What is novel in the clinical management of pemphigus vulgaris?

INTRODUCTION: Pemphigus, an uncommon autoimmune blistering disorder affecting the skin and mucous membranes, currently with mortality primarily attributed to adverse reactions resulting from treatment protocols. Additionally, the existing treatments exhibit a notable recurrence rate. The high incidence of relapse and the considerable adverse effects associated with treatment underscore the imperative to explore safer and more effective therapeutic approaches. Numerous potential therapeutic targets have demonstrated promising outcomes in trials or preliminary research stages. These encompass anti-CD-20 agents, anti-CD-25 agents, TNF-α inhibition, FAS Ligand Inhibition, FcRn inhibition, BAFF inhibition, Bruton's tyrosine kinase (BTK) inhibition, CAAR T Cells, JAK inhibition, mTOR inhibition, abatacept, IL-4 inhibition, IL-17 inhibition, IL-6 inhibition, polyclonal Regulatory T Cells, and autologous hematopoietic stem cell transplantation. AREAS COVERED: The most significant studies regarding the impact and efficacy of the mentioned treatments on pemphigus were meticulously curated through a comprehensive search conducted on the PubMed database. Moreover, the investigations of interest cited in these studies were also integrated. EXPERT OPINION: The efficacy and safety profiles of the other treatments under discussion do not exhibit the same level of robustness as anti-CD20 therapy, which is anticipated to endure as a critical element in pemphigus treatment well into the foreseeable future.

Investigating the impact of added Profhilo mesogel to subcision versus subcision monotherapy in treating acne scars; a single-blinded, split-face randomized trial.

BACKGROUND: Acne scar is an inflammatory condition, which commonly occurs in patients with acne vulgaris, especially in adults. Mesogels have been reported effective in improving atrophic acne scars. AIMS: We investigated the efficacy of adding Profhilo (a hyaluronic acid-based filler) to subcision as a new treatment method. METHODS: Twelve patients aged 18-45 years with atrophic acne scars on both sides of the face participated in this single-blinded, split-face, randomized controlled trial. Each side of the face was randomly assigned to one of the treatment methods, including subcision alone and subcision + Profhilo. Patients in the Profhilo arm received mesogel (1 cc) in addition to the subcision procedure. Both methods were carried out two times at 1-month intervals. Assessments were done based on the sonographic depth of scars, and two blinded observers examined photographs at baseline and 3 months after the final session and the results were reported based on an exclusively made formula as the total score. The Global Improvement Scale and Visual Analogue Scale (VAS) (for patient satisfaction) were also used. RESULTS: The VAS score of patient satisfaction was statistically significant in the Profhilo arm, with a mean improvement of 528.08 and 219.06 in the subcision arm (p = 0.02). No significant difference was seen in total acne scar reduction comparing the two methods (29.74 in the Profhilo arm and 22.27 in the subcision arm, p = 0.56). Sonographic depth reduction was also non-significant, with a mean of 29.21 in the Profhilo arm and 28.53 in the subcision arm (p = 0.4). The mean global improvement was reported as four in both arms, and no statistical significance was observed (p = 0.89). The best response to treatment belonged to the rolling subtype in both methods (p = 0.029 for the Profhilo arm and p = 0.001 for the subcision arm). CONCLUSION: Despite no significant difference between the methods, Profhilo is more effective due to a higher satisfaction rate and better physiologic effects.

DNA repair-related heritable photosensitivity syndromes: Mutation landscape in a multiethnic cohort of 17 multigenerational families with high degree of consanguinity.

Inherited photosensitivity syndromes are a heterogeneous group of genetic skin disorders with tremendous phenotypic variability, characterized by photosensitivity and defective DNA repair, especially nucleotide excision repair. A cohort of 17 Iranian families with heritable photosensitivity syndromes was evaluated to identify their genetic defect. The patients' DNA was analyzed with either whole-exome sequencing or RNA sequencing (RNA-Seq). The interpretations of the genomic results were guided by genome-wide homozygosity mapping. Haplotype analysis was performed for cases with recurrent mutations. RNA-Seq, in addition to mutation detection, was also utilized to confirm the pathogenicity. Thirteen sequence variants, including six previously unreported pathogenic variants, were disclosed in 17 Iranian families, with XPC as the most common mutated gene in 10 families (59%). In one patient, RNA-Seq, as a first-tier diagnostic approach, revealed a non-canonical homozygous germline variant: XPC:c.413-9 T > A. The Sashimi plot showed skipping of exon 4 with dramatic XPC down-expression. Haplotype analysis of XPC:c.2251-1 G>C and XPC:1243 C>T in four families showed common haplotypes of 1.7 Mb and 2.6 Mb, respectively, denoting a founder effect. Lastly, two extremely rare cases were presented in this report: a homozygous UVSSA:c .1990 C>T was disclosed, and ERCC2-related cerebro-oculo-facio-skeletal (COFS) syndrome with an early childhood death. A direct comparison of our data with the results of previously reported cohorts demonstrates the international mutation landscape of DNA repair-related photosensitivity disorders, although population-specific differences were observed.

