1 Medicine,
2 Dermatology and Venereology and
3 Clinical Immunology, Department of Medical Sciences, University Hospital, S-751 85 Uppsala, Sweden
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Abstract |
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Methods. One hundred and fourteen PsoA patients with skin disease of 20±13 yr and joint disease of 11±10 yr duration answered a questionnaire concerning their medical history and underwent clinical examination, including radiology. Serum IgA AGA and IgG AGA, IgA antibodies to endomysium and immunoglobulins, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration were determined.
Results. Five of the 114 patients (4.4%) had coeliac disease. After exclusion of these five patients, the mean IgA AGA concentration was significantly higher (P=0.0005) than that in a reference group. None of the patients had IgA antibodies to endomysium. The mean serum IgA concentration was significantly increased and IgM decreased. Patients with a high concentration of IgA AGA had significantly higher ESR and CRP and a longer duration of morning stiffness than those with a low AGA concentration.
Conclusions. Patients with PsoA have an increased prevalence of raised serum IgA AGA and of coeliac disease. Patients with raised IgA AGA seem to have more pronounced inflammation than those with a low IgA AGA concentration.
KEY WORDS: Crohn's disease, Ulcerative colitis, Endomysium antibodies, Autoimmune thyroid disease, Concomitant diseases.
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Introduction |
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In a study of palmoplantar pustulosis (PPP), which is considered to be a localized form of pustular psoriasis and, like psoriasis, is associated with arthropathy and spondylarthropathy, it was found that 8% of the patients had coeliac disease and 24% had IgA antibodies to gliadin [4]. Recently, we reported that PPP may be an autoimmune disease in which the autoantigen(s) are localized to the dermal papillary endothelium and which is associated with both nicotinic acetylcholine receptor antibodies and antibodies to gliadin and thyroglobulin [5].
Recently, a greatly increased prevalence of coeliac disease has also been reported in Sjögren's syndrome [6]. Interestingly, there is an increased prevalence of antibodies to muscarinic acetylcholine receptors in Sjögren's syndrome [7].
An association between rheumatoid arthritis and coeliac disease has also been discussed, and there are a number of case reports of clearance of the arthritis after coeliac disease had been diagnosed. There is one report of increased prevalence of IgA AGA, but the results were considered to be non-specific as there were no reticulin/endomysium antibodies [8].
Arthritis is a complication of various types of enteropathy [9] as well as of coeliac disease [10]. Twenty-five per cent of patients with coeliac disease were reported to have concomitant arthritis, which was peripheral, axial or both [11]. Bourne et al. [12] reported that six patients with seronegative arthritis improved with a gluten-free diet after diagnosis of coeliac disease.
An increased prevalence of psoriasis has been found both in patients with Crohn's disease [13] and in those with ulcerative colitis [14], whereas it is not known if there is an association between psoriatic arthritis (PsoA) and coeliac disease. We therefore undertook a screening study of patients with PsoA in order to find out whether this group has an increased prevalence of coeliac disease and/or increased levels of AGA and antibodies to endomysium, and if so, to relate the results to the patterns of serum IgA, IgG and IgM concentrations and to anamnestic and clinical data associated with the subgroups of psoriatic arthritis as defined by Moll and Wright [15].
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Patients and methods |
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A structured interview with questions concerning psoriasis and arthritis and also autoimmune diseases, Crohn's disease, ulcerative colitis, coeliac disease, atopic disease, food intolerance, smoking habits and alcohol consumption was conducted with each patient by one of the investigators (UL). Anamnestic data were verified in the patient's previous medical records. The patient's history of inflammatory bowel disease and coeliac disease was accepted if the diagnosis had been verified by biopsy and of lactose intolerance if a lactose tolerance test had been performed.
The patients were examined by both a rheumatologist (UL) and a dermatologist (ÅB). The skin lesions were evaluated by the use of the psoriasis area severity index (PASI) score, including the degrees of erythema, infiltration and scaling, and estimation of the percentage of skin area involved [16]. The numbers of tender (68 joints) and swollen (66 sites) joints were recorded. Patients with inflammatory back pain [17] were evaluated by radiological examination of the sacroiliac joints and symptomatic parts of the spine. Axial enthesitis, including sacroiliitis grade 2, was recorded. Symptomatic peripheral joints were examined radiologically if this examination had not been performed previously.
Disease activity was evaluated with an overall clinical global assessment (five-step categorical rating scale from inactive to very severe disease).
