randomised study design implies that these findings must be nounced in male smokers where the EULAR-good-response and interpreted with caution due to the risk of residual confounding ACR20 response rates were nearly halved compared to male never or uneven distribution of baseline demographics. Two previous smokers. For previous smokers, the effect of smoking on drug studies have described the impact of smoking on TNFi treat- adherence diminished with time and was equivalent to never ment response in PsA. An observational study of 440 patients smokers ∼4 years after smoking cessation. found current smoking to be associated with shorter 3-year The impact of smoking on disease activity and functional TNFi drug survival.12 A single-centre study of 78 TNFi-treated – status is well described in RA17 19 but scarcely investigated in PsA patients reported smokers to have poorer treatment PsA. A cross-sectional study among 283 patients with PsA response and lower drug retention rates after 6 months’ treat- reported that current smokers had higher HAQ.9 It has been ment in univariate analyses.10 Further studies are needed to suggested that smoking alters illness behaviour and causes a confirm the relationship between smoking and treatment more severe perception of musculoskeletal pain.19 This may outcome in PsA. In RA, several studies have reported poorer – lead to higher DAS28 scores among current smokers compared TNFi adherence and treatment response among smokers.62023 to non-smokers with a similar inflammatory activity.22 Thus, It has been suggested that smoking causes higher levels of perhaps the DAS28 score should be interpreted with more TNF-α and other inflammatory markers,22 35 36 altered bioavail- caution among smokers. This may be especially relevant in ability of antirheumatic drugs, cutaneous vasoconstriction and patients with PsA, in whom the validity of the DAS28 measure slower absorption from subcutaneous injection, or increased is debated.33 34 We found shorter disease duration among basal metabolic rate.20 37 38 Few studies analysed the impact of current compared to never smokers upon start of TNFi, which may smoking according to type of TNFi, and found that smoking indicateamoreaggressivediseasecourseamongsmokers.18 mainly affected infliximab treatment.622This might be However, objective markers of disease activity (CRP and SJC) were explained by differences in drug metabolism or formation of independent of smoking status. One may hypothesise that a worse antichimeric antibodies.22 39

2134 Højgaard P, et al. Ann Rheum Dis 2015;74:2130–2136. doi:10.1136/annrheumdis-2014-205389 Downloaded from http://ard.bmj.com/ on February 17, 2016 - Published by group.bmj.com Clinical and epidemiological research

Figure 2 Treatment response rates after 6 months treatment according to smoking status overall and stratiﬁed according to gender. p Values are current vs never smokers (Mann–Whitney). (A) EULAR-good-response rates. (B) ACR20 response rates. (C) ACR50 response rates. (D) ACR70 response rates. Y-axis: percentage of patients achieving response.

We found that previous smokers who had stopped smoking treatment of PsA, most pronounced in men and among patients more than ∼4 years ago had nearly same drug adherence rates treated with infliximab and etanercept. The effects seemed par- as never smokers. This may illustrate a gradual normalisation of tially reversible, which stresses the importance of smoking cessa- pathological processes and smoking-related behaviour, and is tion programmes for these patients. Clinicians should beware noticeable, as tobacco smoking is a potentially modifiable life- that current smokers potentially have higher HAQ and VAS style factor. Studies in RA have found previous smoking to have scores compared with non-smokers, and this might affect the no21 or an intermediate17 impact on the effect of TNFi com- clinical evaluation of this patient group. pared to never smoking, though the influence of the time since Author affiliations smoking cessation was not investigated. 1Department of Rheumatology, Gentofte Hospital, Copenhagen, Denmark The strengths of this study are the high external validity for 2Department of Rheumatology, Frederiksberg Hospital, Copenhagen, Denmark routine care due to inclusion of an unselected nationwide 3Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Glostrup, Denmark population of patients with PsA and the long follow-up time. 4 Our study also has limitations. Smoking status was retrieved The Danish Rheumatologic Database (DANBIO), Copenhagen University Hospital Glostrup, Denmark cross-sectionally although smoking status might alter later 5Department of Clinical Medicine, Faculty of Health and Medical Sciences, University 21 on. An obvious misclassification occurs when previous of Copenhagen, Copenhagen, Denmark smokers resume smoking during follow-up. However, the 6Department of Rheumatology, Holbæk Hospital, Holbæk, Denmark 7 exclusion of previous smokers from all main analyses made Department of Rheumatology, Esbjerg Hospital, Esbjerg, Denmark 8Department of Rheumatology, Svendborg Hospital, Svendborg, Denmark this bias less important. Furthermore, we had no valid data 9Department of Rheumatology, Aalborg University Hospital, Aalborg,Denmark on the number of package years and thus the potential 10Department of Rheumatology, Odense University Hospital, Odense, Denmark dose-response relationship between smoking and outcome 11Department of Rheumatology, Vejle Sygehus, Sygehus Lillebælt, Vejle, Denmark 12 could not be investigated. In Denmark, heavy smokers are Department of Infectious Diseases and Rheumatology, Rigshospitalet, more often men.40 41 One might assume that the stronger Copenhagen, Denmark 13Department of Rheumatology, Helsingør and Hillerød Hospital, Hillerød, Denmark impact of smoking among male patients is associated with 14Department of Rheumatology, Køge Hospital, Køge, Denmark greater exposure to tobacco. Smoking may be linked to 15Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark comorbid disease, depression, socioeconomic and lifestyle 16Department of Rheumatology, Silkeborg Hospital, Denmark factors, which all potentially affect baseline disease activity 17 22 Acknowledgement Thanks to all the departments of rheumatology in Denmark and treatment outcome. Psoriatic manifestations in, for for reporting to the DANBIO registry. example, skin and nails may influence the decision on when Contributors All authors have contributed to acquisition of data, revised the article to start TNFi treatment and the evaluation of treatment for important intellectual content and given approval of this version of the article to effect. However, these data are not included in DANBIO, and be published. PH, BG and LD have given substantial contributions to the study this might have affected our results, as smoking is suspected design, interpretation of data and formation of the article content. PH has been to increase the severity of skin psoriasis and to decrease the responsible for the collection and analyses of data. – effect of TNFi on psoriatic skin lesions.42 44 Competing interests MH-F: UCB, MSD, Roche: Consulting fees, speaking fees, In conclusion, we found current smoking to have a negative honoraria. AGL: Abbvie: Advisory board, Wyeth: Investigator. impact on treatment duration and clinical response in TNFi Provenance and peer review Not commissioned; externally peer reviewed.

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Extended report Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years’ surveillance in the Danish nationwide DANBIO registry Bente Glintborg,1 Mikkel Østergaard,2 Niels Steen Krogh,3 Lene Dreyer,4 Hanne Lene Kristensen,5 Merete Lund Hetland2,6

1 Department of Rheumatology, ABSTRACT of tumour necrosis factor α (TNFα) inhibitors in Gentofte University Hospital, Objectives To use prospectively registered data 2–8 Hellerup, Denmark AS, and the drugs are recommended for the 2Department of Rheumatology, from the Danish nationwide rheumatological database treatment of patients with continuously active Copenhagen University (DANBIO) to describe disease activity, clinical response, disease.9 10 Hospitals at Hvidovre and treatment duration and predictors of drug survival (ie, Randomised clinical trials generally include Glostrup, Denmark number of days individual patients maintained treatment) 3 relatively homogeneous patient-populations who Zitelab Aps, Copenhagen, and clinical response among patients with ankylosing Denmark fulfi l a strict set of inclusion criteria and are fol- 4Department of Rheumatology, spondylitis (AS) receiving their fi rst treatment series with lowed up for a limited time period. Many patients Rigshospitalet, Copenhagen, a tumour necrosis factor α (TNFα) inhibitor. treated with biological agents in ‘real life’ would Denmark Methods 842 TNFα inhibitor naive patients with AS 5 have been excluded from clinical trials owing to Department of Rheumatology, were identifi ed in DANBIO. Clinical response, drug 11 Slagelse Hospital, Slagelse, advanced age, comorbidity or polypharmacy. Denmark survival and predictors thereof were investigated. ‘Clinical Thus, data from observational registries on post- 6The Danish Rheumatological response’ was defi ned as a 50% or 20 mm reduction marketing use provide a valuable supplement to Database (DANBIO), Hvidovre, in Bath Ankylosing Spondylitis Disease Activity Index the knowledge from clinical trials about drug tol- Denmark (BASDAI) within 6 months compared with baseline. erability, drug survival, drug effects and adverse Achievement of a BASDAI <40 mm within 6 months was 12–16 Correspondence to effects. Mrs Bente Glintborg, Gentofte used as a second response parameter. Currently, the reported real-life data for TNFα University Hospital, Niels Results 603 patients (72%) were men, disease inhibitor use among patients with AS are mainly Andersensvej 65, 2900, duration 5 (1–13) years (median (IQR), age 41 (32–50) retrospective analyses of patient fi les or small obser- Hellerup, Denmark; years. 445 (53%) received infl iximab, 247 (29%) 13 14 17–20 [email protected] vational studies. Although prospective adalimumab and 150 (18%) etanercept. Parameters rheumatological registries have been established in at baseline/1-year follow-up were: C-reactive protein 11 Accepted 20 April 2010 several countries and may serve as research tools, (CRP): 14 (7–27)/5 (2–10) mg/l, BASDAI 59 (44–72)/21 21–24 only two clinical registry reports on patients (8–39) mm, Bath Ankylosing Spondylitis Functional with AS have been published25 26 and neither of Index (BASFI) 50 (34–67)/24 (9–45) mm, Bath them assessed predictors of treatment response Ankylosing Spondylitis Metrology Index 40 (20–50)/20 and drug survival. (10–40) mm. Within 6 months, 407/644 patients (63%) The Danish nationwide rheumatological data- achieved a clinical response. Median drug survival base (DANBIO) prospectively registers treatment was 4.3 years. One- and 2-year survival rates were and disease activity in patients with rheumato- 74% and 63%, respectively. Baseline characteristics logical disease treated with biological drugs. The associated with longer drug survival were male mandatory reporting of biological treatment to the gender, CRP >14 mg/l and low visual analogue scale database makes coverage and completeness of data fatigue (Cox regression analysis). Age, TNFα inhibitor high.27 28 The registry currently includes up to 8 and methotrexate use were insignifi cant. CRP >14 years of follow-up. Several papers have previously mg/l, lower BASFI and younger age at baseline was described DANBIO data in patients with rheuma- associated with clinical response and achievement of a toid arthritis,16 27–31 whereas data for patients with BASDAI <40 mm (logistic regression analysis). AS have not been published until now. Conclusion TNFα inhibitors provide a rapid and Our aims were based on DANBIO data to report sustained decrease of disease activity among patients drug effi cacy and drug survival as well as to iden- with AS in clinical practice. Factors associated with tify baseline predictors of drug survival in Danish continued treatment, clinical response and achievement patients with AS receiving their fi rst treatment of a BASDAI <40 mm were identifi ed. course with a TNFα inhibitor in routine care.

INTRODUCTION PATIENTS AND METHODS Ankylosing spondylitis (AS) is a chronic inﬂ am- Patients matory rheumatic disease affecting 0.1–1.4% DANBIO is a Danish nationwide rheumatologi- of the population.1 Several placebo-controlled cal database that collects data on patients treated randomised trials have shown excellent efﬁ cacy with biological and other disease-modifying

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antirheumatic drugs (DMARDs). More than 90% of the patients Treatment duration who are prescribed biological treatment are included in the data- Drug survival was calculated as the number of days individual base.27 28 By 15 November 2008, 5366 patients receiving bio- patients maintained treatment. The start date was the date of logical treatment had been registered in DANBIO. Among these, the fi rst given dose and the stop date was the date of the fi rst 842 patients were diagnosed with AS and included in this study missed dose. All observations were censored at 15 November (table 1). 2008. Reasons for drug discontinuation were registered. The DANBIO data available in patients with AS were base- Queries were sent to treating hospitals about 139 patients line demographics including patient age, gender, disease dura- who had had no follow-up since 30 June 2008 and no registration, previous or current treatment with methotrexate (MTX) tions of stopping date. Subsequently, data on treatment duration or other DMARD. Disease activity parameters are prospec- was complete in 803 of 842 patients (95%). In the 39 patients tively reported to DANBIO by an online system and include with incomplete follow-up, data were censored according to the visual analogue scales (VAS) for pain, patient’s global score and last visit registered in DANBIO. fatigue score. Registrations of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Ethics Functional Index (BASFI) and Bath Ankylosing Spondylitis The DANBIO database has been approved by the Danish Board 31 Metrology Index (BASMI) were introduced in year 2003. A of Health and the Danish Data Registry. The registration of data doctor or a trained nurse measures the BASMI score and regis- among patients treated with biological agents does not require 32 ters the C-reactive protein (CRP) level. Data collection occurs patient consent. Publication of data does not require approval by two to four times annually. HLA-B27 status is not registered in the ethics committee. the database. Statistics Methods All statistical analyses were done by SPSS software (version 16.0, Disease activity and clinical response SPSS, Chicago, Illinois, USA). Demographic and descriptive data Disease activity was evaluated by the CRP, VAS scores, BASDAI, are presented as median and range. Groups were compared by BASFI and BASMI at 0, 2 and 6 weeks, 6 months, 1, 2, 3, 4 and non-parametric testing (unpaired data: χ2 and Mann–Whitney 5 years after initiation of anti-TNF treatment (table 2). Drug effi - tests, paired: Wilcoxon signed ranks test). Kaplan–Meier plots, cacy was primarily evaluated by ‘clinical response’ (reduction log rank tests and Cox regression analyses were used for drug in BASDAI of at least 50% or >20 mm compared with base- survival analysis. We converted each of the continuous baseline line according to the ASAS guidelines (BASDAI 50%/20 mm variables BASDAI, BASFI, BASMI and VAS scores into quartiles 33 34 response)). Arbitrarily, we classifi ed patients as ‘responders’ in order to visualise Kaplan–Meier drug survival curves. CRP was if they achieved a clinical response (yes or no) at least at one converted into a binary variable (below/above the median value registration during the fi rst 6 months’ treatment. As a second 14 mg/l). Logistic regression analysis was used for the identi- measure of drug effi cacy, we identifi ed the number of patients fi cation of factors associated with (a) clinical response and (b) having a BASDAI score <40 mm at least once during the fi rst BASDAI score <40 mm within 6 months of treatment. The fac- 6-month treatment. tors with least signifi cance were excluded stepwise (backward selection), leaving only statistically signifi cant factors in the model. In the Cox and logistic regression analysis, gender, type Table 1 Patient characteristics of TNFα inhibitor, baseline CRP and baseline MTX use were Demographic variables at baseline included as categorical variables, whereas patient age and base- Women (n (%)) 239 (28) line BASDAI were continuous variables. All interactions involv- Age (years (median (quartiles))) 41 (32–50) ing sex, patient age, disease duration, MTX use and drug type Disease duration (years (median (quartiles))) 5 (1–13) Methotrexate use (n (%)) 343 (41) were tested. Each interaction pair was included in the overall TNFα inhibitor used (n (%)) statistical model and thereafter excluded in the backward selec- Adalimumab 247 (29) tion process if the interaction was statistically insignifi cant. A p Etanercept 150 (18) value <0.05 was considered statistically signifi cant. Infl iximab 445 (53) Year of treatment initiation (n (%)) 2000 3 (0) RESULTS 2001 15 (2) Patient characteristics 2002 18 (2) The number of patients with AS initiating their fi rst treatment 2003 48 (6) α 2004 117 (14) series with TNF inhibitors increased over the years. The major- 2005 155 (18) ity of patients received infl iximab (table 1). A total of 310 patients 2006 150 (18) (37%) withdrew from TNFα inhibitor treatment. Table 1 shows 2007 188 (22) January to November 2008 148 (18) reasons for drug discontinuation. Of the 238 cases with a known reason for withdrawal, lack of effi cacy (115/238 patients, 48%) Reasons for drug discontinuation (n (%)) Lack of effi cacy 115 (14) was the most prevalent reason, whereas 69 patients (69/238, Adverse events or side effects 69 (8) 29%) stopped owing to adverse effects. Details of the adverse Planning pregnancy 11 (1) events were provided in several cases and included infections Disease remission 8 (1) Lost to follow-up 8 (1) (13 patients), cardiovascular events—for example, hyperten- Other reasons 27 (3) sion, palpitations, angina (six patients), rashes (nine patients) Not stated 72 (8) or anaphylaxia (three patients) and other allergic reactions (fi ve Total 310 (37) patients). Numbers in brackets show quartiles or percentages of total population (n=842). At baseline, 343 patients (41%) received concomitant TNFα, tumour necrosis factor α. MTX. Among infl iximab users, 254/445 (57%) received MTX

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Table 2 Disease activity at baseline and during follow-up Follow-up time Outcome (median (IQR)) Baseline 2 Weeks 6 Weeks 6 Months 1 Year 2 Years 3 Years 4 Years 5 Years CRP (mg/l) 14 (7–27) 4 (2–8)* 4 (2–10)* 5 (2–10)* 5 (2–10)* 5 (2–10)* 5 (2–10)* 6 (3–10)* 9 (3–16)* BASDAI (mm) 59 (44–72) 36 (19– 56)* 26 (12–49)* 26 (11–45)* 21 (8–39)* 21 (8–41)* 20 (8–36)* 20 (7–32)* 20 (6–32)* BASFI (mm) 50 (34–67) 37 (19–55)* 31 (13–50)* 28 (10–46)* 24 (9–45)* 24 (9–44)* 22 (10–43)* 22 (9–41)* 34 (17–62) BASMI (mm) 40 (20–50) 30 (10–50)* 30 (10–50)* 30 (10–43)* 20 (10–40)* 30 (10–50)* 20 (10–40)* 40 (10–50)** 40 (20–70) Thorax excursion (cm) 3 (2–5) 3 (2–5)* 4 (3–5)* 4 (2–5)* 4 (2–5)* 4 (2–5)** 4 (2–5)*** 4 (3–5)** 3 (2–5) VAS pain (mm) 65 (45–78) 30 (14–56)* 22 (10–46)* 20 (9–48)* 19 (7–40)* 18 (5–39)* 17 (6–26)* 15 (6–28)* 23 (7–35)* VAS fatigue (mm) 68 (48–81) 49 (20–70)* 34 (14–62)* 33 (14–59)* 29 (9–52)* 25 (6–45)* 18 (7–41)* 41 (4–42)* 23 (10–53) VAS global (mm) 67 (48–81) 36 (15–60)* 26 (11–51)* 24 (10–51)* 20 (8–44)* 18 (6–40)* 18 (8–37)* 18 (7–33)* 21 (11–49)* Patients treated (n†) 842 818 794 696 504 345 213 139 61 Patients with a visit (n) 745 395 458 515 390 264 168 128 39

*p<0.001 compared with baseline, **0.001

compared with 40/150 (27%) and 49/247 (20%) among patients receiving etanercept and adalimumab, respectively. Thus MTX use was more prevalent among patients receiving infl iximab than among those receiving adalimumab or etanercept, both at baseline (χ2 test, p<0.001) and during the whole period of observation (p<0.0001). Baseline BASMI and CRP were signifi cantly higher in men than women, whereas women had higher thorax excursion range, BASDAI, BASFI and VAS scores (Mann–Whitney test, all p<0.05, fi gure 1). Age (41 vs 41 years) and disease duration (6 vs 4 years) were similar among men and women (Mann–Whitney test, p>0.05).

Therapeutic effect Figure 1 Baseline disease activity for men (black bars) and women All outcome parameters decreased during follow-up (follow-up (grey bars). *p<0.05. BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; vs baseline, Wilcoxon test, all p<0.05) and thorax excursion BASMI, Bath Ankylosing Spondylitis Metrology Index; CRP, C-reactive increased (follow-up vs baseline, p<0.05) (table 2). At 6 months, protein; VAS, visual analogue scale. CRP levels in men had decreased more than in women (10 vs 3 mg/l respectively, Mann–Whitney, p<0.001), whereas the decrease in BASDAI levels was similar among men and women The crude retention rates were similar among patients receiv- (27 vs 22 mm respectively, p=0.09). ing infl iximab, adalimumab and etanercept (p=0.2). As shown At baseline, 644 of the 842 included patients (76%) had a in fi gure 2, male gender (panel A, log rank test p<0.0001), low BASDAI score registered. Among these, 407 patients (63%) baseline BASDAI (panel B, p<0.007), low VAS fatigue (panel C, achieved a clinical response (BASDAI 50%/20 mm response) p<0.0001) and CRP >14 mg/l (panel D, p<0.0001) were all asso- at least once during the fi rst 6 months and 456 (71%) achieved ciated with improved drug survival. Similar results were found a clinical response at least once during the whole treatment for low BASFI (p=0.003), whereas baseline VAS pain (p=0.09), course. In 338 patients (52%), the majority (>50%) of registered VAS global (p=0.08) and BASMI (p=0.9) did not affect drug BASDAI scores during the observation period were compatible survival. with clinical response. Baseline disease parameters and patient characteristics were Overall, 794 patients (94%) had at least one BASDAI registra- included in a Cox regression analysis in order to identify base- tion at baseline or during follow-up. Among these, 528 patients line factors associated with drug survival. Baseline VAS pain and (66%) had at least one BASDAI score <40 mm during the fi rst VAS fatigue were strongly intercorrelated (Spearman’s r>0.84, 6 months’ treatment and 554 patients (70%) had at least one p<0.0001) and so was baseline BASDAI and VAS pain/VAS BASDAI score <40 mm during the whole treatment course. In global (both r>0.72, p<0.0001). Thus, VAS pain and VAS global 445 patients (56%), the majority of registered BASDAI scores were excluded from the regression analysis. In the fi nal model, during the observation period were <40 mm. male gender, low baseline VAS fatigue and high CRP were associated with better drug survival, whereas patient age, type of Drug survival biological drug, baseline MTX use, BASDAI, BASFI and VAS The patients were treated for a total of 1513 patient-years. fatigue were not associated (table 3). Median drug survival was 4.3 years. Unadjusted 1- and 2-year In a stratifi ed multiple Cox regression analysis including only retention rates were 74% and 63%, respectively. side effects as the event causing drug termination, sex was the

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(A) Sex (B) Baseline BASDAI

1,0 1,0

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0,2 0,2 Black solid: 1. quartile (low) Grey dotted: 2. quartile Black: men Black dotted: 3. quartile 0,0 Grey: women 0,0 Grey solid: 4. quartile (high)

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Figure 2 Crude survival curves of tumour necrosis factor α inhibitor drug use according to (A) sex; (B) baseline BASDAI; (C) baseline VAS fatigue; (D) baseline CRP. x-Axis, treatment duration (years); y-axis, cumulated survival rate. BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CRP, C-reactive protein; VAS, visual analogue scale.

only signifi cant statistical predictor (female gender p<0.001, 6 months’ treatment as the dependent variable, CRP >14 mg/l HR=3.37, 95% CI 2.10 to 5.41). Similarly, including only lack of (OR=0.39, 95% CI 0.26 to 0.60, p<0.001), lower baseline BASFI treatment effect as the event causing drug termination, CRP ≤14 (OR=0.86, 0.77 to 0.99, p=0.02) and younger age (OR=0.98/year, mg/l (p=0.006, HR=1.98 (1.22 to 3.2) and higher baseline VAS 0.97to 1.00/year, p=0.048) were predictive of the patient achiev- fatigue (p<0.001, HR=1.25/cm (1.11 to 1.39)) were statistically ing BASDAI <40 mm. Biological drug, gender, disease duration, signifi cant factors. BASFI, BASMI, VAS scores and MTX use were without signifi - cance (all p>0.05). We tested for interactions between baseline BASDAI, age, Prediction of clinical response and achievement of disease duration, biological drug, MTX use and gender, and no BASDAI <40 mm statistically signifi cant interactions were found. In a logistic regression analysis (backward stepwise selection) with clinical response (BASDAI 50%/20 mm response) as the dependent variable, CRP >14 mg/l (OR=0.45 (low vs high) (95% DISCUSSION CI 0.31 to 0.64) p<0.001), lower baseline BASFI (OR=0.87/cm This report from a nationwide prospective registry of 842 patients increase (0.78 to 0.97) p=0.008) and younger age (OR=0.98/year with AS receiving their fi rst treatment series with a TNFα inhibi- increase (0.97 to 0.99/year) p=0.03) were associated with clini- tor documents the effi cacy of anti-TNFα treatment in clinical cal response, whereas biological drug, gender, disease duration, practice. The measures of disease activity showed a rapid and BASFI, BASMI, VAS scores and baseline MTX use were without sustained decrease and almost two-thirds of patients achieved a statistical signifi cance (all p>0.05). The analysis was adjusted for clinical response within 6 months. Male gender, low baseline VAS the baseline BASDAI level. fatigue and baseline CRP >14 mg/l were associated with longer In a similar logistic regression analysis (backward selection) treatment continuation, whereas younger age, lower BASFI and with achievement of BASDAI <40 mm at least once during higher baseline CRP levels predicted good treatment response.

