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Gluten sensitivity masquerading as systemic lupus erythematosusM Hadjivassiliou, D S Sanders, R A Gru¨newald, M Akil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ann Rheum Dis 2004;63:1501–1503. doi: 10.1136/ard.2003.017947 azathioprine, ANA, double stranded DNA (dsDNA), and Case reports: Three patients are described whose original extractable nuclear antibodies (ENA) were negative.
presentation and immunological profile led to the erroneous At the age of 17 she was referred to an adult SLE clinic. On diagnosis of systemic lupus erythematosus. The correct examination she had a psoriatic palmar skin rash but nothing diagnosis of gluten sensitivity was made after years of else of note. Immunological testing disclosed negative ANA treatment with steroids and other immunosuppressive drugs.
and ENA, dsDNA of 92 IU/ml (0–60), ESR of 29 mm/1st h, Conclusions: The immunological profile of IgA deficiency IgA deficiency, and normal C reactive protein (CRP). The and/or raised double stranded DNA in the absence of possibility of gluten sensitivity was considered on the basis of antinuclear factor together with raised inflammatory markers the history and immunological profile. She tested positive for and symptoms suggestive of an immune diathesis should alert IgG antigliadin antibodies, and a subsequent duodenal the physician to the possibility of gluten sensitivity. The biopsy confirmed gluten sensitive enteropathy. A gluten-free presence of an enteropathy is no longer a prerequisite for the diet was started, azathioprine was stopped, and the steroids diagnosis of gluten sensitivity, which can solely present with withdrawn. Six months after the introduction of the diet she extraintestinal symptoms and signs. Knowledge of the diverse was asymptomatic and receiving no drugs. Her ESR was manifestations of gluten sensitivity is essential in avoiding normal and the skin rash had resolved.
Case 2A 53 year old woman developed blurred vision, headache,and generalised weakness at the age of 20. She improved Glutensensitivityisastateofheightenedimmunologi- spontaneously within several weeks. A year later she cal responsiveness to ingested gluten in genetically presented with identical symptoms and was treated with a susceptible people.1 It represents a spectrum of diverse course of adrenocorticotropic hormone. Three years later she manifestations, of which gluten sensitive enteropathy (also was admitted with a history of recurrent severe headaches, known as coeliac disease (CD)) is one of many.2 We describe heaviness of her legs, and asthenia. Investigations disclosed a three patients who were diagnosed and treated for systemic normal computed tomography (CT) brain scan, visual evoked lupus erythematosus (SLE), but investigations years after the responses, and cerebrospinal fluid examination, a slight original presentation and diagnosis led to the correct increase of anticardiolipin antibodies, raised rheumatoid diagnosis of gluten sensitivity and treatment with a gluten- factor, and dsDNA, but no ANA. An iron deficiency anaemia was attributed to menorrhagia. A brain magnetic resonanceimaging (MRI) scan showed extensive white matter abnorm- alities not typical of multiple sclerosis. In view of the immunological picture and the presence of circulating anti- A 20 month old girl presented with poor weight gain, cardiolipin antibodies a diagnosis of SLE associated with intermittent malaise, and sweating. She was a normal antiphospholipid syndrome was made. She was given aspirin delivery at term. She had chicken pox at the age of 4 months, but remained symptomatic with episodic headaches and which coincided with the onset of her symptoms. Weight gain was poor, but motor development was normal. She was A few years later she complained of generalised arthralgia.
intermittently sleepy and irritable, with tantrums and breath There was no evidence of active synovitis. She was treated holding attacks. On examination she was pale and irritable, with steroids and methotrexate. She continued to complain with mild flexural eczema. She was on the third centile for of fatigue and headaches, which tended to be unilateral and height and weight. Abnormal results included a raised very severe. Examination showed a left sided cataract with a erythrocyte sedimentation rate (ESR) of 70 mm/1st h, weakly divergent squint, mild left hemiparesis, and gait ataxia.
positive antinuclear antibodies (ANA), IgA deficiency, posi- Repeat MRI showed extensive white matter abnormalities tive smooth muscle antibodies, and raised anticardiolipin with mild generalised atrophy. An immunological profile antibodies. Urine analysis and complement levels were showed IgA deficiency, raised dsDNA antibodies, a minimal normal. Her parents reported a facial rash, attributed to sun rise in anticardiolipin IgG antibodies, no ANA or ENA, and normal inflammatory markers (ESR and CRP). She had On the basis of the available evidence a diagnosis of SLE circulating IgG antigliadin antibodies and the HLA typing was made, and treatment was started with steroids. Therewas some improvement in her overall clinical state, but theESR continued to fluctuate. At the age of 4 she was noted to Abbreviations: ANA, antinuclear antibodies; ANF, antinuclear factor; CD, coeliac disease; CRP, C reactive protein; CT, computed tomography; have poor enamel on her teeth and required teeth extractions.
