Whipple arthritis: diagnosis by molecular analysis of synovial fluid—current status of diagnosis and therapy

U. Lange and J. Teichmann1

Kerckhoff Clinic and Foundation, Department of Rheumatology, Bad Nauheim and
1 III Medical Clinic, University of Giessen, Giessen, Germany

Abstract

Whipple's disease (WD) is an uncommon polysystem infectious disease. In the present report, we describe a patient who presented with a chronic illness consistent with WD and an avascular necrosis of the right hip joint. WD and its proposed causative bacillus, Tropheryma whippelii, was identified by molecular analysis (polymerase chain reaction) in bacterial DNA extracted from the synovial fluid. The diagnosis was additionally confirmed by upper gastrointestinal endoscopy and a small bowel biopsy with macrophages positive for periodic acid–Schiff reagent demonstrated by light and electron microscopy.

This demonstrates that WD can be diagnosed without tissue biopsy. False diagnosis of the polymorphous signs and symptoms of WD can lead to invalidism and even death, whereas correct therapy leads to a cure in most cases. Thus, the current status of diagnosis and therapy is of key importance in the treatment of WD.

KEY WORDS: Whipple's disease, Infectious disease, Actinomycete.

Case report

A 60-yr-old male patient was admitted to hospital as a result of rapid decline and general malaise and increasing immobilization. No major health problems up to the age of 50 are registered. Since age 57 recurrent polyarthralgia at differing locations was first manifest bilaterally at the ankle joint for 6 weeks, along with recurrent febrile episodes of temperatures up to 40°C and night sweats. He lost 20 kg of weight over the last 8 months, 13 kg of which were lost in the last 4 months, accompanied by lack of appetite and diarrhoea (frequency: 1–3 times daily). Moreover, hip pain on the right side increased over the last 4 months, resulting in pain on walking and weight-bearing.

Upon admission, deteriorating general and nutritional condition as well as striking hyperpigmentation of the distal limbs (Fig. 1A and BGo) were found. Moreover, swelling and hyperthermia of both ankle joints, painful and limited flexion (up to 80°) of the right hip joint and closed internal and external rotation were observed. The length of the leg decreased by 4 cm on the right side.



View larger version (133K):
[in this window]
[in a new window]
 
FIG. 1. (A and B) Dermal pigmentary changes (hyperpigmentation) of the distal limbs in a patient with WD. (C) Destruction of the right hip joint in a patient with WD. (D) PCR of the synovial fluid from the right hip joint: Lane 1: 100-bp DNA marker; lane 2: positive analytical control prepared using a purified plasmid comprising the 284-bp target region (dilution 10-7); lane 3: negative control; lanes 4 and 5 (extracted in duplicate): synovial fluid. (E) Biopsy specimen of the small-intestinal mucosa: infiltration of intense PAS-positive foamy macrophages in the lamina propria (x60). (F) Appearance of the Whipple bacillus in the electron microscope: dense cell wall, double membrane and a bacteria-like intracellular fibrillary structure (x50 000). (G) Electron microscopy of a small-intestinal biopsy: ‘sickle-form particle-containing cells’—SPC cells (x3660). (H) Electron micrograph of the small-intestinal mucosa: presence of Whipple bacilli extra- and intracellularly (x2330).

 
Additional diagnostics
The laboratory values were: erythrocyte sedimentation rate (ESR) 79–102 mm/h; C-reactive protein (CRP) 74.2 mg/dl; haemoglobin 8.2 g/dl, haematocrit (HCT) 0.27 l/l; platelets 385x109/l; reticulocytes 8%; differential blood count: leucocytes 5.5x109/l; eosinophils 60x106/l.

Standard values in routine laboratory tests, barring pathological findings, were as follows: sodium 130 mmol/l; calcium 1.9 mmol/l; chlorine 95 mmol/l; protein 53 g/l; albumin 23%; iron 16 µg/dl; and ferritin 635 ng/ml. An HIV test was negative.

The cell-surface markers showed CD3 cells 76%; CD4 cells 59%; CD8 cells 11%; B cells, total 5%; activated T cells 3%, the CD4/CD8 ratio was markedly increased with 5.3%. Tumour marker was normal, namely CEA/Ca19-9/Ca 72/Cyfra.

The immunological parameters were as follows: IgG 1120 mg/dl; IgA 642 mg/dl; IgM 40 mg/dl; C3 complement 102 mg/dl; and C4 complement 26 mg/dl.

Urinary status, urinary diagnosis including Bence-Jones proteins, coagulation parameters, tine test, haemoccult test 3-fold, serological microbiological examinations, pulmonary function and parasitological stool examination were all found to be normal.

The pelvic overview revealed a destruction/impression of the right head of the femor and bilateral sacroiliitis (Fig. 1CGo).

Polymerase chain reaction (PCR) detection of Tropheryma whippelii was performed by agarose gel electrophoresis of the synovial fluid from the right hip joint (see Fig. 1DGo).

Distal oesophagitis, normal stomach, fully developed deterioration of the villous relief starting at the bulbus duodeni and petechial, inhomogeneous, whitish staining of the mucous membrane with focal hyperaemia in the duodenum were found during proximal endoscopy.

