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Is It Time to Subdivide RA Into Type 1 and Type 2 Disease?


Differences in long-term outcomes in patients with rheumatoid arthritis (RA) may because RA with and without autoantibodies are actually 2 distinct conditions.

While patients with rheumatoid arthritis (RA) with autoantibodies see their long-term outcomes improve, the same does not happen for patients with RA without autoantibodies. New research in PLOS Medicine has found that reason for this difference is because RA with and without autoantibodies may actually be 2 distinct conditions.

It has only been in the last decade that studies have shown differences in patients with RA with and without autoantibodies.

“When distinct disease mechanisms exist, treatment response may differ,” the authors explained. “Whether autoantibody-positive and autoantibody-negative RA have different mechanisms can therefore be addressed by clinical evaluation of long-term results in response to changes in treatment strategy.”

The researchers analyzed 1285 patients with RA who were included in the Leiden Early Arthritis Clinic cohort between 1993 and 2016. The patients were all followed yearly and 3 long-term outcomes were studied: sustained disease-modifying antirheumatic drug (DMARD)–free remission (SDFR), mortality, and functional disability measured by yearly Health Assessment Questionnaire (HAQ). The Disease Activity Score-28 with erythrocyte sedimentation rate was used to measure treatment response in the short term, or disease activity.

Of the full 1285 patients, 823 had type 1 RA and 462 had type 2 RA. Patients with type 1 RA were younger at first presentation (mean age 55 years) compared with patients with type 2 RA (mean age 60 years). For both groups, disease activity significantly decreased over time, but while SDFR rates increased after the introduction of treat-to-target adjustments in the patients with autoantibody-positive RA, or type 1 RA, but not in patients with autoantibody-negative RA, or type 2 RA.

Functional disability also improved in type 1 RA but not in type 2 RA. There was also a significant decrease in mortality in patients with type 1 RA starting with treat-to-target strategies, but there was no significant association in patients with type 2 RA.

“The disconnection between improvements in disease activity and in several long-term outcomes suggests that the underlying pathogenesis of autoantibody-positive and autoantibody-negative RA is different,” the authors wrote. “We therefore propose that the time has come to subdivide RA into type 1 and type 2.”

They explained that a formal subdivision of RA would allow for more focused pathogenetic studies, treatment protocols that are adapted to disease type, and trials by disease type. These changes would lead to improved personalized care for patients with RA.

"In the last decennia research in RA has largely focused on the autoantibody-positive subset,” lead author Xanthe Matthijssen, MD, PhD, of Leiden University Medical Center in the Netherlands, said in a statement. “More research on autoantibody-negative RA is urgently needed to identify methods to also improve their long-term outcomes."


Matthijssen 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 Medicine. Published online September 22, 2020. doi:10.1371/journal.pmed.1003296

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