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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
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 Hossein C. Nousari, MD,a Robert A. Brodsky, MD,b Richard J. Jones, MD,b Michael R. Grever, MD,b and Grant J. Anhalt, MDa Baltimore, Maryland Paraneoplastic pemphigus (PNP) is a refractory and life-threatening autoimmune mucocutaneous disease. We have recently reported the effectiveness and safety of ablative intravenous cyclophosphamide (200 mg/kg daily over 4 days) without stem cell rescue in patients with refractory autoimmune diseases including systemic lupus erythematosus, autoimmune cytopenias, chronic inflammatory demyelinating polyneuropathy, and aplastic anemia. We report chronic lymphocytic leukemia-associated PNP in a patient who presented with extensive and debilitating painful oral ulcerations and received ablative therapy. The patient tolerated the regimen well and showed a slow but sustained improvement despite persistence of the underlying neoplasm. Eighteen months after therapy, the oral ulcerations were almost completely healed and the circulating autoantibodies became negative. Currently, the patient remains on cyclosporine and a low dose of prednisone. This provides further evidence for the efficacy and safety of this regimen in the management of severe autoimmune diseases including PNP. (J Am Acad Dermatol 1999;40:750-4.)
Paraneoplastic pemphigus (PNP) associated with malignant neoplasms is a progressive and almost invariably fatal disease.1,2 Temporary or partial control of the disease may be achieved with the use of corticosteroids, cyclosporine, and other immunosuppressive drugs.2 Both allogeneic and syngeneic bone marrow transplantation (BMT) have been shown to modify, and in some instances reverse, a variety of animal models of autoimmune disease.3,4 This has prompted many investigators to propose the use of peripheral blood stem cell transplantation (stem cell rescue) for the treatment of autoimmune disease.5,6 Unfortunately, this approach risks infusing untreated autoreactive lymphocyte clones after the immunoablative preparative regimen.7 We have previously demonstrated that high-dose cyclophosphamide without stem cell From the Division of Dermatoimmunology, Department of Dermatology,a and the Division of Hematologic Malignancies, Department of Oncology,b Johns Hopkins University, School of Medicine. Reprint requests: Grant J. Anhalt, MD, Division of Dermatoimmunology, 720 Rutland Ave, Room 771, Baltimore, MD 21205. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/1/97313
750
rescue can induce durable and complete remissions in acquired severe aplastic anemia (SAA),7 a disease that results from autoimmune suppression of hematopoiesis.8 In a recent pilot study, we were also able to demonstrate that immunoablative high-dose cyclophosphamide can induce durable complete remissions in a variety of autoimmune disorders including systemic lupus erythematosus, autoimmune neutropenia, chronic inflammatory demyelinating polyneuropathy, and autoimmune hemolytic anemia.9 It is conceivable that this therapeutic approach may be efficacious for other lifethreatening autoimmune diseases. Therefore we attempted this regimen in a patient with chronic lymphocytic leukemia–associated PNP. CASE REPORT A 70-year-old white man presented with a 4-month history of progressive painful oral erosions, unresponsive to high-potency topical steroids. His medical history was significant for stage 0 of Rai’s classification for chronic lymphocytic leukemia (CLL) for 3 years that had not required therapy. A physical examination revealed exquisitely painful erosions involving the buc-
Journal of the American Academy of Dermatology Volume 40, Number 5, Part 1
Nousari et al 751
Fig 1. Inferior labial mucosa of patient with paraneoplastic pemphigus, before receiving ablative high-dose cyclophosphamide without bone marrow transplant, demonstrating extensive ulceration.
