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Psoriasis in a Nationwide Cohort Study of Patients with Celiac Disease

      Earlier studies on the association between celiac disease (CD) and psoriasis show contradictory results. The purpose of this study was to assess the risk of psoriasis in patients with biopsy-verified CD. Through 28 pathology departments in Sweden, we identified individuals with CD diagnosed between 1969 and 2008 (Marsh 3: villous atrophy; n=28,958 unique individuals). We then used Cox regression to compare individuals with CD with 143,910 sex- and age-matched controls regarding their risk of psoriasis. CD was a risk factor for future psoriasis (hazard ratio (HR)=1.72; 95% confidence interval (CI)=1.54–1.92; during follow-up, 401 individuals with CD and 1,139 controls had a diagnosis of psoriasis). The absolute risk of future psoriasis in patients with CD was 135/100,000 person-years (excess risk=57/100,000). In all, 42% of all psoriasis in patients with CD could be attributed to the underlying CD. Moreover, in children we saw a positive association between CD and psoriasis (HR=2.05; 95% CI=1.62–2.60). The association between CD and psoriasis seems to be independent of a temporal relationship, as we also found a positive association between CD and psoriasis before CD diagnosis (odds ratio=1.91; 95% CI=1.58–2.31). In conclusion, individuals with CD were at increased risk of psoriasis both before and after CD diagnosis.

      Abbreviations

      CD
      celiac disease
      CI
      confidence interval
      HR
      hazard ratio
      ICD
      International Classification of Disease
      VA
      villous atrophy

      Introduction

      Celiac disease (CD) is an immune-mediated disease that occurs in ∼1% of the western population. This disease is triggered by gluten exposure in genetically sensitive individuals. Earlier research suggests that CD is associated with a number of autoimmune diseases (
      • Collin P.
      • Kaukinen K.
      • Valimaki M.
      • et al.
      Endocrinological disorders and celiac disease.
      ;
      • Ludvigsson J.F.
      • Ludvigsson J.
      • Ekbom A.
      • et al.
      Celiac Disease and Risk of Subsequent Type 1 Diabetes: a general population cohort study of children and adolescents.
      ;
      • Elfstrom P.
      • Montgomery S.M.
      • Kampe O.
      • et al.
      Risk of primary adrenal insufficiency in patients with celiac disease.
      ,
      • Elfstrom P.
      • Montgomery S.M.
      • Kampe O.
      • et al.
      Risk of thyroid disease in individuals with celiac disease.
      ;
      • Neuhausen S.L.
      • Steele L.
      • Ryan S.
      • et al.
      Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives.
      ).
      Psoriasis is a chronic autoimmune skin disease. Common symptoms include red scaly patches on the skin. Some patients have affected nails and joints (psoriatic arthritis).
      Earlier research has suggested a link between CD and psoriasis (
      • Ojetti V.
      • Aguilar Sanchez J.
      • Guerriero C.
      • et al.
      High prevalence of celiac disease in psoriasis.
      ;
      • Birkenfeld S.
      • Dreiher J.
      • Weitzman D.
      • et al.
      Coeliac disease associated with psoriasis.
      ;
      • Tursi A.
      • Elisei W.
      • Giorgetti G.M.
      • et al.
      Prevalence of celiac disease and symptoms in relatives of patients with celiac disease.
      ), but such an association has also been questioned (
      • Collin P.
      • Reunala T.
      Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists.
      ) and several papers suffer from limitations including small numbers of patients with CD (
      • Tursi A.
      • Elisei W.
      • Giorgetti G.M.
      • et al.
      Prevalence of celiac disease and symptoms in relatives of patients with celiac disease.
      ) and lack of controls (
      • Tursi A.
      • Elisei W.
      • Giorgetti G.M.
      • et al.
      Prevalence of celiac disease and symptoms in relatives of patients with celiac disease.
      ). A recent paper also found a higher prevalence of CD-associated antibodies in patients with psoriasis (
      • Singh S.
      • Sonkar G.K.
      • Usha
      • et al.
      Celiac disease-associated antibodies in patients with psoriasis and correlation with HLA Cw6.
      ; although data are conflicting;
      • Kia K.F.
      • Nair R.P.
      • Ike R.W.
      • et al.
      Prevalence of antigliadin antibodies in patients with psoriasis is not elevated compared with controls.
      ), and some patients with psoriasis and antigliadin antibodies will improve on a gluten-free diet despite the absence of villous atrophy (VA) on biopsy (
      • Michaelsson G.
      • Gerden B.
      • Hagforsen E.
      • et al.
      Psoriasis patients with antibodies to gliadin can be improved by a gluten-free diet.
      ;
      • Addolorato G.
      • Parente A.
      • de Lorenzi G.
      • et al.
      Rapid regression of psoriasis in a coeliac patient after gluten-free diet. A case report and review of the literature.
      ). It may also be that disease activity in psoriasis correlates with levels of CD-associated antibodies (
      • Lindqvist U.
      • Rudsander A.
      • Bostrom A.
      • et al.
      IgA antibodies to gliadin and coeliac disease in psoriatic arthritis.
      ;
      • Woo W.K.
      • McMillan S.A.
      • Watson R.G.
      • et al.
      Coeliac disease-associated antibodies correlate with psoriasis activity.
      ). In a recent large population-based case–control study,
      • Birkenfeld S.
      • Dreiher J.
      • Weitzman D.
      • et al.
      Coeliac disease associated with psoriasis.
      reported that patients with psoriasis had more CD than matched controls, but the prevalence of CD in that study was only 0.11%, whereas it is generally agreed that CD occurs in about 1% of the normal population (
      • Dube C.
      • Rostom A.
      • Sy R.
      • et al.
      The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review.
      ).
      The main objective of this study was to examine the prevalence of psoriasis in a nationwide population-based sample of patients with biopsy-verified CD.

