Janus kinase inhibitor-Tofacitinib associated with pemphigus: an analysis of the FDA adverse event reporting system data.

OBJECTIVES: To establish the association between the therapy of Janus kinase inhibitors and the adverse event of pemphigus in patients with rheumatologic and inflammatory disorders. METHODS: A disproportionality analysis using multi-item gamma Poisson shrinker was conducted to identify signals between medication and adverse events within the FDA Adverse Event Reporting System. RESULTS: The spontaneous reporting system contained 3,032 pemphigus reports associated with two Janus kinase inhibitors, namely Tofacitinib and Upadacitinib. The year/reporter/geographic area/country/age/sex/indication with the highest number of cases were the year of 2021, physician, North America, Canada, age between 40-49, female and rheumatoid arthritis, respectively. A significant signal was detected in the Tofacitinib group. CONCLUSION: Pemphigus, a rare and potentially fatal adverse event, was found to occur more frequently in patients receiving Tofacitinib. High-risk individuals were identified as female, age between 40-49, or with rheumatoid arthritis. Medication, adverse events, and underlying disease conditions were identified as potential contributing factors. Rheumatology and dermatology specialists should exercise increased vigilance in clinical practice.

What is already known on this topic ­ Orally administered Janus kinase inhibitors exhibit similar therapeutic efficacy and side effects as biologic agents.What this study adds ­ The association between the therapy of Janus kinase inhibitors and the adverse event of pemphigus in patients with rheumatologic and inflammatory disorders was confirmed through this study using real-world data.How this study might affect research, practice or policy. The absence of annotation regarding this topic in package inserts, guidelines, or expert consensus highlights the importance of clinical providers paying attention to high-risk patients. Early recognition and management may reduce the aggravation of the adverse event, benefitting these patients.

Intravenous Immunoglobulin for Autoimmune Bullous Diseases: A Case Series from a Central European Referral Center.

Background and Objectives: Autoimmune bullous diseases (AIBDs) may be treated with intravenous immunoglobulin (IVIG) infusions. This study aimed to evaluate the benefits and safety profiles of high-dose IVIG therapy in AIBD patients, as determined by clinical remission, the glucocorticosteroid-sparing effect, and adverse events at 12 months follow-up in a Central European university dermatology department setting. Materials and Methods: Our case series included 10 patients: five patients with pemphigus vulgaris, one with pemphigus herpetiformis, one with pemphigus foliaceus, one with bullous pemphigoid, two with epidermolysis bullosa acquisita. They underwent 4-12 monthly cycles of IVIG therapy at a dose of 2 g/kg per cycle. Results: The prednisone dosage reduction after 2, 6, and 12 months following the final IVIG course was 65.45%, 70.91%, and 76.37%, respectively. During the 12-month observation period, disease relapse was observed in 20% of patients, while others achieved complete or partial remission without or with minimal therapy. Side effects were seen in 80% of patients; they were transient and did not necessitate discontinuation of IVIG. Conclusions: IVIG demonstrates effectiveness as a treatment with a favorable safety profile. Nevertheless, its high cost remains a significant drawback, particularly in low-income countries. IVIG should be considered, especially in patients opposed to standard therapies or with contraindications to their use.

Rituximab Treatment and Improvement of Health-Related Quality of Life in Patients With Pemphigus.

Pemphigus is an autoimmune blistering disease that can negatively affect patients' lives. Assessing the impact of treatment from a patient's perspective using outcome assessment measures is important and relevant in trials of new pemphigus treatments including rituximab (RTX). We sought to evaluate the effect of RTX on health-related quality of life (HRQOL) in pemphigus patients and peruse the clinical relevance of the patient-reported outcomes. A retrospective cross-sectional study was designed with 96 pemphigus patients given RTX either 3 months earlier or in the last 2 weeks. The treatment was evaluated by patients using HRQOL assessment tools: 36-Item Short Form Survey (SF-36) and Dermatology Life Quality Index (DLQI). Another patient-reported assessment was the patient global assessment (PGA). We found that RTX administration in pemphigus patients led to rapid and notable improvement in HRQOL and patient-assessed measures.

The complicated use of dupilumab in the treatment of atypical generalized pemphigus Erythematous: A report of two cases.