cal, gingival, lingual, palatal, and labial mucosae (Fig 1). Crusting and erosions of the vermillion borders of the lips were also observed. No other mucosal or cutaneous lesions were observed. Histologic examination of the oral lesions revealed intraepithelial acantholysis and a lichenoid infiltrate of the lamina propria. Direct immunofluorescence of an oral biopsy specimen revealed linear IgG and granular C3 on the cell surfaces of the epithelial cells and also along the lamina propria. Indirect immunofluorescence evaluation of patient’s serum on monkey esophagus and murine bladder, liver, and heart as substrates were consistent with a diagnosis of PNP, subsequently confirmed with immunoprecipitation by means of radiolabeledkeratinocyte extracts (Fig 2). The circulating PNP autoantibodies were present at a titer of 1:640 when tested against monkey esophagus epithelium. The patient was placed on 1 mg/kg daily of oral prednisone for 4 months but he continued to have progression of his oral lesions associated with worsening hoarseness and significant reduction of his oral intake. The patient had reported a 10 kg weight loss over 4 months, and required increasing doses of extended-release morphine sulfate for pain control, up to 30 mg every 8 hours. He received cyclosporine 5 mg/kg daily for 6 weeks, but no improvement of his oral condition was noted. He was admitted to the hospital for management of his debilitating oral blistering condition, at which time his hematocrit was 43%, hemoglobin 12.5 mg/dL, white blood cell count (WBC) was 35,300/µL, absolute neutrophil count (ANC) was 15,532/µL, and platelet count was 159,000/µL. Bone marrow aspirate and biopsy revealed the presence of all normal hematopoietic lineages with several lymphoid aggregates. Flow cytometric analysis of the bone marrow demonstrated a phenotypically
Fig 2. Immunoprecipitation of the paraneoplastic pemphigus patient’s serum using metabolically radiolabeled keratinocyte extracts. Left lane is control serum of patient with pemphigus vulgaris (PV), revealing antibodies against a 130 kd protein (desmoglein 3). Right lane (PNP) is serum of paraneoplastic pemphigus patient containing antibodies against characteristic high-molecular weight PNP antigen complex: 250 kd (desmoplakin I), 230 kd (bullous pemphigoid I antigen), 210 kd (doublet band: desmoplakin II and envoplakin), 190 kd (periplakin), and 170 kd (unknown protein).
abnormal B-cell population with monoclonal expression of κ light chains. The abnormal B cells stained positive for CD5, CD23, and relatively dim CD20, consistent with the diagnosis of CLL. Aminotransferases, glucose, creatinine, electrolytes, magnesium, calcium, phosphorus, alkaline phosphatase, bilirubin, and urinalysis were within normal limits. Chest radiography and electrocardiography were also normal. Cyclosporine was discontinued; on hospital day 3, the patient received 50 mg/kg daily of intravenous cyclophosphamide for 4 consecutive days and subsequent granulocyte colony-stimulating factor (5 µg/kg daily) beginning on day 10 and continuing until ANC reached 1000/µL. The patient tolerated this regimen well, but on day 14, his course was complicated by fever. At that
752 Nousari et al
Journal of the American Academy of Dermatology May 1999
rently undetectable. His WBC is 13,700/µL (51% myeloid, 10% monocytes, and 39% lymphoid); 46% of lymphocytes are phenotypically abnormal B cells that show monoclonal expression of κ light chain along with CD5, CD23, and relatively dim CD20. These phenotypic features are characteristically seen in B cell CLL. DISCUSSION
Fig 3. Inferior labial mucosa of same paraneoplastic pemphigus patient showing complete clearing of inferior labial ulcerations 2 months after ablative high-dose cyclophosphamide without bone marrow transplant.
