Autoimmune bullous diseases during COVID-19 pandemic: 2022 update on rituximab and vaccine.

Autoimmune bullous diseases (AIBDs) are a heterogeneous group of life-threatening disorders associated with subepidermal or intraepidermal blistering. Skin barrier alterations and prolonged immunosuppressive treatments increase the risk of infections in patients with AIBDs, who are considered fragile. COVID-19 pandemic had a heavy impact on these patients. Although advances have been made in terms of prevention and treatment of COVID-19, this topic remains significant as the pandemic and its waves could last several years and, so far, a relevant proportion of the population worldwide is not vaccinated. This review is a 2022 update that summarizes and discusses the pandemic's burden on AIBD patients mainly considering relevant studies in terms of: (i) sample dimension; (ii) quality of control populations; (iii) possible standardization by age, gender and country. The findings show that: (i) the risk of COVID-19 infection and its severe course were comparable in AIBD patients and in the general population, except for rituximab-treated patients that presented a higher risk of infection and severe disease; (ii) the mortality rate in COVID-19-infected bullous pemphigoid patients was higher than in the general population, (iii) 121 cases of AIBD onset and 185 cases of relapse or exacerbation occurred after COVID-19 vaccination and a causal relationship has not been demonstrated so far. Altogether, acquired knowledge on COVID-19 pandemic could also be important in possible, albeit undesirable, future pandemic scenarios.

Pemphigus: trigger and predisposing factors.

Pemphigus is a life-threatening autoimmune blistering disease affecting skin and mucous membranes. Despite its etiopathogenesis remains largely unknown, several trigger and predisposing factors have been reported. Pemphigus is caused by autoantibodies that target desmoglein 1 and desmoglein 3, impacting desmosome function. However, circulating autoantibodies are often the consequence of a precipitating factor that occurs in predisposed individuals. This review aims to describe and discuss almost all trigger and predisposing factors reported as possible or probable cause of the disease. Among the reported trigger factors that may induce or exacerbate pemphigus, we have found of particular interest: drug intake (especially thiol- and phenol-containing compounds), vaccines, infections, as well as some reports about pregnancy, radiations, emotional stress, pesticides and physical trauma. Moreover, we discuss the possible role of food intake in pemphigus onset and particular attention is given to dietary factors containing thiol, phenol and tannin compounds. A trigger factor is "the straw that breaks the camel's back," and often acts together with predisposing factors. Here we discuss how pemphigus onset may be influenced by genetic susceptibility and comorbidities like thyroid diseases, malignancies and other autoimmune disorders. To identify other hitherto unknown trigger and predisposing factors, well designed prospective studies are needed. In this context, future research should explore their connection with the aim to advance our understanding of pemphigus pathogenesis.

Case Report: Complete and Fast Recovery From Severe COVID-19 in a Pemphigus Patient Treated With Rituximab.

COVID-19 is characterized by a severe pulmonary disease due to severe acute respiratory syndrome (SARS)-CoV-2 infection. For clinicians involved in the management of patients with chronic autoimmune diseases the risk linked to the conditions itself and to drug-induced immunosuppression during the COVID-19 pandemic is a major topic. Pemphigus is a rare autoimmune blistering disease (AIBD) of the skin and mucous membranes caused by autoantibodies to desmosomal components, desmoglein 1 and 3. Among immunosuppressant therapies, rituximab (RTX) is considered a highly effective treatment with a favorable safety profile, but it induces a prolonged B-cell depletion that can lead to higher susceptibility to infections. For this reason, concerns about its use during the pandemic have been raised. We describe a case of a pemphigus patient in which RTX-induced B cell depletion led to the severe inflammatory phase, whereas corticosteroid treatment allowed a favorable outcome.

Pemphigus vulgaris in two pairs of siblings from two unrelated Italian families: Human leukocyte antigen genotypes, ST18 mutation and immunological profile.