Under light microscopy with periodic acid–Schiff reagent (PAS), massive histiocytic storage of granular and rod-shaped PAS-positive material could be detected in the duodenal biopsies. Staining of acid-resisting rod cells was negative. Using electron microscopy, there was proof of intra- and extracellular bacteria showing the typical configuration of Tropheryma whippelii (Fig. 1E–HGo).

Abnormalities and macroscopic indication of Whipple's disease could not be found during coloscopy. The abdominal CT showed lymph nodes of up to 1.5 cm in the root of the mesentery, but no further indication was observed. Selective representation of the small bowel according to Sellink revealed significant thickening of the plicae circulares, mainly in the jejunum.

Summary of the findings and diagnosis
In the presented case, polyarthralgias, arthritis of the right hip joint, loss of weight, febrile episodes, diarrhoea and hyperpigmentation in the hands and feet were the ambiguous, but characteristic, cardinal symptoms. Laboratory parameters were unspecific and did not indicate a precise diagnosis. The diagnosis was based on detection of T. whippelii after arthrocentesis by PCR, and additionally by proximal intestinoscopy with biopsy of macroscopically obvious duodenal mucous membrane with proof of PAS-positive macrophages in the mucous membrane and electron-microscopic proof of Whipple's bacteria, as well as radiological findings (CT: mesenterial lymph nodes; representation of the small bowel according to Sellink; deteriorating plicae circulares).

Therapy
Initially, co-trimoxazole (160 mg trimethoprim/800 g sulphamethoxazole three times/day) was administered as an intravenous antibiotic. After 10 days the diarrhoea ceased and the patient lost aversion to food and resumed eating.

This was followed by adaption to oral long-term therapy with co-trimoxazole (2x160 mg trimethoprim + 800 mg sulphamethoxazole) together with a prophylactic dose of folic acid (10 mg/week). After 5 months the patient was free of discomfort and in good general condition; even a decrease in the initial hyperpigmentation was observed. The laboratory tests showed normal values for the inflammatory parameters and body weight had stabilized.

Epidemiology

WD is a rare disease, and is probably often either misdiagnosed or missed owing to many non-typical symptoms. Thus, exact data regarding the incidence and prevalence are not available. In autopsy studies, prevalence was below 1 per million [1]. Worldwide, about 800–1000 cases have been reported [2, 3].

The disease is far more common in middle-aged Caucasian men than in women (5–10-fold higher). However, in women the rate increases above the age of 70 [4]. WD has been diagnosed, although rarely, in early infancy and in the elderly [5, 6]. Rare cases in black patients and American Indians have been reported [7, 8].

Demographic data from 664 known cases up to 1985 were compiled by Dobbins [4]. Since 1960, 20 new cases worldwide have been reported yearly. Only about 3% of these were diagnosed before the age of 30. Interestingly, most patients are involved in the building trade or agriculture, having contact with soil and/or animals [9, 10]. A higher incidence was reported in rural environments in Italy, France and North Carolina [7, 11, 12]. The occurrence of the disease among siblings [4, 1315] as well as an association with the histocompatibility antigen B27 [16] were also observed, so that a genetic predisposition cannot be excluded.

Eighty-five years after the first description by George Hoyt Whipple (‘intestinal lipodystrophia’ [17], Relman et al. [18] related the bacterium to a new type of actinomycetes by means of PCR and phylogenetic comparison. In parallel, our group [19] as well as O'Duffy et al. [20] were the first to describe the identification of T. whippelii in synovial fluid by means of PCR. Up to this time, the diagnosis of WD was established by microscopic examination of small bowel biopsy specimens of involved tissue [5, 2124].

Pathology

The keystone to diagnosis is the documentation in biopsies of the presence of intracellular and extracellular Gram-labile, rod-shaped microbes in the affected tissue; Gram labile being those cases where Gram-negative results are observed but structures in the cell wall of characteristic Gram-positive and -negative bacteria are also present [9, 16, 25, 26].

For these bacteria, which could not be cultured up until then, the name Tropheryma whippelii was proposed [27, 28]. The bacteria or cell wall fragments of these correspond to the PAS-positive inclusions of macrophages [29, 30], the so-called SPC (sickle-form particle-containing) cells [31, 32], which are typical for WD.

Although WD must be regarded as an infectious disease after the identification of an associated bacterium, it is astonishing that the mode of transmission of the disease is not yet clarified. Worldwide, only a single publication exists on a supposed mode of transmission in an animal experiment [28]. Most probably, so-called cofactors/dispositions have to be considered in this case [9].

Interestingly, a publication in 1969 from de Grood-Lasseel et al. [33] suggests the possibility that the Whipple pathogen might belong to the actinomycetes.

