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).