Pemphigus

Abstract

Paraneoplastic pemphigus (PNP) is a rare autoimmune mucocutaneous blistering disease that is commonly associated with underlying B-cell neoplasms. There is no standard therapy for PNP. Potent immunosuppression has been the only potentially effective treatment in the setting of malignancy because there is no correlation between tumor burden and activity of disease. Two recent case reports have noted the resolution of lesions of PNP after treatment of the underlying CD20+ B-cell lymphomas with rituximab. Rituximab is an anti-CD20 antibody that has had some success in treating proliferative B-cell disorders. We report a case of PNP in the setting of B-cell lymphoma that did not respond to this novel therapy, and discuss rituximab's putative mechanism of action along with the clinical settings in which this novel therapy may prove useful in the treatment of PNP.

Case Report

A 64-year-old woman presented to the emergency department with painful oral ulcers, intertriginous erosions, and keratitis. She had been diagnosed with Waldenstrom's macroglobulinemia eleven years previously, but had remained asymptomatic for nine years until plasmaphoresis became necessary. One year prior to admission, she developed a small B-cell lymphoma for which she underwent chemotherapy with fludarabine. When she began to suffer from arthralgias, short prednisone tapers were prescribed intermittently to control her pain. Three months prior to her presentation she was started on sulfasalazine for presumed rheumatoid arthritis. Soon after beginning sulfasalazine the patient developed an erythematous macular eruption associated with pruritus. A drug hypersensitivity reaction was suspected and the sulfasalazine was discontinued. Over the next two months, the rash progressed and changed in character despite treatment with systemic prednisone, a complete skin exam at the time of admission revealed extensive erosions involving the buttocks, intertriginous zones, face, neck, and scalp. A blanching, confluent erythema was distributed on her trunk, proximal extremities, and palms (Figure 1). Desquamative keratitis and oral lesions were also noted; the patient could tolerate only liquids secondary to pain on swallowing (Figure 2). She was admitted to the burn unit of the hospital with a presumptive diagnosis of Stevens-Johnson Syndrome. Lesions involved approximately 40% of her body surface area.

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The patient was started on Prednisone 60 mg QD and fluocinonide 0.05% gel for the oral lesions. Local wound care was also instituted. Her initial laboratory values were notable only for low albumin. Skin biopsies were performed. Hematoxylin- and eosinstained tissue sections demonstrated hyperkeratosis, focal parakeratosis, and partial desquamation of the stratum corneum. The underlying epidermis showed acantholysis with individual necrotic cells, and the papillary dermis had a lymphocytic infiltrate with scattered eosinophils (Figure 3). The direct immunofluorescence demonstrated cell surface IgG, C3 and along the dermal-epidermal junction in a granular pattern, and IgM in the vessel walls. Indirect immunofluorescence demonstrated positive IgG binding to monkey esophagus and rat bladder epithelium. A preliminary diagnosis was made of paraneoplastic pemphigus which was later confirmed by immunoprecipitation studies. Soon after admission, the patient developed Gram-negative septicemia. Although she initially defervesced on vancomycin 1 gm BID and ciprofloxacin 400 mg BID, her skin exam did not show improvement. An SPEP was significant for increased alpha globulins and normal gamma globulins with an M spike. Her serum viscosity, however, was not elevated. The patient continued to develop new lesions despite the systemic corticosteroids.

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A novel regimen combining rituximab (375 mg/msq/week), cyclophosphamide (2 mg/kg/d), and prednisone (40 mg/d) was instituted. Our rationale was that rituximab might not only be effective for the patient's underlying CD20+ lymphoma and Waldenstrom's macroglobulinemia, but might also effectively halt the progression of her PNP. She received two of the four weekly doses of the rituximab. Unfortunately, despite this treatment regimen, the patient's condition continued to deteriorate. Ultimately, she progressed to greater than 50% body surface involvement. The patient became septic and in spite of aggressive antibiotic therapy expired 28 days after admission.

Discussion

PNP was characterized as a distinct entity in 1990 (1). Although it shares some features with pemphigus vulgaris, PNP demonstrates different clinical and immunologic findings. It may be associated with both malignant and benign proliferative disease. When associated with a benign neoplasm PNP typically resolves with treatment of the primary disease. However, in the setting of a malignant neoplasm, PNP has a poor prognosis.

