Diagnosis and management of pemphigus: Recommendations of an international panel of experts.

BACKGROUND: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. METHODS: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. RESULTS: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. LIMITATIONS: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus.

Clinical presentation and diagnostic delay in pemphigus vulgaris: A prospective study from Turkey.

BACKGROUND: To evaluate the diagnostic patterns and factors that may influence delays in the diagnosis of pemphigus vulgaris (PV) with oral involvement. MATERIALS AND METHODS: In this prospective cohort study, 36 newly diagnosed PV patients with oral involvement were clinically examined and interviewed about the natural history of the oral lesions, number of medical consultations (Med consultation), medical treatment history, and diagnostic delay time (DD time). RESULTS: Thirty (83%) PV patients presented initially with oral mucosal involvement (OMI) and 6 (17%) presented initially with skin involvement (SI). The mean DD time was 6.19 ± 3.82 months, and the mean number of Med consultation was 5.8 (n = 36). The means of all the parameters were significantly higher for the OMI patients than for the SI patients (P < .05). All of the patients with OMI had been misdiagnosed. The DD time was significantly longer in patients who presented initially with desquamative gingivitis (8.25 ± 3.81) than patients who presented with ulcers and erosions (4.78 ± 1.11) (P < .05). There was a statistically significant positive correlation between DD time and Med consultation (r = 0.91). CONCLUSION: Even with the high frequency of oral involvement and easy access to the oral cavity, diagnostic delays are still common for patients with oral PV. This underlines the need for education to improve healthcare providers' awareness and knowledge of the clinical oral presentation of PV.

The natural course and factors affecting severity of Behçet's disease: a single-center cohort of 368 patients.

Our goal was to determine, retrospectively, the occurrence of the symptoms of Behçet's disease in chronological order and the course of the disease. Additionally, probable factors affecting the clinical severity were investigated. A total of 368 patients (171 females and 197 males; aged 41.11 ± 10.9 years) were included in this retrospective cohort study. The chronological order of the clinical manifestations was recorded. Patients were also assessed for clinical severity score. Oral ulcer was the most common manifestation (100 %) followed by genital ulcer (89.4 %), papulopustular lesions (75 %) and articular involvement (60.1 %). Oral ulcer was the most common onset manifestation (66.8 %) followed by genital ulcer (4.9 %), erythema nodosum (3.3 %) and ocular involvement (1.4 %). The duration between the onset symptom and the fulfillment of the diagnostic criteria was 4.67 ± 5.9 years. The duration between the time point of fulfillment of diagnostic criteria and the diagnosis (2.5 ± 2.1 years) was longer in patients having only mucocutaneous lesions (2.8 ± 2.2 years) than in patients having serious organ involvements (1.9 ± 1.6 years; p < 0.01). Serious involvements such as neurological involvement and large vessel involvement had their onsets later. Mean clinical severity score was higher in male patients (5.3 ± 2.1 vs 4.8 ± 1.7; p < 0.05). In logistic regression analysis, male gender (p = 0.03) and increased number of symptoms at diagnosis (p < 0.001, R (2) = 0.73) were found to be significant risk factors for severity. Mucocutaneous lesions, especially oral and/or genital ulcers, usually precede possible serious involvements; therefore, careful follow-up is mandatory. Males with increased number of organ involvements at the diagnosis are associated with more severe disease.

Cutaneous Alternaria infectoria infection diagnosed by molecular techniques in a renal transplant patient.

Organ transplant recipients under immunosuppressive therapy have a highly increased risk of opportunistic fungal infections. Cutaneous infection caused by Alternaria species are relatively rare in humans and most cases reported in the literature are in immunocompromised individuals. We report here on a 33-year old male renal transplant patient with diabetes mellitus who presented with cutaneous alternariosis caused by Alternaria infectoria, two years after the transplant. The diagnosis was performed by real-time polymerase chain reaction assay and histopathologic examination. The extension of the lesion under itraconazole treatment required treatment consisting of a combination of surgical excision and liposomal amphotericin B.

Serum soluble CD200 level was higher in patients with bullous pemphigoid during the active phase of the disease than for healthy individuals.

