Efficacy and Safety of Rilzabrutinib in Pemphigus: PEGASUS Phase 3 Randomized Study.

TRIAL DESIGN: Pemphigus is a rare but life-threatening autoimmune disease requiring long-term treatment that minimizes corticosteroid (CS) exposure while providing consistent disease control. The phase 2 pemphigus study of oral, reversible, covalent Bruton tyrosine kinase inhibitor rilzabrutinib demonstrated rapid and sustained efficacy with well-tolerated safety. METHODS: Adults (aged 18-80 years) were randomized 1:1 to 400 mg rilzabrutinib (n = 65) or placebo (n = 66) twice daily (with CS ≤ 0.5 mg/kg/d) for 37 weeks in the phase 3 PEGASUS study in moderate-to-severe pemphigus vulgaris/pemphigus foliaceus. RESULTS: The primary endpoint of complete remission from week 29 to week 37 with the amended endpoint CS dose ≤10 mg/d was not significant for 13 of 54 (24%) rilzabrutinib versus 10 of 55 (18%) placebo patients with PV (P = .45). Secondary endpoints showed numerical but nonsignificant improvements with rilzabrutinib (vs placebo) in reduced CS use, prolonged complete remission duration, and faster time to first complete remission. CONCLUSIONS: Overall, rilzabrutinib was well-tolerated, with similar adverse events reported in both groups. Using minimal CS dose ≤10 mg/d and excluding remote observations, the primary efficacy endpoint was not met. However, results from a prespecified sensitivity analysis using CS dose ≤5 mg/d, considering all observations, and including all patients support Bruton tyrosine kinase inhibition as a viable therapeutic approach for pemphigus.

S2k guidelines on diagnosis and treatment of linear IgA dermatosis initiated by the European Academy of Dermatology and Venereology.

INTRODUCTION: Linear IgA dermatosis (LAD) is a rare subepidermal autoimmune bullous disease (AIBD) defined by predominant or exclusive immune deposits of immunoglobulin A at the basement membrane zone of skin or mucous membranes. This disorder is a rare, clinically and immunologically heterogeneous disease occurring both in children and in adults. The aim of this project is to present the main clinical features of LAD, to propose a diagnostic algorithm and provide management guidelines based primarily on experts' opinion because of the lack of large methodologically sound clinical studies. METHODS: These guidelines were initiated by the European Academy of Dermatology and Venereology (EADV) Task Force Autoimmune Bullous Diseases (AIBD). To achieve a broad consensus for these S2k consensus-based guidelines, a total of 29 experts from different countries, both European and non-European, including dermatologists, paediatric dermatologists and paediatricians were invited. All members of the guidelines committee agreed to develop consensus-based (S2k) guidelines. Prior to a first virtual consensus meeting, each of the invited authors elaborated a section of the present guidelines focusing on a selected topic, based on the relevant literature. All drafts were circulated among members of the writing group, and recommendations were discussed and voted during two hybrid consensus meetings. RESULTS: The guidelines summarizes evidence-based and expert opinion-based recommendations (S2 level) on the diagnosis and treatment of LAD. CONCLUSION: These guidelines will support dermatologists to improve their knowledge on the diagnosis and management of LAD.

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.

S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES: These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS: Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS: These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies.

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.

Factors Associated with Early Referral for Pediatric Cutaneous Leishmaniasis.

Determinants of early referral to healthcare providers, which may be useful for health policy, have not been investigated in pediatric cutaneous leishmaniasis with multivariate analyses. We aimed to explore determinants of early healthcare seeking in children with cutaneous leishmaniasis. Records of 1115 children with cutaneous leishmaniasis admitted to our hospital in Adana, Turkey were reviewed. Effects of age, sex, residential distance, lesion number, and faciocervical onset on early referral were evaluated with multivariate logistic regression analyses. The mean duration of the disease was 12.7 months. Early referral was significantly more likely in patients aged 1-5 and 6-10 years (odds ratio 2.32 and 1.32, respectively) than patients aged 11-18 years. A borderline-significant association was present for faciocervical onset. Early referral in younger children might be due to the fact that the younger the child, the greater the parental concerns about their child's health problems. The rate of late referral in older children may be decreased by some school-based health interventions.