Pemphigus vulgaris (PV) is an autoimmune intraepithelial bullous disease. Associations with the class II human leukocyte antigen (HLA) alleles and pemphigus vulgaris have been described. Furthermore, an association between the single nucleotide polymorphism of the ST18 gene and pemphigus vulgaris has been reported. We report two pairs of siblings from two unrelated Italian families affected by pemphigus vulgaris, characterizing their genetic and immunological profile. In order to assess the genetic background, HLA-DQA1, HLA-DQB1, HLA-DRB1 and a relevant ST18 polymorphism were investigated. As for the immunological profiles, anti-desmoglein antibodies were analyzed. In family A, the two pemphigus vulgaris patients had the same HLA genetic profile: HLA-DQA1 *01:04/*03:01, HLA-DQB1 *03:02/*05:03 and HLA-DRB1 *04:02/*14:01. The male patient was heterozygous for the ST18 mutation while the female patient had a wild genotype. In family B, the two pemphigus vulgaris patients were both wild type for the ST18 mutation and showed the same HLA genotype: HLA-DQA1 *03:01/*05:08, HLA-DQB1 *03:01/*03:03 and HLA-DRB1 *04:02/*11:01. Our data show a relevant relationship between the HLA profile and pemphigus vulgaris in our Italian families. In family A, all six alleles are frequently associated with pemphigus vulgaris and were expressed only in the two pemphigus patients; and in family B, two of the six alleles are frequently associated with pemphigus vulgaris. No relevant relationship was found between ST18 polymorphism and pemphigus disease.

Bullous Pemphigoid: Trigger and Predisposing Factors.

Bullous pemphigoid (BP) is the most frequent autoimmune subepidermal blistering disease provoked by autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. Its pathogenesis depends on the interaction between predisposing factors, such as human leukocyte antigen (HLA) genes, comorbidities, aging, and trigger factors. Several trigger factors, such as drugs, thermal or electrical burns, surgical procedures, trauma, ultraviolet irradiation, radiotherapy, chemical preparations, transplants, and infections may induce or exacerbate BP disease. Identification of predisposing and trigger factors can increase the understanding of BP pathogenesis. Furthermore, an accurate anamnesis focused on the recognition of a possible trigger factor can improve prognosis by promptly removing it.

Results of a Multicenter, Randomized, Controlled Trial of a Hydrogen Peroxide-based Kit versus a Benzoyl Peroxide-based Kit in Mild-to-moderate Acne.

Objective:To evaluate the efficacy and tolerability of a novel hydrogen peroxide-based regimen versus a benzoyl peroxide-based regimen in mild-to-moderate acne. Methods: In this eight-week multicenter study, patients were randomized to either a hydrogen peroxide-based or a benzoyl peroxide-based regimen.The primary outcome measure of clinical response was assessed using the Global Acne Grading System (GAGS) at baseline,four weeks, and eight weeks. At Week 8, a patient self-satisfaction questionnaire was administered. Investigators were also queried at that time regarding assessment of tolerability and cosmetic acceptability. Tolerability was also measured at each visit. Results: Both treatment regimens were associated with improvement of GAGS score at Week 8 compared to baseline (p<0.0001). GAGS score did not differ significantly between the two regimens over the same period (p=0.7765). No significant adverse events were reported or observed in either treatment arm. Both patients and investigators found both regimens to be similarly effective and cosmetically acceptable. Conclusion: A novel hydrogen peroxide-based regimen was shown to be comparable in efficacy, safety, and cosmetic acceptability to a benzoyl peroxide-based regimen in the treatment of mild-to-moderate acne.

Use of lipidomics to investigate sebum dysfunction in juvenile acne.

Acne is a multifactorial skin disorder frequently observed during adolescence with different grades of severity. Multiple factors centering on sebum secretion are implicated in acne pathogenesis. Despite the recognized role of sebum, its compositional complexity and limited analytical approaches have hampered investigation of alterations specifically associated with acne. To examine the profiles of lipid distribution in acne sebum, 61 adolescents (29 males and 32 females) were enrolled in this study. Seventeen subjects presented no apparent clinical signs of acne. The 44 affected individuals were clinically classified as mild (13 individuals), moderate (19 individuals), and severe (12 individuals) acne. Sebum was sampled from the forehead with Sebutape(TM) adhesive patches. Profiles of neutral lipids were acquired with rapid-resolution reversed-phase/HPLC-TOF/MS in positive ion mode. Univariate and multivariate statistical analyses led to the identification of lipid species with significantly different levels between healthy and acne sebum. The majority of differentiating lipid species were diacylglycerols (DGs), followed by fatty acyls, sterols, and prenols. Overall, the data indicated an association between the clinical grading of acne and sebaceous lipid fingerprints and highlighted DGs as more abundant in sebum from adolescents affected with acne.

