Isotretinoin Exposure and Risk of Celiac Disease.

BACKGROUND: Isotretinoin (13-cis retinoic acid) is a metabolite of vitamin A and has anti-inflammatory and immunoregulatory effects; however, a recent publication by DePaolo et al. demonstrated that in the presence of IL-15, retinoic acid can act as an adjuvant and promote inflammation against dietary proteins. OBJECTIVE: To evaluate the risk of overt and latent celiac disease (CD) among users of isotretinoin. MATERIAL AND METHODS: Medical records of patients from 1995 to 2011 who had a mention of isotretinoin in their records (N = 8393) were searched for CD diagnosis using ICD-09CM codes. Isotretinoin exposure was compared across overt CD patients and their age- and gender-matched controls from the same pool. To evaluate the risk of latent CD with isotretinoin exposure, patients were overlapped with a community-based list of patients with waste serum samples that were tested for CD serology, excluding those with overt CD (2006-2011). Isotretinoin exposure was defined as the use of isotretinoin prior to CD diagnosis or serology. RESULTS: Of 8393 patients, 25 had a confirmed CD diagnosis. Compared to matched controls (N = 75), isotretinoin exposure was not significantly different between overt CD patients versus controls (36% versus 39%, respectively; P = 0.712). Likewise, latent CD defined as positive serology was not statistically different between isotretinoin exposed (N = 506) versus non-exposed (N = 571) groups (1.8% versus 1.4%, respectively; P = 0.474). CONCLUSIONS: There was no association between isotretinoin use and risk of either overt or latent CD.

Incidence and risk factors for skin cancer following lung transplantation.

BACKGROUND: Relative to other solid-organ transplantations, limited studies characterize skin cancer among lung-transplant recipients. OBJECTIVE: We sought to assess the cumulative incidence, tumor burden, and risk factors for skin cancer among patients with lung transplantation. METHODS: Medical records of patients at Mayo Clinic who had undergone lung transplantation between 1990 and 2011 were reviewed (N = 166). RESULTS: At 5 and 10 years posttransplantation the cumulative incidence was 31% and 47% for any skin cancer, 28% and 42% for squamous cell carcinoma, 12% and 21% for basal cell carcinoma, and 53% and 86% for death, respectively. Four patients died of metastatic squamous cell carcinoma. The cumulative incidence for a subsequent skin cancer of the same type 4 years after an initial skin cancer was 85% and 43% for squamous and basal cell carcinoma, respectively. Increasing age, male gender, skin cancer history, and more recent year of transplantation were associated with increased risk of skin cancer posttransplantation. Sirolimus was not associated with decreased risk, nor did voriconazole show an increased risk for skin cancer. LIMITATIONS: Retrospective and tertiary single-center design of the study is a limitation. CONCLUSIONS: Skin cancers frequently occur in lung-transplant recipients. The risk of subsequent skin cancer is increased substantially in patients who develop a skin cancer after their transplantation.

Isotretinoin exposure and risk of inflammatory bowel disease.

IMPORTANCE Isotretinoin is the standard treatment for refractory severe nodulocystic acne.A true association between prior isotretinoin use and development of inflammatory bowel disease (IBD) is uncertain. Addressing the reality of this association is important in decision making for both the clinician and the patient when isotretinoin treatment is indicated.OBJECTIVE To assess the risk of IBD mainly in patients with acne with and without isotretinoin exposure.DESIGN, SETTING, AND PARTICIPANTS In this retrospective, single-center study, the electronic medical records of patients who were primarily seeking acne treatment were reviewed for isotretinoin exposure. International Classification of Diseases, Ninth Revision (ICD-9) codes were used to search for IBD diagnosis. participants included 1078 patients from 1995 to 2011,with isotretinoin referenced in their medical records, and who had ongoing local medical care defined as having had a serum sample collected between 2006 to 2011 for any reason while an Olmsted County, Minnesota, resident at the time of serum sample collection.EXPOSURES The exposed group included the patients with confirmed prior isotretinoin exposure (n = 576), and the nonexposed group were defined as patients who never received isotretinoin or received it after the diagnosis of IBD (n = 502).MAIN OUTCOMES AND MEASURES Risk of IBD among isotretinoin-exposed vs non exposed patients.RESULTS Both groups were comparable by race, prior systemic antibiotic use, and systemic tetracycline use. Inflammatory bowel disease developed less frequently in the isotretinoin-exposed group vs the nonexposed group (0.9%vs 2.6%; P = .03; unadjusted odds ratio [OR], 0.33; 95%CI, 0.12-0.93; P = .04). The negative association between isotretinoin exposure and IBD remained after adjusting for sex (OR, 0.28; 95%CI, 0.10-0.80;P = .02) and for sex and non acne indication (OR, 0.28; 95%CI, 0.10-0.79; P = .02).CONCLUSIONS AND RELEVANCE Our study did not show an increased risk of IBD with prior isotretinoin use. If anything, the risk seemed to be decreased. Although these results may be due to chance given the small number of IBD cases, the anti-inflammatory and immune-modulating effects of isotretinoin may be worth exploring.

