Editorial: Prevention of Rheumatoid Arthritis: Now Is the Time, but How to Proceed?

In rheumatoid arthritis (RA), current clinical practice as well as the vast majority of reported studies focus on the ability of certain treatments to ameliorate existing disease activity or to prevent worsening disease in patients with established and classifiable disease. In addition, however, several trials have tried to address prevention of the development of classifiable RA in patients with undifferentiated arthritis (UA) or joint symptoms defined as arthralgia and autoantibody positivity without inflammatory arthritis, with overall mixed results (1–4). In particular, one important contribution to RA prevention is designated Probable Rheumatoid Arthritis: Methotrexate versus Placebo Treatment (PROMPT), an innovative and forward-looking clinical trial designed to stop disease progression from UA to classifiable RA. The findings from this study have been reported in several stages. In the original study that was reported in 2007, 110 disease-modifying antirheumatic drug (DMARD)–naive patients with synovitis at baseline yet who did not meet the American College of Rheumatology (ACR) 1987 revised criteria for RA (5) were randomized to receive methotrexate (MTX; starting dosage 15 mg/ week orally) or placebo, without other DMARDs or steroids (6). After follow-up of up to 30 months, there was no overall difference between groups in those whose disease progressed to classifiable RA (5). However, there was a delay in progression to RA in the MTX-treated group, and at 18 months, patients treated with MTX had less radiographic progression. Furthermore, in subgroup analyses solely of patients who were seropositive for anti–citrullinated protein antibodies (ACPAs), those who received MTX had less frequent progression to classifiable RA (67% versus 93%; P , 0.001). The authors concluded in their original article that intervention in this “early” period of RA, especially in individuals who are ACPA positive, may result in longerterm benefits. However, in a follow-up study that included 5 years of follow-up (7), there was no lasting benefit from the initial course of MTX in terms of development of RA, radiographic damage, or drug-free remission, and the conclusion that followed was that perhaps early treatment did not result in lasting improvement in longer-term outcomes, which was somewhat contrary to many findings demonstrating that earlier treatment in RA leads to improved long-term outcomes (8). In this issue of Arthritis & Rheumatology, the PROMPT investigators (Burgers LE, et al) report a further analysis of the data from the original study, this time to address the issue that perhaps earlier analyses yielded false-negative results because patients at low risk of developing classifiable RA were included (9); as such, if the individuals at highest risk of future RA could be identified, a benefit of treatment might be apparent. With this new approach, Burgers et al stratified individuals at baseline as being at high risk of future RA by applying the Leiden prediction rule, a 9-item instrument that includes clinical and biomarker factors and was developed and validated to determine the UA patients in whom disease may progress to classifiable RA (10,11). In this reanalysis, the primary outcome measure was the fulfillment of the ACR 1987 revised criteria, and the secondary outcome measure was the proportion of patients who achieved drug-free remission. Kevin D. Deane, MD, PhD, Christopher C. Striebich, MD, PhD, V. Michael Holers, MD: University of Colorado Denver School of Medicine. The content herein is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Drs. Deane, Striebich, and Holers’ work was supported by the University of Colorado Autoimmunity Center of Excellence through award UM1-AI-110503 from the National Institute of Allergy and Infectious Diseases (NIAID), NIH. Drs. Deane and Holers’ work was supported by NIAID grant U01-AI-101981. Address correspondence to Kevin D. Deane, MD, PhD, University of Colorado Denver School of Medicine, 1775 Aurora Court, Mail Stop B-115, Denver, CO 80045. E-mail: kevin.deane@UCDenver.edu. Submitted for publication December 29, 2016; accepted in revised form January 31, 2017.