Refractory Pemphigus Vulgaris Research Articles

Alternative Therapies to Immunoglobulin for Autoimmune Blistering Diseases


 We did not find any evidence regarding the clinical effectiveness and safety of alternative treatments to IV immunoglobulin (IVIg) compared to IVIg or placebo for bullous pemphigoid (BP) or pemphigus vulgaris (PV) and pemphigus foliaceus (PF) that met our inclusion criteria for this review.
 We identified 6 consensus guidelines presenting treatment algorithms for BP (3 guidelines) or PV and PF (3 guidelines). All guidelines recommend that IVIg may be used as a third-line treatment for severe or refractory cases.
 For severe or refractory BP, other therapeutic options than IVIg include monoclonal antibodies, immunosuppressive drugs, immunoadsorption, and plasma exchange (3 guidelines).
 For severe or refractory PV and PF, other therapeutic options than IVIg include immunosuppressive drugs, dapsone, immunoadsorption, plasma exchange, and IV corticosteroid pulse therapy (3 guidelines).
 The evidence base supporting these guidelines was unclear; recommendations should be interpreted with caution.

Case series of two different dose regimen Rituximab therapy for severe Pemphigus

Rituximab is a monoclonal antibody approved for treatment of adults with severe and refractory pemphigus vulgaris. Concerns about side effects and high costs of conventional doses have rised the hypothesis that low-dose rituximab regimen may be cost-effective with a better safety profile. Here we report our experience of seven patients with extensive/recalcitrant pemphigus, who either were steroid dependent, had contraindications or refused conventional treatment. Two patients received conventional rituximab (1000 mg 2 weeks apart) while five received ultra low-dose rituximab (200 mg 2 weeks apart). At 3 months, the two patients treated with high Rituximab regimen showed respectively a complete remission off therapy (CROT) and a complete remission on minimal therapy (CRMT), while among the five patients treated with ultra low-doses, three achieved CROT, one achieved CRMT and one a partial remission off therapy (PROT). All patients treated with ultra low-dose rituximab achieved complete depletion of cd19+ and cd19/45+ B lymphocytes after three months and all patients except one male manteined the zeroing after 6 months. No serious side effect was documented with low dose regimen except for a case of diziness. Our data suggest that ultra low-dose rituximab can be effective even in patients with extensive/recalcitrant pemphigus, with a lower probability of side-effects respect to higher dose regimen and may act as a steroid sparing strategy.

Refractory pemphigus vulgaris with extrapulmonary tuberculosis: A challenging case management with rituximab

Pemphigus vulgaris is an autoimmune acantholytic blistering disease that affects the skin and mucous membranes and that is due to IgG autoantibodies targeted against adhesion molecules such as desmoglein 1 and 3 in the epidermis. It follows a chronic course with remissions and exacerbations affecting the patient’s quality of life. Since the advent of immunosuppressants, the prognosis of pemphigus has improved but mortality still persists. Long-term use of high-dose corticosteroids and immunosuppressants leads to serious adverse events. Recently, rituximab, a chimeric anti-CD20 monoclonal antibody, which causes B-cell depletion, has been shown to improve disease remission rates with faster tapering of steroids compared to the conventional treatment. Herein, we present a case of refractory pemphigus vulgaris with extrapulmonary tuberculosis and myelosuppression, focusing on unmet challenges due to high-dose systemic steroids, azathioprine, and successful management of the case with rituximab.

Biologics in autoimmune bullous diseases: Current scenario.

Autoimmune bullous diseases can be intraepidermal (pemphigus group of disorders) or subepidermal (pemphigoid group of disorders). The treatment of these disorders chiefly comprises corticosteroids and immunosuppressant adjuvants like azathioprine and mycophenolate mofetil. Autoantibodies are the main mediators of these diseases. Rituximab, a chimeric anti-CD20 monoclonal antibody targeting B-cells, has emerged as an excellent treatment option for refractory pemphigus vulgaris in the last decade. Since then, many new biologics have been proposed/explored for managing autoimmune bullous diseases. These hold potential for greater efficacy and lesser adverse effects than conventional immunosuppressants. In this review, we discuss the role of various biologics in the treatment of autoimmune bullous diseases, followed by a brief discussion on the drawbacks to their use and new developments in this area.

