Rheumatoid arthritis

Why RA should be subdivided into two distinct diseases

Rheumatoid arthritis is two distinct diseases and should be formally subdivided into type 1 (with autoantibodies) and type 2 (without autoantibodies), Dutch researchers say.

The distinction is needed because while disease activity improves over time for most rheumatoid arthritis (RA) patients, long-term outcomes only improve in RA patients with autoantibodies, according to a study by Dr Xanthe Matthijssen of Leiden University Medical Center, Netherlands, and colleagues.

In their study published in PLOS One, they report on disease activity and outcomes for 1,285 RA patients followed between 1993 and 2016 through the Leiden Early Arthritis Clinic cohort.

In the cohort, 823 patients had autoantibody-positive RA and 462 patients had autoantibody-negative RA. Disease activity decreased significantly over time for both groups.

As a new treat-to-target treatment strategy became common in 2006 to 2010, sustained drug-free remission rates increased but only in patients with autoantibody-positive, and not in those with autoantibody-negative RA.

Moreover, mortality and functional disability rates decreased with treat-to-target adjustments only in autoantibody-positive patients.

“The disconnection between improvement in disease activity and subsequent improvement in long-term outcomes in RA without autoantibodies suggests that the underlying pathogenesis of RA with and without autoantibodies is different,” the authors say.

In their paper they note that autoantibodypositive RA has a different genetic background, different environmental risk factors, differences in the preclinical symptomatic phase and first clinical presentation, differences in histology, synovial fluid cytokine profile, and more severe joint destruction when left untreated.

“Nonetheless, the aetiology and pathophysiology of RA is still incompletely understood. It is unclear if there is one pathophysiological genesis—in which the presence of autoantibodies is promoted by certain genetic factors and where autoantibodies act as a “severity” factor—or, alternatively, if there are two different mechanisms of disease development,” they write

“When distinct disease mechanisms exist, treatment response may differ. 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.

“We propose that it is time to formally divide RA into type 1, with autoantibodies, and type 2, without autoantibodies, in the hope that it leads to stratified treatment in autoantibody-positive and autoantibody-negative RA,” the authors conclude.

Dr Matthijssen says a formal distinction between type 1 and type 2 RA would encourage a focused of pathogenetic studies, development of treatment protocols adapted to disease type, and performance of trials by disease type.

“Research in RA has largely focused on the autoantibody-positive subset. More research on autoantibody-negative RA is urgently needed to identify methods to also improve their long-term outcomes,” she writes.

“Ultimately a better distinction leads to improved personalised care.”

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