      Results

      Background data

      Some 60% of participants were female (Table 1), and the median age at study entry was 30 years. Median follow-up was 9 years.
      Table 1Characteristics of study participants
      Matched controlsCeliac disease
      Total143,91028,958
      Age at study entry, years (median, range)0–95 (30)0–95 (30)
      Attained age, years (median, range)1–105 (40)1–100 (41)
      Age 0–19 years (%)58,815 (40.9)11,793 (40.7)
      Age 20–39 years (%)26,305 (18.3)5,295 (18.3)
      Age 40–59 years (%)32,021 (22.3)6,418 (22.2)
      Age ≥60 years (%)26,769 (18.6)5,452 (18.8)
      Entry year (median, range)1969–2008 (1998)1969–2008 (1998)
      Follow-up
      Follow-up time until diagnosis of psoriasis, death from other cause, emigration, or 31 December 2008. In controls, follow-up can end through small intestinal biopsy.
      , years (median, range)
      0–40 (9)0–40 (9)
      Follow-up
      Follow-up time until diagnosis of psoriasis, death from other cause, emigration, or 31 December 2008. In controls, follow-up can end through small intestinal biopsy.
      , years (mean±SD)
      10.4±6.410.2±6.4
      Females (%)89,192 (62.0)17,927 (61.9)
      Males (%)54,718 (38.0)11,031 (38.1)
      Calendar year
       198920,344 (14.1)4,097 (14.1)
       1990–9959,747 (41.5)12,035 (41.6)
       200063,819 (44.3)12,826 (44.3)
      Country of birth
       Nordic
      Sweden, Denmark, Finland, Norway, and Iceland.
      135,703 (94.3)28,010 (96.7)
       Outside the Nordic region8,207 (5.7)948 (3.3)
      Rheumatoid arthritis830 (0.6)287 (1.0)
      Autoimmune thyroid disease319 (0.2)200 (0.7)
      Type 1 diabetes531 (0.4)921 (3.2)
      a Follow-up time until diagnosis of psoriasis, death from other cause, emigration, or 31 December 2008. In controls, follow-up can end through small intestinal biopsy.
      b Sweden, Denmark, Finland, Norway, and Iceland.
      The median age at first diagnosis of psoriasis was 52 years in individuals with CD and 55 years in controls. The median duration from study entry until first recorded diagnosis of psoriasis was 7 years in both those with CD and in their controls.

