Adalimumab induced exacerbation of psoriasis in patients with combined pemphigus: A case report.

RATIONALE: Psoriasis is an immune-related disease caused by genetic factors, abnormalities in the immune system and environmental factors, while pemphigus is an autoimmune disease caused by the autoimmune system attacking the skin and mucosal tissues. Herein, we aimed to report a rare case of adalimumab induced exacerbation of psoriasis patients with pemphigus. The rare disease causes considerable challenges for clinical diagnosis and treatment. PATIENT CONCERNS: The patient was a 43-year-old man with intermittent erythema and scaling all over the body for more than 20 years, and blisters and vesicles on the trunk and limbs for 1 month. Half a year ago, the patient had blisters on the limbs, and was diagnosed with deciduous pemphigus in a hospital, and the blisters subsided after being given traditional Chinese medicine orally. Half a month ago, the erythema area was enlarged, and adalimumab 80 mg intramuscular injection was given for 1 time after consultation in the hospital. On the following day, the area of erythema and scales was suddenly enlarged obviously compared with the previous 1, and obvious blisters and vesicles appeared on the limbs, neck, and trunk, which were aggravated progressively and accompanied by obvious itching and pain. DIAGNOSES: The patient was diagnosed with psoriasis in patients with combined pemphigus. INTERVENTION: After combined treatment with methylprednisolone and cyclosporine, the skin lesions have basically recovered. OUTCOMES: The skin lesions have basically healed. Follow up for 6 months without recurrence. LESSONS: Methylprednisolone combined with cyclosporine may be an option in treating patients with psoriasis patients with pemphigus.

Tacrolimus reverses pemphigus vulgaris serum-induced depletion of desmoglein in HaCaT cells via inhibition of heat shock protein 27 phosphorylation.

BACKGROUND: Glucocorticoids are the first-line treatment for Pemphigus vulgaris (PV), but its serious side effects can be life-threatening for PV patients. Tacrolimus (FK506) has been reported to have an adjuvant treatment effect against PV. However, the mechanism underlying the inhibitory effect of FK506 on PV-IgG-induced acantholysis is unclear. OBJECTIVE: The objective of this study was to explore the effect of FK506 on desmoglein (Dsg) expression and cell adhesion in an immortalized human keratinocyte cell line (HaCaT cells) stimulated with PV sera. METHODS: A cell culture model of PV was established by stimulating HaCaT cells with 5% PV sera with or without FK506 and clobetasol propionate (CP) treatment. The effects of PV sera on intercellular junctions and protein levels of p38 mitogen-activated protein kinase (p38MAPK), heat shock protein 27 (HSP27), and Dsg were assayed using western blot analysis, immunofluorescence staining, and a keratinocyte dissociation assay. RESULTS: PV sera-induced downregulation of Dsg3 was observed in HaCaT cells and was blocked by FK506 and/or CP. Immunofluorescence staining revealed that linear deposits of Dsg3 on the surface of HaCaT cells in the PV sera group disappeared and were replaced by granular and agglomerated fluorescent particles on the cell surface; however, this effect was reversed by FK506 and/or CP treatment. Furthermore, cell dissociation assays showed that FK506 alone or in combination with CP increased cell adhesion in HaCaT cells and ameliorated loss of cell adhesion induced by PV sera. Additionally, FK506 noticeably decreased the PV serum-induced phosphorylation of HSP 27, but had no effect on p38MAPK phosphorylation. CONCLUSION: FK506 reverses PV-IgG induced-Dsg depletion and desmosomal dissociation in HaCaT cells, and this effect may be obtained by inhibiting HSP27 phosphorylation.

l-carnitine downregulate the muscle wasting effect of glucocorticoids in pemphigus patient: A randomized double-blind placebo-controlled study.