How Do Experts Treat Patients with Bullous Pemphigoid around the World? An International Survey.

Many treatments are currently proposed for treating patients with bullous pemphigoid (BP). We assessed treatment modalities of BP depending on the different countries, BP extent, and patients' comorbidities. We surveyed worldwide experts about how they treat patients with BP. A total of 61 experts from 27 countries completed the survey. Severe and moderate BP were treated with oral prednisone (61.4 and 53.7%, respectively) or superpotent topical corticosteroids (CSs) (38.6 and 46.3%, respectively). Conventional immunosuppressants were more frequently combined with oral prednisone (74.5%) than with superpotent topical CS (37.5%) in severe BP. Topical CSs were mainly used in Europe in mild (81.1%), moderate (55.3%), and severe (54.3%) BP. In the United States of America and Asia, systemic CSs were mainly proposed for treating severe (77.8 and 100%, respectively), moderate (70 and 77.8%, respectively), and also mild (47.1 and 33.3%, respectively) BP. Most experts reduced the initial dose of oral CS in patients with diabetes mellitus (48.1%) or cardiac insufficiency (40.2%) but rarely changed BP treatment in patients with neurological disorders or neoplasia. This survey showed major differences in the way patients with BP are treated between AmeriPac countries (United State of America, Latin America, and Australia) and Asia on the one hand and Europe and the Middle East on the other hand.

Long-term experience with rituximab therapy for treatment-resistant moderate-to-severe pemphigus.

BACKGROUND: Rituximab appears to be effective for treating pemphigus, although there are limited long-term data. METHODS: This retrospective single-center study evaluated patients with conventional treatment-resistant pemphigus who received rituximab during September 2010-December 2019. The first rituximab cycle was based on the rheumatoid arthritis protocol in all patients except one patient, and additional single doses (500 mg or 1000 mg) were administered after clinical and/or serological relapse. The consensus definitions were used for complete remission off therapy, complete remission on minimal therapy, and clinical relapse. Serological relapse was defined as a progressive ≥2-fold increase in anti-desmoglein titers (vs. previous the measurement). RESULTS: The study included 52 patients with pemphigus vulgaris and 1 patient with pemphigus foliaceus. The mean number of infusions was 5 and the average follow-up after the first infusion was 56 months. The average time to clinical and/or serological relapse was 12 months. Complete remission was achieved in 84.9% of patients, including after the first rituximab cycle in 25 patients (47.1%). Two patients died during the follow-up period. CONCLUSION: Additional rituximab cycles may help achieve and prolong remission in patients with moderate-to-severe pemphigus resistant to conventional therapies. However, prospective trials are needed to identify the optimal dosing protocol.

A multicentre prospective analysis of the incidence of pemphigoid diseases in Turkey.

BACKGROUND: The differentiation between the pemphigoid diseases is essential for treatment and prognosis. In Turkey, data on the incidence of these diseases are insufficient. Our aim in this study is to determine the incidence, demographics and clinical characteristics associated with diseases of the pemphigoid group. METHODS: We prospectively analysed 295 patients with pemphigoid who visited dermatology clinics of tertiary referral hospitals in 12 different regions of Turkey within a year. The diagnosis was based on clinical, histopathological, direct immunofluorescence (DIF) and serological (multivariant enzyme-linked immunosorbent assay [ELISA], indirect immunofluorescence and mosaic-based BIOCHIP) examinations. Clinical and demographic findings, aetiological factors and concomitant diseases observed in the patients were recorded. RESULTS: A total of 295 (female/male ratio: 1.7/1) patients with pemphigoid were diagnosed in 1-year period. The overall incidence rate of pemphigoid diseases was found to be 3.55 cases per million-years. The ratio of pemphigoid group diseases to pemphigus group diseases was 1.6. The most common pemphigoid type was bullous pemphigoid (BP, 93.2%). The others were epidermolysis bullosa acquisita (3.1%), pemphigoid gestationis (2.4%), linear IgA disease (1%) and mucous membrane pemphigoid (0.3%). The most common (26.8%) possible trigger of the bullous pemphigoid was gliptin derivative drugs. The most common concomitant diseases with pemphigoid were cardiovascular (27.8%) and neurological diseases (23.7%). CONCLUSIONS: This study showed that the increased frequency of bullous pemphigoid reversed the pemphigoid/pemphigus ratio in Turkey. Further studies are warranted regarding the reasons for this increase.