      CD and risk of psoriasis

      During the study period, 401 individuals with CD and 1,139 controls developed psoriasis. This corresponded to a hazard ratio (HR) of 1.72 (95% confidence interval (CI)=1.54–1.92; Table 2). The absolute risk of future psoriasis in patients with CD was 135/100,000 person-years, with an excess risk of 57/100,000. Some 42% of all psoriasis in patients with CD could be attributed to the underlying CD (Table 2).
      Table 2Risk of psoriasis based on follow-up time in 28,958 individuals with celiac disease
      Follow-upObserved eventsExpected eventsHR; 95% CIP-valueAbsolute risk/100,000 PYARExcess risk/100,000 PYARAttributable percentage
      All4012331.72; 1.54–1.92<0.0011355741.9
      <1 Year25131.89; 1.21–2.940.005874147.0
      1–4.99127681.87; 1.53–2.29<0.0011245846.6
      5+2491521.63; 1.42–1.88<0.0011505838.8
      Abbreviations: CI, confidence interval; HR, hazards ratio; PYAR, person-years at risk.
      Reference is general population comparator cohort.
      The HR for psoriasis remained around 1.7 also when we excluded the first year of follow-up (HR=1.71; 95% CI=1.52–1.92). Even 5 years after CD diagnosis did we see a more than 60% increased risk for psoriasis in patients with CD (Table 2).
      Adjustment for type 1 diabetes, rheumatoid arthritis, and autoimmune thyroid disease did not affect the risk estimates (adjusted HR=1.70; 95% CI=1.52–1.91). Neither did adjustment for country of birth (adjusted HR=1.70; 95% CI=1.52–1.90) nor education (adjusted HR=1.72; 95% CI=1.54–1.93) influence the risk estimates. We found similar risk estimates in men and women (Table 3). Interaction tests revealed that the risk of psoriasis in CD did not differ significantly according to sex (P=0.238) or according to age at biopsy (P=0.241). Children (diagnosed <20 years of age) with CD were at a statistically significantly increased risk of later psoriasis (HR=2.05; 95% CI=1.62–2.60; Table 3). Also when we excluded individuals with any skin disease (psoriasis+other skin disease), CD was still associated with future psoriasis (HR=1.69; 95% CI=1.50–1.91).
      Table 3Risk of psoriasis according to characteristics of patients with celiac disease
      SubgroupObserved eventsExpected eventsHR; 95% CIP-valueAbsolute risk/100,000 PYARExcess risk/100,000 PYARAttributable percentage
      Sex
       Males156841.86; 1.55–2.24<0.0011406546.3
       Females2451491.64; 1.42–1.89<0.0011325239.0
      Age
       <20 years96472.05; 1.62–2.60<0.001713751.3
       20–39 years86471.84; 1.44–2.35<0.0011597345.7
       40–59 years148951.56; 1.30–1.88<0.0012187836.0
       60+ years71451.58; 1.21–2.070.0011776536.7
      Calendar period
       198962421.46; 1.10–1.950.010762431.6
       1990–19992131161.83; 1.57–2.14<0.0011436545.4
       2000–2008126751.69; 1.39–2.06<0.0011927940.8
      Abbreviations: CI, confidence interval; HR, hazards ratio; PYAR, person-years at risk.
      Reference is general population comparator cohort.

      Psoriasis confirmed by psoriatic medication

      Individuals with CD were at a 2-fold increased risk of having a diagnosis of psoriasis confirmed by a record of psoriatic medication. However, because of few positive events, this association was not statistically significant (four individuals with CD versus nine controls fulfilled our criteria; HR=2.06; 95% CI=0.63–6.70; P=0.231).

      Comparison with other individuals undergoing small intestinal biopsy

      Compared with individuals undergoing small intestinal biopsy but not having VA, individuals with CD were at no increased risk of psoriasis (compared with inflammation (Marsh 1–2): HR=0.96; 95% CI=0.71–1.30 and compared with those with normal mucosa (Marsh 0) but positive CD serology: HR=0.99; 95% CI=0.83–1.18).

      Previous psoriasis and risk of later CD

      Out of 29,096 individuals with CD, 137 (0.47%) had a previous diagnosis of psoriasis versus 341/144,522 (0.23%). Hence, we found a positive association between CD and psoriasis also before CD diagnosis. A previous psoriasis diagnosis increased the risk for future CD (odds ratio=1.91; 95% CI=1.58–2.31).

