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Thalidomide for autoimmune disease
Medical Hypotheses 10: 437-443, 1983
THALIDOMIDE FOR AUTOIMMUNE DISEASE Sheldon S. Hendler and Mark F. McCarty, 1515 Madison Avenue, San Diego, California 92116 ABSTRACT The therapeutic efficacy of thalidomide in erythema nodosum leprosum suggests that thalidomide might play a useful therapeutic role in other human immune-complex diseases. Thalidomide has shown anti-inflammatory or immunosuppressive actions in several animal models. Current evidence suggests that its rapid activity in ENL may result from suppression of neutrophil chemotaxis and phagocytosis. Scattered anecdotal clinical reports of apparent response to thalidomide in various autoimmune diseases are hardly conclusive, but underline the desirability of appropriate pilot trials of thalidomide in autoimnune diseases, particularly those in which immune complex deposition plays a prominent role. Provided that a contraindication in fertile women is strictly observed, thalidomide therapy appears to be quite safe. INTRODUCTION Erythema nodosum leprosum (ENL) is a dermal vasculitis which occurs episodically in lepromatous leprosy (1). It presents as clusters of painful erythematous subcutaneous nodules, often accompanied by systemic manifestations such as fever, malaise, lymphadenopathy, arthralgia, neuritis, albuminuria, and iridocyclitis. On histological examination, marked perivascular infiltration of PMN leukocytes is the prominent feature. Studies with fluorescent antibodies have revealed the presence of immune complexes, complement, and mycobacterial antigen in these lesions (1, 2). Circulating immune complexes and increased levels of activated complement (C3d) are also observed (3-5). Investigators have noted the similarity between the skin lesions of ENL and those produced by an Arthus reaction, and have cited the systemic manifestations of ENL as symptoms of serum sickness (1, 2). ENL therefore appears to be an immune-complex disease, probably initiated by mycobacterial antigens. ENL typically develops after anti-microbial therapy has produced massive mycobacterial kill, liberating large amounts of mycobacterial antigen. It is less frequently seen in untreated leprosy. The therapeutic efficacy of thalidomide in ENL was fortuitously discovered
437
by Sheskin in 1964, who observed rapid and complete resolution of ENL in a patient receiving thalidomide as a sedative (6). Several controlled trials subsequently confirmed the marked efficacy of thalidomide in ENL (7-9). The effective dose is 400 mg daily, in divided doses. The improvement in the cardinal symptoms - erythema nodosum and fever -is usually rapid, often discernible within 24 hours. Other symptoms, such as arthralgia, neuritis, and iridocyclitis, also respond, though less rapidly (7, 10). Thalidomide's action appears to be immunomodulatory, since examinations of skin scrapings indicate that thalidomide does not alter the course of the mycobacterial infection. At present, ENL is the only clearly established indication for thalidomide. Thalidomide does not appear to be useful for treatment of the lepra reactions seen in tuberculoid leprosy (8), which have been characterized as of the cell-mediated delayed hypersensitivity type. Writing in 1970, Hastings et al (8) remarked that "Due to the close clinical and serological similarities between ENL and various autoimmune or connective tissue diseases, clinical trials of thalidomide in the latter appear to be indicated". This suggestion has lost none of its cogency a decade later. We wish to propose that the therapeutic utility of thalidomide in ENL results from an intervention in immune-complex-mediated inflammation which may well have clinical value in other autoimnune diseases characterized by immune-complex deposition (11). The rapid response to thalidomide often noted in ENL evidently reflects an anti-inflanunatoryaction which could operate at the level of complement activation, PMN leukocyte chemotaxic and diapedesis, lysosome degranulation, mast cell activation, or antigen presentation. An effect on the afferent arm of the immune response is also likely to play a role in longer term response to thalidomide. An alteration of macrophage processing of mycobacterial antigen, or of T-suppressor cell function, might lead to reduced synthesis of anti-mycobacterial antibody. Hastings has recently summarized the results of a comprehensive series of