Cutaneous leishmaniasis: A great imitator.

Cutaneous leishmaniasis (CL) is called "the great imitator," because it can mimic almost all types of dermatoses. This similarity may sometimes lead to misdiagnosis, resulting in inappropriate treatment and morbidities. Atypical forms occur due to the interaction between parasitic factors and the host immune response. Secondary infection or mistreatment of CL can also alter the natural course, resulting in bizarre and misdiagnosed cases. Atypical leishmaniasis should be considered in longstanding and painless lesions that may simulate erysipelas, dermatitis, verruca, herpes zoster, paronychia, and sporotrichosis. Less commonly, sarcoidosis, deep mycosis, basal and squamous cell carcinoma, cutaneous lymphoma, or pseudolymphomalike lesions may need to be considered in the differential diagnosis. A high index of suspicion is required to consider a diagnosis of CL, especially in nonendemic or newly endemic regions. Smear, histopathologic examination, culture, and polymerase chain reaction serve as important tools to differentiate CL from its clinical and histologic look-alikes. CL is discussed from various perspectives, with emphasis on CL and its broad differential diagnosis.

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.

Multicenter prospective study on multivariant diagnostics of autoimmune bullous dermatoses using the BIOCHIP technology.

BACKGROUND: The current standard in the serologic diagnosis of autoimmune bullous diseases (AIBD) is a multistep procedure sequentially applying different assays. In contrast, the BIOCHIP Mosaic technology combines multiple substrates for parallel analysis by indirect immunofluorescence. METHODS: Sera from 749 consecutive, prospectively recruited patients with direct immunofluorescence-positive AIBD from 13 international study centers were analyzed independently and blinded by using (1) a BIOCHIP Mosaic including primate esophagus, salt-split skin, rat bladder, monkey liver, monkey liver with serosa, recombinant BP180 NC16A, and gliadin GAF3X, as well as HEK293 cells expressing recombinant desmoglein 1, desmoglein 3, type VII collagen, and BP230 C-terminus and (2) the conventional multistep approach of the Department of Dermatology, University of Lübeck. RESULTS: In 731 of 749 sera (97.6%), specific autoantibodies could be detected with the BIOCHIP Mosaic, similar to the conventional procedure (725 cases, 96.8%). The Cohen κ for both serologic approaches ranged from 0.84 to 1.00. In 6.5% of sera, differences between the 2 approaches occurred and were mainly attributed to autoantigen fragments not present on the BIOCHIP Mosaic. LIMITATIONS: Laminin 332 and laminin γ1 are not represented on the BIOCHIP Mosaic. CONCLUSIONS: The BIOCHIP Mosaic is a standardized time- and serum-saving approach that further facilitates the serologic diagnosis of AIBD.

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.

Cutaneous leishmaniasis: A neglected disfiguring disease for women.

Leishmaniasis is one of eight neglected tropical diseases currently endemic in 102 countries/areas around the world. In recent years, cutaneous leishmaniasis (CL) has been increasingly observed among migrants, travelers, ecotourists, and military personnel. Because of its great capacity to mimic other dermatoses, CL is one of the great imitators and can mislead practitioners, which can result in untreated lesions that cause scars. CL is a disfiguring disease, especially for women, and often leaves scars on visible body sites, causing psychological, social, and economic problems. CS is a challenge, especially in nonendemic regions, such as Australia, because experience with diagnosis and management of the disease is limited.

Rituximab therapy in pediatric pemphigus patients: A retrospective analysis of five Turkish patients and review of the literature.