      Discussion

      To our knowledge, this is the largest study to date on CD and psoriasis. It was based on almost 29,000 individuals with biopsy-verified CD identified from 28 Swedish pathology departments. Psoriasis was defined according to outpatient or inpatient International Classification of Disease (ICD) codes. Earlier validation has shown high validity for most chronic conditions in the Swedish national patient register (
      • Ragnarson Tennvall G.
      • Apelqvist J.
      • Eneroth M.
      The inpatient care of patients with diabetes mellitus and foot ulcers. A validation study of the correspondence between medical records and the Swedish Inpatient Registry with the consequences for cost estimations.
      ;
      • Hultgren R.
      • Olofsson P.
      • Wahlberg E.
      Gender differences in vascular interventions for lower limb ischaemia.
      ;
      • Smith J.G.
      • Platonov P.G.
      • Hedblad B.
      • et al.
      Atrial fibrillation in the Malmo diet and cancer study: a study of occurrence, risk factors and diagnostic validity.
      ). Almost all Swedish health care is publicly funded, guaranteeing a virtually 100% complete follow-up through linkage with the unique personal identity number.

      Comparison with earlier literature

      As opposed to the recent Israeli study by
      • Birkenfeld S.
      • Dreiher J.
      • Weitzman D.
      • et al.
      Coeliac disease associated with psoriasis.
      ; with an odds ratio of 2.73), our risk estimates were consistently below two. One explanation for our lower risk estimates deals with our ascertaining CD through pathology databases. Ascertaining CD through pathology databases has previously yielded lower risk estimates than similar studies using the inpatient registers to identify CD (compare, e.g., relative risks of death in CD:
      • Ludvigsson J.F.
      • Montgomery S.M.
      • Ekbom A.
      • et al.
      Small-intestinal histopathology and mortality risk in celiac disease.
      : 1.39 with
      • Peters U.
      • Askling J.
      • Gridley G.
      • et al.
      Causes of death in patients with celiac disease in a population-based Swedish cohort.
      : 2.0. Another, perhaps more likely, explanation of our lower risk estimates is the rarity of diagnosed CD in Israel. It is possible that most patients in that study suffered from (severe) symptomatic CD (0.11% of controls had CD (
      • Birkenfeld S.
      • Dreiher J.
      • Weitzman D.
      • et al.
      Coeliac disease associated with psoriasis.
      ), whereas 29,000 patients with CD in the current study equal around 0.3% of the Swedish population).
      Although we did not screen the entire Swedish population for CD, our data indicate a 2-fold increased risk of CD in patients with previous psoriasis. This is consistent with recent data from
      • Montesu M.A.
      • Dessi-Fulgheri C.
      • Pattaro C.
      • et al.
      Association between psoriasis and coeliac disease? A case-control study.
      . In their study, 2% of psoriasis patients had CD (as compared with expected 1% (
      • Dube C.
      • Rostom A.
      • Sy R.
      • et al.
      The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review.
      )), although none of their controls showed a positive CD serology (
      • Montesu M.A.
      • Dessi-Fulgheri C.
      • Pattaro C.
      • et al.
      Association between psoriasis and coeliac disease? A case-control study.
      ).
      • Woo W.K.
      • McMillan S.A.
      • Watson R.G.
      • et al.
      Coeliac disease-associated antibodies correlate with psoriasis activity.
      in a series of 130 psoriatic patients found 3 (2.3%) patients with VA, and also reported that positive CD serology correlated with increased disease activity in psoriasis. An Italian study reported that 4/92 (4.3%) patients with psoriasis versus 0/90 controls had CD (
      • Ojetti V.
      • Aguilar Sanchez J.
      • Guerriero C.
      • et al.
      High prevalence of celiac disease in psoriasis.
      ); and a Swedish study that 5/114 (4.4%) individuals with psoriatic arthritis had CD (the Swedish study used no controls;
      • Lindqvist U.
      • Rudsander A.
      • Bostrom A.
      • et al.
      IgA antibodies to gliadin and coeliac disease in psoriatic arthritis.
      ). Meanwhile, an Iranian study failed to show an increased prevalence of CD in 328 patients with psoriasis (
      • Zamani F.
      • Alizadeh S.
      • Amiri A.
      • et al.
      Psoriasis and coeliac disease; is there any relationship?.
      ).
      Our study was based on histopathological evidence of CD, and is therefore difficult to compare with studies on psoriasis and CD serology (
      • Michaelsson G.
      • Gerden B.
      • Ottosson M.
      • et al.
      Patients with psoriasis often have increased serum levels of IgA antibodies to gliadin.
      ;
      • Kia K.F.
      • Nair R.P.
      • Ike R.W.
      • et al.
      Prevalence of antigliadin antibodies in patients with psoriasis is not elevated compared with controls.
      ;
      • Damasiewicz-Bodzek A.
      • Wielkoszynski T.
      Serologic markers of celiac disease in psoriatic patients.
      ;
      • Sultan S.J.
      • Ahmad Q.M.
      • Sultan S.T.
      Antigliadin antibodies in psoriasis.
      ). Studies on CD serology in psoriatic patients have been both positive (
      • Michaelsson G.
      • Gerden B.
      • Ottosson M.
      • et al.
      Patients with psoriasis often have increased serum levels of IgA antibodies to gliadin.
      ;
      • Damasiewicz-Bodzek A.
      • Wielkoszynski T.
      Serologic markers of celiac disease in psoriatic patients.
      ) and negative (
      • Kia K.F.
      • Nair R.P.
      • Ike R.W.
      • et al.
      Prevalence of antigliadin antibodies in patients with psoriasis is not elevated compared with controls.
      ;
      • Sultan S.J.
      • Ahmad Q.M.
      • Sultan S.T.
      Antigliadin antibodies in psoriasis.
      ). Heterogeneity can probably be explained through the low positive predictive value of CD serology (
      • Hopper A.D.
      • Cross S.S.
      • Hurlstone D.P.
      • et al.
      Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool.
      ), especially antigliadin antibodies (43% in the paper by
      • Hadithi M.
      • von Blomberg B.M.
      • Crusius J.B.
      • et al.
      Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease.
      ).