Pemphigus Vulgaris (PV) is a blistering autoimmune disease caused by autoantibodies against desmoglein 1 and 3. Treatment options are limited to corticosteroids and immunosuppressants. The myotoxic effect of glucocorticoids is a fact that has been elucidated. So, the development of efficacious treatment approaches to combat muscle wasting is of great importance. Considering the adverse effect of glucocorticoid therapy in pemphigus patients and altered muscle metabolism, this study aimed to investigate the effect of l-carnitine supplementation which can be useful in combating muscle-wasting impact of glucocorticoid therapy. In this randomized double-blind placebo-controlled trial 44 pemphigus patients aged from 30 to 65 years, receiving glucocorticoid therapy were selected to evaluate the suitability of l-carnitine (LC) as an anti-wasting substance. Patients were randomly divided into two groups to receive 2 g/d l-carnitine or placebo for 8 weeks; serum markers of muscle metabolism (IGF-1, creatine kinase, myogenin, myostatin) was evaluated before and after the l-carnitine supplementation. Paired T-test was used to analyze the differences between variables before and after the intervention. Therefore, the student's t-test was performed to find any differences in baseline characteristics and dietary intakes between the trial groups. LC intake led to a significant rise in serum IGF-1 and a reduction in CK and myostatin levels compared to baseline (p < 0.05) but there were no significant inter-group differences in IGF-1 and CK levels; There was also a significant reduction in myostatin level in LC group (p < 0/05). Myogenin levels decreased in both LC and placebo groups but the decrease in the placebo group was significant (p = 0/008); it means LC prevent the myogenin decreasing trend in the LC group compared to placebo. In conclusion, LC supplementation beneficially changes the level of IGF-1 and myostatin and improves muscle metabolism and regeneration in PV patients.

Lifestyle medicine approach in managing pemphigus vulgaris: A case report.

A 58-year-old female presented to a lifestyle medicine clinic in 2019 with a one-year history of pemphigus vulgaris (PV) and having itching, burning sensations, and bulla formation all over her body. She further had a recent diagnosis of type 2 diabetes mellitus and also complained of malaise, indigestion, and anxiety due to her skin condition. She was on methyl prednisolone, metformin, and other herbal supplements for 1 year to control her PV and diabetes. Laboratory investigations revealed the presence of autoantibodies Desmoglein 1 and 3 with titers of 3.26 and 3.5, respectively.The patient underwent a yoga & naturopathy-based lifestyle modification program for a period of 53 days in 2019, followed by 10 days in 2020 and 15 days in 2021, and subsequent follow-up measures. This included hydrotherapy, yoga, a vegetarian diet, herbal preparations, massage, etc. By the end of 2020, the patient was tapered from all medications, and there was complete remission from PV. Given the multidimensional impact of PV, a holistic, patient-centered lifestyle approach as described in this case may be beneficial in managing PV. Further research is warranted in this area.

Vitamin D status in patients with autoimmune bullous dermatoses: a meta-analysis.

BACKGROUND: The association between autoimmune bullous dermatoses (AIBD) and serum vitamin D levels has been revealed by some studies, however, inconsistent. OBJECTIVES: We aimed to evaluate the difference in vitamin D status between AIBD patients and controls. METHODS: We searched the studies about the vitamin D status of AIBD patients in electronic databases published before January 2020. Mean difference (MD) and 95% confidence intervals (CI) of eligible studies were calculated in meta-analyses of 25(OH)D levels. Pooled odds ratio (OR) and 95%CI were used in analyses of the prevalence of hypovitaminosis D. Different subgroup analyses, sensitivity analyses and publication bias assessment were conducted. RESULTS: We included nine case-control studies in the meta-analysis. Vitamin D level was significantly lower in both pemphigus (MD: -7.02, 95%CI: -10.30 to -3.74) and bullous pemphigoid (BP) (MD: -6.37, 95%CI: -12.15 to -0.58) patients than that in controls. Active pemphigus patients were at higher risk of presenting hypovitaminosis D (OR: 6.95, 95%CI: 1.37-35.25). CONCLUSIONS: Abnormal vitamin D status are more common in AIBD patients than that in general population. Therefore, regular monitoring of vitamin D levels and vitamin D supplementation should be considered as part of the management strategy for AIBD.