studies intended to define the site of action of thalidomide in imnunecomplex-mediated inflammation (12). Thalidomide was shown to inhibit neutrophil chemotaxis in vitro in chemotaxic chambers; neutrophil phagocytosis of opsonized antigen was also found to be decreased in the presence of thalidomide. Thalidomide did not affect complement activation or neutrophil lysosome stability in these studies. Suppression of neutrophil function therefore appears to be a likely explanation for the rapid therapeutic effect of thalidomide in ENL. Faure et al (13) have simultaneously and independently confirmed the effect of thalidomide on neutrophil chemotaxis. Pre-incubation of human PMN leukocytes with 1 mcg/ml thalidomide was shown to reduce chemotaxis to activated complement by over 50%. Although several studies have found that the high dose thalidomide has rather small and equivocal effects on antibody synthesis (14, 15), Hastings notes (12) that thalidomide suppresses the primary IgM response to a T-dependent antigen in mice. The effect of thalidomide on Tsuppressor activity merits study, since a severe deficit of T-suppressor function has been observed in some cases of leprosy. 438
THALIDOMIDE IN ANIMAL MODELS OF IMFLAMMATION Study of thalidomide as an immunosuppressive agent was prompted by reports from Hellmann et al (16) that thalidomide treatment prolonged homograft survival in mice, and by Sheskin's discovery of thalidomide's effect on ENL. Most of these studies have examined the effect of thalidomide on graft rejection. The results have been contradictory. Some authors report a small enhancement of graft survival (15-18), while others report no effect (19, 20) or have difficulty confirming their prior results(l5). In some cases, significant results were achieved only if the donor animal also received thalidomide pretreatment. With one exception, the doses of thalidomide employed have been so high (at least an order of magnitude greater than those used clinically in humans, on a mg/kg basis) that the results are of questionable clinical relevance. (The one exception was a study in which 10 mg/kg thalidomide 3 times weekly prior to and following renal transplantation in dogs increased survival by about a week (18).) In any case, graft rejection is a form of delayed hypersensitivity that has little similarity to the Arthus-like reaction seen in ENL. More relevant to our purposes is the work of Ulrich et al (21), who found that thalidomide (100 mglkglday) did not modify the size of Arthus reactions induced with egg albumin or lepromin in guinea pigs. Passive Arthus reactions (involving administration of both antigen and antibody) were also unaffected by thalidomide. However, these authors note that guinea pigs may not be a good model for study of thalidomide, since they are insensitive to its sedative effects. Adjuvant disease in rats is produced by injection of killed mycobacteria in Freund's adjuvant. The animals develop secondary dermal inflammatory lesions which initially show some PMN infiltration but are later dominated by mononuclear histiocytes. 400 mg/kg thalidomide daily was found to substantially reduce the number of inflammatory lesions in Wistar rats with adjuvant disease (21); the course of the disease was not significantly affected in Lewis/Mai rats, however. The systemic manifestations of adjuvant disease - fever, malaise inflammation of the joints, skin, and eyes - have been noted to be similar to those seen in ENL (22). Other experimental granulomas (experimental allergic encephalomyelitis and allergic neuritis) in rats and guinea pigs, were not influenced by thalidomide treatment (22, 23). Thalidomide, in human-equivalent doses, has been shown to have an antiinflammatory action in carageenen rat paw edema (12). In particular, it suppresses the infiltration of neutrophils during the late stages of this disorder. ANECDOTAL CLINICAL REPORTS Miller et al (24) were among the first to report on clinical antiinflammatory actions of thalidomide. They noted that thalidomide appeared to have a moderate but inconsistent effect in relieving inflammation and
439
