Separate Gut Plasma Cell Populations Produce Auto-Antibodies against Transglutaminase 2 and Transglutaminase 3 in Dermatitis Herpetiformis.

Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are auto-antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have auto-antibodies reactive with both transglutaminase enzymes. Here it is reported that in DH both gut plasma cells and serum auto-antibodies are specific for either TG2 or TG3 with no TG2-TG3 cross reactivity. By generating monoclonal antibodies from TG3-specific duodenal plasma cells of DH patients, three conformational epitope groups are defined. Both TG2-specific and TG3-specific gut plasma cells have few immunoglobulin (Ig) mutations, and the two transglutaminase-reactive populations show distinct selection of certain heavy and light chain V-genes. Mass spectrometry analysis of TG3-specific serum IgA corroborates preferential usage of IGHV2-5 in combination with IGKV4-1. Collectively, these results demonstrate parallel induction of anti-TG2 and anti-TG3 auto-antibody responses involving separate B-cell populations in DH patients.

Patient-reported burden of skin disorders in coeliac disease.

OBJECTIVES: The current knowledge on the associations between coeliac disease and different skin diseases is contradictory and the patient's perspective on the burden of these is lacking. This study aimed to investigate patient-reported frequency, severity and quality of life effects of skin disorders in coeliac disease patients compared to controls and moreover to study the impacts of gluten-free diet on these skin diseases. MATERIALS AND METHODS: A study questionnaire designed for the purposes of this study and a validated Dermatology Life Quality Index (DLQI) questionnaire were posted to 600 adult members of the Finnish Coeliac Society and 1173 matched controls. Responses from 327 coeliac disease patients and 382 non-coeliac controls were compared. RESULTS: Coeliac disease patients were shown to be at no increased risk of atopic dermatitis, acne, rosacea, psoriasis, alopecia areata, vitiligo or chronic urticaria. The severity of these skin diseases did not differ between study groups, but the risk for at least moderate effects on quality of life caused by dermatological diseases was increased among those with coeliac disease. Positive response from gluten-free diet was most commonly experienced by coeliac disease patients with atopic dermatitis. CONCLUSIONS: Even though the risk for skin diseases was shown not to be increased among coeliac disease patients, there is still an increased burden related to experienced skin symptoms among these patients, which non-dermatologists treating coeliac disease patients should acknowledge.

Risk of vascular diseases in patients with dermatitis herpetiformis and coeliac disease: a long-term cohort study.

INTRODUCTION: Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease. Increased cardiovascular morbidity has been reported in coeliac disease, but in DH only little is known about this. In this cohort study with a long-term follow-up, the risk for vascular diseases in patients with dermatitis herpetiformis (DH) and coeliac disease was assessed. METHODS: The study consisted of 368 DH and 1072 coeliac disease patients with biopsy-proven diagnosis performed between 1966 and 2000. For each DH and coeliac disease patient three matched reference individuals were obtained from the population register. Data regarding all outpatient and inpatient treatment periods between 1970 and 2015 were reviewed for diagnostic codes of vascular diseases from the Care Register for Health Care. Cox proportional hazard model was used to assess the risks for the diseases studied and the HRs were adjusted for diabetes mellitus (aHR). RESULTS: The median follow-up time of DH and coeliac disease patients was 46 years. The risk for cardiovascular diseases did not differ between DH patients and their references (aHR 1.16, 95% CI 0.91-1.47), but among coeliac disease patients, the risk was increased (aHR 1.36, 95% CI 1.16-1.59). The risk for cerebrovascular diseases was found to be decreased in DH patients when compared with references (aHR 0.68, 95% CI 0.47-0.99) and increased in coeliac disease patients (aHR 1.33, 95% CI 1.07-1.66). The risk for venous thrombosis was increased in coeliac disease patients (aHR 1.62, 95% CI 1.22-2.16) but not in DH. CONCLUSIONS: The risk for vascular complications appears to differ between DH and coeliac disease. In DH the risk for cerebrovascular diseases seems to be decreased, while in coeliac disease an elevated risk for cerebrovascular and cardiovascular diseases was observed. These differing vascular risk profiles between the two manifestations of the same disease merit further investigation.

An increased risk for cardiovascular diseases was observed among patients with coeliac disease, but not among patients with dermatitis herpetiformis, a cutaneous manifestation of coeliac disease.The risk for cerebrovascular diseases was shown to be decreased in dermatitis herpetiformis patients, but conversely, an increased risk for cerebrovascular diseases was identified in coeliac disease patients.Coeliac disease, but not dermatitis herpetiformis, was shown to be associated with increased risk for venous thrombosis.

