Rheumatology 2003;42:473–480
doi:10.1093/rheumatology/keg148, available online at www.rheumatology.oupjournals.org
Grand Rounds in Rheumatology
Whipple arthritis: diagnosis by molecular
analysis of synovial fluid—current status
of diagnosis and therapy
U. Lange and J. Teichmann1
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.
and limited flexion (up to 808) 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.
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 408C 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 B) were found. Moreover,
swelling and hyperthermia of both ankle joints, painful
Additional diagnostics
The laboratory values were: erythrocyte sedimentation
rate (ESR) 79–102 mmuh; C-reactive protein (CRP)
74.2 mgudl; haemoglobin 8.2 gudl, haematocrit (HCT)
0.27 lul; platelets 385 3 109ul; reticulocytes 8%; differential
blood count: leucocytes 5.5 3 109ul; eosinophils 60 3 106ul.
Standard values in routine laboratory tests, barring pathological findings, were as follows: sodium
130 mmolul; calcium 1.9 mmolul; chlorine 95 mmolul;
protein 53 gul; albumin 23%; iron 16 mgudl; and ferritin
635 nguml. 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 CD4uCD8 ratio was markedly increased
Kerckhoff Clinic and Foundation, Department of Rheumatology, Bad Nauheim and 1III Medical Clinic, University of Giessen, Giessen, Germany.
Submitted 5 December 2001; revised version accepted 4 September 2002.
Correspondence to: U. Lange, Kerckhoff Clinic and Foundation, Department of Rheumatology, Ludwig Str. 37–39, 61231 Bad Nauheim,
Germany. E-mail: [email protected]
473
ß 2003 British Society for Rheumatology
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U. Lange and J. Teichmann
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 1027); 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 ( 3 60). (F) Appearance of the Whipple bacillus in the electron
microscope: dense cell wall, double membrane and a bacteria-like intracellular fibrillary structure ( 3 50 000). (G) Electron
microscopy of a small-intestinal biopsy: ‘sickle-form particle-containing cells’—SPC cells ( 3 3660). (H) Electron micrograph of the
small-intestinal mucosa: presence of Whipple bacilli extra- and intracellularly ( 3 2330).
Whipple’s disease
with 5.3%. Tumour marker was normal, namely
CEAuCa19-9uCa 72uCyfra.
The immunological parameters were as follows: IgG
1120 mgudl; IgA 642 mgudl; IgM 40 mgudl; C3 complement
102 mgudl; and C4 complement 26 mgudl.
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 destructionuimpression
of the right head of the femor and bilateral sacroiliitis
(Fig. 1C).
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. 1D).
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–H).
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 trimethoprimu800 g
sulphamethoxazole three timesuday) was administered
as an intravenous antibiotic. After 10 days the diarrhoea
ceased and the patient lost aversion to food and resumed
eating.
475
This was followed by adaption to oral long-term
therapy with co-trimoxazole (2 3 160 mg trimethoprim
+ 800 mg sulphamethoxazole) together with a prophylactic dose of folic acid (10 mguweek). 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 w1x. Worldwide, about
800–1000 cases have been reported w2, 3x.
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 w4x. WD has been diagnosed, although rarely, in early
infancy and in the elderly w5, 6x. Rare cases in black
patients and American Indians have been reported w7, 8x.
Demographic data from 664 known cases up to 1985
were compiled by Dobbins w4x. 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 anduor animals w9,
10x. A higher incidence was reported in rural environments in Italy, France and North Carolina w7, 11, 12x.
The occurrence of the disease among siblings w4, 13–15x
as well as an association with the histocompatibility
antigen B27 w16x were also observed, so that a genetic
predisposition cannot be excluded.
Eighty-five years after the first description by George
Hoyt Whipple (‘intestinal lipodystrophia’ w17x, Relman
et al. w18x related the bacterium to a new type of actinomycetes by means of PCR and phylogenetic comparison.
In parallel, our group w19x as well as O’Duffy et al. w20x
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 w5, 21–24x.
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 w9, 16, 25, 26x.
For these bacteria, which could not be cultured up
until then, the name Tropheryma whippelii was proposed
w27, 28x. The bacteria or cell wall fragments of these correspond to the PAS-positive inclusions of macrophages
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U. Lange and J. Teichmann
w29, 30x, the so-called SPC (sickle-form particle-containing)
cells w31, 32x, 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 w28x. Most probably, so-called
cofactorsudispositions have to be considered in this case
w9x.
