Editorial Ann Rheum Dis: first published as 10.1136/ard.2009.111435 on 12 May 2009. Downloaded from

Therefore, while the improved metho- Diagnosing axial dology of this study to define new criteria for IBP are most welcome, whether the . The new new criteria represent a significant advance will, as the authors highlight, depend on further assessment, particu- Assessment in SpondyloArthritis larly validation in the primary care set- ting. international Society criteria: The subsequent two papers focus on the development2 and validation3 of can- didate classification criteria for axial SpA, MRI entering centre stage including patients with and without radiographic . These patients A N Bennett,2 H Marzo-Ortega,1 P Emery,1 without radiographic sacroiliitis have up 1 to now been mostly labelled as undiffer- D McGonagle, on behalf of the Leeds entiated SpA (uSpA) following The European Spondyloarthropathy Study Spondyloarthropathy Group Group criteria (ESSG).5 However, uSpA does not differentiate between patients In this issue of the Annals of Rheumatic where MRI is of recognised value as a with isolated axial or isolated peripheral Disease the Assessment in diagnostic and outcome tool.8914 disease. The data reported in this issue of SpondyloArthritis international Society Furthermore, with the emerging data on the journal show that it is possible to (ASAS) have published three interrelated the efficacy of tumour necrosis factor robustly classify cases of axial SpA hence papers (see pages 770, 777 and 784)1–3 (TNF)a blocking therapies in early dis- facilitating the conduct of future clinical that could contribute to a new era in the ease10 11 a new horizon has opened trials and observational studies. This is diagnosis and classification of axial spon- whereby AS sufferers can be identified particularly critical in the context of dyloathritis (SpA). The first paper focuses and treated in the early stages of their therapeutics as the newly proposed cri- on a new definition of inflammatory back disease process before structural damage teria might serve as a basis for a judicious pain (IBP), the ‘‘expert’’ criteria, followed has occurred. use of TNF blockers in the non-radio- by two reports on the development of In the first report Sieper et al1 propose graphic stage of axial SpA. This is all the new classification criteria for axial SpA new clinical criteria for IBP. The study more likely given the increasing evidence and their validation in a large multicentre adopted a novel approach in which the that MRI can predict the future develop- 14 15 study. These criteria for axial SpA will be ‘‘experts’’ were blinded to patient diag- ment of AS, that early preradiographic welcomed by the spondyloarthropathy nosis, and the criteria judged for an ability axial patients with SpA have just as much http://ard.bmj.com/ community, since the currently available to discriminate for a ‘‘diagnosis’’ of IBP disease activity and pain as established 7 criteria4–6 do not allow for the diagnosis of (rather than for a diagnosis of SpA, as AS and that early preradiographic axial 12 13 preradiographic axial SpA. The proposed previously performed). This, along SpA responds well to anti-TNF thera- 10 11 new set of criteria includes early (pre- with the robust statistical analysis, pies. radiographic) and established ankylosing performed using logistic regression to A strength of the ASAS papers lies (AS), recognising them as a identify which criteria/parameters inde- within the inclusion of international continuum of disease. This is of major pendently contributed specifically to IBP, experts’ opinions on 71 real-life paper on September 26, 2021 by guest. Protected copyright. importance as it is now clear that the are the strong points of the study. patients. Their opinion regarding diagno- burden of early AS is comparable to that However, the need for new criteria to sis, as well as the strength of certainty of of the later stages.7 The benefit of MRI in define IBP might be questioned since it is their opinion were sought with both the diagnosis of early axial SpA is recog- only 3 years after the last set of IBP being subsequently reviewed and accepted or rejected by a five-strong expert panel. nised by the authors and included in the criteria were published by the same core 12 The subsequent validation study3 is a new classification criteria. Indeed, the group. Indeed, the authors point out unique and unprecedented