Efficacy and safety of adjuvant immunoadsorption in pemphigus vulgaris and pemphigus foliaceus (IA-Pem Study): a multicentre randomized controlled trial.

BACKGROUND: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially life-threatening autoimmune blistering diseases. Treatment is based on long-term immunosuppression with high doses of glucocorticosteroids in combination with potentially corticosteroid-sparing agents and/or rituximab. Immunoadsorption (IA) has emerged as a fast-acting adjuvant treatment option. OBJECTIVES: To assess the clinical efficacy of IA in addition to best medical treatment (BMT). METHODS: We conducted a multicentre (26 centres from Germany and Austria) randomized controlled trial in 72 patients with newly diagnosed, relapsed or chronic active PV or PF (34 female patients and 38 male patients, aged 42-72 years) comparing BMT (prednisolone 1.0 mg kg-1 per day plus azathioprine or mycophenolate) with adjuvant IA (BMT + IA). Central 1 : 1 randomization was done at the coordinating centre for clinical trials (KKS Marburg). The primary endpoint was analysed using Kaplan-Meier and Cox regression methods. RESULTS: The study was ended prematurely owing to safety concerns after random allocation of 72 patients to BMT + IA (n = 34) or BMT (n = 38). The primary endpoint, time to complete remission on therapy, was not significantly different for the two groups [hazard ratio (HR) 1.35, 95% confidence interval (CI) 0.68-2.69; P = 0.39]. The cumulative dose of prednisolone was significantly lower in the BMT + IA group compared with BMT alone (difference -1214, 95% CI -2225 to -70; P = 0.03). In a post hoc analysis, patients with more extensive PV/PF showed a tendency towards a shorter time to remission in the BMT + IA group compared with the BMT group (HR 1.87, P = 0.17 in patients with baseline Pemphigus Disease Area Index ≥ 15). While more adverse events were observed in patients in the BMT group (29 vs. 25), severe adverse events were more frequent in patients in the BMT + IA group (17 events in 10 patients vs. 11 events in 8 patients). CONCLUSIONS: In this study, adjuvant IA did not demonstrate a shorter time to clinical remission, but a corticosteroid-sparing effect was observed. In patients with extensive PV/PF, post hoc analysis suggests that adjuvant IA may lead to earlier remission, but potential adverse events must be carefully weighed against the expected benefits.

Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoantibody-driven blistering diseases, which present with erosions or blisters on skin and/or mucous membranes. Treatment is based on long-term immunosuppressive agents. Immunoadsorption (IA) is a procedure that removes autoantibodies from the blood and has emerged as a fast-acting treatment option for pemphigus.We conducted a trial comparing best medical treatment (BMT) (prednisolone 1.0 mg kg per day plus azathioprine or mycophenolate) with best medical treatment plus IA (BMT + IA). A total of 26 centres from Germany and Austria recruited 72 patients with active pemphigus (34 women and 38 men, aged 42­72 years) who were randomly allocated in a ratio of 1 : 1 to the treatment groups.Following inclusion of 72 patients in the BMT + IA (n = 34) or BMT (n = 38) groups, the study ended prematurely owing to safety concerns. The main outcome, time to complete remission (relief of all symptoms) while still receiving therapy, was not significantly different for the two groups. In contrast, the cumulative dose of prednisolone was significantly lower in the BMT + IA compared with BMT alone. In an additional analysis, patients with more extensive pemphigus showed a tendency towards a shorter time to remission in the BMT + IA group compared with the BMT group. While more adverse events were observed in the BMT group (29 vs. 25), severe adverse events were more frequent in the BMT + IA group (17 vs. 11). In this study, IA did not show a shorter time to clinical remission, but a prednisolone-sparing effect was observed. In patients with extensive pemphigus, adjuvant IA may possibly lead to earlier remission, but potential adverse events must be carefully weighed against the expected benefits.

The gut microbiome in bullous pemphigoid: implications of the gut-skin axis for disease susceptibility.

Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects the elderly. An altered skin microbiota in BP was recently revealed. Accumulating evidence points toward a link between the gut microbiota and skin diseases; however, the gut microbiota composition of BP patients remains largely underexplored, with only one pilot study to date, with a very limited sample size and no functional profiling of gut microbiota. To thoroughly investigate the composition and function of the gut microbiota in BP patients, and explore possible links between skin conditions and gut microbiota, we here investigated the gut microbiota of 66 patients (81.8% firstly diagnosed) suffering from BP and 66 age-, sex-, and study center-matched controls (CL) with non-inflammatory skin diseases (132 total participants), using 16S rRNA gene and shotgun sequencing data. Decreased alpha-diversity and an overall altered gut microbial community is observed in BP patients. Similar trends are observed in subclassifications of BP patients, including first diagnoses and relapsed cases. Furthermore, we observe a set of BP disease-associated gut microbial features, including reduced Faecalibacterium prausnitzii and greater abundance of pathways related to gamma-aminobutyric acid (GABA) metabolism in BP patients. Interestingly, F. prausnitzii is a well-known microbiomarker of inflammatory diseases, which has been reported to be reduced in the gut microbiome of atopic dermatitis and psoriasis patients. Moreover, GABA plays multiple roles in maintaining skin health, including the inhibition of itching by acting as a neurotransmitter, attenuating skin lesions by balancing Th1 and Th2 levels, and maintaining skin elasticity by increasing the expression of type I collagen. These findings thus suggest that gut microbiota alterations present in BP may play a role in the disease, and certain key microbes and functions may contribute to the link between gut dysbiosis and BP disease activity. Further studies to investigate the underlying mechanisms of the gut-skin interaction are thus clearly warranted, which could aid in the development of potential therapeutic interventions.

Comorbidity in bullous pemphigoid: up-date and clinical implications.

Bullous pemphigoid is the most common autoimmune blistering disease in industrialized countries and particularly affects the elderly. In this patient population, comorbid diseases are frequent and may complicate management and treatment of bullous pemphigoid. A better understanding why distinct diseases are more frequent in bullous pemphigoid patients may lead to new pathophysiological insights and - as a consequence - result in better patient care. The association of bullous pemphigoid with neurological and psychiatric diseases is well known and confirmed by several case-control studies. Association with further diseases such as malignancy and metabolic diseases are still discussed controversially. In recent years new relationships between bullous pemphigoid and autoimmune as well as inflammatory skin diseases have been reported. This review provides a systematic overview on studies addressing comorbidity in bullous pemphigoid patients. Increasing the awareness of both, common and rare comorbid diseases, may enable clinicians to optimize patient support and individualized treatment of bullous pemphigoid.

Characterization of the skin microbiota in bullous pemphigoid patients and controls reveals novel microbial indicators of disease.

INTRODUCTION: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. It predominately afflicts the elderly and is significantly associated with increased mortality. The observation of age-dependent changes in the skin microbiota as well as its involvement in other inflammatory skin disorders suggests that skin microbiota may play a role in the emergence of BP blistering. We hypothesize that changes in microbial diversity associated with BP might occur before the emergence of disease lesions, and thus could represent an early indicator of blistering risk. OBJECTIVES: The present study aims to investigate potential relationships between skin microbiota and BP and elaborate on important changes in microbial diversity associated with blistering in BP. METHODS: The study consisted of an extensive sampling effort of the skin microbiota in patients with BP and age- and sex-matched controls to analyze whether intra-individual, body site, and/or geographical variation correlate with changes in skin microbial composition in BP and/or blistering status. RESULTS: We find significant differences in the skin microbiota of patients with BP compared to that of controls, and moreover that disease status rather than skin biogeography (body site) governs skin microbiota composition in patients with BP. Our data reveal a discernible transition between normal skin and the skin surrounding BP lesions, which is characterized by a loss of protective microbiota and an increase in sequences matching Staphylococcus aureus, a known inflammation-promoting species. Notably, Staphylococcus aureus is ubiquitously associated with BP disease status, regardless of the presence of blisters. CONCLUSION: The present study suggests Staphylococcus aureus may be a key taxon associated with BP disease status. Importantly, we however find contrasting patterns in the relative abundances of Staphylococcus hominis and Staphylococcus aureus reliably discriminate between patients with BP and matched controls. This may serve as valuable information for assessing blistering risk and treatment outcomes in a clinical setting.

Comorbid diseases among bullous pemphigoid patients in Germany: new insights from a case-control study.

BACKGROUND AND OBJECTIVES: Bullous pemphigoid (BP) is associated with neuropsychiatric disorders. Other comorbid diseases are discussed controversially. We evaluated the prevalence of comorbidity in BP patients in a representative area of Germany. PATIENTS AND METHODS: Medical files of all BP patients treated at the Department of Dermatology, University Hospital Würzburg, Germany, between June 2002 and May 2013 were retrospectively reviewed. Bullous pemphigoid was diagnosed based on established criteria. For each patient, two controls were individually matched. Records were evaluated for age, sex, laboratory values, concomitant medication and comorbidity. Conditional logistic regression, multivariable regression analysis and complex regression models were performed to compare results. RESULTS: 300 BP patients were identified and compared to 583 controls. Bullous pemphigoid was associated with neuropsychiatric disorders as well as laboratory abnormalities including leukocytosis and eosinophilia. Importantly, a highly significant association of BP with anemia (OR 2.127; 95 % CI 1.532-2.953) and renal impairment (OR 2.218; 95 % CI 1.643-2.993) was identified. No association was found with malignancy and arterial hypertension. CONCLUSIONS: Our data revealed an increased frequency of anemia and renal impairment in BP patients. In accordance with previous studies the strong association for neuropsychiatric disorders was confirmed (p < 0.0005).

