A 63-year-old man with an outside diagnosis of rheumatoid arthritis (RA) presented to our medical center for new-onset, progressively worsening dyspnea (New York Heart Association class IV), abdominal bloating, and peripheral edema for 3–4 weeks prior to presentation. A chest radiograph showed mild enlargement of the cardiac silhouette with pulmonary venous hypertension, mild pulmonary edema, and small pleural effusions. Electrocardiogram showed atrial flutter with a 3:1 atrioventricular conduction, left anterior fascicular block, and a prolonged QT interval. A transthoracic echocardiogram (TTE) revealed severe constrictive pericarditis (CP) with pronounced diastolic flow reversal in the hepatic veins. There was no evidence of an intracardiac mass or thrombus. The left ventricular ejection fraction was normal at 70%. He was hospitalized for further evaluation of congestive heart failure (CHF).
Upon arrival at our hospital, the patient was alert and oriented, but appeared fatigued and deconditioned. His blood pressure was 128/88 mm Hg, pulse was 80–98 beats/minute, and oxygen saturation was 94% on oxygen 3 liters/minute by nasal cannula. His jugular venous pressure was elevated. Lung fields showed coarse crepitations at the bases bilaterally. Cardiac examination revealed a 2+ right ventricular heave and normal S1 and S2 with intermittent diastolic filling sounds at the apex. No arterial bruits were evident and peripheral pulses were normal. Lower extremities had pitting edema up to the thighs. Mild ascites was noted on the abdominal examination. No hepatosplenomegaly or lymphadenopathy was detected. The skin and neurologic examination was normal. The joint examination did not show any evidence of active synovitis.
Medical and Surgical History.
He had well-controlled hypertension and hyperlipidemia. There was no history of coronary artery disease, cardiac arrhythmias, acute pericarditis, or CHF. RA was diagnosed 20 years prior with predominantly large joint involvement (hips and ankles) in the setting of elevated inflammatory markers and a positive rheumatoid factor (RF). He was originally treated with methotrexate that was discontinued for unknown reasons. Azathioprine and adalimumab were used briefly and discontinued due to inefficacy. He eventually underwent bilateral total hip arthroplasties but had no apparent extraarticular manifestations until his current presentation.
Medications Prior to Presentation.
The patient was taking aspirin 325 mg daily, nebivolol 5 mg daily, simvastatin 40 mg at bedtime, pantoprazole 40 mg daily, vitamin D 400 IU, and a multivitamin. For RA, he was receiving prednisone 8 mg daily and celecoxib 200 mg once daily.
Family and Social History.
He was married and worked full time. He smoked up to 15 cigars in a year and drank beer 3–4 times a week. He had a family history of premature coronary artery disease in his father (diagnosed in his 50s), who died from colon cancer.
Review of Systems.
His symptoms were not preceded by a viral prodrome. He denied rhinorrhea, cough, chest discomfort, palpitations, orthopnea, paroxysmal nocturnal dyspnea, syncope, or presyncopal episodes. He admitted to worsening fatigue and decreasing appetite over the 3 months prior to admission but denied fever, chills, or night sweats. He also denied any history of skin rash, photosensitivity, alopecia, oral/nasal/genital/cutaneous ulcers, sicca symptoms, inflammatory eye symptoms, pleurisy, pericarditis, hemoptysis, epistaxis, recurrent sinusitis, abdominal pain, or other bowel–bladder symptoms. He did not report any focal neurologic deficits.
Laboratory studies were pertinent for a normocytic anemia (hemoglobin 12.8 gm/dl), leukocytosis (white blood cells 12.6 × 109/liter), elevated brain natriuretic peptide (BNP) of 2,491 pg/ml (normal range 10–83), and a high C-reactive protein (CRP) level of 87.2 mg/liter (normal value <8). Antinuclear antibody, extractable nuclear antigen panel, RF, anti–cyclic citrullinated peptide antibody, antineutrophil cytoplasmic antibody, serum protein electrophoresis, serum urate, QuantiFeron test for Mycobacterium tuberculosis, human immunodeficiency virus (HIV) serology, urinalysis, blood cultures, and liver, kidney, and thyroid function testing were normal or negative. Hand and foot radiographs confirmed marginal erosions at the distal ulnar, metacarpal, and metatarsal heads, supporting the diagnosis of RA.