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Table 3 Baseline predictors of discontinuing treatment with tumour necrosis factor α inhibitors

Unadjusted analysis Adjusted analysis Final model after backwards selection HR p Value HR p Value HR p Value Sex Man 1 – 1 – 1 – Woman 1.96 (1.55 to 2.45) <0.0001 1.46 (1.06 to 2.01) 0.02 1.46 (1.07 to 2.00) 0.02 BASDAI (cm) 1.12 (1.05 to 1.20) 0.001 0.97 (0.86 to 1.10) 0.64 – – BASFI (cm) 1.10 (1.04 to 1.17) 0.002 1.06 (0.97 to 1.16) 0.17 – – VAS fatigue (cm) 1.15 (1.08 to 1.23) <0.001 1.13 (1.03 to 1.24) 0.009 1.14 (1.06 to 1.22) <0.001 VAS pain (cm) 1.07 (1.01 to 1.13) 0.02 – – – – VAS global (cm) 1.07 (1.01 to 1.13) 0.03 – – – – CRP ≤14 mg/l 1.70 (1.33 to 2.12) <0.0001 1.53 (1.13 to 2.07) 0.006 1.53 (1.14 to 2.05) 0.05 >14 mg/l 1 – 1 – 1 – Methotrexate use Used 1 – 1 – – – Not used 1.17 (0.93 to 1.47) 0.18 1.35 (0.98 to 1.86) 0.07 – – Biological treatment Inﬂ iximab 1 – 1 – – – Adalimumab 0.86 (0.66 to 1.13) 0.29 0.73 (0.49 to 1.10) 0.13 – – Etanercept 0.77 (0.57 to 1.05) 0.09 0.71 (0.48 to 1.06) 0.09 – – Age (years) 1.01 (1.00 to 1.02) 0.05 1.01 (0.99 to 1.02) 0.41 – –

Numbers in brackets are 95% CI. Results from multiple Cox regression analysis (n=842). BASDAI, Bath ankylosing spondylitis disease activity index; BASFI, function index; CRP, C-reactive protein.

Our cohort of patients followed for up to 8 years represents A high disease activity at baseline illustrated by a higher VAS the largest cohort of TNFα inhibitor treated patients with AS fatigue was associated with shorter treatment duration. Others with the longest observation time reported till now. Only few have previously reported a similar effect for a high baseline have previously published prospective real-life data in patients BASDAI.18 It is well known from previous studies that disease with AS. Carmona and Gómez-Reino found a 1-year TNFα activity at baseline infl uences treatment outcome and drug inhibitor survival rate of 88% among 657 Spanish patients with survival, although results are not uniform.17 24 38–40 It has been AS,26 whereas a Norwegian study among 249 patients with AS speculated that high subjective disease activity scores might reported a survival rate of 77.5%18 —a number very similar to relate to late disease dominated by irreversible changes and the 74% found in our study. A Finnish group did not report thus a poorer treatment outcome. However, in this study we survival rates but stated that 49/229 patients (21%) discontin- did not fi nd any effect of disease duration on treatment out- ued treatment within up to a 2-year follow-up.25 Thus, real-life come. Furthermore, patients with high baseline activity might retention rates of TNFα inhibitors among patients with AS seem have substantial relative improvements without necessarily uniformly high despite the fact that treatment strategy, attitudes achieving clinical remission.24 37 and actions must be expected to vary considerably between On the other hand, increased CRP levels at baseline were asso- countries.35 Observational data are diffi cult to compare with the ciated with longer treatment duration, good clinical response and tightly controlled setting of a randomised trial. However, in a achievement of a BASDAI <40 mm within 6 months. Similar randomised clinical trial, Braun et al reported that 54/69 (78%) results have previously been reported.37 39 CRP is a biomarker of patients with AS completed their fi rst year of infl iximab treat- infl ammation and increased levels might identify patients with ment4 and similarly, Davis et al found that 95/128 (74%) patients more active disease who are more likely to benefi t from TNFα with AS completed 96 weeks of etanercept treatment.3 Thus inhibitor treatment than patients with chronic, less infl amma- survival rates seem similar across observational and randomised tory active disease.17 38 39 studies. Concomitant MTX is not recommended during biological The treatment response with TNFα inhibitors was rapid treatment of AS.10 However, 41% of our patients received MTX and sustained. Among the patients with a BASDAI measure- at baseline, and it was most prevalent among patients treated ment at baseline, we found that 63% achieved good clinical with infl iximab. This is in agreement with previous studies response within 6 months’ treatment. Until recently, only the reporting frequent use of MTX, especially among patients with total BASDAI score was registered in DANBIO and therefore peripheral joint disease or treated with infl iximab.12 18 25 The a calculation of Assessment of SpondyloArthritis International infl uence of MTX on drug survival varies between studies. In Society response criteria ASAS20 or ASAS40,36 which includes our study, concomitant MTX use did not affect drug survival relative or absolute changes in BASDAI question fi ve and six, or treatment effects. A Norwegian study found similar results,18 was not possible. This makes comparison to studies using ASAS whereas a French study reported poorer drug survival among response criteria diffi cult. Two other studies reporting real-life MTX users.19 The non-randomised design makes interpretation data found a similar response rate when using the BASDAI diffi cult. Confounding by indication cannot be ruled out and 50%/20 mm response parameter—namely, 71% among patients MTX use may be a marker of more serious disease or in other with AS treated with TNFα inhibitors12 or 60% within 3-month ways refl ect the patient’s status—for example, peripheral joint treatment with etanercept.25 In a recent open-label study among involvement.35 1250 patients with AS treated with adalimumab, 57% achieved Overall, the treatment with TNFα inhibitors was well tolerated >50% reduction in BASDAI score within 3 months.37 In ran- and only a few patients stopped owing to adverse events. Our domised controlled studies, 45–58% of patients achieve a 50% fi nding that drug termination occurred more frequently owing to reduction in BASDAI.5–8 Individually tailored treatment, dose lack of effi cacy rather than adverse effects has also been reported adjustments or concomitant use of DMARDs may, at least in by others,19 25 although results are confl icting.18 26 part, explain why TNFα inhibitor treatment might perform bet- We found a signifi cant difference in baseline disease activity ter in clinical practice than in randomised trials.25 between women and men. Furthermore, men responded better

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to treatment evaluated by the achievement of clinical response 11. Zink A, Listing J, Kary S, et al. Treatment continuation in patients receiving biological and reductions in CRP and BASDAI levels. One may hypothesise agents or conventional DMARD therapy. Ann Rheum Dis 2005;64:1274–9. 12. Coates LC, Cawkwell LS, Ng NW, et al. Real life experience confi rms sustained that women scored higher in the subjective parameters BASDAI, response to long-term biologics and switching in ankylosing spondylitis. Rheumatology BASFI and VAS because of weaker musculoskeletal performance (Oxford) 2008;47:897–900. or a general tendency towards reporting poorer scores in ques- 13. Brocq O, Roux CH, Albert C, et al. TNFalpha antagonist continuation rates in 442 tionnaires.18 40–42 Shorter treatment survival and poorer treat- patients with infl ammatory joint disease. Joint Bone Spine 2007;74:148–54. ment outcome has been reported among female patients with 14. Heiberg MS, Nordvåg BY, Mikkelsen K, et al. The comparative effectiveness of tumor necrosis factor-blocking agents in patients with rheumatoid arthritis and patients with 18 26 18 24 40 AS or rheumatoid arthritis. Why women apparently ankylosing spondylitis: a six-month, longitudinal, observational, multicenter study. respond differently to TNFα inhibitors is unclear, and any inter- Arthritis Rheum 2005;52:2506–12. actions between rheumatic disease, gender, sex hormones and 15. Kvien TK, Mikkelsen K, Nordvåg BY. Results from controlled clinical trials: how TNFα inhibitors remain to be further investigated.40 43 relevant for clinical practice? J Rheumatol 2003;30:1135–7. 16. Hetland ML, Christensen IJ, Tarp U, et al. Direct comparison of treatment responses, We render the quality of data high. According to previous remission rates, and drug adherence in patients with rheumatoid arthritis treated reports, >90% of Danish patients treated with biological agents with adalimumab, etanercept, or infl iximab: results from eight years of surveillance are registered in the database,28 probably owing to the manda- of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum tory registration irrespective of a patient’s consent. Thus, the 2010;62:22–32. coverage is much lower in databases using voluntary registra- 17. Luc M, Gossec L, Ruyssen-Witrand A, et al. C-reactive protein predicts tumor necrosis factor-alpha blocker retention rate in axial ankylosing spondylitis. J Rheumatol 26 tion and requiring patient consent. 2007;34:2078–81. In conclusion, this analysis of 842 patients with AS in a 18. Heiberg MS, Koldingsnes W, Mikkelsen K, et al. The comparative one-year nationwide prospective database registry documents that performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid TNFα inhibitors provide a rapid and sustained decrease in dis- arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter study. Arthritis Rheum 2008;59:234–40. ease activity. The majority of patients achieved a good clinical 19. Duclos M, Gossec L, Ruyssen-Witrand A, et al. Retention rates of tumor response. Baseline CRP >14 mg/l and low VAS fatigue was asso- necrosis factor blockers in daily practice in 770 rheumatic patients. J Rheumatol ciated with longer treatment continuation, whereas high CRP, 2006;33:2433–8. low BASFI and younger age predicted good treatment response 20. Gérard S, le Goff B, Maugars Y, et al. Six-month response to anti-TNF drugs in and achievement of BASDAI <40 mm. Men maintained treat- axial spondylarthropathy according to the fulfi llment or not of New-York criteria for ankylosing spondylitis or French recommendations for anti-TNF use. A “real life” ment longer than women. Other parameters, including drug retrospective study on 175 patients. Joint Bone Spine 2008;75:680–7. type and MTX use, did not signifi cantly affect drug survival or 21. Zink A, Listing J, Klindworth C, et al. The national database of the German treatment effi cacy. The treatment was well tolerated and only a Collaborative Arthritis Centres: I. Structure, aims, and patients. Ann Rheum Dis few patients stopped treatment owing to adverse effects. 2001;60:199–206. 22. Buchbinder R, March L, Lassere M, et al. Effect of treatment with biological agents Competing interests MLH has received consulting fees, speaking fees and/or for arthritis in Australia: the Australian Rheumatology Association Database. Intern research grants from Abbott, Centocor, Roche, Schering-Plough, UCB-Nordic and Med J 2007;37:591–600. Wyeth (less than US$10 000 each), and on behalf of DANBIO, she has received 23. Geborek P, Crnkic M, Petersson IF, et al. Etanercept, infl iximab, and lefl unomide grants from Abbott, Bristol-Meyers Squibb, Roche, Schering-Plough, UCB-Nordic and in established rheumatoid arthritis: clinical experience using a structured follow up Wyeth (more than US$10 000 each). MO has received consulting fees, speaking programme in southern Sweden. Ann Rheum Dis 2002;61:793–8. fees and/or research grants from Abbott, Amgen, Bristol-Meyers Squibb, Centocor, 24. Hyrich KL, Watson KD, Silman AJ, et al. Predictors of response to anti-TNF-alpha Genmab, GlaxoSmithKline, Novo, Pfi zer, Roche, Schering-Plough, UCB-Nordic and therapy among patients with rheumatoid arthritis: results from the British Society for Wyeth (less than US$10 000 each). Rheumatology Biologics Register. Rheumatology (Oxford) 2006;45:1558–65. 25. Konttinen L, Tuompo R, Uusitalo T, et al. Anti-TNF therapy in the Provenance and peer review Not commissioned; externally peer reviewed. treatment of ankylosing spondylitis: the Finnish experience. Clin Rheumatol 2007;26:1693–700. 26. Carmona L, Gómez-Reino JJ. Survival of TNF antagonists in spondylarthritis is better REFERENCES than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER. Arthritis Res 1. Braun J, Sieper J. Ankylosing spondylitis. Lancet 2007;369:1379–90. Ther 2006;8:R72. 2. Braun J, Baraliakos X, Listing J, et al. Persistent clinical effi cacy and safety of 27. Hetland ML, Unkerskov J, Ravn T, et al. Routine database registration of anti-tumour necrosis factor alpha therapy with infl iximab in patients with ankylosing biological therapy increases the reporting of adverse events twentyfold in clinical spondylitis over 5 years: evidence for different types of response. Ann Rheum Dis practice. 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Outcomes of a multicentre randomised Denmark and Norway: criteria are becoming less stringent. Ann Rheum Dis clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 2005;64:1220–3. 2004;63:1594–600. 30. Hjardem E, Østergaard M, Pødenphant J, et al. Do rheumatoid arthritis patients in 6. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with clinical practice benefi t from switching from infl iximab to a second tumor necrosis infl iximab: a randomised controlled multicentre trial. Lancet 2002;359:1187–93. factor alpha inhibitor? Ann Rheum Dis 2007;66:1184–9. 7. van der Heijde D, Dijkmans B, Geusens P, et al. Effi cacy and safety of infl iximab in 31. Schefte DB, Hetland ML. An open-source, self-explanatory touch screen in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial routine care. Validity of fi lling in the Bath measures on Ankylosing Spondylitis (ASSERT). Arthritis Rheum 2005;52:582–91. Disease Activity Index, Function Index, the Health Assessment Questionnaire and 8. van der Heijde D, Kivitz A, Schiff MH, et al. Effi cacy and safety of adalimumab in Visual Analogue Scales in comparison with paper versions. Rheumatology (Oxford) patients with ankylosing spondylitis: results of a multicenter, randomized, double- 2010;49:99–104. blind, placebo-controlled trial. Arthritis Rheum 2006;54:2136–46. 32. Danish Rheumatological Database. 2010. https://danbio-online.dk. 9. Zochling J, van der Heijde D, Dougados M, et al. Current evidence for the (accessed May 2010). management of ankylosing spondylitis: a systematic literature review for the ASAS/ 33. Anderson JJ, Baron G, van der Heijde D, et al. Ankylosing spondylitis assessment EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis group preliminary defi nition of short-term improvement in ankylosing spondylitis. 2006;65:423–32. Arthritis Rheum 2001;44:1876–86. 10. 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35. Pincus T, Yazici Y, van Vollenhoven R. Why are only 50% of courses of anti-tumor 39. Davis JC Jr, Van der Heijde DM, Dougados M, et al. Baseline factors that inﬂ uence necrosis factor agents continued for only 2 years in some settings? Need for ASAS 20 response in patients with ankylosing spondylitis treated with etanercept. J longterm observations in standard care to complement clinical trials. J Rheumatol Rheumatol 2005;32:1751–4. 2006;33:2372–5. 40. Sokka T, Toloza S, Cutolo M, et al. Women, men, and rheumatoid arthritis: analyses 36. Sieper J, Rudwaleit M, Baraliakos X, et al. The Assessment of SpondyloArthritis of disease activity, disease characteristics, and treatments in the QUEST-RA study. international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Arthritis Res Ther 2009;11:R7. Rheum Dis 2009;68(Suppl 2):ii1–44. 41. Thompson PW, Pegley FS. A comparison of disability measured by the Stanford 37. Rudwaleit M, Claudepierre P, Wordsworth P, et al. Effectiveness, safety, and Health Assessment Questionnaire disability scales (HAQ) in male and female predictors of good clinical response in 1250 patients treated with adalimumab for rheumatoid outpatients. Br J Rheumatol 1991;30:298–300. active ankylosing spondylitis. J Rheumatol 2009;36:801–8. 42. Katz PP, Criswell LA. Differences in symptom reports between men and women with 38. Rudwaleit M, Listing J, Brandt J, et al. Prediction of a major clinical response rheumatoid arthritis. Arthritis Care Res 1996;9:441–8. (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann 43. Cutolo M, Straub RH, Bijlsma JW. Neuroendocrine-immune interactions in synovitis. Rheum Dis 2004;63:665–70. Nat Clin Pract Rheumatol 2007;3:627–34.

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EXTENDED REPORT Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor α inhibitor therapy: results from the Danish nationwide DANBIO registry Bente Glintborg,1,2 Mikkel Østergaard,3 Niels Steen Krogh,4 Ulrik Tarp,5 Natalia Manilo,6 Anne Gitte Rasmussen Loft,7 Annette Hansen,1 Annette Schlemmer,8 Victoria Fana,9 Hanne M Lindegaard,10 Henrik Nordin,11 Claus Rasmussen,12 Leif Ejstrup,13 Dorte Vendelbo Jensen,14 Peter Mosborg Petersen,15 Merete Lund Hetland2,3

▸ An additional ABSTRACT In Denmark, four TNFi are currently marketed supplementary table is Objective To investigate frequencies and reasons for for the treatment of AS (infliximab, etanercept, published online only. To view this file please visit the journal switching, treatment responses and drug survival in adalimumab and golimumab). The drugs have dif- online (http://dx.doi.org/ patients with ankylosing spondylitis (AS) switching ferent chemical structures, routes of administration 10.1136/annrheumdis-2012- tumour-necrosis-factor-α inhibitor (TNFi) treatment in and pharmacokinetics.4 Thus, if a patient fails to 201933) routine clinical care. achieve adequate response during the first treat- For numbered affiliations see Methods AS patients were identified in the Danish ment or experiences adverse events (AE), a switch end of article. nationwide DANBIO registry. Disease activity, treatment to a second TNFi seems appealing. responses (50% or 20 mm reduction in Bath AS Disease Among patients with rheumatoid arthritis (RA), Correspondence to 5–10 Dr Bente Glintborg, Activity Index (BASDAI)), duration and rates of drug switching has become daily practice and approxi- Department of Rheumatology, survival and predictors thereof were studied in patients mately 55% of RA switchers achieve ACR20 Gentofte University Hospital, receiving ≥2 different biological drugs. response.11 However, the rate and success of switch- Niels Andersensvej 65, Results Of 1436 AS patients starting TNFi treatment, ing may be different in patients with AS.12 13 Hellerup 2900, Denmark; 432 patients (30%) switched to a second and 137 (10%) [email protected] Currently, experiences from switching in to a third biological drug. Compared with non-switchers, patients with AS mainly originate from one large Received 26 April 2012 switchers were more frequently women (33%/22%), had open label trial14 and several smaller observational Accepted 19 July 2012 shorter disease duration (3 years/5 years) and higher studies including few treatment centres or less – Published Online First BASDAI (62(52–76) mm/56(43–69) mm (median than 50 switch episodes.8121522 31 August 2012 (interquartile-range))), Bath AS Functional Index (BASFI) The Danish nationwide DANBIO registry now (54(39–71) mm/47(31–65) mm) and visual-analogue- includes up to 10 years of prospective follow up of scale (VAS) global, pain and fatigue scores when they patients with inflammatory arthritis treated with started the first TNFi (all p<0.01). Main reason for biologicals in routine care.23 We have previously switching was lack of response (56%). During the first, described treatment response and predictors thereof second and third treatment BAS- and VAS scores had in AS patients receiving the first TNFi treatment.24 decreased after 6 months’ treatment (all p<0.05). The aims of the present study were to investigate Median drug survivals were 3.1, 1.6 and 1.8 years frequencies and reasons for switching, treatment respectively (p<0.001). After 2 years of treatment 52% responses, drug survivals and predictors thereof of switchers and 63% of non-switchers had achieved among patients switching TNFi treatment. response (number needed to treat 1.9 and 1.6, respectively, p=0.01). Drug survivals were similar regardless of the reason for switching. Male gender and PATIENTS AND METHODS low BASFI predicted drug survival of the second TNFi. The Danish DANBIO-registry is a nationwide regis- Conclusions Nearly one-third of AS patients in clinical try that was commenced in year 2000 and approved practice switched biological treatment. Response rates as a clinical quality registry in 2006. DANBIO and drug survivals were lower among switchers, covers >90% of adults treated with biologics due to 25–27 however, half of switchers achieved treatment response. rheumatic disease in routine care. According to Danish legislation, any registration and publication of data from clinical registries does not require patient consent or approval by Ethics Committees. INTRODUCTION Biological treatment courses initiated before 1 The beneficial effect of tumour-necrosis-factor- January 2011 were included in the present study α-inhibitor (TNFi) treatment in ankylosing spon- and follow-up was until 20 April 2011. By 1 dylitis (AS) has been documented in several January 2011, 2039 patients with a diagnosis of AS – randomised trials.1 3 However, some patients experi- according to specialists in rheumatology had been ence lack of treatment effect (LOE) and some registered. It is not explicitly stated in DANBIO patients terminate treatment due to side effects. how individual patients fulfill the diagnostic

Ann Rheum Dis 2013;72:1149–1155. doi:10.1136/annrheumdis-2012-201933 1149 Downloaded from http://ard.bmj.com/ on February 17, 2016 - Published by group.bmj.com Clinical and epidemiological research