clinical study inclusion of MRI is the most significant that the existing criteria performed 4–6 reasonably well and that there are only in terms of international collaboration change compared to previous criteria small differences between the new and the recruitment of nearly 650 cases. and is in line with clinical experience criteria and the previous 2006 Berlin Although the mean duration of symp- criteria.12 In addition the new IBP criteria toms of the studied cohort was 6.1 years, surprisingly omit the assessment of early the patient population was representative morning stiffness (EMS) of greater than of the clinical spectrum of disease from 1 Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Chapel Allerton 30 min as well as pain in the second half early preradiographic axial involvement to Hospital, Chapeltown Road, Leeds LS7 4SA, UK; of the night, which were present in the radiographically confirmed sacroiliitis. 2 Defence Medical Rehabilitation Centre, Headley Court, previous criteria. These were dropped Given the emerging power of MRI for Epsom, Surrey KT18 6JN, UK because the duration of EMS and timing predicting the development of AS,14 15 this Correspondence to: Professor P Emery, of nocturnal pain were not specifically imaging modality was importantly Musculoskeletal Disease, Leeds Institute of Molecular analysed. Given the central role of EMS included in the assessment of these Medicine, University of Leeds, Clinical Director (), Director-Leeds MSK Biomedical duration in inflammatory rheumatic dis- patients. Research Unit, Chapel Allerton Hospital, Chapel Town eases this approach seems to lack face Of note, in the first classification Road, Leeds LS7 4SA, UK; [email protected] validity. paper,2 raised C-reactive protein (CRP)

Ann Rheum Dis June 2009 Vol 68 No 6 765 Editorial Ann Rheum Dis: first published as 10.1136/ard.2009.111435 on 12 May 2009. Downloaded from levels were more frequent in the non-SpA have improved the overall sensitivity and New criteria for inflammatory in patients with chronic back pain a real patient (42.1%) than the SpA population (27.8%), specificity of these criteria. exercise of the Assessment in SpondyloArthritis yet elevated CRP was included in set 1 Importantly the definition of active International Society (ASAS). Ann Rheum Dis and set 2 candidate classification criteria. MRI sacroiliitis is needed for research as 2009;68:784–8. 3 2. Rudwaleit M, Landewe´R, van der Heijde D, Listing However, in the validation paper this well as clinical practice. Variable J, Brandt J, Braun J, et al. The development of observation is reversed with raised CRP ‘‘degrees’’ of active MRI sacroiliitis are Assessment of SpondyloArthritis interntional Society being more common in SpA. Likewise in recognised depending on the intensity (ASAS) classification criteria for the initial classification2 of the three and/or extent of the MRI signal when (part I): classification of paper patients by expert 819 opinion including uncertainity appraisal. Ann Rheum studied IBP criteria, the new ‘‘expert’’ using fat suppression techniques which Dis 2009;68:770–6. criteria1 performed worse, with only may lead to different clinical and radio- 3. Rudwaleit M, van der Heijde D, Landewe´R, Listing 57.1% compared to 84.4% for the Calin graphic outcomes.14 Indeed, low grade J, Akkoc N, Brandt J, et al. The development of 13 Assessment of SpondyloArthritis International Society criteria and 85.3% for the Rudwaleit/ bone marrow oedema lesions as identified (ASAS) classification criteria for axial spondyloarthritis Berlin criteria.12 Again however this chan- by MRI are not specific for SpA and are (part II): validation and final selection. Ann Rheum Dis ged considerably in the follow-up valida- also evident in degenerative joint disease 2009;68:777–83. and occasionally in healthy people,818and 4. Amor B, Dougados M, Mijiyawa M. Criteria of the tion study. The proposed new classification of spondylarthropathies. Rev Rhum Mal classification criteria for axial SpA has an hence a clarifying definition of active MRI Osteoartic 1990;57:85–9. 82.9% sensitivity and 84.4% specificity sacroiliitis is essential. 