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  • Review Article
  • Published:

Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges

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

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.

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Figure 1: Generalized ACR20 and ACR70 response rates to different therapies in patients with RA.
Figure 2: Clinical, functional and structural responses to available biologic agents in different populations of patients with RA as derived from the mentioned clinical trials.
Figure 3: Kaplan–Meier estimate of time to loss of LDA plus increase in DAS28 of >0.6 after maintenance, dose-reduction or withdrawal of etanercept in the PRESERVE trial.134
Figure 4: Effect of dose-reduction or withdrawal of etanercept on maintenance of LDA or remission in the PRESERVE trial.134
Figure 5: Effect of withdrawal of certolizumab pegol on maintenance of remission in patients with established RA.
Figure 6: Effect of dose reduction of etanercept, withdrawal of etanercept or withdrawal of both etanercept and MTX on remission and LDA in the PRIZE trial.144
Figure 7: Proposed algorithm for withdrawal of biologic therapy in patients with active RA.

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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, Novo-Nordisk, 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.

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Smolen, J., Aletaha, D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat Rev Rheumatol 11, 276–289 (2015). https://doi.org/10.1038/nrrheum.2015.8

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