Short-Term Intravenous Infusion of Cyclophosphamide in the Treatment of Refractory Pemphigus Vulgaris: A Retrospective Study

Background: Pemphigus is an autoimmune disease of the skin and mucous membranes. Glucocorticoids have been the most effective drug for the treatment of pemphigus; however, some patients are insensitive to glucocorticoid therapy. Cyclophosphamide has been extensively used in the treatment of pemphigus. Objectives: To observe and evaluate the efficacy and safety of high-dose glucocorticoid with weekly intravenous cyclophosphamide in the treatment of refractory pemphigus vulgaris insensitive to glucocorticoids. Methods: Clinical data of 19 patients with refractory pemphigus vulgaris (insensitive to glucocorticoid) who were treated with high-dose glucocorticoids(1.5 mg/kg/day prednisone) and weekly intravenous infusion of cyclophosphamide, and 24 patients who were sensitive to glucocorticoid therapy received a medium dose of glucocorticoid alone (1 mg/kg/day prednisone) were retrospectively analyzed. Results: By the time the disease was brought under control, the average total dose of cyclophosphamide was 2.02 g. Comparison between the glucocorticoid-insensitive and glucocorticoid-sensitive groups showed that the average time to disease control was 2.68 vs. 2 weeks, and the average daily dosage of steroid was 1.33 ± 0.53 vs. 0.90 ± 0.28 mg/kg. At the 12- and 18-month follow-ups, the recurrence rate of the glucocorticoid-insensitive group was significantly lower than that of the sensitive group (5.3 vs. 37.5%, 15.8 vs. 45.8%). No serious adverse reactions were observed. Conclusion: High-dose glucocorticoid plus weekly intravenous infusion of cyclophosphamide safely, effectively, and rapidly controlled the conditions of the patients with refractory pemphigus who were insensitive to glucocorticoids, shortened the duration of hospitalization, avoided the risk of complications that could be caused by further increasing the dose of glucocorticoids (>1.5 mg/kg/day), and lowered the recurrence rate within 18 months.

Aggressive refractory pemphigus vulgaris that responded to plasmapheresis: a\xa0case report

BackgroundPemphigus vulgaris is an autoimmune disorder that involves intraepithelial blistering and sores of the skin and mucous membranes. The average age of onset is between 50 and 70 years. Pemphigus rarely occurs in children. It correlates with the level of circulating autoantibodies; therapeutic plasma exchange is hypothesized to remove pathogenic autoantibodies, and this is necessary in refractory severe cases.Case presentationA 14-year-old Asian girl came to our hospital with blisters and erosions all over her body and in the oral mucosa. She was diagnosed with pemphigus vulgaris by skin biopsy about 3 months before hospitalization. She was admitted to the intensive care unit due to aggressively worsening symptoms, extensive lesions, dehydration, and electrolyte imbalance secondary to excess fluid loss from the skin wounds and sepsis secondary to infection of the exposed wounds. She did not respond to prednisone and azathioprine therapy but was successfully treated with plasmapheresis.ConclusionThe purpose of this case report is to describe an aggressive presentation of pemphigus vulgaris, especially because the onset of the disease in our patient was at an early age. The disease rarely begins in childhood, and this case report highlights the importance of plasmapheresis as a useful intervention in patients with pemphigus vulgaris who are not responding to conventional therapy, taking into account that there is a paucity of studies showing the effectiveness of plasmapheresis in inducing partial or complete remission in young patients.