5. Dougados M, van der Linden S, Juhlin R, Huitfeldt B, out of a large data set of 649 patients with In summary, these are exciting times in Amor B, Calin A, et al. The European Spondylarthropathy Study Group preliminary criteria a positive likelihood ratio of 5.3 for axial the field of research in SpA. Only a decade for the classification of spondylarthropathy. SpA, which increases the post-test prob- ago there was little recognition of early Rheum 1991;34:1218–27. ability of a diagnosis of axial SpA from disease and treatment in early and estab- 6. van der Linden S, Valkenburg HA, Cats A. Evaluation lished AS was woefully inadequate. Now, of diagnostic criteria for . A 60.2% to 89.0%. Furthermore when proposal for modification of the New York criteria. benchmarked against existing long-stand- we have widespread access to the non- Arthritis Rheum 1984;27:361–8. ing criteria such as the Amor and ESSG ionising radiation of fat suppression MRI 7. Rudwaleit M, Haibel H, Baraliakos X, Listing J, criteria,45they were shown to be superior. that can predict progression to AS as well Marker-Hermann E, Zeidler H, et al. The early disease stage in axial spondylarthritis: results from the One important observation is the fact as showing efficacy of TNF blocking German spondyloarthritis inception cohort. Arthritis that the reported studies further support agents in the suppression of Rheum 2009;60:717–27. the diagnostic utility of MRI in axial SpA. leading to major improvements in early 8. Marzo-Ortega H, Mc Gonagle D, O’Connor P, Hensor EMA, Bennett AN, Green M, et al. Baseline and one Indeed MRI of the sacroiliac joints (SIJs) and late disease. Furthermore MRI has a year magnetic resonance imaging of the sacroiliac changed the diagnosis to axial SpA in a major role in the diagnosis of the early joints and lumbar spine in early inflammatory back fifth of cases.2 These findings justify the disease stages. pain. The relationship between HLA-B27, symptoms The present studies have utilised a and disease extent and persistence. Ann Rheum Dis well established use by rheumatologists of 2008;67(Suppl II):377–8. MRI for the assessment of suspected AS breadth of expert knowledge on SpA and 9. Marzo-Ortega H, McGonagle D, O’Connor P, Emery in the real world clinical setting. MRI to take us further along the clinical P. Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: a

However, it also recognises the limita- translational road to a better understand- http://ard.bmj.com/ clinical and magnetic resonance imaging study. tions of MRI given that spinal/SIJ inflam- ing of axial SpA. The formulation of new Arthritis Rheum 2001;44:2112–17. mation is variable in the natural history of international classification criteria for 10. Barkham N, Keen H, Coates LC, O’Connor P, the disease, and that current MRI tech- axial SpA, which embraces early axial Hensor EMA, Fraser A, et al. A randomised SpA and AS, as described in this journal, is controlled trial of infliximab shows clinical and MRI nology has some limitations in detecting efficacy in patients with HLA-B27 positive very early active inflammation.16 This is shown by essential for future research and the ankylosing spondylitis. Arthritis Rheum the fact that only 38% and 65% of sample management of axial SpA. Given the 2007;56(Suppl):L11. 11. Haibel H, Rudwaleit M, Listing J, Heldmann F, falling costs of MRI and its great potential on September 26, 2021 by guest. Protected copyright. patients in the classification and valida- Wong RL, Kupper H, et al. Efficacy of adalimumab in tion paper, respectively, had a positive in SpA the case for using MRI in inception the treatment of axial spondylarthritis without MRI. Hence criteria have been established cohorts of patients with IBP, and other radiographically defined sacroiliitis: results of a that permit a diagnosis of axial SpA on non-IBP diagnosis for comparison, is twelve-week randomized, double-blind, placebo- growing. The present studies produce controlled trial followed by an open-label clinical grounds only without the need for extension up to week fifty-two. Arthritis Rheum a positive MRI. This is essential, partly for compelling evidence for the use of MRI 2008;58:1981–91. the diagnosis of the subgroup of axial SpA for the diagnostic evaluation of SpA in 12. Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. routine practice. However, it is vital to Inflammatory back pain in ankylosing spondylitis: a who present with normal MRI scans but reassessment of the clinical history for application as more importantly for clinicians who have remember that a negative MRI scan does classification and diagnostic criteria. Arthritis Rheum poor or no access to MRI scanning not exclude a diagnosis of SpA and that it 2006;54:569–78. facilities. can still be difficult to discern the basis of 13. Calin A, Porta J, Fries JF, Schurman DJ. Clinical some types of back pain even with IBP history as a screening test for ankylosing spondylitis. It should be noted that only the SIJs JAMA 1977;237:2613–4. were imaged with MRI in the initial and MRI criteria. 