Rheumatoid arthritis RMD Open: first published as 10.1136/rmdopen-2015-000127 on 5 August 2015. Downloaded from REVIEW Biologicals in rheumatoid arthritis: current and future Ali Berkant Avci,1 Eugen Feist,2 Gerd-R Burmester2 To cite: Avci AB, Feist E, ABSTRACT Key messages Burmester G-R. Biologicals in The aim of the review is to highlight the current rheumatoid arthritis: current knowledge about established and new biologicals and ▸ and future. RMD Open Biological disease-modifying antirheumatic to summarise recent advances by focusing on 2015;1:e000127. drugs (DMARDs) have translated the knowledge doi:10.1136/rmdopen-2015- comparative efficacy, safety and possible on molecular pathways into targeted therapies 000127 discontinuation of treatment in patients with and are increasingly used in patients with rheumatoid arthritis (RA). Up to now, comparative rheumatoid arthritis (RA) with excellent efficacy analyses showed only minor differences with respect to ▸ Prepublication history for and acceptable safety. efficacy and safety among the established biologicals. this paper is available online. ▸ Head-to-head studies confirm comparable effi- To view these files please Studies confirmed the excellent drug retention rate as cacy of different biological DMARDs in RA treat- visit the journal online well as efficacy and safety of approved biologicals ment, however, with respect to adalimumab (http://dx.doi.org/10.1136/ including their use in monotherapy. Tapering and in monotherapy the results are favourable for rmdopen-2015-000127). some instances discontinuation of biologicals is tocilizumab. possible in disease remission. In case of relapse, ▸ Discontinuation studies show that patients with Received 24 May 2015 patients usually show full response after reintroduction RA in sustained remission can successfully Revised 16 July 2015 of the same compound. The development of taper and sometimes stop tumour necrosis Accepted 19 July 2015 biologicals continues fast with several new biologicals factor inhibitor without functional or radiological targeting different or established cytokines or cellular deterioration and, in case of relapse, restarting subsets of the immune system. With several new of biologicals is possible and regularly leads to biologicals in the pipeline and different formulations rapid improvement. for established compounds, treatment options for RA ▸ Several new biologicals are in developmental will become even more versatile and sophisticated. status with the potential to further decrease the http://rmdopen.bmj.com/ Although we get closer to the aim of decreasing the proportion of refractory patients. proportion of refractory patients, many questions have to be addressed in the near future regarding emerging biosimilars and biologicals with new modes of action. patients with early RA and in patients with an inadequate response to MTX (MTX-IR) or any csDMARDs (csDMARD-IR). INTRODUCTION Following TNFi, new bDMARDs with differ- on September 29, 2021 by guest. Protected copyright. Disease-modifying antirheumatic drugs ent modes of action were developed. (DMARDs) are the mainstay of rheumatoid Abatacept (ABT), targeting the co-stimulation arthritis (RA) therapy. Institution of conven- between T and B cells, rituximab (RTX), tar- tional synthetic DMARDs (csDMARDs) in geting CD20+ B cells and finally tocilizumab therapy was followed by the development of (TCZ), an interleukin 6 receptor (IL-6R) tumour necrosis factor (TNF) inhibitors antagonist, confirmed their efficacy in active fi (TNFi), the rst biological DMARDs RA including patients with an inadequate 1Department of Internal (bDMARDs) introduced into rheumatology. response to TNFi (TNFi-IR). Medicine, Rheumatology, Today, five different TNFi (infliximab (IFX), Akdeniz University, Medical adalimumab (ADA), etanercept (ETN), cer- School, Antalya, Turkey 2Department of tolizumab (CZP) and golimumab (GLM)) Rheumatology and Clinical are in use. Although distinct by structure, STRATEGY TRIALS Immunology, Charité- route of application and pharmacokinetics, Clinical studies with a predefined strategy University Medicine Berlin, they show overall excellent effects with can teach us a lot about the best treatment Berlin, Germany respect to clinical and radiological outcomes approach by using different available com- Correspondence to especially when used in comedication with pounds. Furthermore, they are usually Dr Ali Berkant Avci; methotrexate (MTX). TNFi are effective in designed to answer relevant issues of daily [email protected] all stages of disease including MTX-naïve practice. Avci AB, et al. RMD Open 2015;1:e000127. doi:10.1136/rmdopen-2015-000127 1 RMD Open RMD Open: first published as 10.1136/rmdopen-2015-000127 on 5 August 2015. Downloaded from Add-on strategies ETN+MTX. However, the higher hurdles such as ACR50, In a large phase IIIb trial (REALISTIC), patients with ACR70, LDA and radiological progression were in favour RA with an inadequate response to at least one DMARD of ETN. The study can be criticised for several method- were randomised to receive CZP or placebo plus current ical