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25 February 2024: Articles  USA

A 40-Year-Old Man with a 7-Year History of Polyarthritis and a Late Diagnosis of Whipple Disease: A Journey to Resolve the Mystery

Challenging differential diagnosis, Diagnostic / therapeutic accidents, Unusual setting of medical care, Rare disease, Educational Purpose (only if useful for a systematic review or synthesis)

Gagan Aulakh1ABCDEF*, Rebekah Lewis1BCE, Arshdeep Singh2DE, Valentin Marian1AF

DOI: 10.12659/AJCR.942896

Am J Case Rep 2024; 25:e942896




BACKGROUND: Whipple disease (WD) is rare, with an incidence of only a few patients per million. It is caused by infection with the gram-positive bacterium Tropheryma whipplei, and presents with symptoms that include joint pain, fever, diarrhea, and weight loss. This report is of a 40-year-old man with a 7-year history of polyarthritis and a late diagnosis of Whipple disease. The atypical nature of his symptoms led to misdirection and misdiagnosis for years.

CASE REPORT: A middle-aged white man with seronegative migratory polyarticular arthritis underwent 7 years of treatment with steroids, disease-modifying anti-rheumatic drugs (DMARDs), and a TNF (tumor necrosis factor)-alpha inhibitor, all without any clinical improvement. Throughout this period, he had persistent loose stools and iron-deficiency anemia. Extensive diagnostic investigations for various possibilities yielded negative results. However, after 7 years, he began displaying clinical signs of malabsorption. This prompted further evaluation, including an upper-gastrointestinal endoscopy and biopsy, which revealed the presence of PAS (periodic acid-Schiff)-positive Treponema whipplei, which led to the diagnosis of WD. Following initiation of appropriate treatment, the patient experienced complete resolution of symptoms. Retrospectively, all the pieces of this puzzle fell into place, providing a comprehensive understanding of the prolonged medical challenge the patient faced.

CONCLUSIONS: This case illuminates the diagnostic challenge faced when dealing with migratory polyarticular inflammatory arthritis and fever. This report has highlighted that Whipple disease can be associated with multiple symptoms and signs, which can result in a delay in diagnosis. However, once the diagnosis is confirmed, antibiotic treatment is effective.

Keywords: delayed diagnosis, Negative Rheumatoid Factor Polyarthritis, Tropheryma, Whipple Disease, Arthritis, Rheumatoid, Axial Spondyloarthritis, Arthralgia, case reports


The typical progression of WD follows 3 distinct phases. The early phase, lasting less than 6 years, is characterized by intermittent arthralgia and fever. The middle phase, spanning from 6 to 8 years, is marked by symptoms such as chronic diarrhea, obstructive issues, weight loss, and abdominal pain. In the late phase, which extends beyond 8 years, neurological symptoms become predominant [1]. In general, there tends to be a delay of several years before reaching a Whipple disease diagnosis. Elchert et al observed a prevalence rate of 9.8 cases per million population over a span of 5 years [2]. Whipple disease has an overall incidence of approximately 1–3 cases per one million people, with symptoms typically emerging around the age of 55. The condition is notably more common in males, with a ratio of 4 to 1 compared to females. The organism responsible for the disease appears to be found in the soil, which accounts for the higher occurrence among individuals involved in farming [3]. This report is of a 40-year-old man with a 7-year history of polyarthritis and a late diagnosis of Whipple disease.

Case Report

A 40-year-old male network engineer, of Polish descent, raised in New Jersey, underwent a comprehensive evaluation due to recurring episodes of migratory (involving the ankles and wrists), and asymmetrical, polyarticular inflammatory arthritis coupled with fever for the last 2 years. These episodes were unpredictable, resolving spontaneously over varying durations, often lasting from hours to days. NSAIDs offered partial relief, and fever was not consistently concurrent with arthritis. The patient’s medical history included iron-deficiency anemia, managed with iron supplements, and a childhood cardiac murmur that had since resolved. Reviewing his health history revealed a long-term problem of loose stools since childhood, without concerning signs. He had no other significant concerns and had a keen interest in fishing and traveling. The examination revealed notable tenderness and restricted range of motion in the affected joints, with no observable rash, deformities, sub-cutaneous nodules, indurations, or crepitations.