The risk of renal comorbidities in celiac disease patients depends on the phenotype of celiac disease.

BACKGROUND: An increased risk of kidney disease in patients with celiac disease has been reported, but the association has remained obscure. Only few studies have investigated the association between renal comorbidities and dermatitis herpetiformis, a cutaneous manifestation of celiac disease. OBJECTIVES: We investigated whether patients with different phenotypes of celiac disease are at higher risk of kidney diseases than age- and sex-matched references. METHODS: The diagnoses of glomerulonephritis, diabetic nephropathy, interstitial nephritis, and end-stage renal disease obtained from the National Hospital Discharge Register between 1970 and 2015 were identified in celiac disease (Marsh III, n = 1072) and dermatitis herpetiformis (n = 368) patients diagnosed at Tampere University Hospital catchment region and in 4296 reference subjects. Using the Cox proportional hazards model, we compared the risk of kidney diseases between patients and references. The study protocol was approved by the Regional Ethics Committee of Tampere University Hospital (R16090). As the study was register based, no consent from patients was required. RESULTS: Even after adjusting for type 1 diabetes, celiac disease was associated with an elevated risk of kidney disease (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.12-3.03), glomerulonephritis (HR 3.37, 95% CI 1.64-6.95), and IgA nephropathy (IgAN) (HR 18.98, 95% CI 2.29-157.63). No similarly elevated risk was found among dermatitis herpetiformis patients (HR 1.50, 95% CI 0.63-3.55; HR 2.21, 95% CI 0.77-6.38; and HR 5.87, 95% CI 0.53-64.79, respectively). CONCLUSION: Celiac disease patients were at increased risk of kidney diseases, notably IgAN. The risk was dependent on the celiac disease phenotype and was not seen in patients with dermatitis herpetiformis. Awareness of possible renal manifestations is recommended when treating celiac disease patients.

Mortality and causes of death in different celiac disease phenotypes during long-term follow-up.

BACKGROUND: Celiac disease has been associated with increased mortality, but data on long-term mortality are scarce. AIMS: To determine long-term mortality in celiac disease. METHODS: The study cohort consisted of all celiac disease patients (n=1,392) diagnosed in Tampere University Hospital catchment area 1960 - 2000. Patients were categorized into subgroups based on demographic (age, gender, decade of diagnosis) and celiac disease characteristics (e.g., phenotype, severity of villous atrophy) collected from medical records. Overall and cause-specific mortality was compared to those of age-, sex-, and place of residence matched reference individuals (n=4,177) over time. RESULTS: During the 41 years of follow-up (median 26.5 years), 376 celiac disease patients and 1,155 reference individuals died. All-cause mortality was not increased (hazard ratio (HR) 0.96, 95% confidence intervals (CI) 0.85-1.08). Mortality from lymphoproliferative diseases and diseases of the central nervous system was increased (HR 2.42, 95% CI 1.38-4.24 and HR 2.14, 95% CI 1.05-4.36 respectively) while the risk from alcohol related diseases was decreased (HR 0.31, 95% CI 0.09-1.00). Examination of various celiac disease phenotypes revealed no significant differences in mortality CONCLUSIONS: Overall mortality was not increased in any celiac disease phenotype during a very long-term follow-up.

Sex-differences in Gluten-free Dietary Adherence and Clinical Symptoms in Patients with Long-term Treated Dermatitis Herpetiformis.

Dermatitis herpetiformis is a blistering autoimmune skin disease, and a cutaneous manifestation of coeliac disease. The burden of coeliac disease is increased especially in females, but studies concerning sex differences in patients with long-term treated dermatitis herpetiformis are scarce. This questionnaire study compared adherence to a gluten-free diet, clinical symptoms and well-being between females and males in a cohort of 237 long-term treated (median 24 years) patients with dermatitis herpetiformis. Females had better adherence to a gluten-free diet (p = 0.022) and they used dapsone significantly less often at the time of the study than did males (4% vs 13%, p = 0.017). The occurrence of skin symptoms was equal in both sexes, but dermatological quality of life was lower in females (p = 0.024), and gastrointestinal symptoms were more severe among females with dermatitis herpetiformis than among males (p = 0.027). In conclusion, long-term treated female patients with dermatitis herpetiformis have better adherence to a gluten-free diet, but they also experience more severe clinical symptoms compared with males.

Persistent Skin Symptoms after Diagnosis and on a Long-term Gluten-free Diet in Dermatitis Herpetiformis.