BACKGROUND/OBJECTIVES: There is inadequate knowledge regarding rituximab (RTX) administration in autoimmune bullous diseases (AIBDs), disease prevalence, clinical characteristics, and treatment outcomes within pediatric populations due to the rarity of AIBDs affecting the pediatric age group. The aim of this retrospective analysis was to evaluate the effectiveness, safety of RTX, and treatment outcomes in Turkish pediatric patients with pemphigus vulgaris (PV) and to review the literature. METHODS: Five patients under 18 years of age and diagnosed with PV received RTX treatment and were identified in four dermatology departments of Turkey. RESULTS: The mean age of the patients at the time of RTX therapy initiation was 15 years (range: 11-17 years), and the total duration of follow-up after RTX therapy was 42.6 months (range: 19-60 months). All patients showed a clinical response. At the last visit, complete remission off therapy was achieved in three patients. The remaining two patients achieved partial remission off therapy. No adverse events were observed. CONCLUSIONS: This retrospective case series of five pediatric patients showed that RTX treatment can be effective and safe for the treatment of recalcitrant PV in pediatric patients. With increasing evidence, RTX is a good treatment choice in adults and pediatric patients with pemphigus.

Effectiveness of clinical pathway for upper respiratory tract infections in emergency department.

OBJECTIVE: We aimed to demonstrate the benefits of implementing a clinical pathway to decrease the inappropriate use of antibiotics in upper respiratory tract infections (URTI) in an emergency department (ED). METHODS: The study was performed in a hospital with 300 beds. All patients who applied with URTI from 1st to 30th of April 2017 were included and the appropriateness of the antibiotics were compared with the patients in the same period in 2016. A checklist for the clinical pathway of URTI was completed by the ED physicians. RESULTS: 351 patients were included, 176 these patients were in pre-ASP period and 175 patients were in post-ASP period. The rate of prescriptions including antibiotics was 49% in pre-ASP period and has decreased to 29% in post-ASP period (p < 0.001). Adherence to clinical pathway has increased from 50% to 80% (p < 0.001). In the post-ASP period, clinical pathway was used in 133 out of 175 patients (76%) and the consequently rate of appropriate antibiotic use was 82%. CONCLUSION: The implementation of clinical pathway for URTI has decreased inappropriate antibiotic use in ED. As the secondary effect, using clinical pathway in ED also has increased the awareness of ED physicians who did not adhere to clinical pathway.

The current clinical and geographical situation of cutaneous leishmaniasis based on species identification in Turkey.

Leishmaniases are a group of vector-borne diseases caused by the members of Leishmania genus, and there are three main clinical forms of the infection as visceral, cutaneous, and mucocutaneous. Cutaneous leishmaniasis is a growing public health problem in Turkey due to increasing detection of autochthonous cases caused by L. major and L. donovani in some regions in addition to Syrian imported cases. For this reason, we aimed to evaluate the current epidemiological situation of CL in the view of causative agents and their geographical distribution throughout Turkey. The samples were collected from 356 CL patients admitted to different centers in 18 provinces between January 2013 and December 2016. Direct microscopy, culture (regular and enriched NNN) and molecular techniques (real-time ITS1 PCR and hsp70 PCR/sequencing) were performed. By molecular techniques, 299, 28, 19 and 10 isolates/clinical samples were identified as L. tropica, L. major, L. infantum and L. donovani, respectively. Most of the patients (65.73%) had one lesion usually on their face/head. Dry-nodular type lesions (n = 291) were mainly associated with L. tropica while L. major was mainly found related to wet-ulcerative ones. Leishmaniasis recidivans was also detected in 2.52% among 356 patients. L. tropica was detected as most widespread species causing CL in Turkey. L. infantum and L. major was also found in one third of the provinces. Enriched NNN culture was worked well for isolating the parasite and 346 isolates were successfully grown and stored in liquid nitrogen. The comparison of all diagnostic techniques showed that the parasitological positivity rate could increase if the combination of direct microscopy and real-time ITS1 PCR is used. Besides well-known anthroponotic L. tropica cases, the increasing detection of CL cases caused by zoonotic species, L. infantum and L. major, is one of the most important findings in the present study. In our opinion to ensure timely and accurate diagnosis, proper treatment and countrywide effective control of CL in Turkey a systematic approach is needed on the base of information about characteristics of lesions and patients and epidemiological features of the disease.