The project was approved by the research ethics committee of Uppsala University and all patients gave their informed consent.
Antigliadin antibodies
IgA and IgG AGA were measured with an enzyme-linked immunosorbent assay (ELISA) [18] with minor modifications as detailed previously [1]. Patients with values above the 90th percentile value of the reference group (IgA AGA 50 U/ml and/or IgG AGA
12 U/ml) were regarded as having an elevated AGA concentration (IgA AGA- or IgG AGA-positive). Reference sera were obtained from 129 blood donors (65 females and 64 males, age range 1864 yr). The patients' sera were kept frozen (-70 °C) until analysed.
Antiendomysium antibodies
Serum IgA antibodies to endomysium (EmA) were assayed with a standard immunofluorescence method using cryostat sections of monkey oesophagus, as described previously [1].
Immunoglobulins in serum
The concentrations of IgA, IgG and IgM were measured with a Beckman nephelometer (Array Protein System). Blood donors (age range 1864 yr) served as a reference group.
Other analyses
In all patients, ESR (reference range: females 215mm/h, males 210 mm/h), CRP (upper reference level 10 mg/l) and serum alanine aminotransferase (ALAT) (upper reference level 0.8 µkat/l) were measured by routine methods.
Statistical analysis
For analyses with the unpaired t-test and simple regression, Statview 4.5 (Abacus Concepts, Berkeley, CA, USA) was used.
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Results |
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The most common aggravating factors for the psoriasis were stress/depression (45%), infections (16%) and alcohol intake (14%). Alcohol intake once or several times a week was reported by 18% of the male and 13% of the female patients. Sixteen per cent were smokers.
Clinical examination
Eighty-eight per cent of the patients had psoriasis vulgaris and 4.3% palmoplantar pustulosis. In 70% of the patients less than 5% of the skin surface was involved. More than 50% of patients were receiving systemic treatment (see below), whereas 15% had more widespread skin lesions. The nails were involved in 54%.
Sixty-three per cent of the patients had polyarthritis, 17% axial involvement, 14% oligoarthritis and 5% distal joint disease. One patient had arthritis mutilans. The mean number of swollen joints was 3.4±4.4 and of tender joints 6.6±8.1. Sixty-five per cent of the patients had a pathological radiology examination; 17% of all patients had sacroiliitis or spondyloarthritis.
Twenty-four per cent of the patients were taking oral methotrexate (dose range 7.515 mg once weekly), 8% sulphasalazine, 7% cyclosporin, 13% systemic corticosteroids and 51% non-steroidal anti-inflammatory drugs (NSAIDs).
IgA AGA
As seen in Table 2, the group of patients had a significantly higher mean value of IgA AGA than the reference group. In the patient group, 17.4% (11 men and eight women) had IgA AGA concentrations >50 U/l. The corresponding figure for the blood donors was 9.3% (six men and six women). The female patients had a lower mean IgA AGA concentration than the male patients, but the difference was not statistically significant (P=0.0681). A raised IgA AGA concentration was not observed in any patient with serum IgA <1.5 g/l (see below under Immunoglobulins in serum).
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IgG AGA
There was no difference in the mean concentration of the 109 patients (4.9±3.2 U/l) and that of the 129 blood donors (5.1±7.4 U/l). Only three patients had an IgG AGA concentration >12 U/l. Two of them also had high concentrations of IgA AGA and one had a high concentration of IgG AGA but normal IgA AGA. There were no differences between the mean values for male and female patients.
IgA antibodies to endomysium
None of the sera were positive for IgA EmA. The two patients with the most recently diagnosed coeliac disease, who had partial villous atrophy, were also IgA EmA-negative before the start of their gluten-free diet.
Immunoglobulins in serum
The concentrations of IgA and IgM are shown in Table 3 and refer to analyses of 107 patient sera (patients with coeliac disease were excluded and values are missing for two patients).
Figure 1 shows the percentile distributions of IgA concentration and
Fig. 2 the percentile distributions of IgM concentration in the AGA-positive and AGA-negative male and female patients and in the reference group. These results show somewhat different patterns in men and women.
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In male patients with a low alcohol intake (23 times a month or less, n=36) the mean IgA concentration was 2.9±1.7 g/l, and in males with a higher intake (once or several times a week, n=12) it was 3.2±1.4 g/l (not significant).
Seventeen per cent of the patients had a mild increase in ALAT values (>0.8 µkat/l), but raised values were more common in patients with low alcohol intake than in those with a high intake.