edema in such conditions as cellulitis and thrombophlebitis. But preand post-operative administration of thalidomide was said to very substantially reduce post-operative edema and pain following hemorrhoidectomy in a series of 17 patients. Waters et al (25) recently reported the case of a Malaysian leprosarium nurse with a five year history of unremitting ulcerative colitis who asked to receive treatment with thalidomide. Marked symptomatic improvement was noticed after five weeks, and after ten weeks macroscopic bleeding ceased. At six months, the colonic mucosa appeared normal on colonoscopy, and only minimal inflammation was noted histologically. Steroids were discontinued without relapse. The authors acknowledged the possibility of spontaneous remission, but suggested the desirability of a trial of thalidomide in ulcerative colitis. A French group has reported the results of thalidomide treatment in 25 cases of chronic discoid lupus erythematosis (26). Of 25 patients, 18 appeared to receive benefit, with complete healing of lesions in 10 cases. These findings confirmed an earlier report by Barba Rubio (27). A Spanish group reported that thalidomide treatment gave "spectacularly good results" in six patients with severe apthous oral lesions (28). Pain was gone within three days of treatment and all lesions were healed within ten days. In one of the patients, the lesions had been continuously present for a year. However, other unpublished studies have failed to confirm this finding (29). A Malaysian patient with Weber-Christian disease (relapsing non-suppurative panniculitis, with skin lesions similar to those of ENL), poorly controlled with steroids for two years, was given a trial of thalidomide (30). The lesions steadily regressed, despite discontinuation of steroids. Thalidomide itself was discontinued after thirteen weeks, without relapse. Actinic prurigo is a lifelong dermatological disorder characterized by papular and eczematous lesions on sun-exposed skin. It is observed only in New World Indians and their descendants. London0 (31) administered thalidomide to 34 patients suffering from this disorder, and reported that 32 showed a good improvement, on average after about 50 days of treatment. Discontinuation of the drug was invariably followed by relapse. In an unpublished study, Convit failed to observe an effect of thalidomide treatment on the course of immune-complex nephropathy in leprosy (29). CONCLUSION Thalidomide has unquestioned value in the treatment of erythema nodosum leprosum, which appears to be an immune-complex disease. The recent anecdotal reports of possible activity in autoimmune disorders such as ulcerative colitis, discoid LE, apthous stomatitis, Weber-Christian disease, and actinic prurigo, cannot help but reinforce the suspicion that thalidomide may have a more general utility in the treatment of autoimmune disease. In particular, it appears that thalidomide may alleviate neutrophil-mediated cytoxicity and inflammation in immunecomplex disease. 440
In males and postmenopausal females, thalidomide can be considered a substantially non-toxic drug (32-351, in marked contrast to most antiinflammatory and immunosuppressive agents, Sedation will be the dose-limiting side effect. (In some cases, moderate sedation will be therapeutically desirable.) Anticholinergic effects (dry mouth, constipation) and exanthemas are occasionally noted. Peripheral neuritis, which is rarely seen, is typically mild and usually remits soon after the drug is discontinued. Unlike many teratogens, thalidomide does not cause point mutations in DNA and is not carcinogenic. Its teratogenic activity is confined to a 16 day period during early fetal development (36). When strong indications are present, fertile women can be given thalidomide in conjunction with oral contraceptives.
We conclude that thalidomide should be given pilot trials in a number of human autoimmune diseases - particularly those with histological and immunological similarities to ENL. This quintessentially taboo drug may yet earn an honored place in the sun. REFERENCES
1.
Wemambu SNC, Turk JL, Waters MFR, Rees RJW. Erythema nodosum leprosum: a clinical manifestation of the Arthrus phenomenon. Lancet ii: 933, 1969.
2.
Waters MFR, Turk JL, Wemambu SNC. Mechanisms of reactions in leprosy. Int J Leprosy 39: 417, 1971.
3.
Gelber RH, Epstein WV, Fasal P, Drutz DJ. Detection of circulating immune complex-like activity in the sera of patients with erythema nodosum leprosum. Int J Leprosy 40: 218, 1972.
4.
Turk JL, Waters MFR. Evidence for circulating immune complexes in lepromatous leprosy. Lancet ii: 572, 1972.
5.
Bjorvatn B, Barnetson RS, Kronvall G, Zubler RH, Lambert PH. Immune complexes and complement hypercatabolism in patients with leprosy. Clin Exp Immunol 26: 388, 1976.