dsDNA, double stranded DNA; ENA, extractable nuclear antibodies; At the age of 6 she developed steroid related side effects and ESR, erythrocyte sedimentation rate; MRI, magnetic resonance imaging; azathioprine was started. While receiving steroids and Hadjivassiliou, Sanders, Gru¨newald, et al DQ2, which is seen in 90% of patients with gluten sensitive IgA deficiency is 10 times commoner in patients with enteropathy. A subsequent duodenal biopsy was normal.
gluten sensitivity than in the healthy population.10 Given that She was diagnosed as having gluten sensitivity with all other gluten related antibodies are of the IgA class neurological manifestations (gluten ataxia, headache, and (endomysium and tissue transglutaminase), IgG antigliadin white matter abnormalities on MRI).3 She was advised to antibodies in this context are the only marker of gluten start a strict gluten-free diet. Six months after the introduc- sensitivity. The high sensitivity of IgG antigliadin antibodies tion of a gluten-free diet her headaches subsided and the in relation to the whole spectrum of gluten sensitivity (with or without an enteropathy) is highlighted by those patientswith no enteropathy but positive IgG antigliadin antibodies, who have the same genetic susceptibility (DQ2) as those with A 54 year old woman originally presented at the age of 40 CD.8 In view of almost 100% specificity antiendomysium with persistent headaches. She was found to have a raised antibodies will only be positive in the presence of an ESR (60 mm/1st h) and mild neutropenia. Temporal artery enteropathy. The common association with other auto- biopsy was normal as was a CT head scan. Two years later she immune diseases, the raised inflammatory markers, and was referred because of epigastric pain. Gastroscopy and the symptoms suggestive of an immune diathesis which abdominal ultrasound were normal. She had a raised ESR, characterise gluten sensitivity often result in a clinical and high globulins, negative antinuclear factor (ANF), and immunological picture that may lead to an erroneous abnormal liver transaminases. An abdominal CT scan was diagnosis, as illustrated by these three cases.
Patients with CD developing SLE and vice versa have been Nine years after the initial presentation she complained of reported, highlighting a possible association.11 12 Another pruritus and intermittent facial oedema. She was diagnosed report has shown that up to 23% of patients with CD have as having urticaria. There was no history of arthralgia, raised anti-dsDNA.13 This reflects our own experience of photosensitivity, or previous thrombotic episodes. She had an patients presenting with neurological dysfunction due to ESR of 76 mm/1st h, raised dsDNA at 301 IU/ml (normal gluten sensitivity, in whom an increase of anti-dsDNA range 0–60 IU/ml) but negative ANF, positive rheumatoid antibodies was seen in up to 20% (unpublished observation).
factor, normal complement levels, neutropenia of 0.9 (range 1.6–6.56109/l) but no lymphopenia, raised anticardiolipin The prevalence of antigliadin antibodies in patients with antibodies, and a negative Schirmer test. Her CRP was SLE has been reported to be 23%.14 None of these patients normal. Her main complaints were a headache and abdom- had an enteropathy on biopsy. The conclusion was that there inal discomfort. A diagnosis of SLE was made. She was is no association between CD and SLE, but an association between gluten sensitivity and SLE cannot be excluded. More A year later she was reviewed by the gastroenterologists likely, however, is the possibility of misdiagnosis of SLE in who performed a colonoscopy, which was normal. A detailed patients with gluten sensitivity. Although it is important to review 13 years after the original presentation suggested that be aware of the possible clustering of autoimmune diseases in the immunological picture (raised dsDNA but normal ANF, the same person, it is more important to consider gluten neutropenia, high ESR) in combination with the gastro- sensitivity in the differential diagnosis of clinical scenarios intestinal symptoms and persistent headache might be such as those described above. Screening for the whole suggestive of gluten sensitivity. Immunological tests showed spectrum of gluten sensitivity may be easily and cost that she was positive for IgG and IgA antigliadin antibodies effectively undertaken by measuring circulating antigliadin and had the HLA typing DQ2. She refused duodenal biopsy antibodies (IgG and IgA), with endomysium and tissue but agreed to the introduction of a gluten-free diet. Her transglutaminase antibodies being used as a marker of the headaches and gastrointestinal symptoms have since sub- presence of an enteropathy. Failure to do so may not only deprive the patient of the correct diagnosis and treatment(gluten-free diet) but also result in the unnecessary use of long term immunosuppressive drugs, with their associatedmorbidity.
