Therapy strategies in psoriatic arthritis L.C. Coates

Leeds Institute of Rheumatic and ABSTRACT RCT and the associated potential risks Musculoskeletal Medicine, University Psoriatic arthritis (PsA) is a heteroge- of these should be elucidated. of Leeds, UK, and Leeds Musculoskeletal neous condition with a myriad of differ- Currently, most clinical practice is to Biomedical Research Unit, Leeds ent clinical presentations. It commonly use a step up approach to minimise Teaching Hospitals Trust, UK; Division of Allergy, Immunology and affects the skin and musculoskeletal potential toxicity, as chosen by the ex- Rheumatology, University of Rochester system causing psoriasis, peripheral pert committee drafting the European Medical Center, Rochester, New York, USA. arthritis, axial arthritis, enthesitis and League Against Rheumatism (EULAR) Laura C. Coates, MBChB, MRCP, PhD dactylitis. Many patients also have re- recommendations for PsA. The com- Please address correrspondence to: lated conditions, such as those within mittee recommends initial use of sin- Dr Laura Coates, the metabolic syndrome and associ- gle DMARDs, followed by a second University of Leeds, ated spondyloarthritis (SpA) conditions DMARD either in series or in combina- Chapel Allerton Hospital, 2nd Floor, including inflammatory bowel disease tion, or an escalation to biologic therapy, Harehills Lane, and uveitis. Any therapeutic strategy depending on the presence or absence of Leeds LS7 4SA, United Kingdom. must be tailored to the individual pa- poor prognostic markers (2). The mark- E-mail: [email protected] tient, taking into account her/his com- ers included are based on prognosis Received and accepted on August 20, 2015. plete clinical presentation and comor- studies investigating predictors of sub- Clin Exp Rheumatol 2015; 33 (Suppl. 93): bidities. New treatment recommenda- sequent joint damage and functional S70-S72. tions from the Group for Research and impairment and include raised inflam- © Copyright Clinical and Assessment of Psoriasis and Psoriatic matory markers, polyarticular involve- Experimental Rheumatology 2015. Arthritis (GRAPPA) provide evidence ment, previous joint damage and func- based recommendations on effective tional impairment. Key words: psoriatic arthritis, therapies for the management of each therapy strategies different manifestation of PsA, and how Early intervention treatment may be affected by comorbidi- Observational data have indicated that ties (1). However, the limited evidence a longer delay in diagnosis is associated comparing different treatment strategies with poorer outcomes in PsA. A shorter in PsA is recognised as a limitation in duration of symptoms prior to diagnosis these recommendations and further in- was associated with improved disease formation is detailed below. activity outcomes at 5-year follow-up (3) in patients in a Swedish early PsA Treatment plans: step up versus registry. Tillett et al. identified that a step down? >12 months delay in diagnosis was a Research into therapeutic strategies significant predictor of functional- im in PsA is limited. When using dis- pairment at 10 years (4). Haroon et al. ease-modifying anti-rheumatic drugs found in 283 patients with PsA that (DMARDs), one of the common ques- patients with more than 6 months of tions, more widely studied in RA, in- symptoms prior to a diagnosis are more volves step up versus step down thera- likely to have erosive peripheral joint py. In step up, one therapy is prescribed disease, arthritis mutilans, joint deform- initially, before moving onto combined ity, functional impairment and sacroili- therapies if there is an incomplete re- itis, and were significantly less likely to sponse (or none) according to defined achieve a drug free remission (5). criteria. By contrast, step down therapy The above evidence supports a likely directs that treatment is initiated aggres- benefit for early intervention in PsA, sively with combination therapies, and but prospective clinical trial evidence these are gradually reduced if patients is limited. The only trial assessing im- Competing interests: L.C. Coates is achieve a predefined goal. To date, no mediate versus delayed DMARD pre- funded by the NIHR as a Clinical Lecturer, and has received research research in PsA has compared these ap- scription did not show a significant dif- funding and/or honoraria from Abbvie, proaches. The potential benefits of early ference at 6 months but it was markedly Boehringer-Ingelheim, Pfizer, UCB, combination or aggressive treatment underpowered with only 35 patients in Celgene, Janssen and MSD. strategies should be examined in an the entire study. This trial also was an