Mycobacterium abscessus hand-and-foot disease in children: rare or emerging disease?

Mycobacterium abscessus is emerging as an important cause of cutaneous infections in sporadic cases and outbreak settings. Although immunosuppressed or elderly patients are most commonly affected, in 2006 an outbreak of clinically distinct cutaneous lesions on the hands and feet caused by M. abscessus in a population of healthy children using a public swimming pool was reported. This article describes an outbreak of skin infection in a population of healthy Italian children attending the same school and using the same swimming pool. In January 2010 we identified three children with multiple, painful nodules on the palms and soles. M. abscessus was isolated from one child's lesions. A public health investigation was conducted and a team of dermatologists and public health officers visited all of the children; 514 children were screened and 29 cases were identified overall. All of the affected children had used the school's swimming pool. These children were treated with oral clarithromycin for 4 to 8 weeks. Because of the long period of time between the presentation and diagnosis of the first cases, the possibility that the number of cases may have been underestimated cannot be excluded. To our knowledge, this is the second largest reported cluster of M. abscessus skin infection suspected to be related to swimming pool exposure in a population of otherwise healthy children. It is unclear whether this disease is rare or should be considered as an emerging clinical entity.

Comprehensive analysis of the major lipid classes in sebum by rapid resolution high-performance liquid chromatography and electrospray mass spectrometry.

Sebum is a complex lipid mixture that is synthesized in sebaceous glands and excreted on the skin surface. The purpose of this study was the comprehensive detection of the intact lipids that compose sebum. These lipids exist as a broad range of chemical structures and concentrations. Sebum was collected with SebuTape(TM) from the foreheads of healthy donors, and then separated by HPLC on a C8 stationary phase with sub 2 µm particle size. This HPLC method provided high resolution and excellent reproducibility of retention times (RT). Compound mining was performed with time of flight (TOF) and triple quadrupole (QqQ) mass spectrometers (MS), which allowed for the classification of lipids according to their elemental composition, degree of unsaturation, and MS/MS fragmentation. The combination of the two MS systems detected 95 and 29 families of triacylglycerols (TAG) and diacylglycerols (DAG), respectively. Assignment was carried out regardless of positional isomerism. Among the wax esters (WE), 28 species were found to contain the 16:1 fatty acyl moiety. This method was suitable for the simultaneous detection of squalene and its oxygenated derivative. A total of 9 cholesterol esters (CE) were identified and more than 48 free fatty acids (FFA) were detected in normal sebum. The relative abundance of each individual lipid within its own chemical class was determined for 12 healthy donors. In summary, this method provided the first characterization of the features and distribution of intact components of the sebum lipidome.

Underestimated clinical features of postadolescent acne.

BACKGROUND: Postadolescent acne is usually described as an inflammatory, mild-to-moderate dermatosis, frequently involving the lower third of the face, the jawline, and the neck. However, we have also frequently observed a clinical form predominantly characterized by retention lesions (microcomedones and macrocomedones), with few inflammatory lesions (comedonal postadolescent acne [CPAA]), which appears significantly correlated with cigarette smoking. OBJECTIVE: We sought to investigate the clinical features of postadolescent acne in a group of female patients affected by acne and its relationship with cigarette smoking. METHODS: A total of 226 women with acne (25-50 years) attending our department were examined by a team of 3 dermatologists, to assess the age of onset of the disease, and the number, type, and distribution of acne lesions. RESULTS: In all, 192 of 226 patients (85.0%) were classified as having CPAA and 34 as having papulopustular postadolescent acne. A smoking habit was confirmed in 150 of 226 (66.3%). Remarkably, 72.9% of patients with CPAA were smokers as compared with only 29.4% of those with papulopustular postadolescent acne (P < .0001). LIMITATIONS: Possible limitations are related to geographic area or to the prevalence of darker skin types (III and IV) (data about skin types have not been collected). Other possible aggravating factors (ie, stress and diet) have not been investigated. CONCLUSIONS: According to our results, CPAA appears as the most frequent clinical form of postadolescent acne and seems to be strictly correlated with cigarette smoking.

