Whipple's disease

Introduction

Whipple’s disease is a rare chronic infectious disorder caused by Tropheryma whipplei. It may present with predominant joint manifestations mimicking rheumatoid arthritis (RA). A retrospective single-center cohort study of seven patients was performed. Clinical symptoms were assessed by review of medical charts and Whipple’s disease was diagnosed by periodic-acid-Schiff-stain and/or Tropheryma whipplei-specific polymerase-chain-reaction. Median age at disease onset was 54 years, six patients were male. Median time to diagnosis was 5 years. All patients presented with polyarthritis with a predominantly symmetric pattern. Three had erosive arthritis. Affected joints were: wrists (5/7), metacarpophalangeal joints (MCPs) (5/7), knees (5/7), proximal interphalangeal joints (PIPs) (3/7), hips (2/7), elbow (2/7), shoulder (2/7). All patients had increased C-reactive-protein concentrations,while rheumatoid factor and anti-CCP-antibodies were absent, and were initially (mis)classified as RA-patients according to EULAR/ACR-criteria (median DAS28 4.3). Six patients received antirheumatic treatment consisting of prednisone with methotrexate and/or leflunomide, three were additionally treated with at least one biologic agent (abatacept, adalimumab, etanercept, rituximab, tocilizumab). Most patients showed insufficient treatment response. In all patients Tropheryma whipplei was detected in synovial fluid by polymerase-chain-reaction; in three patients the diagnosis of Whipple’s disease was further ascertained by periodic-acid-Schiff-staining. Gastrointestinal symptoms and other extra-articular manifestations were absent, mild or non-specific. Treatment was initiated with trimethoprin/sulfamethoxazole in five and doxycycline/hydroxychloroquine in two patients and had to be adapted in five patients. Finally, all patients had good treatment responses with improvement of arthritis and extra-articular manifestations. Conclusion of this study was that Whipple’s disease is rare and can mimic rheumatoid arthritis. Especially patients with seronegative rheumatoid arthritis with a prolonged disease course and insufficient treatment response should be reevaluated for Whipple’s disease. Joint distribution Retrospectively, in 6 of the 7 patients first disease manifestation was an intermittent, asymmetrical arthritis with oligoarthritis in 5 of the 7 patients. At first presentation, five patients had polyarthritis affecting the hands; in others the classical symmetric pattern was suggestive for RA. [1]

Sample case (from StatPearls StatPearls Quiz)

Question #29265

A 30-year-old man presents to the clinic with chronic joint pain. He has a history of pain and swelling in his knees and ankles for the last 2 years. The joint pain resolves spontaneously before moving to another joint. He also complains of occasional abdominal pain and loose stools. He is sexually active and uses condoms for contraception. He also complains of unusual forgetfulness. Vitals are blood pressure 120/80 mm Hg, heart rate 65 bpm, respiratory rate of 16 breaths/min, and a temperature of 98 F (37.2 C). His rheumatological examination reveals inflammatory arthritis affecting his right knee with mild tenderness, movement restriction, and effusion. The rest of his systemic examination is unremarkable. His investigations show white blood cells 13,000/microliter, hemoglobin 10 gm/dl, platelet 200,000 cells/microliter, serum ALT of 50 IU/L, serum creatinine of 0.7 mg/dl, and C-reactive protein of 15 mg/L. Joint aspiration reveals a cloudy fluid, with a cell count of 5,000 per microL, mainly monocytic, and an absence of crystals. Macrophages containing intracellular gram-positive organisms are also seen. Which of the following can be used to confirm the diagnosis before initiating treatment?

Correct answer/ Teaching Points

This patient has an unusual presentation of Whipple disease with migratory oligoarthritis and forgetfulness. The presence of monocytic infiltrates with gram-positive bacteria within the macrophages points towards Whipple arthritis. The patient should have upper GI endoscopy and biopsy to rule out systemic disease.

Whipple arthritis typically is migratory and non-deforming and appears normal on x-rays. Microscopic analysis shows predominantly lymphomonocytic infiltrate with an absence of crystals.