Table 1 Baseline demographics and disease activity when patients Treatment response started the first tumour necrosis factor inhibitor Disease activity was evaluated by the CRP, VAS pain, fatigue Non-switchers Switchers p Value and global, BASDAI, BASFI and BASMI-scores 0, 3 and N=1004 N=432 6 months after initiation of therapy. Treatment response during each treatment course was evalu- – – Age 41 (33 51) 41 (32 49) 0.4 ated as a reduction in BASDAI of at least 50% or >20 mm Women, n (%) 218 (22) 142 (33) 0.0001 (BASDAI 50%/20 mm response).128We classified patients as – – Disease duration (years) 5 (1 14) 3 (1 11) 0.01 ‘responders’ if they achieved a sustained BASDAI 50%/20 mm – – Symptom duration (years) 14 (6 22) 11 (4 19) 0.0001 response (yes/no) at both the 3 and 6-months’ visits compared Use of methotrexate, n (%) 262 (26) 157 (36) 0.0001 with the BASDAI registration at 0 months. Thus only patients – – CRP (mg/l) 13 (5 27) 13 (5 26) 0.4 treated >3 months were included in this analysis. The individual – – VAS fatigue (mm) 65 (46 78) 74 (56 87) 0.0001 components of the BASDAI score were not registered in DANBIO – – VAS global (mm) 66 (46 79) 72 (57 85) 0.0001 until year 2008, and therefore Assessment of SpondyloArthritis – – VAS pain (mm) 62 (44 77) 70 (51 81) 0.0001 international Society (ASAS) response is not reported. – – BASDAI (mm) 56 (43 69) 62 (52 76) 0.0001 The overall long-term treatment response was evaluated at the – – BASFI (mm) 47 (31 65) 54 (39 71) 0.0001 2-year visit (defined as the first visit >104 weeks after initiating – – BASMI 40 (20 60) 40 (20 60) 0.9 the first TNFi). This time point was chosen arbitrarily to allow for Mann-Whitney and χ2 tests. Numbers are median (quartiles) unless otherwise an acceptable number of switch episodes without excluding too stated. many patients with insufficient follow-up time. The BASDAI BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Function Index; BASMI, Bath Ankylosing Spondylitis 50%/20 mm response at the 2-year visit was compared with the Metrology Index; CRP, C reactive protein; VAS, visual analogue scale. baseline BASDAI at the first treatment course, irrespective of switch episodes in the meantime. Thus, only patients with a registration of BASDAI at baseline and follow-up for ≥2yearswere criteria for AS. Patients with psoriatic arthritis were excluded included in this analysis (609 patients). Also, the proportion of from this analysis. We excluded 518 AS patients only treated patients with BASDAI <40 mm at the 2-year visit was evaluated. with disease-modifying anti-rheumatic drugs (DMARDs), 84 In the subgroup of patients with available ASDAS,29 30 disease patients treated with biologicals as part of clinical trials, and activity was reported as the median ASDAS and the proportion one patient who did not receive TNFi as the first biological. of patients attaining ASDAS <2.1 (inactive/moderate disease Thus, 1436 biologically naïve patients, who had been registered activity) at the latest visit registered after ≥2 years follow-up. in DANBIO from the time of initiation of the first TNFi were included. Of these, a subgroup of 432 patients (switchers) had Statistics received treatment with ≥two different biological drugs (TNFi Statistical analyses were performed by SPSS (V.16.0, SPSS Inc., or other) during follow-up (table 1). The total number of treat- Chicago, Illinois, USA) and SAS software (V.9.0, SAS Institute ment courses was 2061. Inc, Cary, North Carolina, USA). Demographic and descriptive Axial disease activity was assessed by Bath AS Disease data are presented by medians/IQR. Groups were compared by Activity Index (BASDAI), Bath AS Function Index (BASFI), non-parametric testing (unpaired data: χ2 and Mann-Whitney Bath AS Metrology Index (BASMI) and thorax excursion range tests, paired: Wilcoxon signed ranks test). The proportion of (introduced in year 2003). C reactive protein (CRP) level patients achieving treatment responses were expressed as (normal range ≤10 mg/l), visual analogue scales (VAS) for pain, Number-Needed-to-Treat (NNT) calculated as the reciprocal global and fatigue scores were also registered. Since year 2010 value of response rates. In all statistical tests, a p value <0.05 the AS Disease Activity Score (ASDAS) was registered. Data was considered statistically significant. collection occurred at minimum biannually. Kaplan Meyer plot and log rank test were used to visualise Queries were sent to the hospitals regarding treatment series drug survival. Unadjusted/univariate and multvariate Cox with incomplete follow-up. All calculations were based on regression analysis with HR were used for the identification of observed data and no imputation of missing data was per- factors associated with drug survival of the second treatment formed. All observations were censored at 20 April 2011. course. Logistic regression analyses and OR were used to iden- Drug adherences tify factors associated with BASDAI 50%/20 mm response. In the regression analyses, patient age, baseline CRP, BASDAI, Drug survival was calculated as the number of days individual BASFI, BASMI and VAS scores were included as continuous patients maintained treatment with the drug. Start date was the variables whereas gender, type of TNFi (current and previous date of the first given dose and stop date was the date of the first treatment), use of methotrexate (yes/no) and reason for discon- missed dose. Temporary treatment interruptions (eg, due to tinuation of the first TNFi (AE/LOE/other) were included as infections or surgery) of <3 months’ duration were allowed. If a categorical variables. The variables with the highest p value patient restarted treatment with the same biological drug after were excluded stepwise (backward selection) leaving only stat- >3 months treatment interruption, the second treatment course istically significant variables in the final model. with the drug was deleted from the dataset (62 cases). In the following, unless otherwise stated, the term baseline is The reasons for drug discontinuation are registered in pre- used to describe disease activity upon starting the individual specified categories: LOE, AE, pregnancy, surgery, infections, loss treatment course. to follow up and other. In the following, switching-AE denotes switching due to side effects, infection, death or cancer. Switching-LOE denotes switching due to lack/loss of effect. RESULTS Switching-other denotes switching due to any other cause (preg- Baseline characteristics and patient disposition nancy, surgery, lost to follow up, disease remission) or several Among the included 1436 patients, 360 (25%) were women reasons for drug discontinuation. and median age was 41 years (IQR 33–50 years). Median

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Figure 1 Flow -chart of treatment course 1,2 and 3 and reasons for drug discontinuation (n= 1,436). Numbers show the number of patients LOE: Lack of effects, AE: adverse events follow-up time was 2.4 years (IQR 1.0–4.8 years). The patient patients), infliximab-etanercept (88 patients), adalimumab- flow is outlined in figure 1. When data were censored, 432 etanercept (84 patients), etanercept-adalimumab (36 patients). patients (32%) had switched treatment and 773 patients were Baseline infliximab doses among patients starting infliximab as still treated with the original TNFi. Switchers were more fre- the first, second and third treatment were 296 mg (3.9 mg/kg), quently women, had shorter disease duration, were more fre- 364 mg (4.6 mg/kg) and 366 mg (5.0 mg/kg), respectively. Similarly, quently treated with methotrexate and had higher VAS scores, the average doses at the latest registered visit were 324 mg (4.2 mg/ BASFI and BASDAI compared with non-switchers when they kg), 382 mg (4.9 mg/kg) and 390 mg (5.4 mg/kg), respectively. At started the first TNFi (table 1). More non-switchers who con- the latest visit, 21% of patients received infliximab every 6 weeks, tinued treatment vs non-switchers who stopped treatment 11% every 7 weeks and 56% every 8 weeks. Baseline use of metho- without starting a new TNFi, were men (80 vs 71%, p=0.002), trexate was more frequent among infliximab users and patients but baseline disease activities were similar in the groups (all with peripheral joint disease (both p<0.01, data not shown). p>0.05, data not shown). A total of 231 patients stopped the first TNFi without starting a The most prevalently used first line drug was infliximab in new. The main reason for switching was LOE (240 patients, 56% year 2001–2008 and adalimumab in year 2009–2010. of switchers) or AE (118 patients, 27%). Among the 432 patients Adalimumab was the most frequently used second (46%) and who started treatment with a second biological, 137 switched to a third line (31%) treatment (table 2). Biologicals other than third (32%), 217 patients continued treatment, and 78 patients TNFi were only initiated in 19 of 2061 treatment series and stopped without starting a new. The main reason for switching to will not be discussed further. The most frequent combinations a third biological was LOE (86 patients, 63% of switchers) (figure of first and second TNFi were: infliximab-adalimumab (161 1). Similarly, 39/137 patients (28%) switched to a fourth biological, and 12/39 patients (31%) switched to a fifth. Among the 432 switchers, baseline disease activity was similar irrespective of the Table 2 Number of treatment courses according to biological drug reason for switching (see supplementary table S1). Treatment course number Biological drug Total (%) 1* 2* 3 4, 5, 6, 7 Drug survival Drug survival decreased after switching (p<0.001) (figure 2). Adalimumab 781 (38) 532 (37) 197 (46) 42 (31) 10 (18) Median drug survival of the first TNFi among switchers was Etanercept 452 (22) 231 (16) 172 (40) 40 (29) 9 (16) 0.7 years (95% CI 0.6 to 0.8 years). Infliximab 741 (36) 653 (45) 42 (10) 37 (27) 9 (16) Golimumab 59 (3) 20 (1) 15 (3) 9 (7) 15 (27) Certolizumab 9 (0) 0 (0) 1 (0) 3 (2) 5 (9) Treatment response ’ Rituximab 8 (0) 0 (0) 3 (1) 2 (1) 3 (5) Most scores decreased after 3 and 6 months treatment during fi Tocilizumab 4 (0) 0 (0) 0 (0) 2 (1) 2 (4) the rst, second and third treatment course (table 3). For fi Abatacept 5 (0) 0 (0) 1 (0) 1 (1) 3 (5) switchers, baseline CRP was signi cantly lower at the second fi Anakinra 1 (0) 0 (0) 0 (0) 1 (1) 0 (0) and third treatment course compared with the rst (p<0.05) fi fi Not stated 1 (0) 0 (0) 1 (0) 0 (0) 0 (0) ( gure 3). Baseline BASDAI and VAS global were signi cantly fi Total 2061 (100) 1436 (100) 432 (100) 137 (100) 56 (100) lower at the second treatment course compared with the rst (p<0.001). For switchers, the delta values for the decrease in Number of patients, number in brackets show percentages of total. *Drug combinations (first-second drug): adalimumab (ada)-etanercept (eta) 84 CRP, BASDAI and VAS global between baseline and 6 months patients, ada-infliximab (ifx) 31, ada-golimumab (gol) 6, ifx-ada: 161, ifx-eta 88, were similar at the second and third treatment course com- ifx-gol 6, eta-ada: 36, eta-ifx: 11, eta-gol: 3 patients. pared with the first (all p>0.05) (figure 3).

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Figure 2 Drug adherences by treatment course. Kaplan Meyer drug survival curves. The table below show the number of patients still treated at the corresponding time points, the proportion of patients maintaining treatment after 2 years and the median drug survival. This ﬁgure is only reproduced in colour in the online version.

During the first treatment course, the proportion of patients 0.9), p=0.008), and lower BASFI (0.6/cm(0.2–0.8), p=0.001) achieving BASDAI 50%/20 mm response within 6 months was 54% (multiple logistic regression analysis corrected for baseline (NNT=1.9). Corresponding rates during the second and third treat- BASDAI). Type of TNFi (current or previous), reason for with- ment course were 37% (NNT=2.7) and 30% (NNT=3.4). drawal of first TNFi, gender, age, BASMI, VAS global, VAS pain At the 2-year visit, 52% of switchers (NNT=1.9) and 63% of and age were not significant. non-switchers (NNT=1.6) (p=0.01) had a BASDAI 50%/20 mm response (compared with the baseline visit of the first TNFi) DISCUSSION and 54% of switchers (NNT=1.9) and 79% (NNT=1.3) of non- In this study of 1432 patients with AS we found that almost switchers (p<0.0001) had a BASDAI <40 mm. Switchers had one third switched TNFi during up to 10 years of follow-up. received a median of two biological drugs (IQR 2–2). Switchers were more frequently women and patients with Among patients treated ≥2 years, 316 patients had an avail- high baseline subjective disease activity. The main reason for able ASDAS-score at their latest visit. The proportion of switching was LOE. The disease activity decreased significantly patients with ASDAS<2.1 was 37% among switchers and 71% during the second and third treatment course. Although of non-switchers (p<0.001). Median ASDAS among switchers switchers had poorer treatment response and shorter drug sur- and non-switchers were 2.5 (IQR 1.8–3.5) and 1.6 (1.0–2.3), vival than non-switchers, approximately half of switchers respectively. achieved clinical response. Two years after switching, half of switchers maintained treatment with the second biological. Predictors of drug survival and response during the second Lack of efficacy explained half of the switch episodes, fol- treatment course lowed by AE in one out of four. Switches were almost exclu- In univariate Cox regression, drug survival of the second bio- sively between TNFi. Previous observational studies have logical was longer in men (p=0.03), patients treated with adali- included a limited number of switch-episodes. Lie et al found mumab (p=0.03), patients previously treated with infliximab switching in 77/514 (15%) AS patients during 9 years of (p=0.004) and patients with lower BASFI (p=0.03). Baseline follow-up mainly due to AE.22 A French study described CRP, BASDAI, BASMI and VAS-scores, age, use of methotrexate switching in 99/377 (26%) patients with spondyloarthropaties and reason for withdrawal of the first TNFi were not statistic- during 8 years of follow-up, the main reason was LOE.20 These ally significant. In multvariate Cox regression, predictors of differences are unexplained but possibly reflect regional differ- longer drug survival were male gender (HR 1.76 (95% CI 1.2 to ences in prescription practice. 2.5), p=0.002) and low baseline BASFI (HR1.07/cm (1.0–1.15), We found that switchers were more often women and had p=0.046), whereas type of TNFi (current or previous), reason higher subjective disease activity compared with non-switchers for withdrawal of first TNFi, use of methotrexate, age, CRP, when starting the first TNFi, CRP and BASMI were similar. BASMI, BASDAI and VAS scores at the start of the second The Norwegian study found no such differences,22 however, treatment were not predictive. the study may have been underpowered as baseline data only Predictors of BASDAI 50%/20 mm response during the second was available in 39% of switchers. Studies performed in RA treatment course were higher CRP at baseline (OR 1.03/mg/l patients report a similar tendency towards higher baseline (95% CI 1.0 to 1.05), p=0.02), lower VAS fatigue (0.6/cm (0.5– disease activity among switchers.59This might reflect that

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Table 3 CRP level, VAS and BAS scores during the first (n=1436), conservative measure than the BASDAI50%/20 mm response second (n=432) and third treatment course (n=137) used in the current study. However, in spite of great variation in Treatment duration p p study design and methodology, previous studies overall describe Treatment 0vs3 0vs6 high response rates among AS patients switching therapy. course 0 months 3 months 6 months months months Increased CRP and low BASFI were associated with treatment response during the second treatment course. A similar pattern CRP (mg/l) has previously been described among AS patients receiving their – – – – 1 13 (5.0 26) 4.0 (1.0 9.0) 4.0 (1.0 9.0) 0.001 0.001 first TNFi.24 31 36 However, one previous study among 99 – – – 2 8.0 (2.0 20) 5.0 (2.0 11) 3.0 (1.0 7.0) 0.09 0.001 patients with spondyloarthropaties switching TNFi found no – – – 3 9.0 (3.0 21) 4.0 (1.0 12) 6.0 (2.0 11) 0.2 0.1 predictors,20 perhaps due to lack of power. Perhaps increased VAS fatigue (mm) levels of CRP identify patients with higher cytokine mediated – – – 1 68 (50 81) 33 (16 60) 32 (12 61) 0.001 0.001 inflammation and therefore better response to TNFi. On the – – – 2 68 (47 82) 49 (17 74) 41 (17 69) 0.001 0.001 contrary, higher BASFI might be associated with chronic disabil- – – – 3 71 (60 82) 61 (39 84) 54 (31 78) 0.02 0.04 ity or psychological factors irresponsive to treatment.31 VAS global (mm) Currently, inflammatory markers and functional status are not – – – 1 68 (49 81) 25 (11 51) 24 (10 52) 0.001 0.001 included in the guidelines for prescribing TNFi in AS. However, – – – 2 68 (45 81) 38 (12 67) 36 (15 65) 0.001 0.001 possible predictors must be interpreted with caution in clinical – – – 3 71 (56 85) 60 (46 76) 57 (30 76) 0.04 0.01 settings: we found increased CRP to predict clinical response VAS pain (mm) after switching and 50% of patients with CRP>10 mg/l achieved – – – 1 65 (46 78) 22 (9 48) 20 (9 47) 0.001 0.001 a BASDAI 50%/20 mm within 6 months. However, 30% of – – – 2 62 (40 78) 36 (12 62) 31 (11 56) 0.001 0.001 patients with normal CRP also achieved response. More compli- – – – 3 66 (45 83) 57 (40 74) 48 (28 75) 0.06 0.04 cated models are needed in order to predict clinical outcome of BASDAI (mm) therapy in individual patients.32 – – – 1 59 (45 71) 28 (11 48) 28 (11 50) 0.001 0.001 We found longer treatment duration of the second biological drug – – – 2 56 (38 73) 36 (19 64) 33 (16 59) 0.001 0.001 inmencomparedwithwomen.Thisisinaccordancewithprevious – – – – 3 64 (48 79) 51 (36 67) 52 (28 63) 0.002 0.001 studies, not only in AS but also RA and psoriatic arthritis.24 36 41 BASFI (mm) Why clinical response differs according to gender is still unclear. – – – 1 50 (34 67) 28 (11 48) 28 (11 50) 0.001 0.001 The main switch patterns were from infliximab to adalimu- – – – 2 52 (35 70) 36 (17 60) 41 (17 58) 0.001 0.001 mab or etanercept. This reflects that infliximab was the first – – – 3 64 (42 79) 51 (30 73) 52 (38 74) 0.02 0.04 TNFi marketed to treat AS. Among patients starting treatment BASMI in year 2008 and thereafter, the most prevalent switch was – – – 1 40 (20 60) 20 (10 50) 30 (10 50) 0.001 0.001 from adalimumab to etanercept (48/157 switches). Drug sur- – – – 2 30 (20 50) 30 (10 40) 30 (10 50) 0.08 0.007 vival during the second treatment course was longer among – – – 3 40 (20 60) 35 (20 50) 40 (20 50) 0.03 0.006 adalimumab treated patients and among patients previously Results from Wilcoxon signed rank test. Values are medians and IQR. treated with infliximab. However, we found no difference in Outcome data were reported according to the registrations in DANBIO at the efficacy among the different TNFi. Due to the non-randomised following time-points: 0 months (upon initiation of therapy), 3 months (10–17 weeks), 6 months (18–32 weeks). If more registrations occurred within a study design, these results must be interpreted with caution. given time interval, the one closest to the given time-point was selected. If a Comorbidity, route of drug administration (subcutaneous/intra- patient had no registrations within a given time interval, data were registered as venously) and altered clinical practice due to marketing of new missing for the given time-point. drugs might have affected the results.13 38 BASDAI, Bath AS Disease Activity Index; BASFI, Bath AS Function Index; BASMI, The treatment response of the second biological drug was Bath AS Metrology Index; CRP, C reactive protein; VAS, visual analogue scale. similar among switchers due to LOE and AE. Some have reported similar results17 20 22—others describe better treat- switchers are patients refractory to treatment for example, due ment effects among AE-switchers.81214Our study was limited 31 to chronic disability or comorbidities. by the fact that it was not possible to distinguish between In the present study, response rates were markedly reduced treatment termination due to lack of or loss of treatment 22 among switchers. Similar results were found by Lie et al effect. According to some studies, patients who stop treatment Rudwaleit et al reported response among 41% of 326 adalimu- due to secondary loss of treatment effect especially benefit mab treated patients with AS who previously failed treatment from switching.12 14 Smoking status, comorbid disease, con- with infliximab and/or etanercept compared with 63% among comitant use of NSAIDs, enthesitis and HLAB27 status are 14 TNFi-naïve patients (p<0.001). Furthermore, we found factors that might influence treatment outcome.32 However decreased drug survival after switching. Similar tendencies have these data are not routinely registered in DANBIO. 9131422 previously been demonstrated. In conclusion, nearly one-third of AS patients switched Although the response rates and drug survivals decreased TNFi in routine care during up to 10 years of follow-up, mainly after switching, the 6 months’ response rate was 37% during due to inefficacy. The response rates and drug adherences the second treatment course. After 2 years’ of treatment, 52% decreased after switching. However, half of the switchers of switchers had achieved BASDAI50/20 mm response and achieved clinical response. Thus, irrespective of the reason for 54% a BASDAI <40 mm. Rudwaleit et al and Lie et al reported discontinuation of the first TNFi, switching to another TNFi 14 22 BASDAI50 response among 41% and 28% of switchers. should be considered. Observational studies including <25 patients report 43–83% 815–18 Author affiliations response rates. A retrospective study among 56 switchers 1 20 Department of Rheumatology, Gentofte University Hospital, Copenhagen, Denmark found a 80% response rate after 3 months’ treatment. It 2 The Danish Rheumatologic Database (DANBIO), Glostrup, Denmark should be noted that several clinical studies measure response 3Department of Rheumatology, Copenhagen University Hospital Glostrup, Glostrup, rates as 50% reductions in BASDAI,14 17 22 which is a more Denmark

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Figure 3 Disease activity for switchers at baseline, 3 months and 6 months during biological treatment course 1 (red). course 2 (grey) and course 3 (green) (n=432). Columns show medians. Panel A: C reactive protein (CRP), panel B: Bath AS Activity Index (BASDAI), panel C: Visual analogue scale (VAS) global. This ﬁgure is only reproduced in colour in the online version.

4Zitelab Aps, Copenhagen, Denmark ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum 5Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark Dis 2006;65:423–32. 6Department of Rheumatology, Frederiksberg Hospital, Copenhagen, Denmark 3. Zochling J, van der Heijde D, Burgos-Vargas R, et al. ASAS/EULAR 7Department of Rheumatology, Vejle Sygehus, Sygehus Lillebælt, Vejle, Denmark recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 8Department of Rheumatology, Aalborg Hospital, Aalborg, Denmark 2006;65:442–52. 9Department of Rheumatology, Køge Hospital, Køge, Denmark 4. Arend WP. The mode of action of cytokine inhibitors. J Rheumatol Suppl 10Department of Rheumatology, Odense University Hospital, Odense, Denmark 2002;65:16–21. 11Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, 5. Wick MC, Ernestam S, Lindblad S, et al. Adalimumab (Humira) restores clinical Denmark response in patients with secondary loss of efficacy from infliximab (Remicade) or 12Department of Rheumatology, Vendsyssel Hospital, Hjørring, Denmark etanercept (Enbrel): results from the STURE registry at Karolinska University 13Department of Rheumatology, Esbjerg Hospital, Esbjerg, Denmark Hospital. Scand J Rheumatol 2005;34:353–8. 14Department of Rheumatology, Helsingør Hospital, Helsingør, Denmark 6. Hyrich KL, Lunt M, Watson KD, et al. Outcomes after switching from one 15Department of Rheumatology, Regionshospital Randers, Randers, Denmark anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort – Acknowledgements Thanks to the departments of rheumatology in Aalborg, study. Arthritis Rheum 2007;56:13 20. Aarhus, Esbjerg, Fredericia, Frederiksberg, Gentofte, Glostrup, Gråsten, Hjørring, 7. Hyrich KL, Lunt M, Dixon WG, et al. Effects of switching between anti-TNF fi Holbæk, Holstebro, Horsens, Helsingør, Kolding, Køge, Næstved/Nykøbing Falster, therapies on HAQ response in patients who do not respond to their rst anti-TNF – Odense, Randers, Rigshospitalet, Roskilde, Silkeborg, Slagelse, Svendborg, Vejle, drug. Rheumatology (Oxford) 2008;47:1000 5. Viborg, Denmark for reporting to the DANBIO registry. 8. Pradeep DJ, Keat AC, Gaffney K, et al. Switching anti-TNF therapy in ankylosing spondylitis. Rheumatology (Oxford) 2008;47:1726–7. Contributors All coauthors fulfilled criteria for co-authorship according to the 9. Hjardem E, Ostergaard M, Podenphant J, et al. Do rheumatoid arthritis patients in Vancouver Protocol. clinical practice benefit from switching from infliximab to a second tumor necrosis Competing interests MØ: Abbott, Centocor, GSK, MSD, Mundipharma, Novo, Pfizer, factor alpha inhibitor? Ann Rheum Dis 2007;66:1184–9. Roche, UCB, Wyeth (less than 10.000 USD each); AGL: MSD, UCB, Abbott (less than 10. Virkki LM, Valleala H, Takakubo Y, et al. Outcomes of switching anti-TNF 10.000 USD each); AS: MSD, Pfizer, Roche (less than 10.000 USD each); HML: Roche, drugs in rheumatoid arthritis—a study based on observational data from the MSD (less than 10.000 USD each); CR: Pfizer, Abbott (less than 10.000 USD each); Finnish Register of Biological Treatment (ROB-FIN). Clin Rheumatol MLH: Abbott, Centocor, Roche, Pfizer (less than 10.000 USD each); BG, NSK, UT, NM, 2011;30:1447–54. AH, VF,HN, LE, DVJ and PMP declare no conflict of interest. 11. Remy A, Avouac J, Gossec L, et al. Clinical relevance of switching to a second tumour necrosis factor-alpha inhibitor after discontinuation of a first tumour necrosis Ethics approval The study reports data from a National Registry. 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Baseline predictors of response and Dis 2011;70:157–63. discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing 23. Danish Rheumatological Database. http://danbio-online.dk. 2012. (GENERIC) Ref spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther Type: Internet Communication. 2011;13:R94. 24. Glintborg B, Ostergaard M, Krogh NS, et al. Predictors of treatment response and 37. Heiberg MS, Koldingsnes W, Mikkelsen K, et al. The comparative one-year drug continuation in 842 patients with ankylosing spondylitis treated with performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid anti-tumour necrosis factor: results from 8 years’ surveillance in the Danish arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, nationwide DANBIO registry. Ann Rheum Dis 2010;69:2002–8. observational, multicenter study. Arthritis Rheum 2008;59:234–40. 25. Hetland ML, Unkerskov J, Ravn T, et al. Routine database registration of biological 38. Carmona L, Gomez-Reino JJ. Survival of TNF antagonists in spondylarthritis is therapy increases the reporting of adverse events twentyfold in clinical practice. better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER. First results from the Danish Database (DANBIO). Scand J Rheumatol Arthritis Res Ther 2006;8:R72. 2005;34:40–4. 39. Hyrich KL, Watson KD, Silman AJ, et al. Predictors of response to anti-TNF-alpha 26. Hetland ML, Lindegaard HM, Hansen A, et al. Do changes in prescription practice therapy among patients with rheumatoid arthritis: results from the British Society for in patients with rheumatoid arthritis treated with biological agents affect treatment Rheumatology Biologics Register. Rheumatology (Oxford) 2006;45:1558–65. response and adherence to therapy? Results from the nationwide Danish DANBIO 40. Sokka T, Toloza S, Cutolo M, et al. Women, men, and rheumatoid arthritis: analyses Registry. Ann Rheum Dis 2008;67:1023–6. of disease activity, disease characteristics, and treatments in the QUEST-RA Study. 27. Hetland ML. DANBIO—powerful research database and electronic patient record. Arthritis Res Ther 2009;11:R7. Rheumatology (Oxford) 2011;50:69–77. 41. Glintborg B, Ostergaard M, Dreyer L, et al. Treatment response, drug survival, and 28. Anderson JJ, Baron G, van der Heijde D, et al. Ankylosing spondylitis assessment predictors thereof in 764 patients with psoriatic arthritis treated with anti-tumor group preliminary definition of short-term improvement in ankylosing spondylitis. necrosis factor alpha therapy: results from the nationwide Danish DANBIO registry. Arthritis Rheum 2001;44:1876–86. Arthritis Rheum 2011;63:382–90.

