Netherton syndrome-A therapeutic challenge in childhood.

Key Clinical Message: High-dose intravenous immunoglobulin exhibits great potential in the treatment of Netherton syndrome. Abstract: Netherton syndrome (NS) is a rare autosomal recessive genodermatosis (OMIM #256500) characterized by superficial scaling, atopic manifestations, and multisystemic complications. It is caused by loss-of-function mutations in the SPINK5 gene, which encode a key kallikrein protease inhibitor. There are two subtypes of the syndrome that differ in clinical presentation and immune profile: ichthyosiform erythroderma and ichthyosis linearis circumflexa. NS is a multisystemic disease with numerous extracutaneous manifestations. Current therapy for patients with NS is mainly supportive, as there is no curative or specific treatment, especially for children with NS, but targeted therapies are being developed. We describe an 8-year-old boy with genetically proven NS treated with intravenous immunoglobulin for recurrent skin and systemic infections from infancy, growth retardation, and associated erythroderma. Under this therapy, his skin status, infectious exacerbations, and quality of life all improved. Knowledge of the cytokine-mediated pathogenesis of NS and the development of new biologic drugs open new possibilities for NS patients. However, the different therapeutic options have been applied in a limited number of cases, and variable responses have been shown. Randomized controlled trials with a sufficient number of patients stratified and treated according to their specific immune profile and clinical phenotype are needed to evaluate the safety and efficacy of treatment options for patients with NS.

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 (BTK) inhibitor rilzabrutinib demonstrated rapid and sustained efficacy with well-tolerated safety. METHODS: Adults (18-80 y) were randomized 1:1 to rilzabrutinib 400 mg (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/foliaceus (PV/PF). RESULTS: The primary endpoint of complete remission (CR) from week 29-37 with the amended endpoint CS dose ≤10 mg/d was not significant for 13/54 (24%) rilzabrutinib vs. 10/55 (18%) placebo patients with PV (P=0.45). Secondary endpoints showed numerical, but non-significant, improvements with rilzabrutinib (vs. placebo) in reduced CS use, prolonged CR duration, and faster time to first CR. 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 BTK 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 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.

Serum reactivity in dermatitis herpetiformis: an international multicentre study.

BACKGROUND: Dermatitis herpetiformis (DH) is a rare gluten-induced skin disorder characterized predominantly by IgA autoantibodies against endomysium, tissue transglutaminase (TG2/tTG), epidermal transglutaminase (TG3/eTG) and deamidated gliadin. To date, circulating autoantibody reactivity has not been systematically described. OBJECTIVES: Characterization of serum reactivities in DH. METHODS: This multicentre international study analysed sera from 242 patients with DH taken at the time of initial diagnosis. DH-specific IgA and IgG serum autoantibodies were analysed by indirect immunofluorescence (IF) on monkey oesophagus, and by enzyme-linked immunosorbent assay (ELISA) based on recombinant TG2/tTG, TG3/eTG and deamidated gliadin (GAF3X). RESULTS: IgA indirect IF microscopy on monkey oesophagus revealed the highest reactivity (84.3%; specificity 100%) followed by IgA TG2/tTG ELISA (78.5%, specificity 99.0%), IgA TG3/eTG ELISA (72.7%, specificity 95.0%) and IgA GAF3X ELISA (69.0%, specificity 98.5%). CONCLUSIONS: Serum IgA and IgG autoantibodies against endomysium, TG2/tTG, TG3/eTG and deamidated gliadin are highly prevalent in DH. Indirect IF microscopy on monkey oesophagus (IgA) provides the highest diagnostic accuracy that can be further enhanced by 4.5% when combined with IgA TG2/tTG ELISA.

Rosacea: The eyes have it.

