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Immunoablative high-dose cyclophosphamide without stem cell rescue in a patient with pemphigus vulgaris
Immunoablative high-dose cyclophosphamide without stem cell rescue in a patient with pemphigus vulgaris Marie V. Hayag, MD,a Jonathan A. Cohen, MD,b and Francisco A. Kerdel, BSc, MBBSa Miami, Florida The use of ablative intravenous cyclophosphamide (50 mg/kg per day for 4 days) without stem cell rescue has been described in patients with refractory autoimmune diseases such as paraneoplastic pemphigus, systemic lupus erythematosus, and aplastic anemia. We describe a 33-year-old patient with pemphigus vulgaris recalcitrant to multiple therapies. The patient presented with numerous oral ulcerations, erosions, and hyperpigmented crusted plaques on his face, trunk, and arms. Findings of a skin biopsy and direct immunofluorescence were consistent with pemphigus vulgaris. The circulating pemphigus vulgaris autoantibodies were present at a titer of 1:640. The patient received immunoablative therapy (50 mg/kg of cyclophosphamide for a total of 4 days) and tolerated the regimen well. Complications such as thrombocytopenia and Pseudomonas septicemia were quickly treated. Four months after the 4-day therapy, his oral and skin lesions completely healed, and his pemphigus titers have decreased to zero. He is no longer receiving prednisone and no new lesions have developed. This provides further evidence that this regimen is relatively safe and provides a potential “cure” for refractory autoimmune diseases such as pemphigus vulgaris. (J Am Acad Dermatol 2000;43:1065-9.)
P
emphigus vulgaris, once a fatal disease, now has a mortality rate below 10% with the introduction of corticosteroids and adjuvant therapy with immunosuppressive drugs.1 Although there are now many agents used in the treatment of pemphigus vulgaris, there is no one therapy that is effective in all patients. Nousari et al2 recently reported the use of immunoablative high-dose cyclophosphamide without stem cell rescue in paraneoplastic pemphigus. This report and other studies have shown that immunoablative high-dose cyclophosphamide can induce complete remissions in a variety of autoimmune diseases.3,4 This therapeutic approach may be efficacious and has been reported to induce long-term remissions in lifethreatening autoimmune diseases. We therefore used a similar regimen in a patient with recalcitrant pemphigus vulgaris.
From the Department of Dermatology and Cutaneous Surgerya and the Department of Medicine, Division of Hematology and Oncology,b University of Miami. Reprints not available from authors. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/110397 doi:10.1067/mjd.2000.110397
CASE REPORT A 33-year-old white man with a history of pemphigus vulgaris presented on May 26, 1999 with a 1month history of formation of an increasing number of bullae and painful oral ulcers as well as painful skin erosions. The patient had not responded to previous multiple different therapies, which included high doses of prednisone, pulse methylprednisolone, azathioprine, dapsone, chlorambucil, and mycophenolate mofetil. Briefly, the patient’s previous treatment over a 2-year span had consisted of variable doses of oral prednisone to a maximum of 120 mg daily but never tapered below 30 mg. He also received azathioprine, 1 mg/kg, for 3 months and chlorambucil 2 mg twice a day for 10 months with a gradual increase over 3 weeks to a maximum dose of 14 mg per day; before his last admission he was changed to a regimen of mycophenolate mofetil up to 3 g/day for 5 months. During the course of his disease he also took dapsone 150 mg daily as a thirdline agent. His medical history was significant for several hospitalizations for exacerbation of his pemphigus vulgaris and more recently osteonecrosis of his hips as a result of corticosteroid use. Physical examination showed a patient with prominent cushingoid facies, ulcers involving the buccal and palatal mucosa, multiple tender erosions, and hyperpig1065
1066 Hayag, Cohen, and Kerdel
J AM ACAD DERMATOL DECEMBER 2000
Fig 1. White blood cell, absolute neutrophil, and platelet counts during the patient’s hospital course.
