Whipple's disease

Whipple's disease is a rare, chronic multisystem illness caused by the bacterium Tropheryma whipplei. Though it primarily affects the gastrointestinal system, it also has widespread systemic involvement, including significant rheumatological manifestations. Diagnosis can be challenging due to its rarity and the nonspecific nature of its early symptoms, which often mimic more common rheumatologic diseases.

T. whipplei is a gram-positive actinomycete. The bacterium is primarily transmitted through the oral-fecal route and colonizes the intestines, leading to infection and widespread dissemination.

Susceptible individuals exhibit an impaired immune response to T. whipplei, allowing the bacteria to invade and persist in macrophages. This process results in tissue infiltration and systemic inflammation.


Up to 80% of patients with Whipple’s disease experience rheumatologic symptoms, often preceding gastrointestinal symptoms by months or years.

Polyarthralgia is the most common initial rheumatological symptom, presenting as migratory, non-erosive arthralgia, affecting large and small joints symmetrically.

True synovitis occurs but is typically non-erosive and does not result in joint deformities.

Other musculoskeletal manifestations may include myalgia and, less commonly, tenosynovitis.

The arthritic symptoms can mimic conditions like rheumatoid arthritis or seronegative spondyloarthropathies. Importantly, arthritis in Whipple's disease does not respond to traditional disease-modifying antirheumatic drugs (DMARDs) or NSAIDs alone, which may be a diagnostic clue.

Whipple’s disease should be suspected in patients with chronic arthralgias and a history of gastrointestinal symptoms (diarrhea, malabsorption, weight loss) or systemic signs like fever and lymphadenopathy.

Polymerase Chain Reaction (PCR): PCR testing of tissue samples, usually from a duodenal biopsy, is highly sensitive for T. whipplei. PCR can also be performed on cerebrospinal fluid (CSF) if there are neurologic symptoms.

A key diagnostic tool is duodenal biopsy where periodic acid–Schiff (PAS)-positive macrophages are seen in the lamina propria of the small intestine. PAS staining highlights the intracellular bacteria-laden macrophages.

Typically, an endoscopic examination reveals a thickened, yellowish, villous mucosa in the duodenum.

Although non-specific, synovial fluid from affected joints often reveals a mild inflammatory response without specific markers.

Joint imaging in Whipple’s disease may show nonspecific findings like mild synovial thickening without erosions, helping distinguish it from conditions like rheumatoid arthritis.

Early and effective antibiotic treatment is essential to prevent irreversible tissue damage and achieve remission.

Treatment typically consists of:

An initial two-week course of IV ceftriaxone or meropenem to penetrate the blood-brain barrier and control infection quickly, followed by a maintenance phase. Qn oral regimen of trimethoprim-sulfamethoxazole (TMP-SMX) is commonly administered for 1-2 years.

Symptomatic improvement, particularly in rheumatologic symptoms, is expected within weeks. Ongoing monitoring includes clinical assessment, repeat PCR, and, if necessary, biopsy to confirm bacterial eradication.

Persistent arthralgia post-infection is sometimes observed; NSAIDs or corticosteroids can be used cautiously for symptomatic relief, though prolonged immunosuppression should be avoided.

There is a risk of relapse, particularly involving the CNS, so vigilant follow-up is required, especially in patients with neurologic or persistent arthralgic symptoms.

Chronic, non-erosive arthritis may persist in some patients even after effective bacterial eradication, likely due to residual immune dysregulation or damage.