A Case of Fatal Pemphigus vulgaris in Association With Beta Interferon and Interleukin-2 Therapy

WILLIAM L. RAMSEUR, MD, FREDERICK RICHARDS 11, MD,* AND DAVID 8. DUGGAN, MDt

Beta interferon @-IFN) and interleukin-2 (IL-2) have been utilized in experimental cancer therapy because of their effects on the immune system. We report here a patient treated with IL-2 and &IFN who rapidly developed an immune-mediated, bullous exfoliative dermatitis and who ultimately died. Various etiologic mechanisms are proposed.

Cancer 63:2005-2007, 1989.

ETA INTERFERON (P-IFN) and interleukin-2 (IL-2) B have been utilized in experimental cancer therapy because of their effects on the immune system. Therefore, toxicities relating to disturbances of immune function are not unexpected.

We report here a patient treated with IL-2 and P-IFN who rapidly developed an immune-mediated, bullous ex- foliative dermatitis and who ultimately died.

Case Report

An otherwise healthy 48-year-old man had developed inguinal adenopathy in 1984. Biopsy revealed a nodular poorly differ- entiated lymphocyic lymphoma. Staging revealed retroperitoneal adenopathy, splenomegaly, and bone marrow involvement. He was treated with Cytoxan (cyclophosphamide), vincristine, and prednisone for 11 months. Progression was noted in November 1985 and he was treated with radiotherapy to cervical, inguinal, paraaortic, pelvic and mantle fields at various times between December 1985 and February 1987 for local palliation. In March of 1987 he received trimetrexate without benefit.

Because of progressive, diffuse lymphadenopathy and an en- larging retroperitoneal mass, he was entered on CALGB study 8653 and he received p-IFN 5 X lo6 U/M2 and IL-2 5 X lo6 U/m2 intravenously (IV) for one dose; two doses were given on days 2 and 4 at a 50% dose reduction because of fever and hy- potension. On days 5 and 6 he noted small vesicles on his hands and torso which rapidly enlarged and spread to involve large

From the *Bowman Gray School of Medicine, Winston-Salem, North

Address for reprints: William L. Ramseur, MD, One Professional Park,

Accepted for publication August 18, 1988.

Carolina, and tSUNY Health Science Center, Syracuse, New York.

Greenwood, SC 29646.

areas of his skin (Figs. 1 and 2).’ A Tzank preparation was neg- ative. A punch biopsy of the skin demonstrated suprabasilar bullous formation and was believed to be most consistent with a diagnosis of Pemphigus vulgaris. Direct immunofluorescence on fixed tissue was nondiagnostic due to high background stain- ing, but indirect immunofluorescence (Mayo Labs, Rochester, MN) of the patient’s serum was positive against an intercellular epidermal antigen. Despite therapy with high-dose corticosteroids his skin lesions progressed and new vesicles continued to form. Repeated episodes of sepsis from cutaneous sources were ag- gressively treated but ultimately led to his death after a 5-week hospitalization.

Discussion

This patient’s treatment with p-IFN and IL-2 was tem- porally related to the development of a severe dermato- logic toxicity and death, and these drugs must be suspected to be causal. P. vulgaris is an autoimmune skin disease with an in-

cidence of less than one per 100,000 in the United States. A high proportion of patients have antibodies directed against the skin.’ Neither pemphigus nor the related dis- ease pemphigoid are strongly associated with non-Hodg- kin’s lymphoma, although there have been scattered case reports linking the two diseases.*-’ Pemphigus has been associated with autoimmune diseases (systemic lupus er- ythematosus, myasthenia gravis, rheumatoid arthritis, and pernicious anemia), some drugs, hyposensitization injec- tions for allergy, and t h y m ~ m a . ~ - ~

A computerized literature search relating pemphigus to IL-2 or interferon for the years 1984 to 1987 revealed three citations. ‘O-” These investigators reported consis-