mented plaques and crusts on his face, chest, abdomen, arms, back, and buttocks. A few flaccid bullae were also present on his left arm. Histologic examination of the skin lesions showed suprabasal acantholysis, acantholytic keratinocytes within the blister cavities, and a sparse lymphocytic perivascular infiltrate. Direct immunofluorescence confirmed the diagnosis of pemphigus demonstrating IgG and C3 on the cell surfaces of the epithelial cells. Indirect immunofluorescence detected circulating pemphigus vulgaris autoantibodies with a titer of 1:640. The patient was admitted to the hospital for management of his debilitating disease. On admission his white blood cell (WBC) count was 8800/µL, absolute neutrophil count (ANC) 7340/µL, hemoglobin 13.6 mg/dL, hematocrit 40.5%, and platelet count was 279,000/µL. Levels of electrolytes, blood urea nitrogen, creatinine, glucose, aminotransferases, bilirubin, alkaline phosphatase, calcium, magnesium, and phosphorus were within normal limits. Findings of chest radiography and electrocardiography were also normal. On the day of admission the patient was started on a regimen of intravenous methylprednisolone, 40 mg every 8 hours. Because the patient had not responded well to the numerous therapies he had already received, it was decided to give him immunoablative high-dose cyclophosphamide without stem cell rescue. The patient was treated with intravenous vancomycin and ceftazidime for 2 days before the highdose cyclophosphamide. On the second day of hospitalization the patient received 50 mg/kg daily of
intravenous cyclophosphamide for 4 consecutive days. He also received mesna, which is a detoxifying agent used to inhibit ifosfamide-induced hemorrhagic cystitis (3 g in 500 mL normal saline over 2 hours every 6 hours) during these 4 days; granisetron was given as an antiemetic. The patient received empirically filgrastin (granulocyte-macrophage colony-stimulating factor) 300 µg subcutaneously every day and erythropoietin 4000 U subcutaneously every day. The patient tolerated the regimen well, but on day 6 (posttreatment) his course was complicated by fever. He was started on a regimen of ticarcillin clavulunate, gentamicin, and fluconazole. On day 10 his blood cultures grew Pseudomonas aeruginosa; his antibiotics were further changed to imipenem-cilastatin and amikacin. The ticarcillin clavulunate, gentamicin, and fluconazole were discontinued. By the next day, his fever had abated. During hospitalization the ANC went down to 10/µL (day 7) (Fig 1); however, his ANC began to recover by day 9. The patient required platelet transfusions (8 U random platelets) on day 9 (platelets 13,000/µL) and day 12 (platelets 16,000/µL). By day 15 the antibiotics were discontinued and the intravenous methylprednisolone was tapered off. On day 17 the patient was discharged with a WBC count of 19,400/µL, ANC 10,476/µL, hemoglobin 10.5 mg/dL, hematocrit 33.1%, and platelet count of 59,000/µL. Pemphigus titer on the day of discharge was 1:160 (Fig 2). Over the next 4 months after cyclophosphamide therapy, his skin lesions and oral ulcerations completely healed and he was tapered off the prednisone. By the end of the fourth month, his pemphigus titers had decreased
Hayag, Cohen, and Kerdel 1067
J AM ACAD DERMATOL VOLUME 43, NUMBER 6
Fig 2. Pemphigus titers after immunoablative cyclophosphamide.
to zero and his disease was in apparent complete remission. At present, 15 months after therapy no new lesions have developed.