Immunological studies

T-cell defects in WD patients have been observed in several studies [3436], but in these cases the question remains open as to whether this is a primary or secondary phenomenon, so that the significance of an immunodeficiency is currently controversial [4, 5, 3740]. Observation of a normalization in the course of the disease of immunological parameters that are initially pathological speaks for an epiphenomenon [41]. Nevertheless, the frequent detection of skin anergy and increased observations of opportunistic infections may be a symptom of immunodeficiency [42]. A cellular T-cell defect of the immune system is regarded as being predisposing. It is supposed that this defect is not acquired but rather inherited [43] as indicated by the detection of HLA-B27 in approximately 40% of the affected patients.

Systemic manifestation

Most organs can be involved in WD. The course of the disease is characterized by two stages: a prodromal stage, which is determined by unspecific findings, and a highly acute stage of the disease with the classic Whipple triad of diarrhoea, weight loss and malabsorption. The classic signs may be missing in about 20% of cases [21, 42, 44]. In such cases, extraintestinal manifestations play a pathognomonic role. Prodromal symptoms are observed over a period of 3–10 yr, but courses lasting over decades can also appear [45]. Peripheral arthritides appear in 65–90% of cases, in which, as a rule, all joints can be affected [4650]. These represent the major primary and extraintestinal symptoms [51], in most cases knee and ankle joints are involved, followed by hip, finger and hand joints [45, 47]. Usually, the arthritis presents a transient course and character with an acute onset and a duration of hours to days with respect to the single attacks [45]. Chronic symptoms are exceptional.

An increased rate in the appearance of leucocytes, mainly granulocytes, and many macrophages can be identified in the synovia [48, 52, 53]. Interestingly, in one patient, electron microscopic analysis of the synovial fluid suggested a direct articular invasion by the Whipple bacillus [53].

Radiomorphologically, erosive or cystic changes in the joints are rarely observed, even after several years. In 25% of patients, the axial skeleton was affected in the form of sacroiliitis or spondylitis [42, 45, 47]. Joint involvement nearly always precedes the intestinal signs and symptoms by an average of about 5–10 yr [42, 45, 51, 54], although a time interval of 35–39 yr has also been reported [42].

Within the scope of multisystemic manifestations in WD, hyperpigmentation, mainly around scars and the skin areas exposed to sunlight, is observed in 20–50% of cases without signs of adrenal insufficiency [54, 55]. In 50% of cases, peripheral lymphoadenopathy and occasionally extended abdominal lymphoma are found [35, 5658]. However, pleural/pericardial effusions are only rarely observed, as are endocarditides, which can lead to heart failure, valvular defects and changes in the ECG [5961]. Central nervous symptoms such as ataxia, headaches, dementia, personality changes, meningitis, peripheral neuropathy and hypothalamic symptoms, as well as ophthalmological involvement (e.g. uveitis, vitritis, chorioretinitis and ophthalmoplegia) are present in 6–10% of patients [3, 37, 54, 59, 6164]. The neurological findings can be clinically subdued, but on the other hand may also determine the major clinical picture without intestinal symptoms. This is especially problematic in late recurrences after initially successful therapy, particularly in cases with antibiotics crossing ineffectively into the cerebrospinal fluid [16, 59]. Some 50% of the patients complain of chronic, non-productive coughing, suggesting pleural involvement, especially when in combination with fever attacks. A diffuse or granulomatous infection of the lung is rare [1, 54].

Laboratory findings

There are no pathognomonic laboratory findings in WD. Mostly an accelerated ESR and an increased CRP is found. Frequently a normocytic hypochromatic anaemia with or without detection of serum iron deficiency, normal or slightly increased leucocyte counts and, seldomly, folic acid or vitamin B12 deficiency are observed. Moreover, eosinophilia or leucopenia may also be present [21, 37, 59]. Levels of IgA are frequently increased, accompanied by normal IgG and IgM levels [65]. Other pathological changes include malabsorption and steatorrhoea [7, 21, 25, 51, 66]. The impaired protein balance causes hypoalbuminaemia due to exudative enteropathy, decreased hepatic synthesis and decreased mucosal assimilation of amino acids [51, 67, 68]. Immunological findings reveal a proportional shifting of T-cell subtypes, such as a decreased CD4/CD8 ratio [34, 35]. Rheumatoid factors and antinuclear factors are typically negative [46, 47].

Diagnosis

The keystone of the diagnosis is examination of biopsies of involved tissue with pathognomonic histological changes. Characteristic histological findings include dilated flattened villi, large extracellular vacuolated fat accumulation in macrophages and partial cuboid deformation and vacuolation of the surface epithelium [6971]. PAS-positive macrophages are found in the upper third of the lamina propria close to the lumen, but rarely below the lamina muscularis mucosae. Numerous polymorphonuclear leucocytes can be detected in the lamina propria, whereas lymphocytes and eosinophils, which are usually found here, are almost totally lacking. Masses of rod-shaped micro-organisms appear near the basal membrane of the surface epithelium as well as pericapillary and intracellularly. This is demonstrated by the typical changes in SPC cells and PAS-positive macrophages in the affected organs (Fig. 1E–H). In exceptional cases, the duodenum as well as other clinically affected organs do not show typical histological changes [43, 63, 72].