Gluten sensitivity has been likened to ‘‘a many-headedhydra’’ because of its diverse manifestations.4 Although most . . . . . . . . . . . . . . . . . . . . .
physicians may be familiar with the classic presentation of gluten sensitivity as an enteropathy (CD), it is worth bearing M Hadjivassiliou, R A Gru¨newald, Department of Neurology, The Royal in mind that the prevalence of CD in the ‘‘healthy’’ population in European countries5 6 and the USA is as high D S Sanders, Department of Gastroenterology, The Royal Hallamshire as 1%. Therefore, for every patient presenting to a gastro- enterologist with the classical presentation of one or more of M Akil, Department of Rheumatology, The Royal Hallamshire Hospital, diarrhoea, abdominal discomfort, bloating, weight loss, steatorrhoea, and/or anaemia, there are eight patients with- Correspondence to: Dr M Hadjivassiliou, Department of Clinical out gastrointestinal symptoms (silent CD).7 Furthermore Neurology, The Royal Hallamshire Hospital, Glossop Road, Sheffield gluten sensitivity may solely present with neurological S10 2JF, UK; m.hadjivassiliou@sheffield.ac.uk dysfunction (ataxia and peripheral neuropathy being thecommonest).2 Only a third of patients presenting with neurological dysfunction due to gluten sensitivity will haveevidence of an enteropathy on duodenal biopsy.8 The presence of an enteropathy is no longer a prerequisite forthe diagnosis of gluten sensitivity. Small bowel mucosal 1 Marsh MN. The natural history of gluten sensitivity: defining, refining and re- lesions in patients with gluten sensitivity range from normal 2 Hadjivassiliou M, Gru¨newald RA, Davies-Jones GAB. Gluten sensitivity as a (grade 0) to irreversible hypoplastic (grade 4).1 Patients with neurological illness. J Neurol Neurosurg Psychiatry 2002;72:560–3.
no enteropathy have antigliadin antibodies and HLA type in 3 Hadjivassiliou M, Gru¨newald RAG, Lawden M, Davies-Jones GAB, Powell T, keeping with gluten sensitivity (for example, cases 2 and 3).
Smith CML. Headache and CNS white matter abnormalities associated withgluten sensitivity. Neurology 2001;56:385–8.
A gluten-free diet appears to be effective in the treatment of 4 Hadjivassiliou M, Gru¨newald RA, Davies-Jones GAB. Gluten sensitivity: a many-headed hydra. BMJ 1999;318:1710–11.
5 Sanders DS, Patel D, Stephenson TJ, Milford-Ward A, McCloskey EV, 10 Cataldo F, Marino V, Bottaro G, Coraza GR. Prevalence and clinical features Hadjivassiliou M, et al. A primary care cross-sectional study of undiagnosed of selective immunoglobulin A deficiency in coeliac disease: an Italian adult coeliac disease. European J Gastroenterol Hepatol 2003;15:407–13.
multicentre study. Gut 1998;42:362–5.
6 West J, Logan RFA, Hill PG, Lloyd A, Lewis S, Hubbard R, et al.
11 Varkel Y, Braester A, Suprum H, Nusem D, Horn Y. Simultaneous occurrence Seroprevalence, correlates and characteristics of undetected coeliac disease in of systemic lupus erythematosus and coeliac disease-like features. Postgrad 7 Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac 12 Komatireddy GR, Marshall JB, Aqel R, Spollen LE, Sharp GC. Association of disease: an evolving spectrum. Gastroenterology 2001;120:636–51.
systemic lupus erythematosus, and gluten enteropathy. South Med J 8 Hadjivassiliou M, Gru¨newald RA, Sharrack B, Sanders DS, Lobo AJ, Williamson C, et al. Gluten ataxia in perspective: epidemiology, genetic 13 Lerner A, Blank N, Lahat N, Shoenfeld Y. Increased prevalence of susceptibility and clinical characteristics. Brain 2003;126:685–91.
autoantibodies in coeliac disease. Dig Dis Sci 1998;43:723–6.
9 Hadjivassiliou M, Davies-Jones GAB, Sanders DS, Gru¨newald RAG.
14 Rensch MJ, Szykowski R, Shaffer RT, Fink S, Kopecky C, Grissmer L, et al. The Dietary treatment of gluten ataxia. J Neurol Neurosurg Psychiatry prevalence of celiac disease autoantibodies in patients with systemic lupus erythematosus. Am J Gastroenterol 2001;96:1113–15.

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