S-70 Therapy strategies in psoriatic arthritis/ L.C. Coates open label study and patients were trat- principally looking for “strategic studies the primary search: “strategic studies ed with relatively low doses of metho- that compared a therapy steered towards that compared a therapy steered towards trexate (10 mg/week) which may not a prespecified treatment target versus a a prespecified treatment target versus be effective. There has been one large conventional non-steered approach”. At a conventional non-steered approach”. randomised controlled trial (RCT) of a the time, they identified that there were The Tight Control of Psoriatic Arthritis tumour necrosis factor inhibitor (TNFi) no studies in any of the SpA, including (TICOPA) study recruited 206 patients in early PsA which showed higher than PsA that fulfilled this description. They with recent onset PsA. They were ran- expected responses in both the metho- did find a small number of studies where domised 1:1 to tight control or standard trexate (control) group and the TNFi treatment was changed based on a pre- care. Patients in the tight control arm group (6), potentially suggesting a bet- specified target, but not with a compari- were reviewed every 4 weeks by the ter outcome when therapies are used son group. The majority of these were research rheumatologists, and treatment earlier in the course of the disease. large RCTs of TNF inhibitors in PsA was escalated if they did not meet MDA However, this study was also open label which had “early escape” arms if a mini- criteria. The study used a treatment al- in comparison to the majority of TNFi mal improvement in joint counts was not gorithm of methotrexate, combination trials in established disease which re- seen at 12 or 16 weeks (15). DMARDs and biologic agents in a step- port double-blind outcomes. There are One issue raised by the EULAR litera- up design. Patients in the standard care obvious cautions in comparing out- ture review and subsequent recommen- arm were reviewed every 12 weeks and comes between two separate trials, so dations on treatment to target in SpA were treated by their usual rheumatolo- again this evidence is inconclusive. (16) was the difficulty in identifying an gist. There were no limitations on their appropriate target. The EULAR task- care, except compliance with UK NICE Treatment to target force recommended remission as the criteria for the use of TNF inhibitors in The concept of “tight control” or “treat- main target for all SpA with low disease PsA which was standard across both to-target” was developed in rheumatoid activity as an alternative target (16). At trial arms (21). arthritis (RA) following clinical and that time, there are were remission crite- The odds of achieving ACR20, the pri- imaging studies suggesting that ac- ria validated in PsA; The best validated mary outcome, at 48 weeks were sig- tive inflammation predicted future joint criteria defining low disease activity nificantly higher in the tight control arm damage (7, 8). A pivotal study was the and remission combined are the mini- (OR 1.91, p=0.0392) using intention to Tight Control of RA (TICORA) study mal disease activity (MDA) criteria for treat analysis. The odds of achieving which showed a significant benefit after PsA (17). These criteria do not provide a ACR50, ACR70 and PASI75 also were 18 months of therapy despite only using disease activity score, only a definition significantly higher for the tight control conventional DMARDs and corticos- of a low disease state. They have been group. Greater improvements were also teroids. Patients in the tight control arm validated in observational cohorts and seen with tight control in patient-report- who continued to have a DAS>2.4 at in RCT data showing responsiveness to ed outcomes including physical func- their monthly visits had their DMARD change, agreement with treatment deci- tion (HAQ), quality of life (PsQOL) therapy escalated and were given addi- sions (18), differentiation between drug and also BASDAI and BASFI for those tional systemic or intra-articular steroids and placebo and correlation with other with axial disease. No difference was up to 120 mg per visit. At the end of the outcome measures. seen in radiographic progression be- study, 82% of tight control patients met These analyses also confirmed prog- tween the two arms; however, the mean the EULAR good response compared to nostic value with patients in consistent change in modified van der Heijde- 44% of controls (p<0.0001) (9). Further MDA having less progression in clinical Sharp score was zero in both groups. studies confirmed the benefit of treating joint damage (18) and radiographic out- The tight control arm was associated to an objective target including using come (19). Proposed definitions of low with increased rates of adverse events computer designed algorithms (10, 11) disease activity have also now been de- and serious adverse events, which may and this approach is now recommended veloped for the new composite measures have been due to the more