Treatment of recalcitrant bullous pemphigoid (BP) with a novel protocol: A retrospective study with a 6-year follow-up.

BACKGROUND: Bullous pemphigoid is an autoimmune blistering skin disease that predominantly affects the elderly. Conventional therapy using high-dose systemic corticosteroids and immunosuppressive agents can be ineffective in some patients and produce adverse events and relapses. Hence, alternate therapies are required. OBJECTIVE: The clinical outcomes of patients with extensive, recalcitrant bullous pemphigoid treated with a combination therapy of rituximab (RTX) and intravenous immunoglobulin were evaluated. METHODS: In this retrospective study, 12 patients (mean age of 68.25 years) unresponsive to previous conventional immunosuppressive therapy, intravenous immunoglobulin, and/or RTX were treated with this combination therapy. RESULTS: Complete clinical resolution occurred in a mean of 4.6 months and previous systemic therapy was discontinued in 6.2 months. Two patients had a recurrence posttherapy and responded to additional RTX infusions. The remaining 10 patients had no recurrences. Patients were followed up for a mean of 73.8 months after discontinuation of all systemic therapy. All have remained in remission without adverse events for 6 years. LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSION: The combination of RTX and intravenous immunoglobulin produced a sustained clinical remission without adverse events, infections, and hospitalizations. This specific combination protocol offers a promising therapy for patients with recalcitrant bullous pemphigoid.

The emerging role of rituximab in autoimmune blistering diseases.

Rituximab is a chimeric monoclonal antibody that selectively binds to the CD20 molecule on B cells, resulting in their lysis. In autoimmune blistering diseases, the auto-antibody-producing B cells are destroyed and auto-antibody levels are reduced or eliminated. In the majority of patients, rituximab produces rapid clinical response and early resolution. In part, this accounts for the increased use of rituximab. Rituximab does not distinguish normal from pathologic B cells. Hence, shortly after its use, B-cell levels are zero and remain so for several months. In most patients, the use of systemic corticosteroids and immunosuppressive agents are continued after rituximab therapy, while their dosages are significantly decreased. In the majority of patients rituximab is used according to the protocol used in treating lymphoma patients or patients with rheumatoid arthritis. Approximately 50% of patients experience a relapse, requiring additional therapy. Serious adverse events and fatal outcomes have been reported, although their incidence is less than that observed with conventional therapy. Nonetheless, the causes, i.e. infections and septicemia, are similar. Several gaps exist in our understanding of how to optimally benefit from the use of this valuable biological agent. Future studies need to be targeted in designing and implanting protocols that maximize the benefit of rituximab and result in producing sustained prolonged remissions with minimal adverse events and a high quality of life.

A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab.

Approximately 500 treatment recalcitrant pemphigus vulgaris patients have been treated with rituximab. They were treated according to the lymphoma protocol (N=224) or rheumatoid arthritis protocol (RAP) (N=209) patients. Others were treated with modifications or combinations of the two. The mean duration of follow-up with the lymphoma protocol was 28.9months and 21.9 in the rheumatoid arthritis protocol. The majority of the patients received corticosteroids and immunosuppressive therapy before, during, and after rituximab therapy. A clinical remission on therapy was observed in 90%-95% of patients within less than six weeks. A complete resolution occurred within three to four months. A small percentage of patients were able to stay in clinical remission without the need for additional systemic therapy. The incidence of relapse was at least 50%. The number of patients who required additional rituximab was 60% to 90%. A majority of patients in clinical remission post-rituximab therapy, were still on CS and ISA, albeit at lower doses. Serious adverse events were reported in a mean of five patients (range 2-9), the most important was infection and frequently resulting in septicemia. The mortality rate related to rituximab was a mean of 2 patients (range 1-3). Hence, the preliminary conclusions that can be drawn are that rituximab is an excellent agent to induce early remission. The protocols that were used were not ideal for producing a prolonged and sustained remission without additional therapy. The advantages and specificity of targeting B-cells demonstrate that rituximab is one of the best biological agents, currently available for treating recalcitrant pemphigus. Its further use is encouraged. Future research needs to focus on modifying, improving and possibly adding additional agents, so that prolonged and sustained remissions can be obtained by its use.

Preliminary analysis of mortality associated with rituximab use in autoimmune diseases.