Does urticaria risk increase in patients with celiac disease? A large population-based cohort study.

BACKGROUND: Case reports and smaller case-control studies suggest an association between celiac disease (CD) and urticaria but risk estimates have varied considerably across studies and as yet there are no studies on CD and the risk of future urticaria. OBJECTIVE: To examine the association between CD and urticaria. METHODS: We identified 28,900 patients with biopsy-verified CD (equal to Marsh stage 3) and compared them with 143,397 age- and sex-matched controls with regards to the risk of urticaria and chronic urticaria (duration ≥6 weeks). Hazard ratios (HRs) were estimated using a Cox regression model. RESULTS: During follow-up, 453 patients with CD and no previous diagnosis of urticaria developed urticaria (expected n = 300) and 79 of these 453 had chronic urticaria (expected n = 41). The corresponding HRs were 1.51 for any urticaria (95%CI = 1.36-1.68) and 1.92 for chronic urticaria (95%CI = 1.48-2.48). The absolute risk for urticaria in CD was 140/100,000 person-years (excess risk = 47/100,000 person-years). Corresponding figures for chronic urticaria were 24/100,000 person-years and 12/100,000 person-years. Patients with CD were also at increased risk of having both urticaria (odds ratio, OR = 1.31; 95%CI = 1.12-1.52) and chronic urticaria (OR = 1.54; 95%CI = 1.08-2.18) prior to the CD diagnosis. CONCLUSION: This study suggests that CD is associated with urticaria, especially chronic urticaria.

From furuncle to axillary web syndrome: shedding light on histopathology and pathogenesis.

Axillary web syndrome (AWS) is defined as a cord-like structure extending from the axilla to the medial arm following axillary surgery in women with breast cancer. There is only limited literature on the pathogenesis of this syndrome and the etiology of the cord. A 57-year-old man presented with a band-like skin depression and tightness over the medial aspect of his arm extending from the axilla to the antecubital fossa following development of a furuncle in the ipsilateral axilla. Histopathologic examination of the 'band' revealed fibroblastic proliferation surrounding the lymphatic vessel which was identified by presence of an obvious valve as well as positive staining for D2-40, a specific marker for lymphatic endothelium. This is the first report of AWS following axillary furunculosis. This case adds to the limited data on the histopathology of AWS, further confirming the etiology of the 'cord' to be of lymphatic origin.

Experiences with animal models of dermatitis herpetiformis: a review.

Dermatitis herpetiformis (DH) is caused by the consumption of gluten, which is also the trigger for celiac disease. DH is currently considered to be the skin manifestation of celiac disease, as both diseases have some degree of gluten-sensitive enteropathy. The human leukocyte antigens class II genes, DQ2 and DQ8, are tightly associated with both diseases, and there is an increased level of anti-gliadin antibodies in both diseases. Animal models of gluten sensitivity have been used to better understand the pathogenesis of both diseases. This paper describes these different models and discusses how certain elements of these models contribute to the development of DH.

Serology of celiac disease in gluten-sensitive ataxia or neuropathy: role of deamidated gliadin antibody.