rapid escala- in the UK as standard of care in the clinic in PsA: the PASDAS, the GRACE index tion of DMARD therapy (22). with newly diagnosed RA patients (12). and the CPDAI (20) but these have not Following the success in RA, the con- yet been validated. The other key con- Reduction or withdrawal of therapy cept of treat to target developed in the sideration for routine clinical use is fea- Given the excellent responses with spondyloarthritides (SpA). In PsA, data sibility. The MDA criteria can be applied newer biological drugs and their rela- support a link between inflammation and in around 5–10 minutes in the clinic, but tively high cost, research has been subsequent radiographic damage, such the PASDAS, CPDAI and GRACE indi- initiated to address whether treatments as evidence from the Toronto cohort ces require more time to perform. could be reduced or withdrawn (23). that active inflamed joints predict future Cantini et al. reported over 50% of PsA radiographic joint damage (14). A large The TICOPA study patients achieving remission by strict, literature review was performed in 2011 Since the EULAR review and recom- though unvalidated, criteria modified by EULAR to identify research relevant mendations have been published, one from the ACR RA criteria. Medica- to treat to target in SpA (15). They were study has been reported which does fit tion was suspended after patients had

S-71 Therapy strategies in psoriatic arthritis/ L.C. Coates been in remission for ≥4 months, and References 15. SCHOELS MM, BRAUN J, DOUGADOS M et the mean duration of remission was 12 1. COATES LC, KAVANAUGH A, MEASE P et al.: al.: Treating axial and peripheral spondyloar- Group for Research and Assessment of Pso- thritis, including psoriatic arthritis, to target: months after this treatment suspension riasis and Psoriatic Arthritis: Treatment Rec- results of a systematic literature search to (24). This report encouraged further ommendations for Psoriatic Arthritis 2015. support an international treat-to-target recom- treatment withdrawal studies; however, Arthritis Rheum 2015: submitted. mendation in spondyloarthritis. Ann Rheum 2. GOSSEC L, SMOLEN JS, GAUJOUX-VIALA C Dis 2014; 73: 238-42. two recent studies have shown a high et al.: European League Against Rheuma- 16. SMOLEN JS, BRAUN J, DOUGADOS M et al.: rate of relapse. In one study, 20 of 26 tism recommendations for the management Treating spondyloarthritis, including anky- patients had disease recurrence after a of psoriatic arthritis with pharmacological losing spondylitis and psoriatic arthritis, to mean of just 74 days (25). In a small therapies. Ann Rheum Dis 2012; 71: 4-12. target: recommendations of an international 3. THEANDER E, HUSMARK T, ALENIUS GM et task force. Ann Rheum Dis 2014; 73: 6-16. pilot study in the UK, 17 patients were al.: Early psoriatic arthritis: short symptom 17. COATES LC, FRANSEN J, HELLIWELL PS: randomised 2:1 to treatment withdrawal duration, male gender and preserved physical Defining minimal disease activity in - psori with 6 of the 11 flaring within 3 months functioning at presentation predict favourable atic arthritis: a proposed objective target for outcome at 5-year follow-up. Results from treatment. Ann Rheum Dis 2010; 69: 48-53. and additional patients flaring beyond the Swedish Early Psoriatic Arthritis Register 18. COATES LC, COOK R, LEE KA, CHANDRAN the follow up time of the trial (26). In (SwePsA). Ann Rheum Dis 2014; 73: 407-13. V, GLADMAN DD: Frequency, predictors, and both studies, most patients were able to 4. TILLETT W, JADON D, SHADDICK G et al.: prognosis of sustained minimal disease activi- Smoking and delay to diagnosis are associat- ty in an observational psoriatic arthritis cohort. recapture their disease control after re- Arthritis Care Res (Hoboken) 2010; 62: 970-6. ed with poorer functional outcome in psoriatic starting therapies (25, 26). arthritis. Ann Rheum Dis 2013; 72: 1358-61. 19. COATES LC, HELLIWELL PS: Validation of Other studies have looked at dose reduc- 5. HAROON M, GALLAGHER P, FITZGERALD O: minimal disease activity for psoriatic arthri- tions with greater success. In Barcelona, Diagnostic delay of more than 6 months con- tis using interventional trial data. Arthritis tributes to poor radiographic and functional Care and Research 2010; 62: 965-69. 153 patients who were taking biologic outcome in psoriatic arthritis. Ann Rheum 20. HELLIWELL PS, FITZGERALD O, FRANSEN agents were reviewed, including 20 Dis 2015; 74: 1045-50. J: Composite disease activity and responder with PsA. Half of the PsA patients had 6. BARANAUSKAITE A, RAFFAYOVA H, KUN- indices for psoriatic arthritis: a report from GUROV NV et al.: Infliximab plus methotrex- the GRAPPA 2013 meeting on development reduced the dose of their therapy with ate is superior to methotrexate alone in the of cutoffs for both disease activity states and no adverse effects (27). In a later study, treatment of psoriatic arthritis in methotrex- response. J Rheumatol 2014; 41: 1212-7. 