time, his ANC was 300/µL, serial blood and urine cultures were negative, and chest and sinus tomographies were normal. The patient was placed empirically on intravenous vancomycin, gentamicin, piperacillin, and doxycycline for 14 days. He also began prophylactic acyclovir, norfloxacin, dapsone, and fluconazole; the latter two drugs were continued until the time of discharge. Fever abated in 48 hours after empiric antibiotic therapy. His ANC began to recover on day 15 after cyclophosphamide therapy. He did not require red blood cell or platelet transfusion, with a nadir hematocrit of 28% and platelet count of 80,000/µL. He was discharged on hospital day 25 with a WBC of 15,300/µL and an ANC of 4578/µL. Medications on discharge included extended-release morphine sulfate 60 mg 3 times a day and morphine sulfate oral solution 5 mg every 4 hours as needed for pain, along with prednisone 80 mg/day. No significant improvement of his oral condition was noted during the hospitalization. However, within 2 months of cyclophosphamide therapy slow but sustained healing of his buccal, gingival, and lingual erosions, and complete clearing of labial and palatal mucosal ulcerations were appreciated (Fig 3). He was able to discontinue morphine and reduce the prednisone dose. However, to achieve more complete clearing of the remaining oral lesions he was given cyclosporine 250 mg/day at 3 months after cyclophosphamide therapy. At present, 18 months after cyclophosphamide therapy, the oral lesions have all healed except for one small persistent ulceration on the right lateral border of the tongue. He is currently receiving prednisone 10 mg every other day and cyclosporine 250 mg/day. He has tolerated this oral regimen without side effects, other than some excessive weight gain. The titers of the circulating antiepithelial antibodies are cur-
PNP is a life-threatening autoimmune mucocutaneous blistering disorder that occurs in the context of known or occult neoplasms that almost invariably fall into the category of lymphoproliferative disorders.1,2 These patients have serum autoantibodies against a complex of high molecular weight proteins including plakin proteins, desmoglein 3 and 1,10 and an unknown protein (170 kd).11 Severe and refractory stomatitis is the most common clinical presentation, but polymorphic lesions including mucocutaneous blistering and lichenoid lesions are also commonly seen.2 PNP is rapidly progressive and usually fatal when associated with a malignant neoplasm, but can clear if associated with a benign neoplasm that can be surgically excised (ie, thymoma and the hyaline vascular variant of Castleman’s disease). In contrast, in PNP associated with malignant neoplasms (as in our patient), reduction of tumor burden by chemotherapy does not ameliorate the autoimmune disease. This same lack of correlation between tumor burden and activity of the autoimmune disease is observed in other paraneoplastic autoimmune diseases, such as CLL-associated immune thrombocytopenic purpura.12 In the management of PNP, many immunosuppressant and immunomodulatory drugs have been used with inconsistent results. Prednisone and cyclosporine have shown some efficacy,2 but, unfortunately, the therapeutic effect of these drugs has often been transient and incomplete. Interestingly, when allogeneic BMT was used in the therapy of hematologic disorders, concurrent autoimmune diseases were eradicated.13-15 However, allogeneic BMT is not routinely used to treat autoimmune disease because of significant associated morbidity and mortality. High-dose cytotoxic therapy with subsequent stem cell rescue (autologous BMT) has been proposed as a novel treatment for severe autoimmune diseases. This approach was prompted by autoimmune animal models demonstrating marked improvement or complete eradication of autoim-
Journal of the American Academy of Dermatology Volume 40, Number 5, Part 1
mune disease after syngeneic BMT.16 However, progression or relapse occurs early in many patients with autoimmune diseases after autologous BMT.17 It is unclear whether reappearance of the disease after autologous transplantation results from (1) failure of the high-dose therapy to eradicate autoaggressive lymphocytes, (2) reinfusion of autoaggressive lymphocytes with the autograft, or (3) rechallenge from the autoantigen.17 A specific example of this phenomenon was previously observed in a patient who experienced PNP 2 years after successful autologous BMT for nonHodgkin’s lymphoma. Although free of detectable tumor at the time of death, the patient died from complications of the PNP.18 However, the success of syngeneic BMT in animal models and allogeneic BMT in patients with autoimmune diseases suggests that the high-dose cytotoxic therapy is sufficient to eradicate autoaggressive lymphocytes.13 We found that the immunoablative doses of cyclophosphamide used for transplantation can induce durable complete remissions (median follow-up 10.8 years), without stem cell rescue, in most patients with SAA, an autoimmune disease.8 Like other autoimmune diseases, damage to the target