Rosacea is a chronic inflammatory dermatosis typically affecting the facial skin but also the eyes. With its chronic course with fluctuating episodes of flashing, redness, papulopustules, and nodules it poses a severe psychologic burden to the affected individuals. In addition to the facial changes, more than half of the patients have ocular involvement ranging from blepharitis and conjunctival hyperemia to more severe ophthalmic damage, and even blindness. Clinically, the ocular involvement in rosacea includes meibomian gland dysfunction with relapsing hordeola and chalazia, diffuse hyperemic conjunctivitis, photophobia, episcleritis, or kerato-conjunctivitis, and in rare cases, corneal ulcers. These are mainly observed in adult patients but can also occur in children. Depending on the degree of cutaneous or ocular findings, patients with rosacea may present first to the dermatologist or to the ophthalmologist. Both specialists should be aware of the potential oculocutaneous involvement. Any ocular complaints expressed by the patient in the setting of a dermatologist's office should be referred promptly for an ophthalmologic examination. Conversely, signs suggestive of rosacea in the eye should lead the ophthalmologist to consider underlying skin disease. A timely interdisciplinary collaboration is paramount for the earlier diagnosis and treatment, thus preventing permanent eye impairment in this chronic dermatosis.

Case Report: Coexistence of bullous pemphigoid and psoriasis: Therapeutic challenge and IL17A-targeted parallel treatment strategy.

Autoimmune blistering diseases of the skin have all been reported in patients with psoriasis, bullous pemphigoid (BP) being the most frequently observed. The pathophysiologic triggers for BP in psoriatic patients are unclear. Recent observational studies have suggested that chronic psoriatic inflammation may cause pathological changes to the basement membrane zone, thus inducing autoimmunity against BP antigens through cross reactivity and "epitope spreading." The coexistence of BP and psoriasis poses challenging therapeutic dilemmas related to the incompatibility of their standard treatments. Considering the probable common immunologic mechanisms in the pathogenesis of these inflammatory skin disorders, a suitable treatment regimen should be applied for their parallel control. We report three patients, who developed BP in the course of preceding long-lasting psoriasis. Secukinumab was administered as first-line treatment with promising therapeutic effect for both skin disorders and long-term disease control in two of the cases. In the third case, parallel disease control was initially achieved with methotrexate. A few years later, secukinumab was used for the treatment of a relapse of both dermatoses but worsening of BP was observed and methotrexate was reintroduced. Our experience on the therapeutic potential of secukinumab in BP is supported by the data in the literature. Recently, it was demonstrated that the proinflammatory cytokine IL17A has a functional role in the process of skin inflammation in BP, similarly to psoriasis. IL17A inhibition has emerged as a promising therapeutic strategy in patients with extensive or refractory BP but paradoxical development of BP after secukinumab treatment for psoriasis has also been described. This controversy emphasizes the need for further investigation into the development of optimal treatment strategies and recommendations.

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.

Efficacy and Safety of 1% Clascoterone Cream in Patients Aged > 12 Years With Acne Vulgaris.

BACKGROUND: Two randomized phase 3 studies evaluated efficacy and safety of 1% clascoterone cream, a topical androgen receptor inhibitor, in patients aged ≥9 years with moderate-to-severe facial acne vulgaris after 12 weeks of treatment. OBJECTIVES: To present a pooled data analysis of the efficacy and safety of 1% clascoterone cream after 12 weeks of treatment in patients aged ≥12 years from the 2 phase 3 trials. METHODS: Patients were randomized 1:1 to twice-daily treatment of the whole face with clascoterone or vehicle. Primary efficacy outcomes were proportion of patients achieving treatment success (Investigator Global Assessment score of "clear" [0] or "almost clear" [1] with ≥2-point reduction from baseline) and absolute change from baseline (CFB) in noninflammatory lesion count and inflammatory lesion count; secondary efficacy outcomes included absolute CFB in total lesion count at week 12. Safety was assessed from treatment-emergent adverse events and local skin reactions. RESULTS: 709/712 patients age ≥12 years were treated with clascoterone/vehicle. After 12 weeks, clascoterone was efficacious compared with vehicle, based on proportion of patients achieving treatment success (19.9% vs 7.7%) and CFB in noninflammatory lesion count (-20.8 vs -11.9), inflammatory lesion count (-19.7 vs -14.0), and total lesion count (-40.0 vs -26.1; all P<0.0001). Frequencies of local skin reactions were low and similar between treatment arms, with no new safety signals. CONCLUSIONS: Clascoterone is efficacious, with a favorable safety profile and low rates of local skin reactions in patients ≥12 years of age with facial acne vulgaris. (Clinicaltrials.gov NCT02608450 and NCT02608476) J Drugs Dermatol. 2023;22(2): doi:10.36849/JDD.7000.

