Refractory Pemphigus Vulgaris Research Articles

An ‘n-of-1’ placebo-controlled crossover trial of intravenous immunoglobulin as adjuvant therapy in refractory pemphigus vulgaris

Pemphigus vulgaris (PV) is an organ-specific autoimmune blistering mucocutaneous disorder that is potentially fatal. High-dose intravenous immunoglobulin (IVIg) is increasingly used in the treatment of autoimmune diseases and it has been reported that it may also be effective in PV. To evaluate prospectively the efficacy of IVIg for PV using an 'n-of-1' placebo-controlled trial. A randomized, placebo-controlled, crossover trial of IVIg was conducted in a single patient with severe PV, comprising two phases of six consecutive months of either IVIg or placebo infusion. Before the commencement of the trial, the patient had received 18 months of IVIg but concerns about the continuing therapeutic efficacy of IVIg led to the double-blind placebo-controlled 'n-of-1' trial of IVIg. Pemphigus autoantibody titres were significantly higher when on placebo compared with IVIg treatment (median 1 : 80 vs. 1 : 20, P = 0.007), desmoglein 3 (126 vs. 79, P = 0.004) and desmoglein 1 antibody levels (126 vs. 94, P = 0.004). There was a significant improvement in subjective disease activity scores while on IVIg compared with placebo (mean overall score 11.6 vs. 20.6, P < 0.0001). The results of this study confirm a beneficial effect of IVIg in the management of refractory PV.

Efficacy of intravenous immunoglobulin therapy in the treatment of refractory pemphigus vulgaris

Objective To evaluate the efficacy of intravenous immunoglobulin (IVIg) in the treatment of refractory pemphigus vulgaris (PV). Methods This study included 12 patients who were diagnosed as active PV by clinical and pathological examination as well as direct and indirect immunofluorescent test. All patients had been treated with high dose of steroids for one month but little improvement was achieved. Besides prednisone, patients were given IVIg 400 mg/kg once a day for 5 consecutive days with a 23-day interval as a treatment course during which the application of azathioprim or cyclophosphamide was stopped. The serum levels of antibodies to desmoglein 3 were detected by ELISA kits. The effects of IVIg were evaluated by the response of patients and required doses of prednisone. Side effects were also evaluated in these patients.Results Remission was achieved in 10 (83%) of the 12 patients one week after the treatment wtih IVIg. The dosage of prednisone declined by 30% 4 weeks later. Severe side effects were observed in none but 1 patient,who developed headache, flushing and tachycardia 30 minutes after the intravenous injection of immunoglobulin, whereas all symptoms were relieved after modulation of injection speed. Following the treatment, serum levels of antibodies to desmoglein 3 were rapidly decreased by 54% in week 1, 70% in week 2,78% in week 3, while the level of IgG remained unchanged. Conclusions Mg treatment combined with prednisone could rapidly control severe PV resistant to conventional therapies. Therefore, it may serve as an adjuvant treatment of PV. Key words: Pemphigus; Infusions, intravenous; Immunoglobulins

Rituximab in refractory pemphigus vulgaris

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.

Gold: an old drug still working in refractory pemphigus

The mainstay of treatment for pemphigus is systemic corticosteroids. Different adjuvants have been used to reduce side-effects of long-term corticotherapy. Gold is an anti-inflammatory drug used in autoimmune diseases, whose use has waned with the advent of new immunosuppressive agents. To study the outcome of the use of intramuscular gold treatment of pemphigus vulgaris refractory to previous therapies. Thirteen patients with pemphigus vulgaris who had failed to respond to several prior therapies were treated with aurothiomalate, as a steroid-sparing agent. Patients were monitored to assess disease activity and gold toxicity. Seven patients achieved complete remission. Four patients were able to taper prednisone doses, although pemphigus flared when prednisone was discontinued or reduced. Toxicity was observed in the other two patients. In 53.4% of the patients, the use of chrysotherapy resulted in the complete clearing of the disease, discontinuation of all systemic therapies and induced a long-term clinical remission. Prednisone doses were able to be reduced in the remaining 46.6%. Any side-effects were reversible with drug discontinuation. Gold therapy showed efficacy as a secondary line treatment in refractory pemphigus vulgaris.

Pemphigus vulgaire évolutif sous corticoïdes et immunosuppresseurs : rémission sous rituximab. Deux observations

Introduction Pemphigus vulgaris frequently requires corticoids and immuno-suppressive drugs. The disease and the side effects of the drugs severely affect the quality of life, and sometime the vital prognosis of the patients. Other treatments than corticosteroids and immunosuppressive drugs are needed. Exegesis We report 2 additional cases of pemphigus vulgaris uncontrolled by corticoids and immuno-suppressive drugs that responded spectacularly to rituximab. One patient had a recently onset disease, that was active despite 1,5 mg/kg/day prednisone and 1,5 g/day mycophenolate. She had a complete remission during 15 months after rituximab treatment. At relapse, another rituximab cycle led to a prompt remission. The other patient had longstanding pemphigus vulgaris complicated by cutaneous infections on prednisone (20 mg/d), immunosuppressive drugs and intravenous immune globulins. She had a prompt and complete remission after rituximab. Conclusion Rituximab seems to be a promising drug for refractory pemphigus vulgaris. The benefit to risk ratio of this drug in this new indication must be precisely documented.