DISCUSSION Pemphigus vulgaris is an autoimmune intraepithelial blistering disorder of the skin and mucous membranes. It occurs equally in men and women; the mean age range at presentation is 50 to 60 years.6 Patients present with painful oral erosions, flaccid bullae that are Nikolsky sign positive,7 and skin erosions that may develop granulation tissue and crusting.6 Healing occurs without scarring, but postinflammatory hyperpigmentation commonly occurs.6 Patients with only oral lesions have been found to have autoantibodies targeted against desmoglein 3; patients with oral and skin lesions have autoantibodies to desmoglein 3 (130-kd glycoprotein) and desmoglein 1 (160-kd transmembrane glycoprotein).8-12 Patients also have autoantibodies against plakoglobin (85-kd glycoprotein found in desmosomes).13 These pemphigus autoantibodies are pathogenic because they are able to produce lesions in experimental animals.14,15 Histologically, the disease presents with suprabasal acantholysis of keratinocytes with a “tombstone row” of basal cells.7 On direct immunofluorescence there is homogeneous staining of the intercellular spaces with IgG and C3 of lesional or perilesional skin.16-19 Circulating autoantibodies often correlate with disease activity.20 Currently, the mainstay of treatment is corticosteroids. Before the availability of corticosteroids,
approximately 75% of patients died of pemphigus, usually within 1 year. The use of corticosteroids in the 1950s reduced the mortality to approximately 25% to 45%.21 However, the use of long-term glucocorticosteroids is linked to severe and life-threatening complications. Side effects from corticosteroids can be the major cause of death in patients with pemphigus.21 The addition of adjuvant therapy with a “steroidsparing” effect has reduced the mortality of pemphigus to less than 10%.1 Adjuvant therapies for pemphigus can be divided according to the mechanism of action. Immunosuppressive drugs include cyclophosphamide, azathioprine, chlorambucil, cyclosporine, methotrexate, and mycophenolate mofetil. Antiinflammatory drugs include antimalarials, dapsone, and gold. Immunomodulatory procedures include plasmapheresis and photopheresis. None of these therapies is fully effective; thus specific regimens have to be tailored for each patient. Because of the severity of our patient’s disease and lack of effectiveness of his previous therapies, we chose a more aggressive approach to his treatment. There have been several reports of the use of immunoablative high-dose cyclophosphamide without stem cell rescue in patients with autoimmune disease such as systemic lupus erythematosus, autoimmune neutropenia, severe aplastic anemia, chronic inflammatory demyelinating polyneuropathy, and autoimmune hemolytic anemia.3,4 Nousari et al2 also recently reported the use of this therapy in a patient with paraneoplastic pemphigus.
1068 Hayag, Cohen, and Kerdel
The use of high-dose cytotoxic therapy with subsequent stem cell rescue was studied in autoimmune animal models and demonstrated complete eradication of the disease or considerable improvement.22 However, progression or relapse occurred in patients with autoimmune diseases after the stem cell rescue.23 There have been several hypotheses of why relapse occurs. Perhaps highdose cytotoxic therapy fails to eradicate the autoimmune lymphocytes or autoimmune lymphocytes and/or an autoantigen are reinfused.23 Brodsky et al3,4 have shown that high-dose cytotoxic therapy sufficient to eradicate autoaggressive lymphocytes need not be followed by stem cell rescue in patients with autoimmune disease. Full hematopoietic recovery occurs because high-dose cyclophosphamide (50 mg/kg per day for 4 days) spares hematopoietic stem cells, which express high levels of aldehyde dehydrogenase, an enzyme responsible for cellular resistance to cyclophosphamide.24,25 More differentiated lymphoid tissues are susceptible to high doses of cyclophosphamide.24,25 Thus, this novel therapy, which eradicates autoaggressive lymphocytes and clears pre-existing autoimmunity, spares the existing stem cells from which peripheral lymphoid tissues are repopulated. There are several advantages of immunoablative cyclophosphamide without stem cell rescue over autologous transplantation. It is less toxic because patients do not undergo total-body irradiation or busulfan, which are toxic to stem cells. It also avoids the problem of reinfusing autoaggressive lymphocytes with the autograft, which can also result in graft-versushost disease. The patient received high-dose corticosteroids that were gradually tapered during hospitalization. Atlthough the patient had previously received highdose corticosteroids without improvement, we cannot disprove that the addition of corticosteroids in combination with immunoablative therapy contributed to the patient’s clinical response. Although more aggressive and possibly more toxic than corticosteroids and adjuvant therapy with immunosuppressive agents, the side effects, as shown in our patient and in previous series, were treatable. This therapy does come with some risk, but it is relatively safe. Our patient, who is now in remission of his disease, had a dramatic response clinically and immunologically to this regimen. This provides further evidence that immunoablative cyclophosphamide without stem cell rescue is relatively safe and offers a potential “cure” for refractory autoimmune diseases such as pemphigus vulgaris. However, it is important to follow up these patients to determine whether relapse occurs.