Pemphigus is a rare autoimmune disease and has the potential to be fatal without treatment. Pemphigus erythematosus (PE) is a benign type of pemphigus foliaceus. Glucocorticoids and immunosuppressive agents are primary therapeutic modalities in pemphigus erythematosus, which may lead to considerable side effects. There is a growing need for new pemphigus therapies with fewer adverse effects. Dupilumab is a humanized monoclonal IgG4 antibody that inhibits the signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13) and has been applied for atopic dermatitis and asthma. Recently, dupilumab was thought to be beneficial in aggressive refractory pemphigus vulgaris. We report two cases: a 39-year-old male and a 59-year-old woman diagnosed with PE with atypical clinical features. With dupilumab, patients' skin lesions significantly improved, and suitable maintenance glucocorticosteroid doses were reached. In conclusion, we reported the short-term effectiveness and safety of dupilumab in two cases of atypical generalized PE. As an adjunct, such a biologic agent is expected to be efficacious in pemphigus erythematosus.

Association of Rituximab With Risk of Long-term Cardiovascular and Metabolic Outcomes in Patients With Pemphigus.

Importance: The association of different therapeutic approaches with long-term cardiovascular and metabolic outcomes in patients with pemphigus remains to be precisely evaluated. Objective: To assess the risk of long-term cardiovascular and metabolic outcomes and all-cause mortality in patients with pemphigus managed by rituximab compared with those receiving treatment with first-line corticosteroid-sparing agents (azathioprine and mycophenolate mofetil [MMF]). Design, Setting, and Participants: A global population-based retrospective cohort study compared 961 patients with pemphigus that was managed with rituximab with those treated with azathioprine or MMF (n = 961) regarding the risk of several cardiovascular and metabolic outcomes. Propensity score matching was performed to optimize comparability. Patients were enrolled from the Global Collaborative Network of TriNetX platform. Main Outcomes and Measures: Risk of myocardial infarction, stroke, peripheral vascular disease, pulmonary embolism, hypertension, hyperlipidemia, type 2 diabetes, obesity, osteoporosis, and avascular bone necrosis. Results: Of 1602 participants, 855 (53.4%) were women and 747 (46.6%) were men; the mean (SD) age was 54.8 (16.6) years for those treated with rituximab and 54.4 (18.2) years for those treated with azathioprine or MMF. Compared with those treated by azathioprine/MMF, patients treated with rituximab experienced a lower risk of myocardial infarction (relative risk [RR], 0.45; 95% CI, 0.24-0.86; P = .01), stroke (RR, 0.42; 95% CI, 0.26-0.69; P < .001), peripheral vascular disease (RR, 0.47; 95% CI, 0.28-0.79; P = .003), hypertension (RR, 0.48; 95% CI, 0.38-0.63; P < .001), hyperlipidemia (RR, 0.45; 95% CI, 0.32-0.64; P < .001), type 2 diabetes (RR, 0.63; 95% CI, 0.51-0.77; P < .001), obesity (RR, 0.49; 95% CI, 0.34-0.72; P < .001), and osteoporosis (RR, 0.46; 95% CI, 0.30-0.71; P < .001). The all-cause mortality was comparable between patients in both groups (hazard ratio, 0.94; 95% CI, 0.62-1.43; log-rank P = .77). Conclusions and Relevance: The results of this cohort study suggest that rituximab was associated with protection against long-term cardiovascular and metabolic outcomes compared with conventional immunosuppressants. This agent might be particularly preferred in individuals with preexisting cardiovascular and metabolic risk factors.

Applicability of glucocorticoid toxicity index in pemphigus: Comparison between two groups of rituximab-treated and rituximab-naïve patients.

Rituximab (RTX) combined with short-term glucocorticoids (GC) is an effective therapeutic option for pemphigus. The newly developed Glucocorticoid Toxicity Index (GTI) tool provides the possibility to measure GC toxicities over time. To compare 1-year GTI between two groups of RTX-treated and RTX-naïve patients with pemphigus. The responsiveness of the GTI was also investigated. A prospective cohort of 129 adults with newly diagnosed pemphigus was conducted. GC-related toxicities were assessed at 3-month intervals according to Composite and Specific lists of the GTI. Of the patients, 76.7% (n = 99) received RTX. Throughout the time intervals, RTX-treated patients had lower GTI compared to RTX-naïve ones (p = 0.036). The mean GTI at 1-year was 34.3 in the RTX-treated group and 50.8 in the RTX-naïve group (p = 0.04). The most commonly observed GC-related toxicity was neuropsychiatric manifestations for 34% (224 events). The relapse rate of RTX-treated patients (1%) was significantly lower than RTX-naïve patients (10%) (p = 0.037). The GTI showed no correlation with cumulative GC consumption in both groups (p > 0.05, both). Patients treated with GC alone had remarkably higher GTI than patients treated with GC plus RTX. The GTI is an applicable tool to quantitatively capture GC toxicities at the patient level in pemphigus.

[Bullous skin diseases].