Photobiomodulation laser therapy in pemphigus vulgaris oral lesions: A randomized, double-blind, controlled study.

OBJECTIVE: Systemic corticosteroids are the mainstay treatment for PV oral lesions; the aim of this study is to evaluate the efficacy of PBMT with a 645 nm diode laser as a supportive topical therapy in patients with PV induced erosive-ulcerative oral lesions. MATERIALS AND METHODS: This double-blind placebo-controlled study divided patients into two groups: A, patients receiving laser therapy (Raffaello 980 Bio, Dental Medical Technologies, Italy with the following parameters: 100 mW power, 645 nm wave length, irradiation area 1 cm2, application time 30 sec/cm2, energy density 3 J/cm2, scanning modality) and B, receiving sham therapy (placebo). All patients were being treated also with a systemic corticosteroid therapy i.e. prednisone 0.5 mg/Kg per day. Size of lesions, VAS and satisfaction were evaluated before the treatment (T0), after 4 weeks (T1) and after 8 weeks as a follow-up (T2). RESULTS: A total of 50 lesions were evaluated. About lesions size, there was a statistical significative difference between the two groups just at T2 (p=0.0193), though VAS significantly decreased both at T1 (p=0.0198) and at T2 (p=0.0087). In general, all patients were satisfied of the treatment received. CONCLUSION: PBMT can be considered a validate supportive therapeutic option, even if further RCTs studies with wide sample sizes and standardized management protocols are suggested.

A multicenter, open-label, uncontrolled, single-arm phase 2 study of tirabrutinib, an oral Bruton's tyrosine kinase inhibitor, in pemphigus.

BACKGROUND: The treatment of pemphigus is based on systemic corticosteroid use and adjuvant therapies, but some patients are resistant to conventional therapy. Tirabrutinib is a highly selective oral Bruton's tyrosine kinase inhibitor that may be clinically effective in treating pemphigus by suppressing B-cell signaling. OBJECTIVE: We investigated the efficacy and safety of tirabrutinib in patients with refractory pemphigus. METHODS: This was a multicenter, open-label, single-arm phase 2 study of Japanese patients with refractory pemphigus receiving appropriate treatment with an oral corticosteroid and adjuvant therapies. Patients received postprandial oral tirabrutinib 80 mg once daily for 52 weeks. After 16 weeks of tirabrutinib treatment, the corticosteroid dose was tapered to ≤10 mg/day of prednisolone equivalent. RESULTS: In total, 16 patients were evaluated (mean age, 52.5 years; 50 % male). The complete remission rate after 24 weeks of treatment (primary endpoint) was 18.8 % (3/16; 95 % confidence interval, 6.6 %-43.0 %). By Week 52, eight patients (50.0 %) achieved complete remission and 10 patients (62.5 %) achieved remission. Over 52 weeks of treatment, the mean prednisolone dose decreased from 17.03 to 7.65 mg/day. Incidences of adverse events (AEs) and adverse drug reactions were 87.5 % and 43.8 %, respectively. A relationship with tirabrutinib was ruled out for all serious AEs and Grade ≥3 AEs. CONCLUSION: Treatment with tirabrutinib enabled remission and reduced oral corticosteroid exposure over time and did not result in any major safety concerns in patients with refractory pemphigus. Thus, oral tirabrutinib may be a new treatment option for patients with refractory pemphigus.

Pemphigus Vulgaris and Bullous Pemphigoid of the Upper Aerodigestive Tract: A Review Article and Novel Approaches to Management.