J AM ACAD DERMATOL DECEMBER 2000
REFERENCES 1. Aberer W, Wolff-Schreiner EC, Stingl G, Wolff K. Azathioprine in the treatment of pemphigus vulgaris. J Am Acad Dermatol 1987;16:527-33. 2. Nousari HC, Brodsky RA, Jones RJ, Grever MR, Anhalt GJ. Immunoablative high-dose cyclophosphamide without stem cell rescue in paraneoplastic pemphigus: report of a case and review of this new therapy for severe autoimmune disease. J Am Acad Dermatol 1999;40:750-4. 3. Brodsky RA, Sensenbrenner LL, Jones RJ. Complete remission in severe aplastic anemia after high-dose cyclophosphamide without marrow transplantation. Blood 1996;87:491-4. 4. Brodsky RA, Petri M, Smith BD, et al. Immunoablative high-dose cyclophosphamide without stem cell rescue for refractory severe autoimmune disease. Ann Intern Med 1998;129:1031-5. 5. Pierelli L, Perillo A, Greggi S, et al. Erythropoietin addition to granulocyte colony-stimulating factor abrogates life-threatening neutropenia and increases peripheral-blood progenitorcell mobilization after epirubicin, paclitaxel, and cisplatin combination chemotherapy: results of a randomized comparison. J Clin Oncol 1999;17:1288. 6. Becker BA, Gaspari AA. Pemphigus vulgaris and vegetans. Dermatol Clin 1993;11:429-52. 7. Lever WF. Pemphigus and pemphigoid. Springfield (IL): Charles C Thomas; 1965. 8. Koch PJ, Mahoney MG, Ishikawa H, et al. Targeted disruption of pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris. J Cell Biol 1997;137:1091-102. 9. Amagai M, Koch PJ, Nishikawa T, et al. Pemphigus vulgaris antigen is localized in the lower epidermis, the site of blister formation in patients. J Invest Dermatol 1996;106:351-5. 10. Ding X, Aoki V, Mascaro JM, et al. Mucosal and mucocutaneous (generalized) pemphigus vulgaris show distinct autoantibody profiles. J Invest Dermatol 1997;109:592-6. 11. Eyre RW, Stanely JR. Identification of pemphigus vulgaris antigen extracted from normal human epidermis and comparison with pemphigus foliaceus antigen. J Clin Invest 1988; 81:807. 12. Kowalczyk AP, Anderson JE, Borgwardt JE, et al. Pemphigus sera recognize conformationally sensitive epitopes in the aminoterminal region of desmoglein 1. J Invest Dermatol 1995;105: 147. 13. Korman NJ, Eyre RW, Klaus-Kovtun V, et al. Demonstration of an adhering-junction molecule (plakoglobin) in the autoantigens of pemphigus foliaceus and pemphigus vulgaris. N Engl J Med 1989;321:631. 14. Anhalt GJ, Labib RS, Voorhees JJ, et al. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med 1982;306:1189-96. 15. Svejaard A, Platz P, Ryder LP. HLA and disease 1982: a survey. Immunol Rev 1983;70:193-218. 16. Judd KP, Lever WF. Correlation of antibodies in skin and serum with disease severity in pemphigus. Arch Dermatol 1979;115: 428-32. 17. Moy R, Jordon RE. Immunopathology in pemphigus. Clin Dermatol 1983;1:72-82. 18. Korman NJ. Pemphigus. J Am Acad Dermatol 1988;18:1219-38. 19. Korman NJ. Pemphigus. Immunodermatology 1990;8:689-700. 20. Fitzpatrick RE, Newcomer VD. The correlation of disease activity and antibody titres in pemphigus. Arch Dermatol 1980;116: 285-90. 21. Rosenberg FR, Sanders S, Nelson CT. Pemphigus: a 20-year review of 107 patients treated with corticosteroids. Arch Dermatol 1976;112:962-70.