Biomarkers for predicting clinical relapse in refractory pemphigus patients treated with rituximab

Background: Rituximab is an effective treatment for inducing remission in pemphigus vulgaris (PV) refractory to conventional immunosuppression. Re-treatment is required on relapse, but there are currently no reliable biomarkers in predicting clinical relapse. Method: We prospectively followed 18 PV patients previously treated with rituximab at Westmead Hospital over a 2-year period. Disease activity was assessed by pemphigus disease activity index (PDAI) along with desmoglein (dsg), intercellular cement substance (ICSA) antibody titres, total B-cell and memory B-cell (CD19+CD27+) counts. Results: 9/18 patients relapsed requiring further rituximab administration. Of these, relapse was preceded by dsg elevation in 5/9 and B-cell return in 2/9 patients. Chronic elevation in dsg antibodies and B-cells were seen in the remaining 2/9 patients with no relationship to PDAI. Of the 9 patients in clinical remission, 5 had normal dsg antibody levels. Review of their clinical data prior to the study suggests correlation of dsg titre elevation with disease relapse. The remaining 4 patients had chronic elevation of dsg antibodies and B-cells. There was no additional information gained from measuring memory B-cells and no correlation between PDAI and ICSA antibody levels. Discussion: Both dsg antibody levels and B-cell counts can predict relapse in subgroups of rituximab-treated refractory PV patients.

Comparison between the efficacy of intralesional rituximab versus intralesional triamcinolone in the treatment refractory Pemphigus Vulgaris lesions: A randomized clinical trial

BackgroundPemphigus Vulgaris (PV) is a vesiculobullous autoimmune disorder characterized by production of autoantibody against cellular adhesion molecules. The treatment of PV is based on the use of systemic corticosteroid along with immunosuppressive therapy, but sometimes there are limited resistant lesions not responding to conventional systemic therapy. This double-blind, randomized clinical trial was designed to evaluate the efficacy of intralesional rituximab versus triamcinolone in treatment of the refractory scalp and mucosal pemphigus lesions. Methods2 refractory lesions of PV were selected in 21 patients, and they were randomly assigned to two groups to be treated with either intralesional triamcinolone or rituximab for 2 times at one-month interval. All of the patients were under treatment with prednisolone and azathioprine. Patients were visited at the baseline, 1 and 6 months after treatment, and all information including demographic characteristics of the patients, Pemphigus Vulgaris Lesion Severity Score (PVLSS), Epithelialization Index (EI) and patient's satisfaction (using Visual Analogue Scale (VAS)) were obtained. The collected data were analyzed using SPSS software (ver18). ResultsThe results showed that, both rituximab and triamcinolone were effective in treatment of the refractory PV lesions (p < 0.05). However, there was no significant difference between the effect of intralesional rituximab and triamcinolone (p > 0.05). In addition, no side effect was observed in both groups. ConclusionRegarding the results of the present study, the use of intralesional rituximab can be suggested for treatment of the resistant PV lesions as an alternative to intralesional triamcinolone or using more aggressive systemic therapy.

A patient with refractory oral pemphigus vulgaris successfully treated with a biologic drug- Rituximab: A case report

Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease affecting mucous membranes and the skin. Rituximab (RTX), a monoclonal antibody against CD20, has been approved by FDAfor the treatment of adults with moderate to severe PV. A42-year-old Indian woman, with refractory oral PV presented to our clinic with painful erosions and ulcers of her oral mucosa. She was treated with available evidence based immunosuppressants with limited success over a period of 8 years. RTX was given observing the lymphoma protocol. Her symptoms improved dramatically after the first month of RTX with sustained resolution on low doses of prednisone, mycophenolate mofetil and no significant new lesions appearing to date. Her quality of life improved significantly. RTX seemed an effective treatment for refractory oral PV. Keywords : Pemphigus vulgaris , rituximab, autoimmune, mucocutaneous.