Normal antibodies and pathogenic autoantibodies are produced by B-cells and plasma cells. Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule on cells that express them on their surface and kills them. Rituximab has been increasingly used to treat several autoimmune diseases. Studies on fatal outcomes associated with rituximab therapy are lacking. A comprehensive and detailed analysis in which the multiple factors that could contribute to a fatal outcome in all the autoimmune diseases in which rituximab has been used would be cumbersome, lack uniformity and would prove difficult in making certain definitive conclusions and comparisons, but more importantly it would not allow to provide specific precautions and recommendations to prevent mortality. Hence, autoimmune mucocutaneous blistering diseases (AMBD) were used as model to study fatal outcomes in patients treated with rituximab between 2000 and 2013, using uniform 13 criteria. Fatal outcomes were found in 14 patients with autoimmune blistering diseases out of 134 patients (10.4%). Patients died due to infections (75%), gastrointestinal (17%) and cardiac events (8%). Causes of death were reported in 101 patients with other autoimmune diseases out of 4320 with a mortality rate of 2.4%. Among them, 44 patients (43.6%) died from infections. A statistical analysis of the data demonstrated that a statistically significant higher mortality rate was observed in patients with AMBD compared to patients with other autoimmune diseases. Similarly, a statistically significant higher rate of death due to infections was reported in patients with AMBD compared to patients with other autoimmune diseases. Use of systemic corticosteroids and immunosuppressive agents as concomitant therapy with rituximab enhanced immunosuppression. In many patients, B-cells were depleted for prolonged periods, even after clinical recovery was observed. Although its main action is depletion of B-cells, rituximab has a significant impact on the immune and inflammatory systems, directly and indirectly and thus enhances susceptibility to infection. These preliminary data suggests that physicians using rituximab to treat autoimmune diseases should monitor their patients closely, especially their B-cell levels until they return to normal, be vigilant for possible sources of infection, and be aware of potential fatal outcomes.

Treatment of bullous pemphigoid with rituximab: critical analysis of the current literature.

The objective of this review was to critically analyze the currently available literature on the use of rituximab to treat patients with bullous pemphigoid (BP). The focus was to highlight clinical outcomes, treatment protocols, and adverse effects. A PubMed search from 2000 to the present day was conducted, using "bullous pemphigoid" and "rituximab" as keywords. Inclusion criteria were a description of the clinical disease, histology and immunopathology typical of BP, the use of at least 1 infusion of rituximab, and the availability of follow-up after rituximab treatment. Sixteen patients (12 adults and 4 children) were identified. Fourteen patients were treated according to the Lymphoma Protocol and 2 patients according to the Rheumatoid Arthritis Protocol. In the final clinical outcome after treatment with rituximab, 11 out of 16 (69%) had Complete Response, 1 (6%) had Partial Response, 1 (6%) had No Response, and 3 (19%) died. Two died of sepsis, including 1 child, and 1 died from cardiac effects. Three (20%) had serious infections. More than 1 cycle of rituximab was required in 38% of the patients who achieved Complete Response. The mean follow-up period was 15.6 months (range 1-36), which is a serious limitation of the available data. Rituximab is a useful option for BP patients who are recalcitrant to conventional therapy. A specific protocol for the use of rituximab to treat BP patients is not yet available. Since infection and mortality rates are of concern, careful and close monitoring may be necessary.

Review on the influence of protocol design on clinical outcomes in rheumatoid arthritis treated with rituximab.