Cardiac catheterization showed patent coronary arteries. The patient underwent diuresis, successful cardioversion, and a radical pericardiectomy. Initial histologic evaluation of the resected pericardium showed nonspecific features of fibrous thickening and nongranulomatous lymphoplasmacytic and neutrophilic infiltrates without rheumatoid nodules. These histologic changes were initially thought to be consistent with the clinical diagnosis of RA.
SUBSEQUENT CLINICAL COURSE
The patient's CP was attributed as an extraarticular manifestation of his RA. Treatment for RA was not modified given the absence of active synovitis and postsurgical status. However, over the next 4 months, he experienced an unintentional weight loss of 30 pounds and developed right ankle synovitis. The CRP level remained persistently elevated at 75.7 mg/liter and the BNP increased to 4,665 pg/ml. Heart failure symptoms that had improved initially recurred again. Cardiac examination revealed a new pericardial rub. A cardiac magnetic resonance image (Figure 1) showed persistent soft tissue thickening in the surgical bed and enhancement of the residual pericardium, suggesting ongoing pericardial inflammation. Functional imaging showed abnormal ventricular septal motion (d-shaped ventricular septum in early diastole) suggestive of a constrictive physiology without definite evidence for ventricular interdependence. Ventricle size and systolic function were normal. Mild tricuspid, aortic, and mitral regurgitation were noted. There was no abnormal myocardial delayed enhancement to suggest infarct, inflammation, or myocardial fibrosis. His immunosuppressive regimen was then intensified to include methotrexate 15 mg/week and subsequently rituximab (1 gm intravenously, 2 weeks apart), with which his joint symptoms improved significantly.
In the subsequent 4 weeks, he lost another 40 pounds (a total of 70 pounds over 1 year). He was hospitalized with an acute exacerbation of his CHF symptoms and severe fatigue. He had a syncopal episode due to tachy-brady syndrome and underwent a pacemaker placement. His anemia worsened (hemoglobin 9.6 gm/dl) and the CRP level continued to rise (99.5 mg/liter).
For evaluation of an underlying malignancy, computed tomography (CT) of the chest, abdomen, and pelvis was obtained and showed sub–centimeter-sized mediastinal and retroperitoneal adenopathy. Positron emission tomography was negative for malignancy or large-vessel vasculitis. An upper gastrointestinal (GI) endoscopy and colonoscopy were essentially unrevealing and consistent with the patient's lack of GI symptoms. Small bowel biopsy did not show changes of celiac disease or identifiable microorganisms. Peripheral blood polymerase chain reaction (PCR) for Tropheryma whipplei was negative on 2 separate tests. TTE showed an ejection fraction of 70%, thickened pericardium, and restrictive physiology. His progressive weight loss and cachexia were attributed to CHF and chronic inflammation.
Several weeks later, the patient reported a change in his bowel habits with loose stools and large-volume bowel movements. He denied hematochezia or melena. Given the constellation of arthritis, weight loss, diarrhea, and cardiac involvement, Whipple's disease (WD) was again considered in the differential diagnosis.
CP can occur following virtually any pericardial disease process, but rarely follows recurrent episodes of acute pericarditis. The most common etiologies found in large case series (1–5) include (Table 1) idiopathic/post–viral infection, post–cardiac surgery, post–radiation therapy to the mediastinum, postinfectious (tuberculous or purulent), rheumatic diseases (including RA, systemic lupus erythematosus, mixed connective tissue disease, and dermatomyositis, among others), and other miscellaneous causes (such as malignancy, sarcoidosis, asbestosis, and trauma). The diagnoses we considered in this patient are listed below.