As shown in Table 3, both male and female patients showed a highly significant decrease in mean IgM concentration compared with the reference group. There was a significant inverse correlation between the IgA and IgM concentrations (r=0.262, P=0.0065).
In contrast to the low IgM concentration in the male IgA AGA-positive patients, the mean IgM concentration in the eight IgA AGA-positive women was not decreased. On the other hand, IgA AGA-negative female patients had a highly significantly decreased mean IgM concentration.
The mean IgG concentration in the patient group (11.0±2.9 g/l) was significantly higher than in the reference group (10.4±2.3 g/l, P=0.0295). The male patients without an increase in IgA AGA also showed a significant increase in their mean IgG concentration (11.2±2.6 g/l, P=0.0247 vs male blood donors), whereas the corresponding value for female patients did not differ from that of the female reference group.
Anamnestic and clinical data in IgA AGA-positive and -negative patients
Three of the five patients with coeliac disease had first-degree relatives with coeliac disease but none had a first-degree relative with inflammatory bowel disease. Among the IgA AGA-positive patients 5.2% had first-degree relatives with Crohn's disease and 5.5% with ulcerative colitis. Among the IgA AGA-negative patients, 2.2% had a first-degree relative with Crohn's disease and 5.5% with ulcerative colitis. Two per cent of the IgA AGA-negative patients had a first-degree relative with gluten intolerance.
When patients with coeliac disease were excluded, 41% of the patients had various gastrointestinal symptoms (nausea, abdominal distension, pain, flatulence, loose stools, constipation), which were equally common in AGA-positive and -negative patients. The symptoms were not related to the medication, as they were equally common in those who did and did not use NSAIDs and/or methotrexate. Sixteen per cent of the AGA-positive and 11% of the AGA-negative patients said that they were intolerant of gluten and/or milk, with gastrointestinal symptoms after intake of these items. Four of the patients with milk intolerance had an abnormal lactose tolerance test; in the other patients no attempts to verify food intolerance had been performed.
The proportion of patients with thyroid disease was similar in those with and without a raised IgA AGA concentration, but two of four women with coeliac disease had hypothyroidism.
Table 4 shows the type of arthritis in coeliac disease patients and in those with and without IgA AGA. None of the patients in the subgroup with distal joint involvement had a raised IgA AGA concentration (n=6, mean IgA AGA 16.0±7.3 U/l), whereas in the other subgroups of arthritis 620% of patients had a raised IgA AGA concentration.
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Compared with patients with a low IgA AGA concentration, patients with a raised IgA AGA concentration had a significantly higher ESR (29 vs 18 mm/h, P=0.037) and CRP concentration (26 vs 16mg/l, P=0.049) and they also reported a longer duration of morning stiffness (1.79 vs 1.09 h, P=0.0102).
All five of the patients with coeliac disease had received treatment with methotrexate, compared with about 25% of both IgA AGA-positive and -negative patients.
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Discussion |
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An increased prevalence of coeliac disease in patients with PsoA has not been reported previously. Among our patients, 4.4% had coeliac disease (ascertained by the presence of villous atrophy) compared with 0.4% in a large Swedish adult population of blood donors [19]. The figure for coeliac disease in the PsoA patients may be underestimated, as some IgA AGA-positive individuals may have coeliac disease. The prevalence of raised IgA AGA concentrations was similar to that observed in patients with PsoV.
Whether the same good results as in AGA-positive PsoV patients can be obtained in PsoA if a gluten-free diet is started early in the course of arthritis is not known, but there is at least one case report of the clearance of PsoA after diagnosis of coeliac disease [20]. That gluten sensitivity can be of importance in PsoA is also illustrated by the observation of a severe exacerbation of arthritis and skin lesions after gluten challenge in two of our PsoA patients with coeliac disease [3]. Furthermore, the patients in this study who had PsoA and coeliac disease or IgA AGA had more pronounced systemic disease activity, with higher ESR and CRP and longer morning stiffness, and also a tendency to more erosions, than the IgA AGA-negative patients.
The relationship between Crohn's disease, ulcerative colitis and coeliac disease has been debated. Elevated levels of IgA AGA have been reported both in Crohn's disease [21] and in ulcerative colitis [22] but have been considered non-specific, as IgA antibodies to endomysium and to reticulin were negative. However, none of our patients with a raised IgA AGA concentration had a history of Crohn's disease or ulcerative colitis, but both AGA-positive and -negative patients had a high percentage of relatives with these diseases.