BACKGROUND: Autoimmune bullous diseases are rare conditions characterized by blistering of the skin and mucous membranes. The 2 commonest forms are pemphigus vulgaris and bullous pemphigoid. The oral cavity or oropharynx may be the initial site of presentation or often the only site involved. SUMMARY: These conditions are often misdiagnosed or overlooked leading to poorer patient outcomes. Due to the chronic nature of these conditions and the systemic effects of treatment, there is a significant associated morbidity and mortality. As such, an understanding of the fundamentals of autoimmune bullous diseases is vital to those working in otolaryngology. The mainstay of management in both conditions is topical and systemic corticosteroids. There is also a role for immunomodulating and non-steroidal anti-inflammatory drugs as adjunct or alternative therapies. Surgical intervention may be required to protect the airway. Often multimodality treatment is required involving multidisciplinary input from otolaryngologists, oral surgeons, dermatologists, and rheumatologists. This review article will highlight the aetiology, pathology, clinical features, investigations, and management of both pemphigus vulgaris and bullous pemphigoid including recent advances in management.

Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease.

Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcγR signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, FcεR-dependent immune mechanisms in human basophils and mast cell-dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib's unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of immune-mediated diseases.

The effect of l-carnitine supplementation on serum levels of omentin-1, visfatin and SFRP5 and glycemic indices in patients with pemphigus vulgaris: A randomized, double-blind, placebo-controlled clinical trial.

Pemphigus vulgaris (PV) is a chronic autoimmune disorder with potentially fatal outcomes. The aim of this study was to investigate the effect of l-carnitine (LC) on secreted frizzled-related protein-5 (SFRP5), omentin, visfatin, and glycemic indices in PV patients under corticosteroid treatment. In this randomized, double-blind, placebo-controlled clinical trial, 52 patients with PV were divided randomly into two groups to receive 2 g of LC or a placebo for 8 weeks. Serum levels of SFRP5, omentin, visfatin, and also glycemic indices were evaluated at the baseline and end of the study. LC supplementation significantly decreased the serum level of visfatin (95% CI [-14.718, -0.877], p = .05) and increased the serum levels of SFRP5 (95%CI [1.637, 11.380], p < .006) and omentin (95% CI [9.014, 65.286], p < .01). However, LC supplementation had no significant effects on the serum levels of glycemic factors such as insulin (95% CI [-1.125, 3.056], p = .426), fasting blood sugar (95% CI [-4.743, 3.642], p = .894), homeostatic model assessment of insulin resistance (95% CI [-0.305, 0.528], p = .729), and quantitative insulin-sensitivity check index (95% CI [-0.016, -0.010], p = .81). LC supplementation decreased visfatin serum level and increased omentin-1 and SFRP5 serum levels in patients with PV. However, it has no significant effect on the serum levels of insulin and glycemic indices.

Grover disease: review of subtypes with a focus on management options.

Grover disease (GD) is a benign eruption that causes a papulovesicular rash on the trunk and proximal extremities. It often resolves spontaneously but can follow a more chronic and fluctuating course that may last several years. Although the etiology remains unknown, several associated triggers have been identified including heat and sweating, cool and dry air, renal failure, malignancy, and the initiation of several drugs. Since the disease tends to resolve on its own, management is aimed at disease prevention and symptomatic relief. First-line therapy includes topical steroids and vitamin D analogues with adjuvant antihistamines. In more severe cases that are refractory to less aggressive therapy, systemic corticosteroids, retinoids, and phototherapy may lead to successful resolution. Novel therapies are few and have little evidence but involve innovative use of light therapy and immune modulators. Herein, we review the literature and new trends of GD with a focus on established and novel treatments.

Effects of l-carnitine supplementation on cardiovascular and bone turnover markers in patients with pemphigus vulgaris under corticosteroids treatment: A randomized, double-blind, controlled trial.