Immunoadsorption in dermatology

Autoimmmune bullous diseases are mediated by pathogenetically relevant autoantibodies against components of the epidermis and/or superficial mucous membranes (in pemphigus) and structural proteins of the dermal-epidermal junction (in pemphigoid diseases). Using immunoadsorption (IA), an already well-established procedure in cardiac and rheumatic disorders, antibodies can be removed from the plasma. At present, most data on the adjuvant use of IA in dermatology are derived from patients with severe and/or refractory pemphigus vulgaris or pemphigus foliaceus and also from patients with pemphigoid diseases. Additionally, in the last few years different protocols for IA in patients with severe atopic dermatitis and elevated total serum IgE levels have been published. While panimmunoglobulin adsorbers are mainly used in dermatology, an IgE-specific adsorber has been used in some patients with atopic dermatitis and in the future, antigen-specific adsorbers are to be expected that will enable the specific reduction of autoantibodies.

48 - Chromosomal Aberrations in Therapy-Related Myelodysplastic Syndromes – Relations to Primary Disease, Therapy and Prognostic Significance

Pemphigus vulgaris (PV) is a rare autoimmune disease due to the production of pathogenic autoantibodies directed against desmoglein 1 and 3, usually affecting both skin and mucous membranes. Recently, rituximab, a chimeric IgG1 monoclonal antibody which targets the CD20 molecules have been regarded as a promising treatment for PV. In this study, a systematic review was conducted to conclude on how and which PV patients could benefit from rituximab infusion. Search in PubMed results in 114 relevant studies, which met the criteria. Total of 1085 PV patients with different conditions, including unresponsive childhood/juvenile or adult PV patients, women of childbearing age, those with chronic infections with the risk of reactivation have been evaluated. Although the majority of these patients well responded to rituximab, some of them did not respond, and the paucity of patients experienced exacerbation of disease. In addition to the rituximab monotherapy or its combination with conventional therapies, different novel combination therapies of rituximab with immunoadsorption and/or IVIg have shown promising results. Moreover, using rituximab as the first-line treatment has emerged recently. Pneumocystis carinii pneumonia and septicemia were found as the two fatal and serious adverse events associated with rituximab. Moreover, development or reactivation of herpes simplex and herpes zoster and cytomegalovirus should be warned. Similar to the adults, those with childhood and juvenile PV could be successfully treated with rituximab. Although rituximab seems to trigger reactivation of chronic infections, such as viral hepatitis and HIV infection, no related report was found. Administration of rituximab in approximately ten months before conception also was found safe and effective for a successful pregnancy. In conclusion, rituximab is very effective in adult and childhood/juvenile PV. However, there is a risk of not responding, exacerbation of disease and development of fatal infections. Moreover, it seems to be a promising first-line treatment for refractory PV.

Rituximab therapy improves recalcitrant Pemphigus vulgaris

Pemphigus is a severe life-threatening blistering disease associated with autoantibodies against cell adhesion proteins desmogleins 1 and 3. Patients with severe pemphigus commonly show high rates of relapse after conventional immunosuppressive therapy. The newly developed drug Rituximab showed impressing promises in the treatment of refractory pemphigus vulgaris (PV). In the present study the efficacy of a single course rituximab therapy in the treatment of PV was investigated. Eighteen patients with severe recalcitrant PV were recruited to this study. Pemphigus disease activity index (PDAI), anti-desmoglein 1 and anti-desmoglein 3 antibody titers, and percent of CD20 positive cells were measured at baseline, 10 ± 1, and 22 ± 2 weeks after rituximab therapy. Rituximab was given intravenously at dose 375 mg/m2 once weekly for 4 weeks. Rituximab therapy caused a dramatic reduction in the PDAI, accompanied by decreases in anti-desmoglein 1 and anti-desmoglein 3 antibody titers over the follow-up course. The B-cell population decreased at the first follow-up, but returned to its baseline levels at the second follow-up. Rituximab therapy decreased the dose of immunosuppressive drugs required to control the disease. It seems that the rituximab may be effective and safe for treatment of refractory PV.

