Treatment of severe refractory pemphigus vulgaris with rituximab

Pemphigus vulgaris is a potentially fatal autoimmune bullous disease. High doses of immunosuppressive drugs are used in managing severe cases of pemphigus. Rituximab, an anti-CD20 monoclonal antibody, has proven to be effective in patients with refractory pemphigus vulgaris and pemphigus foliaceus. We review cases of pemphigus vulgaris and pemphigus foliaceus not associated with lymphoma that were treated with rituximab, and we report a new case of severe refractory pemphigus vulgaris successfully treated with rituximab.     

Recommendations for the use of rituximab (anti‐CD20 antibody) in the treatment of autoimmune bullous skin diseases§

Autoimmune bullous skin disorders are induced by autoantibodies against distinct adhesion complexes of the epidermal and dermal‐epidermal junction. Since most of these disorders are characterized by a severe, potentially lethal course,they require long‐term immunosuppressive treatment to reduce the de novo synthesis of pathogenic autoantibodies by B lymphocytes. Rituximab, a chimeric monoclonal antibody against CD20 on B lymphocytes, has shown promise in several case reports or cohort studies in the treatment of paraneo‐plastic pemphigus,refractory cases of pemphigus vulgaris and foliaceus and in other autoimmune bullous disorders.Treatment with rituximab leads to depletion of pathogenic B‐cells which may last up to 12 months resulting in a reduction of plasma cells secreting pathogenic autoantibodies.Rituximab is usually administered in an adjuvant setting at a dose of 375 mg/m² i.v.in weekly intervals for four consecutive weeks in addition to the standard immunosuppressive treatment.The present consensus statement of German‐speaking derma‐tologists,rheumatologists and oncologists summarizes and evaluates the current evidence for the use and mode of application of rituximab in autoimmune bullous skin disorders.     

Nonendemic pemphigus foliaceus presenting as fatal bullous exfoliative erythroderma

Pemphigus foliaceus is a cutaneous autoimmune blistering disease that is characterized by lower morbidity and mortality than those observed in pemphigus vulgaris or paraneoplastic pemphigus. However, erythrodermic forms of the endemic variant of pemphigus foliaceus have been associated with a higher mortality. We report a case of nonendemic pemphigus foliaceus that presented as fatal bullous exfoliative erythroderma, and thus, we will emphasize the inclusion of this entity in the differential diagnosis and the use of skin direct immunofluorescence in the evaluation of patients with erythroderma.     

Nocardiosis in a patient with pemphigus foliaceus treated with rituximab

Rituximab is a chimeric human/murine monoclonal anti‐CD20 antibody. This agent is an effective therapeutic option in severe types of pemphigus. However, rituximab may cause opportunistic infections if used in immunosuppressed patients. We reported a case of diffuse Nocardia infection following rituximab treatment in pemphigus foliaceus. Rheumatoid arthritis protocol applied in our patient. Rituximab was used at a dose of 1000 mg every 2 weeks. Because the disease was not adequately controlled, rituximab treatment was administered six times every 15 days. One week after the sixth dose of the rituximab, she presented lassitude and multiple palpable masses in soft tissue of the upper extremity. Thereafter, the aspirate culture of the abscess on the left shoulder was taken and confirmed to be disseminated nocardiosis. She was treated with linezolid and meropenem for 1 month; however, amikacin was added because the patient did not respond adequately to linezolid and meropenem therapy. The patient died of cardiac arrest because of her comorbidities. In this case, prolonged administration of rituximab therapy may have caused the development of nocardiosis. Therefore, all patients should have a sensible balance of risk and benefit, considering the use of rituximab.     

Rituximab in refractory pemphigus vulgaris

ABSTRACT:  Pemphigus vulgaris (PV) is a severe chronic autoimmune blistering disease of skin and mucous membranes. The use of systemic corticosteroids in pemphigus has dramatically reduced its mortality rate, but the long-term use of steroids leads to severe side effects, many of which are serious. For this reason it is often necessary to add immunosuppressive agents to the regimen. However, there are occasional refractory cases in which therapy with conventionally accepted modalities is either not efficacious or not possible on account of side effects. Rituximab is a therapeutic monoclonal antibody targeting CD20, an integral membrane protein highly expressed on the surface of pre-B lymphocytes and activated mature B lymphocytes. We present an instance of refractory PV successfully treated with rituximab. The successful treatment of pemphigus described here demonstrates that rituximab is a viable therapeutic option for patients with refractory PV.     

