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Therapy of refractory pemphigus vulgaris with monoclonal anti-CD20 antibody (rituximab)
Brief reports 817
J AM ACAD DERMATOL VOLUME 51, NUMBER 5
Therapy of refractory pemphigus vulgaris with monoclonal anti-CD20 antibody (rituximab) Lynne H. Morrison, MD Portland, Oregon 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. ( J Am Acad Dermatol 2004;51:817-9.)
P
emphigus vulgaris (PV), an antibody-mediated autoimmune bullous disease, causes significant morbidity and the current mortality rate is 5% to 10%.1 Treatment generally includes high dose corticosteroids and, frequently, immunosuppressive agents. Despite these medications, some patients never attain remission and others remain poorly controlled. This, and the adverse effects of chronic corticosteroids and immunosuppressives, spurs continued interest in new therapies. Rituximab, a monoclonal antibody directed against the CD20 antigen on the surface of mature B lymphocytes,2-4 markedly reduces B-cell counts. It is approved for the treatment of CD20 positive Bcell lymphoma. It is also effective in treating several antibody-mediated autoimmune diseases,4-10 offering a novel therapeutic approach for PV patients. We report 3 patients with refractory PV treated successfully with rituximab.
CASE REPORTS All patients had PV confirmed by histology and direct immunofluorescence. All received intravenous (IV) rituximab (375 mg/m2) once weekly for 4 consecutive weeks. Indirect immunofluorescence (IIF) studies were performed immediately before starting rituximab and following the last infusion. All patients tolerated the infusions without adverse From the Department of Dermatology, Oregon Health Sciences University. Funding sources: None. Conflicts of interest: None identified. Correspondence: Lynne H. Morrison, MD, Department of Dermatology OP06, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239. E-mail: [email protected]. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.06.007
immediate effects. Chemistry and complete blood cell count (CBC) studies were unremarkable. Case 1 A 51-year-old white male with PV involving 75% of his scalp and oral cavity responded to prednisone 60 mg/day but flared with reduction to 25 mg/day. Courses of methotrexate 20 mg per week, dapsone 100 mg, minocycline 150 mg/day, azathioprine 2.5 mg/kg, mycophenylate mofetil 2 gm/day, and intravenous immunoglobulin (IVIG) in conjunction with prednisone 30 mg-60 mg daily over 4 years failed to improve the skin lesions (Fig 1). Cyclophosphamide 2 mg/kg was added for 5 months, then increased to 2.5 mg/kg for 3 months. He continued to get new blisters, involving 30% body surface area. Rituximab was then started without any change in cyclophosphamide dosage. After 4 weeks, the erosions were 95% re-epithelialized. Prednisone was tapered and cyclophosphamide continued at the same dose. Prednisone and cyclophosphamide were discontinued 9 and 10 months respectively after rituximab. He has remained in complete remission for 18 months (Fig 2). The patient’s initial pemphigus autoantibody titer was 1:2560. It decreased to 1:640 immediately after, and 1 and 3 months after rituximab therapy. Titer 10 months post treatment was 1:40. Case 2 A 37-year-old Asian male with PV for 4 years was admitted with disease involving 80% of his body surface. He required cyclophosphamide 2 mg/kg/ day, prednisone 2 mg/kg/day and plasmapheresis for control. After discharge, he received cyclophosphamide 2 mg/kg, dapsone 100 mg/day, IVIG monthly, and a tapering dose of prednisone for the next 22 months. His disease persisted, involving 10%-15% of his body, with intermittent flares requiring increased prednisone ranging from 10 mg to
818 Brief reports
Fig 1. Patient’s scalp before rituximab therapy, while he was on mycophenylate mofetil and prednisone.
J AM ACAD DERMATOL NOVEMBER 2004
rituximab treatment. Antibody titers decreased from 1:2560 to 1:640, but her disease remained unchanged. Four months later, mild leukopenia developed and cyclophosphamide was discontinued but restarted 2 weeks later at 1.4 mg/kg as sole therapy. After 2 weeks, a second course of rituximab was begun for persistent oral disease. Her oral erosions began to heal after the fourth rituximab infusion and continued to heal over the next 9 months. She now has mild oral disease and can eat most foods. Her antibody titers have fallen from 1:640 to 1:320. Cyclophosphamide was held again near the end of the rituximab infusions but restarted at 1.2 mg/kg after 3 weeks, and now is 0.5 mg/ kg/day.
DISCUSSION
Fig 2. Patient’s scalp 11 months after finishing rituximab therapy. He had no blisters or erosions elsewhere on his skin. Regrowth of hair began as his pemphigus came under control.