Dermatitis herpetiformis is a cutaneous manifestation of coeliac disease treated with a gluten-free diet. However, the itching and blistering rash alleviates slowly after gluten withdrawal and occasionally persists despite a long-term gluten-free diet. This study investigated the prevalence and factors associated with prolonged (i.e. >2 years) and ongoing skin symptoms in 237 patients with dermatitis herpetiformis. Data were gathered from medical records and via questionnaires. Among patients with dermatitis herpetiformis, 38% had prolonged symptoms after diagnosis, and 14% had ongoing skin symptoms at follow-up (median duration of gluten-free diet 24 years). A severe rash at diagnosis was associated with both prolonged and ongoing cutaneous symptoms. In addition, patients with dermatitis herpetiformis with ongoing skin symptoms at follow-up had been on the dietary treatment for a shorter time (median duration 16 vs 25 years) and were less often on a strict diet (53% vs 78%) compared with patients with dermatitis herpetiformis without ongoing skin symptoms.

Anaemia in Dermatitis Herpetiformis: Prevalence and Associated Factors at Diagnosis and One-year Follow-up.

Dermatitis herpetiformis is a cutaneous manifestation of coeliac disease. Anaemia is a common finding in patients with untreated coeliac disease, but little is known about the occurrence of anaemia in those with dermatitis herpetiformis. This study investigated the prevalence of anaemia and factors associated with anaemia in 250 patients with dermatitis herpetiformis, at diagnosis and one year after diagnosis. As controls, 139 patients with coeliac disease were included. Patient records were reviewed to gather baseline clinical, histological, and laboratory data. Follow-up data for patients with dermatitis herpetiformis were collected from patient records and via questionnaires or at follow-up visits. The prevalence of anaemia was 12% in patients with dermatitis herpetiformis and 17% in patients with coeliac disease at diagnosis (p = 0.257). Anaemia in patients with dermatitis herpetiformis was not associated with the severity of skin symptoms or small bowel damage. The prevalence of anaemia at a 1-year follow-up had increased to 19%, but it was associated mainly with dapsone treatment.

Dermatitis Herpetiformis: An Update on Diagnosis and Management.

Dermatitis herpetiformis (DH), presenting with an intense itch and blistering symmetrical rash, typically on the elbows, knees, and buttocks, is a cutaneous manifestation of celiac disease. Though overt gastrointestinal symptoms are rare, three-fourths of patients with DH have villous atrophy in the small bowel, and the rest have celiac-type inflammatory changes. DH affects mostly adults and slightly more males than females. The mean age at onset is about 50 years. DH diagnosis is confirmed by showing granular immunoglobulin A deposits in the papillary dermis. The DH autoantigen, transglutaminase 3, is deposited at the same site in tightly bound immune complexes. At present, the DH-to-celiac disease prevalence is 1:8. The incidence of DH is decreasing, whereas that of celiac disease is increasing, probably because of improved diagnostics. In DH, the treatment of choice for all patients is a gluten-free diet (GFD) in which uncontaminated oats are allowed. At onset, most patients need additional dapsone to rapidly control the rash and itching. Dapsone can be stopped after a mean of 2 years, and a strict lifelong GFD alone is required. Dietary adherence offers an excellent long-term prognosis for patients with DH, with a normal quality of life and all-cause mortality.

Autoantibodies Against the Immunodominant Bullous Pemphigoid Epitopes Are Rare in Patients With Dermatitis Herpetiformis and Coeliac Disease.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of coeliac disease (CD). Patients with DH have an elevated risk of development of another autoimmune blistering skin disease, bullous pemphigoid (BP). In this study we investigated whether patients with DH and CD (mean age for both 49 years) have circulating autoantibodies against BP180, the major BP autoantigen. ELISA tests showed that only a few DH (3/46) and CD (2/43) patients had BP180-NC16A IgG autoantibodies. Immunoblotting found that more than half of the DH samples contained IgG autoantibodies against full-length BP180. Epitope mapping with 13 fusion proteins covering the BP180 polypeptide revealed that in DH and CD patients, IgG autoantibodies did not target the NC16A or other epitopes typical of BP but recognized other intracellular and mid-extracellular regions of BP180. None of the analyzed DH and CD patients with either ELISA or immunoblotting positivity had IgG or IgA reactivity against the cutaneous basement membrane in indirect immunofluorescence analysis or skin symptoms characteristic of BP. Although only a minority of middle-aged DH patients had IgG autoantibodies against the immunodominant epitopes of BP180, our results do not exclude the possibility that intermolecular epitope spreading could explain the switch from DH to BP in elderly patients.