Pemphigus vulgaris (PV) is a severe, bullous, autoimmune disease of the skin and mucous membranes. Corticosteroids are usually the main core treatment for controlling PV, which could lead to several side effects such as insulin resistance, osteoporosis, and cardiovascular disorders. The aim of this study is to evaluate the protective effects of l-carnitine (LC) supplementation in PV patients under corticosteroid treatment. In this randomized, double-blind, placebo-controlled clinical trial, 48 patients with PV were divided randomly into two groups to receive 2 g LC (n = 24) or a placebo (n = 24) for 8 weeks, respectively. Serum levels of osteopontin (OPN), bone morphogenic protein 4 (BMP4), cystatin C, systolic and diastolic blood pressure, 25 hydroxyvitamin D3, and LC were evaluated at the beginning and at the end of the study. LC supplementation demonstrated a significant increase in serum carnitine (p < .001). In addition, at the end of the trial, LC supplementation significantly decreased serum BMP4 (p = .003), OPN (p = .03), and cystatin C (p = .001) levels. There was no significant effect on blood pressure in comparison with the placebo. During study, no harmful side effects were reported by patients. These findings indicate that LC supplementation significantly leads to favorable changes in OPN, BMP4, and cystatin C in PV patients under corticosteroid therapy. However, further investigations are required to confirm these results.

Skin ulcers infected with conditional pathogenic strains treated with local hydrogen water packing in two pemphigus vulgaris patients: Case reports with follow-up for 2 months.

We are the first to report on a new, safe, and effective treatment of infections induced by conditional pathogenic strains with local wet packing with hydrogen water. The new treatment method may also shed light on the therapy of chronic, inflammatory skin ulcers.

Subjective well-being in patients with pemphigus: a path analysis.

BACKGROUND: Pemphigus is a chronic autoimmune blistering disease of the skin and mucosa severely impairing patients' health-related quality of life (HRQoL). To date, no studies have measured subjective well-being in terms of life satisfaction in pemphigus. Our main objective was to evaluate satisfaction with life in patients with pemphigus, and to analyse its relationship with clinical severity and HRQoL. METHODS: A cross-sectional survey was carried out enrolling 77 patients with pemphigus. Subjective well-being was measured using the Satisfaction with Life Scale (SWLS). HRQoL was assessed by the Dermatology Life Quality Index (DLQI) and EQ-5D-5L. Disease severity was measured by Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). RESULTS: Mean ABSIS, DLQI, EQ-5D-5L and SWLS scores of patients were 11.7 (SD 17.3), 5.4 (6.8), 0.84 (0.22) and 4.76 (SD 1.52), respectively. The proportion of patients indicating extreme dissatisfaction, dissatisfaction, slightly below average in life satisfaction, average satisfaction, high satisfaction and very high satisfaction with life was 6 (7.8%), 5 (6.5%), 14 (18.2%), 16 (20.8%), 21 (27.3%) and 15 (19.5%), respectively. Life satisfaction was independent from age, gender, level of education and type of disease. A path analysis revealed that there was no direct relationship between ABSIS and SWLS (beta = - 0.09; p = 0.428); however, the following indirect path was confirmed: ABSIS → DLQI → EQ-5D-5L → SWLS. CONCLUSIONS: Disease severity and HRQoL measures regularly used to assess patients' health status may be complemented with a measure of subjective well-being, such as SWLS, to achieve a more holistic assessment of patients' lives and optimise pemphigus care.

Retrospective analysis of a single-center clinical experience toward development of curative treatment of 123 pemphigus patients with a long-term follow-up: efficacy and safety of the multidrug protocol combining intravenous immunoglobulin with the cytotoxic immunosuppressor and mitochondrion-protecting drugs.