Bullous pemphigoid, malignant acanthosis nigricans, and erysipeloid carcinoma in a woman with gastric adenocarcinoma.

Key Clinical Message: Bullous pemphigoid did not follow the course of Gastric Carcinoma relapse and remisson, unlike the malignant acanthosis nigricans which was in alignment with the paraneoplastic effect of the Gastric Carcinoma. Abstract: Acanthosis nigricans (AN) is a dermatosis characterized by the presence of hyperpigmented, velvety cutaneous thickening in the flexural areas, posterior neck, and occasionally the extensor surfaces of hand, face, and oral mucosa. AN is commonly associated with insulin resistance, drugs, and rarely internal malignancy (malignant AN). Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by tense blisters involving the skin of mainly elderly patients. The association of BP and malignancy is not well established and the co-existence of BP with AN has not been reported. Here we report a 58-year-old, event-free gastric adenocarcinoma with three types of skin findings with different pathogenesis- BP, malignant AN, and erysipelas-like metastasis.

Association of alternative healthy eating index and severity of pemphigus vulgaris: A cross-sectional study.

BACKGROUND: Evidence on the association between following healthy eating and the severity of pemphigus vulgaris (PV) is scarce. Therefore, the aim of this cross-sectional study aimed to investigate the relationship between adherence to the alternative healthy eating index (AHEI) and the severity of Pemphigus vulgaris disease in adults. METHODS: In this hospital-based cross-sectional study, a total of 138 pemphigus vulgaris cases were studied, of which 108 had pemphigus disease area index (PDAI) ≤15, and 30 had PDAI>15. Dietary intakes were assessed using a valid 168-item food frequency questionnaire (FFQ). To calculate the AHEI, the data received from the diet were used. The subjects of this index received a score of 1-10. The final AHEI was calculated by summing the component scores. RESULTS: After adjusting for age and sex, we found that individuals with the highest AHEI score were 72% less likely to have increased PV severity compared with those with the lowest score (OR: 0.28; 95% CI: 0.08-0.92, P trend = 0.020). Further control for another potential confounder, intake energy, made the association stronger (OR: 0.24; 95% CI: 0.06-0.88, P trend = 0.017). Also, after controlling the body mass index (BMI) confounding factor, it maintained its strong relationship (OR: 0.24; 95% CI: 0.06-0.88, P trend = 0.016). CONCLUSION: The evidence of our study shows that following the healthy eating index is associated with a reduction in the severity of pemphigus vulgaris. Prospective cohort studies are needed to confirm these findings.

Detection of herpes simplex viruses in the oral lesions of patients with pemphigus vulgaris: Is it diagnostic or predictive of disease severity?

Background: Some studies emphasise the relationship between the herpes simplex virus (HSV) and pemphigus. Although the possible role of HSV in the pathogenesis of pemphigus and the severity of the disease is obscure, we aimed to evaluate the presence of herpes simplex viruses (HSV 1/2) in the oral lesions of patients with pemphigus vulgaris and also assess its association with disease severity and types of lesions. Methods: A retrospective study was conducted on collected data in the form of collecting paraffin blocks, slides, and relevant pathology reports and referring to patients' medical records. A questionnaire containing details on the degree of skin, scalp, and mucosal involvement (Pemphigus Disease Area Index (PDAI)) was fulfiled. The immunoassay result was also collected to check the anti-desmoglein 3 and 1 antibodies (using ELISA technique). Results: In this study, 52 patients of pemphigus vulgaris with oral lesions (case) and 52 patients with oral lesions not related to the disease (control) were evaluated. HSV1 was detected in 13.5% of oral pemphigus lesions and 1.9% of the control group (p = 0.0598). There were no positive cases of HSV2 in either group. There was no significant association between the positivity of HSV1 and the site of lesions (p = 1.00) or disease severity (p = 0.28). However, we found a strong correlation between the PDAI disease severity score with the titre of the AntiDsg3 antibody (r = 0.487, p = 0.001) and AntiDsg1 antibody (r = 0.309, p = 0.026). Conclusion: This study demonstrated a significant prevalence of HSV1 in oral pemphigus lesions, and acyclovir therapy may play a significant role in managing these patients. However, HSV's role in the pathogenesis of pemphigus vulgaris cannot be clearly determined.

