Annals of the Rheumatic Diseases, 1984, 43, 91-94

Case report

Selective C4 deficiency, systemic lupuserythematosus, and Whipple's diseaseMICHAEL EHRENFELD, MURRAY B. UROWITZ, AND M. E. PLATTS

From the Rheumatic Disease Unit, the Wellesley Hospital, University of Toronto, Canada

SUMMARY A 45-year-old female with selective deficiency of C4 and systemic lupus erythematosusdeveloped puzzling gastrointestinal and systemic symptoms in the last 6 months of her life.Extensive investigation of the gastrointestinal tract did not yield any diagnosis, and the patient diedshortly afterwards. Autopsy revealed evidence of a typical Whipple's disease of the jejunum andlymph nodes. This association has not been previously described. The disease is reviewed withemphasis on its being an opportunistic infection in an immunosuppressed host with a complementdeficiency and SLE.

A 45-year-old female previously described as the 4thcase of SLE developing in a patient with C4 defi-ciency' is reported on now because of the develop-ment of unexplained multiple systemic and gastroin-testinal symptoms in the latter part of her life. Theseconsisted of abdominal pain, diarrhoea, fever,anaemia, and some features of malabsorption. Atautopsy she was found to have Whipple's disease.

This association between Whipple's disease, asystemic infection, and SLE has not been previouslydescribed. In view of the preceding complement defi-ciency and SLE in this patient the Whipple's diseasecould be regarded as an opportunistic infection.

Case report

This 45-year-old woman first presented to the lupusclinic in 1976 with a photosensitive malar rash anddystrophic nail changes. SLE had been diagnosed in1955 in the Netherlands. The diagnosis was based onfacial rash, fatigue, photosensitivity, proteinuria,thrombocytopenia, and a positive LE test. She wasinitially treated with oral prednisone for 2 years. Sheimproved somewhat but subsequently had a splenec-tomy and was treated with chloroquine for 15 years.Between 1970 and 1975 she received no treatment.The malar rash persisted and became much worse in1975, while she also developed alopecia, nailchanges, arthralgias, and mucous membrane ulcers.

Accepted for publication 11 January 1983.Correspondence to Dr M. B. Urowitz, Wellesley Hospital, Room649 N, 160 Wellesley Street East, Toronto, Canada M4Y 1J3.

Laboratory investigations revealed a positive LE celltest and fluorescent antinuclear antibody test(ANA). DNA binding and C3 were normal. A lupusband test was negative. In an attempt to control therash chloroquine therapy was reinstituted in 1976.CH50 was undetectable and C4 was absent byimmunochemical and haemolytic assays.2 Over thepast 5 years she continued to have undetectablelevels of C4 and positive LE and ANA tests. She hashad intermittent nail lesions, nasal septal erythema,arthralgias, photosensitivity, and pleuritic chest pain.

In 1980 she suffered from polyserositis, includingpleuritis and pericarditis, and was investigated forproteinuria, which was then attributed to lupusglomerulonephritis. She suffered a deep vein throm-bosis complicated by pulmonary embolism. Becauseof the diagnosis of lupus nephritis she was treatedwith 40 mg of prednisone per day. During the last 6months of her life she developed new symptomn con-sisting of cramping abdominal pain, diarrhoea,nausea, and vomiting, along with increasing fatigue,chills, and fever which ranged between 38 and 40°C.Abdominal examination revealed a slightly dis,

tended abdomen with normal bowel sounds. Thehypochondrium was slightly tender, and the liver wasnot enlarged. Laboratory investigations at this stagerevealed an anaemia of 9-3 g/dl with a bone marrowshowing decreased iron stores. The Coombs test wasnegative, and there was no occult blood in the stool.The total protein was 62 g/l with albumin 26 g/l. Thecholesterol was 85 mg/dl (2-2 mmoLl) and tri-glycerides 100 mg/dl (1.1 mmolI). Liver functiontests and amylase were normal. Extensive investiga-