Ann Rheum Dis 2013;72:1149–1155. doi:10.1136/annrheumdis-2012-201933 1155

Rheumatology Advance Access published November 30, 2015

RHEUMATOLOGY 263

Original article doi:10.1093/rheumatology/kev392 Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry

Bente Glintborg1,2, Pil Højgaard1, Merete Lund Hetland2,3,4, Niels Steen Krogh5, Gina Kollerup6, Jørgen Jensen7, Stavros Chrysidis8, Inger Marie Jensen 9 10 11 Hansen , Mette Holland-Fischer , Torben Højland Hansen , Downloaded from Christine Nilsson12, Jakob Espesen13, Henrik Nordin7, Anne Gitte Rasmussen Loft14, Randi Pelck15, Tove Lorenzen16, Sussi Flejsborg Oeftiger17, Barbara Unger18, Frank Jaeger19, Peter Mosborg Petersen20, 21 1

Claus Rasmussen and Lene Dreyer http://rheumatology.oxfordjournals.org/

Abstract Objectives. To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses in patients with AS treated with their first tumour necrosis factor- alpha inhibitor (TNFi) therapy in routine care. Methods. Observational cohort study based on the Danish nationwide DANBIO registry. KaplanMeier plots, Cox and logistic regression analyses by smoking status (current/never/previous) were calculated for treatment adherence and BASDAI 50%/20 mm-response. Additional stratified analyses were performed for gender and TNFi-type. at Danish Regions on December 1, 2015 Results. Of 1576 AS patients included in the study, 1425(90%) had known smoking status (current/never/ previous: 43%/41%/16%). The median follow-up time was 2.02 years (IQR 0.695.01). At baseline, current smokers compared with never smokers had longer disease duration (4 years (112)/2 years (010)), higher BASDAI (61 mm (4773)/58 mm (4470)), BASFI (53 mm (3569)/46 mm (3166)) and BASMI (40 mm SCIENCE

(2060)/30 mm (1050)) scores (all P < 0.01). Current and previous smokers had shorter treatment adher- CLINICAL ence than never smokers (current: 2.30 years (1.812.79) (median (95% CI)); previous: 2.48 years (1.563.40), never: 4.12 years (3.294.95)), P < 0.0001). Similar results were found in multivariate analyses (current versus never smokers, HR 1.41 (95% CI 1.211.65), P < 0.001), most pronounced among men. Current smokers had poorer 6 months’ BASDAI50%/20 mm-response rate than never smokers (42%/58%, P < 0.001). In multivariate analyses, current smokers had lower odds of achieving

1Department of Rheumatology, Gentofte University Hospital, 13Department of Rheumatology, Vejle Hospital, Vejle, Denmark, Copenhagen, Denmark, 2The Danish Rheumatologic Database, 14Department of Rheumatology, Aarhus University Hospital, Aarhus, Rigshospitalet, Glostrup Hospital, Glostrup, Denmark, 3Copenhagen Denmark, 15Department of Rheumatology, Køge Hospital, Køge, Centre for Arthritis Research, Centre for Rheumatology and Spine Denmark, 16Department of Rheumatology, Silkeborg University Diseases, Rigshospitalet, Glostrup Hospital, Glostrup, Denmark, Hospital, Silkeborg, Denmark, 17Department of Rheumatology, 4Department of Clinical Medicine, Faculty of Health and Medical Slagelse Hospital, Slagelse, Denmark, 18Department of Sciences, University of Copenhagen, Copenhagen, Denmark’ Rheumatology, Horsens Hospital, Horsens, Denmark, 19Department 5Zitelab Aps, Copenhagen, Denmark, 6Department of Rheumatology, of Rheumatology, Holstebro Hospital, Holstebro, Denmark, Frederiksberg Hospital, Frederiksberg, Denmark, 7Department of 20Department of Rheumatology, Randers Hospital, Randers, Rheumatology, Rigshospitalet, Glostrup Hospital, Glostrup, Denmark and 21Department of Rheumatology, Sygehus Vendsyssel, Denmark, 8Department of Rheumatology, Esbjerg Hospital, Esbjerg, Hjørring, Denmark Denmark, 9Department of Rheumatology, Svendborg Hospital, Submitted 14 April 2015; revised version accepted 27 October 2015 Svendborg, Denmark, 10Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark, 11Department of Correspondence to: Bente Glintborg, Department of Rheumatology, Rheumatology, Holbæk Hospital, Holbæk, Denmark, 12Department Gentofte University Hospital, Copenhagen, 2900, Denmark. of Rheumatology, Odense University Hospital, Odense, Denmark, E-mail: [email protected]

! The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected] 1 Bente Glintborg et al.

BASDAI50%/20 mm-response than never smokers, both overall (OR 0.48 (95% CI 0.350.65), P < 0.0001) and for the different TNFi-types (adalimumab 0.45 (0.270.76)/etanercept 0.24 (0.100.61)/infliximab 0.57 (0.340.95)). Conclusion. In this study of TNFi-treated AS patients in clinical practice, current and previous smokers had significantly poorer patient-reported outcomes at baseline, shorter treatment adherence and poorer treatment response compared with never smokers. Key words: Ankylosing spondylitis, Smoking, Tumour necrosis factor-alpha inhibitors, Outcome, Routine care

Rheumatology key messages

. Current smoking was frequent among TNF inhibitor treated Danish patients with AS. . Upon start of TNF inhibitor treatment, smokers with AS had higher disease activity than never smokers. . In AS, smokers (current or previous) had poorer TNF inhibitor treatment response and adherence than never

smokers. Downloaded from

Introduction disease treated in routine care with biologics [24, 26]. According to Danish legislation, the registration and pub- The introduction of TNF-a inhibitor (TNFi) treatment has lication of data from clinical registries do not require pa- improved outcomes in AS. Nevertheless, approximately tient consent or approval by ethics committees. http://rheumatology.oxfordjournals.org/ half of the patients terminate treatment owing to side ef- Physicians are recommended to report data prospectively fects or lack of effect [14]. Several studies have aimed to by an online system at least biannually and when medica- identify effect modifiers and predictors of treatment re- tion is changed (www.danbio-online.dk). sponse [57], but it has proven difficult to pinpoint the Baseline demographics include smoking habits, age, patients who are most likely to benefit from therapy [7]. gender, BMI, disease duration, current treatment with Smoking is an important and potentially modifiable risk MTX or other conventional synthetic DMARDs factor in axial spondyloarthritis (axSpA) and AS [8]. (csDMARD). In addition to CRP level (normal ran- Current smokers seem to have poorer patient-reported ge 410 mg/l) and visual analogue scales (VASs) for outcomes, a higher disease activity [913] and a higher scores of pain, patient’s global, fatigue and physician’s risk of progressive, structural damage compared with global assessments, the patient’s functional status and non-smokers [14, 15]. Studies on the impact of smoking disease activity are monitored by BASDAI, BASFI and at Danish Regions on December 1, 2015 on effectiveness of TNFi treatment in AS patients are few. BASMI, which are validated disease outcome measures In a recent Swiss study, current smokers with axSpA had in AS [27, 28]. By 1 January 2014, 1775 patients with a poorer response rates compared with non-smokers in a diagnosis of AS had been registered and treated with a real-life cohort treated with TNFi [16]. However, smoking biologic drug (bDMARD), according to the treating did not modify health-related quality of life among TNFi- rheumatologist. We excluded patients treated with certo- treated Australian AS patients [17]. Previous studies have lizumab pegol (n = 5) and bDMARDs other than TNFi reported a negative impact of smoking on the effective- (n = 12), patients participating in clinical trials (n = 140), pa- ness of TNFi treatment in patients with RA [1821] and tients not followed in DANBIO since the commencement PsA [22, 23]. of their first TNFi (n = 19) or with erroneous baseline regis- The nationwide DANBIO registry includes clinical data trations (n = 23), leaving 1576 patients in the study. on patients with rheumatic diseases treated with TNFi in routine care in Denmark [24, 25]. We have previously Tobacco smoking described demographics and clinical outcomes in pa- Patients were divided into three groups according to tients with AS treated with TNFi [1]. The primary aim of smoking status: current (51 cigarette/day), previous and the present study was to compare effectiveness in current never smokers. In previous smokers, the number of years smokers, previous smokers and never smokers regarding since smoking cessation was recorded. Smokers who had disease activity, treatment responses and adherence stopped smoking the year they started TNFi were classi- rates in patients with AS initiating their first TNFi therapy fied as previous smokers (n = 25). Queries were sent to the in routine care. The secondary aim was to study whether departments regarding patients with incomplete data on the impact of smoking was influenced by gender and TNFi smoking status. A rheumatologist then obtained the infor- type. mation from the medical records or by asking the patients.

Treatment adherence Methods Treatment adherence was calculated as the number of The DANBIO registry was initiated in the year 2000 and years each patient maintained treatment. Start date was covers >90% of Danish adults suffering from rheumatic the date of the first given dose and stop date was the date

2 www.rheumatology.oxfordjournals.org Impact of tobacco smoking in AS

of the first missed dose. Temporary treatment interrup- calculated hazard ratios (HRs) for treatment discontinu- tions (e.g. due to infections or surgery) of 43 months’ ation with time in study as the underlying time scale. duration were allowed. All observations were censored Univariate and multivariate logistic regression analyses by 1 September 2014. Among patients with no follow-up and odds ratios (ORs) were calculated to identify the since June 2014, data were censored according to the impact of smoking (current/previous/never) on the last visit registered. achievement of clinical response. The following baseline The reasons for drug discontinuation are registered in factors were considered a priori as confounders and DANBIO in pre-specified categories: lack of effect, ad- included in all multivariate analyses: age (in quartiles), verse events, disease remission, pregnancy, surgery, gender, disease duration (in tertiles), calendar year of cancer, death, infections, loss to follow-up and other rea- starting TNFi (in tertiles). Age, disease duration and year sons. In the following, reasons for discontinuation are of treatment start were included as categorical variables divided into three categories: adverse events (including to allow for possible non-linear effects. Baseline MTX use infection, death or cancer), lack of effect and other (yes/no) and TNFi type (adalimumab/etanercept/golimu- (including pregnancy, surgery, loss to follow-up, remission mab/infliximab) were considered potential confounders and other reasons for discontinuation). and were added one by one to the multivariate model, but were only included if they altered the OR/HR of smok- Downloaded from Treatment response ing by >10%. Baseline VAS scores, CRP, BMI, BASDAI, Disease activity was evaluated at baseline and after 3 and BASFI and BASMI were considered intermediate variables 6 months’ therapy. The baseline visit was defined as a visit between tobacco smoking and outcomes and not within the time frame that ranged from 60 days before until included in the main multivariate analyses. For sensitivity six days after initiation of therapy. For the 3 months’ visit, we performed multivariate logistic regression analyses the time frame was 1017 weeks, and for the 6 months’ (current vs never smokers) that besides the a priori con- http://rheumatology.oxfordjournals.org/ visit the time frame was 1832 weeks after treatment start. founders additionally included all the variables in which If more than one registration occurred within a given time the baseline values differed significantly among current frame for an individual patient, the registration closest to vs never smokers. The latter analysis was also performed the given time-point was selected for analysis. If a patient where the confounding effect of all variables was adjusted had no registrations within a given time window, data for by use of propensity score. Stratified analyses were were registered as missing for the given visit. performed according to gender and TNFi type (adali- In accordance with international recommendations, mumab/etanercept/infliximab, but not for golimumab, clinical response was defined as achievement of either a owing to limited data). 50% or a 20-mm reduction in BASDAI (BASDAI50%/ 20 mm response) [27, 28]. Arbitrarily and in agreement

with previous studies, we classified patients as re- Results at Danish Regions on December 1, 2015 sponders if they achieved clinical response (yes/no) at both the 3 and 6 months’ visits compared with baseline. Characteristics at baseline In the case of missing data at either the 3 or 6 months’ A total of 1576 bDMARD-naı¨ve patients initiating treat- visit, one registration of clinical response was sufficient to ment with adalimumab, etanercept, golimumab or inflixi- classify the patient as a responder. Patients who stopped mab as the first TNFi were included (Table 1). Among the treatment within the first 3 months of therapy were con- 1425 patients (90%) with known smoking status, 43% sidered non-responders (n = 112). Response rates were were current, 41% never and 16% previous smokers, calculated as the proportion of patients who achieved a and 39% of women and 44% of men were current smo- BASDAI50%/20 mm response. kers. Patients with missing smoking status were more often men and were more often treated with golimumab, Statistics in contrast to patients with available smoking information Statistical analyses were performed by SPSS (version (Table 1). 20.0, SPSS Inc., Chicago, Illinois, USA). Demographic At baseline, current smokers had higher BASDAI, and descriptive data are presented by medians/interquar- BASMI and BASFI scores compared with never smokers tile ranges (IQRs). Groups were compared by non- and had higher BASDAI, patient global and pain scores parametric tests (2, KruskalWallis and MannWhitney compared with previous smokers (Table 1). Previous smo- tests). In all tests, P-values <0.05 were considered statis- kers were older and had longer disease duration than cur- tically significant. Calculations were based on observed rent and never smokers. The reasons for stopping TNFi data and no imputation of missing data was performed. treatment were independent of smoking status (Table 1). KaplanMeier plots and log rank tests were performed Male current smokers had significantly higher BASDAI, for analyses of treatment adherence for current, previous BASFI, BASMI and physician global scores and a longer and never smokers. Additional testing was done in order disease duration than male never smokers, whereas age, to ensure that proportionality was present during the ob- CRP, BMI, patient’s pain, fatigue and global scores were servation period (data not shown). We performed univari- similar (data not shown). Female current smokers had sig- ate and multivariate Cox regression analyses to study the nificantly higher BASFI and physician global scores than impact of smoking on treatment adherence and female never smokers, whereas age, BMI, disease

www.rheumatology.oxfordjournals.org 3 Bente Glintborg et al.

TABLE 1 Demographics and patient characteristics

Smoking status

Current Never Previous Current Current versus versus Smoking never previous status P valuea P valueb unknown

Baseline Number, n (%) 614 (39) 578 (37) 233 (15) — — 151 (10) Age, median (IQR), years 41 (3250) 39 (3250) 48 (4057) 0.3 <0.0001 41 (3251) Disease duration, median (IQR), years 4 (112) 2 (010) 9 (119) 0.01 0.003 3 (015) Women, n (%) 161 (26) 192 (33) 57 (24) 0.008 0.6 32 (21)c Body mass index, median (IQR), kg/m2 25 (2329) 26 (2228) 26 (2429) 0.4 0.1 25 (2228) TNFi drug type, n (%) Adalimumab 231 (38) 230 (40) 110 (47) 0.4 0.03 54 (36)c

Etanercept 104 (17) 107 (19) 42 (18) 21 (14) Downloaded from Infliximab 231 (38) 193 (33) 74 (32) 49 (32) Golimumab 48 (8) 48 (8) 7 (3) 27 (17) TNFi start year, n (%) 200004 81 (13) 68 (12) 25 (11) 0.4 0.2 23 (15)c 200509 335 (55) 302 (52) 122 (52) 61 (40)

201013 198 (32) 208 (36) 86 (37) 67 (44) http://rheumatology.oxfordjournals.org/ MTX use, n (%) 171 (28) 149 (26) 50 (31) 0.4 0.06 37 (25) CRP, median (IQR), mg/l 13 (526) 10 (423) 10 (421) 0.07 0.8 13 (623) BASDAI, median (IQR) 61 (4773) 58 (4470) 56 (4169) 0.009 0.002 62 (4471) BASFI, median (IQR) 53 (3569) 46 (3166) 51 (3369) 0.002 0.3 50 (3670) BASMI, median (IQR) 40 (2060) 30 (1050) 40 (2060) <0.0001 0.7 40 (1550) Patient global (0100), median (IQR), mm 69 (5282) 69 (4983) 67 (4679) 0.3 0.04 71 (5284) Patient pain (0100), median (IQR), mm 67 (4978) 65 (4579) 62 (4476) 0.3 0.02 65 (4578) Patient fatigue (0100), median (IQR), mm 69 (5182) 70 (4681) 68 (4677) 0.3 0.07 71 (5684) Physician global (0100), median (IQR), mm 40 (2558) 35 (2249) 38 (2155) 0.001 0.07 33 (2147) Stop reason, n (%)d Lack of efficacy 162 (40) 140 (44) 67 (46) 0.4 0.5 39 (46) Adverse events 117 (29) 77 (24) 38 (26) 21 (25)

Other 117 (29) 88 (28) 40 (27) 24 (29) at Danish Regions on December 1, 2015 Unknown 10 (2) 10 (3) 2 (1) 0 (0) Changes at 3 monthse Change in Patient global, median (IQR), mm 26 (648) 33 (1659) 22 (743) 0.003 0.6 — Change in Patient pain, median (IQR), mm 28 (849) 37 (1355) 22 (746) 0.03 0.4 — Change in Patient fatigue, median (IQR), mm 19 (238) 24 (651) 20 (233) 0.009 1.0 — Change in BASDAI, median (IQR) 23 (741) 29 (1445) 18 (935) 0.004 0.4 — Change in BASFI, median (IQR) 14 (129) 18 (635) 12 (126) 0.005 0.6 — Change in BASMI, median (IQR) 10 (020) 10 (020) 10 (020) 0.9 0.9 —

Baseline demographics, disease activity and reasons for terminating TNFi treatment, according to smoking status at the baseline visit (n = 1576) and changes in disease activity measures between baseline and 3 months’ follow-up. aMannWhitney or 2. bMannWhitney or 2. cSignificantly different (P < 0.05) compared with all patients with known smoking status. dPercentages of patients who have terminated treatment according to smoking status. eChange at three months compared with baseline, shown as decreases. Patients with available data at baseline (percentage/%): smoking (90), age (100), disease duration (89), gender (100), BMI (61), drug type (100), start year (100), MTX use y/n (100), CRP (75), BASDAI (76), BASFI (76), BASMI (65), patient global (69), pain (69), fatigue (58), physicians global (56). IQR: interquartile range; TNFi: TNF-a inhibitor; VAS: Visual Analogue Scale; n: number. duration, patient’s pain, fatigue and global scores, gender, but the results reached statistical significance BASDAI and BASMI were similar (data not shown). mainly in men (Table 2). Among previous smokers, patients who had stopped Treatment adherence smoking during the previous 5 years (n = 106) had similar The total follow-up time was 5983 patient years, with a drug survival to the patients who had stopped 56 years median follow-up time of 2.02 years (IQR 0.695.01). previously (n = 111) (KaplanMeier, log rank P = 0.8). Current and previous smokers had poorer treatment ad- Patients with missing smoking data had similar treatment herence than never smokers (Fig. 1 and Table 2). The ten- adherence to patients with known smoking status (log dency was the same in stratified analyses according to rank, P = 0.6).

4 www.rheumatology.oxfordjournals.org Impact of tobacco smoking in AS

FIG.1Treatment adherence according to smoking sta- There was no statistically significant interaction be- tus—results from KaplanMeier analysis [median (95% CI)] tween smoking and gender or between smoking and TNFi drug type (both P > 0.05 in Cox and logistic regression analyses).

Discussion

In this study of patients with AS who initiated treatment with the first TNFi in a real-life setting, more than half were current or previous smokers. At the start of treatment, current smokers had higher disease activity compared with never and previous smokers. Both current and previous smoking had a negative impact on treatment effectiveness and increased the risk of withdrawing from treatment. These findings are important, since smoking is potentially modifiable. We found that current smokers had significantly higher Downloaded from BASMI, BASDAI and BASFI scores and a trend towards a higher CRP level at the start of TNFi treatment compared with never smokers. The negative impact of smoking on disease activity has previously been described in cross-

sectional studies among patients with AS [9, 1113, 29, http://rheumatology.oxfordjournals.org/ 30]. In an English survey of 612 patients with established AS, smoking was associated with aggravation in patient- reported outcomes, including function, pain and quality of life [9]. Similar results have been reported in patients with Hazard ratios for withdrawal from univariate Cox regres- early axSpA [10]. However, these studies included none or sion analysis: current versus never smokers 1.32 (95% CI only low numbers of TNFi-treated patients [911, 29, 30]. 1.141.53), previous versus never smokers 1.24 The negative impact of smoking may be caused by (1.021.50). n: number. increased systemic inflammation [29, 31]. accelerated radiographic progression [8, 14, 32, 33], decreased functional activity, reduced lung capacity, as well as comor- Treatment adherence was poorer among current vs bidities or socioeconomic challenges [9, 10, 29, 34]. never smokers in patients, regardless of type of Finally, smoking might exacerbate the development of ab- at Danish Regions on December 1, 2015 TNF-inhibitor (Cox regression analyses, Table 3). normal neuromuscular processing and chronic pain due to Previous smokers had poorer treatment adherence than vasoconstriction and psychological sensitivity [9, 35]. never smokers for adalimumab and etanercept (Table 3). The fact that only approximately half of AS patients benefit from treatment with their first TNFi [1, 4, 36, 37] Disease activity and treatment response has fuelled the search for baseline predictors of treatment Measures of disease activity had improved less in current response in individual patients [6]. However, many previ- smokers than in never smokers at 3 months’ follow-up ous observational and randomized studies have not (Table 1). Similar tendencies were observed at 6 months included data on smoking status [5, 6, 38, 39]. We found for patient global, BASDAI and BASFI scores (data not that current smokers had significantly poorer TNFi treat- shown). Both current and previous smokers had lower ment adherence and treatment effect than never smokers. response rates than never smokers (Fig. 2). This is in accordance with a recent Swiss cohort study of Current and previous smokers had significantly lower 698 patients with axSpA, of whom 20% had non-radio- odds of achieving response than never smokers, both graphic axSpA, and in which current smokers had an OR overall and stratified according to gender (Table 4). For of 0.54 (0.31 to 0.95) for achieving BASDAI50% reduction stratified analyses according to TNFi drug type, similar after one year’s treatment compared with never smokers results were found among current versus never smokers [16]. Other studies have found no such association. for all three TNFi and a tendency of lower odds of re- Among 422 Australian TNFi-treated AS patients, smoking sponse in previous smokers (Table 4). had no effect on health-related quality of life [17]. The A sensitivity analysis using multivariate regression authors suggested that their inclusion of educational including all the variables that differed among current vs level in the multivariate analyses partly explained this be- never smokers at baseline (BASDAI, BASFI, BASMI, dis- cause they found significant differences when educational ease duration, VAS physician global) showed similar re- level was omitted from the regression model [17]. In the sults (current vs never smokers, OR = 0.49 (95% CI current study, we had no data on educational level, and 0.320.75, P < 0.001)). When the same covariates were this may have influenced our results. An English cohort adjusted for in the regression analysis as a propensity study based on data from the British Society for score, the results were unaltered (data not shown). Rheumatology Biologics Register (BSRBR) did not find

www.rheumatology.oxfordjournals.org 5 Bente Glintborg et al.