organ (ie, the bone marrow) is felt to be mediated by cytotoxic T lymphocytes that can be, in fact, demonstrated in the blood and marrow.19,20 There were no deaths attributable to the high-dose cyclophosphamide in this study, and none of the responders have relapsed or experienced a clonal disease. Therefore the response rate for this therapy in SAA is comparable with response rates seen after allogeneic BMT,21,22 but it avoids the need for an HLA-identical donor and the risk of graftversus-host disease.7 High-dose cyclophosphamide spared hematopoietic stem cells, because full hematopoietic recovery occurred.7,9 Hematopoietic stem cells are resistant to the cytotoxic effects of cyclophosphamide because they express high levels of aldehyde dehydrogenase, an enzyme responsible for cellular resistance to cyclophosphamide.23,24 However, more differentiated lymphoid tissues are susceptible to high doses of the drug.23,24 After the infusion, peripheral lymphoid tissues are repopulated from existing stem cells, with apparent clearing of preexisting autoimmunity. Our previous experience with high-dose cyclophosphamide encouraged us to implement this therapeutic modality in a patient
Nousari et al 753 with malignancy-associated PNP. Although highdose cyclophosphamide could potentially be viewed as being more toxic than conventional immunosuppression, in our case as well as in previous series, this therapy was associated with acute side effects that were self-limited or treated without significant complications. Our patient had a slow but dramatic response to this therapeutic regimen, similar to the effect we have observed in our patients with SAA7 and systemic lupus erythematosus.9 Despite the steady improvement after therapy, there was an unexpectedly slow decrease in circulating PNP autoantibodies and the need for maintenance cyclosporine to maintain near complete healing of mucosal lesions. This may reflect the persistence of a small clone of PNP autoreactive lymphocytes or just a slow response of these lymphocytes to cyclophosphamide. Nevertheless, this patient illustrates that this therapeutic regimen can achieve a satisfactory and prolonged clinical remission in malignancy-associated PNP. The promising results in this notoriously aggressive autoimmune disease, and the continued lack of significant complications from the therapy will hopefully spur further investigation in the use of ablative cyclophosphamide in additional cases of PNP and other life-threatening autoimmune disorders. REFERENCES 1. Anhalt GJ, Kim S-C, Stanley JR, et al. Paraneoplastic pemphigus: an autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 1990;323: 1729-35. 2. Anhalt GJ. Paraneoplastic pemphigus. Adv Dermatol 1997;12:77-96. 3. Levite M, Zinger H, Zisman E, Reisner Y, Mozes E. Beneficial effect of bone marrow transplantation on the serological manifestations and kidney pathology of experimental systemic lupus erythematosus. Cell Immunol 1995;162:138-45. 4. Karussis DM, Slavin S, Ben-Nun A, et al. Chronicrelapsing experimental autoimmune encephalomyelitis (CR-EAE): treatment and induction of tolerance, with high dose cyclophosphamide followed by syngeneic bone marrow transplantation. J Neuroimmunol 1992;39: 201-10. 5. Burt RK. SCR for severe autoimmune diseases: an idea whose time has come. Oncology 1997;11:1001-14. 6. Snowden JA, Brooks PM, Biggs JC. Haemopoietic stem cell transplantation for autoimmune disease. Br J Haematol 1997;99:9-22. 7. Brodsky RA, Sensenbrenner LL, Jones RJ. Complete remission in severe aplastic anemia after high-dose cyclophosphamide without marrow transplantation. Blood 1996;87:491-4. 8. Young NS. Autoimmunity and its treatment in aplastic anemia. Ann Intern Med 1997;126:166-8. 9. Brodsky RA, Petri M, Smith BD, et al. Immunoablative
Journal of the American Academy of Dermatology May 1999
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10.
11.
12.
13.
14. 15.
16.
high-dose cyclophosphamide without stem cell rescue for refractory severe autoimmune disease. Ann Intern Med 1998;129:1031-5. Amagai M, Nishikawa T, Nousari HC, Anhalt GJ, Hashimoto T. Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice. J Clin Invest 1998;102:775-82. Kim S-C, Kwon YD, Lee IJ, et al. cDNA cloning of the 210-kDa paraneoplastic pemphigus antigen reveals that envoplakin is a component of the antigen complex. J Invest Dermatol 1997;109:365-9. Diehl LF, Ketchum LH. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia. Semin Oncol 1998;25:80-97. Snowden JA, Kearney P, Kearney A, et al. Long-term outcome of autoimmune disease following allogeneic bone marrow transplantation. Arthritis Rheum 1998;41: 453-9. Lopez-Cubero SO, Sullivan KM, McDonald GB. Course of Crohn’s disease after allogeneic marrow transplantation. Gastroenterology 1998;114:433-40. Nelson JC, Torrez R, Lovie FM, et al. Pre-existing autoimmune diseases in patients with long term survival after allogeneic bone marrow transplantation. J Rheumatol 1997;24(suppl 48):23-9. Good RA, Ikehara S. Preclinical investigations that subserve efforts to employ bone marrow transplantation for
17.
