Efficacy and safety of rituximab in pemphigus: experience of the German Registry of Autoimmune Diseases

Background: Rituximab has been reported to be effective in various small case series of patients with severe and/or refractory pemphigus. However, no systematic evaluation is available to corroborate this observation. The aim of this study was to systematically determine efficacy and safety of rituximab in treatment-resistant pemphigus. Patients and Methods: Multicenter retrospective, observational study of 36 patients with severe pemphigus vulgaris (n = 33) and pemphigus foliaceus (n = 3) treated with rituximab before August 31(st) , 2008 and enrolled in a national observational registery between December 2008 and June 2009. Results: Within a mean period of observation of 11 (1-37) months, 21 (58 %) pemphigus patients showed complete, 13 (36 %) partial, and 2 (6 %) no response to rituximab treatment. This correlates with a mean improvement of the visual analog scale for well-being of 34 (20-60) at baseline to 75 (40-95) at the last control visit. In 4 (11 %) patients, severe adverse events were recorded including 1 (3 %) serious infection. Conclusions: Data collected in this systematic registry indicate that rituximab is an effective and relatively safe adjuvant treatment option for refractory pemphigus. To further extend our knowledge on efficacy and safety of this drug, controlled prospective trials are required.     

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.     

Effektivität und Sicherheit von Rituximab beim Pemphigus: Ergebnisse aus dem Deutschen Register für Autoimmunerkrankungen

Background: Rituximab has been reported to be effective in various small case series of patients with severe and/or refractory pemphigus. However, no systematic evaluation is available to corroborate this observation. The aim of this study was to systematically determine efficacy and safety of rituximab in treatment‐resistant pemphigus. Patients and Methods: Multicenter retrospective, observational study of 36 patients with severe pemphigus vulgaris (n = 33) and pemphigus foliaceus (n = 3) treated with rituximab before August 31^st, 2008 and enrolled in a national observational registery between December 2008 and June 2009. Results: Within a mean period of observation of 11 (1–37) months, 21 (58 %) pemphigus patients showed complete, 13 (36 %) partial, and 2 (6 %) no response to rituximab treatment. This correlates with a mean improvement of the visual analog scale for well‐being of 34 (20–60) at baseline to 75 (40–95) at the last control visit. In 4 (11 %) patients, severe adverse events were recorded including 1 (3 %) serious infection. Conclusions: Data collected in this systematic registry indicate that rituximab is an effective and relatively safe adjuvant treatment option for refractory pemphigus. To further extend our knowledge on efficacy and safety of this drug, controlled prospective trials are required.     

Treatment of severe pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins

BACKGROUND: Pemphigus is a life-threatening autoimmune blistering disease usually treated with high-dose corticosteroids and other immunosuppressants. However, this regimen may prove inadequate in severe cases and cause dangerous side-effects. While protein A immunoadsorption (PAIA) induces a rapid remission in severe pemphigus, the disease usually recurs once the treatment is stopped. In contrast, anti-CD20 antibody rituximab has a delayed onset of action but may lead to a long-term remission of pemphigus. OBJECTIVE: To develop a treatment protocol combining the rapid remission induced by PAIA with the positive long-term effects of rituximab. PATIENTS AND METHODS: Five patients with pemphigus vulgaris and two patients with pemphigus foliaceus were treated with a combination of PAIA, rituximab and conventional immunosuppressants. Patients who failed to respond to this therapy subsequently received intravenous immunoglobulins (IVIg). RESULTS: All seven patients showed a sharp decline of circulating autoantibody levels and rapid improvement of cutaneous and mucosal lesions within 4 weeks of therapy. Long-term remission was induced in three patients and one further patient showed a partial improvement of his disease. The three remaining patients who could not be weaned off PAIA and remained resistant to rituximab treatment showed a good response to IVIg therapy. CONCLUSION: The combination of PAIA and rituximab induces a rapid and durable remission in a subset of patients with severe pemphigus. IVIg therapy appears to be a good treatment option for rituximab nonresponders.     