The lab results revealed elevated levels of erythrocyte sedimentation rate 52 mm/hr ( reference <15 mm/hr), C-reactive protein 50 mg/dL (reference <0.3 mg/dL), angiotensin-converting enzyme 73 µg/L ( reference <40 µg/L ), antistreptolysin O 689 IU/mL (reference <200 IU/mL), DNAase, and a low albumin/globulin ratio 0.6 (1.1–2.5). Tests for rheumatoid factor, anti-neutrophil cytoplasmic antibody (ANCA), MPO antibodies, human leukocyte antigen B27, hepatitis panel, Lyme disease, uric acid, and sexually transmitted diseases consistently returned negative results. The differential diagnoses considered at this stage included spondyloarthritis, palindromic rheumatism, rheumatic fever, crystalline arthropathy, and Lofgren syndrome. After ruling out valvular vegetations and infectious causes, prednisone treatment was initiated. However, the symptoms persisted, leading to addition of methotrexate to the treatment regimen. Over the following 6 months, the symptoms persisted, and the C-reactive protein levels remained elevated at 40 mg/dL. As a response, the methotrexate dosage was augmented while simultaneously reducing the prednisone dosage. In response to the patient’s fever reaching 38.9°C, the Infectious Disease specialist recommended initiating empirical treatment for both Lyme’s disease and rheumatic fever.

Despite these interventions, the patient developed bilateral hip and lower back pain with prolonged morning stiffness and wrist joint immobility, suggesting axial spondyloarthritis with peripheral involvement. Adalimumab was added to the methotrexate treatment. However, even with adalimumab and continued rheumatic fever treatment, the symptoms persisted, accompanied by a generalized pruritic maculopapular rash. This prompted consideration of adult-onset Still’s disease. However, the patient’s lack of response to corticosteroids and normal ferritin levels remained perplexing. Subsequent follow-ups revealed inadequate symptom control and the onset of painful oral and painless penile sores, along with erythematous tender nodular leg lesions. This redirected consideration toward Lofgren syndrome versus Behcet syndrome, and colchicine was added to the existing treatment regimen.

While CT chest scans, human leukocyte antigen B51 testing, ophthalmology evaluations, and pathergy tests yielded no significant findings, a bone scan indicated increased isotope up-take in the ribs and proximal femur, suggesting sarcoidosis, with normal bone biopsy results. Malignancies such as lymphomas, hypernephroma, and multiple myeloma were ruled out through laboratory tests, imaging (serum protein electrophoresis, urine protein electrophoresis, CT scans), and hematology evaluations.

For the next few months, attempts were made with tofacitinib and later tocilizumab, but there was no notable improvement in the patient’s condition. However, his condition deteriorated, evident in bilateral lower-extremity pitting edema, explosive diarrhea, and unintentional weight loss exceeding 45 kg. Fecal calprotectin levels were normal, and colonoscopy results were unremarkable. Laboratory findings consistently pointed to iron-deficiency anemia, despite iron supplementation, a reversed albumin/globulin ratio, albumin levels of 2.6 g/dL (reference range: 3.4–5.4 g/dL), and a positive anti-Saccharomyces cerevisiae antibody (ASCA) IgA. Malabsorptive pathology was suspected, prompting an upper-GI endoscopy and biopsy. Surprisingly, the results were consistent with Whipple disease, showing PAS (periodic acid-Schiff)-positive Treponema whipplei (Figures 1, 2) and positive PCR results. Treatment commenced with IV ceftriaxone and PO maintenance doxycycline, alongside hydroxychloroquine. The patient’s symptoms resolved completely, finally shedding light on the unresolved mystery of the past 7 years.