Anti-CD20 monoclonal antibody (rituximab) in the treatment of pemphigus

BACKGROUND: Pemphigus is a severe autoimmune blistering disorder caused by autoantibodies to desmoglein 1 and 3. The disease course is typically severe, thus requiring multiple immunosuppressive agents. The treatment is still challenging and in some patients with recalcitrant disease, therapies fail and therapeutic options are limited. OBJECTIVES: To investigate whether depletion of B lymphocytes that are thought to produce disease-causing autoantibodies shows a long-term benefit in pemphigus. METHODS: Five patients diagnosed as having pemphigus vulgaris and pemphigus foliaceus were treated with the monoclonal antibody rituximab. Rituximab was administered intravenously at a dosage of 375 mg m(-2) once weekly for 4 weeks. RESULTS: The treatment was well tolerated and all patients showed a good response over a follow-up period of up to 3 years, allowing immunosuppressive treatment to be reduced or terminated. B-cell depletion persisted for 6-12 months, and in one patient for almost 3 years. CONCLUSIONS: This study highlights the prolonged effect and disease control after one single course of rituximab and further extends the spectrum of treatments of bullous autoimmune disorders.     

Immunoablative high-dose cyclophosphamide without stem cell rescue in pemphigus foliaceus

BACKGROUND: There is growing evidence that immunoablative high-dose cyclophosphamide without stem cell rescue is effective and safe in patients with refractory autoimmune diseases such as paraneoplastic pemphigus, systemic lupus erythematosus, aplastic anemia, and more recently pemphigus vulgaris. METHODS: We report a 51-year-old patient with severe pemphigus foliaceus, which was recalcitrant to multiple medical regimes. The patient presented with multiple thick hyperpigmented and scaly, ill-defined plaques on the face. In addition, she had multiple superficial erosions and crusts on her scalp, thorax, upper and lower extremities. The patient also had a few discrete intact flaccid bullae. A skin biopsy and direct immunofluorescence was consistent with pemphigus foliaceus. The patient's circulating pemphigus autoantibodies were present at a titer of 1 : 2560. The patient received immunoablative high-dose cyclophosphamide (50 mg/kg/day) for 4 consecutive days, and tolerated the regime well. RESULTS: Approximately 3 months after therapy, the skin lesions had healed and her prednisone, which had been as high as 80 mg daily, was tapered to 30 mg daily. In addition, her circulating autoantibodies decreased after treatment. Nearly 10 months after treatment, the patient did relapse. However, her disease was less severe and more easily managed with lower doses of immunosuppressive therapy. CONCLUSION: This case contributes to the growing evidence of high-dose cyclophosphamide's efficacy without stem cell rescue in recalcitrant autoimmune diseases, including pemphigus foliaceus.     

Successful treatment of refractory childhood pemphgus vulgaris with anti-CD20 monoclonal antibody (rituximab)

Abstract:  Pemphigus vulgaris is an uncommon autoimmune blistering skin disorder that is particularly rare in children. Immunosuppressive treatment can be challenging. Rituximab (anti-CD20 monoclonal antibody) has been used to treat autoimmune disorders by depletion of CD20 B cells. Successful rituximab therapy has been reported in adults with refractory pemphigus vulgaris. We present a girl with childhood pemphigus vulgaris unresponsive to treatment with azathioprine, mycophenolate mofetil, plasmapheresis, and intravenous immunoglobulin with systemic prednisone who responded to treatment with rituximab. She had a corresponding decline in circulating antibodies against desmoglein 1 and 3 and a decline in diphtheria and tetanus-specific antibody titers.     

Anti-B- cell-directed immunotherapy (rituximab) in the treatment of refractory pemphigus--an update

Rituximab is a monoclonal antibody directed against the CD20 surface antigen present on B lymphocytes. Following its application, B cells are rapidly and specifically depleted. Rituximab has been approved for the treatment of relapsed and therapy-refractory non-Hodgkin lymphoma and has been incorporated into numerous chemotherapy regimes with promising results. Eradication of auto-reactive B cell clones is the rationale for its application in a variety of autoimmune disorders including the pemphigus group where B cells are thought to play a critical role in the pathogenesis. Preliminary reports in autoimmune disorders are encouraging. Adverse effects are generally well controlled and although severe infections have been reported following rituximab, the overall risk does not seem to be significantly increased. In the pemphigus group, rituximab has been successfully employed in refractory cases and a recent study suggests that a single course induces long-term remission in this patient group.     

Childhood pemphigus vulgaris successfully treated with rituximab

Pemphigus is a potentially fatal autoimmune epidermal bullous disorder. Rituximab is a novel therapy for the treatment of refractory pemphigus. However, there is limited clinical data on safety and efficacy of rituximab in pediatric age group. Herein, we report an 11-year-old boy of childhood pemphigus vulgaris who failed to respond to dexamethasone pulse therapy and was subsequently treated with rituximab and achieved complete remission.     