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92 Ehrenfeld, Urovwit:z, Platts

tion, including 3 x-ray views of the abdomen, uppergastrointestinal studies. gastroscopN and colonos-copy. barium enema, and CT scan and ultrasound ofthe abdomen, revealed onlx signs of slight gastritis.No specific cause for the continuous abdominal painswas elucidated. The prednisone dose was brought upto 80 mg/day with a gradual tapering because of akidney biopsy which showed evidence of diffuse pro-liferative glomerulonephritis.Her final admission was necessitated because of

fever, chills, abdominal pains and diarrhoea, accom-panied by shortness of breath. When admitted shewas cachectic and in respiratory distress. Her temp-erature was 39 5°C and she was hypotensive. She hada very stormy and short spell in hospital. The gas-trointestinal symptoms persisted. A repeat gastro-scopy revealed very extensive candidiasis of thewhole upper gastrointestinal tract, and high-dosenystatin (Mycostatin) was started. She developedmultiple lung infiltrates with severe hypoxaemia,hypotension, and oliguria. Despite vigorous treat-ment which included assisted respiration, pericar-diocentesis, intensive fluid, antibiotic, and steroids,the patient became more hypoxic and acidotic. Shedied after ventricular asystole.At autopsy both pericardial surfaces were covered

by an organising haemorrhagic and fibrinous exudate.The pericardial cavity contained 50 ml of serousfluid. Centrilobular congestion was evidence of rightheart failure and heavy congested lungs of left heartfailure. The lungs also showed focal broncho-pneumonia bilaterally, and there was a small recentpulmonary embolus to the right lower lobe. In addi-tion to the pericarditis further evidence of

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Fig. I Lymph node showing foams macrophages andmultinuclear giant cells separated by large Ptm vacuoles wit/ilittle lYmphloid tissue remaining. (H and E. x203).

Fig. 2 Submucosa ofjejunum showing PAS-positive smallbodies in the cytoplasm of macrophages. (PAS, x203).

polyserositis was noted both in the pleural cavities,which had fibrous adhesions and effusions of 200 ml,and in the peritoneal cavity with similar adhesionsand ascites of 500 ml. The only evidence of lupus inthe kidneys was the presence of focal basementmembrane thickening of the glomeruli along withnumerous proteinaceous casts in the tubules. Theoesophagus was superficially ulcerated, but there wasno evidence of candidiasis.The unexpected finding was the presence of Whip-

ple's disease. The mesenteric and para-aortic lymphnodes were enlarged, soft, and grey. Microscopicallythey contained large numbers of foamy macrophagesand multinucleated giant cells, separated by large fatvacuoles (Fig. 1). Little lymphoid tissue remained.These macrophages were packed with small periodicacid Schiff (PAS)-positive bodies. The jejunum waserythematous grosslv, and both the lamina propriaand the submucosa contained large numbers ofPAS-positive macrophages (Fig. 2). Electron micros-copy was performed on tissue from one of theformalin-fixed nodes. It revealed that the cytoplasmof the macrophages was packed with the typical bacil-lary bodies of Whipple's disease (Fig. 3). None of theserous membranes contained these bacillarx bodies.

Discussion

This patient, who had a hereditary C4 deficiency withSLE, developed gastrointestinal symptoms in the lastfew months of her life which were found to be due toWhipple's disease at autopsy. Functional studies ofthe patient's polvmorphonuclear cells and serumdone before she had developed the gastrointestinalsymptoms suggested that both the chemotactic andopsonic activities in the serum were diminished 2

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SLE, C4 deficiency, Whipple's disease 93

- Fig. 3 Electron microscopy ofamacrophage in a mesenteric lymphnode showing typical bacillarybodies of Whipple's disease.(EM, xS2 OJS).

These functions are complement mediated and couldexplain the abnormal host defence and increased sus-ceptibility to opportunistic infections as expected incomplement deficiency states.

Congenital complement deficiencies have beenassociated with a number of clinical syndromes. C3and C3 inactivator deficiency are often found inassociation with severe recurrent infections.Deficiencies of the terminal complement com-ponents (from C5 to C9) may predispose to recurrentneisserial infections. Deficiencies of early comple-ment components Cl, C2, or C4, as in the casereported here, have an increased frequency of recur-rent bacterial infections, vasculitis, nephritis, andSLE.3 The effects of congenital deficiencies of majorcomplement components suggest a compromise onthe host defence in patients with or without a pictureof SLE. Infection is in fact a major cause of morbidityand mortality among these patients.