60 mg/day. Rituximab was then added to cyclophosphamide 2 mg/kg, IVIG every 6 weeks, and prednisone 10 mg to 20 mg/day, all of which had been unchanged for 7 months. IVIG was discontinued as rituximab was started, but cyclophosphamide and prednisone doses were not changed during or after rituximab. After 4 infusions, lesions began to heal. He was entirely clear 4 months after finishing rituximab, free of disease for the first time in 6 years. His autoantibody titers were 1:320 before rituximab and 1:160 afterward. Unfortunately, he developed pneumocystis carinii pneumonia 4 months after rituximab and died 5 weeks later. Case 3 A 47-year-old woman had a 1-year history of moderately severe PV involving her oral mucosa, which limited eating. Over the next 14 months, she received azathioprine, up to 2.5 mg/kg/day, then mycophenylate mofetil 3 g/day, plus monthly IVIG. Mycophenylate mofetil was replaced with cyclophosphamide 1.6 mg/kg/day for 4 months, but lesions extended onto her scalp and neck. Rituximab was added and IVIG discontinued, without change in cyclophosphamide during or after
Three PV patients who failed to respond to multiple immunosuppressive therapies over 1.5 to 6 years improved shortly after addition of rituximab. Two patients went into remission, one of whom has been disease-free off all medications for 18 months. The third patient has had steady improvement, but has not yet cleared. All 3 patients tolerated the rituximab infusions well. Autoantibody titers fell sharply during the 4 weeks of therapy, suggesting that the clinical improvement was related to a fall in pathogenic antibodies, presumably from reduction in autoreactive B-cell clones. It is possible that these patients improved because of cyclophosphamide and prednisone therapy alone. However, the lack of response to appropriate doses of these medications over many months makes this unlikely, in addition to the temporal relationship of rituximab therapy and the clinical improvement. One of our patients developed fatal pneumocystis carinii pneumonia (PCP) 4 months after finishing rituximab therapy, while also on cylcophosphamide and prednisone. It is not clear that PCP was related to the use of rituximab, because this can occur in immunosuppressed patients.11 However, in a previous report of 3 PV patients treated with rituximab and immunosuppressive medications, one developed Pseudamonas aeruginosa hip infection 12 weeks after finishing rituximab, and another developed pneumonia after 8 weeks.12 These infections all occurred during the time that the patients’ B cells would be decreased from rituximab.9,12 Combining this with our own series, 50% of these PV patients treated with rituximab have developed serious infectious complications. This raises concern that autoimmune disease patients treated with rituximab combined with immunosuppressives may be at higher risk for infections.
J AM ACAD DERMATOL VOLUME 51, NUMBER 5
Rituximab may represent an effective new treatment of refractory PV patients. This deserves further evaluation in larger numbers of patients, with particular attention to development of infectious complications. REFERENCES 1. Bystryn J, Steinman N. The adjuvant therapy of pemphigus: An update. Arch Dermatol 1996;132:203-12. 2. Reff ME, Carner C, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD 20. Blood 1994;83:435-45. 3. Johnson PW, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer 2001;85:1619-23. 4. Maloney G. Mechanism of action of rituximab. Anti-cancer Drugs 2001;12:S1-4. 5. Arzoo K, Sadeghi S, Liebman HA. Treatment of refractory antibody mediated autoimmune disorders with an anti-CD-20 monoclonal antibody (rituximab). Ann Rheum Dis 2002;61: 922-4. 6. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001;98: 952-7.
Brief reports 819
7. Mori A, Tamaru J, Sumi H, Kondo H. Beneficial effects of rituximab on primary cold agglutinin disease refractory to conventional therapy. Eur J Haematol 2002;68:243-6. 8. Salopek TG, Logsetty S, Tredget EE. Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder. J Am Acad Dermatol 2002;47:785-8. 9. Ahrens N, Kingreen D, Seltsam A, Salama A. Treatment of refractory autoimmune haemolytic anaemia with anti-CD20 (rituximab). Br J Haematol 2001;114:244-5. 10. Borradori L, Lombardi T, Samson J, Girardet C, Saurat JH, Hugli A. Anti-CD20 monoclonal antibody (rituximab) for refractory erosive stomatitis secondary to CD201 follicular lymphomaassociated paraneoplastic pemphigus. Arch Dermatol 2001; 137:269-72. 11. Roblot F, Godet C, Le Moal G, Garo B, Faouzi Souala M, Dary M, et al. Analysis of underlying diseases and prognostic factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis 2002;21:523-31. 12. Dupuy A, Viguier M, Bedane C, Cordoliani F, Blaise S, Aucouturier F, et al. Treatment of refractory pemphigus vulgaris with rituximab (anti cd20 monoclonal antibody). Arch Dermatol 2004;140:91-6.