      Mechanisms

      Several mechanisms might explain the positive association between CD and psoriasis described in this study. First, malabsorption in CD, both before and after diagnosis, increases the risk of vitamin D deficiency (
      • Bode S.
      • Hassager C.
      • Gudmand-Hoyer E.
      • et al.
      Body composition and calcium metabolism in adult treated coeliac disease.
      ) and besides the gluten-free diet is often low in vitamin D (
      • Kupper C.
      Dietary guidelines and implementation for celiac disease.
      ). Vitamin D deficiency predisposes to psoriasis, and exposure to sun light as well a administration of vitamin D analog creams have a beneficial effect on psoriasis (
      • Lehmann B.
      Role of the vitamin D3 pathway in healthy and diseased skin−facts, contradictions and hypotheses.
      ). Second, in patients with CD (before and after diagnosis), exposure to gliadin will trigger a CD4+ T-cell response and a cascade of proinflammatory cyotkines such as IFN-γ (
      • Nilsen E.M.
      • Jahnsen F.L.
      • Lundin K.E.
      • et al.
      Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease.
      ). The increased number of T cells in the blood may affect also the dermis and epidermis, thereby stimulating the development of psoriasis (
      • Monteleone G.
      • Pallone F.
      • MacDonald T.T.
      • et al.
      Psoriasis: from pathogenesis to novel therapeutic approaches.
      ). The psoriatic plaque is characterized by a marked infiltration of activated CD4+ and CD8+ T cells. CD4+ T cells infiltrate mainly the dermis, whereas CD8+ T cells are present in the epidermis (
      • Nestle F.O.
      • Di Meglio P.
      • Qin J.Z.
      • et al.
      Skin immune sentinels in health and disease.
      ). Third, shared genetic factors could have a role.
      • Liu Y.
      • Helms C.
      • Liao W.
      • et al.
      A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.
      first described a psoriatic locus on chromosome 4q27 that harbors both IL-2 and IL-21. This locus (IL2/21) has previously been linked to CD (
      • van Heel D.A.
      • Franke L.
      • Hunt K.A.
      • et al.
      A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.
      ;
      • Adamovic S.
      • Amundsen S.S.
      • Lie B.A.
      • et al.
      Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families.
      ). A fourth potential mechanism regards the increase in intestinal permeability (
      • Abenavoli L.
      • Proietti I.
      • Zaccone V.
      • et al.
      Celiac disease: from gluten to skin.
      ) seen in patients with psoriasis (
      • Humbert P.
      • Bidet A.
      • Treffel P.
      • et al.
      Intestinal permeability in patients with psoriasis.
      ). Affected intestinal permeability is a hallmark of CD. Still, further studies are needed to explore the underlying mechanism for the positive association between CD and psoriasis, as our study lacks individual-based immunological and genetic data.