Pemphigus Disease and Area Index: Unmet needs in the real-world management of pemphigus.

Over the past few decades, a number of scoring instruments have been developed to assess the severity and activity of autoimmune bullous diseases (AIBDs) (Daneshpazhooh et al., 2019; Nili et al., 2020; Nili et al., 2021; Nili et al., 2022). The Pemphigus Disease Area Index (PDAI), developed by the International Pemphigus Definitions Group, is an easy-to-use, quick, and reliable method for determining pemphigus severity. As a reliable and effective tool in clinical trials, PDAI may also have some limitations and might require some revisions to be used on a daily basis. Here, we propose some recommendations to improve the use of PDAI in the clinical setting.

Comparing the efficacy of plasma exeresis and cryotherapy for the treatment of seborrheic keratosis: A randomized controlled trial.

BACKGROUND: Seborrheic keratoses (SK) is a benign epithelial skin tumor and plasma exeresis is a new technique. AIMS: To compare the efficacy and safety of plasma exeresis and cryotherapy for treating SK. METHODS: This study is a randomized controlled trial (RCT). One side of each patient was randomly treated with plasma exeresis (peak-to-peak voltage of 3.44 kV and a frequency of 62.5 kHz) and the other side with cryotherapy. RESULTS: Thirty-five males were enrolled. At week 3, 37.1 % (N = 13) of lesions treated by plasma exeresis were clear, which was higher than those treated by cryotherapy 17.1% (N = 6). However, this difference was not significant (p-value: 0.06). At week 6, 16 (57.1 %) out of 28 remaining lesions, treated by plasma exeresis were clear, which was significantly higher (p-value: 0.005) than those completely cleared by cryotherapy in 6 out of 29 remaining lesions (20.7%). The mean physician assessment scale score was significantly reduced in both groups in the second follow-up (plasma group first follow-up 0.91 ± 0.89 vs. second follow-up 0.5 ± 0.64 and p-value: 0.0031; cryo group first follow-up 1.4 ± 0.84 vs. second follow-up 1.1 ± 0.72 and p-value: 0.0002). Regarding side effects, no significant difference was seen (p = 0.438). The most common complications in the plasma and cryotherapy groups were erythema (10/19, 52.63%) and hypo pigmentation (5/13, 38.46%). CONCLUSIONS: Both cryotherapy and plasma exeresis are effective. We observed a significantly higher cleared lesions treated with plasma exeresis in 6 weeks and after two sessions.

COVID outcome in pemphigus: Does rituximab make pemphigus patients susceptible to more severe COVID-19?

BACKGROUND: The COVID-19 pandemic has raised some concerns regarding the management of chronic skin diseases, especially in patients on immunosuppressive therapy including patients with pemphigus vulgaris (PV). Literature review reveals conflicting results about the effect of monoclonal antibodies such as rituximab on clinical outcome of COVID-19. OBJECTIVES: To assess the reciprocal interaction of COVID-19 and pemphigus and the effect of rituximab on prognosis of COVID-19 in patients. METHODS: We set up a retrospective study on adult patients with a confirmed diagnosis of pemphigus vulgaris and a history of COVID-19 with or without symptoms during 2020. RESULTS: Thirty-six adults with pemphigus vulgaris and SARS-CoV-2 infection were included. The SARS-CoV-2 infection was confirmed with positive RT-PCR test results in 31 cases (86.1%) and suspected in the 5 others (13.9%). Gender, total dose of rituximab, number of rituximab cycles, and involvement of head and neck were not associated to duration of COVID-19 symptoms (p values: 0.32, 0.23, 0.84, and 0.51, respectively), severity of disease (hospitalization) (p values: 0.46, 0.39, 0.23, and 0.72, respectively), or the percentage of lung involvement on CT scan (p values: 0.07, 0.36, 0.38, and 0.09, respectively). Regarding the impact of COVID-19 on pemphigus, the majority of patients did not experience any changes in their pemphigus regarding clinical phenotype (100%) or severity (83.3%), but PV was worsened in 6 (16.9%) patients which was controlled with increasing the prednisolone dosage. CONCLUSION: Rituximab appears to be safe with no increased risk of severe form of COVID-19 in patients with pemphigus vulgaris.

Serologic Biomarkers in Pemphigus Monitoring: C-reactive Protein, Macrophage Migration Inhibitory Factor, and Prolactin Levels Versus Autoantibody Assays.