Interestingly, a publication in 1969 from de GroodLasseel et al. w33x 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 w34–36x, 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 w4, 5, 37–40x.
Observation of a normalization in the course of the
disease of immunological parameters that are initially
pathological speaks for an epiphenomenon w41x. Nevertheless, the frequent detection of skin anergy and
increased observations of opportunistic infections may
be a symptom of immunodeficiency w42x. 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 w43x 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 w21, 42, 44x.
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 w45x. Peripheral arthritides appear in 65–90%
of cases, in which, as a rule, all joints can be affected
w46–50x. These represent the major primary and extraintestinal symptoms w51x, in most cases knee and ankle
joints are involved, followed by hip, finger and hand
joints w45, 47x. 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 w45x.
Chronic symptoms are exceptional.
An increased rate in the appearance of leucocytes,
mainly granulocytes, and many macrophages can be
identified in the synovia w48, 52, 53x. Interestingly, in one
patient, electron microscopic analysis of the synovial
fluid suggested a direct articular invasion by the Whipple
bacillus w53x.
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 w42, 45, 47x. Joint
involvement nearly always precedes the intestinal signs
and symptoms by an average of about 5–10 yr w42, 45,
51, 54x, although a time interval of 35–39 yr has also
been reported w42x.
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 w54, 55x. In
50% of cases, peripheral lymphoadenopathy and occasionally extended abdominal lymphoma are found w35,
56–58x. However, pleuralupericardial effusions are only
rarely observed, as are endocarditides, which can lead
to heart failure, valvular defects and changes in the
ECG w59–61x. 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 w3, 37, 54, 59, 61–64x. 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 w16, 59x. 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 w1, 54x.
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 w21, 37, 59x. Levels of IgA are frequently
increased, accompanied by normal IgG and IgM levels
w65x. Other pathological changes include malabsorption
and steatorrhoea w7, 21, 25, 51, 66x. The impaired protein
balance causes hypoalbuminaemia due to exudative
enteropathy, decreased hepatic synthesis and decreased
mucosal assimilation of amino acids w51, 67, 68x. Immunological findings reveal a proportional shifting of T-cell
subtypes, such as a decreased CD4uCD8 ratio w34, 35x.
Rheumatoid factors and antinuclear factors are typically
negative w46, 47x.
Diagnosis
The keystone of the diagnosis is examination of biopsies
of involved tissue with pathognomonic histological
Whipple’s disease
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
w69–71x. 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
w43, 63, 72x.
Therapy
When WD is diagnosed an adequate antibiotic therapy can lead to a dramatic improvement, and the
majority of patients can be cured w73–76x. 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, tetracyclineudoxycycline, penicillinuampicillin,
trimethoprim–sulphamethoxazole, rifampicin and streptomycin w73–77x. 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 w73, 74, 78, 79x. 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 w74x, 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 w51, 80, 81x. 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 w44, 74, 75, 82, 83x. 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 w76x. 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 w79, 83,
84x. The administration of ampicillinuchloramphenicol
represents an alternative w54x, and successful treatment
with rifampicin has also been reported w85x.
477
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 w51, 59, 86x, whereas remaining bacteria in
the cytoplasm of macrophages can be detected after
antibiotic treatment even after several years of therapy
w59, 66x. Recurrence signals an extracellular reinfection
in control biopsies w51, 59, 66, 70, 87x. When antibiotics
are consequently given, a lethal course of this disease
should be avoidable.
Outlook
Lowsky et al. w88x 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. w89, 90x 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 w19x and O’Duffy et al. w20x 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 anduor 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 w91, 92x, sprue w75x, infectious
diseases such as tuberculosis w14, 93x, yersiniosis w94x,
AIDS w95–97x and non-Hodgkin’s lymphoma w96x.
Patients with HIV infection may have symptoms
similar to those in WD that are caused intracellularly
by Mycobacterium avium w50, 98–100x.
Sarcoidosis, malignant non-Hodgkin’s lymphoma and
abdominal tuberculosis show numerous pathogenetic
and clinical similarities to WD w101, 102x.
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U. Lange and J. Teichmann
In monosymptomatic arthritis, all diseases accompanying arthritis should be taken into consideration w45,
103–105x. Moreover, the seronegative spondylarthritides
must be taken into consideration in case of additional
spine symptoms and signs w45x.
Acknowledgement
We thank H. Dotzlaw for critical reading of the
manuscript.
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