TABLE 2 Impact of smoking on treatment adherence stratified by gender

Overall Men Women

HR (95% CI) P HR (95% CI) P HR (95% CI) P

Univariate Smoking status analyses Current 1.32 (1.14, 1.53) <0.0001 1.41 (1.17, 1.69) <0.0001 1.32 (1.04, 1.70) 0.03 Previous 1.24 (1.02, 1.50) 0.03 1.35 (1.06, 1.71) 0.01 1.18 (0.83, 1.68) 0.4 Never 1 1 1 Multivariate Smoking status analyses Current 1.41 (1.21, 1.65) <0.0001 1.49 (1.23, 1.82) <0.0001 1.21 (0.93, 1.59) 0.15 Previous 1.38 (1.12, 1.65) 0.003 1.39 (1.07, 1.80) 0.01 1.34 (0.93, 1.93) 0.12 Never 1 1 1 Gender Women 1.64 (1.41, 1.91) <0.0001 — —— — Men 1 Disease duration, Downloaded from years 01 1.45 (1.22, 1.73) <0.0001 1.28 (1.04, 1.59) 0.02 1.97 (1.41, 2.74) <0.0001 27 1.34 (1.11, 1.63) 0.003 1.21 (0.96, 1.52) 0.11 1.77 (1.22, 2.57) 0.004 581 1 1 Age, years

431 1.02 (0.82, 1.25) 0.9 0.91 (0.71, 1.19) 0.5 1.23 (0.86, 1.78) 0.3 http://rheumatology.oxfordjournals.org/ 3239 0.86 (0.70, 1.06) 0.17 0.77 (0.59, 1.00) 0.05 1.03 (0.72, 1.46) 0.9 4049 1.08 (0.89, 1.31) 0.4 1.05 (0.84, 1.32) 0.7 1.09 (0.77, 1.55) 0.6 550 1 1 1 TNFi start year 200006 0.70 (0.58, 0.86) <0.0001 0.69 (0.54, 0.88) 0.003 0.79 (0.57, 1.11) 0.18 200709 0.89 (0.74, 1.06) 0.2 0.93 (0.74, 1.17) 0.5 0.86 (0.64, 1.15) 0.3 201013 1 1 1

Univariate and multivariate Cox regression analyses (including a priori confounders). MTX use and TNFi drug type did not alter the HR of smoking by >10% and was not included in the multivariate analyses. HR: hazard ratio for withdrawal; TNFi: TNF-a inhibitor. at Danish Regions on December 1, 2015 that smoking status among the baseline factors predicted by the fact that previous smokers were older and had a BASDAI response in AS patients. However, with only 261 longer disease duration than never smokers—although patients (94 current smokers) that study may have been adjustment for these differences did not alter the associ- insufficiently powered to answer this question [36]. ation. Any potential differences in the effect of modifica- Furthermore, the multivariate analyses included possible tion of smoking across rheumatic diseases remain intermediate variables (CRP, BASDAI and BASFI) between unexplained. However, these diseases have different smoking and outcome. This might have caused overad- age and gender profiles, inflammatory and immune re- justment bias. Any negative effect of smoking on TNFi sponses, and a uniform smoking effect is not necessarily treatment effects may be due to elevated inflammatory to be expected [17]. Furthermore, previous studies in the biologic parameters or increased matrix metalloprotei- general population have shown that smoking increases nase levels, which are also predictive factors [40]. the prevalence of lower back pain and degenerative dis- According to our study and the Swiss results [16], smok- eases of the back [4244], which may contribute to the ing status seems to be an important risk factor, and future negative impact of ever smoking in AS. studies should consider including such data. The strengths of this study are the high external validity In the current study, previous smokers had similar treat- for routine care, owing to the inclusion of an unselected, ment duration and treatment effects to those of current nationwide, large population of patients with AS with long smokers. Previous smokers who had stopped follow-up time and known smoking status in 90% of smoking 56 years prior to TNFi start had similar treatment cases. Base-line characteristics and drug adherence duration to the patients who had stopped smoking in were largely the same in patients with missing and recent years. This indicates a permanent negative known smoking status, which contradicts substantial se- impact of smoking. Contrasting results were found by lection bias. Our study also has limitations. Smoking Ciurea et al. [16] among PsA and RA patients, where pre- status was retrieved cross-sectionally at commencement vious smokers resemble never smokers—especially if of the first TNFi, although smoking status might later smoking cessation happened many years ago [21, 22, change [21]. An obvious misclassification occurs when 41]. The negative effects of previous smoking on outcome previous smokers resume smoking during follow-up. We measures in the current study might partly be explained had no data on duration of smoking or pack-years to

6 www.rheumatology.oxfordjournals.org Impact of tobacco smoking in AS

TABLE 3 Impact of smoking on treatment adherence stratified by TNFi drug type

Treatment adherence, KaplanMeier analyses

Adalimumab Etanercept Infliximab

Median Median Median (95% CI) P (95% CI) P (95% CI) P

Treatment adherencea, Smoking status years Current 2.80 (2.01, 3.59) 0.02 2.29 (0.39, 4.20) 0.009 1.93 (1.19, 2.67) 0.07 Never 5.73 (4.08, 7.38) 7.56 (4.03, 11.08) 3.50 (2.46, 4.53) Multivariate Cox regression analyses

HR (95% CI) P HR (95% CI) P HR (95% CI) P

Multivariate analyses Smoking status Downloaded from Current 1.33 (1.02, 1.74) 0.04 2.09 (1.38, 3.18) <0.001 1.33 (1.05, 1.69) 0.02 Previous 1.41 (1.02, 1.94) 0.04 2.16 (1.24, 3.77) 0.006 1.21 (0.85, 1.73) 0.3 Never 1 1 1 Gender Women 1.79 (1.41, 2.27) <0.000 1.92 (1.28, 2.89) 0.002 1.42 (1.12, 1.81) 0.004

Men 1 1 1 1 http://rheumatology.oxfordjournals.org/ Disease duration, years 01 1.51 (1.12, 2.02) 0.006 1.32 (0.85, 2.04) 0.2 1.42 (1.08, 1.88) 0.01 27 1.43 (1.04, 1.96) 0.03 1.02 (0.60, 1.73) 0.9 1.43 (1.07, 1.91) 0.02 581 1 1 Age, years 431 1.03 (0.73, 1.45) 0.9 1.05 (0.60, 1.85) 0.9 1.07 (0.76, 1.50) 0.7 3239 0.79 (0.56, 1.11) 0.2 1.15 (0.69, 1.94) 0.6 0.90 (0.65, 1.25) 0.5 4049 1.07 (0.78, 1.47) 0.7 0.92 (0.57, 1.48) 0.9 1.14 (0.85, 1.54) 0.4 550 1 1 1 TNFi start year 200006 0.62 (0.42, 0.90) 0.01 0.38 (0.23, 0.64) <0.0001 0.67 (0.47, 0.95) 0.02

200709 0.87 (0.67, 1.13) 0.3 0.66 (0.41, 1.06) 0.09 0.86 (0.61, 1.23) 0.4 at Danish Regions on December 1, 2015 201013 1 1 1

Log rank testsa and multivariate Cox regression analyses (including a priori confounders). MTX use did not alter the HR of smoking by >10% and was not included in the multivariate analyses. HR: hazard ratio for withdrawal; TNFi: TNF-a inhibitor

FIG.2BASDAI50%/20 mm-response rates after 6 months’ treatment according to smoking status for all patients and stratified according to gender

70 % P <0.0001 P =0.001 P =0.001 58 59 60 54 50 42 43 45 45 40 37 31 30

20 10

0 stneitapllA neM nemoW

Current Previous Never

P-values are response rates among current versus never smokers (Chi square).

www.rheumatology.oxfordjournals.org 7 Bente Glintborg et al.

TABLE 4 Impact of smoking on treatment response for all patients, stratified by gender and TNFi drug type

Overall Men Women

OR (95% CI) P OR (95% CI) P OR (95% CI) P

Smoking status Current 0.48 (0.35, 0.65) <0.0001 0.55 (0.38, 0.80) 0.001 0.34 (0.19, 0.62) <0.001 Previous 0.53 (0.35, 0.80) 0.002 0.60 (0.37, 0.97) 0.04 0.40 (0.18, 0.88) 0.02 Never 1 1 1 Adalimumab Etanercept Infliximab

OR (95% CI) P OR (95% CI) P OR (95% CI) P

Smoking status Current 0.45 (0.27, 0.76) 0.002 0.24 (0.10, 0.61) 0.003 0.57 (0.34, 0.95) 0.03 Previous 0.58 (0.31, 1.10) 0.1 0.29 (0.10, 0.91) 0.03 0.58 (0.29, 1.14) 0.11 Downloaded from Never 1 1 1

Multivariate logistic regression analyses including a priori confounders (odds ratios for confounders not shown in table). MTX use did not alter the HR of smoking by >10% and was not included in the analyses. OR: odds ratio; TNFi: TNF-a inhibitor.

illustrate any doseresponse relationship [9, 15]. In from MSD. All other authors have declared no http://rheumatology.oxfordjournals.org/ Denmark, heavy smokers are more often men [45, 46]. conflicts of interest. One might assume that the stronger impact of smoking among male patients was associated with greater exposure to tobacco. Smoking may be linked to comorbid disease, depression, socioeconomic factors and lifestyle, References which all potentially affect baseline disease activity and 1 Glintborg B, Ostergaard M, Krogh NS et al. Predictors of treatment outcomes. We had no data with which to ex- treatment response and drug continuation in 842 patients plore these issues further. In DANBIO, the clinical diagno- with ankylosing spondylitis treated with anti-tumour ne- sis for individual patients was registered according to the crosis factor: results from 8 years’ surveillance in the expert opinion of the treating physician. Currently, data Danish nationwide DANBIO registry. Ann Rheum Dis 2010;69:20028. regarding HLAB27 status, radiographic data and periph- at Danish Regions on December 1, 2015 eral joint disease are not uniformly available in DANBIO. In 2 Ren L, Li J, Luo R et al. Efficacy of antitumor necrosis conclusion, this study of AS patients treated with TNFi in factor(alpha) agents on patients with ankylosing spondyl- clinical practice showed that current and previous smo- itis. Am J Med Sci 2013;346:45561. kers had significantly poorer patient-reported outcomes at 3 Escalas C, Trijau S, Dougados M. Evaluation of the treat- baseline, shorter treatment adherence and poorer treatment effect of NSAIDs/TNF blockers according to different ment response compared with never smokers. domains in ankylosing spondylitis: results of a meta- analysis. Rheumatology 2010;49:131725. 4 Machado MA, Barbosa MM, Almeida AM et al. Treatment Acknowledgements of ankylosing spondylitis with TNF blockers: a meta- analysis. Rheumatol Int 2013;33:2199213. We should like to thank all the Departments of 5 Vastesaeger N, van der Heijde D, Inman RD et al. Rheumatology in Denmark for reporting to the DANBIO Predicting the outcome of ankylosing spondylitis therapy. registry. Ann Rheum Dis 2011;70:97381. Funding: No specific funding was received from any fund- 6 Arends S, van der Veer E, Kallenberg CG, Brouwer E, ing bodies in the public, commercial or not-for-profit sec- Spoorenberg A. Baseline predictors of response to TNF- alpha blocking therapy in ankylosing spondylitis. Curr tors to carry out the work described in this article. Opin Rheumatol 2012;24:2908. Disclosure statement: C.R. has received a grant for re- 7 Arends S, Brouwer E, van der Veer E et al. Baseline pre- search from Abbvie and Pfizer. M.H.-F. has received con- dictors of response and discontinuation of tumor necrosis sulting fees from Abbvie, speaking fees from UCB and factor-alpha blocking therapy in ankylosing spondylitis: a MSD and is an investigator for Roche. T.L. is a consultant prospective longitudinal observational cohort study. for Roche and Pfizer. G.K. has received speaking fees Arthritis Res Ther 2011;13:R94. from MSD. A.G.R.L. is a consultant for AbbVie, MSD 8 Braun J, Sieper J, Zink A. The risks of smoking in patients and Novartis, a member of speakers’ bureau for AbbVie, with spondyloarthritides. Ann Rheum Dis 2012;71:7912. MSD, Pfizer and UCB and a shareholder/stock ownership 9 Mattey DL, Dawson SR, Healey EL, Packham JC. of Novo Nordisk A/S. L.D. has received speaking fees Relationship between smoking and patient-reported

8 www.rheumatology.oxfordjournals.org Impact of tobacco smoking in AS

measures of disease outcome in ankylosing spondylitis. results from the DANBIO registry. Ann Rheum Dis J Rheumatol 2011;38:260815. 2015;74:21306. 10 Chung HY, Machado P, van der Heijde D, D’Agostino MA, 23 Fagerli KM, Lie E, van der Heijde D et al. The role of Dougados M. Smokers in early axial spondyloarthritis methotrexate co-medication in TNF-inhibitor treatment in have earlier disease onset, more disease activity, inflam- patients with psoriatic arthritis: results from 440 patients mation and damage, and poorer function and health- included in the NOR-DMARD study. Ann Rheum Dis related quality of life: results from the DESIR cohort. Ann 2014;73:1327. Rheum Dis 2012;71:80916. 24 Danish Rheumatological Database. https://danbio-online. 11 Reed MD, Dharmage S, Boers A et al. Ankylosing spon- dk (November 2015, last accessed). dylitis: an Australian experience. Intern Med J 25 Hetland ML. DANBIO—powerful research database and 2008;38:3217. electronic patient record. Rheumatology 2011;50:6977. 12 Chen CH, Chen HA, Lu CL et al. Association of cigarette 26 Hetland ML, Unkerskov J, Ravn T et al. Routine database smoking with Chinese ankylosing spondylitis patients in registration of biological therapy increases the reporting of Taiwan: a poor disease outcome in systemic inflammation, adverse events twentyfold in clinical practice. First results functional ability, and physical mobility. Clin Rheumatol from the Danish Database (DANBIO). Scand J Rheumatol 2013;32:65963. 2005;34:404. Downloaded from 13 Averns HL, Oxtoby J, Taylor HG et al. Smoking and out- 27 Anderson JJ, Baron G, van der Heijde D, Felson DT, come in ankylosing spondylitis. Scand J Rheumatol Dougados M. Ankylosing spondylitis assessment group 1996;25:13842. preliminary definition of short-term improvement in anky- 14 Poddubnyy D, Haibel H, Listing J et al. Baseline radio- losing spondylitis. Arthritis Rheum 2001;44:187686. graphic damage, elevated acute-phase reactant levels, 28 Braun J, Davis J, Dougados M et al. First update of the and cigarette smoking status predict spinal radiographic international ASAS consensus statement for the use of http://rheumatology.oxfordjournals.org/ progression in early axial spondylarthritis. Arthritis Rheum anti-TNF agents in patients with ankylosing spondylitis. 2012;64:138898. Ann Rheum Dis 2006;65:31620. 15 Poddubnyy D, Haibel H, Listing J et al. Cigarette smoking 29 Kaan U, Ferda O. Evaluation of clinical activity and func- has a dose-dependent impact on progression of structural tional impairment in smokers with ankylosing spondylitis. damage in the spine in patients with axial spondyloarthri- Rheumatol Int 2005;25:35760. tis: results from the GErman SPondyloarthritis Inception Cohort (GESPIC). Ann Rheum Dis 2013;72:14302. 30 Bodur H, Ataman S, Rezvani A et al. Quality of life and related variables in patients with ankylosing spondylitis. 16 Ciurea A, Scherer A, Weber U et al. Impaired response to Qual Life Res 2011;20:5439. treatment with tumour necrosis factor alpha inhibitors in smokers with axial spondyloarthritis. Ann Rheum Dis 31 Colombo G, Clerici M, Giustarini D et al. Pathophysiology 2015; Advance Access published 9 February 2015, doi: of tobacco smoke exposure: recent insights from com- 10.1136/annrheumdis-2013-205133. parative and redox proteomics. Mass Spectrom Rev 2014;33:183218. at Danish Regions on December 1, 2015 17 Kydd AS, Chen JS, Makovey J et al. Smoking did not modify the effects of anti-TNF treatment on health-related 32 Ward MM, Weisman MH, Davis JC Jr, Reveille JD. Risk quality of life among Australian ankylosing spondylitis factors for functional limitations in patients with long- patients. Rheumatology 2015;54:3107. standing ankylosing spondylitis. Arthritis Rheum 2005;53:7107. 18 Hyrich KL, Watson KD, Silman AJ, Symmons DP. Predictors of response to anti-TNF-alpha therapy among 33 Ward MM, Hendrey MR, Malley JD et al. Clinical and patients with rheumatoid arthritis: results from the British immunogenetic prognostic factors for radiographic se- Society for Rheumatology Biologics Register. verity in ankylosing spondylitis. Arthritis Rheum Rheumatology 2006;45:155865. 2009;61:85966. 19 Abhishek A, Butt S, Gadsby K, Zhang W, Deighton CM. 34 Cavelaars AE, Kunst AE, Geurts JJ et al. Educational dif- Anti-TNF-alpha agents are less effective for the treatment ferences in smoking: international comparison. BMJ of rheumatoid arthritis in current smokers. J Clin 2000;320:11027. Rheumatol 2010;16:158. 35 Mitchell MD, Mannino DM, Steinke DT et al. Association of 20 Soderlin MK, Petersson IF, Geborek P. The effect of smoking and chronic pain syndromes in Kentucky women. smoking on response and drug survival in rheumatoid J Pain 2011;12:8929. arthritis patients treated with their first anti-TNF drug. 36 Lord PA, Farragher TM, Lunt M et al. Predictors of re- Scand J Rheumatol 2012;41:19. sponse to anti-TNF therapy in ankylosing spondylitis: re- 21 Saevarsdottir S, Wedren S, Seddighzadeh M et al. sults from the British Society for Rheumatology Biologics Patients with early rheumatoid arthritis who smoke are Register. Rheumatology 2010;49:56370. less likely to respond to treatment with methotrexate and 37 Braun J, Baraliakos X, Heldmann F, Kiltz U. Tumor ne- tumor necrosis factor inhibitors: observations from the crosis factor alpha antagonists in the treatment of axial Epidemiological Investigation of Rheumatoid Arthritis and spondyloarthritis. Expert Opin Investig Drugs the Swedish Rheumatology Register cohorts. Arthritis 2014;23:64759. 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www.rheumatology.oxfordjournals.org 9 Bente Glintborg et al.

39 Davis JC Jr, van der Heijde DM, Dougados M et al. 43 Kepler CK, Ponnappan RK, Tannoury CA, Risbud MV, Baseline factors that influence ASAS 20 response in pa- Anderson DG. The molecular basis of intervertebral disc tients with ankylosing spondylitis treated with etanercept. degeneration. Spine J 2013;13:31830. J Rheumatol 2005;32:17514. 44 Kauppila LI. Atherosclerosis and disc degeneration/low- 40 Wendling D, Prati C. Spondyloarthritis and smoking: to- back paina systematic review. Eur J Vasc Endovasc Surg wards a new insight into the disease. Expert Rev Clin 2009;37:66170. Immunol 2013;9:5116. 45 Danskernes rygevaner 2012. Tabelrapport for hele 41 Manfredsdottir VF, Vikingsdottir T, Jonsson T et al.The befolkningen. Danish Health and Medicines Authority. effects of tobacco smoking and rheumatoid factor https://sundhedsstyrelsen.dk/da/sundhed/tobak/tal-og- seropositivity on disease activity and joint damage in undersoegelser/danskernes-rygevaner//media/29DD77 early rheumatoid arthritis. Rheumatology B5D497489F99D75F1AC757862E.ashx (November 2015, 2006;45:73440. last accessed). 42 Shiri R, Karppinen J, Leino-Arjas P, Solovieva S, 46 Berner O, Etwil P, Graversen T et al.50a˚ rs Viikari-Juntura E. The association between smoking oversigten. Danmarks statistik. https://www.dst.dk/ and low back pain: a meta-analysis. Am J Med Site/Dst/Udgivelser/GetPubFile.aspx?id=3189&sid= 2010;123:8735. halvtres (November 2015, last accessed). Downloaded from http://rheumatology.oxfordjournals.org/ at Danish Regions on December 1, 2015

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Bente Glintborg, Inge J. Sørensen, Mikkel Østergaard, Lene Dreyer, Abdiweli A. Mohamoud, Niels S. Krogh, Oliver Hendricks, Lis S. Andersen, Johnny L. Raun, Marcin R. Kowalski, Laura Danielsen, Randi Pelck, Henrik Nordin, Jens K. Pedersen, Dorte G.A. Kraus, Susan R. Christensen, Inger M.J. Hansen, Jakob Esbesen, Annette Schlemmer, Anne G. Loft, Nabil al Chaer, Lone Salomonsen, and Merete L. Hetland ABSTRACT. Objective. To compare baseline disease activity and treatment effectiveness in biologic-naive patients with nonradiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) who initiate tumor necrosis factor inhibitor (TNFi) treatment and to study the role of potential confounders (e.g., HLA-B27 status). Methods. Observational cohort study based on prospectively registered data in the nationwide DANBIO registry. We used Kaplan-Meier plots, Cox, and logistic regression analyses to study the effect of diagnosis (nr-axSpA vs AS) and potential confounders (sex/age/start yr/HLA-B27/disease duration/TNFi-type/smoking/baseline disease activity) on TNFi adherence and response [e.g., Bath Ankylosing Spondylitis Activity Index (BASDAI) 50%/20 mm]. Results. The study included 1250 TNFi-naive patients with axSpA (29% nr-axSpA, 50% AS, 21% lacked radiographs of sacroiliac joints). Patients with nr-axSpA were more frequently women (50%/27%) and HLA-B27–negative (85/338 = 25%), compared to AS (81/476 = 17%; p < 0.01). At TNFi start patients with nr-axSpA had higher visual analog scale scores [median (quartiles)] for pain: 72 mm (55–84)/65 mm (48–77); global: 76 mm (62–88)/68 mm (50–80); fatigue: 74 mm (55–85)/67 mm (50–80); and BASDAI: 64 (54–77)/59 (46–71); all p < 0.01. However, patients with nr-axSpA had lower C-reactive protein: 7 mg/l (3–17)/11 mg/l (5–22); and BAS Metrology Index: 20 (10–40)/40 (20–50); all p < 0.01. Median (95% CI) treatment adherence was poorer in nr-axSpA than in AS: 1.59 years (1.15–2.02) versus 3.67 years (2.86–4.49), p < 0.0001; but only in univariate and not confounder- adjusted analyses (p > 0.05). Response rates were similar in AS and nr-axSpA (p > 0.05). HLA-B27 negativity was associated with poorer treatment adherence [HLA-B27 negative/positive, nr-axSpA: HR 1.74 (1.29–2.36), AS: HR 2.04 (1.53–2.71), both p < 0.0001]; and lower response rates (nr-axSpA: 18/61 = 30% vs 93/168 = 55%; AS: 17/59 = 29% vs 157/291 = 54%, both p < 0.05). Conclusion. In this nationwide cohort, patients with nr-axSpA had higher subjective disease activity at start of first TNFi treatment, but similar outcomes to patients with AS after confounder adjustment. HLA-B27 positivity was associated with better outcomes irrespective of axSpA subdiagnosis. (J Rheumatol First Release December 1 2016; doi:10.3899/jrheum.160958)

Key Indexing Terms: AXIAL SPONDYLOARTHRITIS TUMOR NECROSIS FACTOR-Α OUTCOME REGISTRY

From the DANBIO registry and Copenhagen Center for Arthritis Research Rheumatology, Horsens Hospital, Horsens; Department of Rheumatology, (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Zealand University Hospital, Køge; Center for Rheumatology and Spine Head and Orthopedics, Rigshospitalet, Glostrup; Department of Diseases, Centre of Head and Orthopedics, Rigshospitalet, Blegdamsvej; Rheumatology, Herlev and Gentofte University Hospital, Copenhagen; Department of Rheumatology, Odense University Hospital (OUH), Department of Clinical Medicine, Faculty of Health and Medical Odense; Department of Rheumatology, Silkeborg Hospital, Silkeborg; Sciences, University of Copenhagen, Copenhagen; Zitelab, Copenhagen; Department of Rheumatology, OUH, Svendborg Hospital, Odense; Kong Christian X’s Gigthospital, Gråsten; The Parker Institute, Department of Rheumatology, Vejle Hospital, Vejle; Department of Bispebjerg and Frederiksberg; Department of Internal Medicine, Rønne Rheumatology, Aalborg University Hospital, Aalborg; Department of Hospital, Rønne; Department of Rheumatology, Sygehus Lillebælt, Rheumatology, Aarhus University Hospital, Aarhus; Department of Fredericia; North Denmark Regional Hospital, Hjørring; Department of Rheumatology, Slagelse Hospital, Slagelse, Denmark.