2005

2006 CANCER May 15 1989 Vol. 63

molytic anemia, as well as cutaneous vasculitis, nephrotic syndrome, maculopapular skin eruptions, and interstitial nephritis. 14-20

Interleukin-2 regularly causes hypotension, chills, and fever at the doses used in this study. Life-threatening tox- icities associated with high-dose therapy (myocardial in- farction, respiratory failure, gross edema) have not been seen at these Dermatologic and immune tox- icities have been noted for these drugs. Interleukin-2 alone has been associated with development of a Coombs pos- itive hemolytic anemia, eosinophilia, and exacerbations of polymyositis/dermatomyositis.21 Therapy with IL-2 has been associated with the development of macular and dif- fuse erythrodermas with pruritis and burning which re- solves with desquamation after cessation of IL-2.23 Ery- thema nodosum has also been noted with IL-2.24

Interleukin-2 and p-IFN have also been extensively studied in vitro and in animal models. Both have been demonstrated to directly affect B-cell growth and im- munoglobulin prod~ct ion .~~-~’ Alpha interferon is also capable of accelerating autoimmune disease in ani- m a l ~ . ~ ~ * ~ ~ It is possible that these actions of IL-2 and 6- IFN led to the in vivo appearance of an autoantibody to skin in the patient described herein. It is interesting to

FIG. 1 . Vesicular lesions on leg.

tently low levels of IL-2 production and IL-2 receptor expression in phytohemagglutinin (PHA)-stimulated lymphocytes from patients with pemphigus. These levels returned to normal with successful treatment. Whether these abnormalities are pathogenic or reactive is unknown, but they suggest that IL-2 plays a role in the disease.

Beta interferon has had no direct dermal toxicity in animal tests. In human studies p-IFN has been exceedingly well tolerated as a single agent at doses ranging up to 500 X lo6 U/m2. Flu-like symptoms are common. Derma- tologic toxicities have not been noted.I3 Beta interferon administration to patients has not been associated with autoimmune phenomena, however the experience with p-IFN is comparatively small. Alpha interferon (alpha- IFN), which is functionally similar to and shares a receptor with p-IFN, has been used much more widely and has been associated with the development of several autoim- mune diseases, including immune thrombocytopenic purpura, autoimmune thyroid disease, and immune he- FIG. 2. Vesicular lesions on back.

No. 10 P. vulgaris WITH p-IFN AND IL-2 * Ramseur et a/. 2007

notice that the expression of pemphigus-like antibodies by tumor cells of patients with lymphoma or myeloma has been This could not be evaluated in this patient, but one could hypothesize that direct stim- ulation of B-cells by IL-2 or 0-IFN could lead to over- expression of such a clone. It is also possible that the effects of IL-2 or p-IFN on the immunoregulatory functions of T-cells could lead to autoantibody expression. Further investigations will be required to establish the mechanisms involved.

RE F'E R E N C E S

1. Fitzmaurice M. The immunopathology of pemphigus vulgaris: Re- cent advances. CIeve Clin Q 53:283-289.

2. Katz AL, Nashel DJ, Goard CP, Bauer H. Pemphigus vulgaris and lymphoma in a patient with scleroderma. South Med J 197? 72: 1463- 1466.

3. Sarnoff DS, DeFeo CP. Coexistence of pemphigus foliaceus and mycosis fungoides. Arch Dermatol 1985; 121:669-672.

4. Jauregui HO. Lymphomatoid granulomatosis after immuno- suppresion for pemphigus. Arch Dermatol 1978; 114:1052-1055.

5. Krain LS. Pemphigus vulgaris and internal malignancy. Cancer

6. Fellner MJ. Immunology of Skin Diseases. New York: Elsevier, 1980; 147.

7. Krain L. The association of pemphigus with thymoma or malig- nancy: A critical review. Br J Dermatol 1974; 90:397.

8. Martin RL. Fatal pemphigus vulgaris in a patient taking Piroxicam. N Engl JMed 1983; 309:795.

9. McCombs CC. Case 26-1980: Pemphigus vulgaris after hyposen- sitization injections. N Engl J Med 303: 1 179.

10. Kermani-Arab V, Hirji J, Ahmed AR, Fahey JL. Deficiency of interleukin-2 production and interleukin-2 receptor expression on pe- ripheral blood leukocytes after phytohemagglutinin stimulation in pem- phigus. J Invest Dermatol 1984; 83:lOl-104.

