Annals of Rheumatology
Susan M Knight, Deborah P M Symmons
Department of Rheumatology,
Macclesfield District General Hospital, Victoria Road, Macclesfield, Cheshire
Correspondence to: Dr Symmons.
Accepted for publication 15
A 44 year old, previously healthy, white man, who was a milk depot manager, was referred to a general physician in November 1991 with a 16 month history of febrile episodes, lasting for three or four days, which recurred approximately every six weeks. During the episodes his temperature rose to 40°C, he felt flu-like and had aching limbs and profuse night sweats. He had no other symptoms of note and in particular no rash, no weight loss, no joint swelling, and no gastrointestinal or genitourinary symptoms. There was a family history of thyroid disease. He smoked 15-20 cigarettes a day. He had been on holiday to Tunisia in 1987, the Greek islands in 1990 and Portugal in 1991. He weighed 81.2 kg. No abnormalities were found on examination. Initial investigations focused on screening for infection. Full blood count, erythrocyte sedimentation rate, renal function, liver function, thyroid function, chest radiography, and computed tomography of the abdomen were normal. Blood cultures were negative, as were a Mantoux test and early morning urine analysis for tuberculosis. He also had negative serology for syphilis, brucella, toxoplasma, and leptospirosis.
In May 1992 the
febrile episodes became more frequent and he was referred for a second opinion
to an infectious diseases unit. The differential diagnosis included
an occult infection and a connective disease. An infection screen was
again negative. Rheumatoid factor, anti-nucleur antibodies, and ds-DNA
antibodies were negative and immunoglobulin concentrations were
normal. It was suggested that he might have adult onset Still's
disease. In November 1992 he was referred and admitted to a
teaching hospital rheumatology unit for further investigation of his
intermittent fevers and arthralgia. The arthralgia affected
predominantly the left knee and shoulder. Examination was again
normal with no rash, no lymphadenopathy and no synovitis. The
differential diagnosis included occult infection, a malignancy (in
particular a lymphoproliferative malignancy), inflammatory bowel
disease, and a connective disease.
The working diagnosis remained adult onset Still's disease and he was treated with indomethacin. In April 1993 he was given prednisolone 10 mg daily because his joint symptoms were becoming more prominent, and he had some pleuritic chest pain although he still had no documented synovitis. Three months later his symptoms were no better and methotrexate was added. By September 1993 his fevers had largely settled but he began to complain of back pain. His modified Schober's index was 6 cm.
By July 1994 he had begun to experience joint swelling as well as pain. He had documented synovitis of a number of small joints including the right wrist. There were no other new symptoms. He was taking prednisolone 5 mg daily (which he increased to 15 mg when he experienced fevers) and methotrexate 12.5 mg weekly. His erythrocyte sedimentation rate was 56 mm 1st h. In October 1994 he lost his job and subsequently became depressed, requiring treatment with dothiepin.
During 1995 he was referred to another rheumatologist in a nearby town for a further opinion but the diagnosis was not changed. He was then referred back to the original hospital for follow up in the newly established rheumatology department. He had synovitis of several peripheral joints. At this point he remained rheumatoid factor negative, had no radiological erosions or sacroiliitis. He was HLA-B27 negative. The differential diagnosis included undifferentiated seronegative spondarthritis and adult onset Still's disease. Follow up was continued.
In January 1997 his
weight was 82.6 kg. In April 1997 he had an abrupt onset of watery
diarrhoea with a stool frequency of up to 10 times per 24 hours.
This was associated with gripping lower abdominal pain especially
after meals. There was no blood or mucus in the stools. His weight
fell rapidly to 73.0 kg within four weeks of onset. Differential
diagnosis included intestinal infection, inflammatory bowel disease,
and malignant disease. Stool cultures were negative. Barium enema was
normal and flexible sigmoidoscopy showed only diffuse mild erythema.
Barium follow through showed appearances consistent with
malabsorption with a slow rate of passage through the small bowel,
some dilatation of the small bowel, straightening of the valvulae
conniventes, and moulage. A duodenal biopsy was performed to look for
the organisms of Whipple's disease. It showed large macrophages in
the lamina propria, the cytoplasm of which contained large amounts of
diastase resistant PAS positive material. Bacterial rods
characteristic of Whipple's disease were seen on electron microscopy
(fig 1). Because Whipple's disease can affect the
central nervous system, baseline magnetic resonance imaging of the
brain was performed. It was normal. By the time the diagnosis of
Whipple's disease was confirmed in early July 1997 his weight
had fallen to 62.6 kg. His methotrexate was stopped and he was
given high dose co-trimoxazole. Within three days his diarrhoea had
stopped. By December 1997 his weight had returned to 78.7 kg
and he had no peripheral synovitis. His depression had resolved. He
did however have increasing lower back pain and his Schober had
fallen to 4.7 cm. His sacroiliac radiographs were normal.
