A Brief History of Rheumatoid Arthritis Mimics Save

Imagine that 100 years from now, your great granddaughter, an eminent rheumatologist, reviews the history of rheumatoid arthritis (RA) mimics. She takes a historical approach, recognizing that advances in understanding pathogenesis and RA heterogeneity improve differentiation of RA from its mimics. 

She begins in 1800 with the description of RA as a gout mimic by Augustin Jacob Landre- Beauvais. He described a cohort of impoverished women with “goutte asthenique primitive” (primary asthenic gout).  Later in the 19th century, Alfred Garrod recognized the role of uric acid in gout and separated gout from RA, which he referred to as “rheumatic gout.” In 1890, Alfred Garrod’s son Archibald introduced the term “rheumatoid arthritis.” [1]

Your great granddaughter moves on to the 20th century when RA received several biomarkers, first rheumatoid factors (RF). These were described by Meyer in 1922 and Waaler in 1940 and linked to RA by Rose in 1948. [2] Although RF is found in many infections, inflammatory diseases, and malignancies, recognition of RF helped separate rheumatoid arthritis from ankylosing spondylitis and related “rheumatoid variants.” A second, more specific biomarker based on anti-cyclic citrullinated peptide antibodies (ACPAs) demonstrated that loss of tolerance to citrullinated peptides is important in RA pathogenesis.  This biomarker also suggested that RF negative, ACPA negative RA should be considered as a separate disease, “seronegative RA”.  

When, your great granddaughter reaches the beginning of the 21st century, she recognizes that understanding of RA genetics, pathogenesis, and biomarkers was still so primitive that multiple RA “mimics” were inevitable. Rheumatologists sought more accurate discrimination of RA from it mimics, but their tools to achieve this goal were limited. These limitations were demonstrated in the 2010 American College of Rheumatology/European League Against Rheumatism Rheumatoid Arthritis Classification Criteria. [3] These criteria relied on “at least one joint with definite clinical synovitis” that “was not better explained by another disease.” The criteria awarded further points for distribution of joints affected and available biomarkers. [3] With these limited criteria, it was a testament to the clinical skills of 21st century rheumatologists that they were usually successful in distinguishing RA from its inevitable mimics.

And there were many mimics.

Apart from some cancers and other rheumatic diseases such as the spondyloarthropathies, polymyalgia rheumatica, systemic lupus erythematosus and gout, the most challenging RA mimics were infectious. [4] Recognition of infectious mimics was particularly important, since 21st century RA therapy was immunosuppressive. Numerous viruses, including parvovirus B19, Hepatitis B and C, HIV, HTLV-1, chikungunya and related alphaviruses, COVID-19, and others, were recognized to sometimes cause joint pain and swelling in a pattern similar to RA. A broad spectrum of bacterial infections, including staphylococcal, streptococcal, and gonococcal infections, mycobacterial infections, tuberculosis and atypical, leprosy, Lyme disease, classical Reactive arthritis and others could mimic RA. It was also sometimes challenging to determine whether an infection caused RA-like symptoms, or an RA patient had developed a secondary infection. [4]

RA mimics were found to be more likely to have asymmetrical joint involvement, arthralgia rather than arthritis, involve large joints and have historical or extra articular clues such as fever and constitutional symptoms, but these differences were not always present. [4] False positive RF and anti-citrullinated protein antibody tests were seen in a significant minority of RA infectious mimic patients. 

Many infectious RA mimics resolved without specific intervention. In these patients, the goal was to avoid unnecessary treatment. In others, anti-microbial therapy may be required. But some RA mimics are inflammatory and chronic. In some of these, disease modifying (DMARD) therapy, similar to RA treatment, may be beneficial. When your great granddaughter reviewed the history of RA mimics, this was the most important group. Infectious RA mimics that fail to respond to anti-microbial therapy, but benefit from DMARD therapy, are likely to result from a post-infectious inflammatory pathogenesis in which the causative infection is known. Is RA itself a post-infectious inflammatory process? Over the next 100 years, will the study of infectious RA mimics improve outcomes in both the mimic and in RA? 

References:
1. Entezami P, Fox DA, Clapham PJ. Historical perspective on the etiology of rheumatoid arthritis. Hand Clin 2011; 27:1-10. 

2. Ingegnoli F, Castelli R, Gualtierotti R. Rheumatoid factors: clinical applications. Dis Markers 2013;35: 727-734.

3. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism initiative. Ann Rheum Dis 2010; 69: 1580-1588.

4. Sharma V, Sharma A. Infectious mimics of rheumatoid arthritis. Best Pract Res Clin Rheumatol 2022; 36: 1-12.