102 PsA patients on treatment were as- ate-naive patients: the RESPOND study. Ann 21. COATES LC, NAVARRO-COY N, BROWN SR et al.: The TICOPA protocol (TIght COntrol of sessed using clinical outcome measures Rheum Dis 2012; 71: 541-8. 7. PLANT MJ, WILLIAMS AL, O’SULLIVAN MM, Psoriatic Arthritis): a randomised controlled and musculoskeletal ultrasound. One LEWIS PA, COLES EC, JESSOP JD: Relation- trial to compare intensive management ver- quarter were receiving tapered doses ship between time-integrated C-reactive sus standard care in early psoriatic arthritis. of biologic agents following a period protein levels and radiologic progression in BMC Musculoskelet Disord 2013; 14: 101. patients with rheumatoid arthritis. Arthritis 22. COATES LC, MOVERLEY AR, McPARLAND L of time in remission or MDA. No sig- Rheum 2000; 43: 1473-7. et al.: Results of a randomised controlled tri- nificant differences were seen in any of 8. McQUEEN FM, BENTON N, PERRY D et al.: al comparing tight control of early psoriatic the outcomes for those taking full dose, Bone edema scored on magnetic resonance arthritis (TICOPA) with standard care: tight imaging scans of the dominant carpus at control improves outcome. Arthritis Rheum or those who had reached satisfactory presentation predicts radiographic joint dam- 2013; 65: S346. disease control and had their treatment age of the hands and feet six years later in 23. TANAKA Y, HIRATA S, SALEEM B, EMERY P: doses reduced (28). patients with rheumatoid arthritis. Arthritis Discontinuation of biologics in patients with Rheum 2003; 48: 1814-27. rheumatoid arthritis. Clin Exp Rheumatol 9. GRIGOR C, CAPELL H, STIRLING A et al.: 2013; 31 (Suppl. 78): S22-7. Summary Effect of a treatment strategy of tight control 24. CANTINI F, NICCOLI L, NANNINI C et al.: The key to managing PsA effectively for rheumatoid arthritis (the TICORA study): Frequency and duration of clinical remission in patients with peripheral psoriatic arthritis is to tailor treatment to the individual a single-blind randomised controlled trial. Lancet 2004; 364: 263-9. requiring second-line drugs. Rheumatology patient depending on the manifestation 10. FRANSEN J, MOENS HB, SPEYER I, van RIEL (Oxford) 2008; 47: 872-6. of their disease. Recent international PL: Effectiveness of systematic monitor- 25. ARAUJO EG, FINZEL S, ENGLBRECHT M et treatment recommendations provide ing of rheumatoid arthritis disease activity al.: High incidence of disease recurrence in daily practice: a multicentre, cluster ran- after discontinuation of disease-modifying evidence based and expert opinion domised controlled trial. Ann Rheum Dis antirheumatic drug treatment in patients with based therapy options, but considerable 2005; 64: 1294-8. psoriatic arthritis in remission. Ann Rheum research is required to establish optimal 11. VERSTAPPEN SM, JACOBS JW, van der VEEN Dis 2015; 74: 655-60. MJ et al.: Intensive treatment with methotrex- 26. MOVERLEY A, COATES L, MARZO-ORTEGA H treatment algorithms for patients with ate in early rheumatoid arthritis: aiming for et al.: A feasibility study for a randomised con- PsA. There is evidence that treating to remission. Computer Assisted Management trolled trial of treatment withdrawal in psoriatic target using the MDA criteria can im- in Early Rheumatoid Arthritis (CAMERA, arthritis (REmoval of treatment for patients in prove outcomes across multiple meas- an open-label strategy trial). Ann Rheum Dis REmission in psoriatic ArThritis (RETREAT 2007; 66: 1443-9. (F)). Clin Rheumatol 2015; 34: 1407-12. ures in patients with recent onset PsA. 12. National Institute for Health and Clini- 27. INCIARTE-MUNDO J, HERNANDEZ MV, In those responding well to therapy, cal Excellence: The management of rheu- ROSARIO V et al.: Reduction of biological treatment withdrawal often has been matoid arthritis in adults. 2009. agent dose in rheumatic diseases: descriptive 13. GLADMAN DD, FAREWELL VT: Progression in analysis of 153 patients in clinical practice associated with recurrence of disease, psoriatic arthritis: role of time varying clinical conditions. Reumatol Clin 2014; 10: 10-6. but there is an increasing observational indicators. J Rheumatol 1999; 26: 2409-13. 28. JANTA I, MARTINEZ-ESTUPINAN L, VALOR L body of evidence for safe dose reduc- 14. BOND SJ, FAREWELL VT, SCHENTAG CT et et al.: Comparison between full and tapered al.: Predictors for radiological damage in dosages of biologic therapies in psoriatic tion after remission or low disease ac- psoriatic arthritis: results from a single cen- arthritis patients: clinical and ultrasound as- tivity has been reached. tre. Ann Rheum Dis 2007; 66: 370-6. sessment. Clin Rheumatol 2015; 34: 935-42.

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