Glintborg, et al: TNFi treatment in axSpA 1 Downloaded from www.jrheum.org on December 20, 2016 - Published by The Journal of Rheumatology Dr. Glintborg has received research support from AbbVie. Dr. Hetland has on objective signs of inflammation, e.g., increased C-reactive received research support from AbbVie, BMS, MSD, Pfizer, Roche, and UCB. Dr. Hansen has received research support from Roche. protein (CRP) level and/or active inflammation on 5,14,15,16,17 B. Glintborg, MD, PhD, The DANBIO registry, COPECARE, Center for MRI . Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Few previous observational studies have compared TNFi Rigshospitalet, Glostrup, and Department of Rheumatology, Gentofte and treatment outcomes among patients with nr-axSpA versus Herlev University Hospital; I.J. Sørensen, MD, PhD, COPECARE, Center 9,18,19 for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, AS . These studies included < 100 patients with 18,19 18,19 Rigshospitalet, Glostrup, and Department of Clinical Medicine, Faculty of nr-axSpA , were not nationwide , did not include data Health and Medical Sciences, University of Copenhagen; M. Østergaard, on longterm outcomes or treatment duration9, reported results MD, PhD, Dr. Med. Sci., Professor, COPECARE, Center for 19 Rheumatology and Spine Diseases, Centre of Head and Orthopedics, only from univariate analyses , or did not include in multi- Rigshospitalet, Glostrup, and Department of Clinical Medicine, Faculty of variate analyses data on relevant potential confounders, e.g., Health and Medical Sciences, University of Copenhagen; L. Dreyer, MD, HLA-B27 status, smoking status, or year of starting TNFi9,18. PhD, Department of Rheumatology, Gentofte and Herlev University Hospital, and The Parker Institute; A.A. Mohamoud, MD, COPECARE, The primary aim of our present study was to compare Center for Rheumatology and Spine Diseases, Centre of Head and baseline disease activity and treatment effectiveness by Orthopedics, Rigshospitalet, Glostrup; N.S. Krogh, MS, Zitelab; univariate and confounder-adjusted analyses in a large cohort O. Hendricks, MD, Kong Christian X’s Gigthospital; L.S. Andersen, MD, PhD, Department of Internal Medicine, Rønne Hospital; J.L. Raun, MD, of biologic-naive patients with AS versus nr-axSpA, who Department of Rheumatology, Sygehus Lillebælt; M.R. Kowalski, MD, initiated TNFi treatment in clinical practice. Secondarily, our PhD, North Denmark Regional Hospital; L. Danielsen, MD, Department aim was to explore the effect of potential confounders, e.g., of Rheumatology, Horsens Hospital; R. Pelck, MD, Department of Rheumatology, Zealand University Hospital; H. Nordin, MD, Center for HLA-B27 status and CRP. Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Blegdamsvej; J.K. Pedersen, MD, PhD, Department of MATERIALS AND METHODS Rheumatology, Odense University Hospital; D.G. Kraus, MD, Department The DANBIO quality registry was initiated in 2000 and covers > 90% of of Rheumatology, Silkeborg Hospital; S.R. Christensen, MD, Department Danish adults with rheumatic diseases treated in routine care with biologic of Rheumatology, Silkeborg Hospital; I.M. Hansen, MD, Dr. Med. Sci., 20 Associate Professor, Department of Rheumatology, OUH, Svendborg disease-modifying antirheumatic drugs (DMARD) . In accordance with Hospital; J. Esbesen, MD, Department of Rheumatology, Vejle Hospital; national treatment guidelines and quality indicators, patients are monitored A. Schlemmer, MD, MLP, Department of Rheumatology, Aalborg prospectively by online registrations (www.danbio-online.dk) of disease University Hospital; A.G. Loft, MD, Dr. Med. Sci., Associate Professor, activity and outcomes at least biannually and when medication is Department of Rheumatology, Aarhus University Hospital; N. al Chaer, changed20,21. According to Danish legislation, registration and publication MD, Department of Rheumatology, Slagelse Hospital; L. Salomonsen, of data from clinical registries do not require patient consent or approval by MD, Department of Rheumatology, Aarhus University Hospital; M.L. ethics committees. Hetland, MD, PhD, Dr. Med. Sci., Professor, The DANBIO registry and Baseline demographics include smoking habits, age, sex, body mass COPECARE, Center for Rheumatology and Spine Diseases, Centre of index, disease duration, and current treatment with conventional synthetic Head and Orthopedics, Rigshospitalet, Glostrup, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of DMARD. Disease activity and functional status are monitored by serum Copenhagen. CRP level (normal range ≤ 10 mg/l); visual analog scales (VAS) for patient’s global assessment (PtGA), pain, fatigue, and physician’s global assessment Address correspondence to Dr. B. Glintborg, Gentofte University Hospital, Department of Rheumatology, Niels Andersensvej 65, Hellerup 2900, (PGA); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); Denmark. E-mail: [email protected] Bath Ankylosing Spondylitis Function Index (BASFI); and Bath Ankylosing Spondylitis Metrology Index (BASMI). Registration of classification criteria Accepted for publication October 21, 2016. (ASAS classification criteria, modified New York criteria) is optional and only available in a subset of patients. The disease spectrum of axial spondyloarthritis (axSpA) All TNFi-naive patients were identified in DANBIO if they had initiated includes patients with radiographic axSpA (ankylosing treatment with a biological drug between January 1 2005, and July 1, 2014, spondylitis, AS), who fulfill the modified New York criteria, and had one of the International Classification of Diseases–10 diagnoses of and patients with nonradiographic axSpA (nr-axSpA)1,2,3. AS (M45.9), sacroiliitis (M46.1), or inflammatory spondylopathy (M46.8, M46.9). All Danish departments of rheumatology were invited to participate Since the introduction of the Assessment of Spondylo - in the study and to enter data regarding which classification criteria individual arthritis international Society (ASAS) classification criteria patients fulfilled upon start of their first biological drug. The additional data aiming to identify patients with axSpA at earlier disease were collected from patient files [laboratory results (CRP, HLA-B27), patient stages, it has been discussed how patients with nr-axSpA history, objective examinations] and radiographic data. No second reading of differ from patients with AS4,5. Only a minority of patients radiographs or MRI was performed and no additional prospective laboratory testing or examinations were made. Thus, patients were classified as having with nr-axSpA develops radiographic changes and AS within 2 6,7 axSpA if they fulfilled the ASAS criteria upon TNFi start . According to 10 years of followup . Further, patients with nr-axSpA are available radiology descriptions of radiographs of the sacroiliac (SI) joints more frequently women with a lower grade of spinal inflam- (sacroiliitis grade, uni- or bilaterally)3, patients were classified as having AS mation on spinal and sacroiliac magnetic resonance imaging or nr-axSpA. Patients with no available SI joint radiographs at treatment start (MRI)8,9, and other studies have demonstrated similar levels were classified as “unspecified axSpA” (Figure 1). of pain and disability among patients with nr-axSpA and Treatment adherence. Treatment adherence was calculated as the number of AS9,10,11. days each patient maintained treatment. Start date was the date of the first given dose and stop date was the date of the first missed dose. Temporary The beneficial effect of tumor necrosis factor inhibitors treatment interruptions (e.g., infections, surgery) of ≤ 3 months were (TNFi) on treatment outcomes is well established in allowed. All observations were censored by August 15, 2015. 10,12,13 AS . In nr-axSpA, the effect of TNFi seems to depend Reasons for drug discontinuation are registered in DANBIO in prespec-

2 The Journal of Rheumatology 2017; 44:1; doi:10.3899/jrheum.160958 Downloaded from www.jrheum.org on December 20, 2016 - Published by The Journal of Rheumatology Figure 1. Patient disposition, inclusion and exclusion. * 238/266 patients (89%) with unspecified axSpA had inflammation on magnetic resonance images of the SI joints. DANBIO: DANBIO registry of rheumatic diseases; TNFi: tumor necrosis factor inhibitor; mNYC: modified New York criteria; ASAS: Assessment of Spondyloarthritis international Society; SI: sacroiliac; axSpA: axial spondyloarthritis; AS: ankylosing spondylitis; nr-axSpA: nonradiographic axSpA. ified categories: lack of effect, adverse events, disease remission, pregnancy, analysis. If a patient had no registrations within a given time window, data surgery, cancer, death, infection, loss to followup, and other reasons. In our were registered as missing for that visit. Clinical and laboratory outcome study, reasons for discontinuation were categorized into adverse events measures included BASDAI, BASFI, BASMI, PtGA, fatigue, pain, PGA, (including infection, death, or cancer), lack of effect, and other (pregnancy, and CRP. surgery, loss to followup, remission, other, several reasons for discontinuation). Clinical response was defined as achievement of either a 50% or a 22,23 Treatment response. Disease activity was evaluated at baseline and after 3 20-mm reduction in BASDAI (BASDAI 50%/20-mm response) . and 6 months of therapy. The baseline visit was defined as a visit within the Arbitrarily, we classified patients as responders if they achieved clinical time frame that ranged from 60 days before until 6 days after initiation of response (yes/no) at both the 3- and 6-month visits compared with baseline. TNFi treatment. For the 3-month visit, the time frame was between 10 and In the case of missing data at either of those visits, 1 registration of clinical 17 weeks, and for the 6-month visit, 18–32 weeks after treatment start. If response was sufficient to classify the patient as a responder. Patients who more than 1 registration occurred within a given time frame for an individual stopped treatment within the first 3 months of therapy were considered patient, the registration closest to the given timepoint was selected for nonresponders (n = 74). Response rates were calculated as the proportion of

Glintborg, et al: TNFi treatment in axSpA 3 Downloaded from www.jrheum.org on December 20, 2016 - Published by The Journal of Rheumatology patients who achieved BASDAI 50%/20-mm response. As secondary frequently of dactylitis (Table 1). Patients with AS more often outcomes, ASAS response criteria for 40% improvement in disease activity started treatment before 2008 and were more frequently (ASAS 40) and ASAS criteria for partial remission were calculated23,24. Since November 2010, the ASAS Disease Activity Score (ASDAS) has treated with IFX, had higher CRP and BASMI but lower been registered in DANBIO. Among patients with available data, we calcu- global, fatigue, and pain scores and lower BASDAI lated the proportion of patients who achieved inactive disease (ASDAS compared to patients with nr-axSpA (Table 1). Patients with < 1.3) at the 3- or 6-month visit (similar to the algorithm described for unspecified axSpA more frequently started treatment after BASDAI 50%/20 mm response). Similarly, the proportion of patients with 2008 compared to patients with AS or nr-axSpA, and fewer clinically important improvement in ASDAS (change of ≥ 1.1 between baseline and 3- or 6-month visit) was calculated25. were HLA-B27–positive (both p < 0.05). Statistics. Statistical analyses were performed by SPSS (version 20.0, SPSS Treatment adherence, AS versus nr-axSpA. The cumulated Inc.). Demographic and descriptive data are presented by medians followup time was 3359 patient-years (median followup [interquartile ranges (IQR)]. Groups were compared by nonparametric tests time: 2.5 yrs; 95% CI 2.01–3.00). Patients with nr-axSpA had (chi-square, Kruskal-Wallis, and Mann-Whitney U tests). P values < 0.05 were considered statistically significant. poorer treatment adherence than patients with AS [median Kaplan-Meier plots and log rank tests were performed for analyses of treatment duration, AS: 3.67 (2.86–4.49), nr-axSpA: 1.59 treatment adherence stratified by diagnosis (nr-axSpA/AS/unspecified (1.15–2.02); p < 0.0001]. However, this was found only in axSpA). We performed univariate and multivariate Cox regression analyses univariate (Figure 2A) but not in multivariate analysis (Table to study the effect of diagnosis on treatment adherence and calculated HR 2). Men had longer treatment adherence than women in both for treatment discontinuation. The following baseline factors were included as potential confounders a priori: age, sex, disease duration (since diagnosis AS and nr-axSpA (not shown). The treatment adherence was of axSpA), calendar year of starting TNFi (2005–2008/2009–2011/ similar among patients with nr-axSpA who fulfilled the 2012–2014), TNFi drug [adalimumab/etanercept/infliximab (IFX)/golimu - imaging classification criteria versus the clinical criteria [1.59 mab/certolizumab pegol], methotrexate use (yes/no), HLA-B27 status yrs (1.16–2.01) vs 1.33 yrs (0.0–3.27), p = 0.5]. (positive/ negative), CRP (≤ 10 mg/l/> 10 mg/l), smoking status (current/ Patients with nr-axSpA more often stopped treatment previous/never), BASDAI, and BASMI. Because PtGA, fatigue, pain and ρ because of lack of effect compared to AS (Supplementary BASFI strongly correlated with BASDAI (Spearman’s = 0.69–0.73, p < 0.01), only BASDAI was included. The variables that by univariate analysis Table 1, available with the online version of this article). gained p < 0.1 were included in the multivariate model and stepwise backward Response rates, AS versus nr-axSpA. Changes in disease selection was conducted, leaving only statistically significant variables in the activity at the 3-month followup were similar among patients model. Age, sex, and the interaction terms HLA-B27*sex and diagnosis*sex remained in the model irrespective of p value. with nr-axSpA and AS for most scores but not for BASMI Response rates were reported by percentages. The numbers needed to (Supplementary Table 2, available with the online version of treat (NNT) to achieve response were calculated as the reciprocal values of this article). Treatment responses were similar among patients the response rates. with AS and nr-axSpA (Figure 3A). All primary analyses were based on observed data without imputation of missing data. For the multivariate analysis, the following sensitivity Treatment adherence and response rates, effect of HLA-B27. analyses were performed: (1) multiple imputation of missing data (SPSS, 5 HLA-B27–positive patients stayed on treatment longer than imputation steps)26; (2) exclusion of patients with nr-axSpA diagnosed HLA-B27–negative patients (Table 2). The same was true according to the clinical arm of the classification criteria (n = 70; Figure 1); when stratified according to axSpA subgroup (univariate and (3) classification of all patients with unspecified axSpA as either AS or nr-axSpA. comparisons; log rank, Mantel-Cox test, both p < 0.0001; Figure 2B). Similar results were found in the sensitivity RESULTS analyses. Study population. Among 2462 biologic-naive patients with HLA-B27–positive patients, regardless of diagnosis, had axSpA registered in DANBIO with a relevant diagnosis who significantly higher response rates compared to HLA-B27– initiated TNFi treatment between January 1, 2005, and July negative patients (Figure 3B). NNT to achieve BASDAI 1, 2014 (Figure 1), the diagnosis was validated retrospec- 50%/20 mm response was 2 for patients with AS who were tively in 1336. Most of the patients who did not have the HLA-B27–positive versus NNT = 4 for patients with AS who diagnosis validated came from departments that did not were HLA-B27–negative; similar values were found in participate in the study. A total of 1250 patients (93%) nr-axSpA. fulfilled the ASAS criteria for axSpA and were included Treatment adherence and response rates, effect of increased (Figure 1). Of these, 622 patients fulfilled the classification CRP at baseline. At baseline, 51% (238/469) of patients with criteria for AS, 362 for nr-axSpA, and 266 patients had AS and 39% (113/290) of patients with nr-axSpA had unspecified axSpA. Withdrawal analysis showed that the increased CRP (> 10 mg/l). Treatment adherence lasted included and excluded patients had similar sex and age distri- longer among patients with increased CRP (Table 2), but bution (p > 0.05, not shown). mainly in AS (Supplementary Figure, available online at Characteristics at baseline. Patients with AS had longer jrheum.org). In contrast, BASDAI 50%/20 mm response disease duration, were older, more frequently men, and rates were higher among patients with CRP > 10 mg/l in both HLA-B27–positive compared to patients with nr-axSpA, and AS and nr-axSpA [AS: 58% (118/204) vs 39% (76/196); they more frequently had a history of uveitis but less nr-axSpA: 60% (52/87) vs 41% (55/134), both p < 0.005].

4 The Journal of Rheumatology 2017; 44:1; doi:10.3899/jrheum.160958 Downloaded from www.jrheum.org on December 20, 2016 - Published by The Journal of Rheumatology Table 1. Baseline demographics according to classification criteria at baseline (start of the first TNFi treatment course) for nr-axSpA, AS, and unspecified axSpA. Data are medians (interquartile ranges) unless otherwise stated.

No. Pts. with All Pts. Nr-axSpA AS Unspecified AxSpA# p* Available Data, n

N 1250 362 622 266 Age, yrs 1250 40 (31–49) 38 (30–46) 42 (33–52) 38 (29–46) < 0.001 Male, n (%) 1250 792 (63) 183 (51) 455 (73) 154 (58) < 0.0001 HLA-B27–positive, n (%) 1045 811 (65) 253 (70) 395 (83) 163 (61) 0.005 BMI, kg/cm2 728 25 (23–29) 25 (22–30) 26 (23–29) 24 (23–28) 0.4 MTX, yes, n (%) 1250 222 (18) 59 (16) 129 (21) 34 (13) 0.09 Manifestations ever, n (%) Inflammatory back pain 1177 1131 (91) 326 (90) 562 (90) 243 (91) 0.07 Family disposition 885 199 (16) 67 (19) 98 (16) 34 (13) 0.9 Peripheral arthritis 1119 441 (35) 146 (40) 190 (31) 105 (39) 0.05 Enthesitis 909 218 (17) 72 (20) 95 (15) 51 (19) 0.5 Uveitis 1042 249 (20) 67 (19) 145 (23) 37 (14) 0.02 Psoriasis 1018 75 (6) 31 (9) 35 (6) 9 (3) 0.2 Dactylitis 871 40 (3) 21 (6) 9 (1) 10 (4) < 0.0001 IBD 1031 104 (8) 31 (9) 42 (7) 31 (12) 0.5 NSAID response 876 614 (49) 179 (49) 310 (49) 125 (47) 0.9 Elevated CRP 1093 575 (46) 164 (45) 307 (49) 104 (39) 0.003 Symptom duration, yrs 1040 9 (3–18) 6 (3–13) 13 (6–23) 5 (2–11) < 0.0001 Disease duration, yrs 1155 1 (0–6) 1 (0–3) 3 (1–12) 1 (0–3) < 0.0001 Smoking status, n (%) 976 Current 377(30) 97 (27) 216 (41) 64 (24) Previous 177 (14) 42 (12) 103 (20) 32 (12) 0.2 Never 422 (33) 119 (33) 204 (39) 99 (37) First TNFi drug, n (%) 1250 Adalimumab 519 (41) 151 (42) 258 (41) 110 (41) < 0.0001 Certolizumab pegol 8 (1) 5 (1) 2 (0) 1 (0) Etanercept 183 (15) 53 (14) 100 (16) 30 (11) Golimumab 246 (20) 85 (23) 88 (14) 73 (27) Infliximab 294 (24) 68 (19) 174 (28) 52 (20) First TNFi start yr, n (%) 1250 2005–2008 376 (30) 79 (21) 259 (41) 38 (14) < 0.0001 2009–2011 442 (35) 132 (36) 194 (31) 116 (45) 2012–2014 432 (34) 151 (41) 169 (27) 112 (42) CRP, mg/l 964 9 (3–20) 7 (3–17) 11 (5–22) 6 (2–16) < 0.0001 BASDAI, mm 1012 61 (49–73) 64 (54–77) 59 (46–71 63 (51–74) < 0.0001 BASDAI, question 5, mm 783 73 (52–86) 75 (55–91) 71 (51–84) 74 (54–86) 0.02 BASDAI, question 6, mm 785 60 (36–86) 68 (39–90) 56 (32–83) 59 (39–86) 0.02 BASFI, mm 980 50 (34–68) 52 (33–69) 49 (34–67) 51 (31–67) 0.7 PGA, mm 676 37 (22–51) 38 (22–53) 38 (22–53) 35 (22–45) 0.6 BASMI 848 30 (10–40) 20 (10–40) 40 (20–50) 20 (10–40) < 0.0001 PtGA, mm 938 72 (53–85) 76 (62–88) 68 (50–80) 74 (59–88) < 0.0001 Pain, mm 937 67 (50–80) 72 (55–84) 65 (48–77) 68 (50–81) < 0.0001 Fatigue, mm 846 70 (52–83) 74 (55–85) 67 (50–80) 72 (54–85) 0.001

# No baseline radiograph of sacroiliac joints available. * Nr-axSpA versus AS. Chi square or nonparametric testing (Mann-Whitney U test) for continuous data. TNFi: tumor necrosis factor inhibitor; AS: ankylosing spondylitis; axSpA: axial spondyloarthritis; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Function Index; BASMI: Bath Ankylosing Spondylitis Metrology Index; BMI: body mass index; MTX: methotrexate; CRP: C-reactive protein; IBD: inflammatory bowel disease; NSAID: nonsteroidal antiinflammatory response; nr-axSpA: nonradiographic axSpA; VAS: visual analog scale; PGA: physician’s global assessment; PtGA: patient’s global assessment.

DISCUSSION nr-axSpA was observed in univariate analyses. HLA-B27 In this nationwide study of patients with nr-axSpA and AS status was strongly associated with outcomes irrespective of initiating TNFi treatment in routine care, we found differ- axSpA subtype. ences in baseline demographics and disease activity at Since the implementation of the ASAS criteria and the treatment start, but similar response rates after 6 months of expansion of the axSpA disease spectrum with the nr-axSpA treatment. Treatment adherence was independent of diagnosis patient group, it has been discussed whether nr-axSpA and in adjusted analyses, while poorer adherence for patients with AS represent a continuum or 2 different disease entities.