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.

Differences among Indian and European pemphigus patients based on demographics, clinical parameters and propensity for relapse: results of a prospective bicontinental cohort study.

Limited studies have explored pemphigus variations among different ethnic groups residing in their respective geographical locations. This bicontinental study aimed to compare clinical and immunological parameters in Indian and European pemphigus patients in complete remission, off therapy, or on minimal therapy. 105 patients (India, n= 75; Bulgaria, n=15; Greece, n=15) with pemphigus vulgaris (PV) or pemphigus foliaceous (PF) in complete remission on minimal therapy (n=64) or complete remission off therapy (n=41) were recruited. Demographic, clinical, and immunological parameters were compared. Indian patients were significantly younger, the maximal disease severity during the preceding active disease phase was significantly lower, and treatment duration until complete remission was significantly shorter, compared to European patients. European patients had significantly higher anti-Dsg3 serum levels and higher IgG positivity rate based on direct immunofluorescence microscopy at baseline. Furthermore, European patients revealed higher CD19, CD19+ CD27+ cell counts, compared with patients from India. Of note, none of the European patients (n=30) relapsed within the study period, in contrast to 29/75 (38.6%) Indian patients. Treatment strategies differed significantly between the two cohorts, with more frequent utilization of rituximab to achieve remission in the Indian cohort, while prednisolone was more widely used for maintaining remission in the European cohort. The observed heterogeneity of pemphigus among patients of different ethnicities in terms of demographics, clinical parameters, and propensity for relapse may be due to genetic background or different treatment strategies.

Clinicopathologic features among different viral epidemic outbreaks involving the skin.

The current coronavirus disease 2019 pandemic has exceeded any epidemiologic prevision, but increasing information suggests some analogies with the major viral outbreaks in the last century, and a general warning has been issued on the possibility that coinfections can make the differential diagnosis and treatment difficult, especially in tropical countries. Some reports have noted that the presence of high dengue antibodies can give a false-negative result when testing for severe acute respiratory syndrome coronavirus 2. Mucocutaneous manifestations are very frequent, with an apparent overlap among different pathogens. However, strong clinicopathologic correlation might provide some clues to address differentials. Waiting for laboratory and instrumental results, the timing and distribution of skin lesions is often pathognomonic. Histopathologic findings characterize certain reaction patterns and provide insights on pathogenetic mechanisms. Unfortunately, skin assessment, especially invasive examinations such as biopsy, takes a back seat in severely ill patients. A literature retrieval was performed to collect information from other epidemics to counteract what has become the most frightening disease of our time.

Association of specific HLA alleles and haplotypes with pemphigus vulgaris in the Bulgarian population.

Pemphigus vulgaris (PV) is an autoimmune bullous dermatosis with uneven geographic distribution and higher incidence in certain populations. In previous studies, a relatively high incidence of PV was reported in Bulgaria (0.47/100,000/year) comparable to that in other countries. The genetic background was considered responsible for the disease susceptibility, and multiple reports have proven PV to be an HLA-associated condition. The aim of our study was to analyze the role of genetic factors in the development of PV in Bulgaria. HLA genotyping was performed in 56 PV patients, ethnic Bulgarians whose diagnosis was confirmed based on clinical, histological, and immunofluorescent findings. The control group consisted of 204 healthy individuals from the Bulgarian population without evidence for HLA-associated autoimmune diseases. HLA-A,-B,-DRB1,-DQB1 analysis was performed by PCR-SSP. Our results revealed predisposing associations with DRB1*14, DRB1*04:02, and B*38, B*55, while allele DRB1*03:01 and the corresponding haplotypes were significantly decreased in the PV patients. The predisposing role of these alleles has been observed in other populations. All reported predisposing DRB1 alleles have the same amino acids at key positions of the beta chain of the HLA molecules, 26 (Phe), 67 (Leu or Ileu), 70 and 71 (hydrophobic AA: Gln, Arg, Asp, or Glu), and 86 (Val), which is important for the selective presentation of desmoglein 3 peptides. Additionally, specific alleles HLA-A*01 and DRB1*11 were identified with decreased frequencies in the patients' group, the last one being a common protective allele for autoimmune diseases in the Bulgarian population. The elucidation of the role of genetic factors for the development of pemphigus will help explain its higher incidence and clinical variability in certain populations.