Can rituximab be used in the treatment of pemphigus vulgaris during the COVID‐19 pandemic?

Rituximab is a monoclonal antibody that targets CD20, a B‐lymphocyte antigen; that leads to a decline in the B‐cell counts for at least a year. The patients who have received rituximab treatment in the previous 5 years with the diagnosis of pemphigus group of diseases at Cerrahpa?a Medical Faculty were questioned for COVID‐19 infection. A total of 48 patients were included in this study; only one male patient had COVID‐19 infection which had a mild course. There is no significant difference in the total number of lymphocytes between patients who have received rituximab within the previous 5 years or last year. The number of lymphocytes is independent of the number of courses of rituximab treatment received. Therefore, we suggest that all pemphigus patients who have received rituximab treatment within the previous 5 years should be careful of the preventive measures against the COVID‐19 infection irrespective of the number of treatment courses or the number of years which has passed since the treatment. The disease course was mild in the only infected patient. Thus, rituximab may be used in the treatment of pemphigus vulgaris during the COVID‐19 pandemic if its use is necessary.     

A review of rituximab in cutaneous medicine

The rituximab antibody is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Rituximab is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphoma. Rituximab is also commonly used to treat chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, and immune or idiopathic thrombocytopenic purpura (ITP). Rituximab is an effective treatment for primary cutaneous B-cell lymphoma and other cutaneous lymphomas. Rituximab is an effective treatment for mixed cryoglobulinemia. Rituximab is a promising treatment for systemic lupus erythematosus, dermatomyositis, pemphigus, vasculitis, and a variety of hematologic diseases. Black-box warnings on rituximab include fatal infusion reactions, tumor lysis syndrome, and severe mucocutaneous reactions. A variety of cardiac, pulmonary, renal, and hematologic side effects can occur. It commonly causes mild cutaneous side effect and rarely has caused paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.     

Low-dose rituximab is effective in pemphigus

Background Rituximab, an anti‐CD20 antibody, was shown in open series studies to be effective in treating pemphigus at a dose of 4 × 375 mg m^?2 as approved for B‐cell malignancies. Objectives We investigated whether a lower dose of rituximab is also effective for pemphigus. Methods Patients with pemphigus were treated with a single course of two infusions of rituximab (500 mg each) at an interval of 2 weeks. Clinical consensus late end points, B‐cell number, desmoglein 1 and desmoglein 3 indices were monitored. Results We enrolled 15 patients in the study: three with pemphigus foliaceus (PF) and 12 with pemphigus vulgaris (PV). The follow‐up was 32–152 weeks (median 94). All 15 patients responded to therapy. Eight patients achieved complete remission in a median period of 51 weeks (four on minimal therapy, four off therapy). Seven patients achieved partial remission in a median period of 34·5 weeks (five on minimal therapy, two off therapy). Relapses (40%) were seen between 53 and 103 weeks (median 97) after start of therapy. B‐cell numbers dropped to < 1% after first infusion, and remained undetectable in patients with sustained remission. The antidesmoglein 1 index correlated well with the clinical severity in PF, but this was less obvious in PV. Conclusions A low dose of rituximab is an effective and safe treatment for pemphigus. Relapses may occur, mostly at the end of the second year. Cost–effectiveness studies with a long follow‐up are required to determine the proper dosage of this expensive drug in pemphigus.     

Rituximab therapy for refractory autoimmune bullous diseases: A multicenter,open‐label,single‐arm,phase 1/2 study on 10 Japanese patients

This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m² of body surface area). The primary end‐points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD19‐positive B lymphocytes in the peripheral blood decreased on day 29 following rituximab treatment, and remained at low levels throughout the observation period (280 days). Our results confirmed the efficacy of rituximab therapy for refractory autoimmune bullous diseases in Japan.     

Coexistence of pemphigus foliaceus and mycosis fungoides

Mycosis fungoides was documented in a patient two years after pemphigus foliaceus had been diagnosed and treated with corticosteroids. Eight years later, the patient was found to have stage IV lymphomatous disease with generalized erythroderma and palpable, histologically positive lymph nodes. Hematoxylin-eosin staining of a specimen of erythroderma revealed mycosis fungoides, while direct immunofluorescence of this tissue revealed intercellular IgG deposits diagnostic of pemphigus foliaceus.     

Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature

BACKGROUND: Treatment of pemphigus vulgaris can be challenging. Systemic steroids associated with other immunosuppressant agents are the mainstay of therapy and have dramatically reduced morbidity and mortality from pemphigus vulgaris. In some patients, however, these agents are not able to control the disease or have severe adverse effects. Rituximab (MabThera; Roche, Basel, Switzerland), a chimeric monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We report 10 cases of pemphigus vulgaris and 2 cases of pemphigus foliaceous treated with rituximab--to our knowledge the largest series of patients so far--and review the existing literature on the topic. OBSERVATION: The 12 patients were selected for treatment with the anti-CD20 antibody. Rituximab was administered intravenously at a dosage of 375 mg/m(2) once weekly for 4 weeks. The treatment was well tolerated, and all 12 patients showed a good clinical response during an 18-month follow-up period, along with a consensual decline of the serum antidesmoglein titers. No infectious complications were observed. CONCLUSIONS: Rituximab is able to induce a prolonged clinical remission in patients with both pemphigus vulgaris and pemphigus foliaceous after a single course of 4 treatments. The preliminary experiences worldwide make rituximab a promising therapeutic option for patients with autoimmune diseases. The high costs and the limited knowledge of long-term adverse effects, however, limit its use to selected patients with treatment-resistant or life-threatening disease.     

生物制剂和生物技术治疗天疱疮进展

天疱疮是一种慢性、复发性表皮内棘层松解性大疱性皮肤病,生物制剂和生物工程技术在天疱疮治疗中发挥一定作用。利妥昔单抗作为一种生物制剂,被国际专家共识推荐为天疱疮一线治疗方案。造血干细胞移植可重建患者的免疫系统,基于前期临床试验确切的疗效,造血干细胞移植已被应用于难治性天疱疮的治疗。调节性T细胞（regulatory T cells,Tregs）在维持自身免疫耐受和避免免疫反应过度损伤中发挥重要作用,应用Tregs过继回输治疗天疱疮前期试验疗效显著。本文综述了利妥昔单抗、干细胞技术以及Tregs过继治疗天疱疮的进展。     

Delayed response of oral pemphigus vulgaris to rituximab treatment

Rituximab is a monoclonal antibody directed against the CD20 antigen of B cells, which has been developed for the treatment of lymphomas and has been successfully used in the treatment of recalcitrant pemphigus vulgaris. Here, we report on a 26-year-old patient with an 18 month history of pemphigus vulgaris of the oral mucosa where treatment with rituximab led to a delayed but sustained therapeutic response. This case is of interest since most of the previous reports have described a more rapid clinical improvement of refractory pemphigus by rituximab treatment. The delayed clinical response to rituximab of the present case may be explained by the persistence of long-lived plasma cells that continued to produce pathogenic autoantibodies against desmoglein 3.     

Adjuvant rituximab treatment for pemphigus: A retrospective study of 45 patients at a single center with long‐term follow up

To evaluate the long‐term outcomes of rituximab in the treatment of pemphigus and the influence of disease duration and different dose of rituximab on the clinical response, 45 patients with refractory pemphigus treated with at least one cycle of two infusions of rituximab (375 mg/m² per infusion weekly) were retrospectively studied. All patients were followed up for more than 2 years. All patients achieved complete or partial remission within 8 months of the first cycle. Thirty‐four (76%) patients relapsed at a median of 17 months. All patients who received additional cycles after relapse achieved new remissions. Early use of rituximab within 1 year of disease duration and high‐dose therapy induced better outcomes, although the results in early use were not statistically significant. Acute respiratory distress syndrome occurred in one patient. Rituximab is effective in treating pemphigus, but relapses are frequent during long‐term follow up, and additional cycles are beneficial in relapsed cases. Early and high‐dose rituximab therapy may be more effective.     

Psoriasiform pemphigus foliaceus: a report of two cases

Pemphigus foliaceus (PF) represents an autoimmune blistering disease characterized by the disruption of epidermal intercellular adhesion proteins. Clinical findings include superficial crusted erosions in a seborrheic distribution; however, the disease can rarely present as an exfoliative erythroderma. Histopathologic findings include acantholysis with cleavage within the granular layer. Direct immunofluorescence studies show intercellular IgG and complement deposition. We present two patients, to our dermatology department, with a previous diagnosis of psoriasis, with an exfoliative erythroderma, which ultimately proved to be because of PF based on histopathological features, direct immunofluorescence results and levels of antibodies against desmoglein 1. Both patients responded well to oral prednisone and rituximab. This variant of PF should be entertained in both the clinical differential diagnosis of psoriasiform erythroderma and in the microscopic differential diagnosis of psoriasiform epidermal hyperplasia with focal acantholysis, particularly in patients for whom the clinical history is not classic for psoriasis or for whom conventional psoriasis therapies have not proven beneficial.