14. Bennett AN, McGonagle D, O’Connor P, classification paper, and in the validation Hensor EM, Sivera F, Coates LC, et al. Severity of Competing interests: PE and HM-O are members of baseline magnetic resonance imaging-evident paper only a proportion of the 650 patients Assessment in SpondyloArthritis international Society sacroiliitis and HLA-B27 status in early inflammatory had spinal as well as SIJ MRI. Spinal (ASAS). back pain predict radiographically evident ankylosing inflammation is well recognised in SpA Accepted 10 March 2009 spondylitis at eight years. Arthritis Rheum 2008;58:3413–8. and it has been reported that as many as Ann Rheum Dis 2009;68:765–767. 15. Oostveen J, Prevo R, den Boer J, van de Laar M. 23% of patients with clinically active AS doi:10.1136/ard.2009.111435 Early detection of sacroiliitis on magnetic resonance have normal MRI of the SIJ17 and that imaging and subsequent development of sacroiliitis on thoracic spinal lesions are as common as SIJ plain radiography. A prospective, longitudinal study. J Rheumatol 1999;26:1953–8. 18 REFERENCES lesions. Therefore classification criteria 1. Sieper J, van der Heijde DM, Landewe´RBM, 16. Appel H, Kuhne M, Spiekermann S, Ebhardt H, that include spinal as well as SIJ MRI could Brandt J, Burgos-Vargas R, Collantes Este´vez E, et al. Grozdanovic Z, Kohler D, et al. Immunohistologic

766 Ann Rheum Dis June 2009 Vol 68 No 6 Editorial Ann Rheum Dis: first published as 10.1136/ard.2009.111435 on 12 May 2009. Downloaded from analysis of zygapophyseal joints in patients with ankylosing spondylitis. Ann Rheum Dis 19. Puhakka KB, Jurik AG, Schiottz-Christensen B, ankylosing spondylitis. Arthritis Rheum 2008;67:1276–81. Hansen GV, Egund N, Christiansen JV, et al. 2006;54:2845–51. 18. Bennett AN, Rehman A, Hensor EMA, Marzo-Ortega MRI abnormalities of sacroiliac joints 17. Rudwaleit M, Schwarzlose S, Hilgert ES, Listing J, H, Emery P, Mc Gonagle D. Evaluation of the in early spondylarthropathy:a 1-year follow-up Braun J, Sieper J. MRI in predicting a major clinical diagnostic utility of spinal MRI in axial study. Scand J Rheumatol response to anti-tumour necrosis factor treatment in spondyloarthritis. Arthritis Rheum 2009. In press. 2004;33:332–8.

drug development, the length of the New tumour necrosis factor regulatory process and the risks of first agents in a class not achieving registra- inhibitors for rheumatoid tion. It seems unlikely that ‘‘me too’’ products stifle the development of novel agents; recent history suggests ‘‘me too’’ arthritis: are there benefits from agents are an inevitable part of the process of finding new products.7 extending choice? Two RCT reported in this issue evalu- ated the new TNF inhibitors combined 1 2 with methotrexate in disease-modifying David L Scott, Andrew Cope antirheumatic drug (DMARD) non-respon- ders. American College of Rheumatology Certolizumab pegol (UCB, Brussels, too’’ replications, although the latter 50% improvement (ACR50) responder Belgium) and golimumab (Centocor, products might perform better. Lee4 has rates at 6 months can be used to place the Horsham, Pennsylvania, USA) are the elegantly summarised the arguments for results in context. With golimumab–meth- latest tumour necrosis factor (TNF) inhibi- ‘‘me too’’ products, indicating that their otrexate ACR50 responder rates were 35% 2 tors evaluated in double-blind, multicentre presence ‘‘does not mean that imitation compared with 14% with controls; in a randomised controlled trials (RCT). has replaced innovation’’. Successful ‘‘me previous dose-ranging trial ACR50 respon- Certolizimab is the pegylated (polyethy- too’’ treatments improve efficacy, reduce der rates were 31% with active treatment 8 lene glycolated) Fab9 fragment derived toxicity and increase ‘‘cost effectiveness’’. and 6% in controls. Certolizumab pegol/ from a high affinity humanised anti- With biological agents such as TNF methotrexate gave ACR50 responder rates 1 TNFa monocolonal antibody (mAb). Fab9 inhibitors their added benefits may of 33% compared with 3% with controls; fragments lack the Fc portion of immuno- include more favourable routes or fre- in a previous phase III trial ACR50 respon- globulin, and so the repertoire of Fc- quencies of administration. der rates were 37–40% compared with 8% 9 mediated effector responses, such as com- There are cogent reasons to anticipate with controls. We extended this analysis plement or antibody-dependent cell- that ‘‘me too’’ biological agents will be of ACR50 responder rates at 6 months