Glintborg, et al: TNFi treatment in axSpA 5 Downloaded from www.jrheum.org on December 20, 2016 - Published by The Journal of Rheumatology Figure 2A. Treatment duration of first tumor necrosis factor inhibitor. A. Results stratified by diagnosis (AS/nr-axSpA).

Further, it is debated whether the TNFi treatment effects in frequency of HLA-B27 positivity among patients with axSpA AS can be extrapolated to nr-axSpA15,27. In Denmark, seems to vary among different cohorts8,11,19. patients with nr-axSpA and AS are approached similarly in daily In the early years (2005–2008), patients with AS practice: a clinical evaluation must ensure that the correct dominated, in contrast to the later years (2012–2014), diagnosis has been made (based on ASAS or modified New York mirroring the gradual implementation of the ASAS classifi- classification criteria), and ≥ 2 measurements of high disease cation criteria from 20091,2 and explaining why patients with activity (BASDAI ≥ 40 mm) and failure of 2 nonsteroidal anti - AS more frequently received IFX (the first TNFi available). inflammatory drugs (NSAID) must be documented in DANBIO Patients with AS had higher CRP18,19 and BASMI at TNFi before TNFi treatment starts28,29,30. The TNFi treatment is treatment start, which may reflect more active inflammation tax-paid and provided free of charge to individual patients. Thus, and structural damage, respectively9,31,32. In contrast, patients treatment with TNFi in nr-axSpA does not require elevated CRP with nr-axSpA had higher subjective measures of disease or active inflammation on MRI at baseline, in contrast to the activity compared to patients with AS. A similar tendency guidelines applied in some countries5,14. was observed in the Swiss cohort9. However, 2 previous In accordance with previous studies, patients with observational studies18,19 and several randomized nr-axSpA were more frequently women8,9,11,19,31,32 and had trials8,9,11,34,35 found similar baseline BASDAI and VAS shorter disease duration9,11,19,33. Further, they were more scores in nr-axSpA and AS. These differences between often HLA-B27–negative compared to patients with AS33. In cohorts are difficult to account for, but may reflect national a Swiss cohort of nr-axSpA and AS patients, HLA-B27 differences in the management of these patient groups and positivity was present in 70% (nr-axSpA) and 84% (AS)9, the selection of patients for biological treatment. The higher nearly identical to the rates found in our study. However, the prevalence of women in the nr-axSpA group might also

6 The Journal of Rheumatology 2017; 44:1; doi:10.3899/jrheum.160958 Downloaded from www.jrheum.org on December 20, 2016 - Published by The Journal of Rheumatology Figure 2B. Results stratified by diagnosis (AS/nr-axSpA) and HLA-B27 status (positive/negative). Median treatment duration (95% CI): AS and HLA-B27–positive: 4.3 years (3.1–5.5); AS and HLA-B27–negative: 1.3 years [0.7–1.8; HR 2.04 (1.53–2.71)]; nr-axSpA and HLA-B27–positive: 2.2 years (1.0–3.3); nr-axSpA and HLA-B27–negative: 0.7 years [1.9–3.2; HR 1.74 (1.29–2.36)]. In a subanalysis including only HLA-B27– positive patients, patients with AS had significantly better treatment adherence than patients with nr-axSpA (p = 0.002). AS: ankylosing spondylitis; nr-axSpA: nonradiographic axial spondyloarthritis. contribute to higher scores in patient-reported outcomes36,37. switching40. The association between HLA-B27 status and In accordance with previous observational9,18,19,38 and TNFi treatment outcomes has not been reported previously, randomized studies33,34,35, we found that patients with to our knowledge. In early axSpA, HLA-B27 positivity is nr-axSpA and AS had similar response rates after 6 months. associated with younger age at disease onset11, spinal inflam- Patients with nr-axSpA, however, had poorer treatment mation, and radiographic changes41. Thus, HLA-B27 may be adherence and more often stopped owing to lack of effect in linked to disease severity and outcomes potentially crude analyses, but not after adjustment for differences in modifiable to TNFi treatment. It cannot be excluded that baseline characteristics, which may be considered con - inconsistencies in the interpretation of radiographs and founders (CRP, sex, BASFI, HLA-B27 positivity). Previous MRI16,42 may have resulted in misclassification of patients. studies have shown conflicting results18,19. Poorer treatment Because no such misclassification is possible for HLA-B27, adherence has been demonstrated in female TNFi-treated this might have had an effect on the statistical analyses. It patients with axSpA36,39. Further, patients with nr-axSpA was beyond the scope of our present study to explore this more often started treatment during recent years where more issue further, and our results reflect clinical routine, where different TNFi were available, enabling more frequent drug images are read by local radiologists.

Glintborg, et al: TNFi treatment in axSpA 7 Downloaded from www.jrheum.org on December 20, 2016 - Published by The Journal of Rheumatology Table 2. HR for stopping treatment. Univariate and multivariate Cox regression analyses (backwards selection) included a priori confounders.

Univariate Analyses Final Multivariate Model, Backward Selection HR (95% CI) p HR (95% CI) p

Diagnosis AS 1 < 0.0001 —— Nr-axSpA 1.41 (1.20–1.67) Sex Men 1 < 0.0001 1 0.002 Women 1.72 (1.46–2.03) 1.52 (1.16–1.97) Disease duration, yrs 0.99 (0.98–0.99) 0.02 —— Age < 45 yrs 0.91 (0.77–1.07) 0.2 1.05 (0.83–1.33) 0.6 ≥ 45 yrs 11 TNFi start year 2005–2008 0.58 (0.47–0.72) < 0.0001 —— 2009–2011 0.82 (0.67–1.01) 2012–2014 1 HLA-B27+ 1 < 0.0001 1 < 0.0001 HLA-B27–negative 1.93 (1.61–2.32) 2.15 (1.51–3.06) TNFi drug type Adalimumab 1 0.10 Etanercept 1.01 (0.79–1.28) —— Infliximab 1.01 (0.82–1.23) Golimumab 1.35 (1.05–1.73) Smoking Current 1.52 (1.25–1.86) < 0.0001 Previous 1.34 (1.04–1.72) —— Never 1 Baseline BASDAI, mm 1.01 (1.01–1.02) < 0.0001 1.01 (1.00–1.02) 0.002 Baseline BASMI, mm 0.99 (0.99–1.00) 0.6 —— Baseline CRP ≤ 10 mg/l 1.52 (1.26–1.84) < 0.0001 1.36 (1.08–1.71) 0.01 > 10 mg/l 11

Similar results regarding effects of HLA-B27 and axSpA subdiagnosis were found when (1) applying multiple imputation of missing data; and (2) patients with nr-axSpA diagnosed according to the clinical arm were excluded. AS: ankylosing spondylitis; axSpA: axial spondyloarthritis; TNFi: tumor necrosis factor inhibitor; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASMI: Bath Ankylosing Spondylitis Metrology Index; CRP: C-reactive protein; nr-axSpA: nonradiographic axSpA.

In the general population, the ratio of nr-axSpA to AS is pain as nr-axSpA27. Reassuringly, sensitivity analyses in about 1:15,43. In contrast, more patients in our study had AS which the clinical arm was excluded showed similar results than nr-axSpA. This difference may be explained, at least in for axSpA subgroups. part, by the selection of patients for biological therapy in It has previously been shown that fibromyalgia (FM) routine care: Rheumatologists more often assign TNFi occurs in 15%–20% of patients with axSpA44 and that FM is treatment to patients with AS9. Further, the study included associated with poorer TNFi adherence rates and higher patients initiating TNFi before the ASAS criteria were imple- disease activity scores45. In a recent study, HLA-B27 mented (2005–2009). One in 5 patients had unspecified positivity rates and imaging results were, however, similar in axSpA (i.e., lacked radiographs of the SI joints at TNFi a cross-sectional cohort of axSpA patients with/without treatment start), and most of these started TNFi after 2009. FM45. It is possible that uneven distribution of FM among This indicates that the clinicians seem to put more emphasis patients with nr-axSpA and AS in the present study affected on MRI findings than on radiographic results after the intro- the results, but we had no data to explore this further. duction of the ASAS classification criteria. The strength of our study is that it includes a large In our present study, the majority of patients with nationwide cohort of patients treated in routine care with nr-axSpA fulfilled the “imaging arm” of the ASAS criteria. valid data from a clinical registry collected independently of Concerns have been raised regarding the “clinical arm” and treatment and subdiagnosis. Further, comprehensive data the risk of erroneously diagnosing chronic mechanical back regarding several potential confounders were available, e.g.,

8 The Journal of Rheumatology 2017; 44:1; doi:10.3899/jrheum.160958 Downloaded from www.jrheum.org on December 20, 2016 - Published by The Journal of Rheumatology Figure 3. Response rates (3–6 mos). A. Stratified by diagnosis (AS vs nr-axSpA). Percentage of patients with available response rates: BASDAI 50%/20-mm response rates 690/984 = 70%; ASAS 40 451/984 = 46%; ASAS partial remission 307/984 = 57%; ASDAS inactive disease 307/984 = 31%; ASDAS improvement 211/984 = 21%. B. Stratified by HLA-B27 status and axSpA subdiagnosis. * Patients with unspecified axSpA not included. ** For all comparisons of response rates (AS HLA-B27–positive vs AS HLA-B27–negative, etc.), p < 0.05. NS: non-significant; AS: ankylosing spondylitis; axSpA: axial spondyloarthritis; nr-axSpA: nonradiographic axSpA; ASAS: Assessment of Spondyloarthritis international Society classification criteria; BASDAI: Bath Ankylosing Spondylitis Activity Index; ASDAS: ASAS Disease Activity Score.

smoking status, disease duration, HLA-B27 status, and effect on inflammation and outcomes46,47, so this might have baseline disease activity. affected our results. We were able to validate the diagnosis Current NSAID use is not registered routinely in in about half of the Danish biologically treated patients with DANBIO. Concomitant use of NSAID is known to have an axSpA by a retrospective, voluntary review of the patient

Glintborg, et al: TNFi treatment in axSpA 9 Downloaded from www.jrheum.org on December 20, 2016 - Published by The Journal of Rheumatology files. The withdrawal analysis revealed similar age and sex management of ankylosing spondylitis. Ann Rheum Dis distribution among included and excluded patients, which 2006;65:442-52. 13. Braun J, van den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, indicate that selection bias was minimal and we therefore Collantes-Estevez E, et al. 2010 update of the ASAS/EULAR consider the results to be generalizable. recommendations for the management of ankylosing spondylitis. Patients with nr-axSpA had higher subjective disease Ann Rheum Dis 2011;70:896-904. activity at the start of first TNFi treatment, but had outcomes 14. Concept paper on clinical investigation of medicinal products for similar to patients with AS after adjustment for confounders. the treatment of axial spondyloarthritis. 2015. [Internet. Accessed October 26, 2016.] Available from: HLA-B27 positivity was associated with better outcomes www.ema.europa.eu/docs/en_GB/document_library/Scientific_guid irrespective of axSpA subdiagnosis. eline/2015/04/WC500185187.pdf 15. Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, et al. ACKNOWLEDGMENT American College of Rheumatology/Spondylitis Association of Thanks to all the Danish departments of rheumatology for reporting to the America/Spondyloarthritis Research and Treatment Network 2015 DANBIO registry. Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol ONLINE SUPPLEMENT 2016;68:282-98. Supplementary material accompanies the online version of this article. 16. Sieper J, van der Heijde D, Dougados M, Mease PJ, Maksymowych WP, Brown MA, et al. Efficacy and safety of adalimumab in REFERENCE LIST patients with non-radiographic axial spondyloarthritis: results of a 1. 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Classification of axial SpA based on positive patients referred because of chronic back pain and performance of imaging (radiographs and/or MRI of the sacroiliac joints) by local classification criteria: experience from the Spondyloarthritis Caught rheumatologists or radiologists versus central trained readers in the Early (SPACE) cohort. Rheumatology 2013;52:1492-9. DESIR cohort. Ann Rheum Dis 2015;74:2016-21. 33. Landewe R, Braun J, Deodhar A, Dougados M, Maksymowych WP, 43. Poddubnyy D, Vahldiek J, Spiller I, Buss B, Listing J, Rudwaleit M, Mease PJ, et al. Efficacy of certolizumab pegol on signs and et al. Evaluation of 2 screening strategies for early identification of symptoms of axial spondyloarthritis including ankylosing patients with axial spondyloarthritis in primary care. J Rheumatol spondylitis: 24-week results of a double-blind randomised placebo- 2011;38:2452-60. controlled Phase 3 study. Ann Rheum Dis 2014;73:39-47. 44. Salaffi F, De Angelis R, Carotti M, Gutierrez M, Sarzi-Puttini P, 34. Callhoff J, Sieper J, Weiss A, Zink A, Listing J. Efficacy of Atzeni F. Fibromyalgia in patients with axial spondyloarthritis: TNFalpha blockers in patients with ankylosing spondylitis and non- epidemiological profile and effect on measures of disease activity. radiographic axial spondyloarthritis: a meta-analysis. Ann Rheum Rheumatol Int 2014;34:1103-10. Dis 2015;74:1241-8. 45. Bello N, Etcheto A, Beal C, Dougados M, Molto A. Evaluation of 35. Song IH, Weiss A, Hermann KG, Haibel H, Althoff CE, Poddubnyy the impact of fibromyalgia in disease activity and treatment effect in D, et al. Similar response rates in patients with ankylosing spondyloarthritis. Arthritis Res Ther 2016;18:42. spondylitis and non-radiographic axial spondyloarthritis after 1 year 46. Kroon FP, van der Burg LR, Ramiro S, Landewe RB, Buchbinder R, of treatment with etanercept: results from the ESTHER trial. Ann Falzon L, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) Rheum Dis 2013;72:823-5. for axial spondyloarthritis (ankylosing spondylitis and non- 36. Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL, radiographic axial spondyloarthritis). Cochrane Database Syst Rev Hetland ML. Predictors of treatment response and drug continuation 2015;(7):CD010952. in 842 patients with ankylosing spondylitis treated with anti-tumour 47. Kroon F, Landewe R, Dougados M, van der Heijde D. Continuous necrosis factor: results from 8 years’ surveillance in the Danish NSAID use reverts the effects of inflammation on radiographic nationwide DANBIO registry. Ann Rheum Dis 2010;69:2002-8. progression in patients with ankylosing spondylitis. Ann Rheum Dis 37. Sokka T, Toloza S, Cutolo M, Kautiainen H, Makinen H, Gogus F, 2012;71:1623-9. et al. Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study. Arthritis Res Ther 2009;11:R7.

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Concise report A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry Bente Glintborg,1,2 Inge Juul Sørensen,3,4 Anne Gitte Loft,5 Hanne Lindegaard,6 Asta Linauskas,7 Oliver Hendricks,8 Inger Marie Jensen Hansen,9 Dorte Vendelbo Jensen,2,3 Natalia Manilo,10 Jakob Espesen,11 Mette Klarlund,12 Jolanta Grydehøj,13 Sabine Sparre Dieperink,3 Salome Kristensen,14 Jimmi Sloth Olsen,15 Henrik Nordin,16 Stavros Chrysidis,17 Dorte Dalsgaard Pedersen,18 Michael Veedfald Sørensen,19 Lis Smedegaard Andersen,20 Kathrine Lederballe Grøn,3 Niels Steen Krogh,21 Lars Pedersen,22 Merete Lund Hetland,1,4 On behalf of all departments of rheumatology in Denmark

►► Additional material is Abstract CT-P13, Remsima. Due to their complex biochem- published online only. To view Objectives According to guidelines, a nationwide ical structure, a biosimilar drug is never an exact please visit the journal online copy of the originator.1 Before marketing, the (http://dx. doi.org/ 10.1136/ non-medical switch from originator (INX, Remicade) to annrheumdis-2016- 210742). biosimilar infliximab R( emsima, CT-P13) was conducted equivalence of CT-P13 compared with origi- in Danish patients with rheumatoid arthritis (RA), nator infliximab (Remicade, INX) was demon- For numbered affiliations see psoriatic arthritis (PsA) and axial spondyloarthritis strated in pharmacokinetic studies and randomised end of article. (AxSpA). We investigated disease activity before/after controlled trials (RCT).1–3 However, it is debated switching and retention rates in the DANBIO registry. whether the biosimilars perform equally to the orig- Correspondence to Dr Bente Glintborg, Center Methods Disease activities 3 months before and after inator when INX-treated patients are switched to for Rheumatology and Spine switch and changes over time were calculated. Flare biosimilar in routine care, as small differences in Diseases, Centre of Head and was defined as change in 28 Joint Disease Activity Score immunogenicity potentially may influence tolera- Orthopaedics, Rigshospitalet, (∆DAS28) ≥1.2 (RA/PsA) or Ankylosing Spondylitis bility and outcomes. Postmarketing observational Glostrup, Denmark; glintborg@ Disease Activity Score (∆ASDAS) ≥1.3 (AxSpA). Crude studies contribute important knowledge regarding dadlnet.dk and adjusted retention rates were compared with a biosimilar effectiveness in clinical practice.1 Received 28 October 2016 historic cohort of INX-treated patients. In Denmark, public hospital owners provide Revised 21 March 2017 Results eight hundred and two patients switched bDMARDs via a tax-based system. A national guide- Accepted 23 March 2017 (403 RA/120 PsA/279 AxSpA; 51% women, age line by May 2015 dictated a non-medical switch, Published Online First 4 May 2017 (median (IQR): 55 (44-66)) years). Follow-up was 413 that is, all patients treated with INX should switch (339–442) days. Prior INX treatment duration was to CT-P13 for economic reasons.4 The patients (and 6.8 (4.3–9.5) years. Disease activities were similar physicians) had no say in the matter. The potential 3 months before/after switch. Crude 1-year CT-P13 implications of the switch were economic savings retention rate (84.1 (95% CI 81.3 to 86.5)) was similar without loss of beneficial treatment outcomes.5 to the historic IFX cohort (86.2 (95% CI 84.0 to 88.0), Thus, on marketing in Denmark, the costs of CT-P13 p=0.22). The adjusted absolute retention rates were was 36% of that of INX. However, the experience 83.4 (95% CI 80.8 to 86.2) and 86.8% (95% CI 84.8 with non-medical switching is limited and stem to 88.8), respectively (p=0.03). In total 132 patients from open-label studies,6 7 small cohorts8–13 and the withdrew (lack of effect: 71/132=54%, adverse events: NOR-SWITCH trial.14 37/132=28%). Patients with previous INX treatment In the nationwide quality registry, DANBIO, treat- duration >5 years had longer CT-P13 retention. ment outcomes of Danish adult patients with inflam- Conclusion in 802 arthritis patients treated with INX matory arthritis are monitored prospectively.15 The for median >6 years, a nationwide non-medical switch aims of the present observational study were to inves- to CT-P13 had no negative impact on disease activity. tigate the impact of the nationwide switch from INX Adjusted 1-year CT-P13 retention rate was slightly lower to CT-P13 on (1) 3 months’ disease activity and flare than for INX in a historic cohort. rates and (2) 1-year retention rates.

Methods T Glintborg B,o cite: Background DANBIO covers >95% of adults with rheumatic Sørensen IJ, Loft AG, As patents on the originator biological disease diseases treated in routine care with bDMARDs. et al. Ann Rheum Dis modifying agents (bDMARDs) expire, less expen- According to national treatment guidelines, 2017;76:1426–1431. sive biosimilars are marketed – the first being disease activity and outcomes are monitored at

1426 Glintborg B, et al. Ann Rheum Dis 2017;76:1426–1431. doi:10.1136/annrheumdis-2016-210742 Downloaded from http://ard.bmj.com/ on December 21, 2017 - Published by group.bmj.com Clinical and epidemiological research

Table 1 Baseline demographics and clinical characteristics of the CT-P13 cohort and the subgroup of switch patients who withdrew from treatment during ≈1 year of follow-up stratified by diagnosis. Reasons for CT-P13 withdrawal are also shown Patients switched from INX to CT-P13 RA* PsA AxSpA† Total Number of patients, n 403 120 279 802 Women, n (%) 281 (70) 58 (48) 73 (26) 412 (51) Age, years 63 (51–71) 52 (44–61) 47 (39–55) 55 (44–66) Number of comorbidities ≥1, n (%)‡ 99 (25) 28 (23) 48 (17) 175 (22) Biological treatment number, INX 1 (1–1) 1 (1–2) 1 (1–2) 1 (1–1) Concomitant methotrexate, n (%) 330 (82) 84 (69) 89 (32) 501 (62) Methotrexate dose, mg/week§ 15 (10–20) 15 (10–20) 10 (10–15) 15 (10–20) Concomitant oral prednisolone, n (%) 25 (6) 5 (4) 6 (2) 36 (4) On disease remission, n (%)¶ 191/309 (62) 55/92 (60) 42/199 (21) 288/600 (48) Start of INX, year, n 2000–2004 76 (19) 11 (9) 36 (13) 123 (15) 2005–2009 203 (50) 58 (48) 133 (48) 394 (49) 2010–2015 124 (31) 51 (43) 110 (39) 285 (36) CT-P13 dose, mg/kg 3.4 (3.0–4.5) 4.6 (3.1–5.1) 4.8 (3.7–5.1) 4.0 (3.1–5.0) CT-P13 dose interval, weeks 8 (7–8) 7 (6–8) 8 (6–8) 8 (6–8) Prior INX treatment duration, years 7.3 (4.9–9.8) 6.3 (3.1–8.5) 6.5 (3.9–9.3) 6.8 (4.3–9.5) Prior INX treatment duration, years, mean (SD) 7.3 (3.6) 6.2 (3.4) 6.6 (3.5) 6.9 (3.6) Subgroup of patients withdrawn from CT-P13 within RA* PsA AxSpA† Total‡ ≈1 year of follow-up Number of patients, n 76 16 40 132 Women, n 56 11 17 84 Baseline CT-P13 dose, mg/kg 3.6 (3.0–4.6) 4.8 (3.0–5.5) 5.0 (4.6–5.5) 4.4 (3.1–5.2) Concomitant methotrexate, n 52 12 10 74 Prior INX treatment duration, years 6.4 (3.5–9.8) 5.7 (2.6–9.6) 4.8 (1.8–6.6) 5.9 (2.9–9.2) Number of comorbidities ≥1, n 26 4 5 35 Reasons for CT-P13 withdrawal, n=132 Lack of effect: 71 patients; adverse events: 37; remission: 5; cancer: 5; death: 2; several reasons: 3; other reasons (eg, pregnancy, surgery): 8; unknown: 1. Numbers are medians (interquartile ranges) unless otherwise stated. *RA including other types of peripheral arthritis (juvenile arthritis, reactive arthritis etc, n=39). †AxSpA including non-radiographic axSpA (n=85) and ankylosing spondylitis (n=194). ‡The number of comorbidities was calculated according to the groups in the Charlson Comorbidity Index excluding musculoskeletal comorbidity. §Median dose of methotrexate per week among methotrexate-treated patients. ¶The numbers of patients with available data are shown as denominator. AxSpA, axial spondyloarthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis. least biannually and when medication is changed.15 According Statistics to Danish legislation, registration and publication of data from Statistical analyses were performed by SPSS 22 and SAS 9.4. clinical registries do not require patient consent or approval by Descriptive data are presented by medians (IQR). Non-para- ethics committees. metric statistics were used for comparisons. p Values <0.05 were Patients with inflammatory arthritis in DANBIO who had considered statistically significant. been followed since start of first bDMARD and who switched Disease activity 3 months before switch (preswitch), at the from INX to CT-P13 before 1 January 2016 were included time of switch, after 3 months (postswitch) and changes over (table 1). In addition, 28 patients from two hospitals, where time (∆preswitch and ∆postswitch) were calculated in each the switch guideline was adapted later, were included. A time patient. Missing data at the 3 months’ visit were imputed with gap between planned INX and start of CT-P13 of 0–120 days the 6 months’ visit. For patients who withdrew ≤3 months was allowed to comply with differences in registration prac- postswitch (n=18), data from the latest registered visit after tice. All departments of rheumatology were invited to vali- baseline were carried forward. date data regarding switch date, disease activities and reasons Disease flare was defined as changes in 28 Joint Disease for CT-P13 withdrawal. Data were censored 9 September Activity Score (DAS28) ≥0.6 or ∆DAS28 ≥1.2 (rheumatoid 2016. arthritis (RA), psoriatic arthritis (PsA)), and ∆Ankylosing Spon- The variables collected in DANBIO have been described dylitis Disease Activity Score (ASDAS) ≥1.3 (axial spondyloar- previously.15 Predefined time windows were applied for visits thritis (AxSpA)). Remission was defined as DAS28 <2.6 and on switch (=baseline) and 3 months preswitch/postswitch (see ASDAS <1.3, respectively. notes to table 2). Treatment retention among switchers was explored with Through linkage by social security numbers, comorbid- Kaplan-Meier plots and log-rank tests. Univariable and multi- ities were identified in national registries (hospitalisations variable Cox regression analyses and HR stratified by diagnosis and outpatient care 10 years back) and numbers (0–7) (RA/PsA/AxSpA) were used to identify baseline predictors of calculated. 16 CT-P13 retention (gender/age/methotrexate(yes–no)/CT-P13