18. 19. 20.
21. 22. 23.
24.
rheumatoid or autoimmune diseases. J Rheumatol 1997; 24(suppl 48):5-12. Euler HH, Marmont AM, Bacigalupo A, et al. Early recurrence or persistence of autoimmune disease after unmanipulated autologous stem cell transplantation. Blood 1996;88:3621-5. Fullerton SH, Woodley DT, Smoller B, Anhalt GJ. Paraneoplastic pemphigus with immune deposits in bronchial epithelium. JAMA 1992;267:1500-2. Baranski BG, Young NS. Autoimmune aspects of aplastic anemia. In Vivo 1988;2:9-14. Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol 1995;91:245-52. May WS, Sensenbrenner LL, Burns WH, et al. Bone marrow transplant for severe aplastic anemia using cyclosporine. Bone Marrow Transplant 1993;11:459-64. Marmont AM. Stem cell transplantation for severe autoimmune disorders with special reference to rheumatic diseases. J Rheumatol 1997;24 suppl 48:13-8. Gordon MY, Goldman JM, Gordon-Smith EC. 4Hydroperoxycyclophosphamide inhibits proliferation by human granulocyte-macrophage colony forming cells (GM-CFC) but spares more primitive progenitor cells. Leuk Res 1985;9:1017-21. Jones RJ, Collector MI, Barber JP, et al. Characterization of mouse lymphohematopoietic stem cells lacking spleen colony-forming activity. Blood 1996;88:487-91.
Paraneoplastic pemphigus (PNP) associated with malignant neoplasms is a progressive and almost invariably fatal disease.1,2 Temporary or partial control of the disease may be achieved with the use of corticosteroids, cyclosporine, and other immunosuppressive drugs.2 Both allogeneic and syngeneic bone marrow transplantation (BMT) have been shown to modify, and in some instances reverse, a variety of animal models of autoimmune disease.3,4 This has prompted many investigators to propose the use of peripheral blood stem cell transplantation (stem cell rescue) for the treatment of autoimmune disease.5,6 Unfortunately, this approach risks infusing untreated autoreactive lymphocyte clones after the immunoablative preparative regimen.7 We have previously demonstrated that high-dose cyclophosphamide without stem cell From the Division of Dermatoimmunology, Department of Dermatology,a and the Division of Hematologic Malignancies, Department of Oncology,b Johns Hopkins University, School of Medicine. Reprint requests: Grant J. Anhalt, MD, Division of Dermatoimmunology, 720 Rutland Ave, Room 771, Baltimore, MD 21205. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/1/97313
750
rescue can induce durable and complete remissions in acquired severe aplastic anemia (SAA),7 a disease that results from autoimmune suppression of hematopoiesis.8 In a recent pilot study, we were also able to demonstrate that immunoablative high-dose cyclophosphamide can induce durable complete remissions in a variety of autoimmune disorders including systemic lupus erythematosus, autoimmune neutropenia, chronic inflammatory demyelinating polyneuropathy, and autoimmune hemolytic anemia.9 It is conceivable that this therapeutic approach may be efficacious for other lifethreatening autoimmune diseases. Therefore we attempted this regimen in a patient with chronic lymphocytic leukemia–associated PNP. CASE REPORT A 70-year-old white man presented with a 4-month history of progressive painful oral erosions, unresponsive to high-potency topical steroids. His medical history was significant for stage 0 of Rai’s classification for chronic lymphocytic leukemia (CLL) for 3 years that had not required therapy. A physical examination revealed exquisitely painful erosions involving the buc-
Journal of the American Academy of Dermatology Volume 40, Number 5, Part 1
Nousari et al 751
Fig 1. Inferior labial mucosa of patient with paraneoplastic pemphigus, before receiving ablative high-dose cyclophosphamide without bone marrow transplant, demonstrating extensive ulceration.