      Strengths and limitations

      This study was based on almost 29,000 patients with CD. The large numbers allowed for important subanalyses and, for instance, we were able to examine the relationship between CD and psoriasis in children. Although we cannot rule out that our HR is slightly inflated by ascertainment bias, such bias is unlikely to fully explain the positive association seen in this study, as the risk increase remained more than 5 years after CD diagnosis. VA has been the gold standard for CD diagnosis in Sweden since the 1970s (
      • Cavell B.
      • Stenhammar L.
      • Ascher H.
      • et al.
      Increasing incidence of childhood coeliac disease in Sweden. Results of a national study.
      ;
      • Stenhammar L.
      • Hogberg L.
      • Danielsson L.
      • et al.
      How do Swedish paediatric clinics diagnose coeliac disease? Results of a nationwide questionnaire study.
      ), and in a recent survey, 96% of adult gastroenterologists and 100% of pediatricians perform a small intestinal biopsy in at least 90% of patients with suspected CD before assigning a diagnosis of CD (
      • Ludvigsson J.F.
      • Brandt L.
      • Montgomery S.M.
      • et al.
      Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers.
      ). When we reviewed 114 randomly selected patient charts from patients with VA, 108 (95%) had CD. Moreover, when we manually reviewed more than 1,500 biopsy reports, we found that other diagnoses than CD seldom explain VA (0.3% of those with VA had inflammatory bowel disease and 0.2% suffered from Helicobacter pylori;
      • Ludvigsson J.F.
      • Brandt L.
      • Montgomery S.M.
      • et al.
      Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers.
      ). Although we did not require a positive CD serology for our CD diagnosis, 88% of validated individuals with VA and available serology data had positive CD serology at the time of biopsy (
      • Ludvigsson J.F.
      • Brandt L.
      • Montgomery S.M.
      • et al.
      Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers.
      ).
      We would also like to underline our use of different reference groups. Compared with individuals with inflammation or normal mucosa but positive CD serology, those with CD were at no increased risk of psoriasis. This suggests that the risk increase for psoriasis may not require severe mucosal abnormalities but that microscopic inflammation including intraepithelial lymphocytosis may be sufficient. Moreover, we were able to link our data to the Swedish Prescribed Drug Register. Although that register covers only a short time span, the relative risk in that analysis (HR=2.06) indicates that the positive association seen in our main analysis is not a chance finding. However, the small number of individuals with medication registered in the Prescribed Drug Register meant that the association was not statistically significant.
      This study also had some weaknesses. We were unable to measure the activity of psoriasis. We did not have access to smoking data. Smoking is, however, inversely related to CD (
      • Snook J.A.
      • Dwyer L.
      • Lee-Elliott C.
      • et al.
      Adult coeliac disease and cigarette smoking.
      ; if at all related (
      • Ludvigsson J.F.
      • Montgomery S.M.
      • Ekbom A.
      Smoking and celiac disease: a population-based cohort study.
      )), but positively associated with psoriasis (
      • Naldi L.
      • Chatenoud L.
      • Linder D.
      • et al.
      Cigarette smoking, body mass index, and stressful life events as risk factors for psoriasis: results from an Italian case-control study.
      ;
      • Jankovic S.
      • Raznatovic M.
      • Marinkovic J.
      • et al.
      Risk factors for psoriasis: a case-control study.
      ). Hence, confounding by smoking cannot explain the positive association between CD and psoriasis seen in this study. Neither did we have data on alcohol consumption. Alcohol consumption has been linked to psoriasis (
      • Poikolainen K.
      • Reunala T.
      • Karvonen J.
      • et al.
      Alcohol intake: a risk factor for psoriasis in young and middle aged men?.
      ) but not to CD (
      • McMillan S.A.
      • Johnston S.D.
      • Watson R.G.
      • et al.
      Dietary intake, smoking, and transient anti-gliadin antibodies.
      ). When
      • Zingone F.
      • Bucci C.
      • Tortora R.
      • et al.
      Body mass index and prevalence of skin diseases in adults with untreated coeliac disease.
      examined risk factors for psoriasis in patients with CD, they found that the risk of psoriasis was higher in patients with undiagnosed CD and a high body mass index, as opposed to those with normal body mass index. Unfortunately the current study did not have access to data on body mass index. Finally we had no data on dietary compliance and vitamin D status. This means that we were unable to estimate the importance of adhering to a gluten-free diet for the risk of psoriasis, and what role vitamin D status may have had for the development of psoriasis.
      In conclusion, we found an increased risk of psoriasis in patients with CD. This risk increase was seen both before and after diagnosis of CD. It was seen in all age strata and remained more than 5 years after CD diagnosis.