The role and relevance of deamidated gliadin antibodies specific for celiac disease in gluten-sensitive ataxia/neuropathy is unknown. We investigated the association of celiac-specific serology with gluten-sensitive ataxia/neuropathy, in patients with and without gliadin-induced enteropathy. 51 patients with unexplained ataxia/neuropathy suspected to have gluten sensitivity were included in the study and their serum celiac-specific markers were measured. Deamidated gliadin-IgA (83% vs. 22%), deamidated gliadin-IgG (50% vs. 3%), tissue transglutaminase-IgA (78% vs. 11%), and anti-endomysial-IgA (70% vs. 0%), were significantly more positive in ataxia/neuropathy patients with celiac disease versus those without enteropathy (P<0.001). Our findings suggest that the serological profile of gluten-sensitive ataxia/neuropathy without intestinal involvement lacks the recognition of deamidated gliadin and tissue transglutaminase epitopes.

Celiac disease in the elderly.

It has become apparent recently that celiac disease, once believed to be primarily a childhood disease, can affect people of any age. Epidemiologic studies have suggested that a substantial portion of patients are diagnosed after the age of 50. Indeed, in one study, the median age at the diagnosis was just under the age of 50 with one-third of new patients diagnosed being older than 65 years. The purpose of this review is to address the prevalence, clinical features, diagnosis, and consequences of celiac disease in the elderly. The authors also review management strategies for celiac disease and adjust these with emphasis on the particular nutritional and nonnutritional consequences or associations of celiac disease as they pertain to the elderly.

Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic Abo Dq8 transgenic mice.

Active delivery of recombinant autoantigens or allergens at the intestinal mucosa by genetically modified Lactococcus lactis (LL) provides a novel therapeutic approach for the induction of tolerance. Celiac disease is associated with either HLA-DQ2- or HLA-DQ8-restricted responses to specific antigenic epitopes of gliadin, and may be treated by induction of Ag-specific tolerance. We investigated whether oral administration of LL-delivered DQ8-specific gliadin epitope induces Ag-specific tolerance. LL was engineered to secrete a deamidated DQ8 gliadin epitope (LL-eDQ8d) and the induction of Ag-specific tolerance was studied in NOD AB degrees DQ8 transgenic mice. Tolerance was assessed by delayed-type hypersensitivity reaction, cytokine measurements, eDQ8d-specific proliferation, and regulatory T cell analysis. Oral administration of LL-eDQ8d induced suppression of local and systemic DQ8-restricted T cell responses in NOD AB degrees DQ8 transgenic mice. Treatment resulted in an Ag-specific decrease of the proliferative capacity of inguinal lymph node (ILN) cells and lamina propria cells. Production of IL-10 and TGF-beta and a significant induction of Foxp3(+) regulatory T cells were associated with the eDQ8d-specific suppression induced by LL-eDQ8d. These data provide support for the development of effective therapeutic approaches for gluten-sensitive disorders using orally administered Ag-secreting LL. Such treatments may be effective even in the setting of established hypersensitivity.

Correlation analysis of celiac sprue tissue transglutaminase and deamidated gliadin IgG/IgA.

AIM: To indirectly determine if tissue transglutaminase (tTG)-specific T cells play a crucial role in the propagation of celiac disease. METHODS: Anti-deamidated gliadin peptide (DGP) and anti-tTG IgA and IgG were measured in the sera of celiac patients (both untreated and treated). The correlations were determined by Spearman's rank correlation test. RESULTS: In celiac patients, we found a very significant correlation between the production of DGP IgA and IgG (r = 0.75), indicating a simultaneous and ongoing production of these two isotypes reminiscent of oral vaccination studies. However, there was far less association between the production of tTG IgA and tTG IgG in celiac patients (r = 0.52). While tTG IgA was significantly correlated with DGP IgA (r = 0.80) and DGP IgG (r = 0.67), there was a weak correlation between production of anti-tTG IgG and the production of anti-DGP IgA (r = 0.38) and anti-DGP IgG (r = 0.43). CONCLUSION: These data demonstrate that the production of anti-tTG IgA is directly correlated to the production of anti-DGP IgG and IgA, whereas anti-tTG IgG is only weakly correlated. This result therefore supports the hapten-carrier theory that in well-established celiac patients anti-tTG IgA is produced by a set of B cells that are reacting against the complex of tTG-DGP in the absence of a tTG-specific T cell.

Celiac sprue: a unique autoimmune disorder.

