REVIEWS Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges Josef S. Smolen and Daniel Aletaha Abstract | Rheumatoid arthritis (RA) is considered a chronic disease that cannot be cured. Biologic agents have enabled good therapeutic successes; however, the response to biologic therapy depends on treatment history and, especially, disease duration. In general, the more drug-experienced the patients, the lower the response rates, although this limitation can be overcome by promptly adjusting or switching treatment in a treat-to-target approach. Another challenge is the question of how long therapy should be continued once the treatment target, which should be remission or at least a state of low disease activity, has been reached. The data available suggest that, in most patients with established disease, cessation of biologic therapy will be followed by disease flares, whereas a reduction of dose or an increase in the interval between doses enables maintenance of treatment success. Induction therapy very early in the disease course followed by withdrawal of the biologic agent might also be a feasible approach to attain sustained good outcomes, but currently available data are not strong enough to allow for such a conclusion to be reached. Taken together, this underscores the importance of research into the cause(s) of RA so that curative therapies can be developed. Smolen, J. S. & Aletaha, D. Nat. Rev. Rheumatol. 11, 276–289 (2015); published online 17 February 2015; doi:10.1038/nrrheum.2015.8
Introduction
Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Waehringer Guertel 18‑20, A‑1090 Vienna, Austria (J.S.S., D.A.). Correspondence to: J.S.S. josef.smolen@ wienkav.at
Rheumatoid arthritis (RA) is regarded as an incurable chronic disease; its aetiology is unknown and, therefore, no causal treatment is available. In the treatment of other incurable chronic diseases, such as diabetes mellitus or hypertension, the aim of treatment is usually a particular target that is associated with prevention of organ damage,1–6 but one would not ordinarily stop treatment upon normalization of the respective disease markers. On the contrary, such restitution of health ‘on drug’ is regarded to reflect therapeutic success and, thus, is an indication to continue therapy. At a time when such a targeted strategy was already long studied and implemented in these other diseases, the approach to treating RA still employed a slow step-up strategy;7 the notion that the disease process in RA could be modified emerged gradually,8 and only relatively recently (around the mid‑1990s) did it become clear that early intervention improves outcomes.9,10 However, despite early intervention with conventional synthetic DMARDs, progression of joint damage and suboptimal functional outcomes were still seen, and even after biologic agents had long been available, clinical trial data revealed that patients were being maintained on insufficiently effective conventional Competing interests J.S.S. has received research support from Abbvie, BMS, MSD, Pfizer, Roche and UCB, and has acted as a consultant and is a member of the speakers’ bureau for Abbvie, Amgen, BMS, Celgene, Glaxo, Infinity, Janssen, Lilly, Medimmune, MSD, NovoNordisk, Pfizer, Roche, Samsung, Sanofi, Sandoz and UCB. D.A. has received research support from BMS, MSD and Roche, and has acted as a consultant and is a member of the speakers’ bureau for Abbvie, BMS, Janssen, Medac, MSD, Pfizer and Roche.
276 | MAY 2015 | VOLUME 11
synthetic DMARD therapies for many years.11 Indeed, even in a trial that enrolled patients in 2008–2010, almost 60% of patients with RA of mean duration 9 years had received only two or fewer DMARDs at baseline.12 Thus, the treatment target for RA, and the strategy for reaching this target, had not been sufficiently elucidated and communicated with patients and/or caretakers, with the consequence that outcomes of the disease were frequently poor, and often still are. Efforts to change this situation led to the development of recommendations for optimizing treatment outcomes in RA by using a treat-to-target (T2T) approach.13 For patients with RA who do achieve the desired disease state, biologic-free and even drug-free strategies have been investigated repeatedly in recent years. The overall results of these efforts vary slightly, but they seem to follow certain patterns. In this article, we go into more detail of these strat egic approaches, and the benefits and limitations of currently available therapies for RA (with a focus on biologic agents), in the context of relevant issues such as how treatment success is defined and the ‘window of opportunity’ hypothesis. In evaluating the evidence supporting current concepts of RA treatment, we also address some inconsistencies that seem to characterize insights gleaned from therapeutic studies in RA.