J AM ACAD DERMATOL VOLUME 51, NUMBER 5
Therapy of refractory pemphigus vulgaris with monoclonal anti-CD20 antibody (rituximab) Lynne H. Morrison, MD Portland, Oregon 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. ( J Am Acad Dermatol 2004;51:817-9.)
P
emphigus vulgaris (PV), an antibody-mediated autoimmune bullous disease, causes significant morbidity and the current mortality rate is 5% to 10%.1 Treatment generally includes high dose corticosteroids and, frequently, immunosuppressive agents. Despite these medications, some patients never attain remission and others remain poorly controlled. This, and the adverse effects of chronic corticosteroids and immunosuppressives, spurs continued interest in new therapies. Rituximab, a monoclonal antibody directed against the CD20 antigen on the surface of mature B lymphocytes,2-4 markedly reduces B-cell counts. It is approved for the treatment of CD20 positive Bcell lymphoma. It is also effective in treating several antibody-mediated autoimmune diseases,4-10 offering a novel therapeutic approach for PV patients. We report 3 patients with refractory PV treated successfully with rituximab.
CASE REPORTS All patients had PV confirmed by histology and direct immunofluorescence. All received intravenous (IV) rituximab (375 mg/m2) once weekly for 4 consecutive weeks. Indirect immunofluorescence (IIF) studies were performed immediately before starting rituximab and following the last infusion. All patients tolerated the infusions without adverse From the Department of Dermatology, Oregon Health Sciences University. Funding sources: None. Conflicts of interest: None identified. Correspondence: Lynne H. Morrison, MD, Department of Dermatology OP06, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239. E-mail: [email protected]. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.06.007
immediate effects. Chemistry and complete blood cell count (CBC) studies were unremarkable. Case 1 A 51-year-old white male with PV involving 75% of his scalp and oral cavity responded to prednisone 60 mg/day but flared with reduction to 25 mg/day. Courses of methotrexate 20 mg per week, dapsone 100 mg, minocycline 150 mg/day, azathioprine 2.5 mg/kg, mycophenylate mofetil 2 gm/day, and intravenous immunoglobulin (IVIG) in conjunction with prednisone 30 mg-60 mg daily over 4 years failed to improve the skin lesions (Fig 1). Cyclophosphamide 2 mg/kg was added for 5 months, then increased to 2.5 mg/kg for 3 months. He continued to get new blisters, involving 30% body surface area. Rituximab was then started without any change in cyclophosphamide dosage. After 4 weeks, the erosions were 95% re-epithelialized. Prednisone was tapered and cyclophosphamide continued at the same dose. Prednisone and cyclophosphamide were discontinued 9 and 10 months respectively after rituximab. He has remained in complete remission for 18 months (Fig 2). The patient’s initial pemphigus autoantibody titer was 1:2560. It decreased to 1:640 immediately after, and 1 and 3 months after rituximab therapy. Titer 10 months post treatment was 1:40. Case 2 A 37-year-old Asian male with PV for 4 years was admitted with disease involving 80% of his body surface. He required cyclophosphamide 2 mg/kg/ day, prednisone 2 mg/kg/day and plasmapheresis for control. After discharge, he received cyclophosphamide 2 mg/kg, dapsone 100 mg/day, IVIG monthly, and a tapering dose of prednisone for the next 22 months. His disease persisted, involving 10%-15% of his body, with intermittent flares requiring increased prednisone ranging from 10 mg to
818 Brief reports
Fig 1. Patient’s scalp before rituximab therapy, while he was on mycophenylate mofetil and prednisone.
J AM ACAD DERMATOL NOVEMBER 2004
rituximab treatment. Antibody titers decreased from 1:2560 to 1:640, but her disease remained unchanged. Four months later, mild leukopenia developed and cyclophosphamide was discontinued but restarted 2 weeks later at 1.4 mg/kg as sole therapy. After 2 weeks, a second course of rituximab was begun for persistent oral disease. Her oral erosions began to heal after the fourth rituximab infusion and continued to heal over the next 9 months. She now has mild oral disease and can eat most foods. Her antibody titers have fallen from 1:640 to 1:320. Cyclophosphamide was held again near the end of the rituximab infusions but restarted at 1.2 mg/kg after 3 weeks, and now is 0.5 mg/ kg/day.
DISCUSSION
Fig 2. Patient’s scalp 11 months after finishing rituximab therapy. He had no blisters or erosions elsewhere on his skin. Regrowth of hair began as his pemphigus came under control.