BACKGROUND: CD200 is a novel immunosuppressive molecule, existing both as cell membrane bound and as a soluble form in serum (sCD200), which acts to regulate inflammatory and acquired immune responses. Recently, our study group showed that sCD200 was found in serum and blister fluid in a patient with bullous pemphigoid and that anti-IgE therapy impacted those levels. We therefore planned this study to evaluate the soluble serum CD200 levels of bullous pemphigoid patients and compare it with that of healthy controls. We also analysed the association between the sCD200 levels and the clinical severity of the disease in bullous pemphigoid patients. METHODS: We investigated 5 consecutive patients with bullous pemphigoid, and 15 healthy controls were included in this study. Assessment of clinical examination and measurement of laboratory investigation were performed on the same day. Bullous pemphigoid patients were also assessed for Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). Concentrations of anti-BP180 and soluble CD200 in the serum samples were quantified using ELISA kits. RESULTS: The serum soluble CD200 level was observed to be statistically significantly higher in patients with BP (77.6 +/- 15.7 pg/mL) compared with healthy controls (26.1 +/- 6.7 pg/mL), (p < 0.001). Nevertheless, there was no statistically significant correlation between serum soluble CD200 levels and clinical severity scores and Anti-BP180 values (p = 0.402, p = 0.395, respectively). However, there was a statistically significant correlation between ABSIS and Anti-BP180 levels in patients with BP (p = 0.036). CONCLUSIONS: CD200 might play a role in the immune response in the pathogenesis of bullous pemphigoid. However, we do not know the exact mechanism of CD200 in the disease initiation and/or progression.

Modified Chalazion Clamp: Novel Applications in Dermatologic Surgery.

Biopsies and excisions of mucosal surfaces can be challenging due to poor visualization and bleeding control. Surgeons have utilized chalazion clamps to overcome these challenges. However, its original design incorporates a locking mechanism which restricts its use to more proximal mucosal surfaces, does not allow for flexible exertional pressure control by the operator, and it is only available in one size. We designed a modified chalazion clamp without a locking mechanism and in two different sizes and ring diameters to overcome these challenges. In this report, we demonstrate the enhanced utility and effectiveness of the modified chalazion clamp in dermatological procedures through different cases.

There might be a role for CD200 in the pathogenesis of autoimmune and inflammatory skin disorders.

BACKGROUND: Soluble CD200 (sCD200) is a novel immuno-effective molecule, which acts to regulate inflammatory and acquired immune responses. Recently, our study group showed that sCD200 was present in serum and blister fluid in a patient with bullous pemphigoid and a patient with toxic epidermal necrolysis. We therefore planned this study to evaluate the sCD200 levels of autoimmune and inflammatory skin disorder patients and to compare them with that of healthy controls. MATERIAL/METHODS: Our study included 30 consecutive patients with psoriasis vulgaris, 15 with pemphigus vulgaris, and 15 healthy controls. Clinical examination and laboratory tests were performed on the same day. Psoriasis patients were also assessed with the Psoriasis Area and Severity Index (PASI) and pemphigus patients were assessed using the Pemphigus Disease Area Index (PDAI). Levels of sCD200 in the serum samples were quantified using ELISA kits. RESULTS: The serum sCD200 level was observed to be statistically significantly higher in patients with psoriasis vulgaris (96.7±15.8) compared to patients with pemphigus vulgaris (76.2±14.6), (p<0.001) and healthy controls (26.8±7.0) (p<0.001). The serum sCD200 levels were observed to be statistically significantly higher in patients with pemphigus vulgaris compared with that in healthy controls (p<0.001). In addition, there was a statistically significant correlation between serum sCD200 levels and PDAI (r=0.987, p=0.001). Nevertheless, there was no statistically significant correlation between serum sCD200 levels and PASI (r=0.154, p=0.407). CONCLUSIONS: sCD200 might play a role in immune response in the pathogenesis of autoimmune and inflammatory skin disorders. However, it remains to be fully elucidated how sCD200 can orchestrate inflammatory response in psoriasis and pemphigus.

The Role of T Follicular Helper Cells in Clinical Remission and Relapse in Patients with Pemphigus Treated with Rituximab.

BACKGROUND: Pemphigus is a rare chronic autoimmune disease. Recent studies have found that T follicular helper (Tfh) cells may play a role in autoimmune diseases. In this study, Tfh cells frequency, BCL6 gene expression, IL-21, and IL-6 cytokines levels were examined, with the aim of understanding the effect of RTX on these cells in the onset of clinical remission or relapse in patients with pemphigus. METHODS: 20 patients with pemphigus vulgaris and 20 healthy controls without any autoimmune diseases that were admitted to the Dermatology and Venereology Clinic of the Akdeniz University Hospital were included. Peripheral blood sample was taken from all individuals and studied to analyze Tfh cell distribution, IL-21 and IL-6 distribution in CD3+CD4+CXCR5+ lymphocytes with flow cytometry, plasma IL-21 levels with ELISA, and mRNA levels that refer to BCL6 expression with PCR. RESULTS: Circulating Tfh cell distribution and IL-21 and IL-6 distribution in CD3+CD4+CXCR5+ lymphocytes and mRNA levels that refer to BCL6 expression showed no difference between patient and control groups. However, in patients who had received rituximab treatment there was a significant reduction in Tfh cells compared with other groups. Plasma IL-21 levels were significantly higher in the patient group. CONCLUSIONS: We found that plasma concentrations of the cytokine IL-21 were greatly increased in the pemphigus compared with the control group. There were no significant differences in Tfh cell percentages between the patient and control groups. Tfh cells were decreased in patients who received rituximab treatment. Our findings show that the response to RTX in pemphigus causes a reduction in circulating T follicular helper cells, but not in the plasma IL-21 level. Further studies are required to clarify the role of Tfh cells in pemphigus vulgaris.