Treatment of Pemphigus

Ninety-eight cases of various types of pemphigus were treated between 1978-1987. Sixty-one cases were pemphigus vulgaris (PV), 22 cases were pemphigus foliaceus, generalized type (PFG) in which one case developed pemphigus vegetans, 11 cases were pemphigus foliaceus localized type (PFL), and four cases were pemphigus erythematosus (PE). Fifteen mild cases of PV and three mild PFG were treated with corticosteroid (prednisolone or prednisone) alone, and dapsone or cyclophosphamide (CP) were added as treatment failed in two cases of each. Dapsone alone was used effectively in three cases of mild PV. Eight cases of moderate and three cases of severe PV, as well as five cases of moderate PFG, failed to respond to corticosteroid alone but were cleared by the addition of CP. Thirty-two moderate cases of PV and PFG treated with a combination of corticosteroid 60 mg/day plus initial CP and 14 severe cases of PV and PFG treated with corticosteroid 120 mg/day plus initial CP, resulted in clearing skin lesions in 2 months. Azathioprine or chlorambucil were substituted in three cases who developed CP toxicity. Addition of gold sodiumthiomalate in six refractory cases when the above regimens failed, caused a complete remission in two and partial control in four. Higher dosage of prednisolone or prednisone more than 120 mg/day has never been used. Eleven cases of PFL and four cases of PE were treated with uneventfully good results. Intercellular antibody titers became negative within 4.67 months except in refractory cases, however, the treatment was continued for at least 3 years. Herpes simplex superimposed infection was more common than herpes zoster infection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rituximab as a dual therapeutic option for pemphigus and primary cutaneous B‐cell lymphomas: Two case reports

It is known that individuals with immune dysregulation have an increased risk of non‐Hodgkin lymphoma. This association has been proven for pemphigus as well as for other autoimmune disease. We describe the development of cutaneous B‐cell lymphoma in two patients affected by long‐standing pemphigus vulgaris and pemphigus foliaceus (i.e., characterized by histological and immunopathological features different from those of paraneoplastic pemphigus). In both cases, a therapy with rituximab allowed to achieve the complete remission for the lymphoproliferative disease (never recurred at follow up) and a substantial long‐term improvement of the clinical manifestations of pemphigus, although persistent to serological disease and occasional recurrences. We suggest that clinicians should consider that patients with long‐standing pemphigus, both vulgaris and foliaceus, may develop primary cutaneous B‐cell lymphomas, as shown in our report, and in these cases the treatment with rituximab is elective, providing a therapeutic option for both low‐grade or follicular, CD20‐positive, B‐cell non‐Hodgkin lymphomas and pemphigus. Nevertheless, as shown in our cases, a constant surveillance for pemphigus is necessary.     

Erfolgreiche Therapie des Pemphigus foliaceus mit Rituximab

Treatment of autoimmune bullous diseases, especially of the pemphigus diseases, regularly requires the use of immunosuppressive drugs, often with insufficient clinical benefit but considerable side effects. A variety of autoimmune diseases (such as rheumatoid arthritis, lupus erythematosus, pemphigus vulgaris) have been successfully treated with rituximab, a chimeric monoclonal antibody against CD20, leading to a transient depletion of B cells. We report on three patients with pemphigus foliaceus who responded to rituximab after failing multiple other immunosuppressive therapies. We also examine the controversial issue of continuation therapy with rituximab in detail.     

Refractory pemphigus vulgaris treated with rituximab and mycophenolate mofetil

The main treatment for pemphigus vulgaris are systemic corticosteroids and immunosuppressive agents, but due to adverse reactions and therapeutic failure, new drugs such as rituximab and mycophenolate mofetil have been used. In this case report are described two cases of severe pemphigus vulgaris refractory to various treatments, with resolution after use of rituximab and mycophenolate mofetil, associated with corticosteroids. A higher-than-usual dose of rituximab was employed, without the occurrence of serious adverse reactions. Mycophenolate mofetil was added as adjunctive therapy due to lack of response to azathioprine.     

IgG/IgA pemphigus in a patient with a history of pemphigus vulgaris: An example of epitope spreading?

We report a case of IgG/IgA pemphigus presenting as pemphigus foliaceus following diagnosis and treatment of classic IgG‐mediated pemphigus vulgaris. The dual presentation of IgG and IgA positivity on direct immunofluorescence (DIF) constitutes a rare form of pemphigus with a wide variety of clinicopathologic manifestations. The progression of pemphigus vulgaris is commonly because of epitope spreading. However, the patient's disease was partially refractory to rituximab and showed a change in the DIF with dual staining for IgG and IgA. This indicates that class‐switching may have occurred with epitope spreading or that there was autoreactive IgA at the onset of disease below the threshold of detection by DIF. Our case indicates that in progressive autoimmune disease refractory to treatment, re‐evaluation of the patient for antibody isotypes absent on initial diagnosis may offer key information in better identifying the cause of progression as well as in directing the necessary treatment.     