The prognosis of paraneoplastic pemphigus (PNP) is dependent to high degree on the underlying neoplasm. The majority of patients with benign neoplasms have complete resolution of symptoms after tumor excision (1). Patients with underlying malignancy tend to fare far worse. Although there have been some recent notable exceptions, the mortality rate remains very high with survival being the exception rather than the rules (2-6). The cause of death in PNP is usually secondary to sepsis, gastrointestinal bleeding, multi-organ system failure, and respiratory failure. The last may be due to direct antibody targeting of respiratory endothelium (7).

PNP may occur in a variety of settings, and its etiology is not completely understood. Two main theories have been put forth regarding the pathogenesis of PNP. The first is based on the idea that the tumors may express certain anomalous epithelial proteins. The host anti-tumor response then simply cross-reacts with normal epithelial tissue in its attack against tumor tissue. There are precedents for this kind of pathogenic cross-reactivity in other malignancy-related disease, and this would be consistent with the fact that both humoral and cell mediated immunity play a role in the disease (1,8). An alternative hypothesis regarding the development of PNP is that cytokine dysregulation plays a key role in the disease process. It has been noted that the onset of PNP may coincide with cytokine therapy for the underlying neoplasm (9). In addition, an increased cytokine level has been detected in PNP. Specifically, IL-6 may be elevated in certain neoplasms such as non-Hodgkin's lymphoma, CLL, Waldenstrom's macroglobulinemia, and Castleman's tumor (1,9). IL-6 is known to induce B-cell proliferation and differentiation and thus antibody production.

Two case reports noted the resolution of PNP lesions in patients treated with rituximab (10,11). In the first report, Borradori et al. noted the resolution of PNP related stomatitis after a patient underwent therapy with rituximab for follicular B-cell lymphoma (11). In that report, the patient had only mucosal disease and did not manifest cutaneous lesions. Similarly in a report by Heizmann et al., a patient with limited PNP and underlying follicular lymphoma was treated with rituximab and the PNP resolved (12). In both cases, the patient's stomatitis was recalcitrant to other treatment modalities. and in both cases, the underlying malignancy was CD 20+ follicular lymphoma.

Rituximab is a specific mouse/human chimeric antiCD20 antibody. It was approved in 1997 for the treatment of refractory B-cell lymphoma (12,13). In low-grade lymphomas, significant response rates have been achieved (14). The side effects are usually minimal compared with traditional chemotherapeutics, and are generally limited to mild hypersensitivity reactions during the infusion. The most common adverse effects are fever, chills, and headache. Angioedema has also been reported (11,13,15).

CD20 is a 32 kD transmembrane protein expressed on the surface of pre-B and mature B-cells as well as malignant B-cells. Rituximab (an IgG 1 k antibody) binds to the B cells and effectively depletes the B cell population, thus decreasing antibody production (13,15). The mechanism is likely via induction of apoptosis in addition to complement and antibody mediated cytotoxicity (16). This B-cell depletion occurs in peripheral blood, bone marrow, and to a lesser degree in lymph nodes (13). By targeting CD20+ B cells, rituximab may be particularly useful in the treatment of PNP associated with B-cell malignancies.

Given this mechanism of action, it has been proposed that rituximab might be effective in other B-cell mediated diseases. It is known from flow cytometry studies that 75-100% of malignant plasma cells in Waldenstrom's macroglobulinemia express CD20 (16). Use of Rituximab in patients with Waldenstrom's macroglobulinemia has been evaluated. In the largest study of 30 patients, 27% had partial response, measured as a >50% reduction in IgM levels. 33% had a minor response, and in 30% the disease remained stable (17).

Our patient's PNP was far more extensive than in the two previously reported cases of PNP resolving with rituximab; however, given the patient's susceptibility to infection, an alternative to global immunosuppression was sought. The extent of denudation, poor nutritional status, and underlying disease made standard chemotherapeutics and plasmaphoresis too risky. Rituximab offered the possibility of addressing both the patient's PNP as well as her underlying malignancy. Unfortunately, rituximab was not effective in halting the progression of her disease.