      Materials and Methods

      We linked nationwide biopsy data on CD with inpatient and outpatient data on psoriasis. Through Cox regression, we estimated HRs for psoriasis in the Swedish Patient Register and in a subanalysis also when the diagnosis of psoriasis was confirmed by a record of medication in the Swedish Prescribed Drug Register.

      Data collection

      Between October 2006 and February 2008, we collected computerized biopsy data from all Swedish pathology departments (n=28), with biopsies performed between 1969 and 2008. Data from biopsies included arrival date of biopsies, personal identity number (
      • Ludvigsson J.F.
      • Otterblad-Olausson P.
      • Pettersson B.U.
      • et al.
      The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research.
      ), morphology, and topography (duodenum and jejunum).
      We defined CD as having VA (Marsh 3) according to the Swedish SnoMed classification (for a translation of the SnoMed classification, please see the Supplementary Appendix online).
      We did not request a positive CD serology for the diagnosis of CD, although earlier validation of a subset of randomly selected individuals with CD has shown that 88% had positive CD serology at time of biopsy (
      • Ludvigsson J.F.
      • Brandt L.
      • Montgomery S.M.
      • et al.
      Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers.
      ). Of individuals with VA and available data, 2,268/3,374 (67.2%) had positive IgA tissue transglutaminase/endomysial, whereas 1,106 (32.8%) were positive for IgA Gliadin or IgG tissue transglutaminase/endomysial/gliadin. In the current study, 95% of individuals with VA (108/114) had CD according to patient charts (
      • Ludvigsson J.F.
      • Brandt L.
      • Montgomery S.M.
      • et al.
      Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers.
      ) and 79% of individuals had gastrointestinal symptoms before biopsy.

      Controls

      For each individual undergoing biopsy, Statistics Sweden selected up to five controls matched for age, sex, calendar period, and county from the Total Population Register. Controls were sampled from all Swedish residents who had no previous duodenal/jejunal biopsy.

      Secondary reference groups of individuals undergoing biopsy

      For comparative reasons, we also collected biopsy data of patients with inflammation without VA (Marsh 1–2) and normal mucosa but positive CD serology (Marsh 0 with positive IgA/IgG for antigliadin, endomysial, or tissue transglutaminase) (
      • Ludvigsson J.F.
      • Brandt L.
      • Montgomery S.M.
      Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa.
      ). These two cohorts were used as secondary reference groups. In the most commonly used Swedish histopathology classification (Committee for Quality and Standardization), inflammation is equal to intraepithelial inflammation. More information on the data collection method has been published in two validation papers (
      • Ludvigsson J.F.
      • Brandt L.
      • Montgomery S.M.
      Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa.
      ,
      • Ludvigsson J.F.
      • Brandt L.
      • Montgomery S.M.
      • et al.
      Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers.
      ).

      Exclusions

      After matching to (primary) controls, we excluded 174 individuals where the biopsy (VA, inflammation, or normal mucosa) could potentially have been from the ileum, those with no matched control, or those who lacked a serial number from Statistics Sweden (n=35). We excluded 247 controls because of data irregularities and an additional 921 controls who could not be matched. The remaining individuals are identical to those in our study on mortality in CD (
      • Ludvigsson J.F.
      • Montgomery S.M.
      • Ekbom A.
      • et al.
      Small-intestinal histopathology and mortality risk in celiac disease.
      ).
      Additional exclusions are shown in Figure 1. For the purpose of our initial analyses, we excluded anyone with a diagnosis of psoriasis before study entry (date of first biopsy). As each stratum (one individual with CD and his/her controls) was analyzed separately, a number of controls were excluded as their index individual with CD had been excluded.
      Figure thumbnail gr1
      Figure 1Flow chart of study participants. The symbol ‘*’ denotes that 272 controls were excluded because their matched individual undergoing biopsy had been excluded (and all analyses were matched on strata, see Materials and Methods). The symbol ‘#’ denotes Marsh pathology grades 1–2 and ‘§’ denotes Marsh pathology grade 0 in individuals with positive celiac disease (CD) serology (antigliadin, antiendomysial, or antitransglutaminase antibodies).
      The main analyses of this paper were based on 28,958 individuals with CD and 143,910 general population controls. The secondary reference groups consisted of 13,223 individuals with inflammation and 3,686 individuals with normal mucosa but positive CD serology.