Diagnosis and demarcation of skin malignancy using elastic light single-scattering spectroscopy: a pilot study.

BACKGROUND: Elastic light single-scattering spectroscopy (ELSSS) is a noninvasive and real-time technique that has been used to differentiate tumors from surrounding nontumor tissue in animal models and humans. OBJECTIVE: To investigate potential application of ELSSS as an adjunctive tool for noninvasive, in vivo, real-time differentiation of malignant and benign skin lesions and to detect positive surgical margins of excised biopsy samples. METHODS: In vivo spectroscopic measurements were performed on 28 lesions in 23 patients. The distribution of the lesions was as follows: nine basal cell carcinoma (BCC), four melanoma, two squamous cell carcinoma (SCC), and 13 benign lesions. Intraoperative margin assessments were performed on the 28 biopsy samples using ELSSS. RESULTS: The sign of the spectral slopes was positive for benign and negative for malignant tissues. It was used as a discrimination parameter between malignant and benign lesions with a sensitivity and specificity of 87% and 85%, respectively. Sensitivity and specificity of the system in detecting positive surgical margins on 14 excised biopsy samples were 80% and 90%, respectively. CONCLUSION: ELSSS has the potential for use as an adjunctive tool to reduce the number of negative biopsies and to detect positive surgical margins in real time.

Standard Patch Test Results and Clinical Relevance: A Cross-Sectional Study of 10-year Retrospective Experience.

Background: Allergic contact dermatitis (ACD) is a type IV hypersensitivity reaction, and The European Standard Series (ESS) Patch Test (PT) is widely used in determining the possible responsible allergens causing ACD. The dynamic nature of the industrial products, socioeconomic and environmental factors cause the frequency of common allergens to change over the years and among different regions. Aims and Objectives: This study aimed to retrospectively evaluate the results of ESS PT of our centre in the last decade, and determine the current spectrum of allergens and their clinical relevance. Materials and Methods: The data of patients who underwent ESS PT in our clinic between January 2010 and March 2020 were included in the study. The patient files were examined retrospectively. The clinical relevance was evaluated according to the COADEX system. Statistical analysis used: SPSS for Windows version 23.0 software program. Results: The data of 1037 patients [623 (60.1%) female, 414 (39.9%) male] were analysed. The mean age was 38.34 ± 14.55 years. The five most common allergens were nickel sulphate (23.1%), cobalt chloride (12%), potassium dichromate (9.5%), Fragrance mix II (7.3%) and balsam of Peru (5.7%). According to the COADEX coding system, current relevance was detected in 319 (49.3%) of 646 patients who had a positive reaction to any substance in the patch test. Conclusion: Our study showed that with increasing awareness in society, the tendency to avoid some well-known allergenic substances and consumer products causes changes in common allergens. These results prove the value of long-term surveillance of contact allergy.

International eDelphi Study to Reach Consensus on the Methotrexate Dosing Regimen in Patients With Psoriasis.

Importance: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide. Objective: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics. Design, Setting, and Participants: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience). Main Outcomes and Measures: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree. Results: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In the consensus meeting, consensus was achieved on 4 proposals. More research is needed, especially for the proposals on folic acid and the dosing of methotrexate for treating subpopulations such as children and vulnerable patients. Conclusions and Relevance: In this eDelphi consensus study, consensus was reached on 20 of 21 proposals involving methotrexate dosing in patients with psoriasis. This consensus may potentially be used to harmonize the treatment with methotrexate in patients with psoriasis.

Integrated Cadaveric Nail Surgery Course Improves Self-Assessed Knowledge and Competency of Dermatologists.