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22. Good RA, Ikehara S. Preclinical investigations that subserve efforts to employ bone marrow transplantation for rheumatoid or autoimmune diseases. J Rheumatol 1997;24(Suppl 48):5-12. 23. Euler HH, Marmont AM, Bacigalupo A, et al. Early recurrence or persistence of autimmune disease after unmanipulated autologous stem cell transplantation. Blood 1996;88:3621-5. 24. Gordon MY, Goldman JM, Gordon-Smith EC. 4-Hydroperoxycyclophosphamide inhibits proliferation by human
O
granulocyte-macrophage colony forming cells (GM-CFC) but spares more primitive progenitor cells. Leuk Res 1985;9:101721. 25. Jones RJ, Collector MI, Barber JP, et al. Characterization of mouse lymphohematopoietic stem cells lacking spleen colony-forming activity. Blood 1996;88:487-91.
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P
emphigus vulgaris, once a fatal disease, now has a mortality rate below 10% with the introduction of corticosteroids and adjuvant therapy with immunosuppressive drugs.1 Although there are now many agents used in the treatment of pemphigus vulgaris, there is no one therapy that is effective in all patients. Nousari et al2 recently reported the use of immunoablative high-dose cyclophosphamide without stem cell rescue in paraneoplastic pemphigus. This report and other studies have shown that immunoablative high-dose cyclophosphamide can induce complete remissions in a variety of autoimmune diseases.3,4 This therapeutic approach may be efficacious and has been reported to induce long-term remissions in lifethreatening autoimmune diseases. We therefore used a similar regimen in a patient with recalcitrant pemphigus vulgaris.
From the Department of Dermatology and Cutaneous Surgerya and the Department of Medicine, Division of Hematology and Oncology,b University of Miami. Reprints not available from authors. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/110397 doi:10.1067/mjd.2000.110397
CASE REPORT A 33-year-old white man with a history of pemphigus vulgaris presented on May 26, 1999 with a 1month history of formation of an increasing number of bullae and painful oral ulcers as well as painful skin erosions. The patient had not responded to previous multiple different therapies, which included high doses of prednisone, pulse methylprednisolone, azathioprine, dapsone, chlorambucil, and mycophenolate mofetil. Briefly, the patient’s previous treatment over a 2-year span had consisted of variable doses of oral prednisone to a maximum of 120 mg daily but never tapered below 30 mg. He also received azathioprine, 1 mg/kg, for 3 months and chlorambucil 2 mg twice a day for 10 months with a gradual increase over 3 weeks to a maximum dose of 14 mg per day; before his last admission he was changed to a regimen of mycophenolate mofetil up to 3 g/day for 5 months. During the course of his disease he also took dapsone 150 mg daily as a thirdline agent. His medical history was significant for several hospitalizations for exacerbation of his pemphigus vulgaris and more recently osteonecrosis of his hips as a result of corticosteroid use. Physical examination showed a patient with prominent cushingoid facies, ulcers involving the buccal and palatal mucosa, multiple tender erosions, and hyperpig1065
1066 Hayag, Cohen, and Kerdel
J AM ACAD DERMATOL DECEMBER 2000
Fig 1. White blood cell, absolute neutrophil, and platelet counts during the patient’s hospital course.