      Outcome

      Our main outcome was a diagnosis of psoriasis defined according to relevant ICD codes (ICD-7 (1964–1968, code 706.0), ICD-8 (1969–1986, code 696.00-19), ICD-9 (1987–1996 code 696A-B) and ICD-10 (1997-, code L40);
      • Ji J.
      • Shu X.
      • Sundquist K.
      • et al.
      Cancer risk in hospitalised psoriasis patients: a follow-up study in Sweden.
      ) in the Swedish Patient Register. This register contains both inpatient data (from 1964 and nationwide since 1987) and hospital outpatient data (since 2001 and nationwide from the start).
      In a subanalysis, we examined the risk of having a diagnosis of psoriasis confirmed by a record of psoriatic medicine (including biological treatments) in the Swedish Prescribed Drug Register. This register was initiated in mid-2005 and contains outpatient data on medication according to relevant Anatomical Therapeutic Chemical Classification System codes (see Supplementary Appendix online). When we only included individuals with a follow-up until, at least, 1 July 2005 this subanalysis was based on 26,219 individuals with CD and 132,007 controls.

      Statistics

      Prospective analyses: CD and risk of later psoriasis

      We used internal stratified Cox regression to estimate HRs for psoriasis. The internal stratification means that the index individual was only compared with his or her controls within the same stratum and then a summary risk estimate was calculated. The proportional hazards assumption was tested through plotting log-minus-log curves. Follow-up started on the date of the first biopsy with VA and the corresponding date in matched controls. Follow-up ended with psoriasis diagnosis, death, emigration, or on 31 December 2008, whichever happened first. Attributable risks (%) were calculated as (1-1/HR), and absolute risk as number of incident cases with psoriasis divided by years of follow-up.
      In a priori subanalyses, we examined the risk of psoriasis by follow-up period, sex, age, and calendar year at CD diagnosis. Incidence rates were calculated as the number of first recorded psoriasis diagnoses per person-years at risk.
      In a subanalysis, we also adjusted for type 1 diabetes mellitus, rheumatoid arthritis, autoimmune thyroid disease (see Supplementary Appendix online for ICD codes), level of education, and country of birth (Nordic country vs non-Nordic country). Individualized data on education were retrieved from Statistics Sweden and grouped according to seven pre-defined levels. In a post hoc analysis, we excluded all individuals with any skin disease before study entry (this analysis was based on 27,051 individuals with CD and 138,808 matched reference individuals).
      Finally, we examined the risk of psoriasis in individuals with CD compared with the risk in secondary reference groups undergoing small intestinal biopsy but not having VA.

      Case–control study: previous psoriasis and risk of later CD

      In a case–control study we used conditional logistic regression to examine the relationship between previous psoriasis and later CD. Moreover, in this analysis did we define psoriasis according to relevant ICD codes. We based this analysis on 29,096 individuals with CD and 144,522 controls matched for sex, age, calendar period, and county (Figure 1). We then looked at the number of individuals with a previous diagnosis of psoriasis.
      We used SPSS 18.0 (Chicago, IL) to perform all analyses. Relative risks with 95% CIs that did not include 1 were regarded as statistically significant.

      Ethics

      The study was approved by the Research Ethics Committee of Karolinska Institutet. As none of the participants was contacted and individual information was anonymized before the analyses, informed consent was not required by the Research Ethics Committee.

      ACKNOWLEDGMENTS

      JFL was supported by a grant from the Örebro University Hospital while writing this article. This project was supported by grants from the Swedish Society of Medicine, the Swedish Research Council (medicine, 522-2A09-195), the Sven Jerring Foundation, the Örebro Society of Medicine, the Karolinska Institutet, the Clas Groschinsky Foundation, the Juhlin Foundation, the Majblomman Foundation, Uppsala–Örebro Regional Research Council, and the Swedish Celiac Society. None of the funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

      SUPPLEMENTARY MATERIAL

      Supplementary material is linked to the online version of the paper at http://www.nature.com/jid

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