Whipple disease predominantly affects males of white ethnicity from North American and European backgrounds [3]. Later onset of the disease and those experiencing cardiovascular (eg, endocarditis, pleuropericarditis) and neurological symptoms (eg, cognitive impairment, frontal lobe syndrome, cerebellar ataxia, or upper motor neuron, extrapyramidal symptoms) have been reported to have higher mortality and relapse rates [4]. Increased infection risk is associated with occupations that entail exposure to contaminated water sources, such as farming and sanitation. In this particular instance, it is probable that the patient’s engagement in fishing contributed to their exposure. The exact mortality rates for Whipple disease are still unclear [3].

Whipple disease typically has a chronic, systemic progression. Symptoms are categorized into intestinal and extraintestinal manifestations. Intestinal symptoms include abdominal pain, diarrhea, weight loss, and potential issues like steatorrhea or gastrointestinal bleeding. Extraintestinal manifestations affect organs like the heart, joints, nervous system, and skin, and these can involve valvular issues, arthritis, neurologic symptoms, and skin abnormalities [4]. In our case, the patient underwent a normal colonoscopy and biopsy for experiencing persistent loose stools since adolescence. At the early stages of the disease, there were no other overt signs that necessitated an endoscopy.

During the initial evaluation, the patient exhibited criteria resembling seronegative RA with oligo-poly-inflammatory arthritis persisting for over 6 weeks, accompanied by elevated inflammatory markers and wrist joint effusion. However, certain inconsistencies were noted, such as the presence of fever and the absence of involvement of the small joints and asymmetrical pattern [5]. Palindromic rheumatism was also considered due to recurrent asymmetrical joint involvement with fever, but there were discrepancies such as the lack of joint erythema and the sustained elevation of erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) without symptom resolution [6]. Considering rheumatic fever, the patient met 1 major (joint involvement) and 4 minor criteria (elevated ESR and CRP, fever, arthralgia) with elevated ASO titers [7]. Adult-onset Still disease was contemplated, as the patient met 3 major criteria (fever, arthralgia, rash) and 1 negative criterion (negative RF and ANA), although the lack of improvement with steroids and normal ferritin posed a contradiction [8]. Lofgren syndrome was considered due to migratory polyarthritis and elevated angiotensin-converting enzyme levels, but normal chest imaging ruling out lymphadenopathy and not being self-limiting was contradictory [9]. Sarcoidosis was suggested by increased isotope uptake in a bone scan, although it did not respond to immunosuppression. Behcet syndrome was also considered due to recurrent oral and penile ulcers with erythematous, tender nodular leg lesions, despite negative HLAB 51 and negative pathergy test, making it less probable [10].

The criterion standard for confirming a Whipple disease diagnosis involves histopathological validation through a biopsy. Biopsies are usually extracted from the small bowel, although they can also be effectively taken from sites where the primary active disease is observed. Periodic acid-Schiff staining via histochemistry can reveal the presence of foamy macrophages. Furthermore, disease evidence can be substantiated by detecting nucleic acids using polymerase chain reaction [11].

Supportive diagnostic methods typically involve a detailed medical history, comprehensive physical examination, and relevant lab results suggesting malabsorption. Complete blood counts gauge anemia and neutrophilia. A comprehensive metabolic panel assesses hypoalbuminemia and key electrolyte imbalances. Additional evaluations often include iron studies and measuring folate and cobalamin levels.

Despite the availability of various diagnostic methods, numerous individuals afflicted with Whipple disease endure extended periods, sometimes spanning years, before receiving a definitive diagnosis [12]. Consequently, it is of utmost importance to expedite the diagnostic process to enhance clinical outcomes. Here, we presented a challenging case involving a middle-aged man experiencing persistent and chronic intestinal and extraintestinal symptoms, ultimately diagnosed as Whipple disease.

A precise understanding of the pathophysiology underlying Whipple disease is still elusive. However, current proposed mechanisms suggest the potential involvement of dysfunctional macrophages and suppressed T cell activation in immune surveillance among active carriers. Additional research emphasizes a growing association with HLA-B27 and similar antigenic structures between T. whipplei and Streptococcal species, pointing towards a significant role in the disease’s onset [13].