Case Report: Rowell Syndrome-Like Flare of Cutaneous Lupus Erythematosus Following COVID-19 Infection.

The current COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had an important impact on dermatology practice, posing diagnostic and therapeutic challenges especially in patients with inflammatory and autoimmune skin disorders. Disease-specific and nonspecific cutaneous manifestations have been increasingly reported in the spectrum of COVID-19 but the influence of the infection on pre-existing dermatologic diseases has not been clearly defined. There has been a debate in the literature as to whether patients suffering from autoimmune dermatoses, including cutaneous lupus erythematosus (CLE), are at increased risk of SARS-CoV-2 infection, as well as if they experience worsening of their lupus erythematosus (LE)-related clinical symptoms. This article reports on a case of Rowell syndrome occurring after COVID-19 in a 67-year old woman with pre-existing chronic CLE manifesting with few discoid lesions on the face, scalp, and upper chest, successfully controlled with topical corticosteroids and photoprotection. Erythema multiforme (EM)-like eruption developed approximately two weeks after the SARS-CoV-2 infection, the latter being confirmed by positive nasopharyngeal swab and successfully treated with systemic antibiotics and antiaggregants. Diffuse hair loss and patches of cicatricial alopecia were also present upon scalp examination. Laboratory workup, including routine tests, histologic, immunofluorescent, and serologic investigations, was supportive to the diagnosis. Administration of topical and systemic corticosteroids along with peroral hydroxychloroquine resulted in the progressive improvement of the cutaneous lesions. Rowell syndrome is a rare entity in the spectrum of LE, characterized by EM-like lesions, photosensitivity, and positive antinuclear and anti-Ro antibodies, that is currently considered to be a variant of subacute CLE (SCLE). Several cases of SCLE have been described in association with medications, including anti-SARS-CoV-2 vaccines but only a few reports incriminate the infection itself as a potential exacerbating factor. Based on the clinical course of the disease, we suggest that the observed Rowell syndrome-like flare of CLE was related to the COVID-19 infection in this patient.

Impact of COVID-19 on autoimmune blistering diseases.

Since the beginning of the COVID-19 outbreak, attention has gradually moved from the respiratory manifestations of the disease toward its dermatologic aspects. The need for wearing personal protective measures and their cutaneous side effects, detection of related or specific COVID-19 skin eruptions, and the evaluation of certain risk groups of immunosuppressed dermatologic patients have initiated significant discussions about various therapeutic interventions and, in particular, about biologic therapy for psoriasis and for autoinflammatory, orphan, or malignant cutaneous disorders. Autoimmune bullous dermatoses have been of concern due to their chronic course, at times life-threatening prognosis, and the need for prolonged and often aggressive immunomodulatory therapy. We have summarized the current knowledge regarding the impact of COVID-19 infection on autoimmune bullous dermatoses, including recommendations for the main treatment strategies, available patient information, and the registries organized for documentation during the COVID-19 pandemic.

Clinicopathologic features between different viral epidemic outbreaks involving the skin.

The current coronavirus disease 2019 pandemic has exceeded any epidemiologic prevision, but increasing information suggests some analogies with the major viral outbreaks of the last century. A general warning has been issued on the possibility that coinfections can make differential diagnosis and treatment difficult, especially in tropical countries. Some reports have pointed out that the presence of high Dengue antibodies can give a false-negative result for severe acute respiratory syndrome coronavirus 2. Mucocutaneous manifestations are very frequent, with an apparent overlap among different pathogens. A strong clinicopathologic correlation, however, may provide some clues to address the differential. Waiting for laboratory and instrumental results, the timing and distribution of skin lesions is often pathognomonic. Histopathologic findings characterize certain reaction patterns and provide insights on pathogenetic mechanisms. Unfortunately, skin assessments, especially invasive exams such as biopsy, are less important in severely ill patients. A literature review was performed to collect information from other epidemics to counteract what has become the most frightening disease of our time.