None of the PsoA patients had a raised IgA EmA concentration. This observation is similar to the findings in the patients with PsoV; in this group only one out of 33 of those who were AGA-positive was positive for IgA EmA and one was on the borderline [3]. Whether the negativity for EmA in PsoA reflects less pronounced mucosal lesions or a different type of reactivity to gluten compared with those who are positive for EmA is not known. It is established, however, that not all patients with gluten sensitivity are EmA-positive [23]. Thus, in a recent study only one in six patients with partial atrophy had a raised EmA concentration, and patients with increased lymphocyte infiltration in the duodenal epithelium but without villous atrophy are usually EmA-negative [24].
The serum IgA concentration was increased and the IgM concentration was decreased in both AGA-positive and AGA-negative PsoA patients. A similar pattern is present in patients with coeliac disease and dermatitis herpetiformis. The increase in serum IgA is more pronounced in PsoA than in PsoV; the serum IgA concentration was raised in male patients, whereas in female patients the serum IgA concentration was significantly increased only in those with a raised serum IgA AGA concentration [1]. The mean serum IgM concentration was not decreased in PsoV. On the other hand, in PPP the mean serum IgA concentration was elevated and the IgM concentration decreased, with mean concentrations similar to those in PsoA [4]. In PPP, inflammation in the skin is very intense and PPP is also the variant of psoriasis with the highest prevalence of coeliac disease and of IgA AGA.
In PsoA as well as in PsoV [1] and in PPP [4], patients with a raised serum IgA AGA concentration had the highest serum IgA concentration, and therefore it seems likely that reactivity to gliadin stimulates IgA production.
Whether the increase in IgA concentration in the AGA-negative patients can be linked to other processes in the gut is not known. For instance, increased levels of IgA anti-bodies to cytokeratin 18 and epidermal keratins have been reported in both PsoA and rheumatoid arthritis and might contribute to the raised serum level of IgA [25]. It has also been speculated that bacterial infections in the mucosal system might be responsible for an increase in the serum IgA concentration [26]. Schatteman et al. [27] performed ileocolonoscopy and found inflammatory lesions in 20% of the patients with psoriatic oligoarthritis and in 30% of those with axial involvement, indicating that the gut may play a role in the inflammation. However, there was no information about AGA or serum IgA and IgM in their report. Some types of PsoA might be more common than others in AGA-positive patients. Thus, none of our patients with distal joint arthritis were AGA-positive, whereas in the other subgroups 620% were AGA-positive.
A high alcohol intake may contribute to raised serum IgA concentration. There was a tendency to higher serum IgA concentrations in male patients consuming alcohol once or several times weekly than in those who consumed less alcohol. On the other hand, raised ALAT values were more common in those with low alcohol intake. Therefore, it seems less likely that the high serum IgA concentration can be linked to alcohol consumption. Another possibility is that disturbed liver function in PsoA leads to less effective elimination of IgA. In this context, it is of interest that associations of both psoriasis [28] and coeliac disease [29] with biliary cirrhosis have been reported.
Some of the anamnestic and clinical data deserve comment. Gastrointestinal symptoms and a history of intolerance to various food items were equally common in AGA-positive and -negative patients and could not be linked to the use of NSAIDs or methotrexate.
The food items thought not to be tolerated were predominantly gluten and milk. This assumption needs confirmation by objective methods, as in many cases subjective food intolerance cannot be proved in provocations. The question of whether the symptoms might be associated with abnormalities in the intestinal mucosa needs to be addressed in further studies.
Autoimmune thyroid disease was more common among the female PsoA patients than in the population at large. The prevalence of vitiligo was also increased. In north-west Europe, the prevalences of these disorders are 2.7% [30] and 0.38% [31] respectively. This indicates that there may be a link to autoimmune disorders in PsoA, as has also been reported recently in PPP [4]. It is not yet known if PsoA as well as PsoV and PPP patients with AGA carry the same genes, i.e. DQ A1*0501/DQ B1*0102 and DQ A 1*0301/DQ B1*0302, which predominate in patients with coeliac disease [32].
In this study of patients with PsoA, we found an increased prevalence of coeliac disease and of raised IgA AGA as well as an increased serum IgA concentration and a decreased IgM concentration. Studies of the gastrointestinal mucosa in PsoA patients are therefore needed. Controlled studies of the effects of a gluten-free diet on the severity of PsoA are also required.
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Acknowledgments |
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Notes |
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References |
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