Table 1. Differential diagnosis of constrictive pericarditis
3Post–mediastinal radiation therapy (for Hodgkin's lymphoma, breast cancer, and esophageal or metastatic testicular cancer)
Pericarditis is the most common cardiac manifestation of RA (up to 40% of patients in autopsy studies), but only 2% develop clinical symptoms. CP occurs as an infrequent yet life-threatening sequela. Affected patients are frequently seropositive and present with dyspnea, orthopnea, cough, chest discomfort, and peripheral edema. The onset of CP does not seem to correlate with the disease duration or severity of arthritis and may occur even when RA is quiescent or well controlled. The diagnosis of CP is established by echocardiography or CT, and merits urgent treatment to avoid catastrophic hemodynamic consequences. Surgery is the only definitive treatment option, but concomitant immunosuppression (with steroids, disease-modifying antirheumatic drugs, or biologics) is often equally important to control inflammation. In patients unresponsive to standard treatment, a comprehensive evaluation to determine possible alternate etiologies for their “refractoriness” is necessary. A particularly concerning etiology in the setting of immunosuppression is infection.
Tuberculosis (TB) is the most common infectious cause of CP worldwide, but the incidence is much lower in developed nations. It is more frequent among those receiving immunosuppression or those with HIV. Our patient did not have any prior exposure to TB and was checked for latent TB with a QuantiFeron test for M tuberculosis and HIV serology, which were negative. Other rare infectious etiologies include parasitic, fungal, and purulent pericarditis. Our patient had negative bacterial and fungal blood cultures.
WD is a rare multisystem infectious disease caused by T whipplei, commonly presenting with abdominal pain, diarrhea, weight loss, arthritis, and neurologic symptoms. Previously found on autopsy studies, cardiac involvement in WD is now being increasingly recognized, manifesting as endocarditis, and/or less often, myocarditis or CP. Our patient did not have GI symptoms until later in his course. Peripheral blood PCR for WD was negative and a small bowel biopsy was negative for T whipplei organisms.
There are a few reported cases of patients with inflammatory arthritides who deteriorated dramatically on biologic therapy and were eventually found to have WD that was masquerading as RA or spondylarthropathy (6).
The pericardial tissue obtained at pericardiectomy was retrieved and evaluated with a periodic acid–Schiff (PAS) stain. Numerous PAS-positive microorganisms were seen in macrophages (Figure 2) that were confirmed as T whipplei by PCR. The patient was diagnosed with CP secondary to WD and Whipple's arthropathy.
In 1907, Whipple described the case of a 36-year-old physician who died after 5 years of polyarthritis, chronic diarrhea, abdominal pain, and weight loss (7). Postmortem examination showed fat deposition in the intestinal mucosa and mesenteric and retroperitoneal lymph nodes that he termed “intestinal lipodystrophy.” WD, as it is now called, is a rare multisystemic chronic infectious disease clinically characterized by a triad of diarrhea, abdominal pain, and weight loss. It was considered uniformly fatal until microscopic visualization of a bacterial organism led to the first successful treatment with chloramphenicol by Paulley in 1952 (8). In 1961, the bacterium was visualized in macrophages by electron microscopy (9). It was later identified as a gram-positive actinomycete and given the name Tropheryma whippelii (in Greek, “Trophe” means nourishment and “eryma” means barrier), representing the malabsorption associated with WD. It is ubiquitous in the environment often found in soil. In 1992, PCR enabled amplification of the bacterium's 16S ribosomal RNA from duodenal lesions, and successful in vitro culture of the slow-growing bacillus in 2000 (10) led to a major breakthrough in the understanding of pathogenesis, diagnosis, and treatment. Its name was officially changed to T whipplei (Whipple's bacillus) in 2001 and genomic sequencing was completed in 2003.