Therapy

When WD is diagnosed an adequate antibiotic therapy can lead to a dramatic improvement, and the majority of patients can be cured [7376]. The first successful use of antibiotics was reported by Paulley in 1952, which led to the suggestion of a bacterial aetiology. Effective antibiotics include chloramphenicol, cephalosporin, tetracycline/doxycycline, penicillin/ampicillin, trimethoprim–sulphamethoxazole, rifampicin and streptomycin [7377]. Owing to a lack of controlled studies the most important publications of the last few years are retrospective and as such suffer somewhat from selection effects [73, 74, 78, 79]. However, adequate administration of antibiotics must be as long-term therapy for a period of years, since recurrences are to be expected. In the largest study of medication involving 88 patients suffering from WD, the average duration of therapy with different antibiotics was approximately 1 yr [74], with a high recurrence rate being observed in the long-term course (31 patients after an average of 4 yr). Recent studies have shown that recurrences appear in up to 50% of cases under tetracycline therapy, especially when the CNS is involved [51, 80, 81]. In this respect it should be noted that, mainly in the case of cerebral invovement, some antibiotics are superior owing to a more advantageous liquor patency [44, 74, 75, 82, 83]. The efficacy of a shorter antibiotic treatment (lasting on average 8 weeks) was examined in another study involving 17 patients, which included clinical follow-up of several years [76]. Here, 21% of the patients treated with tetracycline had recurrences of disease, although the CNS was not involved.

In summary, it can be stated that several oral antibiotics and combinations are effective. Although an optimal antibiotic regimen has yet to be established, trimethoprim–sulphamethoxazole appears to be superior at present, especially when the CNS is involved [79, 83, 84]. The administration of ampicillin/chloramphenicol represents an alternative [54], and successful treatment with rifampicin has also been reported [85].

Follow-up

In the case of extraintestinal manifestation, half-yearly small intestinal biopsies and corresponding organ biopsies serve as follow-up. Only the extracellular bacteria have been seen to disappear completely after antibiotic treatment [51, 59, 86], whereas remaining bacteria in the cytoplasm of macrophages can be detected after antibiotic treatment even after several years of therapy [59, 66]. Recurrence signals an extracellular reinfection in control biopsies [51, 59, 66, 70, 87]. When antibiotics are consequently given, a lethal course of this disease should be avoidable.

Outlook

Lowsky et al. [88] published two cases in which cultivatable erythrocyte-associated Gram-positive bacteria could be found in the peripheral blood, where the occurrence of T. whippelii was demonstrated by sequence analysis. Recently, Raoult et al. [89, 90] cultured and immunologically detected T. whippelii and identified it in the cytoplasm of blood monocytes. However, how far ‘haematotropy’ of the bacterium can be suggested generally in every case needs further clarification.

Our work group [19] and O'Duffy et al. [20] described in parallel the first direct detection of T. whippelii in synovial fluid, and demonstrated that WD can be diagnosed without tissue biopsy. PCR of the synovial fluid is an important new tool in the diagnosis of WD. Whether the detection of T. whippelii by PCR in synovial fluid is always associated with WD, or whether the detection is associated with erosive changes and/or bone destruction needs to be evaluated in further studies. Molecular methods for early diagnosis may have a decided advantage over microscopic techniques owing to their high sensitivity and specificity, and because the method is less invasive than gastrointestinal biopsies.

The question of whether PCR may represent an advantageous step in the diagnosis of WD that could replace the classic mode of diagnosis (PAS staining of involved biopsy tissue) remains open. Nevertheless, we can look forward with great anticipation to further applications of PCR in the diagnosis of WD.

Differential diagnosis of WD

The differential diagnosis of WD includes diseases with primarily gastroenterological manifestations and the ability to show extraintestinal involvement such as skin lesions and arthritis; for example, chronic inflammatory intestinal infections [91, 92], sprue [75], infectious diseases such as tuberculosis [14, 93], yersiniosis [94], AIDS [9597] and non-Hodgkin's lymphoma [96].

Patients with HIV infection may have symptoms similar to those in WD that are caused intracellularly by Mycobacterium avium [50, 98100].

Sarcoidosis, malignant non-Hodgkin's lymphoma and abdominal tuberculosis show numerous pathogenetic and clinical similarities to WD [101, 102].

In monosymptomatic arthritis, all diseases accompanying arthritis should be taken into consideration [45, 103–105]. Moreover, the seronegative spondylarthritides must be taken into consideration in case of additional spine symptoms and signs [45].

Acknowledgments

We thank H. Dotzlaw for critical reading of the manuscript.