issues including change of outcome parameters and therapy.1 The primary end point (week 12 American potentially reduced power due to non-achieved recruit- College of Rheumatology 20 (ACR20)) was met, and dif- ment goal. ferences were already evident at week 2. Of note, the disease activity and physical function improved both in Role of MTX dose in combination with bDMARDs patients with or without previous TNFi use, regardless of In the CONCERTO trial, biological and MTX-naïve their baseline MTX use. patients with early RA were randomised to open-label A recently performed, open-label, prospective study ADA plus weekly blinded 2.5, 5, 10 or 20 mg MTX.7 fi (GO-MORE) evaluated the ef cacy and safety of sub- With increasing doses of MTX, significant increasing cutaneous GLM as add-on therapy in csDMARD-IR 2 trends were observed in the proportion of patients patients with active RA. In this large study with 3366 achieving the outcomes. Of note, differences comparing patients, 82.1% achieved good-to-moderate European 10 and 20 mg MTX were minimal. ADA serum concen- League Against Rheumatism (EULAR) responses and trations increased with ascending dose up to 10 mg 23.9% attained remission at month 6. MTX. The authors related this significant trend with an In the ACT-RAY study, MTX-IR patients with active RA effect of MTX on ADA pharmacokinetic profile. were randomised to add-on TCZ or to switch to TCZ plus placebo.3 After 1 year there was a trend favouring add-on strategy, however, both strategies demonstrated HEAD-TO-HEAD COMPARISONS OF BIOLOGICALS meaningful clinical and radiographic responses. First eagerly awaited studies for head-to-head (H2H) The aforementioned studies confirm efficacy of comparisons of biologicals were performed recently. In add-on strategies with biologicals in csDMARD-IR the RED SEA trial, 125 adults with active RA despite patients with RA, however, for TCZ, monotherapy also treatment with two csDMARDs including MTX were ran- has convincing results. domised to add-on therapy with ADA or ETN.8 There was no significant difference between treatment arms. Early aggressive treatment The 2-year results of the AMPLE study, a H2H com- The TEAR study has been designed to answer whether parison of ABT and ADA in MTX-IR patients with RA, early aggressive treatment is comparable to a step-up confirmed similar efficacy based on clinical, functional 4 approach in early RA. Patients were randomised to and radiographic outcome.9 Safety outcomes were com- receive ETN+MTX or triple therapy (TT) consisting of parable between both groups with fewer local injection http://rmdopen.bmj.com/ MTX, sulfasalazine and hydroxychloroquine, or site reactions (ISRs) and slightly lower discontinuation MTX-monotherapy. If low disease activity (LDA) was not rate under ABT. reached, patients with MTX-monotherapy were allowed Another H2H trial, ADACTA, compared monotherapy to advance to one of the combination therapies. Finally, with TCZ versus ADA in patients with RA who were the clinical outcomes were similar between all groups, intolerant or inappropriate candidates for MTX.10 Of but only the ETN+MTX group showed a significant note, mean DAS28 improvement was significantly higher radiological benefit. Results of a similar study with IFX in the TCZ (−3.3) than in the ADA group (−1.8) (differ- 5 (Swefot) were also consistent with these findings. These ence −1.5, 95% CI −1.8 to −1.1; p<0.0001) from base- on September 29, 2021 by guest. Protected copyright. two studies support the current strategy of a step-up line to week 24, while safety findings were comparable therapy beginning with MTX in patients with early RA. between the treatment arms. In summary, these studies confirm comparable efficacy TT versus TNFi+MTX in MTX-IR patients with RA of different bDMARDs in RA treatment. However, with The RACAT study was designed to answer the critical respect to monotherapy, the results are favourable for question of whether TT is equivalent to ETN+MTX in TCZ. patients with RA after MTX failure.6 In this 48-week, double-blinded, non-inferiority trial, patients were ran- domised to one of the arms, and if patients did not ALTERNATIVE ROUTES OF ADMINISTRATION improve at 24 weeks they were switched to the other Since different routes of administration allow for more arm. After 24 weeks, both groups of patients improved flexibility, trials for subcutaneous versus intravenous biolo- significantly (p=0.001) with a switch rate of 27%. Of gicals were performed in recent years. The ACQUIRE trial note, the degree of significant improvement and compared efficacy and safety of subcutaneous ABT versus response rates were similar between both groups after intravenous ABT in MTX-IR patients with RA with a non- switching. The primary outcome, changes in disease inferiority design.11 At month 6, similar proportions of activity score 28 (DAS28), at 48 weeks, was similar in patients in both arms achieved the primary outcome of both groups (−2.1 with TT and −2.3 with ETN+MTX, ACR20 response (estimated difference: 0.3%, 95% CI −4.2 p=0.26) suggesting non-inferiority for TT compared with to 4.8).