Rituximab therapy improves recalcitrant Pemphigus vulgaris.

Pemphigus is a severe life-threatening blistering disease associated with autoantibodies against cell adhesion proteins desmogleins 1 and 3. Patients with severe pemphigus commonly show high rates of relapse after conventional immunosuppressive therapy. The newly developed drug Rituximab showed impressing promises in the treatment of refractory pemphigus vulgaris (PV). In the present study the efficacy of a single course rituximab therapy in the treatment of PV was investigated. Eighteen patients with severe recalcitrant PV were recruited to this study. Pemphigus disease activity index (PDAI), anti-desmoglein 1 and anti-desmoglein 3 antibody titers, and percent of CD20 positive cells were measured at baseline, 10 ± 1, and 22 ± 2 weeks after rituximab therapy. Rituximab was given intravenously at dose 375 mg/m(2) once weekly for 4 weeks. Rituximab therapy caused a dramatic reduction in the PDAI, accompanied by decreases in anti-desmoglein 1 and anti-desmoglein 3 antibody titers over the follow-up course. The B-cell population decreased at the first follow-up, but returned to its baseline levels at the second follow-up. Rituximab therapy decreased the dose of immunosuppressive drugs required to control the disease. It seems that the rituximab may be effective and safe for treatment of refractory PV.

Herpes simplex virus reactivation as a trigger of mucous lesions in pemphigus vulgaris

Although infectious agents have long been implicated in the induction or exacerbation of pemphigus vulgaris (PV), a convincing role for the agent in the aetiology of PV has not been established. To establish the association with PV and herpes simplex virus (HSV). We examined saliva for the presence of HSV DNA after the onset of PV initially localized to the oral lesions in addition to conventional serological tests and immunohistochemistry. We successfully detected high levels of HSV DNA in the saliva samples from six of 16 patients with PV at the earliest stage, who had no episodes of herpes simplex. The prevalence (37·5%) of detecting HSV DNA in the patients with PV was lower than that of eczema herpeticum (56·5%), but comparable to that in patients with herpes labialis (30·0%). Copy numbers of the HSV DNA were rather higher than those with herpes labialis and with eczema herpeticum. In general, detection of HSV DNA in saliva was transient and restricted to the earliest phase of the disease. In addition, anti-HSV immunoglobulin (Ig) G titres in patients with PV were significantly higher than those in patients with virologically confirmed HSV-induced disorders. All salivary HSV DNA-positive patients with PV had run a more complex, intractable course refractory to conventional therapy. Detection of HSV DNA in saliva is a useful and noninvasive, quantitative method for establishing the role of HSV in the pathogenesis of PV and for identifying individuals at greater risk for subsequently developing refractory PV.

Adjuvant rituximab therapy in pemphigus: a single-center experience of 18 cases

Background: Pemphigus vulgaris (PV) follows a chronic relapsing course where the mainstay of therapy has been oral corticosteroids and second-line immunosuppressive and immunomodulating therapies. Successful responses have been reported with rituximab, a chimeric monoclonal anti-CD20 antibody targeting B lymphocytes, although its use in recalcitrant pemphigus is still being studied. Methods: A retrospective analysis is presented of 18 patients with cutaneous and mucous membrane involvement after disease relapse following steroid and other adjuvant therapies who were treated with rituximab (4 intravenous infusions of 375 mg/m2 once weekly for 4 consecutive weeks). Results: At 3 months follow-up, 44% (8/18) of cases achieved complete disease remission with a further 44% (8/18) showing partial remission. Further follow-up showed 5/8 partial responders achieving a complete response with 4 cases experiencing disease relapse (72% response at 9 months). There were no adverse drug-related events and its use resulted in a significant reduction in steroid dosage during follow-up. Conclusion: Rituximab is beneficial in the management of refractory PV, resulting in clinical remission and a steroid-sparing effect. Further study needs to examine rituximab dosage and scheduling as well as its place within the treatment algorithm.