Notes

Correspondence to: U. Lange, Kerckhoff Clinic and Foundation, Department of Rheumatology, Ludwig Str. 37–39, 61231 Bad Nauheim, Germany. E-mail: uwe.lange{at}kerckhoff.med.uni-giessen.de Back

References

  1. Enzinger FM, Helwig EB. Whipple's disease: a review of the literature and report of fifteen patients. Virchows Arch A 1963;336:238–69.
  2. Riederer J. Über Whipple's intestinale Lipodystrophie, ihre Sonderstellung im Spruegeschehen, ihre Beziehung zum Rheumatismus und den Speicherkrankheiten. Dtsch Z Verd Stoffwechselkr 1956;16:210–2.
  3. Riggs JE. The evolving natural history of neurologic involvement in Whipple's disease: a hypothesis (letter). Arch Neurol 1988;45:830.[ISI][Medline]
  4. Dobbins WO. Whipple's disease. Springfield, Illinois: Charles C. Thomas, 1988.
  5. Dobbins WO. Whipple's disease. Springfield, Illinois: Charles C. Thomas, 1987.
  6. Feuerle GE. Der M. Whipple. Therapiewoche 1985;43:4944–51.
  7. Maizel H, Ruffin JM, Dobbins WO. Whipple's disease: a review of 19 patients from one hospital and a review of the literature since 1950. Medicine 1970;49:175–205.[ISI][Medline]
  8. Keren DF, Weisbuger WR, Yardley JH, Salyer WR, Arthur RR, Charache P. Whipple's disease: demonstration by immunofluorescence of similar bacterial antigens in macrophages from three cases. Johns Hopkins Med J 1976;139:51–9.[ISI][Medline]
  9. Kniehl M. M.Whipple—Epidemiologie und Ätiologie. Der Mikrobiologe 1994;4:123–6.
  10. Riederer J. Ein Jahrzehnt Fieberschübe, Gewichtsabnahme und wandernde Rheumaschmerzen bei einem 52 jährigen Mann. Internist 1994;35:759–63.[ISI][Medline]
  11. Capron JP, Thevinin A, Delamarre J. La maladie de Whipple. Etude de 3 cas et remarques epidemiologiques et radiologiques. Lille Medical 1975;20:842–5.[ISI][Medline]
  12. Lopatin RN, Grossmann ET, Horine J, Saeedi M, Screenath B. Whipple's disease in neighbours. J Clin Gastroenterol 1982;4:223–36.[ISI][Medline]
  13. Gross JB, Wollaeger EE, Sauer WG, Huizenga KA, Dahlin DC, Power MH. Whipple's disease; report of four cases, including two brothers, with observation and pathologic physiology, diagnosis and treatment. Gastroenterology 1959;36:65–93.[ISI]
  14. Paraf F, Guettier C, Bruneval P et al. Whipple's disease and tuberculosis. Am J Path 1991;11:191–4.
  15. Puite RH, Tesluk H. Whipple's disease. Am J Med 1955;19:383–400.[ISI]
  16. Dobbins WO. Whipple's disease: an historical perspective. Q J Med 1985;56:523–31.[ISI][Medline]
  17. Whipple GH. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Johns Hopkins Hosp Bull 1907;18:382–91.
  18. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple's disease. N Engl J Med 1992;327:293–301.[Abstract]
  19. Lange U, Teichmann J. Diagnosis of Whipple's disease by molecular analysis of synovial fluid. Arthritis Rheum 1999;42:1777–8.
  20. O'Duffy JD, Griffing WL, Li C-Y, Abdelmalek MF, Persing DH. Whipple's arthritis. Arthritis Rheum 1999;42:812–7.[CrossRef][ISI][Medline]
  21. Flemming JL, Rusell H, Wiesner MD. Whipple's disease: clinical, biochemical and histopathologic features and assessment of treatment in 29 patients. Mayo Clin Proc 1988;63:593–651.
  22. Bolt RJ, Pollard HM, Standaert L. Transoral small bowel biopsy as an aid in the diagnosis of malabsorption states. New Engl J Med 1958;259:32–5.[ISI]
  23. Wilson KH, Blitchington R, Frotingham R, Wilson JAP. Phylogeny of the Whipple's disease-associated bacterium. Lancet 1991;338:474–5.[ISI][Medline]
  24. Yardley JH, Fleming II WH. Whipple's disease: a note regarding PAS-positive granules in the original case. Johns Hopkins Hosp Bull 1961;109:76–9.
  25. Dobbins WO, Ruffin JM. A light- and electronmicroscopic study of bacterial invasion in Whipple's disease. Am J Pathol 1967;51:225–42.[ISI][Medline]
  26. Dobbins WO, Kawanishi H. Bacillary characteristics in Whipple's disease: an electronmicroscopic study. Gastroenterology 1981;80:1468–75.[ISI][Medline]
  27. Cho C, Linscher W, Hirschkorn A, Ashutosh K. Sarcoidlike granulomas as an early manifestation of Whipple's disease. Gastroenterology 1984;87:941–7.[ISI][Medline]
