Rheumatoid Arthritis As Two Diseases

October 12, 2020

The underlying pathogenesis of rheumatoid arthritis with and without autoantibodies may be different. Researchers say that "it is time to formally subdivide RA into type 1 (with autoantibodies) and type 2 (without autoantibodies)."

Rheumatoid arthritis should be formally divided into two disease subtypes based on patients’ autoantibody status, researchers argue, to support research into their differing pathophysiology and ultimately the development of more stratified treatment approaches to improve long-term patient outcomes.

Over the last decade it has become increasingly apparent that differences exist between rheumatoid arthritis patients with and without autoantibodies, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), in terms of the in the genetics of their disease, the environment risk factors that influence it and how it first presents clinically.

Now, a cohort study, believed to be the largest to look at long-term outcomes, has found that patients with autoantibody-negative rheumatoid arthritis have improved less in terms of long-term outcomes than those with autoantibody-positive disease.

The study focuses on 1,285 consecutive rheumatoid arthritis patients in Leiden in the Netherlands enrolled between 1993 and 2016 and followed yearly for up to 25 years. Of these 823 patients had autoantibody-positive RA and 462 patients had autoantibody-negative disease and their average ages were 55 and 60 years respectively.

Using time of enrollment as a proxy for treatment strategy and 1993–1996 as a baseline, the data showed that routine care improved over the period, not only as a result of the introduction of new drugs, but also through earlier initiation of treatment initiation and treat-to-target strategies. As a result, disease activity significantly decreased over time within both autoantibody-positive and autoantibody-negative patients.

But the data also showed that there was a marked difference in improvement of long-term outcomes between autoantibody-positive and autoantibody-negative patients.

“While disease activity has decreased in autoantibody-negative RA over the last 25 years, long-term outcomes such as mortality, functional ability, and ability to stop anti-rheumatic drugs have not improved in autoantibody-negative RA. The ultimate aim of lowering disease activity in the short-term is to improve long-term outcomes. Until now, this aim has not been achieved in autoantibody-negative RA,” said Dr. Xanthe Matthijssen from the department of rheumatology, Leiden University Medical Center, Leiden in the Netherlands.

Following the introduction of a treat-to-target strategy (2006–2010), the results showed that death rates decreased significantly in autoantibody-positive patients (hazard ratio (HR) 2006–2010: 0.56 [95% confidence interval 0.34 to 0.92; p = 0.023]; HR 2011–2016: 0.33 [95% CI 0.14 to 0.77; p = 0.010]), but not in autoantibody-negative patients (HR 2006–2010: 0.79 [95% CI 0.40 to 1.56; p = 0.50]; HR 2011–2016: 0.36 [95% CI 0.10 to 1.34; p = 0.13]).

At the same time autoantibody-positive patients experienced greater sustained DMARD-free remission (SDFR) (hazard ratio [HR] 2006–2010: 3.35 [95% CI 1.46 to 7.72; p = 0.004]; HR 2011–2016: 4.57 [95% CI 1.80 to 11.6; p = 0.001]), while autoantibody-negative patients did not.

Improvements in functional disability were evident in autoantibody-positive patients from 2000 onwards (range −0.16 [95% CI −0.29 to −0.03; p = 0.043] to −0.32 [95% CI −0.44 to −0.20; p < 0.001]), but not in autoantibody-negative patients (range 0.10 [95% CI −0.12 to 0.31; p = 0.38] to −0.13 [95% CI −0.34 to 0.07; p = 0.20]).

Currently, the treatment strategy is the same for both autoantibody-positive and autoantibody-negative rheumatoid arthritis, but the findings suggest that lowering disease activity in the short-term might not lead to improved long-term outcomes in autoantibody negative rheumatoid arthritis, “It implicates that autoantibody-positive and autoantibody-negative RA should be treated differently,” Dr Matthijssen said.“We hope that this study leads to more research on optimal treatment in autoantibody-negative RA. We hope that this in the end leads to stratified treatment in RA and improvement of long-term outcomes in both RA types.”

Research into rheumatoid arthritis has largely focused on the autoantibody-positive patients (type 1 rheumatoid arthritis), she explained. “The large majority of identified genetic and environmental risk factors contribute to the development of type 1 rheumatoid arthritis. Less is known about the pathophysiology of the development of type 2 RA. More research on autoantibody-negative RA is urgently needed to identify methods to also improve their long-term outcomes.”

Dr Matthijssen emphasized: “It important to formally consider type 2 rheumatoid arthritis as a separate entity, but we cannot exclude the possibility that type 2 rheumatoid arthritis consists of different subtypes.”


REFERENCEMatthijssen XME, Niemantsverdriet E, Huizinga TWJ, van der Helm-van Mil AHM. Enhanced treatment strategies and distinct disease outcomes among autoantibody-positive and -negative rheumatoid arthritis patients over 25 years: A longitudinal cohort study in the Netherlands. PLoS Med 2020; 17(9): e1003296. doi.org/10.1371/journal.pmed.1003296