Infliximab therapy failure in two patients with pemphigus vulgaris

To the Editor: Pemphigus vulgaris (PV) is a severe autoimmune intraepidermal blistering disease associated with autoantibodies against desmoglein-1 and -3; its treatment is generally challenging. High-dose corticosteroids, along with other immunosuppressants, is the mainstay of therapy.1 We report the cases of two patients with refractory PV unsuccessfully treated with the tumor necrosis factor (TNF)–alpha antagonist infliximab.

A Case Report of Refractory Pemphigus Vulgaris Treated by Rituximab

A Case Report of Refractory Pemphigus Vulgaris Treated by Rituximab

Refractory pemphigus vulgaris associated with herpes infection: case report and review

Pemphigus vulgaris (PV) is an autoimmune disease characterized by blistering of the skin and mucosa, which develops due to the interaction between predisposing genetic and environmental factors. Infections caused by members of the Herpesviridae family have been suggested as a possible triggering factor for PV. In this report, we investigate the presence of herpesviruses in refractory lesions on the right upper eyelid. The lesion has persisted despite the treatment with corticosteroids. Polymerase chain reaction (PCR) and DNA sequence analysis have been used to detect the DNA of HSV 1/2, VZV, EBV, CMV, HHV-6, HHV-7, and HHV-8. The sample collected from the right upper eyelid has tested positive for HSV 1/2. Sequence analysis has confirmed the PCR results and allowed the identification of the HSV strain as belonging to type 1. After treatment with acyclovir, the lesion of the right upper eyelid has cleared and not relapsed. When patients present PV lesions which are refractory to corticosteroid therapy, herpetic infection should be considered.

Rituximab for the treatment of corticosteroid - refractory pemphigus vulgaris with oral and skin manifestations

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease affecting the skin and mucosa and is associated with increased morbidity and mortality. Once the diagnosis is established, the main stay of treatment of PV is with systemic corticosteroids to control the disease and then to consolidate the management with other immunosuppressive agents. A small group of patients with severe pemphigus, however, remain relcalcitrant to both steroids and azathioprine, and disease is difficult to control. When considering the treatment of refractory PV, there is increasing evidence for the successful use of the monoclonal anti-CD20 antibody, rituximab. We report here six cases of patients presenting with oral and skin PV with recalcitrant or rapidly progressive disease treated with a novel dosing regimen of rituximab as a single agent. All patients achieved a complete response to a maximum follow-up of 34 months.

Enteric‐coated mycophenolate sodium in the treatment of refractory pemphigus

One of the major goals of pemphigus therapy is to reduce the patient's cumulative exposure to systemic corticosteroids. To investigate the efficacy of enteric-coated mycophenolate sodium (EC-MPS), 10 patients with active, refractory pemphigus vulgaris (PV) or foliaceous (PF) were treated with EC-MPS (1440 mg daily) and prednisone (75 mg daily) over 18 months. Following EC-MPS/prednisone therapy, disease progression was inhibited between days 30 and 45 in 9/10 patients (8 PV; 1 PF). At 18 months, 8/9 PV patients had clinically quiescent disease; EC-MPS therapy was no longer required in two patients as a result of disease remission. The remaining PV patient showed no response to treatment. The PF patient also had clinically quiescent disease but with high levels of anti-desmoglein-1. ECMPS dose was reduced to 720 mg daily in 4/9 patients by month 6. Average daily prednisone requirement decreased to 25 mg at 6 months and to 15 mg at 18 months. Three adverse events were reported: headache (two cases; one mild and one moderate) and significant increase in blood glucose (one case; moderate). Enteric-coated mycophenolate sodium is effective and safe as an adjuvant therapy in patients with refractory pemphigus and may be effective even in patients whose disease is unresponsive to azathioprine.