6.
Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Pharm Ther 6: 303, 1965.
7.
Sheskin J, Convit J. Results of a double blind study of the influence of thalidomide on the lepra reaction. Int J Leprosy 37: 135, 1969.
8.
Hastings RC, Trautman JR, Enna CD, Jacobson RR. Thalidomide in treatment of erythema nodosum leprosum. Clin Pharm Ther 11: 481, 1970.
9.
Waters MFR. An internally-controlled double-blind trial of thalidomide in severe erythema nodosum leprosum. Leprosy Rev 42: 26, 1971.
10.
Sheskin J.
Thalidomide in lepra reaction.
Int J Derm 14: 575, 1975.
11. Theofilopoulos AN, Dixon FJ. Imnune complexes in human diseases. A review. AmJ Path01 100: 531, 1980. 441
12.
Hastings RC. Kellersberger Memorial Lecture 1979: immunosuppressive/anti-inflammatory thalidomide analogues. Ethiop Med J 18: 65, 1980.
13.
Faure M, Thivolet J, Gauchesand M. Inhibition of PMN leukocyte chemotaxis by thalidomide. Arch Derm Res 269: 275, 1980.
14.
Gusdon JP, Jr., Cohen C. Effect of thalidomide on the antibody response. Am J Obstet Gynec 100: 952, 1968.
15.
Dukor P, Dietrich FM. i: 569, 1967.
16.
Hellmann K, Duke DJ, Tucker DF. Prolongation of skin homograft survival by thalidomide. Brit Med J 2: 687, 1965.
17.
Mouzas GL, Gershon RK. The effect of thalidomide on skin allografts in mice: survival of the grafts. Transplantation 6: 476, i968.
18.
Murphy GP, Brede HD, Weber HW, Groenewald JH, Williams PD. Thalidomide immunosuppression in canine renal transplantation. J Med 1: 66, 1970.
19.
Bore PJ, Scothorne RJ. homografts in rabbits.
20.
Florsheim GL. 1966.
21.
Ulrich M, de Salas B, Convit J. Thalidomide activity in experimental Arthus and anaphylactic reactions. Int J Leprosy 39: 131, 1971.
22.
Goihman-Yahr M, Requena MA, Vallecalle-Suegart E, Convit J. Autoimmune diseases and thalidomide. II. Adjuvant disease, experimental allergic encephalomyelitis and emxperimentalallergic neuritis of the rat. Int J Leprosy 42: 266, 1974.
23.
Goihman-Yahr M, Requena MA, Vallecalle-Suegart E, Convit J. Autoimmune diseases and thalidomide. I. Experimental allergic encephalomyelitis and experimental allergic neuritis of the guinea pig. Int J Leprosy 40: 133, 1972.
24.
Miller JM, Ginsberg M, McElfatrick GC, Shonberg IL. The antiinflammatory effect and the analgesic property of contergan-268. Antibiotic Med Clin Ther 7: 743, 1960.
25.
Water MFR, Laing ABG, Ambikapathy A, Lennard-Jones JE. Treatment of ulcerative colitis with thalidomide. Brit Med J 1: 792, 1979.
26.
Samsoen M, Grosshans E, Basset A. La thalidomide dans Je traitement du lupus erythemateux chronique (L.E.C.). Ann Dermatol Venereal 107: 515, 1980.
Immunosuppression by thalidomide? Lancet
Effect of thalidomide on survival of'skin Lancet i: 1240, 1966.
Another chance for thalidomide. Lancet i: 207,
442
27.
Barba Rubio J, Gonzalez Franc0 F. Lupus erithematojo discoide y thalidomina. Dermatol Rev Mex 19: 131, 1975,
28.
Mascaro JM, Lecha M, Torras H. Thalidomide in the treatment of recurrent, necrotic, and giant mucocutaneous aphthae and aphthosis. Arch Derm 115: 636, 1979.
29.
Hastings RC, personal comnunication.
30.
Eravelly J, Waters MFR. Lancet i: 251, 1977.