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.     

Pulse therapy in pemphigus: report of 11 cases

In this study, five cases of pemphigus vulgaris and two cases of pemphigus foliaceus were treated with cyclophosphamide pulse therapy associated with prednisone, resulting in the need for a smaller maintenance dose of prednisone. In three cases of pemphigus vulgaris and one case of pemphigus foliaceus, dexamethasone and cyclophosphamide pulse therapy associated with prednisone helped the lesions to heal more rapidly. Neither treatment however prevented the recurrence of the disease. Amenorrhea, myelotoxicity and Stevens-Johnson syndrome were among the cyclophosphamide side effects. All the patients treated with prednisone experienced known side effects.     

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.     

Childhood pemphigus

BACKGROUND: Five children with pemphigus are reported: three with pemphigus vulgaris, one with pemphigus vegetans, and one with pemphigus foliaceus. Only one case of juvenile pemphigus vegetans has been published in the literature. MATERIALS AND METHODS: All three patients with pemphigus vulgaris were treated with oral corticosteroid; in two cases, azathioprine was added for steroid-sparing effect. The patient with pemphigus vegetans had a clinical presentation resembling pemphigus vulgaris, but the lesions in the perianal area healed as hypertrophic granulation tissue. He was treated with oral corticosteroid, azathioprine, and intralesional corticosteroid. The patient with pemphigus foliaceus presented with exfoliative dermatitis, and was treated with oral corticosteroid; methotrexate was added later for steroid-sparing purposes RESULTS: The patients were followed up for 1-4 years; the prognosis of childhood pemphigus is good. CONCLUSIONS: Long-term follow-up is needed to detect flaring of the disease and the side-effects of immunosuppressive drugs.     

Comparative study of pemphigus vulgaris and pemphigus foliaceus in Singapore

This is a retrospective study of all patients diagnosed to have pemphigus in our centre over a 3 year period. The case records of all patients with pemphigus from January 1995 to December 1997 were analysed. Fifty patients were diagnosed to have pemphigus during the study period. The diagnoses were pemphigus vulgaris in 31 patients, pemphigus foliaceus in 16, paraneoplastic pemphigus in two and IgA pemphigus in one. The average titre of anti-intercellular antibodies in patients with pemphigus vulgaris (1:96) was higher than the titre in patients with pemphigus foliaceus (1:69). The average initial dose of prednisolone required for disease control in patients with pemphigus vulgaris (62 mg/day) was significantly higher than that required for patients with pemphigus foliaceus (44 mg/day). In our study population, pemphigus vulgaris is a more severe and chronic disease than pemphigus foliaceus, as reflected in the higher titre of anti-intercellular antibodies, higher dose of systemic corticosteroids required for control of the disease, the longer duration to achieve complete remission and longer follow-up period.     

Validity of the EQ-5D in patients with pemphigus vulgaris and pemphigus foliaceus

Pemphigus is a group of autoimmune skin diseases that cause blisters and wounds on the skin and/or mucous membranes such as inside the mouth. It is an uncommon disease with around 15 new cases yearly per million people. The two most common clinical forms are pemphigus vulgaris and foliaceus. Pemphigus can still be life threatening, and the symptoms may cause significant difficulties for patients in their everyday life. This study, from Hungary, aimed to assess the health status and quality of life in patients with pemphigus vulgaris and foliaceus. The authors surveyed 109 pemphigus patients, and collected data on demographics and clinical characteristics. Quality of life was assessed by the EQ-5D general health status questionnaire. Overall, 50%, 43%, 43%, 42% and 19% of pemphigus patients reported problems regarding pain/discomfort, mobility, anxiety/depression, usual activities and self-care, respectively. Patients having skin and mucosal symptoms, a larger number of comorbidities (other diseases occurring alongside pemphigus) and more severe disease experienced greater impairment of quality of life. No difference was found in quality of life scores between pemphigus vulgaris and foliaceus patients or between females and males. This study demonstrates that the EQ-5D questionnaire is an accurate measure of quality of life in pemphigus patients. The EQ-5D questionnaire allows comparisons between patients across a broad range of disease areas and people without those diseases. The EQ-5D scores reported in this study can be useful for cost-effectiveness analyses of new pemphigus treatments such as rituximab, and might help to improve patients’ access to more effective medicines, in a condition for which only limited treatment options have been available so far.     

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.     