  28. Clancy RL, Tomkins WAF, Muckle TJ, Richardson H, Rawls WE. Isolation and characterization of an aetiological agent in Whipple's disease. Br Med J 1975;3:568–70.[ISI][Medline]
  29. Black-Schaffer B. The tinctorial demonstration of a glycoprotein in Whipple's disease. Proc Soc Exp Biol Med 1949;72:225–7.
  30. Chears Jr WC, Ashworth CT. Electron microscopic study of the intestinal mucosa in Whipple's disease: demonstration of encapsulated bacilloform bodies in the lesions. Gastroenterology 1961;41:129–38.[ISI]
  31. Sieracki JC. Whipple's disease. Observation on systemic involvement I. Cytologic observation. Arch Pathol 1958;66:464–7.[ISI]
  32. Babaryka I, Thorn L, Langer E. Epitheloid cell granulomata in the mucosa of the small intestine in Whipple's disease. Virchows Archiv A 1979;382:227–35.[ISI]
  33. de Grood-Lasseel M, Martin JJ. Etude ultrastructurale des lésions du système nerveux central dans la maladie de Whipple. Pathol Biol 1969;17:121–31.[ISI][Medline]
  34. Feuerle GE, Dörken B, Schöpf E, Lenhard V. HLA-B27 and defects in the T-cell-system in Whipple's disease. Eur J Clin Invest 1979;9:385–9.[ISI][Medline]
  35. von Herbay A, Windler F, Heckmayr M, Langkowski J. Abdomineller Pseudotumor als klinische Manifestation eines M.Whipple. T-Zell-Index als Indikator der Krankheitsaktivität und Parameter der Therapiedauer? Dtsch Med Wochenschr 1987;112:1621–5.[ISI][Medline]
  36. Marth T, Neurath F, Cuccherini BA, Strober W. Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease. Gastroenterology 1997;113:442–8.[ISI][Medline]
  37. Dobbins WO. Is there an immune deficit in Whipple's disease? Arthritis Rheum 1987;30:102–5.[ISI][Medline]
  38. Ectors N, Geboes K, De Vos R et al. Whipple's disease: a histological, immunocytochemical and electronmicroscopic study of the immune response in the small intestine mucosa. Histopathology 1992;21:1–12.[ISI][Medline]
  39. Ectors N, Geboes K, Wynants P, Desmet V. Granulomatous gastritis in a patient with Whipple's disease. Am J Gastroenterol 1992;87:509–13.[ISI][Medline]
  40. Feldman M. Whipple's disease. Am J Med Sci 1979;291:56–67.
  41. Stock KP, Burmester GR, Kalden JR, Schmidt H, Riemann JF. Immunologische und elektronenmikroskopische Befunde eines ungewöhnlichen Falles von M. Whipple. Klin Wochenschr 1985;63:176–82.[ISI][Medline]
  42. Witte P, Jehn E, Huchzermeyer H. M. Whipple (Kasuistik). Klinikarzt 1995;12
  43. Meier J, Berwanger I, Zangana N, Hellerich O. Morbus Whipple mit unauffälliger Duodenalhistologie—Eine Kasuistik und Übersicht. Z Rheumatol 1994;53:357–62.[ISI]
  44. Rowedder A, Bauer S, Wegmann W, Schlup P, Meier R. Two cases of Whipple disease with different outcomes. Schweiz Med Wochenschr Suppl 1996;79:47S–52S.[Medline]
  45. Krüger M. Rheumatologie in Praxis und Klinik: Arthritis bei gastrointestinalen Erkrankungen/Whipple-Erkrankung. In: Fehr K et al., eds. Stuttgart: Georg Thieme, 1989: 7.231–7.234.
  46. Wollheim FA. Enteropathic arthritis. In: Kelly NW, Harris ED, Ruddy S, Sledge CB, eds. Textbook of Rheumatology, 3rd edn, Vol. II. Philadelphia: WB Saunders,1989:1064–75.
  47. Kelly JJ, Weisiger BB. The arthritis of Whipple's disease. Arthritis Rheum 1963;6:615.[ISI]
  48. Rubinow A, Canoso JJ, Goldenberg DL, Cohen AS, Shirahama T. Arthritis in Whipple's disease. Isr J Med Sci 1981;17:445–52.[ISI][Medline]
  49. Yardley JH, Hendrix TR. Combined electron and light microscopy in Whipple's disease: demonstration of ‘bacillary bodies' in the intestine. Johns Hopkins Hosp Bull 1961;109:80–98.
  50. Zighelboim J, Carpenter HA, Talley NJ. A patient with diarrhoea, arthralgias and fever. Gastroenterology 1993;105:923–30.[ISI][Medline]
  51. Rünzi M, Breuer N. Die Whipple'sche Erkrankung. Med Klin 1993;88:105–10.[ISI][Medline]
  52. Caughey DE, Bywaters EGL. The arthritis of Whipple's syndrome. Ann Rheum Dis 1963;22:327–35.[ISI][Medline]
  53. Hawkins CF, Farr M, Morris CJ, Hoare AM, Williamson N. Detection by electron microscope of rodshaped organism in synovial membrane from a patient with the arthritis of Whipple's disease. Ann Rheum Dis 1976;35:502–9.[Abstract]
  54. Labenz J, Peitz U, Madeya S, Wieczorek M, Erdelkamp J, Börsch G. Arthralgien, Gewichtverlust und Polyserositis als Leitsymptome eines M.Whipple. Med Klin 1993;88:427–31.[ISI][Medline]