WD is uncommon, with approximately 1,000 cases reported until 2007 (11). It has intrigued many clinicians and pathologists and has been detected only in cases where it was suspected or sought. There is a long prodromal period (∼6.7 years) (12) and clinical manifestations overlap with many chronic inflammatory diseases, making early diagnosis difficult. The majority of patients are middle-aged white men (mean age 49 years) (13). GI involvement is the most common presentation and may include chronic diarrhea, abdominal pain, mesenteric/retroperitoneal lymphadenopathy, ascites secondary to hypoalbuminemia, and a wasting syndrome. There are no specific blood tests or serologic markers, although nonspecific acute-phase reactants may be elevated. The gold standard test for diagnosis is an upper GI endoscopy with multiple small bowel biopsies. Pale yellow, shaggy mucosa alternating with erythematous, friable mucosa may be seen endoscopically in the duodenum or jejunum (11). Histologic evaluation with PAS staining reveals magenta inclusions within macrophages, but these are nonspecific and may be seen in other diseases such as Mycobacterium avium complex. PCR-based testing for T whipplei DNA is needed for confirmation. It is also important to remember that there is a considerable number of patients who have WD without GI involvement, and those may be missed when using the gold standard test. When performed on peripheral blood, PCR has a much lower sensitivity than when done on an involved tissue site (duodenum, lymph node, heart valve, cerebrospinal fluid, synovial fluid/tissue) (11).
GI symptoms may be absent in one-quarter of patients (14) at disease onset. Neurologic involvement occurs late and usually as part of a recurrence or relapse in inadequately treated patients. Joint manifestations are seen in up to 67% of patients and may precede typical GI symptoms for up to 8 years (15). These include migratory arthralgias involving large joints, nondeforming seronegative oligo-/polyarthritis, spondylodiscitis, spondylarthropathy, or rarely erosive arthritis closely resembling RA. WD can therefore mimic RA for several years before displaying symptoms associated with visceral involvement. Immunosuppression with biologic response modifiers (anti–tumor necrosis factor [anti-TNF] therapy, rituximab, etc.) can exacerbate preexisting WD and trigger visceral presentation, as in our patient (6, 15). It therefore becomes necessary to consider this rare yet curable infectious disease in middle-aged men with RF-negative long-term arthritis that is resistant to standard therapy, particularly prior to starting biologics. It must be specifically sought by obtaining and/or repeating appropriate tissue (duodenal or synovial biopsy with PAS staining and PCR) or fluid (synovial fluid PCR) for testing.
In 1952, Upton first reported cardiac involvement as a component of WD (16). The presence of a pericardial rub and signs of CHF or systolic heart murmurs may be early clinical signs of cardiac involvement. Enzinger reported PAS-positive structures within endocardial vegetations in 34% (32 of 94) of autopsied patients with WD (17). Cardiac involvement in WD is common and may involve any of the 3 layers of the heart. It has been reported in up to 17–55% (18, 19) of patients with WD. Pancarditis was detected on autopsy in up to two-thirds of patients in one series (20). WD should also be considered in the differential diagnosis of patients with culture-negative endocarditis. McAllister and Fenoglio (21) described 19 male patients with WD, 56% of whom had clinical cardiac findings. Seventy-nine percent had gross cardiac lesions at autopsy, with pericardial adhesions in 79%, valvular fibrosis/deformity in 53%, and myocardial fibrosis in 11%. The mitral valve was thickened and deformed in all 10 patients with valvular involvement. All cardiac specimens had macrophages containing PAS-positive structures, and electron microscopy demonstrated rod-shaped organisms in the cardiac valves and myocardium. Coronary arteritis (22), aortitis (23), pulmonary hypertension (24), myocarditis (lymphocytic and granulomatous), and sudden death (25) have also been reported with cardiac WD. No clear relationship between the extent of cardiac involvement and the duration or severity of the systemic disease has been shown (21), and the efficacy of antibiotic treatment for cardiac lesions remains to be demonstrated. Most patients evolve to needing surgery, but CHF responsive to antibiotics has been reported (26).