Evaluation and monitoring of pemphigus vulgaris (PV) typically involve autoantibody detection by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IIF). We aimed to determine the levels of antipemphigus immunoglobulin (Ig) G autoantibodies using ELISA and IIF (as standard biomarkers), and compare it to prolactin, macrophage migration inhibitory factor (MIF), and C-reactive protein (CRP) (as nonstandard biomarkers) to determine which of these non-standard biomarkers is appropriate for PV monitoring. The experiment was performed before and during therapy. Anti-Dsg immunoglobulin G autoantibodies were measured using ELISA and IIF (as standard biomarkers) versus prolactin, MIF, and CRP (nonstandard), before 1 and 3 months after the treatment. Before beginning the treatment, the severity of the disease was determined using the pemphigus disease area Index (PDAI). We enrolled 60 newly diagnosed patients with PV (32 men and 28 women; mean age=43.8±14.2 years). Before treatment, the levels of anti-Dsg1, anti-Dsg3, and IIF were high and had a significant relationship with PDAI. PDAI also had a connection with the levels of CRP and prolactin. The anti-Dsg1, anti-Dsg3, IIF, and CRP titers decreased in patients treated with conventional (prednisolone plus azathioprine) and rituximab therapy during and after treatment. In conclusion, anti-Dsg1, anti-Dsg3, and IIF autoantibody titers remain standard biomarkers for assessing disease activity, severity, and PV monitoring. The trend of CRP was similar to that of anti-Dsg1, anti-Dsg3, and IIF. Thus, CRP may be used for PV monitoring.

A systematic review on efficacy, safety and treatment durability of intravenous immunoglobulin in autoimmune bullous dermatoses: Special focus on indication and combination therapy.

Autoimmune bullous diseases (AIBDs) are a group of rare blistering dermatoses of the mucous membrane and/or skin. The efficacy, safety and treatment durability of intravenous immunoglobulin (IVIg) as an alternative treatment should be explored to systematically review the available literature regarding treatment outcomes with IVIg in AIBD patients. The predefined search strategy was incorporated into the following database, MEDLINE/PubMed, Embase, Scopus and Web of Science on 18 July 2022. Sixty studies were enrolled using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The use of IVIg alone or combined with rituximab was reported in 500 patients with pemphigus, 82 patients with bullous pemphigoid, 146 patients with mucous membranes pemphigoid and 19 patients with epidermolysis bullosa acquisita. Disease remission with IVIg therapy and RTX + IVIg combination therapy were recorded as 82.8% and 86.7% in pemphigus, 88.0% and 100% in bullous pemphigoid and 91.3% and 75.0% in mucous membrane pemphigoid, respectively. In epidermolysis bullosa acquisita, treatment with IVIg led to 78.6% disease remission; no data were available regarding the treatment with RTX + IVIg in this group of patients. Among all the included patients, 37.5% experienced at least one IVIg-related side effect; the most common ones were headaches, fever/chills and nausea/vomiting. The use of IVIg with or without rituximab had a favourable clinical response in patients with AIBDs. IVIg has no major influence on the normal immune system, which makes its utilization for patients with AIBDs reasonable.

Drug Adherence and its Association with Health Literacy Among Patients with Autoimmune Bullous Diseases.

Background: Despite the emergence of novel medications, poor drug adherence is an obstacle toward disease management in patients with autoimmune bullous dermatoses (AIBDs). Objectives: We sought to evaluate medication adherence among patients with AIBDs and determine the impact of health literacy on adherence. Methods: We performed a cross-sectional survey of patients with AIBDs who attended Razi Hospital from May to October 2021. Drug adherence and health literacy were assessed using the Morisky Medication Adherence Scale-8 (MMAS-8; scored 0-8) and Health Literacy for Iranian Adults (HELIA; scored 0-100) questionnaires, respectively. Multivariable ordinal regression, including the covariates age, sex, education level, and annual income, were employed for analyses. Results: Two hundred participants with a mean±standard deviation (SD) age of 50.3±13.5 years were recruited. The female:male ratio was 1.2. About half (53%) of the patients reported good adherence (MMAS-8 score of 8) to their AIBD medications. Moreover, limited health literacy, with a mean±SD score of 57.8±25.8, was noted. Multivariable ordinal regression indicated that literacy score was significantly associated with good drug adherence (odds ratio [OR]: 0.11 per 1 score of health literacy increase, 95% confidence interval [CI]: 0.09-0.14). Conclusion: These findings showed suboptimal drug adherence and health literacy of patients with AIBDs. Improving patient health literacy might be a way to increase drug adherence.