Targeted therapies for RA
The therapeutic approach to RA has changed dramatically over the past two decades. Beyond improvements in the assessment of RA in the context of clinical trials and clinical practice around the turn of the millennium,14,15
www.nature.com/nrrheum © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Responses to biologic therapies for rheumatoid arthritis (RA) decrease depending on the patient population: early RA, methotrexate-naive; established RA, methotrexate-experienced; or late RA, anti‑TNF experienced ■■ Within these populations, approved biologic agents that target different molecules have similar efficacy, possibly because they all ultimately inhibit a common pathway, namely proinflammatory cytokines such as TNF or IL‑6 ■■ The best outcomes are achieved by timely adaptation or switching of therapies in accordance with disease activity, in a treat-to-target approach, with the aim of remission or at least low disease activity ■■ Once a good outcome has been reached, reducing the dose or expanding the interval between doses is a feasible approach that enables maintenance of the outcome in most patients ■■ There exists a ‘window of opportunity’ soon after symptom onset to prevent the occurrence of damage, but treatment at this stage cannot reverse the disease in most patients ■■ Reversal of disease might become possible by use of preventative therapies that interfere with the pre-arthritic process before the disease has manifested clinically
RA
MTX-naive ACR20 ACR70
MTX-experienced Anti-TNF-experienced ACR20 ACR70 ACR20 ACR70
Anti-TNF
Anti-IL-1
Anti-IL-6 Patients fulfilling ACR criteria
Anti-T-cellcostimulation
>70–100% >50–70%
Anti-B-cell
>20–50% 10–20% 0.6 after maintenance, dose-reduction or withdrawal of etanercept in the 134 PRESERVE trial. The graph compares continuation of full-dose (50 mg; orange line) or reduced-dose (25 mg; blue line) etanercept or switch to placebo (grey line), all in combination with MTX. Abbreviations: DAS28, 28-joint disease activity score; LDA, low disease activity; MTX, methotrexate. Reproduced from Smolen, J. S. et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet 381, 918–929 © (2013),134 with permission from Elsevier.
Patients (%)
100 90 80 70 60 50 40
Etanercept 50 mg + MTX Etanercept 25 mg + MTX MTX monotherapy 84*82*
83*79* 67* 60*
54
43
30 20 10 0
38* 31*
29
12 DAS28 LDA
DAS28 remission SDAI LDA Efficacy at week 88
SDAI remission
Figure 4 | Effect of dose-reduction or withdrawal of etanercept on maintenance of Nature Reviews | Rheumatology LDA or remission in the PRESERVE trial.134 Proportions of patients maintaining LDA (DAS28
Introduction
Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Waehringer Guertel 18‑20, A‑1090 Vienna, Austria (J.S.S., D.A.). Correspondence to: J.S.S. josef.smolen@ wienkav.at
Rheumatoid arthritis (RA) is regarded as an incurable chronic disease; its aetiology is unknown and, therefore, no causal treatment is available. In the treatment of other incurable chronic diseases, such as diabetes mellitus or hypertension, the aim of treatment is usually a particular target that is associated with prevention of organ damage,1–6 but one would not ordinarily stop treatment upon normalization of the respective disease markers. On the contrary, such restitution of health ‘on drug’ is regarded to reflect therapeutic success and, thus, is an indication to continue therapy. At a time when such a targeted strategy was already long studied and implemented in these other diseases, the approach to treating RA still employed a slow step-up strategy;7 the notion that the disease process in RA could be modified emerged gradually,8 and only relatively recently (around the mid‑1990s) did it become clear that early intervention improves outcomes.9,10 However, despite early intervention with conventional synthetic DMARDs, progression of joint damage and suboptimal functional outcomes were still seen, and even after biologic agents had long been available, clinical trial data revealed that patients were being maintained on insufficiently effective conventional Competing interests J.S.S. has received research support from Abbvie, BMS, MSD, Pfizer, Roche and UCB, and has acted as a consultant and is a member of the speakers’ bureau for Abbvie, Amgen, BMS, Celgene, Glaxo, Infinity, Janssen, Lilly, Medimmune, MSD, NovoNordisk, Pfizer, Roche, Samsung, Sanofi, Sandoz and UCB. D.A. has received research support from BMS, MSD and Roche, and has acted as a consultant and is a member of the speakers’ bureau for Abbvie, BMS, Janssen, Medac, MSD, Pfizer and Roche.
