When it's not RA: unmasking Whipple's disease in seronegative, difficult-to-treat rheumatoid arthritis

Whipple's disease (WD) is a rare systemic infection caused by Tropheryma whipplei, often misdiagnosed as seronegative rheumatoid arthritis (RA) due to overlapping clinical features. Delayed diagnosis may lead to multisystem complications, particularly in patients treated with immunosuppressive or biologic therapies.

We describe two cases of WD initially misdiagnosed as refractory seronegative rheumatoid arthritis. Both patients were middle-aged men with persistently elevated inflammatory markers and poor responses to multiple biologic treatments. One developed constrictive pericarditis-the first reported to be successfully treated with anakinra-while the other presented with immune reconstitution inflammatory syndrome (IRIS)-related myositis, representing the first reported IRIS myositis in WD.

A literature review of 215 cases of WD misdiagnosed as RA or RA-like arthritis (including the two current cases) revealed that 77% were male, and most were seronegative. Among 139 patients with serologic data, 13.6% were RF-positive; of 132 with ACPA results, only 3.7% were positive. Erosive disease was reported in 33%. The median diagnostic delay was 7 years (range: 3-35 years). Gastrointestinal and constitutional symptoms were the most frequent triggers for reevaluation. Non-invasive PCR testing (saliva, stool) has emerged as a sensitive and practical diagnostic approach, particularly in localized or rheumatology-predominant presentations.

WD remains underrecognized in rheumatology practice. Early consideration in patients with refractory seronegative arthritis-especially middle-aged men with persistent inflammation-may prevent unnecessary immunosuppression and life-threatening complications. Based on accumulated evidence, we propose a pragmatic, tiered diagnostic algorithm to guide screening and confirmation of WD in rheumatologic settings, emphasizing the integration of noninvasive PCR-based testing to improve diagnostic yield and reduce delays. Key Points • Whipple's disease should be considered in inflammatory arthritis that is refractory to treatment and often seronegative with elevated CRP despite multiple immunosuppressive therapies. • Structured screening strategies may be warranted in rheumatology settings for patients meeting "high-risk criteria". Further studies are needed to assess the utility and cost-effectiveness of such approaches. • Saliva and stool PCR testing demonstrate high negative predictive value in the literature and are proposed as suitable non-invasive tools for initial screening. • Immune reconstitution inflammatory syndrome (IRIS) is a potentially serious complication following antimicrobial therapy for Whipple's disease, especially in patients previously treated with immunosuppressive agents. Early recognition is critical for appropriate management.