Sustained DMARD-free remission in rheumatoid arthritis - about concepts and moving towards practice

Abstract

Sustained DMARD-free remission (SDFR) is the best possible outcome in RA. It is characterized by sustained absence of clinical arthritis, which is accompanied by resolution of symptoms and restoration of normal physical functioning. Therefore it's the best proxy for cure in RA. The mechanisms underlying SDFR-development are yet unidentified. Hypothetically, there are two possible scenarios. The first hypothesis is based on the concept of regaining immune-tolerance, which implies that RA-patients are similar at diagnosis and that disease-processes during the disease-course shift into a favorable direction, resulting in regaining a state in which arthritis is persistently absent. This could imply that SDFR is theoretically achievable for all RA-patients. The alternative hypothesis is that RA-patients who achieve SDFR are intrinsically different from those who cannot. This would imply that DMARD-cessation could be restricted to a subgroup of RA-patients. Since the 1990s, DMARD-discontinuation and SDFR have been increasingly studied as long-term-outcome in RA. In this review, we describe hitherto results of clinical, genetic, serological, histological and imaging studies and looked for arguments for the first or second hypothesis in both auto-antibody-positive and auto-antibody-negative RA. In auto-antibody-negative RA, SDFR is presumably restricted to a subgroup of patients with high serological-markers of inflammation at diagnosis and a rapid and sustained decrease in inflammation after treatment-start. Identifying these RA-patients could be helpful in realizing personalized-medicine. In auto-antibody-positive RA, only few patients achieve SDFR and no definite conclusions can be drawn, but data could suggest that SDFR-patients might be a subgroup with relatively low inflammation from disease-presentation onwards.

Keywords: Auto-antibodies; DMARD-free remission; Drug-free remission; Rheumatoid arthritis.

Fig. 1. Hypotheses which could explain sustained DMARD-free remission in rheumatoid arthritis.

RA-patients achieving sustained DMARD-free remission escape the ongoing process of inflammation. For disease-resolution, it could either be proposed that processes shift into a favorable direction in which markers of disease chronicity − yet unidentified − are lost over time, allowing to achieve SDFR (hypothesis 1). Or, SDFR could be determined by specific characteristics of a subgroup of RA-patients; then patient achieving SFDR are intrinsically different (hypothesis 2). LDA: low disease activity; HDA: high disease activity; DMARD: disease-modifying anti-rheumatic drugs; RA: rheumatoid arthritis.

Fig. 2. Disease course of rheumatoid arthritis and subsequent development of (sustained) DMARD-free remission.

RA-patients could either have persistent disease (upper timeline) or achieve remission and are subsequently able to discontinue their DMARD-therapy (lower two timelines). The middle timeline illustrates the situation in which RA-patients were able to discontinue their DMARD-treatment but were not able to maintain remission after DMARD-stop. In the lower timeline, patients were not only able to discontinue their DMARD-treatment but were also able to sustain remission for minimally one year after DMARD-stop (and the subsequent follow-up thereafter).

Fig. 3. Scientific substantiation for both hypotheses to understand disease-resolution in auto-antibody-positive-RA.

Scientific evidence on biomarkers related to SDFR in auto-antibody-positive RA, summarized from the perspective of both hypotheses. A tick symbol indicates that findings on this topic are suggestive for the specific hypothesis. Crosses indicate that findings are suggestive that the hypothesis is not plausible. A question mark indicates that there is no data on this topic which can be related to one of the two hypotheses.

Fig. 4. Scientific substantiation for both hypotheses to understand disease-resolution in auto-antibody-negative-RA.

Scientific evidence on biomarkers related to SDFR in auto-antibody-negative RA, summarized from the perspective of both hypotheses. A tick symbol indicates that findings on this topic are suggestive for the specific hypothesis. Crosses indicate that findings are suggestive that the hypothesis is not plausible. A question mark indicates that there is no data on this topic which can be related to one of the two hypotheses.