The classic periodic acid Schiff staining macrophages containing intracellular Tropheryma whipplei are rarely seen. The synovial fluid can be subjected to PCR analysis for T. whipplei, or synovial biopsies can be obtained.

A duodenal biopsy can confirm the disease and assess the extent before initiating treatment. Rheumatoid factor is present in rheumatoid arthritis, which may have a similar presentation but lack the PAS-positive macrophages. Reactive arthritis can be confused with Whipple arthritis in sexually active individuals with high-risk sexual behavior and urinary complaints. Anti-Smith (Sm) antibody is specific for systemic lupus erythematosus (SLE). 

Radiology

 3/7 patients had erosive disease on imaging. [1]

 Lab 

All patients were negative for rheumatoid factor and anti-CCP-antibodies. [1]

 Diagnosis 

Arthrocentesis was performed in six patients and analysis yielded a positive TW PCR in all. In one patient TW was detected by PAS-staining and PCR in a synovial biopsy specimen of the knee. Leucocyte count in synovial fluid was within the range of 1000 to 7000 cells/μl reflecting a mild to moderate inflammation of the joints in four patients. PCR-analysis of synovial fluid may be the most sensitive diagnostic procedure to detect TW; histopathological evaluation of PAS-stained duodenal biopsies alone is not sufficient to exclude WD. [1]

Extra Articular manifestations 

Extra-articular manifestations of WD were frequent but mainly mild and not indicative for WD. [1]

 GI 

In particular gastrointestinal symptoms occurred only infrequently and were rather mild. None of the patients showed “classic” symptoms with dyspepsia and diarrhea and only one patient reported on previously unexplained weight loss. Gastrointestinal symptoms were mild or absent even in five patients in which TW was detected in small intestinal biopsies. [1]

Skin 

CNS 

Extra-articular manifestations of WD were frequent but mainly mild and not indicative for WD. [1]

 GI 

In particular gastrointestinal symptoms occurred only infrequently and were rather mild. None of the patients showed “classic” symptoms with dyspepsia and diarrhea and only one patient reported on previously unexplained weight loss. Gastrointestinal symptoms were mild or absent even in five patients in which TW was detected in small intestinal biopsies. [1]

Testing of small bowel biopsy — Upper gastrointestinal endoscopy with biopsies of the small intestine is the diagnostic test of choice. It is generally the first test performed for the evaluation of Whipple’s disease in patients with gastrointestinal symptoms, but it is also performed in patients with suspected extraintestinal Whipple’s disease to clarify or confirm the diagnosis. [2]

A prothrombin time should be checked prior to biopsy because of the frequent occurrence of vitamin K malabsorption. To improve the yield, we generally take 7 to 10 biopsies from different parts of the duodenum. The biopsy specimens should be submitted for PAS staining and PCR testing. Clinical pathology laboratories can perform PAS staining, and PCR testing is available through commercial laboratories. If these are unrevealing and the suspicion remains high, immunohistochemistry can be performed, but this test is generally available only through a reference center. [2]

Biopsy specimens should be obtained when Whipple's disease is suspected even if there are no gross small bowel abnormalities, as many patients with Whipple's disease have normal appearing mucosa. In one study of 191 patient with Whipple's disease, only 26 percent had an abnormal appearing duodenum; 11 percent had findings that have been considered characteristic for Whipple's disease (ie, dilated villi, ectatic lymph vessels, prominent or discrete edema) and 10 percent had evidence of duodenitis [2].

Whipple's disease is characterized by PAS-positive macrophages on small bowel biopsy, which is usually readily apparent and unlikely to be confused with other diseases. The main histologic features are extensive PAS-positive material in the lamina propria and villous atrophy. 

Results of PCR testing can also be used to make the diagnosis; the amplified DNA should be sequenced. [2]

Antibiotics 

Doxycycline

 Ceftriaxone

 trimethoprim/sulfamethoxazole