cal, gingival, lingual, palatal, and labial mucosae (Fig 1). Crusting and erosions of the vermillion borders of the lips were also observed. No other mucosal or cutaneous lesions were observed. Histologic examination of the oral lesions revealed intraepithelial acantholysis and a lichenoid infiltrate of the lamina propria. Direct immunofluorescence of an oral biopsy specimen revealed linear IgG and granular C3 on the cell surfaces of the epithelial cells and also along the lamina propria. Indirect immunofluorescence evaluation of patient’s serum on monkey esophagus and murine bladder, liver, and heart as substrates were consistent with a diagnosis of PNP, subsequently confirmed with immunoprecipitation by means of radiolabeledkeratinocyte extracts (Fig 2). The circulating PNP autoantibodies were present at a titer of 1:640 when tested against monkey esophagus epithelium. The patient was placed on 1 mg/kg daily of oral prednisone for 4 months but he continued to have progression of his oral lesions associated with worsening hoarseness and significant reduction of his oral intake. The patient had reported a 10 kg weight loss over 4 months, and required increasing doses of extended-release morphine sulfate for pain control, up to 30 mg every 8 hours. He received cyclosporine 5 mg/kg daily for 6 weeks, but no improvement of his oral condition was noted. He was admitted to the hospital for management of his debilitating oral blistering condition, at which time his hematocrit was 43%, hemoglobin 12.5 mg/dL, white blood cell count (WBC) was 35,300/µL, absolute neutrophil count (ANC) was 15,532/µL, and platelet count was 159,000/µL. Bone marrow aspirate and biopsy revealed the presence of all normal hematopoietic lineages with several lymphoid aggregates. Flow cytometric analysis of the bone marrow demonstrated a phenotypically
Fig 2. Immunoprecipitation of the paraneoplastic pemphigus patient’s serum using metabolically radiolabeled keratinocyte extracts. Left lane is control serum of patient with pemphigus vulgaris (PV), revealing antibodies against a 130 kd protein (desmoglein 3). Right lane (PNP) is serum of paraneoplastic pemphigus patient containing antibodies against characteristic high-molecular weight PNP antigen complex: 250 kd (desmoplakin I), 230 kd (bullous pemphigoid I antigen), 210 kd (doublet band: desmoplakin II and envoplakin), 190 kd (periplakin), and 170 kd (unknown protein).
abnormal B-cell population with monoclonal expression of κ light chains. The abnormal B cells stained positive for CD5, CD23, and relatively dim CD20, consistent with the diagnosis of CLL. Aminotransferases, glucose, creatinine, electrolytes, magnesium, calcium, phosphorus, alkaline phosphatase, bilirubin, and urinalysis were within normal limits. Chest radiography and electrocardiography were also normal. Cyclosporine was discontinued; on hospital day 3, the patient received 50 mg/kg daily of intravenous cyclophosphamide for 4 consecutive days and subsequent granulocyte colony-stimulating factor (5 µg/kg daily) beginning on day 10 and continuing until ANC reached 1000/µL. The patient tolerated this regimen well, but on day 14, his course was complicated by fever. At that
752 Nousari et al
Journal of the American Academy of Dermatology May 1999
rently undetectable. His WBC is 13,700/µL (51% myeloid, 10% monocytes, and 39% lymphoid); 46% of lymphocytes are phenotypically abnormal B cells that show monoclonal expression of κ light chain along with CD5, CD23, and relatively dim CD20. These phenotypic features are characteristically seen in B cell CLL. DISCUSSION
Fig 3. Inferior labial mucosa of same paraneoplastic pemphigus patient showing complete clearing of inferior labial ulcerations 2 months after ablative high-dose cyclophosphamide without bone marrow transplant.