Celiac sprue (CS) is a gluten-sensitive enteropathy with many autoimmune features. CS involves multiple organs through immune and nonimmune processes, and is frequently associated with other autoimmune disorders. This article reviews the co-occurrence of CS with autoimmune disorders of the cutaneous, nervous, endocrine, musculoskeletal, gastrointestinal and cardiovascular systems. The types of autoimmune disorders associated with CS and the prevalence of CS in other autoimmune disorders are also discussed. A brief review of the literature on the potential mechanisms behind these associations and the therapeutic effects of a gluten-free diet for autoimmune comorbidities in CS is also provided.

Skin involvement in systemic autoimmune diseases.

Autoimmune diseases present with varied and broad-ranging cutaneous manifestations. Connective tissue disorders have a plethora of skin manifestations such as rheumatoid nodules in rheumatoid arthritis, psoriatic plaques in psoriatic arthritis, acne and pustulosis in SAPHO syndrome, livedo reticularis and ulceration in antiphospholipid antibody syndrome and xerosis in Sjögren syndrome. Cutaneous manifestations of autoimmune vasculitides such as polyarteritis nodosa, Kawasaki disease, Henoch-Schönlein purpura, cryoglobulinemic vasculitis, Behcet disease, Wegener granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome range from papules, subcutaneous nodules and livedo reticularis, to palpable purpura, hemorrhagic bulla and ulcerating lesions. Pathological skin manifestations in autoimmune endocrinopathies include pretibial myxedema/dermopathy in Graves' disease, diabetic dermopathy and necrobiosis lipoidica in type I autoimmune diabetes mellitus, candidiasis, ectodermal dysplasia, vitiligo and alopecia areata in APECED and uniform hyperpigmentation of the skin in Addison's disease. Autoimmune gastrointestinal disorders such as inflammatory bowel disease (with erythema nodosum), gluten-sensitive enteropathy (with dermatitis herpetiformis), autoimmune hepatitis and primary biliary cirrhosis (with jaundice and pruritus), hematologic/oncologic disorders such as acute and chronic graft-versus-host disease (with skin manifestations ranging from pruritic maculopapular eruptions and lichen planus-like lesions to generalized scleroderma), and paraneoplastic autoimmune dermatoses are discussed as well.

Comparative usefulness of deamidated gliadin antibodies in the diagnosis of celiac disease.

BACKGROUND & AIMS: Serologic tests are used frequently in celiac disease diagnosis. Gliadin antibodies generally lack the accuracy required for proper diagnosis. We evaluated the value of deamidated gliadin antibody measurements in the diagnosis and follow-up evaluation of celiac disease and compared their potential usefulness with that of gliadin and tissue-transglutaminase antibodies. METHODS: We tested deamidated gliadin, gliadin, and tissue-transglutaminase-immunoglobulin (Ig)A and -IgG in 216 biopsy-selected subjects including 92 biopsy-proven untreated celiac patients (46% with total villous atrophy and 54% with partial villous atrophy) and 124 biopsy-proven nonceliac controls. Fifty-nine celiac patients also were tested after treatment with a gluten-free diet. Antibodies were measured by commercial enzyme-linked immunosorbent assays. Deamidated gliadin-IgA+G was detected using a conjugate reactive to both isotypes, which gives a positive if either isotype is present. RESULTS: The sensitivity, specificity, and accuracy of deamidated gliadin-IgA (74%, 95%, and 86%), deamidated gliadin-IgG (65%, 98%, and 84%), and deamidated gliadin-IgA+G (75%, 94%, and 86%) were superior to gliadin-IgA (63%, 90%, and 79%) (P < .05) and gliadin-IgG (42%, 90%, and 69%) (P < .01), and were similar to tissue-transglutaminase-IgA (78%, 98%, and 90%) before treatment. The sensitivity of IgA isotype for all tests was significantly greater in celiac patients with total villous atrophy compared with those with partial villous atrophy (P < .05). The proportion of positive test results for all tests decreased significantly after treatment (P < .0001). CONCLUSIONS: Deamidated gliadin antibody is a better diagnostic test for celiac disease than the conventional gliadin antibody testing; although histopathology remains the gold standard test for diagnosis of celiac patients.