Whipple's disease is a systemic disease with mig-ratory polyarthritis, polyserositis, and various CNSmanifestations.4 5 Diarrhoea and considerable loss ofweight due to malabsorption are the most frequentpresenting complaints. Other presenting symptoms

are abdominal pain, lymphadenopathy, fever,hypotension, and hyperpigmentation. The symp-tomatology depends largely on the areas involvedwith the masses of foamy histiocytes. The laboratoryshows all the haematological, biochemical, and stoolfeatures of malabsorption. Radiological studies ofthe gastrointestinal tract are usually abnormal, withthickened mucosal folds visible on small bowelbarium study. Evidence of lymphadenopathy andhepatosplenomegaly can also be found. Thesechanges are nonspecific, and the diagnosis must beestablished on biopsy findings.Endoscopy shows a yellow-white granular appear-

ance on the surface which correlates with thickenedenlarged villi. Light microscopy of the small bowelshows the lamina propria to be packed with foamymacrophages, occasionally giant cells and neutro-phils. These foamy macrophages contain a glyco-protein that stains strongly with PAS. This PASpositivity supports the suggestion that Whipple's dis-ease is a systemic disease, as PAS-positive cells can befound in peripheral lymph nodes, heart, lung, spleencapsule, Kupffer cells of the liver, kidney, and inter-stitium of the pancreas.

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94 Ehrenfeld, Urowitz, Platts

The central nervous system is also involved, espe-cially when Whipple's disease recurs after antibiotictherapy.

Electron microscopy was the one technique thatdemonstrated the morphology of the causativeagent.6 Affected tissue is seen on EM to containbacilliform bodies which have a distinct cell wall andan outer capsule. The rod-shaped bodies again con-firmed the suggestion of Whipple's disease being asystemic bacterial infection, as they have been foundin abundance in the lamina propria, in the centralnervous system, heart, synovium, lymph node, lung,and liver. They have been found in both macrophagesand polymorphonuclear leucocytes as well as lyingfree in the lamina propria of the bowel and they arepresent in smooth muscle cells, mast cells,eosinophils, and intraepithelial lymphocytes. Elec-tron microscopy of small bowel biopsy specimens hasalso been shown to be important in following theresponse to antibiotic therapy. If treatment is suc-cessful, the bacillary bodies within phagocytes dimin-ish until only membranous material remains.A variety of micro-organisms have been isolated

from tissues of patients with Whipple's disease, but sofar no one has cultured the bacillus in vitro or trans-ferred it into animals. This might be due to its uniqueouter 'membrane', extemal to the cell wall. Therecent demonstration6 of the bacillus in smooth mus-cle, intraepithelial lymphocytes, and mast cells sug-gests that this bacillus is an intracellular pathogen,which unlike bacteria may survive within mac-rophages.The patient described in this report developed

systemic lupus erythematosus in association with a

complement deficiency state. Infection is a commonand serious complication in SLE, in some series beingthe most frequent cause of death. Steroid therapy, asthis patient had, may obviously be a contributoryfactor to the increased incidence of infection.Most of the patient's puzzling gastrointestinal

symptoms in the last 6 months of her life could easilybe explained as being due to the complicating Whip-ple's disease. It is not likely that all of her illness couldbe explained on this basis, as she did have positive LEand ANA tests and glomerulonephritis. In additionno bacillary bodies were found in the areas ofpolyserositis at autopsy. This report draws attentionto this previously undescribed infectious complica-tion in a patient with a C4 complement deficiency andsystemic lupus erythematosus.

References

1 Urowitz M B, Gladman D D, Minta J 0. Systemic lupuserythematosus in a patient with C4 deficiency. J Rheumatol1981; 8: 741-6.

2 Minta J 0, Urowitz M B, Gladman D D, et al. Selective defi-ciency of the fourth component of complement in a patient withsystemic lupus erythematosus (SLE). Clin Exp Immunol 1981;45: 72-80.

3 Minta J 0, Movat H Z. The complement system and inflamma-tion. In: Movat H Z, ed. Current topics in pathology. Berlin:Springer, 1979: 68: 136-78.

4 Miksche L W, Blumcke S, Fritsche D, et al. Whipple's disease:etiopathogenesis, treatment, diagnosis, and clinical course. ActaHepatogastroenterol (Stuttg) 1974; 21: 307-26.

5 Keren D F. Whipple's disease: a review emphasizing immunol-ogy and microbiology. CRC Crit Rev Clin Lab Sci 1981; 14:75-108.

6 Dobbins W 0, Kawanishi H. Bacillary characteristics in Whip-ple's disease: an electron microscopic study. Gastroenterology1981; 80: 1466-75.

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