31.
Londo3ioF. Thalidomide in the treatment of actinic prurigo. J Derm 12: 326, 1973.
32.
Somers GF. Pharmacological properties of thalidomide ( cC-phthalimido glutarimide), a new sedative drug. Brit J Pharm 15: 111, 1960.
33.
Grabstald H, Golbeg R.
34.
Cohen S.
35.
Bresnahan TJ. Attempted suicide with thalidomide: a case report. Appl Ther 3: 621, 1961.
36.
Fabro S. Biochemical basis of thalidomide teratogenesis. In: The Biochemical Basis of Chemical Teratogenesis, Juchau MR, ed. Elsevier, Amsterdam, 1981, p. 160.
Thalidomide in Weber-Christian disease. Int
Clinical experience with thalidomide in patients with cancer. Clin Pharm Ther 6: 292, 1965. Thalidomide polyneuropathy. N Eng J Med 266: 1268, 1962.
443
THALIDOMIDE FOR AUTOIMMUNE DISEASE Sheldon S. Hendler and Mark F. McCarty, 1515 Madison Avenue, San Diego, California 92116 ABSTRACT The therapeutic efficacy of thalidomide in erythema nodosum leprosum suggests that thalidomide might play a useful therapeutic role in other human immune-complex diseases. Thalidomide has shown anti-inflammatory or immunosuppressive actions in several animal models. Current evidence suggests that its rapid activity in ENL may result from suppression of neutrophil chemotaxis and phagocytosis. Scattered anecdotal clinical reports of apparent response to thalidomide in various autoimmune diseases are hardly conclusive, but underline the desirability of appropriate pilot trials of thalidomide in autoimnune diseases, particularly those in which immune complex deposition plays a prominent role. Provided that a contraindication in fertile women is strictly observed, thalidomide therapy appears to be quite safe. INTRODUCTION Erythema nodosum leprosum (ENL) is a dermal vasculitis which occurs episodically in lepromatous leprosy (1). It presents as clusters of painful erythematous subcutaneous nodules, often accompanied by systemic manifestations such as fever, malaise, lymphadenopathy, arthralgia, neuritis, albuminuria, and iridocyclitis. On histological examination, marked perivascular infiltration of PMN leukocytes is the prominent feature. Studies with fluorescent antibodies have revealed the presence of immune complexes, complement, and mycobacterial antigen in these lesions (1, 2). Circulating immune complexes and increased levels of activated complement (C3d) are also observed (3-5). Investigators have noted the similarity between the skin lesions of ENL and those produced by an Arthus reaction, and have cited the systemic manifestations of ENL as symptoms of serum sickness (1, 2). ENL therefore appears to be an immune-complex disease, probably initiated by mycobacterial antigens. ENL typically develops after anti-microbial therapy has produced massive mycobacterial kill, liberating large amounts of mycobacterial antigen. It is less frequently seen in untreated leprosy. The therapeutic efficacy of thalidomide in ENL was fortuitously discovered
437
by Sheskin in 1964, who observed rapid and complete resolution of ENL in a patient receiving thalidomide as a sedative (6). Several controlled trials subsequently confirmed the marked efficacy of thalidomide in ENL (7-9). The effective dose is 400 mg daily, in divided doses. The improvement in the cardinal symptoms - erythema nodosum and fever -is usually rapid, often discernible within 24 hours. Other symptoms, such as arthralgia, neuritis, and iridocyclitis, also respond, though less rapidly (7, 10). Thalidomide's action appears to be immunomodulatory, since examinations of skin scrapings indicate that thalidomide does not alter the course of the mycobacterial infection. At present, ENL is the only clearly established indication for thalidomide. Thalidomide does not appear to be useful for treatment of the lepra reactions seen in tuberculoid leprosy (8), which have been characterized as of the cell-mediated delayed hypersensitivity type. Writing in 1970, Hastings et al (8) remarked that "Due to the close clinical and serological similarities between ENL and various autoimmune or connective tissue diseases, clinical trials of thalidomide in the latter appear to be indicated". This suggestion has lost none of its cogency a decade later. We wish to propose that the therapeutic utility of thalidomide in ENL results from an intervention in immune-complex-mediated inflammation which may well have clinical value in other autoimnune diseases characterized by immune-complex deposition (11). The