INTRODUCTION: Dermatologists see many patients with nail disorders requiring surgical interventions. However, nail surgery is often found to be difficult by dermatologists. The aim of this study was to evaluate the effectiveness of an integrated nail surgery course. METHODS: A nail surgery course model, combining anatomy, pathology, and dermatology with theoretical lectures and hands-on training on fresh-frozen cadaver, was designed for dermatologists. Before and after the course, the participants were asked to complete a questionnaire in which they assessed their knowledge and competence levels. RESULTS: Twenty-eight dermatologists completed the questionnaires. The majority of the dermatologists (79.6%) had limited nail surgery experience, previously. The most commonly cited reasons for lack of knowledge or low or moderate theoretical and/or practical level of knowledge of nail surgery were not having received theoretical and practical education during dermatology residency. The median scores of self-assessed knowledge and competency improved significantly after the course (p < 0.001). The majority (82.1%) of the participants were "quite" or "very" well satisfied. CONCLUSION: An integrative nail surgery course model seems beneficial and encouraging for dermatologists. Organizing this type of nail surgery course, especially in medical schools using fresh-frozen cadavers, may significantly improve dermatologists' knowledge and skills.

Clinical practice guidelines for the diagnosis and treatment of cutaneous leishmaniasis in Turkey.

BACKGROUND: Cutaneous leishmaniasis (CL) is a vector-born parasitic disease characterized by various skin lesions that cause disfiguration if healed spontaneously. Although CL has been endemic for many years in the southern regions of Turkey, an increasing incidence in nonendemic regions is being observed due to returning travelers and, more recently, due to Syrian refugees. Thus far, a limited number of national guidelines have been proposed, but no common Turkish consensus has emerged. OBJECTIVES: The aim of this study was to develop diagnostic and therapeutic guidelines for the management of CL in Turkey. METHODS: This guideline is a consensus text prepared by 18 experienced CL specialists who have been working for many years in areas where the disease is endemic. The Delphi method was used to determine expert group consensus. Initially, a comprehensive list of items about CL was identified, and consensus was built from feedback provided by expert participants from the preceding rounds. RESULTS: Evidence-based and expert-based recommendations through diagnostic and therapeutic algorithms according to local availability and conditions are outlined. CONCLUSION: Because CL can mimic many other skin diseases, early diagnosis and early treatment are very important to prevent complications and spread of the disease. The fastest and easiest diagnostic method is the leishmanial smear. The most common treatment is the use of local or systemic pentavalent antimony compounds.

PUVA Induced Bullous Pemphigoid in a Patient with Mycosis Fungoides.

Background. Bullous pemphigoid is an autoimmune subepidermal blistering skin disease in which autoantibodies are directed against components of the basement membrane. The disease primarily affects the elderly people and in most of the patients inducing factors cannot be identified. Herein, we report a case of BP that occurred in a patient who was receiving PUVA therapy for the treatment of mycosis fungoides. Main Observation. A 26-year-old woman with mycosis fungoides developed blisters while receiving PUVA therapy. On physical examination tense bullae on the normal skin, remnants of blisters, and erosions were observed on her breasts, the chest wall, and the upper abdomen. Histopathological investigations revealed subepidermal blisters with eosinophilic infiltration and in direct immunofluorescence examination linear deposition of IgG along the basement membrane zone was observed. The diagnosis of bullous pemphigoid was also confirmed by ELISA and BIOCHIP mosaic-based indirect immunofluorescence test. Conclusions. PUVA therapy is an extremely rare physical factor capable of inducing bullous pemphigoid. So the development of blistering lesions during PUVA therapy may be suggestive sign of a bullous disease such as bullous pemphigoid and it should be excluded with proper clinical and laboratory approaches immediately after withdrawal of PUVA therapy.

Successful Treatment of a Bullous Pemphigoid Patient with Rituximab Who Was Refractory to Corticosteroid and Omalizumab Treatments.

Omalizumab is a humanized monoclonal antibody which is an FDA-approved treatment of severe allergic asthma and inhibits IgE binding to FcεRI. According to increasing evidence of IgE inhibition, omalizumab was suggested as a therapeutic approach for bullous pemphigoid (BP). Rituximab has been reported to be effective in various autoimmune diseases, including autoimmune bullous dermatoses. A specific protocol for the use of rituximab to treat BP patients is not yet available. There are only small case series and case reports about the efficacy and safety of rituximab in BP. Here we present a young BP patient who responded well to rituximab therapy and was refractory to conventional and omalizumab therapies although he had elevated IgE levels and eosinophilia. Our case supports the knowledge about the effectiveness and safety of rituximab not only in pemphigus but also in BP. On the other hand, although it did not work in our case, omalizumab may be a potentially effective agent in some carefully selected patients with certain subtypes of BP.

Efficacy and safety of rituximab therapy in patients with pemphigus vulgaris: first report from Turkey.