The complications of cardiac involvement can be potentially fatal, warranting early diagnosis and treatment. CP is one such complication seen with untreated WD and can mimic rheumatoid CP, particularly in patients with concomitant arthritis. Patients present with dyspnea, peripheral edema, ascites, or pleural effusions. These can often be overlooked or attributed to other factors such as anemia or hypoalbuminemia secondary to malabsorption in patients with WD (21). Examination may show elevated jugular venous pressure, pericardial rub, or cardiac murmurs. TTE reveals thickened pericardium and restrictive physiology. CT can also demonstrate pericardial thickening and calcification. Only 6 cases of WD associated with CP have been reported in the literature until 2009, but none with CP as the presenting manifestation. Definitive treatment is radical pericardiectomy. Fibrinous pericarditis with dense adhesions, fibrosis, and inflammation has been described on histopathologic examination of pericardial tissue in WD, which also often shows PAS-positive structures within macrophages. Again, PCR performed on the paraffin-embedded tissue may help to confirm the presence of T whipplei.
Surgery should be followed by antibiotic therapy to prevent recurrence or relapse, particularly central nervous system disease. Intravenous ceftriaxone (2 gm/day) or streptomycin (1 gm/day) with penicillin G (1.2 million units/day) for 14 days followed by trimethoprim/sulfamethoxazole (160/800 mg/day) for at least 1–2 years is the standard regimen (13). These are favored because they cross the blood–brain barrier. Alternatively, a combination of doxycycline (200 mg/day) with hydroxychloroquine (200 mg 3 times a day; alkalinizing agent) for 1–2 years may be used (13). This regimen works by increasing the intravacuolar pH, making it bactericidal for the organism, which usually requires an acidic pH to remain viable in vitro. Recurrences have been reported despite adequate treatment with any of the above regimens. There is no serologic marker that can help determine the appropriate duration of treatment and the patient needs to be followed clinically. It is uncertain if antibiotics can prevent Whipple's pericarditis from progressing to constriction if started early in the course, and further studies to ascertain this are needed.
WD, like any other infection, can progress in the setting of immunosuppression. We suspect this is what actually led to the diagnosis in our patient. He rapidly developed GI manifestations for the first time after initiation of rituximab, which prompted careful reevaluation and eventual diagnosis of WD. Interestingly, however, the small bowel biopsy did not demonstrate changes of WD, which may have been due to very early disease in the bowel. Similar exacerbation of visceral symptoms leading to the diagnosis of WD has been noted upon initiating anti-TNF therapy for presumed RA (6).
To summarize, WD is an often overlooked etiology of oligo-/polyarthritis and must be considered when evaluating and treating middle-aged white men with seronegative RA. WD is a systemic disease and presents without GI symptoms in up to 25% of patients. Patients with unusual and refractory extraarticular manifestations, especially occurring in the context of a seronegative arthropathy, should prompt consideration of alternative diagnoses and must be evaluated for possible WD. A thorough search for WD should be considered prior to starting biologic therapy because this may lead to progressive manifestations of WD. Efforts to recognize and treat this potentially fatal infection early can help prevent life-threatening complications.
The patient received 2 weeks of intravenous ceftriaxone followed by oral trimethoprim/sulfamethoxazole for a year. Immunosuppressive therapy was discontinued and prednisone was gradually tapered off. Over the next several months, he gained weight and his dyspnea, peripheral edema, fatigue, and synovitis improved remarkably. After 1 year of antibiotic therapy, he was asymptomatic. BNP improved to 459 pg/ml and the CRP level was 7.8 mg/liter (Figure 3). A subsequent CT scan of the chest and abdomen showed resolution of the mediastinal and retroperitoneal adenopathy.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Makol had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Makol, Warrington.
Acquisition of data. Makol, Maleszewski.
Analysis and interpretation of data. Makol, Maleszewski, Warrington.