rapid response to thalidomide often noted in ENL evidently reflects an anti-inflanunatoryaction which could operate at the level of complement activation, PMN leukocyte chemotaxic and diapedesis, lysosome degranulation, mast cell activation, or antigen presentation. An effect on the afferent arm of the immune response is also likely to play a role in longer term response to thalidomide. An alteration of macrophage processing of mycobacterial antigen, or of T-suppressor cell function, might lead to reduced synthesis of anti-mycobacterial antibody. Hastings has recently summarized the results of a comprehensive series of studies intended to define the site of action of thalidomide in imnunecomplex-mediated inflammation (12). Thalidomide was shown to inhibit neutrophil chemotaxis in vitro in chemotaxic chambers; neutrophil phagocytosis of opsonized antigen was also found to be decreased in the presence of thalidomide. Thalidomide did not affect complement activation or neutrophil lysosome stability in these studies. Suppression of neutrophil function therefore appears to be a likely explanation for the rapid therapeutic effect of thalidomide in ENL. Faure et al (13) have simultaneously and independently confirmed the effect of thalidomide on neutrophil chemotaxis. Pre-incubation of human PMN leukocytes with 1 mcg/ml thalidomide was shown to reduce chemotaxis to activated complement by over 50%. Although several studies have found that the high dose thalidomide has rather small and equivocal effects on antibody synthesis (14, 15), Hastings notes (12) that thalidomide suppresses the primary IgM response to a T-dependent antigen in mice. The effect of thalidomide on Tsuppressor activity merits study, since a severe deficit of T-suppressor function has been observed in some cases of leprosy. 438
THALIDOMIDE IN ANIMAL MODELS OF IMFLAMMATION Study of thalidomide as an immunosuppressive agent was prompted by reports from Hellmann et al (16) that thalidomide treatment prolonged homograft survival in mice, and by Sheskin's discovery of thalidomide's effect on ENL. Most of these studies have examined the effect of thalidomide on graft rejection. The results have been contradictory. Some authors report a small enhancement of graft survival (15-18), while others report no effect (19, 20) or have difficulty confirming their prior results(l5). In some cases, significant results were achieved only if the donor animal also received thalidomide pretreatment. With one exception, the doses of thalidomide employed have been so high (at least an order of magnitude greater than those used clinically in humans, on a mg/kg basis) that the results are of questionable clinical relevance. (The one exception was a study in which 10 mg/kg thalidomide 3 times weekly prior to and following renal transplantation in dogs increased survival by about a week (18).) In any case, graft rejection is a form of delayed hypersensitivity that has little similarity to the Arthus-like reaction seen in ENL. More relevant to our purposes is the work of Ulrich et al (21), who found that thalidomide (100 mglkglday) did not modify the size of Arthus reactions induced with egg albumin or lepromin in guinea pigs. Passive Arthus reactions (involving administration of both antigen and antibody) were also unaffected by thalidomide. However, these authors note that guinea pigs may not be a good model for study of thalidomide, since they are insensitive to its sedative effects. Adjuvant disease in rats is produced by injection of killed mycobacteria in Freund's adjuvant. The animals develop secondary dermal inflammatory lesions which initially show some PMN infiltration but are later dominated by mononuclear histiocytes. 400 mg/kg thalidomide daily was found to substantially reduce the number of inflammatory lesions in Wistar rats with adjuvant disease (21); the course of the disease was not significantly affected in Lewis/Mai rats, however. The systemic manifestations of adjuvant disease - fever, malaise inflammation of the joints, skin, and eyes - have been noted to be similar to those seen in ENL (22). Other experimental granulomas (experimental allergic encephalomyelitis and allergic neuritis) in rats and guinea pigs, were not influenced by thalidomide treatment (22, 23). Thalidomide, in human-equivalent doses, has been shown to have an antiinflammatory action in carageenen rat paw edema (12). In particular, it suppresses the infiltration of neutrophils during the late stages of this disorder. ANECDOTAL CLINICAL REPORTS Miller et al (24) were among the first to report on clinical antiinflammatory actions of thalidomide. They noted that thalidomide appeared to have a moderate but inconsistent effect in relieving inflammation and