across TNF inhibitor–methotrexate combi- http://ard.bmj.com/ mediated cytotoxicity, is distinct from commonplace as experience with these nations, using key RCT in established RA those of other anti-TNF mAb. agents solidifies and their use increases. identified in a previous systematic Nonetheless, it still neutralises membrane There may be special factors with biolo- review.10–13 Although this analytical TNFa. Derivatisation of the Fab9 fragment gicals, particularly around their mechan- approach has its limitations as the trials prolongs the plasma half-life to 2 weeks. ism of action, which may complicate the were undertaken at different times and in Certolizumab pegol is administered by comparison of different ‘‘me too’’ pro- subcutaneous injection (200 or 400 mg) different populations, it is possible to gain

ducts. Nevertheless, it is generally appro- on September 26, 2021 by guest. Protected copyright. some understanding of the overall efficacy every 2 weeks. Golimumab is a human priate to assume that what holds for of different TNF inhibitors from this type anti-TNF mAb administered by subcuta- conventional drugs also holds for large neous injections (50 or 100 mg) every of comparative analysis. The number molecules with regard to the benefits of 4weeks. Three RCT in this issue of needed to treat (NNT) to achieve an ‘‘me too’’ products. Indeed, regulatory Annals of the Rheumatic Diseases,1–3 (see ACR50 response compared with metho- developments have paved the way for pages 789, 797 and 805) which report trexate monotherapy ranges from 3 to 5 future biosimilars or follow-on biologicals their use in active (table 1). These results show that both to be developed as the patent life of (RA), raise two questions. First, do we need established and new TNF inhibitors have established molecules draws to a close.5 more TNF inhibitors? Second, how effec- similar efficacy when combined with There are many critics of ‘‘me too’’ tive and safe are these new TNF inhibitors? methotrexate. conventional drugs.6 Clinicians often use Successful drugs are invariably repli- Established TNF inhibitors prevent ero- only one or two drugs in each class and cated. ‘‘Breakthrough’’ treatments sound sive progression over 12 months and may not need wide choices. Furthermore, more impressive than subsequent ‘‘me beyond. Comparative 6-month data for much expenditure on drugs is attributable certolizumab pegol suggest it reduces to high-cost ‘‘me too’’ products. However, 1 Academic Department of Rheumatology, King’s College erosive damage and its efficacy is similar 11213 London School of Medicine, Weston Education Centre, this issue is complex because it could to etanercept and adalimumab (fig 1). King’s College London, London, UK; 2 Academic represent either high expenditure on Whereas conventional assessments of Department of Rheumatology, King’s College London unneeded replication or a realistic prefer- erosive damage use 12-month changes, 6- School of Medicine, Guy’s Hospital, London, UK ence for refined ‘‘me too’’ products over month changes are equally impressive Correspondence to: Professor D L Scott, Academic less effective or more toxic ‘‘break- with all these agents. Although compar- Department of Rheumatology, King’s College London through’’ products. Overall, the prolifera- School of Medicine, Weston Education Centre, King’s able 6-month data on erosive progression College London, 10 Cutcombe Road, London SE5 9RS, tion of agents in a successful treatment are not available for infliximab and UK; [email protected] class reflects the competitive nature of golimumab, their absence is most likely

Ann Rheum Dis June 2009 Vol 68 No 6 767 Corrections

The department of one of the authors who co-authored all of the below papers has found that the affi liations were not correct. The correct affi liations for Professor P Emery, for all of the below articles, are: 1Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds; 2NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, UK.