time, his ANC was 300/µL, serial blood and urine cultures were negative, and chest and sinus tomographies were normal. The patient was placed empirically on intravenous vancomycin, gentamicin, piperacillin, and doxycycline for 14 days. He also began prophylactic acyclovir, norfloxacin, dapsone, and fluconazole; the latter two drugs were continued until the time of discharge. Fever abated in 48 hours after empiric antibiotic therapy. His ANC began to recover on day 15 after cyclophosphamide therapy. He did not require red blood cell or platelet transfusion, with a nadir hematocrit of 28% and platelet count of 80,000/µL. He was discharged on hospital day 25 with a WBC of 15,300/µL and an ANC of 4578/µL. Medications on discharge included extended-release morphine sulfate 60 mg 3 times a day and morphine sulfate oral solution 5 mg every 4 hours as needed for pain, along with prednisone 80 mg/day. No significant improvement of his oral condition was noted during the hospitalization. However, within 2 months of cyclophosphamide therapy slow but sustained healing of his buccal, gingival, and lingual erosions, and complete clearing of labial and palatal mucosal ulcerations were appreciated (Fig 3). He was able to discontinue morphine and reduce the prednisone dose. However, to achieve more complete clearing of the remaining oral lesions he was given cyclosporine 250 mg/day at 3 months after cyclophosphamide therapy. At present, 18 months after cyclophosphamide therapy, the oral lesions have all healed except for one small persistent ulceration on the right lateral border of the tongue. He is currently receiving prednisone 10 mg every other day and cyclosporine 250 mg/day. He has tolerated this oral regimen without side effects, other than some excessive weight gain. The titers of the circulating antiepithelial antibodies are cur-
PNP is a life-threatening autoimmune mucocutaneous blistering disorder that occurs in the context of known or occult neoplasms that almost invariably fall into the category of lymphoproliferative disorders.1,2 These patients have serum autoantibodies against a complex of high molecular weight proteins including plakin proteins, desmoglein 3 and 1,10 and an unknown protein (170 kd).11 Severe and refractory stomatitis is the most common clinical presentation, but polymorphic lesions including mucocutaneous blistering and lichenoid lesions are also commonly seen.2 PNP is rapidly progressive and usually fatal when associated with a malignant neoplasm, but can clear if associated with a benign neoplasm that can be surgically excised (ie, thymoma and the hyaline vascular variant of Castleman’s disease). In contrast, in PNP associated with malignant neoplasms (as in our patient), reduction of tumor burden by chemotherapy does not ameliorate the autoimmune disease. This same lack of correlation between tumor burden and activity of the autoimmune disease is observed in other paraneoplastic autoimmune diseases, such as CLL-associated immune thrombocytopenic purpura.12 In the management of PNP, many immunosuppressant and immunomodulatory drugs have been used with inconsistent results. Prednisone and cyclosporine have shown some efficacy,2 but, unfortunately, the therapeutic effect of these drugs has often been transient and incomplete. Interestingly, when allogeneic BMT was used in the therapy of hematologic disorders, concurrent autoimmune diseases were eradicated.13-15 However, allogeneic BMT is not routinely used to treat autoimmune disease because of significant associated morbidity and mortality. High-dose cytotoxic therapy with subsequent stem cell rescue (autologous BMT) has been proposed as a novel treatment for severe autoimmune diseases. This approach was prompted by autoimmune animal models demonstrating marked improvement or complete eradication of autoim-
Journal of the American Academy of Dermatology Volume 40, Number 5, Part 1