  55. Lange U, Doppl W, Teichmann J et al. Leitsymptome einer Whipple-Erkrankung—Polyarthralgien, Gewichtsabnahme, Fieberschübe und Hyperpigmentierung. Med Welt 1996;47:290–6.[ISI]
  56. Gaist D, Ladefoged K. Whipple disease. Ugeskr Laeger 1993;155:3394–6.[Medline]
  57. Hollerbach S, Holstege A, Muscholl M et al. Maskierter Verlauf eines M. Whipple mit Uveitis, Sepsis, Endokardbeteiligung und abdominellen Lymphomen—Fallbericht und Übersicht. Z Gastroenterol 1995;33:362–7.[ISI][Medline]
  58. Girgardin MS, Zafrani ES, Chaumatte ML, Delchier J, Metreau J, Dhumeaux D. Hepatic granulomas in Whipple's disease. Gastroenterology 1984;86:753–6.[ISI][Medline]
  59. Comer GM, Brandt LJ, Abissi CJ. Whipple's disease: a review. Am J Gastroenterol 1983;78:107–14.[ISI][Medline]
  60. Jeserich M, Ihling C, Holubarsch C. Aortic valve endocarditis with Whipple disease (letter). Ann Intern Med 1997;126:920.[Free Full Text]
  61. Rickman LS, Freeman WR, Feldman ST, Sullivan J, Russack V, Relamn DA. Brief report: Uveitis caused by Tropheryma whippelii. New Engl J Med 1995;332:363–6.[Free Full Text]
  62. Cooper GS, Blades EW, Remler BF, Salata RA, Bennert KW, Jacobs GH. Central nervous system in Whipple's disease: relapse during therapy with trimethoprim–sulfamethoxazole and remission with cefixime. Gastroenterology 1994;106:782–6.[ISI][Medline]
  63. Dobbins WO. The diagnosis of Whipple's disease. New Engl J Med 1995;332:390–2.[Free Full Text]
  64. Martenet AC. Die Uveitis. Dt Ärztebl 1994;19:1026–31.
  65. Le Bodic L, Le Bodic MF, Delumeau G et al. Immunological aspects of Whipple's disease. Gastroenterol Clin Biol 1977;1:9–21.[ISI][Medline]
  66. Otto HF. M. Whipple. Stuttgart: Thieme Verlag, 1975.
  67. Brice RS Jr, Owen EE, Tyor MP. Amino acid uptake and fatty acid esterfication by intestinal mucosa from patients with Whipple's disease and nontropical sprue. Gastroenterology 1965;48:584–92.[ISI][Medline]
  68. Laster L, Waldmann TA, Fenster LF, Singleton JW. Albumin metabolism in patients with Whipple's disease. J Clin Invest 1966;45:637–44.[ISI][Medline]
  69. Bostwick DG, Bensch KH, Burke JS et al. Whipple's disease presenting as aortic insufficiency. New Engl J Med 1981;305:995–8.[ISI][Medline]
  70. Trier JS, Phelps PC, Eidelman S, Rubin E. Whipple's disease: light and electron microscopy correlation of jejunal mucosal histology with antibiotic treatment and clinical status. Gastroenterology 1965;48:648–707.[ISI][Medline]
  71. Gonzales-Licea A, Yardley JK. Whipple's disease in the rectum. Light and electron microscopic findings. Am J Pathol 1968;52:1191–206.[ISI][Medline]
  72. Dobbins WO. Whipple's disease. Mayo Clin Proc 1988;63:623–4.[ISI][Medline]
  73. von Herbay A, Otto HF. Whipple's disease: A report of 22 patients. Klin Wochenschr 1988;66:533–9.[ISI][Medline]
  74. Keinath RD, Merell DE, Vliestra R, Dobbins WO. Antibiotic treatment and relapse in Whipple's disease. Long-term follow-up of 88 patients. Gastroenterology 1985;88:1867–73.[ISI][Medline]
  75. Trier JS. Celiac sprue. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal disease, 5th edn, Vol. 2. Philadelphia: WB Saunders, 1993;1078–85.
  76. Paulley JW. A case of Whipple's disease (intestinal lipodystrophy). Gastroenterology 1952;22:128–33.[ISI]
  77. Boni R, Capasso A, de Nucci C, de Simone R, Sessa E. Whipple disease. Report of a case with unusual therapeutic aspects. Recenti Prog Med 1995;86:201–3.[Medline]
  78. Bai JC, Crosetti EE, Maurino EC, Martinez CA, Samuelli A, Boerr LA. Short-term antibiotic treatment in Whipple's disease. J Clin Gastroenterol 1991;13:303–7.[ISI][Medline]
  79. Feuerle GE, Marth T. Eine Evaluierung der Antibiotika-Behandlung des M.Whipple Tetracyclin vs. Trimethoprim-Sulfmethoxazol. Dig Dis Sci 1994;39:1642–8.[ISI][Medline]
  80. Bambroschke S, Günther M, Dienst C. M. Whipple mit zentraler Beteiligung. Med Klin 1987;81:839–43.
  81. Geboes K, Ectors N, Heidbuchel H, Rutgeerts P, Desmet V, Vantrappen G. Whipple's disease: endoscopic aspects before and after therapy. Gastrointest Endosc 1990;36:247–52.[ISI][Medline]