The condition is rare. In 1985 Dobbins estimated that there had been 2000 cases since the original description in 1907.2 The great majority have been middle aged white men from the US and Europe. The disease seems to be more common in farmers and people in farm related trades.3 Our patient worked in a milk depot. The causal organism has recently been identified as a Gram positive actinomycete, which has been named Tropheryma whippelii from the Greek trophi (nourishment) and eryma (barrier) because of the malabsorption syndrome it causes.4 The actinomycetes are a diverse group of bacteria most of which are aerobic soil organisms which may account for the link with farming.
manifestations of Whipple's disease are many and diverse. Almost all organ
systems can be involved. Table 2 lists the more
commonly reported features. In approximately two thirds of patients,
the disease begins insidiously with either arthralgia or a migratory,
non-erosive, non-deforming seronegative arthritis. This may precede
any other features by up to 24 years.5 6
Clearly the differential diagnosis depends on what other clinical features
are present. In our patient, fever was the most prominent symptom
apart from arthralgia. This led an infectious disease consultant, a
professor of medicine, and two rheumatologists to the conclusion
that, once infection had been excluded, adult onset Still's disease
was the most likely diagnosis. But, of course, infection had not been
differential diagnosis between adult onset Still's disease and Whipple's disease
has not received much attention in the medical literature. This is
rather surprising as the fever of Whipple's disease occurs most
commonly in patients who also have arthritis.6
Table 3 shows a comparison of the epidemiological and
clinical features of the two diseases. If a patient has fever and
arthritis (but no diarrhoea) then the most important distinguishing features
are the presence of a characteristic salmon-pink evanescent rash in
most patients with adult onset Still's disease as well as a marked
There are no
widely accepted diagnostic or classification criteria for adult onset Still's
disease. Some authors have used the EULAR or ACR criteria for
systemic onset juvenile arthritis (which require an arthritis to be
present for three months or six weeks respectively, plus daily
intermittent temperature increases to 39.5°C or more). Our patient
would have satisfied these criteria by July 1994 when he first
had documented synovitis. An alternative set of criteria was proposed
by Cush et al10 (table 4)
and these are likely to be more specific. Although our patient
satisfied the four mandatory criteria, he only had one of the
additional criteria (serositis). However, both serositis and
reticuloendothelial involvement occur in Whipple's disease and so a
patient with Whipple's could satisfy the Cush criteria.
Black-Schaffer first described in 1949 the characteristic histological changes on which the diagnosis of Whipple's disease has since been based.11 He found that foamy macrophages in the lamina propria of the intestinal mucosa of affected patients contained large amounts of PAS positive, diastase resistant material. Electron microscopy of affected tissue shows characteristic rod shaped bacilli that are both intracellular and extracellular12 (fig 1). PAS positive macrophages and the characteristic bacilli have also been found in non-intestinal tissues including liver, lung, heart, brain, lymph node, and synovium.13 Intestinal infection with Mycobacterium avium or Mycobacterium intracellulare (such as occurs in patients with AIDS) also gives infiltration of the lamina propria with PAS positive macrophages but the latter bacilli are acid fast whereas the Whipple's organism is not. Intestinal biopsy may be positive in Whipple's disease before the onset of diarrhoea but this is not always the case.14
The possibility of making an early diagnosis of Whipple's disease has been increased with the recent advent of polymerase chain reaction (PCR) based techniques. These genetic techniques permit the identification of a species specific 16s ribosomal RNA gene of Tropheryma whippelii in affected tissues.4 The PCR tests could demonstrate T whippelii in tissues that showed no evidence of disease histologically. Ramzan et al looked at 30 patients with histologically confirmed Whipple's disease and eight in whom the disease was suspected but could not be confirmed.15 Results from tissues were positive in 29 of 30 patients with confirmed Whipple's disease and seven of eight of those suspected to have the disease. On biopsies taken after treatment, results from PCR were found to be better than conventional histology at predicting relapse.
T whippelii has also been identified in peripheral blood and pleural effusion cells.16 Clearly it would be a major advance if Whipple's disease could be diagnosed by PCR techniques on peripheral blood mononuclear cells, before the onset of intestinal symptoms. Unfortunately, this does not seem to be a sufficiently sensitive test. Müller et al obtained positive results from peripheral blood on two out of four confirmed cases of Whipple's disease.17 They concluded that the blood test could not be used as a substitute for biopsy.
© 1998 by
Annals of the Rheumatic Diseases
Reprinted with permission
The materials and information on this server are intended for educational and informational purposes only. The materials and information are not intended to replace the services of a trained health professional or to be a substitute for medical advice of physicians and/or other health care professionals. The International Still's Disease Foundation is not engaged in rendering medical or professional medical services. You should consult your physician on specific medical questions, particularly in matters requiring diagnosis or medical attention. The International Still's Disease Foundation makes no representations or warranties with respect to any treatment, action, application medication or preparation by any person following the information offered or provided within this website. Any information used from other websites was done so with permission from each site, with an exception to those of "public domain", whereas we believe any site without a cited reference was a "public domain site" and for our use. The International Still's Disease Foundation is a non-profit organization. This page was last updated on January 17, 2001
Copyright© 1999-2001 International Still's Disease Foundation