Shared meditation involving cancer patients, health professionals and third persons is relevant and improves well-being: IMPLIC pilot study.

BACKGROUND: Alleviating suffering and improving quality of life are universally shared goals. In this context, we implemented a pilot study to assess the feasibility and acceptability of a mindfulness intervention in the form of meditation involving together cancer patients, health professionals, and third persons. METHODS: Two groups of 15 participants equally composed of patients, health professionals and third persons were constituted. A dedicated programme on mindfulness and compassion was constructed, including 12 weekly sessions of 1.5 h and a half-day retreat. Adherence and satisfaction with the programme were evaluated. All participants completed questionnaires on perceived stress, quality of life, mindfulness, empathy, and self-efficacy. Burnout was assessed in health professionals. RESULTS: Shared meditation was feasible as 70% of participants attended ≥ 80% of the 13 meditation sessions. Satisfaction with the programme was high (median satisfaction score: 9.1 out of 10) and all participants expressed positive attitudes towards shared meditation and a benefit on their global quality of life. Participants reported significant improvement in stress (p < 0.001), global quality of life (p = 0.004), self-efficacy (p < 0.001), and mindfulness skills (p < 0.001) from baseline to post-programme. CONCLUSIONS: This study demonstrated the feasibility of a shared dedicated meditation programme in terms of participation and acceptability of participants. The measured benefits observed among participants furthermore justify the interest of a subsequent randomized study aiming to demonstrate the potential added value of shared meditation by promoting bridge-building between cancer patients, health professionals and others. TRIAL REGISTRATION: ClinicalTrials.gov. NCT04410185 . Registered on June 1, 2020.

Meditation involving people with cancer, medical staff and witnesses: a pilot study exploring improvement in wellness and connectedness.

INTRODUCTION: Mindfulness meditation is likely to promote better management of stress, pain and negative emotions. We propose to address the benefit of meditation in an open setting associating people with cancer (target population), medical staff and witnesses (neither patient nor medical staff). This study aims (1) to evaluate the effects of meditation on wellness improvement and (2) to identify criteria and modalities for a subsequent randomised study. METHODS AND ANALYSIS: We propose a longitudinal pilot study consisting of a non-randomised experimental preintervention/postintervention survey. The intervention consists in delivering a meditation programme (12 weekly meditation sessions of 1.5 hours each), specifically adapted to our target population and addressing our research hypothesis in an open setting involving people with cancer, medical staff and witnesses (equally distributed in two groups of 15 participants). The main objective is to evaluate participants' adherence to the programme. The effects of meditation will be evaluated on stress, quality of life, feeling of personal effectiveness, on the development of mindfulness and empathy, and on satisfaction and perception of a change in quality of life. We will also measure the putative added value of 'meditating together'. This study is expected to allow validating the evaluation tools and refining the modalities of the workshops. We expect to demonstrate the evolution that this meditation-based intervention induces in the participants. We aim to promote bridge-building, between patients, medical staff but also others. In this way, one's own suffering may be understood in the light of others' suffering, thereby promoting the sense of otherness and giving insights into 'living better with'. This exploratory study will investigate the relevance of this hypothesis, which could then be explored by a randomised study. ETHICS AND DISSEMINATION: The protocol was approved by the local ethics committee (Comité de Protection des Personnes Est II). Trial findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04410185.

Identification of two novel bullous pemphigoid- associated alleles, HLA-DQA1*05:05 and -DRB1*07:01, in Germans.

Bullous pemphigoid (BP) is the most common autoimmune skin blistering disease characterized by autoimmunity against the hemidesmosomal proteins BP180, type XVII collagen, and BP230. To elucidate the genetic basis of susceptibility to BP, we performed the first genome-wide association study (GWAS) in Germans. This GWAS was combined with HLA locus targeted sequencing in an additional independent BP cohort. The strongest association with BP in Germans tested in this study was observed in the two HLA loci, HLA-DQA1*05:05 and HLA-DRB1*07:01. Further studies with increased sample sizes and complex studies integrating multiple pathogenic drivers will be conducted.

Neutropenia resulting from high-dose intravenous immunoglobulin in dermatological patients.