Rituximab plus IV immune globulin is an effective treatment for patients with refractory pemphigus vulgaris,

Rituximab plus IV immune globulin is an effective treatment for patients with refractory pemphigus vulgaris,

Treatment of Pemphigus Vulgaris with Rituximab and Intravenous Immune Globulin

Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous blistering disease. Conventional therapy consists of high-dose corticosteroids, immunosuppressive agents, and intravenous immune globulin. We studied patients with refractory pemphigus vulgaris involving 30% or more of their body-surface area, three or more mucosal sites, or both who had inadequate responses to conventional therapy and intravenous immune globulin. We treated the patients with two cycles of rituximab (375 mg per square meter of body-surface area) once weekly for 3 weeks and intravenous immune globulin (2 g per kilogram of body weight) in the fourth week. This induction therapy was followed by a monthly infusion of rituximab and intravenous immune globulin for 4 consecutive months. Titers of serum antibodies against keratinocytes and numbers of peripheral-blood B cells were monitored. Of 11 patients, 9 had rapid resolution of lesions and a clinical remission lasting 22 to 37 months (mean, 31.1). All immunosuppressive therapy, including prednisone, could be discontinued before ending rituximab treatment in all patients. Two patients were treated with rituximab only during recurrences and had sustained remissions. Titers of IgG4 antikeratinocyte antibodies correlated with disease activity. Peripheral-blood B cells became undetectable shortly after initiating rituximab therapy but subsequently returned to normal values. Side effects that have been associated with rituximab were not observed, nor were infections. The combination of rituximab and intravenous immune globulin is effective in patients with refractory pemphigus vulgaris.

Tratamiento de pénfigo vulgar grave resistente con 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.

Response of pemphigus vulgaris to anti-CD20 antibody therapy (rituximab) may be delayed.

Conflict of interest: none declared. Recent reports have documented swift responses in refractory pemphigus vulgaris to anti‐CD20 antibody therapy (rituximab).1, 2 We report a case in which improvement was delayed following an initial exacerbation. A 37‐year‐old woman presented with a 4‐month history of blisters affecting the trunk, vagina and mouth. The clinical diagnosis of pemphigus vulgaris was confirmed by histology and direct immunoflorescence. Prednisolone (up to 2 mg/kg daily) either alone or in combination with azathioprine (up to 3 mg/kg daily), mycophenolate mofetil (up to 5 g daily), ciclosporin (up to 6 mg/kg daily) or cyclophosphamide (up to 2 mg/kg daily) failed to control her disease over 2.5 years. Intermittent 5‐day infusions of intravenous immunoglobulins (400 mg/kg daily) and intravenous methylprednisolone pulses (1 g daily for 3 days) were only partially effective. In an attempt at better disease control, an anti‐CD20 antibody therapy (rituximab) was administered (375 mg/m2) once weekly for 4 weeks with oral paracetamol and intravenous chlorpheniramine maleate pre‐medication. This produced an immediate exacerbation of her pemphigus despite concomitant prednisolone (14 mg daily) and mycophenolate mofetil (4 g daily), necessitating a 3‐day course of pulsed intravenous methylprednisolone (1 g daily). The exacerbation was not associated with any significant change in antiepidermal antibody titres.

Successful Treatment of Refractory Childhood Pemphgus Vulgaris with Anti‐CD20 Monoclonal Antibody (Rituximab)

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.

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.

Rituximab was effective in three patients with severe refractory pemphigus vulgaris,

Rituximab was effective in three patients with severe refractory pemphigus vulgaris,

Oral cyclophosphamide for treatment of pemphigus vulgaris and foliaceus

Background Cyclophosphamide is an alkylating adjuvant used in refractory cases of pemphigus. Objective We sought to evaluate the effectiveness and safety of oral cyclophosphamide in the treatment of patients with pemphigus vulgaris (PV) and pemphigus foliaceus (PF) with refractory disease. Patients We studied 23 patients with pemphigus (20 with PV; 3 with PF) who failed to achieve clinical remissions with the use of prednisone and antimetabolites. Results Complete remission was achieved in 17 patients with PV and 2 with PF. A total of 3 patients with PV failed therapy. A partial remission was achieved in 1 patient with PF. The treatment was administered for a median duration of 17 months with a follow-up period of 27 months. The median time to complete remission was 8.5 months. A total of 9 patients who were severely affected received concomitant plasma exchange. Adverse reactions included 5 cases of hematuria, 6 nonlife-threatening infections, and the development of transitional cell carcinoma of the bladder 15 years after discontinuation of cyclophosphamide in 1 patient. No death was associated with cyclophosphamide treatment. Conclusion Oral cyclophosphamide is an effective adjuvant in the treatment of severe and refractory PV and PF, but requires close monitoring.

Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder

Rituximab, a chimeric monoclonal antibody directed against CD20 of B cells, has been reported to be effective in the treatment of B-cell lymphomas and malignant and nonmalignant plasma cell-dependent diseases. We describe a 30-year-old woman with refractory pemphigus vulgaris who experienced a partial remission after treatment with rituximab. (J Am Acad Dermatol 2002;47:785-8.)

Pemphigus vulgaris: a review of treatment over a 19-year period.

Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes with a high mortality if left untreated. We present a retrospective analysis of 159 patients with pemphigus vulgaris and pemphigus vegetans who were admitted to the Department of Dermatology and Venereology, Zagreb University Hospital Center (Zagreb, Croatia) from 1980 to 1998. Female to male ratio was approximately 2:1. The mean age was 53 years. During the war years in Croatia (1991-95) we noticed a low incidence of pemphigus vulgaris, and from 1996 to 1998 the incidence almost doubled. Diagnosis was based on histopathology [showing typical pemphigus vulgaris changes in 156 (98%) patients], indirect immunofluorescence [positive in 122 (77%) patients], direct immunofluorescence [positive in 141 (89%) patients], and blister smear cytology (Tzanck test) [positive in 115 (72%) patients]. High dosages of prednisone (100-150 mg) were given to 129 patients, which was combined with azathioprine. Patients with refractory pemphigus vulgaris were treated with intramuscular gold (14 patients) and plasmapheresis (five patients). All patients were treated with local ointments. The prolonged use of high doses of corticosteroids and immunosuppressants caused several complications, in particular, steroid diabetes (37 patients), skin infections (26 patients), arterial hypertension (23 patients), cardiorespiratory diseases (22 patients), sepsis (nine patients), etc. During the hospital treatment, 14 patients died, 10 during 1980-89 and only four during the 1990-98 period. The main causes of death were cardiorespiratory failure (six patients) and sepsis (five patients). Although pemphigus vulgaris is still a life-threatening disease, today it can be successfully treated with a combination of immunosuppressive agents. Early diagnosis and treatment of pemphigus vulgaris allow a better prognosis with lower mortality rates.

Plasmapheresis and Pulse Cyclophosphamide Therapy in Pemphigus Vulgaris: A Novelty or a Reappraisal?

To the Editor.— I have read with interest the article published in the September 1987 issue of theArchivesdealing with long-lasting and complete remission in a patient with refractory pemphigus vulgaris using an experimental treatment protocol based on synchronization of plasmapheresis with subsequent pulse cyclophosphamide therapy. 1 Plasmapheresis was applied both as a means of rapid elimination of circulating intercellular antibodies (abs) and also as a means for rebound stimulation of the ab-producing cells (feedback cycle between circulating abs and their production). In that way, the subsequent high-dose cyclophosphamide treatment, by exerting its cytotoxic effect during the period of assumed maximum proliferation and, thus, vulnerability of abproducing cell clones, could act optimally. In the Comment section of their article, the authors have pointed out that two new elements characterized the therapeutic approach in the case reported: the high dose of cyclophosphamide (total dose of the cyclophosphamide pulse, 1500 mg)

Synchronization of Plasmapheresis and Pulse Cyclophosphamide Therapy in Pemphigus Vulgaris

Long-lasting and complete remission was obtained in a 48-year-old patient with refractory pemphigus vulgaris by an experimental treatment protocol that tries to synchronize plasmapheresis with subsequent pulse cyclophosphamide therapy. The rationale of the approach tries to utilize the plasmapheresis-induced increased proliferation of pathogenic cell clones for partial deletion of these clones through application of maximum pulse immunosuppression treatment during the period of assumed maximum proliferation and, thus, maximum vulnerability of the antibody-producing cells. The treatment schedule consisted of initial withdrawal of immunosuppressive drug therapy, repeated large-volume plasmaphereses substituted with immunoglobulin-free albumin solutions, subsequent application of high-dose (36 mg/kg of body weight) cyclophosphamide therapy, and low-dose maintenance immunosuppression for several months. As a result, our patient remained disease free over a follow-up period of 40 months without any further immunosuppressive treatment. Stimulation of postexchange antibody production and subsequent application of high-dose cytotoxic drugs might be a valuable tool in the management of refractory pemphigus vulgaris and, possibly, in the management of other autoantibody-mediated diseases.