mune disease after syngeneic BMT.16 However, progression or relapse occurs early in many patients with autoimmune diseases after autologous BMT.17 It is unclear whether reappearance of the disease after autologous transplantation results from (1) failure of the high-dose therapy to eradicate autoaggressive lymphocytes, (2) reinfusion of autoaggressive lymphocytes with the autograft, or (3) rechallenge from the autoantigen.17 A specific example of this phenomenon was previously observed in a patient who experienced PNP 2 years after successful autologous BMT for nonHodgkin’s lymphoma. Although free of detectable tumor at the time of death, the patient died from complications of the PNP.18 However, the success of syngeneic BMT in animal models and allogeneic BMT in patients with autoimmune diseases suggests that the high-dose cytotoxic therapy is sufficient to eradicate autoaggressive lymphocytes.13 We found that the immunoablative doses of cyclophosphamide used for transplantation can induce durable complete remissions (median follow-up 10.8 years), without stem cell rescue, in most patients with SAA, an autoimmune disease.8 Like other autoimmune diseases, damage to the target organ (ie, the bone marrow) is felt to be mediated by cytotoxic T lymphocytes that can be, in fact, demonstrated in the blood and marrow.19,20 There were no deaths attributable to the high-dose cyclophosphamide in this study, and none of the responders have relapsed or experienced a clonal disease. Therefore the response rate for this therapy in SAA is comparable with response rates seen after allogeneic BMT,21,22 but it avoids the need for an HLA-identical donor and the risk of graftversus-host disease.7 High-dose cyclophosphamide spared hematopoietic stem cells, because full hematopoietic recovery occurred.7,9 Hematopoietic stem cells are resistant to the cytotoxic effects of cyclophosphamide because they express high levels of aldehyde dehydrogenase, an enzyme responsible for cellular resistance to cyclophosphamide.23,24 However, more differentiated lymphoid tissues are susceptible to high doses of the drug.23,24 After the infusion, peripheral lymphoid tissues are repopulated from existing stem cells, with apparent clearing of preexisting autoimmunity. Our previous experience with high-dose cyclophosphamide encouraged us to implement this therapeutic modality in a patient
Nousari et al 753 with malignancy-associated PNP. Although highdose cyclophosphamide could potentially be viewed as being more toxic than conventional immunosuppression, in our case as well as in previous series, this therapy was associated with acute side effects that were self-limited or treated without significant complications. Our patient had a slow but dramatic response to this therapeutic regimen, similar to the effect we have observed in our patients with SAA7 and systemic lupus erythematosus.9 Despite the steady improvement after therapy, there was an unexpectedly slow decrease in circulating PNP autoantibodies and the need for maintenance cyclosporine to maintain near complete healing of mucosal lesions. This may reflect the persistence of a small clone of PNP autoreactive lymphocytes or just a slow response of these lymphocytes to cyclophosphamide. Nevertheless, this patient illustrates that this therapeutic regimen can achieve a satisfactory and prolonged clinical remission in malignancy-associated PNP. The promising results in this notoriously aggressive autoimmune disease, and the continued lack of significant complications from the therapy will hopefully spur further investigation in the use of ablative cyclophosphamide in additional cases of PNP and other life-threatening autoimmune disorders. REFERENCES 1. Anhalt GJ, Kim S-C, Stanley JR, et al. Paraneoplastic pemphigus: an autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 1990;323: 1729-35. 2. Anhalt GJ. Paraneoplastic pemphigus. Adv Dermatol 1997;12:77-96. 3. Levite M, Zinger H, Zisman E, Reisner Y, Mozes E. Beneficial effect of bone marrow transplantation on the serological manifestations and kidney pathology of experimental systemic lupus erythematosus. Cell Immunol 1995;162:138-45. 4. Karussis DM, Slavin S, Ben-Nun A, et al. Chronicrelapsing experimental autoimmune encephalomyelitis (CR-EAE): treatment and induction of tolerance, with high dose cyclophosphamide followed by syngeneic bone marrow transplantation. J Neuroimmunol 1992;39: 201-10. 5. Burt RK. SCR for severe autoimmune diseases: an idea whose time has come. Oncology 1997;11:1001-14. 6. Snowden JA, Brooks PM, Biggs JC. Haemopoietic stem cell transplantation for autoimmune disease. Br J Haematol 1997;99:9-22. 7. Brodsky RA, Sensenbrenner LL, Jones RJ. Complete remission in severe aplastic anemia after high-dose cyclophosphamide without marrow transplantation. Blood 1996;87:491-4. 8. Young NS. Autoimmunity and its treatment in aplastic anemia. Ann Intern Med 1997;126:166-8. 9. Brodsky RA, Petri M, Smith BD, et al. Immunoablative
Journal of the American Academy of Dermatology May 1999
754 Nousari et al
10.
11.
12.
13.
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