TG6 Auto-Antibodies in Dermatitis Herpetiformis.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of gluten sensitivity, in which an autoimmune response is directed against transglutaminase 3 (TG3), an epidermal transglutaminase. TG2 is the autoantigen in celiac disease (CD), defined by the presence of enteropathy, and TG6 is the autoantigen in neurological manifestations of gluten sensitivity. The interplay between B cell responses to these 3 transglutaminases in developing the clinical spectrum of disease manifestations is not completely understood. Also, the individual or combined diagnostic and predictive value of the respective autoantibodies is not fully explored. We examined the prevalence of TG6 antibodies in a cohort of patients with DH. TG6 positivity was found in 13/33 (39%), with IgA detected in 11 patients, IgG in 3, and both in 1. This was significantly higher compared to what is seen in the classic CD cases (14%) in a Finnish population. TG6 positive baseline samples constituted 60% of DH patients with no enteropathy (n = 10), as opposed to 17% positivity in those with overt enteropathy (n = 12; Marsh IIIB). Repeat testing after adherence to a gluten-free diet for 1 year showed reduced titers for TG6 antibodies in 11/13 (85%), whereby 7 patients were now TG6 antibody-negative. Four patients seroconverted and tested positive for TG6 antibodies at one year, due to the ongoing exposure to gluten. We report another patient who presented with neurological manifestations (encephalopathy) leading to the diagnosis of CD, who was intermittently adhering to a gluten-free diet. Serological testing at baseline showed him to be positive for antibodies to all 3 transglutaminases. Eleven years later, he developed DH. He also subsequently developed ataxia and peripheral neuropathy. Although TG3 and TG6 autoantibodies are linked to certain disease manifestations, TG2, TG3, and TG6 autoantibodies can be present across the spectrum of GRD patients and might develop years before onset of symptoms of extraintestinal manifestations. This is consistent with gluten-dependent adaptive immunity being a necessary but not sufficient pretext to organ-specific damage. TG6 antibodies appear to develop more frequently in patients where tolerance to gluten was broken but, either there was no development of the molecular state driving the tissue destruction at the level of the gut, or perhaps more likely, there was more resistance to developing this phenotype.

The Long-Term Safety and Quality of Life Effects of Oats in Dermatitis Herpetiformis.

The treatment of choice for dermatitis herpetiformis (DH), a cutaneous manifestation of coeliac disease, is a life-long gluten-free diet (GFD). In a GFD, wheat, rye and barley should be strictly avoided, but the role of oats is more controversial. This study aimed to investigate the safety and long-term quality of life and health effects of oat consumption in 312 long-term treated DH patients. Baseline data were gathered from patient records and follow-up data from questionnaires or interviews, and validated questionnaires were used to assess quality of life. We found that altogether 256 patients (82%) were consuming oats as part of their GFD at the follow-up. Long-term follow-up data showed that there were no differences in the presence of long-term illnesses, coeliac disease complications or the usage of medication between those consuming and not consuming oats. However, oat consumers had a better quality of life and reported ongoing gastrointestinal symptoms less frequently (4% vs 19%, p = 0.004) at the follow-up than those not consuming oats. The study established that oats are safe for DH patients and in the long-term seem to improve the quality of life of DH patients.

Intestinal TG3- and TG2-Specific Plasma Cell Responses in Dermatitis Herpetiformis Patients Undergoing a Gluten Challenge.

Dermatitis herpetiformis (DH), a cutaneous manifestation of coeliac disease, is characterized by transglutaminase (TG) 3-targeted dermal immunoglobulin A (IgA) deposits. The treatment for DH is the same as for coeliac disease, namely a life-long gluten-free diet. DH patients typically have gluten-dependent circulating autoantibodies targeting TG3 and TG2, and plasma cells secreting such autoantibodies have been detected in the small intestinal mucosa. This study investigates the gluten-responsiveness of intestinal TG3 and TG2 antibody-secreting plasma cells in 16 treated DH patients undergoing a gluten challenge. The frequency of both plasma cell populations increased significantly during the challenge, and their frequency correlated with the corresponding serum autoantibody levels at post-challenge. TG3-specific plasma cells were absent in all 18 untreated coeliac disease patients and seven non-coeliac control subjects on gluten-containing diets. These findings indicate that, in DH, both intestinal TG3- and TG2-antibody secreting plasma cells are gluten-dependent, and that TG3-antibody secreting plasma cells are DH-specific.

Current Concepts of Dermatitis Herpetiformis.