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Table 2 Disease activity 3 months prior to versus 3 months after the switch from INX to CT-P13 stratified by diagnosis Disease activity Changes over time 3 Months preswitch Switch 3 Months postswitch ∆Preswitch ∆Postswitch p* RA, n=403 Patients with available data, n‡ 319 310 309 276 265 – DAS28 2.2 (1.7–2.9) 2.2 (1.8–3.0) 2.2 (1.8–3.2) 0.1 (−0.2 to 0.5) 0.0 (−0.4 to 0.4) 0.8 HAQ (0–3) 0.6 (0.1–1.0) 0.6 (0.1–1.0) 0.6 (0.2–1.1) 0.0 (0.0–0.1) 0.1 (−0.1 to 0.1) 0.3 CRP, mg/L (<10 mg/L) 4 (2–7) 4.5 (2–8) 5 (2–8) 0 (−1 to 2) 0 (−2 to 3) 0.4 Patient’s global score, mm 26 (12–51) 25 (11–51) 26 (12–56) 0.0 (−7 to 8) 0.0 (−7 to 9) 0.5 PsA, n=120 Patients with available data, n‡ 94 92 94 78 81 – DAS28 2.5 (1.7–3.1) 2.3 (1.7–3.1) 2.4 (1.8–3.3) 0.0 (−0.4 to 0.2) 0.1 (−0.4 to 0.6) 0.10 HAQ (0–3) 0.5 (0.1–1.1) 0.6 (0.1–1.1) 0.5 (0.1–1.1) 0.0 (−0.1 to 0.1) 0.0 (0.0–0.1) 0.5 CRP, mg/L (<10 mg/L) 4 (1–6) 4 (1–6) 3 (2–7) 0 (−1 to 1) 0 (−1 to 2) 0.046 Patient’s global score, mm 32 (10–56) 34 (10–67) 35 (11–62) −3 (−12 to 4) 0 (−7 to 11) 0.01 AxSpA, n=279 Patients with available data, n‡ 202 199 204 160 169 – BASDAI, mm 23 (8–40) 24 (10–40) 25 (11–45) 0 (−4 to 5) 0 (−4 to 7) 0.3 CRP, mg/L 3 (1–6) 4 (1–8) 4 (1–8) 0 (−1 to 1) 0 (−1 to 2) 0.2 Patient’s global score, mm 26 (10–53) 31 (14–56) 27 (11–59) 1 (−4 to 8) −1 (−7 to 7) 0.7 ASDAS 1.8 (1.2–2.6) 2.0 (1.4–2.6) 2.0 (1.2–2.9) 0.0 (−0.3 to 0.4) 0.0 (−0.3 to 0.3) 0.8 3 Months’ flare rates preswitch versus postswitch† RA and PsA (ΔDAS28 ≥0.6), % 22 22 RA and PsA (ΔDAS28 ≥1.2), % 10 10 AxSpA (ΔASDAS), % 3 4 Numbers are medians (interquartile ranges) unless otherwise stated (%). Including only patients with complete data gave virtually identical results, supporting that data were missing at random. Comparisons of before versus after the switch were done in the patients who had complete data for that variable. Notes: Missing data at the 3 months' visit were imputed with the 6 months’ visit according to the following time windows: Time windows preswitch: 3 months’ window: 0–25 weeks, 6 months’ window: 25–32 weeks before start of CT-P13. Time window switch: 12 weeks before until 1 week after start of CT-P13. Time window postswitch: 3 months’ window: 9–17 weeks, 6 months’ window: 17–32 weeks after start of CT-P13. Overlapping time windows at baseline were allowed to reduce missing data. Any visit was only used once, and the registration closest to the given time point was selected. If a patient had no registrations, data were registered as missing for that visit. *Comparison of ∆preswitch versus ∆postswitch, Wilcoxon matched-pair signed-rank test. †There was no overlap between the patients who had a flare preswitch versus postswitch. ‡The number of patients with available data varied slightly across measures of disease activity. Exact numbers are shown for DAS28 and ASDAS. Individual patients might not have complete data for all variables at a certain time point. ASDAS, Ankylosing Spondylitis Disease Activity Score; AxSpA, axial spondyloarthritis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CRP, C reactive protein; DAS28, 28 Joint Disease Activity Score (four variables, CRP-based); HAQ, Health Assessment Questionnaire; RA, rheumatoid arthritis; PsA, psoriatic arthritis. dose/CT-P13 interval/comorbidities (number) and baseline day. In 76%, INX was the first biological drug. Follow-up time disease activity (patient’s global score/Bath Ankylosing Spon- was 413 (339–442) days during which 16% stopped CT-P13, dylitis Disease Activity Index score/ASDAS/DAS28)). Age and mostly due to lack of effect (71/132=54%) or adverse events gender were forced into the model. Variables with p<0.1 on (37/132=28%) (table 1 and online supplementary table 1). univariate analysis were included in the multivariate model Disease activity 3 months preswitch/postswitch was largely (stepwise backwards selection). unchanged in the majority of patients (table 2) with no clini- The 1-year treatment retention was compared with that of cally meaningful differences observed. Flare rates preswitch/ a cohort of all patients in DANBIO receiving treatment with postswitch were similar (table 2). INX by 1 January 2014. Cox proportional hazards regression The characteristics of the comparison and switch cohorts analysis was used to compare the crude 1-year retention rate in were similar (see online supplementary table 2). One-year crude the two groups with a robust variance calculation implemented retention rates (INX: 86.2% (95% CI 84.0 to 88.0) and CT-P13: to account for repeated subjects. Multivariable Cox regression 84.1% (95% CI 81.3 to 86.5), p=0.22) are shown in figure 1A. analysis with left truncation (1 January 2014) and years since The adjusted absolute rates were 86.8% (95% CI 84.8 to 88.8) start of INX as timescale was performed to calculate HR for versus 83.4% (95% CI 80.8 to 86.2) (p=0.03), corresponding withdrawal adjusted for the following baseline variables — age/ to an absolute difference of 3.4%. Correspondingly, CT-P13- gender/diagnosis/methotrexate(yes–no)/comorbidities(number)/ treated patients had significantly higher relative risk of with- patient’s global score — and to calculate adjusted 1-year reten- drawal than the INX cohort (HR 1.31 (1.02–1.68), p=0.03). tion rates for INX and CT-P13. CT-P13 retention rate tended to be poorer for RA than for PSA and AxSpA (figure 1B). Duration of INX treatment (<5 Results years) was associated with poorer retention (figure 1C) as was We included 802 switch patients (table 1). The median (IQR) not being in DAS28 remission at baseline (RA, figure 1D). Higher time gap between planned INX and first CT-P13 was 1 (1–1) patient global score at baseline (RA (borderline significant),

1428 Glintborg B, et al. Ann Rheum Dis 2017;76:1426–1431. doi:10.1136/annrheumdis-2016-210742 Downloaded from http://ard.bmj.com/ on December 21, 2017 - Published by group.bmj.com Clinical and epidemiological research

Figure 1 (A–D) Kaplan-Meier plots of crude treatment retention rates among CT-P13 switch patients: (A) compared with a historic comparison cohort of INX-treated patients; (B) stratified by diagnosis; (C) stratified by duration of previous INX treatment; and (D) stratified by baseline DAS28 remission (yes/no) (only RA patients). AxSPA, axial spondyloarthritis; DAS28, 28 Joint Disease Activity Score; PsA, psoriatic arthritis; RA, rheumatoid arthritis.

AxSpA), higher CT-P13 doses (AxSpA) and monotherapy (RA) outcomes.13 In the open-label extension studies of two RCTs were associated with poorer retention (table 3). (PLANETRA and PLANETAS), INX-treated patients switched to CT-P13 after 1 year (144 and 86 patients, respectively).6 7 Discussion These trials indicated similar safety, immunogenicity and effi- This study of a nationwide non-medical switch in routine care cacy between the two drugs. Preliminary data in a subgroup of included 802 patients with arthritis previously treated with INX patients in our study indicated that infliximab drug levels and for >6 years. Three-months’ disease activity and flare rates were presence of antidrug antibodies were unaffected by the switch.18 largely unaffected by the switch. One-year crude retention rate The NOR-SWITCH RCT, which examined non-medical of CT-P13 was not statistically different from that of INX in switch of CT-P13 across indications, included 481 patients (198 a comparison cohort, and just reached statistical significance in with arthritis).14 Across diagnoses, the proportion of patients adjusted analysis. with flare in NOR-SWITCH was 26.2% for INX versus 29.6% To our knowledge, this is the first study of large-scale, non-med- for CT-P13. The higher flare rates might be explained by the ical switching in routine care with prospective data collec- different time periods (1 year in NOR-SWITCH and 3 months tion. Similar results of largely unchanged disease activity after in the present), inclusion of patients with inflammatory bowel the switch have been reported in smaller observational studies disease and the randomised controlled design of NOR-SWITCH. of <40 patients with inflammatory arthritis8 9 and inflamma- Retention rates were slightly lower in the CT-P13 cohort tory bowel disease,10 12 17 whereas few have reported negative versus the historic INX cohort, with an adjusted absolute risk

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Table 3 Baseline variables associated with CT-P13 treatment withdrawal Univariate analyses Final multivariable model Rheumatoid arthritis HR p HR p Gender, women versus men 1.26 (0.73 to 2.03) 0.4 1.33 (0.76 to 2.32) 0.3 Age, years 1.01 (0.99 to 1.02) 0.4 1.01 (0.99 to 1.03) 0.3 Methotrexate use, no versus yes 2.27 (1.40 to 3.69) 0.001 2.17 (1.27 to 3.68) 0.004 Patient’s global score, mm 1.01 (1.00 to 1.02) 0.049 1.01 (1.00 to 1.02) 0.085 DAS28 1.20 (0.99 to 1.46) 0.06 – – CRP, mg/L 1.00 (0.99 to 1.02) 0.8 – – Longer CT-P13 interval, weeks 0.96 (0.82 to 1.13) 0.6 – – Higher CT-P13 dose, mg/kg 1.14 (0.94 to 1.38) 0.14 – – INX start year, 2000–2007 versus 2008–2015 0.83 (0.53 to 1.30) 0.8 – – Number of comorbidities 1.36 (1.04 to 1.76) 0.025 – – Psoriatic arthritis Univariate Final model HR p HR p Gender, women versus men 2.46 (0.86 to 7.08) 0.1 2.48 (0.86 to 7.17) 0.09 Age, years 1.00 (0.96 to 1.04) 1.0 1.00 (0.96 to 1.04) 0.9 Methotrexate use, no versus yes 0.68 (0.22 to 2.12) 0.5 – – Patient’s global score, mm 1.01 (1.00 to 1.03) 0.2 – – DAS28 1.21 (0.79 to 1.85) 0.4 – – CRP, mg/L 0.99 (0.92 to 1.07) 0.9 – – Longer CT-P13 interval, weeks 0.84 (0.60 to 1.19) 0.3 – – Higher CT-P13 dose, mg/kg 1.11 (0.74 to 1.67) 0.6 – – INX start year, 1.11 (0.42 to 2.98) 0.8 – – 2000–2007 versus 2008–2015 Number of comorbidities 0.93 (0.45 to 1.93) 0.8 – – Axial spondyloarthritis Univariate Final model HR p HR p Gender, women versus men 2.29 (1.22 to 4.29) 0.01 1.85 (0.81 to 4.25) 0.15 Age, years 0.98 (0.96 to 1.02) 0.15 0.99 (0.95 to 1.03) 0.6 Methotrexate use, no versus yes 1.36 (0.68 to 2.86) 0.4 – – Patient’s global score, mm 1.02 (1.01 to 1.03) 0.003 1.02 (1.01 to 1.04) 0.009 BASDAI 1.02 (1.01 to 1.04) 0.003 – – ASDAS 1.09 (0.76 to 1.56) 0.6 – – CRP, mg/L 0.92 (0.84 to 1.01) 0.08 0.90 (0.81 to 1.00) 0.04 Longer CT-P13 interval, weeks 0.69 (0.54 to 0.88) 0.002 – – Higher CT-P13 dose, mg/kg 1.66 (1.22 to 2.26) 0.001 1.63 (1.06 to 2.51) 0.03 INX start year 2000–2007 versus 2008–2015 0.32 (0.16 to 0.65) 0.002 – – Number of comorbidities 0.67 (0.34 to 1.39) 0.3 – – Results from univariable and multivariable Cox regression analyses stratified by diagnosis. Cox regression analyses stratified by diagnosis. Numbers are HR (95% CI). p Values <0.1 are marked with bold and the corresponding variables were included in multivariable analysis. Age and gender remained in the model irrespective of p value. ASDAS, Ankylosing Spondylitis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CRP, C reactive protein; DAS28, 28 Joint Disease Activity Score. difference of 3.4%. This difference is not necessarily attrib- was a tendency towards poorer retention among women and utable to CT-P13, but could also represent a ‘nocebo-effect’, patients with RA with more comorbidities. No new safety signals that is, negative expectations towards the drug19 or residual were detected for CT-P13. confounding. The long average INX treatment duration of >6 years at the In the present study ≈84% of patients were still on drug after time of switching reflects that INX was not first-line bDMARD 1 year, which was lower than in NOR-SWITCH (96%).14 This in Denmark prior to the switch.4 As longer treatment with INX may reflect differences between ‘real-life’ patients and patients was associated with better CT-P13 retention, extrapolation of included in an RCT. Differences in study design (patients with our results to other cohorts of shorter treatment duration should arthritis in the current study versus patients from rheumatology/ be done with caution. dermatology/gastroenterology in NOR-SWITCH) may also have This study of a large cohort of real-life patients contrib- contributed. The 14% 1-year withdrawal rate in our historic utes important knowledge of postmarketing effectiveness of INX cohort illustrates that cessation of treatment also occurs non-medical switching.1 The availability of historic DANBIO after many years of treatment.20 data enabled us to use the patients as their own controls regarding CT-P13 retention rates across diagnoses were comparable. fluctuations in disease activity before and after switch, and to This is reassuring, as treatment of PsA with CT-P13 had not been identify a historic INX cohort for comparison of retention rates. investigated before marketing. Patients with RA who were on Limitations include incomplete data due to the observational monotherapy were at increased risk of withdrawal, and there study design, for example skin status and 66/68 joint counts in

1430 Glintborg B, et al. Ann Rheum Dis 2017;76:1426–1431. doi:10.1136/annrheumdis-2016-210742 Downloaded from http://ard.bmj.com/ on December 21, 2017 - Published by group.bmj.com Clinical and epidemiological research

PsA. We applied a time interval of 13 weeks around the base- infliximab in patients with ankylosing spondylitis: 54-week results from the line visit to reduce missing data at baseline, but in the majority randomized, parallel-group PLANETAS study. Arthritis Res Ther 2016;18:25. of patients data were available within few days before/after the 3 Yoo DH, Racewicz A, Brzezicki J, et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with switch date. active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res In conclusion, a nationwide non-medical switch from INX to Ther 2016;18:82. CT-P13 in 802 patients with inflammatory arthritis, who had 4 the danish regions, RADS, guidelines for use of biosimilar infliximab and etanercept. previously been treated with INX for >6 years, had no apparent http://www.regioner. dk/media/ 3488/rads- notat-om- anvendelsen-af- biosimilaere-juni- 2016.pdf (Accessed Jan 2017). negative impact on disease activity. The adjusted retention 5 Brodszky V, Baji P, Balogh O, et al. Budget impact analysis of biosimilar infliximab rate during ≈1 year of follow-up was slightly reduced (3.4%) (CT-P13) for the treatment of rheumatoid arthritis in six Central and Eastern European compared with a historic cohort. countries. Eur J Health Econ 2014;15(S1):65–71. 6 Yoo DH, Prodanovic N, Jaworski J, et al. Efficacy and safety of CT-P13 (biosimilar Author affiliations infliximab) in patients with rheumatoid arthritis: comparison between switching from 1The DANBIO registry and Copenhagen Center for Arthritis Research (COPECARE), reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, study. Ann Rheum Dis 2017;76:355–63. Rigshospitalet, Glostrup, Denmark 7 park W, Yoo DH, Miranda P, et al. Efficacy and safety of switching from reference 2 Department of Rheumatology, Gentofte and Herlev University Hospital, Gentofte, infliximab to TC -P13 compared with maintenance of CT-P13 in ankylosing Denmark spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis 3 COPECARE, Center for Rheumatology and Spine Diseases, Centre of Head and 2017;76:346–54. Orthopaedics, Rigshospitalet, Glostrup, Denmark 8 Abdalla A, Byrne NE, Conway R, et al. THU0120 Long Term Safety and Efficacy of 4 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University Biosimilar Infliximab among Patients with Inflammatory Arthritis Switched from of Copenhagen, Copenhagen, Denmark Reference Product: Table 1. Ann Rheum Dis 2016;75(Suppl 2):223.2–223. 5 Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark 9 nikiphorou E, Kautiainen H, Hannonen P, et al. Clinical effectiveness of CT-P13 6 Department of Rheumatology, Odense University Hospital, Odense, Denmark (Infliximab biosimilar) used as a switch from remicade (infliximab) in patients with 7 Department of Rheumatology, North Denmark Regional Hospital, Hjørring, Denmark established rheumatic disease. report of clinical experience based on prospective 8 King Christian 10th Hospital for Rheumatic Diseases, Graasten, Denmark observational data. Expert Opin Biol Ther 2015;15:1677–83. 9 Department of Rheumatology, OUH, Svendborg Hospital, Svendborg, Denmark 10 Jung YS, Park DI, Kim YH, et al. Efficacy and safety of CT-P13, a biosimilar of 10 Department of Rheumatology, Frederiksberg Hospital, Copenhagen, Denmark infliximab, in patients with inflammatory bowel disease: a retrospective multicenter 11Department of Rheumatology, Vejle Hospital, Vejle, Denmark 12 study. J Gastroenterol Hepatol 2015;30:1705–12. Department of Rheumatology, Hillerød Hospital, Hillerød, Denmark 11 Kang YS, Moon HH, Lee SE, et al. Clinical experience of the use of CT-P13, a biosimilar 13Department of Rheumatology, Holstebro Hospital, Holstebro, Denmark 14 to infliximab in patients with inflammatory bowel disease: a case series. Dig Dis Sci Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark 2015;60:951–6. 15Department of Rheumatology, Silkeborg Hospital, Silkeborg, Denmark 16 12 Buer LC, Moum BA, Cvancarova M, et al. Switching from INX(R) to CT-P13(R) is safe Department of Rheumatology, Zealand University Hospital, Køge, Denmark and feasible: a prospective, open-label study. J Crohns Colitis 2016. EPUB ahead of 17Department of Rheumatology, Esbjerg Hospital, Esbjerg, Denmark 18 print. Department of Rheumatology, Viborg Hospital, Viborg, Denmark 13 Gentileschi S, Barreca C, Bellisai F, et al. Switch from infliximab to infliximab biosimilar: 19Department of Rheumatology, Horsens Hospital, Horsens, Denmark 20 efficacy and safety in a cohort of patients with different rheumatic diseasesResponse Department of Internal Medicine, Rønne Hospital, Rønne, Denmark to: Nikiphorou E, Kautiainen H, Hannonen P, et al. Clinical effectiveness of CT-P13 21ZiteLab ApS, Copenhagen, Denmark 22 (Infliximab biosimilar) used as a switch from Remicade (infliximab) in patients with Department of Clinical Epidemiology (KEA), Aarhus University Hospital, Aarhus, established rheumatic disease. Report of clinical experience based on prospective Denmark observational data. Expert Opin Biol Ther. 2015;15:1677-1683. Expert Opin Biol Ther Acknowledgements Thanks to all the Danish departments of rheumatology for 2016;16:1311–2. reporting to the DANBIO registry. 14 Jørgensen KK, Olsen IC, Goll GL, et al. Switching from originator infliximab to biosimilar CT-P13 compared to maintained treatment with originator infliximab Contributors BG and MLH contributed to the study design. BG, MLH, NSK and (NOR-SWITCH): a 52-week randomised double-blind non-inferiority trial. Lancet 2017 LP contributed to data analyses and interpretation. All authors contributed to data (Accepted for publication). collection and contributed to and approved the final manuscript. 15 ibfelt EH, Jensen DV, Hetland ML. The danish nationwide clinical register for patients Funding The study was funded in part by a research grant from AbbVie. with rheumatoid arthritis: DANBIO. Clin Epidemiol 2016;8:737–42. 16 Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic Competing interests BG: AbbVie; IMJH: Roche; AGL, MLH: AbbVie, BMS, MSD, comorbidity in longitudinal studies: development and validation. J Chronic Dis Pfizer, Roche and UCB; the remaining authors: none declared. 1987;40:373–83. Ethics approval According to Danish legislation, registration and publication of 17 smits LJ, Derikx LA, de Jong DJ, et al. Clinical outcomes following a switch from data from clinical registries do not require patient consent or approval by ethics remicade® to the biosimilar CT-P13 in inflammatory bowel disease patients: a committees. prospective observational cohort study. J Crohns Colitis 2016;10:1287–93. EPUB Provenance and peer review Not commissioned; externally peer reviewed. ahead of print. 18 Glintborg B, Kringelbach TM, Høgdall E, et al. Non-medical switch from © Article author(s) (or their employer(s) unless otherwise stated in the text of the originator to biosimilar infliximab in patients with inflammatory arthritis – article) 2017. All rights reserved. No commercial use is permitted unless otherwise impact on s-infliximab and antidrug-antibodies. Results from the Danish expressly granted. Rheumatologic Biobank and the DANBIO registry. Abstract. Arthritis Rheumatol 2016;68(suppl 10). References 19 planès S, Villier C, Mallaret M. The nocebo effect of drugs. Pharmacol Res Perspect 1 Dörner T, Strand V, Cornes P, et al. The changing landscape of biosimilars in 2016;4:e00208. rheumatology. Ann Rheum Dis 2016;75:974–82. 20 Favalli EG, Pregnolato F, Biggioggero M, et al. Twelve-Year retention rate of First-Line 2 park W, Yoo DH, Jaworski J, et al. Comparable long-term efficacy, as assessed by tumor necrosis factor inhibitors in rheumatoid arthritis: real-life data from a local patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference registry. Arthritis Care Res 2016;68:432–9.

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