439
edema in such conditions as cellulitis and thrombophlebitis. But preand post-operative administration of thalidomide was said to very substantially reduce post-operative edema and pain following hemorrhoidectomy in a series of 17 patients. Waters et al (25) recently reported the case of a Malaysian leprosarium nurse with a five year history of unremitting ulcerative colitis who asked to receive treatment with thalidomide. Marked symptomatic improvement was noticed after five weeks, and after ten weeks macroscopic bleeding ceased. At six months, the colonic mucosa appeared normal on colonoscopy, and only minimal inflammation was noted histologically. Steroids were discontinued without relapse. The authors acknowledged the possibility of spontaneous remission, but suggested the desirability of a trial of thalidomide in ulcerative colitis. A French group has reported the results of thalidomide treatment in 25 cases of chronic discoid lupus erythematosis (26). Of 25 patients, 18 appeared to receive benefit, with complete healing of lesions in 10 cases. These findings confirmed an earlier report by Barba Rubio (27). A Spanish group reported that thalidomide treatment gave "spectacularly good results" in six patients with severe apthous oral lesions (28). Pain was gone within three days of treatment and all lesions were healed within ten days. In one of the patients, the lesions had been continuously present for a year. However, other unpublished studies have failed to confirm this finding (29). A Malaysian patient with Weber-Christian disease (relapsing non-suppurative panniculitis, with skin lesions similar to those of ENL), poorly controlled with steroids for two years, was given a trial of thalidomide (30). The lesions steadily regressed, despite discontinuation of steroids. Thalidomide itself was discontinued after thirteen weeks, without relapse. Actinic prurigo is a lifelong dermatological disorder characterized by papular and eczematous lesions on sun-exposed skin. It is observed only in New World Indians and their descendants. London0 (31) administered thalidomide to 34 patients suffering from this disorder, and reported that 32 showed a good improvement, on average after about 50 days of treatment. Discontinuation of the drug was invariably followed by relapse. In an unpublished study, Convit failed to observe an effect of thalidomide treatment on the course of immune-complex nephropathy in leprosy (29). CONCLUSION Thalidomide has unquestioned value in the treatment of erythema nodosum leprosum, which appears to be an immune-complex disease. The recent anecdotal reports of possible activity in autoimmune disorders such as ulcerative colitis, discoid LE, apthous stomatitis, Weber-Christian disease, and actinic prurigo, cannot help but reinforce the suspicion that thalidomide may have a more general utility in the treatment of autoimmune disease. In particular, it appears that thalidomide may alleviate neutrophil-mediated cytoxicity and inflammation in immunecomplex disease. 440
In males and postmenopausal females, thalidomide can be considered a substantially non-toxic drug (32-351, in marked contrast to most antiinflammatory and immunosuppressive agents, Sedation will be the dose-limiting side effect. (In some cases, moderate sedation will be therapeutically desirable.) Anticholinergic effects (dry mouth, constipation) and exanthemas are occasionally noted. Peripheral neuritis, which is rarely seen, is typically mild and usually remits soon after the drug is discontinued. Unlike many teratogens, thalidomide does not cause point mutations in DNA and is not carcinogenic. Its teratogenic activity is confined to a 16 day period during early fetal development (36). When strong indications are present, fertile women can be given thalidomide in conjunction with oral contraceptives.
We conclude that thalidomide should be given pilot trials in a number of human autoimmune diseases - particularly those with histological and immunological similarities to ENL. This quintessentially taboo drug may yet earn an honored place in the sun. REFERENCES
1.