BACKGROUND AND OBJECTIVES: Current guidelines recommend high-dose intravenous immunoglobulin (IVIG) as a rescue therapy to treat severe cutaneous autoimmune disorders. Data on IVIG-induced hematological adverse events are limited in dermatological patients. We assessed the incidence and clinical implications of IVIG-induced neutropenia. PATIENTS AND METHODS: Patients who received one or several cycles of IVIG between 2014 and 2019 were retrospectively evaluated. IVIG was given according to standardized infusion protocols. Daily differential blood counts were performed. Information on clinical baseline data, dermatological diagnosis, immunosuppressive pre-treatment, and IVIG-related adverse events was retrieved from patient files. RESULTS: Seventeen patients received 106 IVIG treatment cycles. Neutrophil counts below 1,500/µL were documented during 36 (34.0 %) cycles, and neutrophils fell below 1,000/µL in 14 (13.2 %) cases. The average drop of neutrophils from day one (pre-dose) to days 2 and 3 of IVIG therapy was statistically significant (p = 0.006, and p = 0.002, respectively) despite correction for hemodilution, and so was a slight decrease of thrombocytes (p = 0.029, and p = 0.011, respectively). Four patients developed seven episodes of bacterial infections during or immediately after IVIG therapy. CONCLUSIONS: IVIG-induced neutropenia is frequent in dermatological patients. A risk of secondary bacterial infections cannot be excluded.

Memory CD4+ T cells lacking expression of CCR7 promote pro-inflammatory cytokine production in patients with diffuse cutaneous systemic sclerosis.

Systemic sclerosis (SSc) is a predominantly T-cell-mediated autoimmune disorder with a characteristic sequence of Th1 and Th2 inflammation resulting in fibrosis. The contribution of differentiated memory T-cell subpopulations and methylation of CpG regions of Th1- or Th2-specific transcription factor genes on the inflammatory cytokine signature in SSc is not well understood. The study aimed to investigate phenotypic differentiation, the cytokine signature, sensitivity of memory T cells to in vitro suppression by autologous regulatory T cells (Tregs), and methylation of Th1- and Th2-specific transcription factor genes in patients with limited (lcSSc) and diffuse cutaneous SSc (dcSSc) compared to healthy donors (HD). Phenotype/intracellular cytokine production and methylation of Th1- and Th2-specific transcription factor genes were determined by flow cytometry and epigenetic analysis, respectively, and compared between patients with lcSSc, dcSSc and HD. Discrimination of CD4+ T cells that lack CCR7 expression revealed that CCR7- CD4+ memory T cells and effectors are producers of intracellular TNFα, IL-13 and IL-4, particularly in dcSSc. A proportional increase in CCR7- memory T cells was demonstrated by SSc-derived CD4+ T-cells after insufficient suppression by Tregs. A higher level of methylation of GATA3 or STAT4 (Th2- and Th1-specific transcription factor genes, respectively) was observed in dcSSc. An abundance of specific CD4+ memory T-cell subpopulations strongly contributes to the production of pro-inflammatory cytokines in dcSSc. Our results suggest that therapeutic concepts should focus more intensively on the memory phenotype to control T cell-mediated inflammation in SSc patients.

Polymorphisms in the Mitochondrial Genome Are Associated With Bullous Pemphigoid in Germans.

Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230. Most intriguingly, BP is distinct from other autoimmune diseases because it predominantly affects elderly individuals above the age of 75 years, raising the question why autoantibodies and the clinical lesions of BP emerges mostly in this later stage of life, even in individuals harboring known putative BP-associated germline gene variants. The mitochondrial genome (mtDNA) is a potential candidate to provide additional insights into the BP etiology; however, the mtDNA has not been extensively explored to date. Therefore, we sequenced the whole mtDNA of German BP patients (n = 180) and age- and sex-matched healthy controls (n = 188) using next generation sequencing (NGS) technology, followed by the replication study using Sanger sequencing of an additional independent BP (n = 89) and control cohort (n = 104). While the BP and control groups showed comparable mitochondrial haplogroup distributions, the haplogroup T exhibited a tendency of higher frequency in BP patients suffering from neurodegenerative diseases (ND) compared to BP patients without ND (50%; 3 in 6 BP with haplogroup T). A total of four single nucleotide polymorphisms (SNPs) in the mtDNA, namely, m.16263T>C, m.16051A>G, and m.16162A>G in the D-loop region of the mtDNA, and m.11914G>A in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 gene (MT-ND4), were found to be significantly associated with BP based on the meta-analysis of our NGS data and the Sanger sequencing data (p = 0.0017, p = 0.0129, p = 0.0076, and p = 0.0132, respectively, Peto's test). More specifically, the three SNPs in the D-loop region were negatively, and the SNP in the MT-ND4 gene was positively associated with BP. Our study is the first to interrogate the whole mtDNA in BP patients and controls and to implicate multiple novel mtDNA variants in disease susceptibility. Studies using larger cohorts and more diverse populations are warranted to explore the functional consequences of the mtDNA variants identified in this study on immune and skin cells to understand their contributions to BP pathology.

The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris-Analysis of Four Different Ethnic Cohorts.

IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variation with PV risk, but not with BP risk. Our results suggest a hitherto unknown role for the function of IgG3 in the pathogenesis of PV.