mented plaques and crusts on his face, chest, abdomen, arms, back, and buttocks. A few flaccid bullae were also present on his left arm. Histologic examination of the skin lesions showed suprabasal acantholysis, acantholytic keratinocytes within the blister cavities, and a sparse lymphocytic perivascular infiltrate. Direct immunofluorescence confirmed the diagnosis of pemphigus demonstrating IgG and C3 on the cell surfaces of the epithelial cells. Indirect immunofluorescence detected circulating pemphigus vulgaris autoantibodies with a titer of 1:640. The patient was admitted to the hospital for management of his debilitating disease. On admission his white blood cell (WBC) count was 8800/µL, absolute neutrophil count (ANC) 7340/µL, hemoglobin 13.6 mg/dL, hematocrit 40.5%, and platelet count was 279,000/µL. Levels of electrolytes, blood urea nitrogen, creatinine, glucose, aminotransferases, bilirubin, alkaline phosphatase, calcium, magnesium, and phosphorus were within normal limits. Findings of chest radiography and electrocardiography were also normal. On the day of admission the patient was started on a regimen of intravenous methylprednisolone, 40 mg every 8 hours. Because the patient had not responded well to the numerous therapies he had already received, it was decided to give him immunoablative high-dose cyclophosphamide without stem cell rescue. The patient was treated with intravenous vancomycin and ceftazidime for 2 days before the highdose cyclophosphamide. On the second day of hospitalization the patient received 50 mg/kg daily of
intravenous cyclophosphamide for 4 consecutive days. He also received mesna, which is a detoxifying agent used to inhibit ifosfamide-induced hemorrhagic cystitis (3 g in 500 mL normal saline over 2 hours every 6 hours) during these 4 days; granisetron was given as an antiemetic. The patient received empirically filgrastin (granulocyte-macrophage colony-stimulating factor) 300 µg subcutaneously every day and erythropoietin 4000 U subcutaneously every day. The patient tolerated the regimen well, but on day 6 (posttreatment) his course was complicated by fever. He was started on a regimen of ticarcillin clavulunate, gentamicin, and fluconazole. On day 10 his blood cultures grew Pseudomonas aeruginosa; his antibiotics were further changed to imipenem-cilastatin and amikacin. The ticarcillin clavulunate, gentamicin, and fluconazole were discontinued. By the next day, his fever had abated. During hospitalization the ANC went down to 10/µL (day 7) (Fig 1); however, his ANC began to recover by day 9. The patient required platelet transfusions (8 U random platelets) on day 9 (platelets 13,000/µL) and day 12 (platelets 16,000/µL). By day 15 the antibiotics were discontinued and the intravenous methylprednisolone was tapered off. On day 17 the patient was discharged with a WBC count of 19,400/µL, ANC 10,476/µL, hemoglobin 10.5 mg/dL, hematocrit 33.1%, and platelet count of 59,000/µL. Pemphigus titer on the day of discharge was 1:160 (Fig 2). Over the next 4 months after cyclophosphamide therapy, his skin lesions and oral ulcerations completely healed and he was tapered off the prednisone. By the end of the fourth month, his pemphigus titers had decreased
Hayag, Cohen, and Kerdel 1067
J AM ACAD DERMATOL VOLUME 43, NUMBER 6
Fig 2. Pemphigus titers after immunoablative cyclophosphamide.
to zero and his disease was in apparent complete remission. At present, 15 months after therapy no new lesions have developed.