Wemambu SNC, Turk JL, Waters MFR, Rees RJW. Erythema nodosum leprosum: a clinical manifestation of the Arthrus phenomenon. Lancet ii: 933, 1969.
2.
Waters MFR, Turk JL, Wemambu SNC. Mechanisms of reactions in leprosy. Int J Leprosy 39: 417, 1971.
3.
Gelber RH, Epstein WV, Fasal P, Drutz DJ. Detection of circulating immune complex-like activity in the sera of patients with erythema nodosum leprosum. Int J Leprosy 40: 218, 1972.
4.
Turk JL, Waters MFR. Evidence for circulating immune complexes in lepromatous leprosy. Lancet ii: 572, 1972.
5.
Bjorvatn B, Barnetson RS, Kronvall G, Zubler RH, Lambert PH. Immune complexes and complement hypercatabolism in patients with leprosy. Clin Exp Immunol 26: 388, 1976.
6.
Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Pharm Ther 6: 303, 1965.
7.
Sheskin J, Convit J. Results of a double blind study of the influence of thalidomide on the lepra reaction. Int J Leprosy 37: 135, 1969.
8.
Hastings RC, Trautman JR, Enna CD, Jacobson RR. Thalidomide in treatment of erythema nodosum leprosum. Clin Pharm Ther 11: 481, 1970.
9.
Waters MFR. An internally-controlled double-blind trial of thalidomide in severe erythema nodosum leprosum. Leprosy Rev 42: 26, 1971.
10.
Sheskin J.
Thalidomide in lepra reaction.
Int J Derm 14: 575, 1975.
11. Theofilopoulos AN, Dixon FJ. Imnune complexes in human diseases. A review. AmJ Path01 100: 531, 1980. 441
12.
Hastings RC. Kellersberger Memorial Lecture 1979: immunosuppressive/anti-inflammatory thalidomide analogues. Ethiop Med J 18: 65, 1980.
13.
Faure M, Thivolet J, Gauchesand M. Inhibition of PMN leukocyte chemotaxis by thalidomide. Arch Derm Res 269: 275, 1980.
14.
Gusdon JP, Jr., Cohen C. Effect of thalidomide on the antibody response. Am J Obstet Gynec 100: 952, 1968.
15.
Dukor P, Dietrich FM. i: 569, 1967.
16.
Hellmann K, Duke DJ, Tucker DF. Prolongation of skin homograft survival by thalidomide. Brit Med J 2: 687, 1965.
17.
Mouzas GL, Gershon RK. The effect of thalidomide on skin allografts in mice: survival of the grafts. Transplantation 6: 476, i968.
18.
Murphy GP, Brede HD, Weber HW, Groenewald JH, Williams PD. Thalidomide immunosuppression in canine renal transplantation. J Med 1: 66, 1970.
19.
Bore PJ, Scothorne RJ. homografts in rabbits.
20.
Florsheim GL. 1966.
21.
Ulrich M, de Salas B, Convit J. Thalidomide activity in experimental Arthus and anaphylactic reactions. Int J Leprosy 39: 131, 1971.
22.
Goihman-Yahr M, Requena MA, Vallecalle-Suegart E, Convit J. Autoimmune diseases and thalidomide. II. Adjuvant disease, experimental allergic encephalomyelitis and emxperimentalallergic neuritis of the rat. Int J Leprosy 42: 266, 1974.
23.
Goihman-Yahr M, Requena MA, Vallecalle-Suegart E, Convit J. Autoimmune diseases and thalidomide. I. Experimental allergic encephalomyelitis and experimental allergic neuritis of the guinea pig. Int J Leprosy 40: 133, 1972.
24.
Miller JM, Ginsberg M, McElfatrick GC, Shonberg IL. The antiinflammatory effect and the analgesic property of contergan-268. Antibiotic Med Clin Ther 7: 743, 1960.
25.
Water MFR, Laing ABG, Ambikapathy A, Lennard-Jones JE. Treatment of ulcerative colitis with thalidomide. Brit Med J 1: 792, 1979.
26.
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