This review finds that topical corticosteroids and systemic corticosteroids are the mainstays of initial treatment for bullous pemphigoid and pemphigus diseases. Additional immunomodulatory therapies such as methotrexate, azathioprine and mycophenolatmofetil should be added early during treatment to minimize the adverse effects of chronic corticosteroid therapy and to augment improvement in the disease. Rituximab is a first-line immunomodulatory treatment for moderate to severe pemphigus disease.

Long-term efficacy and safety analysis of single cycle of biosimilar rituximab in pemphigus: A retrospective study of 76 patients from India.

Pemphigus poses a therapeutic challenge and rituximab is increasingly used in its treatment. Long-term data regarding efficacy and safety of rituximab in pemphigus is limited. This study was a retrospective analysis of 76 pemphigus patients with primary endpoint being the percentage of patients achieving complete remission (CR) on/off therapy. Secondary endpoints were time to relapse, mean cumulative dose of prednisolone after rituximab infusion, mean duration of follow up, and adverse events to rituximab if any. A total of 62 (82.7%) attained complete remission on/off treatment, out of which 42 were off therapy. Mean interval between rituximab administration and complete remission off treatment was 6.9 ± 3.7 months. Complete remission off treatment was sustained for a mean duration of 21.4 ± 17.8 months before relapse. Over a mean follow-up duration of 42.7 ± 24.9 months (median 41, maximum 83 months), 22 of 62 patients (35.5%) who had achieved complete remission after the first cycle of rituximab relapsed. A mean total cumulative dose of 8716.3 ± 10533.8 mg prednisolone was prescribed over a mean duration of 18.05 ± 15.64 months after the first cycle of rituximab. Adverse events were noted in 18 out of 76 patients (23.7%) which included infusion reactions (n = 3), minor infections (n = 7), transitory disease flare (n = 6), and mortality (n = 2). No statistically significant correlation was found between remission/relapse rates and age, gender or pemphigus subtype. This study substantiates the long-term efficacy and safety of single cycle of rituximab in pemphigus.

Pemphigus Vulgaris Aggravated: Rifampicin Found at the Scene of the Crime.

Pemphigus vulgaris (PV) is a rare life-threatening condition of the pemphigus group of autoimmune blistering diseases. Systemic glucocorticoids are the cornerstone of management for PV, but complications can arise from their long-term use. We report a case of recurrence of a well-controlled case of PV that could not be alleviated by a combination of steroids, mycophenolate mofetil, and high-dose intravenous immune proteins. The patient had developed numerous complications during previous glucocorticoid therapy, including hypertension, diabetes, glaucoma, cataracts, optic nerve atrophy, aseptic necrosis of the femoral head, osteoporosis, and pulmonary tuberculosis. We determined that recurrence of PV and treatment resistance were consequences of the interaction between the antitubercular agent rifampicin that the patient was taking and corticosteroids. Pemphigus vulgaris was quickly controlled after the rifampicin was discontinued.

Assessing the use of methotrexate as an alternate therapy for pemphigus vulgaris and pemphigus foliaceus.

Methotrexate is historically recognized as an effective treatment of pemphigus but its utility as a single or alternate steroid-sparing agent was not recognized in recent consensus recommendations in pemphigus management. We aimed to evaluate the efficacy and safety of a treatment course for pemphigus that involves methotrexate as a single or steroid-sparing agent. In a retrospective cohort study, we examined patients with pemphigus vulgaris or pemphigus foliaceus who were on ≥3 months of methotrexate therapy. Efficacy and safety were evaluated by established pemphigus disease endpoints. Of the 34 patients who met inclusion criteria, 25 (73.5%) were on glucocorticoids at time of methotrexate initiation (median follow-up: 5.4 years; median time on methotrexate: 3.7 years). An appreciable proportion achieved disease control (91.2%), with some achieving clinical remission off all systemic therapies (23.5%). For patients on glucocorticoids, median time to control was 42 days, median time to minimal steroid dose tapering (5 mg prednisone) was 161 days, and median time to complete steroid tapering was 308 days. For patients on methotrexate as a single agent, median time to control was 119 days. Among all patients, relapse commonly occurred (88.2%). At last follow-up, 26.5% were managed on topical therapies alone and 11.8% required systemic steroid therapy. Methotrexate was largely tolerated with a low incidence of adverse events leading to treatment discontinuation (2.9%). Methotrexate has the potential to be an effective and well-tolerated option for patients and may be considered for use as an alternate single or steroid-sparing agent for pemphigus.

Cutaneous manifestations following COVID-19 vaccination: A report of 25 cases.