Dermatitis herpetiformis (DH) is an autoimmune skin disease that causes itchy, blistering rash, typically on the elbows, knees and buttocks. DH and coeliac disease share the same genetic background, gluten-dependent enteropathy and antibody response against tissue transglutaminase. DH is currently considered a cutaneous manifestation of coeliac disease, and the prevailing hypothesis is that DH develops as a late manifestation of subclinical coeliac disease. The incidence of DH is decreasing contemporarily with the increasing incidence of coeliac disease. The IgA immune response in DH skin is directed against epidermal transglutaminase, while the autoantigen in the gut is tissue transglutaminase. Granular IgA deposition in the papillary dermis is pathognomonic for DH, and is a finding used to confirm the diagnosis. The treatment of choice for DH is a life-long gluten-free diet, which resolves the rash and enteropathy, increases quality of life, and offers a good long-term prognosis.

Risk of fractures in dermatitis herpetiformis and coeliac disease: a register-based study.

Objectives: Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease. Bone fracture risk is increased in coeliac disease, but little knowledge exists about bone complications in DH. This study aimed to evaluate the risk of hip and other hospital-treated fractures in DH and coeliac disease in a high prevalence area with good adherence to a gluten-free diet. Materials and methods: Hip, proximal humerus, wrist and ankle fractures in 368 treated DH and 1076 coeliac disease patients between 1970 and 2015 were reviewed from the National Hospital Discharge Register. Hip fracture incidence rates for DH and coeliac disease patients were compared to those for the general population. The overall fracture risk for DH was compared to coeliac disease. Results: The hip fracture incidence rates for DH and coeliac disease patients did not differ from the general population. In females aged 80-89, the hip fracture incidence was higher in DH than in coeliac disease, but the risk for any hospital-treated fracture was lower in DH compared to coeliac disease (adjusted HR 0.620, 95% CI 0.429-0.949). The DH and coeliac disease patients with hospital-treated fractures were diagnosed at an older age, but the degree of small bowel mucosal damage did not significantly differ between patients with and without fractures. Conclusion: The incidence of hip fracture is not increased in treated DH or coeliac disease in an area with high awareness and dietary compliance rates. However, patients with DH seem to have a lower risk for fractures overall compared to coeliac disease.

Gluten Challenge Induces Skin and Small Bowel Relapse in Long-Term Gluten-Free Diet-Treated Dermatitis Herpetiformis.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of celiac disease causing an itchy, blistering rash. Granular IgA deposits in the skin are pathognomonic for DH, and the treatment of choice is a lifelong gluten-free diet (GFD). Preliminary evidence suggests that there are patients with DH who redevelop gluten tolerance after adherence to a GFD treatment. To evaluate this, we performed a 12-month gluten challenge with skin and small-bowel mucosal biopsy samples in 19 patients with DH who had adhered to a GFD for a mean of 23 years. Prechallenge biopsy was negative for skin IgA and transglutaminase 3 deposits in 16 patients (84%) and indicated normal villous height-to-crypt depth ratios in the small bowel mucosa in all 19 patients. The gluten challenge caused a relapse of the rash in 15 patients (79%) in a mean of 5.6 months; of these 15 patients, 13 had skin IgA and transglutaminase 3 deposits, and 12 had small-bowel villous atrophy. In addition, three patients without rash or immune deposits in the skin developed villous atrophy, whereas one patient persisted without any signs of relapse. In conclusion, 95% of the patients with DH were unable to tolerate gluten even after long-term adherence to a GFD. Therefore, lifelong GFD treatment remains justified in all patients with DH.

Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease.

Dermatitis herpetiformis (DH) is a common extraintestinal manifestation of coeliac disease presenting with itchy papules and vesicles on the elbows, knees, and buttocks. Overt gastrointestinal symptoms are rare. Diagnosis of DH is easily confirmed by immunofluorescence biopsy showing pathognomonic granular immunoglobulin A (IgA) deposits in the papillary dermis. A valid hypothesis for the immunopathogenesis of DH is that it starts from latent or manifest coeliac disease in the gut and evolves into an immune complex deposition of high avidity IgA epidermal transglutaminase (TG3) antibodies, together with the TG3 enzyme, in the papillary dermis. The mean age at DH diagnosis has increased significantly in recent decades and presently is 40⁻50 years. The DH to coeliac disease prevalence ratio is 1:8 in Finland and the United Kingdom (U.K.). The annual DH incidence rate, currently 2.7 per 100,000 in Finland and 0.8 per 100,000 in the U.K., is decreasing, whereas the reverse is true for coeliac disease. The long-term prognosis of DH patients on a gluten-free diet is excellent, with the mortality rate being even lower than for the general population.