A more complete understanding of how rituximab functions in suppressing the autoimmune reaction involved in PNP would help to determine whether rituximab has a role in the treatment of PNP regardless of the underlying neoplasm. Rituximab may prove to be a viable therapeutic option in PNP, but may need to be instituted early in the course of disease. As discussed in the two previous case reports, rituximab may have a role in limited cases of PNP (12,15). Further studies are clearly needed to evaluate the therapeutic benefit of rituximab in patients with PNP, and to better define the appropriate clinical settings. PNP remains an exceedingly difficult disease to treat and rituximab may prove to be a valuable addition to the armamentarium in the fight against this devastating illness.

References

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(2.) Korman NJ. New and emerging therapies in the treatment of blistering diseases. Dermatol Clin 2000; 18(1):127-137.

(3.) Schoen H, Foedinger D, Derfler K, Amann, et al. Immunoapheresis in paraneoplastic pemphigus. Arch Dermatol 1998; 134:706-710.

(4.) Williams JV, Marks JG Jr., Billingsley EM. Use of mycophenolate mofetil in the treatment of paraneoplastic pemphigus. Br J Dermatol 2000; 142(3):506-8.

(5.) 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(5):750-754.

(6.) Perniciaro C, Kuechle MK, Colon-Otero G, Raymond MG, Spear KL, Pittelkow MR. Paraneoplastic pemphigus: A case of prolonged survivaI. Mayo Clin Proc 1994; 69:851-855.

(7.) Nousari HC, Deterding R, Wojiczack H, Aho S, Uitto J, Hashimoto T, Anhalt GJ. Brief Report: The Mechanism of Respiratory Failure in Paraneoplastic Pemphigus. N Eng1 J Med 1999; 340:1406-1410.

(8.) Robinson ND, Hashimoto T, Amagai M. Chan LS. The new pemphigus variants. J Am Acad Dermatol 1999; 40(5):649-671.

(9.) Kirsner RS. Anhalt GJ, Kerdel FA. Treatment with alpha interferon associated with the development of paraneoplastic pemphigus. Br J Dermatol 1995; 132:474-8.

(10.) Borradori L, Lombardi T, et al. Anti-CD20 monoclonal antibody (rituximab) for refractory erosive stomatitis secondary to CD20+ follicular lymphoma-associated paraneoplastic pemphigus. Arch Dermatol 2001; 137:269-271.

(11.) Heizmann M, Itin P. Wernli M. Borradori L, Bargetzi MJ. Successful treatment of paraneoplastic pemphigus in follicular NHL with rituximab: Report of a case and review of treatment for paraneoplastic pemphigus in NHL and CLL. AmJ Hematol 2001; 66(2):142-144.

(12.) Grillo-Lopez AJ, White CA, Varns C, Shen D, Wei A, MeClure A. Dallaire BK. Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 1999; 26 (5 suppl 14):66-73.

(13.) Grillo-Lopez AJ. Rituximab: An Insider's Historical Perspective. Semin Oncol 2000; 27(6 suppl 12):9-16.

(14.) Foon KA, Monoclonal antibody therapies for lymphomas. Cancer J 2000; 6(5):273-278.

(15.) Garcia-Manero G, Thomas DA. Salvage therapy for refractory or relapsed acute lymphocytic leukemia. Hematol Oncol Clin North Am 2001; 15(1):163-205.

(16.) Treon SP, Anderson KC. The use of Rituximab in the treatment of malignant and nonmalignant plasma cell disorders. Semin Oncol 2000; 27(6 suppl 12):79-85.

ADDRESS FOR CORRESPONDENCE:

Monica B Schadlow MD

Department of Dermatolology

New York Weill Cornell Medical Center

525 East 68th Street

New York, NY 10021

T: (212) 746-2000

F: (212) 746-8656

E: mschadlow@yahoo.com

MONICA B SCHADLOW MD, GRANT J ANHALT MD, ANIMESH A SINHA MD PHD

1 DEPARTMENT OF DERMATOLOGY; NEW YORK CORNELL MEDICAL COLLEGE AND NEW YORK PRESBYTERIAN HOSPITAL NEW YORK, NEW YORK

2 DEPARTMENT OF DERMATOLOGY; JOHNS HOPKINS UNIVERSITY, SCHOOL OF MEDICINE BALTIMORE, MARYLAND

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