Various adverse effects particularly cutaneous manifestations associated with different COVID-19 vaccines have been observed in practice. The aim of our study was to evaluate all patients who presented to our tertiary center with skin manifestations following COVID-19 vaccines injection from September to December 2021. All patients with skin manifestation within 30 days or less following COVID-19 vaccination were enrolled in our case-series. All cases included in our study were diagnosed based on clinical and/or histopathological evaluation and all other possible differential diagnoses were ruled out. Twenty-five individuals including 16 (64%) males and 9 (36%) females with the mean age of 47 ± 17.62 years (range 18-91) were enrolled in our study. Twenty-two (88%) patients developed lesions after Sinopharm vaccine injection and 3 (12%) cases manifested lesions after the AstraZeneca vaccine. Six (24%) patients developed new-onset lichen planus (LP) and 1 (4%) patient manifested LP flare-up. Two (8%) individuals developed psoriasis and 1 (4%) case showed psoriasis exacerbation. One (4%) patient developed new-onset pemphigus vulgaris (PV) and 1 (4%) case experienced a flare of PV lesions. One (4%) patient manifested pityriasis lichenoides et varioliformis acuta (PLEVA) flare-up. Other new-onset cases were as follows: toxic epidermal necrolysis (TEN) (n = 1, 4%), bullous pemphigoid (BP) (n = 2, 8%), alopecia areata (AA) (n = 2, 8%), pytriasis rosea (n = 1, 4%), herpes zoster (n = 1, 4%), cutaneous small vessel vasculitis (n = 1, 4%), erythema multiform (EM) and urticaria (n = 3, 12%), and morphea (n = 1, 4%). Physicians should be aware of the possible side effects especially cutaneous manifestations associated with COVID-19 vaccines.

COVID-19 severity and SARS-Cov-2 vaccine safety in pemphigus patients.

There are safety concerns in the treatment of pemphigus patients with immunosuppressants, particularly rituximab (RTX), in times of the COVID-19 pandemic. In the beginning, the reports were more pessimistic. However, few reports have recently pointed to manageable courses in this patient group. Therefore, we investigated the disease characteristics and demographic features of pemphigus patients in the period of the COVID-19 pandemic. We aimed to investigate the impact of immunosuppressants on the course of COVID-19 in pemphigus patients. Also, we tried to find out the rate of flares due to COVID-19 and SARS-Cov-2 vaccines. This multicenter study included 247 patients with pemphigus from three tertiary dermatology clinics with the specialized outpatient clinic for autoimmune blistering diseases. Patients were asked standardized questions in person or via telephone calls. Also, demographic data were collected from patients' files. Two hundred forty-four of 247 patients took the survey between August and September 2021. The data of three patients were obtained from the National Health System. We collected the data of all pemphigus patients who visited the clinics at least once in the past 3 years. Among 51 patients having COVID-19, 40 had a non-serious disease, whereas 11 required hospitalization. One patient died because of COVID-19 infection. The number of patients is limited, and data depends mainly on patients' statements. RTX treatment does not require additional safety cautions than other immunosuppressives.

Development of severe pemphigus vulgaris following ChAdOx1 nCoV-19 vaccination and review of literature.

Vaccines are indeed a boon for tackling the present COVID-19 pandemic. In India, ChAdOx1 nCoV-19 (Covishield) is the most commonly used vaccine in the government vaccination program for adults more than 18 years of age. It is a recombinant vaccine developed by Oxford-Astra Zeneca and manufactured in India by Serum Institute of India (SSI). Here, we report a case of severe pemphigus vulgaris following the second dose of ChAdOx1 nCoV-19 vaccination in an adult male. The patient developed septicemia during the course of hospital stay, and he was managed with systemic steroids, parenteral antibiotics, and intravenous immunoglobulins (IVIg) along with proper wound care. Patient started improving within 1 month of therapy. This case is being reported in view of the rarity of pemphigus vulgaris following ChAdOx1 nCoV-19 vaccine.

Treatment of pemphigus in Australia: Aligning current practises with global recommendations.

Pemphigus encompasses of a group of rare, and often severe, intraepidermal bullous dermatoses that are mediated by autoantibodies that act against adhesion proteins of the desmosome. The current international consensus is that the use of intravenous CD20 inhibitors should be first-line in the management of moderate-to-severe cases of pemphigus, however Australia is yet to adopt this. Systemic corticosteroids, combined with conventional corticosteroid-sparing immunosuppressive agents such as azathioprine, mycophenolate mofetil, cyclosporin and methotrexate is still recommended as first-line therapy in Australia despite overwhelming evidence that combining rituximab with a rapid corticosteroid tapering regime is more effective in the treatment of moderate-to-severe pemphigus, and leads to fewer severe adverse effects. We propose a therapeutic approach that echoes the international consensus and recommend that rituximab, an anti-CD20 monoclonal antibody, be listed in the formularies of Australian Public Hospitals and on the Pharmaceutical Benefits Scheme for use in moderate to severe pemphigus.