Acne and smoking.

BACKGROUND.: Post-adolescent acne is an inflammatory disorder, whose cause is unknown. Contrasting data are available on correlation between acne and smoking habit. OBJECTIVES.: To verify the frequency of clinically non-inflammatory (atypical) post-adolescent acne (APAA) among women, a possible correlation with cigarette smoking, possible differences in sebum composition in a group of female smokers with acne compared to healthy smokers and non-smokers. METHOD AND RESULTS.: 1046 randomly selected women (25-50-years-old) participated at the study. In 60 selected female subjects we analyzed sebum composition for alpha-tocopherol, squalene and squalene monohydroperoxide. We found a high prevalence of APAA among women (74.6%), a strong correlation with smoking habit (p < 0.0001), as well as an increase in the grade of sebum peroxidation (p < 0.05) with a reduction in vitamin E (p = 0.02), in the subjects with acne compared to the controls. CONCLUSIONS.: Clinical evidence and experimental data showed a straight correlation between smoking habit and post-pubertal acne in which the clinically non-inflammatory type-APAA-is the most frequent. In the more severe cases we could consider APAA as a new entity (smoker's acne).

Antigen specific cytokine response in pediatric patients with atopic dermatitis.

The physiopathology of atopic dermatitis (AD) has still to be elucidated. T effector cells with cutaneous homing receptors or T-cell derived cytokines have been assumed to be implicated in the pathogenetic mechanisms in AD and to be responsible for the different immunologic responses of patients. In fact, the large majority of AD patients display high IgE levels while others do not develop an abnormal IgE response. Although, there are not significant clinical features characterizing the two different groups, patients with normal IgE belong to a younger age range, raising the possibility that the hypothesized dichotomy of AD might be due to age. In the present study we included 172 outpatient children attending the Pediatric Department of our institution. Serum IgE levels and percentages of peripheral T lymphocytes expressing the cutaneous homing antigen (CLA) were evaluated and results were analyzed in relation to the activity of the disease (SCORAD index) or age. In the overall patients, the IgE levels increased significantly with age (0-1 yr: 19.50 IU/ml; 1-3 yr: 62.0 IU/ml; 3-8 yr: 96.0 IU/ml; >8 yr: 148.5 IU/ml; p<0.001) and with the severity of the disease (SCORAD low: 46.80 IU/ml; medium: 42.90 IU/ml; high: 148.5 IU/ml; p=0.01). Percentages of CLA+ peripheral T lymphocytes also increased with age (0-1 yr: 3.3; 1-3 yr: 4.85; 3-8 yr: 10.6; >8 yr: 12.5; p<0.001), although they were not significantly different in patients with different SCORAD (p=0.89). We further investigated the cellular immune response to a specific antigen in 25 subjects, matched for age, SCORAD, and CLA+ T-cell percentages. Among them, 13 patients had casein serum specific IgE and 12 had no evidence of casein sensitization. Peripheral blood mononuclear cells were kept in short-term culture with endotoxin-free casein fractions and IFN-gamma, TNF-alpha, IL-5, IL-10 cytokine-producing cells were detected by ELISpot. Statistical analysis showed significant higher numbers of TNF-alpha- or IL-10-producing cultures (stimulation index >3) in the 'allergic' patients than in the milk tolerant subjects (p=0.01 and 0.05). The analysis of individual responses confirmed this finding but also provide evidence of a significant increase in IFN-gamma-producing cells (p=0.05) induced by casein stimulation in the group of 'non-allergic' children. Our data showed that immunologic parameters as IgE levels or CLA+ T cells in AD pediatric patients are influenced by the age, confirming that age could represent a bias in the analysis of immune response in those patients. Although, we demonstrated in children with AD the existence of different cytokine patterns of the lymphocyte response that could account for the different immunologic features between the two hypothesized forms of AD, which are not dependent on age.