1. Keystone E, Emery P, Peterfy CG, et al. Rituximab inhibits structural joint damage in 21. Machold KP, Landewé R, Smolen JS, et al. The Stop Arthritis Very Early (SAVE) trial, patients with rheumatoid arthritis with an inadequate response to tumour necrosis an international multicentre, randomised, double-blind, placebo-controlled trial on factor inhibitor therapies. Ann Rheum Dis 2009;68:216–21. glucocorticoids in very early arthritis. Ann Rheum Dis 2010;69:495–502. 2. Doward LC, McKenna SP, Whalley D, et al. The development of the L-QoL: a 22. Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to quality-of-life instrument specifi c to systemic lupus erythematosus. Ann Rheum Dis target: results of a systematic literature search. Ann Rheum Dis 2010;69:638–43. 2009;68:196–200. 23. Smolen JS, Aletaha D, Bijlsma JW, et al.; T2T Expert Committee. Treating 3. Potter C, Hyrich KL, Tracey A, et al. Association of and anti- rheumatoid arthritis to target: recommendations of an international task force. cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 Ann Rheum Dis 2010;69:631–7. susceptibility variants, with anti-TNF response in RA. Ann Rheum Dis 2009;68:69–74. 24. Burr ML, Naseem H, Hinks A, et al.; BIRAC Consortium; YEAR Consortium. PADI4 4. Smolen JS, Han C, van der Heijde DM, et al.; Active-Controlled Study of Patients genotype is not associated with rheumatoid arthritis in a large UK Caucasian Receiving Infl iximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) population. Ann Rheum Dis 2010;69:666–70. Study Group. Radiographic changes in rheumatoid arthritis patients attaining 25. Emery P, Durez P, Dougados M, et al. Impact of T-cell costimulation modulation different disease activity states with methotrexate monotherapy and infl iximab plus in patients with undifferentiated infl ammatory arthritis or very early rheumatoid methotrexate: the impacts of remission and tumour necrosis factor blockade. arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann Rheum Dis Ann Rheum Dis 2009;68:823–7. 2010;69:510–16. 5. Buch MH, Boyle DL, Rosengren S, et al. Mode of action of abatacept in rheumatoid 26. Bennett AN, Rehman A, Hensor EM, et al. The fatty Romanus lesion: a non- arthritis patients having failed tumour necrosis factor blockade: a histological, gene infl ammatory spinal MRI lesion specifi c for axial spondyloarthropathy. Ann Rheum Dis expression and dynamic magnetic resonance imaging pilot study. Ann Rheum Dis 2010;69:891–4. 2009;68:1220–7. 27. Nam JL, Winthrop KL, van Vollenhoven RF, et al. Current evidence for the 6. Emery P, Van Vollenhoven R, Ostergaard M, et al. Guidelines for initiation of anti- management of rheumatoid arthritis with biological disease-modifying antirheumatic tumour necrosis factor therapy in rheumatoid arthritis: similarities and differences drugs: a systematic literature review informing the EULAR recommendations for the across Europe. Ann Rheum Dis 2009;68:456–9. management of RA. Ann Rheum Dis 2010;69:976–86. 7. Bejarano V, Conaghan PG, Proudman SM, et al. Long-term effi cacy and toxicity of 28. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the ciclosporin A in combination with methotrexate in poor prognosis rheumatoid arthritis. management of rheumatoid arthritis with synthetic and biological disease-modifying Ann Rheum Dis 2009;68:761–3. antirheumatic drugs. Ann Rheum Dis 2010;69:964–75. 8. Rudwaleit M, Landewé R, van der Heijde D, et al. The development of 29. Tan RJ, Gibbons LJ, Potter C, et al.; BRAGGSS. Investigation of rheumatoid arthritis Assessment of SpondyloArthritis international Society classifi cation criteria for axial susceptibility genes identifi es association of AFF3 and CD226 variants with response spondyloarthritis (part I): classifi cation of paper patients by expert opinion including to anti-tumour necrosis factor treatment. Ann Rheum Dis 2010;69:1029–35. uncertainty appraisal. Ann Rheum Dis 2009;68:770–6. 30. Robinson JI, Barrett JH, Taylor JC, et al.; YEAR Consortium; BRAGGSS. Dissection of 9. Bennett AN, Marzo-Ortega H, Emery P, et al.; Leeds Spondyloarthropathy Group. the FCGR3A association with RA: increased association in men and with autoantibody Diagnosing axial spondyloarthropathy. The new Assessment in SpondyloArthritis positive disease. Ann Rheum Dis 2010;69:1054–7. international Society criteria: MRI entering centre stage. Ann Rheum Dis 2009;68:765–7. 