60 mg/day. Rituximab was then added to cyclophosphamide 2 mg/kg, IVIG every 6 weeks, and prednisone 10 mg to 20 mg/day, all of which had been unchanged for 7 months. IVIG was discontinued as rituximab was started, but cyclophosphamide and prednisone doses were not changed during or after rituximab. After 4 infusions, lesions began to heal. He was entirely clear 4 months after finishing rituximab, free of disease for the first time in 6 years. His autoantibody titers were 1:320 before rituximab and 1:160 afterward. Unfortunately, he developed pneumocystis carinii pneumonia 4 months after rituximab and died 5 weeks later. Case 3 A 47-year-old woman had a 1-year history of moderately severe PV involving her oral mucosa, which limited eating. Over the next 14 months, she received azathioprine, up to 2.5 mg/kg/day, then mycophenylate mofetil 3 g/day, plus monthly IVIG. Mycophenylate mofetil was replaced with cyclophosphamide 1.6 mg/kg/day for 4 months, but lesions extended onto her scalp and neck. Rituximab was added and IVIG discontinued, without change in cyclophosphamide during or after
Three PV patients who failed to respond to multiple immunosuppressive therapies over 1.5 to 6 years improved shortly after addition of rituximab. Two patients went into remission, one of whom has been disease-free off all medications for 18 months. The third patient has had steady improvement, but has not yet cleared. All 3 patients tolerated the rituximab infusions well. Autoantibody titers fell sharply during the 4 weeks of therapy, suggesting that the clinical improvement was related to a fall in pathogenic antibodies, presumably from reduction in autoreactive B-cell clones. It is possible that these patients improved because of cyclophosphamide and prednisone therapy alone. However, the lack of response to appropriate doses of these medications over many months makes this unlikely, in addition to the temporal relationship of rituximab therapy and the clinical improvement. One of our patients developed fatal pneumocystis carinii pneumonia (PCP) 4 months after finishing rituximab therapy, while also on cylcophosphamide and prednisone. It is not clear that PCP was related to the use of rituximab, because this can occur in immunosuppressed patients.11 However, in a previous report of 3 PV patients treated with rituximab and immunosuppressive medications, one developed Pseudamonas aeruginosa hip infection 12 weeks after finishing rituximab, and another developed pneumonia after 8 weeks.12 These infections all occurred during the time that the patients’ B cells would be decreased from rituximab.9,12 Combining this with our own series, 50% of these PV patients treated with rituximab have developed serious infectious complications. This raises concern that autoimmune disease patients treated with rituximab combined with immunosuppressives may be at higher risk for infections.
J AM ACAD DERMATOL VOLUME 51, NUMBER 5
Rituximab may represent an effective new treatment of refractory PV patients. This deserves further evaluation in larger numbers of patients, with particular attention to development of infectious complications. REFERENCES 1. Bystryn J, Steinman N. The adjuvant therapy of pemphigus: An update. Arch Dermatol 1996;132:203-12. 2. Reff ME, Carner C, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD 20. Blood 1994;83:435-45. 3. Johnson PW, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer 2001;85:1619-23. 4. Maloney G. Mechanism of action of rituximab. Anti-cancer Drugs 2001;12:S1-4. 5. Arzoo K, Sadeghi S, Liebman HA. Treatment of refractory antibody mediated autoimmune disorders with an anti-CD-20 monoclonal antibody (rituximab). Ann Rheum Dis 2002;61: 922-4. 6. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001;98: 952-7.
Brief reports 819
7. Mori A, Tamaru J, Sumi H, Kondo H. Beneficial effects of rituximab on primary cold agglutinin disease refractory to conventional therapy. Eur J Haematol 2002;68:243-6. 8. Salopek TG, Logsetty S, Tredget EE. Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder. J Am Acad Dermatol 2002;47:785-8. 9. Ahrens N, Kingreen D, Seltsam A, Salama A. Treatment of refractory autoimmune haemolytic anaemia with anti-CD20 (rituximab). Br J Haematol 2001;114:244-5. 10. Borradori L, Lombardi T, Samson J, Girardet C, Saurat JH, Hugli A. Anti-CD20 monoclonal antibody (rituximab) for refractory erosive stomatitis secondary to CD201 follicular lymphomaassociated paraneoplastic pemphigus. Arch Dermatol 2001; 137:269-72. 11. Roblot F, Godet C, Le Moal G, Garo B, Faouzi Souala M, Dary M, et al. Analysis of underlying diseases and prognostic factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis 2002;21:523-31. 12. Dupuy A, Viguier M, Bedane C, Cordoliani F, Blaise S, Aucouturier F, et al. Treatment of refractory pemphigus vulgaris with rituximab (anti cd20 monoclonal antibody). Arch Dermatol 2004;140:91-6.