DISCUSSION Pemphigus vulgaris is an autoimmune intraepithelial blistering disorder of the skin and mucous membranes. It occurs equally in men and women; the mean age range at presentation is 50 to 60 years.6 Patients present with painful oral erosions, flaccid bullae that are Nikolsky sign positive,7 and skin erosions that may develop granulation tissue and crusting.6 Healing occurs without scarring, but postinflammatory hyperpigmentation commonly occurs.6 Patients with only oral lesions have been found to have autoantibodies targeted against desmoglein 3; patients with oral and skin lesions have autoantibodies to desmoglein 3 (130-kd glycoprotein) and desmoglein 1 (160-kd transmembrane glycoprotein).8-12 Patients also have autoantibodies against plakoglobin (85-kd glycoprotein found in desmosomes).13 These pemphigus autoantibodies are pathogenic because they are able to produce lesions in experimental animals.14,15 Histologically, the disease presents with suprabasal acantholysis of keratinocytes with a “tombstone row” of basal cells.7 On direct immunofluorescence there is homogeneous staining of the intercellular spaces with IgG and C3 of lesional or perilesional skin.16-19 Circulating autoantibodies often correlate with disease activity.20 Currently, the mainstay of treatment is corticosteroids. Before the availability of corticosteroids,
approximately 75% of patients died of pemphigus, usually within 1 year. The use of corticosteroids in the 1950s reduced the mortality to approximately 25% to 45%.21 However, the use of long-term glucocorticosteroids is linked to severe and life-threatening complications. Side effects from corticosteroids can be the major cause of death in patients with pemphigus.21 The addition of adjuvant therapy with a “steroidsparing” effect has reduced the mortality of pemphigus to less than 10%.1 Adjuvant therapies for pemphigus can be divided according to the mechanism of action. Immunosuppressive drugs include cyclophosphamide, azathioprine, chlorambucil, cyclosporine, methotrexate, and mycophenolate mofetil. Antiinflammatory drugs include antimalarials, dapsone, and gold. Immunomodulatory procedures include plasmapheresis and photopheresis. None of these therapies is fully effective; thus specific regimens have to be tailored for each patient. Because of the severity of our patient’s disease and lack of effectiveness of his previous therapies, we chose a more aggressive approach to his treatment. There have been several reports of the use of immunoablative high-dose cyclophosphamide without stem cell rescue in patients with autoimmune disease such as systemic lupus erythematosus, autoimmune neutropenia, severe aplastic anemia, chronic inflammatory demyelinating polyneuropathy, and autoimmune hemolytic anemia.3,4 Nousari et al2 also recently reported the use of this therapy in a patient with paraneoplastic pemphigus.
1068 Hayag, Cohen, and Kerdel
The use of high-dose cytotoxic therapy with subsequent stem cell rescue was studied in autoimmune animal models and demonstrated complete eradication of the disease or considerable improvement.22 However, progression or relapse occurred in patients with autoimmune diseases after the stem cell rescue.23 There have been several hypotheses of why relapse occurs. Perhaps highdose cytotoxic therapy fails to eradicate the autoimmune lymphocytes or autoimmune lymphocytes and/or an autoantigen are reinfused.23 Brodsky et al3,4 have shown that high-dose cytotoxic therapy sufficient to eradicate autoaggressive lymphocytes need not be followed by stem cell rescue in patients with autoimmune disease. Full hematopoietic recovery occurs because high-dose cyclophosphamide (50 mg/kg per day for 4 days) spares hematopoietic stem cells, which express high levels of aldehyde dehydrogenase, an enzyme responsible for cellular resistance to cyclophosphamide.24,25 More differentiated lymphoid tissues are susceptible to high doses of cyclophosphamide.24,25 Thus, this novel therapy, which eradicates autoaggressive lymphocytes and clears pre-existing autoimmunity, spares the existing stem cells from which peripheral lymphoid tissues are repopulated. There are several advantages of immunoablative cyclophosphamide without stem cell rescue over autologous transplantation. It is less toxic because patients do not undergo total-body irradiation or busulfan, which are toxic to stem cells. It also avoids the problem of reinfusing autoaggressive lymphocytes with the autograft, which can also result in graft-versushost disease. The patient received high-dose corticosteroids that were gradually tapered during hospitalization. Atlthough the patient had previously received highdose corticosteroids without improvement, we cannot disprove that the addition of corticosteroids in combination with immunoablative therapy contributed to the patient’s clinical response. Although more aggressive and possibly more toxic than corticosteroids and adjuvant therapy with immunosuppressive agents, the side effects, as shown in our patient and in previous series, were treatable. This therapy does come with some risk, but it is relatively safe. Our patient, who is now in remission of his disease, had a dramatic response clinically and immunologically to this regimen. This provides further evidence that immunoablative cyclophosphamide without stem cell rescue is relatively safe and offers a potential “cure” for refractory autoimmune diseases such as pemphigus vulgaris. However, it is important to follow up these patients to determine whether relapse occurs.