Treatment for Whipple disease typically begins with a daily intravenous dose of 2 to 4 g of ceftriaxone for 2–4 weeks. An alternative initial treatment could involve administering 2 million units of penicillin G every 4 hours instead of ceftriaxone, or meropenem for individuals allergic to penicillin. After the initiation therapy phase, patients transition to a maintenance phase lasting 1–2 years, during which they are prescribed perioral trimethoprim-sulfamethoxazole at a dose of 160–800 mg twice daily. Alternatively, maintenance options include 200 mg of doxycycline in combination with 600 mg of hydroxychloroquine daily. Treatment plans often encompass vitamin and mineral supplementation, including fo-late, cholecalciferol, calcium, iron, and magnesium. Therapeutic agents may also be introduced to alleviate specific symptoms.

Meunir et al observed during 34 years that the median age of onset was 55 years, which is less than in our patient, and the median time of diagnosis was 5 years, which is more than in our case. They also observed chronic, intermittent, seronegative, and nonerosive polyarthritis, which were seen in our patient [14].


This report presents a perplexing case of a chronic multisystemic ailment that was eventually identified as Whipple disease. Despite years of administering multiple treatments with no clear resolution and facing uncertain differential diagnoses, the final diagnosis of Whipple disease was conclusively established through an endoscopic-guided biopsy investigation. In a retrospective view, all the symptoms and manifestations neatly align within their respective categories. The key takeaway point from this case is that if arthralgias do not respond to standard treatments, considering Whipple disease as a potential differential diagnosis is advisable.


1.. Kucharz EJ, Kramza J, Grosicka A, Pieczyrak R, Clinical manifestations of Whipple’s disease mimicking rheumatic disorders: Reumatologia, 2021; 59(2); 104-10

2.. Elchert JA, Mansoor E, Abou-Saleh M, Cooper GS, Epidemiology of Whipple’s disease in the USA between 2012 and 2017: A population-based national study: Dig Dis Sci, 2019; 64(5); 1305-11

3.. Antunes C, Singhal M, Whipple Disease: StatPearls, 2023, StatPearls Publishing https://www.ncbi.nlm.nih.gov/books/NBK441937/

4.. Dolmans RA, Boel CH, Lacle MM, Clinical manifestations, treatment, and diagnosis of tropheryma whipplei infections: Clin Microbiol Rev, 2017; 30(2); 529-55

5.. Baker JF, O’Dell JR, Seo P, Diagnosis and differential diagnosis of rheumatoid arthritis: UpToDate Published July 28, 2023

6.. Sanmartí R, Frade-Sosa B, Morlà R, Palindromic rheumatism: Just a prerheumatoid stage or something else?: Front Med (Lausanne), 2021; 8; 657983

7.. Alqanatish J, Alfadhel A, Albelali A, Acute rheumatic fever diagnosis and management: Review of the global implications of the new revised diagnostic criteria with a focus on Saudi Arabia: J Saudi Heart Assoc, 2019; 31(4); 273-81

8.. Mitrovic S, Feist E, Kalliolias GD, Georgountzos A: Periodic and non-periodic fevers, 2019; 93-132, Cham, Springer

9.. , Lofgren syndrome: StatPearls https://www.ncbi.nlm.nih.gov/books/NBK482315/

10.. Davatchi F, Diagnosis/classification criteria for Behcet’s disease: Patholog Res Int, 2012; 2012; 607921

11.. Herbette M, Cren JB, Joffres L, Société de Rhumatologie de l’Ouest and the network VICTOR HUGO. Usefulness of polymerase chain reaction for diagnosing Whipple’s disease in rheumatology: PLoS One, 2018; 13(7); e0200645

12.. Viegas AF, Lopes AM, Venade G, Why is Whipple’s disease still a challenging diagnosis? A case report and brief review of literature: Cureus, 2023; 15(1); e34029

13.. Hujoel IA, Johnson DH, Lebwohl B, Tropheryma whipplei infection (whipple disease) in the USA: Dig Dis Sci, 2019; 64(1); 213-23

14.. Meunier M, Puechal X, Hoppé E, Rheumatic and musculoskeletal features of Whipple disease: a report of 29 cases: J Rheumatol, 2013; 40(12); 2061-66

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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923