31. Cohen SB, Keystone E, Genovese MC, et al. Continued inhibition of structural 10. Marzo-Ortega H, McGonagle D, O’Connor P, et al. Baseline and 1-year magnetic damage over 2 years in patients with rheumatoid arthritis treated with rituximab in resonance imaging of the sacroiliac joint and lumbar spine in very early infl ammatory combination with methotrexate. Ann Rheum Dis 2010;69:1158–61. back pain. Relationship between symptoms, HLA-B27 and disease extent and 32. Haugeberg G, Bennett AN, McGonagle D, et al. Bone loss in very early infl ammatory persistence. Ann Rheum Dis 2009;68:1721–7. back pain in undifferentiated spondyloarthropathy: a 1-year observational study. 11. Gilworth G, Emery P, Gossec L, et al. Adaptation and cross-cultural validation Ann Rheum Dis 2010;69:1364–6. of the rheumatoid arthritis work instability scale (RA-WIS). Ann Rheum Dis 33. Schoels M, Aletaha D, Smolen JS, et al. Follow-up standards and treatment targets 2009;68:1686–90. in rheumatoid arthritis: results of a questionnaire at the EULAR 2008. Ann Rheum Dis 12. Gilworth G, Emery P, Gossec L, et al. Adaptation and cross-cultural validation of the 2010;69:575–8. RA-WIS (Work Instability Scale). Ann Rheum Dis 2009;68:1686–90. 34. Eyre S, Flynn E, Martin P, et al. No evidence for association of the KLF12 gene with 13. Jarrett SJ, Sivera F, Cawkwell LS, et al. MRI and clinical fi ndings in patients with rheumatoid arthritis in a large UK cohort. Ann Rheum Dis 2010;69:1407–8. ankylosing spondylitis eligible for anti-tumour necrosis factor therapy after a short 35. Eyre S, Hinks A, Flynn E, et al. Confi rmation of association of the REL locus course of etoricoxib. Ann Rheum Dis 2009;68:1466–9. with rheumatoid arthritis susceptibility in the UK population. Ann Rheum Dis 14. Haugeberg G, Conaghan PG, Quinn M, et al. Bone loss in patients with active early 2010;69:1572–3. rheumatoid arthritis: infl iximab and methotrexate compared with methotrexate 36. Orozco G, Eyre S, Hinks A, et al.; Wellcome Trust Case Control consortium YEAR treatment alone. Explorative analysis from a 12-month randomised, double-blind, Consortium. Association of CD40 with rheumatoid arthritis confi rmed in a large UK placebo-controlled study. Ann Rheum Dis 2009;68:1898–901. case-control study. Ann Rheum Dis 2010;69:813–16. 15. Genovese MC, Breedveld FC, Emery P, et al. Safety of biological therapies 37. Emery P, Durez P, Dougados M, et al. Impact of T-cell costimulation modulation following rituximab treatment in rheumatoid arthritis patients. Ann Rheum Dis in patients with undifferentiated infl ammatory arthritis or very early rheumatoid 2009;68:1894–7. arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann Rheum Dis 16. Kekow J, Moots RJ, Emery P, et al. Patient-reported outcomes improve with 2010;69:510–16. etanercept plus methotrexate in active early rheumatoid arthritis and the improvement 38. Saleem B, Keen H, Goeb V, et al. Patients with RA in remission on TNF blockers: when is strongly associated with remission: the COMET trial. Ann Rheum Dis 2010;69:222–5. and in whom can TNF blocker therapy be stopped? Ann Rheum Dis 2010;69:1636–42. 17. Furst DE, Keystone EC, Fleischmann R, et al. Updated consensus statement on 39. Barkham N, Coates LC, Keen H, et al. Double-blind placebo-controlled trial of biological agents for the treatment of rheumatic diseases, 2009. Ann Rheum Dis etanercept in the prevention of work disability in ankylosing spondylitis. Ann Rheum Dis 2010;69(Suppl 1):i2–29. 2010;69:1926–8. 18. Freeston JE, Wakefi eld RJ, Conaghan PG, et al. A diagnostic algorithm for 40. Emery P, Deodhar A, Rigby WF, et al. Effi cacy and safety of different doses and persistence of very early infl ammatory arthritis: the utility of power Doppler ultrasound retreatment of rituximab: a randomised, placebo-controlled trial in patients who when added to conventional assessment tools. Ann Rheum Dis 2010;69:417–9. are biological naive with active rheumatoid arthritis and an inadequate response to 19. Jones E, Churchman SM, English A, et al. Mesenchymal stem cells in rheumatoid methotrexate (Study Evaluating Rituximab’s Effi cacy in MTX iNadequate rEsponders synovium: enumeration and functional assessment in relation to synovial infl ammation (SERENE)). Ann Rheum Dis 2010;69:1629–35. level. Ann Rheum Dis 2010;69:450–7. 41. Dixon WG, Hyrich KL, Watson KD, et al.; BSRBR Control Centre Consortium; British 20. Alten RE, Zerbini C, Jeka S, et al. Effi cacy and safety of pamapimod in patients with Society for Rheumatology Biologics Register. Infl uence of anti-TNF therapy on mortality active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis in patients with rheumatoid arthritis-associated interstitial lung disease: results from the 2010;69:364–7. British Society for Rheumatology Biologics Register. Ann Rheum Dis 2010;69:1086–91.

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