J AM ACAD DERMATOL DECEMBER 2000
REFERENCES 1. Aberer W, Wolff-Schreiner EC, Stingl G, Wolff K. Azathioprine in the treatment of pemphigus vulgaris. J Am Acad Dermatol 1987;16:527-33. 2. Nousari HC, Brodsky RA, Jones RJ, Grever MR, Anhalt GJ. Immunoablative high-dose cyclophosphamide without stem cell rescue in paraneoplastic pemphigus: report of a case and review of this new therapy for severe autoimmune disease. J Am Acad Dermatol 1999;40:750-4. 3. Brodsky RA, Sensenbrenner LL, Jones RJ. Complete remission in severe aplastic anemia after high-dose cyclophosphamide without marrow transplantation. Blood 1996;87:491-4. 4. Brodsky RA, Petri M, Smith BD, et al. Immunoablative high-dose cyclophosphamide without stem cell rescue for refractory severe autoimmune disease. Ann Intern Med 1998;129:1031-5. 5. Pierelli L, Perillo A, Greggi S, et al. Erythropoietin addition to granulocyte colony-stimulating factor abrogates life-threatening neutropenia and increases peripheral-blood progenitorcell mobilization after epirubicin, paclitaxel, and cisplatin combination chemotherapy: results of a randomized comparison. J Clin Oncol 1999;17:1288. 6. Becker BA, Gaspari AA. Pemphigus vulgaris and vegetans. Dermatol Clin 1993;11:429-52. 7. Lever WF. Pemphigus and pemphigoid. Springfield (IL): Charles C Thomas; 1965. 8. Koch PJ, Mahoney MG, Ishikawa H, et al. Targeted disruption of pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris. J Cell Biol 1997;137:1091-102. 9. Amagai M, Koch PJ, Nishikawa T, et al. Pemphigus vulgaris antigen is localized in the lower epidermis, the site of blister formation in patients. J Invest Dermatol 1996;106:351-5. 10. Ding X, Aoki V, Mascaro JM, et al. Mucosal and mucocutaneous (generalized) pemphigus vulgaris show distinct autoantibody profiles. J Invest Dermatol 1997;109:592-6. 11. Eyre RW, Stanely JR. Identification of pemphigus vulgaris antigen extracted from normal human epidermis and comparison with pemphigus foliaceus antigen. J Clin Invest 1988; 81:807. 12. Kowalczyk AP, Anderson JE, Borgwardt JE, et al. Pemphigus sera recognize conformationally sensitive epitopes in the aminoterminal region of desmoglein 1. J Invest Dermatol 1995;105: 147. 13. Korman NJ, Eyre RW, Klaus-Kovtun V, et al. Demonstration of an adhering-junction molecule (plakoglobin) in the autoantigens of pemphigus foliaceus and pemphigus vulgaris. N Engl J Med 1989;321:631. 14. Anhalt GJ, Labib RS, Voorhees JJ, et al. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med 1982;306:1189-96. 15. Svejaard A, Platz P, Ryder LP. HLA and disease 1982: a survey. Immunol Rev 1983;70:193-218. 16. Judd KP, Lever WF. Correlation of antibodies in skin and serum with disease severity in pemphigus. Arch Dermatol 1979;115: 428-32. 17. Moy R, Jordon RE. Immunopathology in pemphigus. Clin Dermatol 1983;1:72-82. 18. Korman NJ. Pemphigus. J Am Acad Dermatol 1988;18:1219-38. 19. Korman NJ. Pemphigus. Immunodermatology 1990;8:689-700. 20. Fitzpatrick RE, Newcomer VD. The correlation of disease activity and antibody titres in pemphigus. Arch Dermatol 1980;116: 285-90. 21. Rosenberg FR, Sanders S, Nelson CT. Pemphigus: a 20-year review of 107 patients treated with corticosteroids. Arch Dermatol 1976;112:962-70.
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