INTRODUCTION: Whipple’s disease is a rare, chronic multisystemic infection caused by Tropheryma whipplei, a Gram-positive bacillus. Its low prevalence and non-specific presentation lead to diagnostic delay, although early treatment is essential as the disease can be fatal.

CASE REPORT: A 40-year-old man with no relevant medical history was admitted to the rheumatology department for axial and peripheral arthralgias of 3-year duration. He developed acute-onset diarrhea lasting less than one week, without pathological products. He reported constitutional symptoms, including 5-kg weight loss over the previous year, asthenia, fever, and cervical lymphadenopathy. Laboratory tests indicated malabsorption with iron-deficiency anemia, hypoproteinemia, and low vitamin D, along with elevated acute-phase reactants. Upper and lower endoscopy revealed only mild, non-specific erythema in the duodenum and distal ileum. Capsule endoscopy (CE) demonstrated marked villous atrophy, multiple ulcerations, and whitish infiltrates—more prominent in the proximal small bowel—suggestive of lymphangiectasia. Terminal ileum biopsies showed periodic acid–Schiff (PAS)-positive foamy macrophages. Based on CE findings and histology, treatment with intravenous ceftriaxone 2 g daily for 14 days was initiated. Extraintestinal involvement was excluded by transthoracic echocardiography and cerebrospinal fluid polymerase chain reaction (PCR). Stool PCR for T. whipplei was positive. The patient then received oral trimethoprim–sulfamethoxazole 800/160 mg every 12 hours for one year, with significant clinical improvement.

DISCUSSION: Whipple’s disease is caused by T. whipplei, a ubiquitous actinomycete with an incidence of 1–3 cases per 1,000,000, occurring mainly in predisposed individuals. Its clinical course is typically long-standing and non-specific, mimicking several rheumatologic conditions. The onset of gastrointestinal symptoms increases diagnostic specificity. Neurological involvement is associated with poorer prognosis. Diagnosis relies on identifying PAS-positive foamy macrophages in affected tissue or detecting the microorganism by PCR in stool, urine, or cerebrospinal fluid. The intestinal mucosa may appear normal on endoscopy in up to 30% of cases, and PCR can yield false positives. Immunohistochemistry is not universally available. In this case, CE was decisive in guiding the diagnosis by identifying characteristic patterns—villous atrophy, edema, lymphangiectasia, and denuded mucosa with petechiae—previously reported in other cases. CE also avoided the need for deep enteroscopy. Antibiotic therapy leads to clinical improvement within weeks, but long-term follow-up is required to prevent relapse. CE may represent a valuable non-invasive tool for disease monitoring. Given the limited literature, additional CE-based case reports may improve recognition of this rare entity.