OBJECTIVE: To critically analyze the influence of protocol design on clinical outcome in patients with rheumatoid arthritis (RA) treated with rituximab. DATA SOURCES: A PubMed and EMBASE search (January 2000-January 2012) using the key words rheumatoid arthritis and rituximab was performed. STUDY SELECTION AND DATA EXTRACTION: A search of English-language studies from the data sources was conducted for randomized, double-blind, placebo-controlled studies with 100 patients or more assessing the efficacy and safety of rituximab in the treatment of RA. From these studies, 2 authors independently extracted, compiled, and aggregated the data. DATA SYNTHESIS: Eight studies met the inclusion criteria. In these studies, some patients had not been treated with tumor necrosis factor-alfa (TNF-α) inhibitors, while most did not respond to it. The variables compared included dose (500 vs 1000 mg), duration of study (24 vs 48 weeks), and number of cycles (1 vs 2). They were statistically analyzed using the χ(2) test. There was a statistically significant difference in the response to rituximab compared to the control (methotrexate) (p < 0.001). In patients who were studied for only 24 weeks, given 500 or 1000 mg for 1 or 2 cycles, a 90% or greater response rate was reported in those who achieved an ACR 20, but no statistically significant differences were observed (p = 0.75). In patients studied for 48 weeks who received 2 cycles of either 500 mg or 1000 mg of rituximab and achieved an ACR 20, a statistically significant difference (p < 0.001) was observed in those who received a dose of 1000 mg for 2 cycles (42.77% vs 67.49%). CONCLUSIONS: In patients who are nonresponsive to disease-modifying antirheumatic drugs and TNF-α inhibitors, rituximab may be a promising and well-tolerated biologic agent. The capacity of rituximab to produce long-term, sustained remissions could not be evaluated because the duration of the studies was limited to 24 weeks or 48 weeks. Studies with longer periods of observation are warranted.

Critical analysis of the use of rituximab in mucous membrane pemphigoid: a review of the literature.

BACKGROUND: Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease. In patients who do not respond to conventional therapy, rituximab (RTX) may be an option. The current literature on the treatment of MMP with RTX is limited. OBJECTIVE: In this review, the data on 28 patients with MMP treated with RTX are critically analyzed. The goal is to provide objective information useful in decision making and treatment. METHODS: A PubMed search using the key words "rituximab" and "mucous membrane pemphigoid" was made in the English language only. The studies were divided into case reports and case series. RESULTS: In the final analysis, 20 of 28 patients had a complete response, 3 had a partial response, 2 were nonresponders, and 1 had stabilization of disease. In 1 patient, stabilization of upper airway disease was observed but the patient developed bilateral blindness as a result of progression of disease. Hence, the patient was considered a treatment failure. One died from infection. At least half of the patients were treated with a second cycle because of relapse or lack of response. LIMITATIONS: Long-term follow-up after RTX therapy is lacking. Hence, the clinical benefit of inducing long-term remissions cannot be assessed. Responses of individual mucosal sites cannot be differentiated. Studies on B-cell levels and antibody responses are lacking. CONCLUSION: Using the protocol described, RTX benefits patients with recalcitrant MMP. Some patients fail treatment or experience a relapse. The ability of RTX to influence the clinical course of MMP remains to be determined.

Rituximab in the treatment of pemphigus vulgaris.

INTRODUCTION: Rituximab is increasingly used in patients with pemphigus vulgaris (PV) who are nonresponders to conventional therapy. METHODS: A PubMed search was conducted using the words pemphigus vulgaris and rituximab therapy from papers published between 2000 and 2012. Two protocols were used. In the lymphoma protocol, patients received four weekly infusions of rituximab (dose 375 mg/m(2)). The rheumatoid arthritis (RA) protocol consisted of two infusions of 1,000 mg each 15 days apart. The variables recorded from each study included clinical remission off or on therapy, relapse rate, incidence of serious adverse events, concomitant therapies, duration of follow-up, and when available, levels of B cells and autoantibodies. RESULTS: Forty-two studies were found, which reported 272 patients; 180 were treated by the lymphoma protocol and 92 by the RA protocol. Both protocols were effective in treating recalcitrant PV. The lymphoma protocol had a lower response rate, relapse rate and serious infections, but higher mortality, and there were nonresponders. The RA protocol produced a higher response rate, relapse rate, number of infections, but lower mortality rate, and lacked nonresponders. The cumulative follow-up for patients treated with the lymphoma protocol was 15.44 months (range 1-41) and 21.04 months (range 8.35-29) for the RA protocol. A major concern in both protocols was the high infection rates, some of which were fatal. A different protocol using a combination of rituximab with intravenous immunoglobulin in a defined manner with a definitive endpoint, used in a limited cohort of patients, showed promising results. CONCLUSION: Neither protocol produced a sustained clinical remission and both required continued systemic therapy. Before initiation of treatment, physicians should have a specific goal and endpoint and be aware of its potential side effects and lack of information on its long-term effects. Patients should be carefully monitored during and after therapy.