BACKGROUND: Pemphigus vulgaris (PV) is a severe, chronic, and potentially life-threatening autoimmune blistering disease that affects the skin and mucous membranes. Rituximab is a monoclonal anti-CD20 antibody which has been used increasingly in the therapy of PV. METHODS: The present study sought to test the efficacy and safety of rituximab as an adjuvant therapy by retrospective analysis of clinical and immunological data for 29 patients with PV who were treated with rituximab between 2010 and 2015. Response to therapy, duration of clinical remission, serology of the response, and adverse effects of rituximab were evaluated. RESULTS: The mean ± standard deviation (SD) follow-up time was 17.48 ± 13.18 months. In all patients, findings showed either a decrease in antibody titers or that antibodies were completely undetectable after therapy. Rituximab use resulted in a significant reduction in steroid dosage during follow-up. At the end of the follow-up period, 26 patients (96.2%) had achieved complete remission with or without therapy (one patient had no follow-up and one patient had died, most probably as the result of a thromboembolic event). In 44.4% of patients, a clinical relapse occurred after a mean ± SD period of 13.1 ± 4.7 months after the initiation of rituximab therapy. Relapses were managed with additional infusions of rituximab. CONCLUSIONS: Rituximab is a beneficial and relatively safe adjuvant treatment for PV that facilitates prolonged clinical remission and has a significant steroid-sparing effect.

Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid.

Autoimmune bullous diseases are rare, organ-specific, a group of blistering disease of skin and mucous membranes. Recent studies suggest that the frequency of the autoimmune bullous diseases has been increasing. Pemphigus vulgaris and bullous pemphigoid are the most frequently reported autoimmune bullous diseases. High incidence of autoimmune bullous diseases in some ethnic groups such as pemphigus in Ashkenazi Jewish, or in some regions such as pemphigus foliaceus in Brazil has been shown to be related to genetic and environmental factors, respectively. Pemphigus has been reported more frequently in the female gender. Although it is most frequently diagnosed between the ages 50 and 60 in European countries, in the remaining countries in the world, it is seen between the ages of 30 and 50. Bullous pemphigoid is generally seen above 70 years of age. Although overall incidence is slightly higher in females, after the age of 80 years it is more frequent in males. Both pemphigus vulgaris and bullous pemphigoid has a chronic course with recurrences. Mortality risk of the patients with bullous pemphigoid was found at least 2 times higher and the mortality risk of the patients with pemphigus was found approximately 3 times higher than that of the general population. In this review, the results obtained from the epidemiological studies were analyzed according to geographic regions, and especially epidemiologic features of two prevalent autoimmune bullous diseases, pemphigus and bullous pemphigoid have been discussed.

Human leukocyte antigens class I and class II in patients with pemphigus in southern Turkey.

BACKGROUND: Genetic factors that predispose individuals to pemphigus are considered to play important roles in the development of the disease. Furthermore, population studies of patients with pemphigus have clearly shown that the most prevalent alleles differ across ethnic groups. OBJECTIVES: This controlled study was designed to detect the distribution of human leukocyte antigen (HLA) class I and II alleles in Turkish patients with pemphigus. METHODS: Sixty patients diagnosed with pemphigus according to clinical findings, histology, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were enrolled in the study. The control group consisted of 60 healthy adult transplant donors. HLA typing was carried out using a polymerase chain reaction (PCR) with sequence-specific primers (SSP) method. RESULTS: The frequencies of HLAs A*11, CW*01, DRB1*04, DRB1*14, DQB1*05, and DPB1*0401 were found to be statistically significantly higher in the disease group than in controls. By contrast, the frequencies of HLAs B*18, B*50, DRB1*11, DQB1*02, DQB1*06, DPB1*0301, and DPB1*1102 were statistically significantly lower in the pemphigus group than in controls. Linkage dysequilibrium analysis showed that DRB1*14/DQB1*05, A*11/DQB1*05, and A*11/DRB1*14 alleles were detected frequently in pemphigus patients, and DRB1*11/DQB1*05, DRB1*14/DQB1*02, B*50/DQB1*02, and B*50/DPB1*0301 alleles appeared frequently in healthy controls. CONCLUSIONS: The results suggest that DRB1*04, DRB1*14, DQB1*05, and DPB1*0401 class II HLAs and A*11 and CW*01 class I HLAs are associated with pemphigus in southern Turkey. Observed differences in LD patterns between patients and controls suggest that the coexistence of the respective alleles is strongly determinant of predisposition towards (DRB1*14/DQB1*05 and A*11/DQB1*05) or protection against (B*50/DQB1*02) the disease.