BACKGROUND: Pemphigus vulgaris (PV) is a life-long IgG autoantibody-mediated blistering disease affecting the mucosal surfaces lined by the stratified epithelium (oral, nasal, genital) and sometimes also the skin. While corticosteroid treatment is life saving, the high dose and prolonged courses required for disease control are associated with significant adverse effects, including death. Although introduction of rituximab (RTX) provided for a favorable outcome, the high relapse rate, that is, up to 80%, precludes successful use of RTX as a monotherapy. Intravenous immunoglobulin (IVIg) is being increasingly utilized as off-label therapy for a variety of autoimmune and inflammatory diseases, including PV and pemphigus foliaceus (PF). AIMS: The goal of pemphigus research is to develop an effective treatment modality that would allow patients to achieve and maintain a stable clinical remission without the need for additional treatments, or cure. MATERIALS AND METHODS: This article summarizes clinical outcome of 123 pemphigus patients treated with a combination of IVIg, an immunosuppressive cytotoxic drug (ICD) and mitochondrion-protecting drugs in the Blistering Disease Clinic at the University of California, Irvine from 2007 to 2017. RESULTS: The mean time to disease control was 0.2 months and time to complete remission - 1.7 months. Duration of complete remission on drugs until relapse or end of treatment was 19.3 months. The mean duration of complete remission off drugs until relapse was 15.8 months. That until end of follow up was 48.4 months, with a minimum of 14 and a maximum of 91 months. The overall complete remission rate off all drugs was 100%, with 12% overall relapse rate. Most relapses, 8.1 vs. 3.3%, occurred during the time of treatment, compared to posttreatment. No patients had more than a single relapse. The duration of the posttreatment follow-up ranged from 9 to 97 months with a mean of 64.8 months, or 5.4 years. The total number of IVIg cycles ranged from 26 in patients without a relapse to 37 in patients with a relapse. The clinical outcome in patients that received IVIg with RTX or another ICD were found to be very similar. DISCUSSION: Thus, the multidrug IVIg regimen allowed to achieve three principal treatment objectives: (i) rapid control of pemphigus symptoms; (ii) stable disease remission; and (iii) overall safety of treatment. CONCLUSIONS: While the individualized therapeutic approaches to eradicate the autoreactive B cell clones causing disease in each particular PV or PF patient are being developed, all pemphigus patients can benefit from the treatment protocol described in this study.

Biological therapy of autoimmune blistering diseases.

INTRODUCTION: Autoimmune blistering skin diseases are a group of disorders subdivided according to the location of blister formation: intraepidermal blistering in the pemphigus group and subepidermal in the pemphigoid group. These conditions are clinically heterogeneous and are treated with systemic corticosteroids and/or other forms of immunosuppression on the basis of clinical subtype and disease severity. These approaches may not be effective for the induction and maintenance of clinical response or need to be stopped because of intolerable side effects. AREAS COVERED: Biological therapies can represent a valid alternative strategy in various autoimmune blistering disorders and this review article will address this issue with a special focus on pemphigus vulgaris and bullous pemphigoid. These biological approaches are designed to target B cells, autoantibodies, complement proteins, and several cytokines. EXPERT OPINION: Innovative strategies for the treatment of autoimmune blistering conditions primarily depend on the use of drugs with a high degree of specificity targeting crucial steps in the immunopathology of these disorders. Novel biological agents offer treatment alternatives to patients with autoimmune blistering conditions by targeting B cells, pathogenic autoantibodies, complement and cytokines.

[Curative effect of ozone hydrotherapy for pemphigus].

OBJECTIVE: To determine clinical curative effects of ozone therapy for pemphigus vulgaris.
 Methods: Ozone hydrotherapy was used as an aid treatment for 32 patients with pemphigus vulgaris. The hydropathic compression of potassium permanganate solution for 34 patients with pemphigus vulgaris served as a control. The main treatment for both groups were glucocorticoids and immune inhibitors. The lesions of patients, bacterial infection, usage of antibiotics, patient's satisfaction, and clinical curative effect were evaluated in the 2 groups.
 Results: There was no significant difference in the curative effect and the average length of staying at hospital between the 2 groups (P>0.05). But rate for the usage of antibiotics was significantly reduced in the group of ozone hydrotherapy (P=0.039). The patients were more satisfied in using ozone hydrotherapy than the potassium permanganate solution after 7-day therapy (P>0.05).
 Conclusion: Ozone hydrotherapy is a safe and effective aid method for pemphigus vulgaris. It can reduce the usage of antibiotics.