Therapy of refractory pemphigus vulgaris with monoclonal anti-CD20 antibody (rituximab)

Three patients with refractory pemphigus vulgaris improved after rituximab, an anti-CD20 monoclonal antibody directed against B cells. Treatment was well tolerated immediately, but one patient developed fatal pneumocystis carinii pneumonia. Serious infections have occurred in several pemphigus patients treated with rituximab and immunosuppressive medications, warranting further evaluation of risk-benefit ratio.     

Prevalence of Metabolic Syndrome and its components in a Brazilian sample of pemphigus patients

BACKGROUND

Pemphigus foliaceus and pemphigus vulgaris are endemic in the northeastern region of São Paulo State, Brazil. They are treated mainly with systemic corticosteroids, which may provoke osteoporosis; atherosclerosis, higher blood pressure, insulin resistance, glucose intolerance, hyperlipidemia and abdominal obesity. These side effects of corticoids also constitute criteria for the diagnosis of metabolic syndrome.

OBJECTIVE

The prevalence of metabolic syndrome and each component of metabolic syndrome in Pemphigus foliaceus and pemphigus vulgaris groups was compared with Brazilian casuistic samples.

METHODS

Data of 147 patients (pemphigus foliaceus 48.9% and pemphigus vulgaris 51.1%) were compiled from medical records regarding metabolic syndrome and its components, and included in the analysis.

RESULTS

There was no significant difference regarding the prevalence of metabolic syndrome in pemphigus groups compared with the Brazilian casuistic samples. The analysis of each component of metabolic syndrome showed a higher prevalence of: higher blood pressure in male subjects with pemphigus vulgaris, and in pemphigus foliaceus in both genders; diabetes mellitus in both genders for pemphigus vulgaris and pemphigus foliaceus; obesity in females for pemphigus vulgaris and pemphigus foliaceus, and hypertriglyceridemia in both genders for pemphigus vulgaris and pemphigus foliaceus groups that were statistically significant compared to the Brazilian reports. Furthermore, the study noted a higher incidence of cardiovascular events in both genders in pemphigus foliaceus and pemphigus vulgaris groups than in Brazilian casuistic samples.

CONCLUSION

The components of metabolic syndrome are more numerous in pemphigus when compared with Brazilian casuistic samples. Future studies are necessary to assure that metabolic syndrome may be associated with pemphigus per se, including a greater casuistic sample of patients who have not taken corticoids.     

Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients.

Pemphigus refers to a group of autoimmune blistering skin diseases, mainly identified as pemphigus vulgaris and pemphigus foliaceus, both characterized by the presence of autoantibodies against keratinocyte adhesion molecules, leading to loss of cell-cell adhesion with consequent blister formation. Pemphigus vulgaris is reported to be associated with human leukocyte antigen DR4 and/or DR6 whereas no data are available on pemphigus foliaceus, except for the endemic Brazilian form (fogo selvagem), which is reported to be associated with DR1 and DR4. We here report human leukocyte antigen molecular typing on a total of 87 patients, 61 with pemphigus vulgaris and 26 with pemphigus foliaceus, versus 128 healthy matched controls. Generic typing showed an increase of DRB1*04 and DRB1*14 and a decrease of DRB1*07 in both pemphigus vulgaris and pemphigus foliaceus patients. Molecular subtyping of DR4+ and DR14+ subjects showed a highly significant association between the DRB1*1401 and both pemphigus vulgaris (p < 0.0001) and pemphigus foliaceus patients (p < 0.0001) together with a significant increase of the linked DQB1*0503 (pemphigus vulgaris p < 0.0001; pemphigus foliaceus p < 0.0001). Moreover, whereas the association between DRB1*0402 and pemphigus vulgaris (p < 0.0001) has been confirmed, no significant association between a specific allele of the DR4 group and pemphigus foliaceus, has been found. Therefore, at least in Italian patients, pemphigus vulgaris and pemphigus foliaceus share DRB1*1401 and DQB1*0503, as susceptible human leukocyte antigen alleles, whereas DRB1*0402 is only found associated with pemphigus vulgaris. The observation that both diseases, pemphigus vulgaris and pemphigus foliaceus, carry the same susceptible human leukocyte antigen alleles has been interpreted as a common genetic background predisposing to pemphigus as, like in other autoimmune disorders, it is not sufficient to explain the onset of the disease on the basis of the sole aforementioned alleles. Other linked genes and/or environmental factors should play a facilitating role in the outbreak of pemphigus, either pemphigus vulgaris or pemphigus foliaceus.     

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.