276 | MAY 2015 | VOLUME 11
synthetic DMARD therapies for many years.11 Indeed, even in a trial that enrolled patients in 2008–2010, almost 60% of patients with RA of mean duration 9 years had received only two or fewer DMARDs at baseline.12 Thus, the treatment target for RA, and the strategy for reaching this target, had not been sufficiently elucidated and communicated with patients and/or caretakers, with the consequence that outcomes of the disease were frequently poor, and often still are. Efforts to change this situation led to the development of recommendations for optimizing treatment outcomes in RA by using a treat-to-target (T2T) approach.13 For patients with RA who do achieve the desired disease state, biologic-free and even drug-free strategies have been investigated repeatedly in recent years. The overall results of these efforts vary slightly, but they seem to follow certain patterns. In this article, we go into more detail of these strat egic approaches, and the benefits and limitations of currently available therapies for RA (with a focus on biologic agents), in the context of relevant issues such as how treatment success is defined and the ‘window of opportunity’ hypothesis. In evaluating the evidence supporting current concepts of RA treatment, we also address some inconsistencies that seem to characterize insights gleaned from therapeutic studies in RA.
Targeted therapies for RA
The therapeutic approach to RA has changed dramatically over the past two decades. Beyond improvements in the assessment of RA in the context of clinical trials and clinical practice around the turn of the millennium,14,15
www.nature.com/nrrheum © 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Responses to biologic therapies for rheumatoid arthritis (RA) decrease depending on the patient population: early RA, methotrexate-naive; established RA, methotrexate-experienced; or late RA, anti‑TNF experienced ■■ Within these populations, approved biologic agents that target different molecules have similar efficacy, possibly because they all ultimately inhibit a common pathway, namely proinflammatory cytokines such as TNF or IL‑6 ■■ The best outcomes are achieved by timely adaptation or switching of therapies in accordance with disease activity, in a treat-to-target approach, with the aim of remission or at least low disease activity ■■ Once a good outcome has been reached, reducing the dose or expanding the interval between doses is a feasible approach that enables maintenance of the outcome in most patients ■■ There exists a ‘window of opportunity’ soon after symptom onset to prevent the occurrence of damage, but treatment at this stage cannot reverse the disease in most patients ■■ Reversal of disease might become possible by use of preventative therapies that interfere with the pre-arthritic process before the disease has manifested clinically
RA
MTX-naive ACR20 ACR70
MTX-experienced Anti-TNF-experienced ACR20 ACR70 ACR20 ACR70
Anti-TNF
Anti-IL-1
Anti-IL-6 Patients fulfilling ACR criteria
Anti-T-cellcostimulation
>70–100% >50–70%
Anti-B-cell
>20–50% 10–20% 0.6 after maintenance, dose-reduction or withdrawal of etanercept in the 134 PRESERVE trial. The graph compares continuation of full-dose (50 mg; orange line) or reduced-dose (25 mg; blue line) etanercept or switch to placebo (grey line), all in combination with MTX. Abbreviations: DAS28, 28-joint disease activity score; LDA, low disease activity; MTX, methotrexate. Reproduced from Smolen, J. S. et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet 381, 918–929 © (2013),134 with permission from Elsevier.
Patients (%)
100 90 80 70 60 50 40
Etanercept 50 mg + MTX Etanercept 25 mg + MTX MTX monotherapy 84*82*
83*79* 67* 60*
54
43
30 20 10 0
38* 31*
29
12 DAS28 LDA
DAS28 remission SDAI LDA Efficacy at week 88
SDAI remission
Figure 4 | Effect of dose-reduction or withdrawal of etanercept on maintenance of Nature Reviews | Rheumatology LDA or remission in the PRESERVE trial.134 Proportions of patients maintaining LDA (DAS28