1 1. Blitstein-Willinger E, Stuttgen G. Interleukin-2 deficiency in pemphigus vulgaris. Z Hautkr 1986 61:82-85 (in German).

12. Blitstein-Willinger E. Normalization of defective interleukin-1 and interleukin-2 production in patients with pemphigus vulgaris following crysotherapy. Clin Exp Immunol 1985; 62:705-7 14.

13. Investigator brochure. Recombinant Beta Interferon. Triton Bio- sciences, Inc.

1974; 33: 1091-1099.

14. McLaughlin P. Immune thrombocytopenia following alpha in- terferon therapy in patients with cancer. JAMA 1985; 254:1353.

15. Burman R. Thyroid autoimmunity in patients on long term ther- apy with leukocyte-derived interferon. J Clin Endocrinol Metab 1986; 63: 1086.

16. Akard LP. Alpha interferon and immune hemolytic anemia. Ann Intern Med 1986; 105:306.

17. Sangster G. Cutaneous vasculitis associated with interferon. Eur J Cancer Clin Oncol 1983; 19: 1647.

18. Selby P. Nephrotic syndrome during treatment with interferon. BrMedJ[ClinRes] 1985; 290:1180.

19. Quesada JR. Clinical toxicity of interferons in cancer patients: A review. J Clin Oncol 1986; 2:234-243.

20. Auerbach SD. Acute interstitial nephritis with the nephrotic syn- drome following recombinant leucocyte A interferon therapy for mycosis fungoid. N Engl JMed 1984; 310:32.

2 I . Investigator brochure. Recombinant Interleukin-2, Cetus Cor- poration.

22. Lotze MT. Clinical effects and toxicity of interleukin-2 in patients with cancer. CA 1986; 58:2764.

23. Gaspori AA, Lotze MT, Rosenberg SA, Steven JB, Katz SI. Der- matologic changes associated with interleukin-2 administration. JAMA

24. Weinstein A, Bujak D, Mittelman A, Davidian M. Erythema no- dosum in a patient with renal cell carcinoma treated with interleukin-2 and lymphokine-activated killer cells (letter). JAMA 1987; 258:3 120- 3121.

25. Nakagawa T, Hirano T, Nakagawa N et al. Effect of recombinant IL-2 and gamma IFN on proliferation and differentiation of human B- cells. J Immunol 1985; 134:959-965.

26. Jung L, Hara T, Fu SM. Detection and functional studies of p60- 65 (TAC antigen) on activated human B cells. J Exp Med 1984; 160:

27. Shalaby MR, Weck PK, Rinderknecht E et al. Effects of bacteria- produced human alpha, beta, and gamma interferons on in vitro immune function. Cell Immunol 1984; 84:380-392.

28. Heremans H, Billiau A, Colombatti A et al. Interferon treatment of NZB mice: Accelerated progression of autoimmune disease. Infect Immunol 1978; 21:925-930.

29. Gresser I, Maury C, Tovey M et al. Progressive glomemlonephritis in mice treated with interferon preparations at birth. Nature 1976; 263:

30. Saikia NK. Extraction of pemphigus antibodies from a lymphoid neoplasm and its possible relationship to pemphigus vulgaris. Br J Der- matol 1972; 86:411-414.

3 I . Vincendeau P, Claudy A, Thivolet J, Tessier R, Texier L. Bullous dermatosis and myeloma: Monoclonal anticytoplasmic antibody activity. Arch Dermatol 1980; 116:681-682.

1987; 258: 1624-1629.

1597-1 602.

420-423.