  82. Alba D, Molina F, Vazquez JJ. Neurologic manifestations of Whipple disease. An Med Interna 1995;12:508–12.[Medline]
  83. Haastrup B, Knudsen JB. Whipple disease. A rare systemic disorder with multiple manifestations. Ugeskr Laeger 1993;155:3033–5.[Medline]
  84. Schrenk M, Metz K, Heiligenhaus A, Layer P, Bornfeld N, Wessing A. Ocular involvement in Whipple disease. Klin Monatsbl Augenheilkd 1994;204:538–41.[ISI][Medline]
  85. Singer R, von Herbay A, Willig F. Successful therapy of cerebral Whipple disease with rifampicin. Med Klin 1995;90:117–8.[ISI][Medline]
  86. Lange U, Teichmann J, Doppl W, Klör H-U. Whipple's disease—current status of diagnostics and therapy. Eur J Med Res 1998;3:331–9.[Medline]
  87. Kojecky Z, Malinsky J, Kondonsek R, Marsalek E. Frequency of occurrence of microbes in the intestinal mucosa and in the lymph nodes during long-term observation of a patient suffering from Whipple's disease. Gastroenterology 1964;101:163.
  88. Lowsky R, Archer GL, Fyles G et al. Brief report: Diagnosis of Whipple's disease by molecular analysis of peripheral blood. New Engl J Med 1994;20:1343.[CrossRef]
  89. Raoult D, La Scola B, Lecocq P, Lepidi H, Fournier PE. Culture and immunological detection of Tropheryma whippelii from the duodenum of a patient with Whipple disease. J Am Med Assoc 2001;285:1039–43.[Abstract/Free Full Text]
  90. Raoult D, Lepidi H, Harle JR. Tropheryma whippelii circulating in blood monocytes. N Engl J Med 2001;345:548.[Free Full Text]
  91. Ammann R. Diarrhoen. In: Siegenthaler W: Differentialdiagnose innerer Krankheiten, 25th edn. Stuttgart: Thieme Verlag, 1984:21.19.
  92. Greenstein AJ, Janowitz HD, Sachar DB. The extraintestinal manifestations of Crohn's disease and ulcerative colitis: A study of 700 patients. Medicine 1976;55:401–7.[ISI][Medline]
  93. Schonfield PF. Abdominal tuberculosis. Gut 1985:1275–83.
  94. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med 1989;321:16.[ISI][Medline]
  95. Meier-Willersen HJ, Maiwald M, von Herbay A. M. Whipple in Assoziation mit opportunistischen Infektionen. Dtsch Med Wochenschr 1993;118:854–60.[ISI][Medline]
  96. Nadler LM. The malignant lymphomas. In: Harrison's principles of internal medicine, 12th edn, Vol. 2. London: McGraw-Hill, 1991:1599–610.
  97. Schneider T, Ullrich R, Zeitz M. Gastrointestinale Manifestationen bei der HIV-Infektion. Z Gastroenterol 1994;32:174–81.[ISI][Medline]
  98. Gillin JS, Urmacher C, Wes R, Shike M. Disseminated Mycobacterium avium-intracellulare infection in aquired immunodeficiency syndrome mimicking Whipple's disease. Gastroenterology 1983;85:187–91.
  99. Maliha GM, Hepps KS, Maia DM, Gentry KR, Fraire AE, Goodgame RW. Whipple's disease can mimic AIDS enteropathy. Am J Gastroenterol 1991;86:79–81.[ISI][Medline]
  100. Vazquez-Iglesias JL, Yanez J, Durana J, Arnal F. Infection by Mycobacterium avium intracellulare in AIDS: endoscopic duodenal appearance mimicking Whipple's disease. Endoscopy 1988;20:279–80.[ISI][Medline]
  101. Crystal RG. Sarcoidosis. In: Harrison's principles of internal medicine, 12th edn, Vol. 2. London: McGraw-Hill, 1991:1463–6.
  102. Wilcox GM, Tronic BS, Schecter DJ et al. PAS neg. granulomatous lymphadenopathy in patients with Whipple's disease. Am J Med 1987;83:165–70.[ISI][Medline]
  103. Utsinger PD, Weiner SR, Utsinger JH. Human models: Whipple's disease, coeliac disease and jejunal bypass. Baillieres Clin Rheumatol 1996;10:77–103.[ISI][Medline]
  104. Weiner SR, Utsinger PD. Whipple's disease. Semin Arthritis Rheum 1986;15:157–70.[CrossRef][ISI][Medline]
  105. Gheorghiu T. Der M. Whipple—eine Herausforderung für die klinische Differentialdiagnostik. Med Klin 1987;82:844–5.[ISI][Medline]
Submitted 5 December 2001; Accepted 4 September 2002





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
42/3/473    most recent
keg148v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (3)
Disclaimer
Request Permissions
Google Scholar
Articles by Lange, U.
Articles by Teichmann, J.
PubMed
PubMed Citation
Articles by Lange, U.
Articles by Teichmann, J.
Related Collections
Other Rheumatology