Drug-induced systemic lupus erythematosus: A critical review

Drug-induced By

Systemic Lupus Erythematosus: A Critical Review Stanley L. Lee and P. Harvey Chase

INCE 1945,’ more than 300 patients with elements of the systemic lupus erythematosus (SLE) syndrome”*” have been reported as having developed the syndrome following drug therapy given for another disease. Comprehensive reviews of this material have been published in 1961,4 1966,“.6 1968,’ and 1972,’ and the problem of drug-induced SLE has been the subject of editorials in widely circulated journals.g-‘l More and more drugs continue to be implicated, and attempts to explain the pathogenetic mechanisms proliferate. Thus another review now appears worthwhile, not only in order to attempt to analyze the problem of drug-induced SLE, but also to attempt to relate it to SLE as it occurs without drug provocation.

S

DEFINITION

OF DRUG-INDUCED

SLE

Many different drugs, of varying chemical structure, used for a variety of indications and having widely different metabolic fates have been implicated. In any specified patient, it may be very difficult to know whether the attribution of the disease syndrome to drug treatment is justified. Certain features of the syndrome seem, however, to be constant for all drugs, and thus to permit definition of druginduced SLE as such. The clinical criteria for the diagnosis of drug-induced SLE are (or should be) the same as those for the diagnosis of SLE. The criteria of Siegel et al.2 or of the American Rheumatism Association3 which are virtually coincident are applicable. To them must be added the following: (1) A drug must have been administered before the onset of any sign or symptom used as one of the criteria for the SLE diagnosis. In most reported cases which meet this criterion, the offending drug has been given continuously for a period ranging from 3 wk to 2 yr. (Alarcon-Segovia”,’ argues that for some drugs the period of prior administration is very much shorter than for others. A critical reading does not appear to support that interpretation.) (2) The disease process must reverse itself promptly upon cessation of drug treatment. Clinical signs and symptoms must begin to clear within days; serologic findings, however, may not change for months or even years. Resumption of drug therapy, in the few cases where it has been tried, seems to result in From rhe Departments of Medicine, Jewish Hospital and Medical Center of Brooklyn and State University of New York Downstate Medical Center, Brooklyn, N. Y. Supported by a General Research Support Grant (GRS-5503) f ram the National Institutes of Health, and b.y grants from The Lupus Erythematosus Foundation and the Joan Kramer Memorial Fund. Stanley L. Lee, M.D.: Director of Medicine, Jewish Hospital and Medical Center of Brooklyn, Professor of Medicine, State University of New York Downstate Medical Center, Brooklyn, N. Y. P. Harvey Chase, M.D.: j4ssociare Director of Medicine. Jew&h Hospital and Medical Center of Brooklyn, Brooklyn, N. Y. 0 1975 by Grune & Stratton, Inc.

Seminars

in Arthritis

and Rheumatism,

Vol. 5, No. 1 (August). 1975

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very prompt (hours or a few days) recrudescence of symptoms,12-17 with only one reported exception.ls Once it has been established that a given drug has produced the SLE syndrome, the question of the mechanism of action arises. This question has been investigated for only a few of the agents, and, in no case, is the answer clear. In the following review, the evidence implicating each drug will be examined, as well as whatever evidence has been adduced for pathogenetic mechanisms. HYDRALAZINE

(L-HYDRAzINOPHTHALAZINE)

This drug was first introduced as an antihypertensive agent in 1952. By 1955, nine instances12~13~20-26 of a syndrome resembling SLE had been reported, following administration of the drug, for periods ranging from 3 to 13 mo and in one large series of treated patients, 17 out of 211 had developed some suggestive signs or symptoms.27 Not all of the patients had syndromes which met, in full, the diagnostic criteria for SLE (as later established), and one patient who otherwise appeared to meet all criteria, died of her SLE.25 Nevertheless, this early flurry of case reports appeared to establish a firm basis for the cause and effect relationship between the drug and the syndrome. Subsequent reports have described more than 150 patients with hydralazineinduced SLE. Prospective studies of hypertensive patients treated with the drug have indicated the development of some parts of the syndrome, in from 2% to Case reports have become scarce in recent years, but 21% of patients. 28*2g*30,31,32 epidemiologic studies indicate a steady incidence rate.33 Although most patients who develop SLE after hydralazine administration do so only after receiving a total dosage of at least 100 g of the drug,2g susceptibility varies widely. At least one patient has become symptomatic after only 2 g, administered over a 3 wk period. A variable susceptibility, together with the finding that even among patients who receive 100 g or more of the drug, the incidence of the complete syndrome is probably not more than 1% gave rise to the hypothesis of a “lupus diathesis.“6,34,35 In a series of 50 patients with hydralazineinduced SLE,35 74% had past histories and 34% had family histories suggestive of “rheumatic disease;” patients receiving similar amounts of hydralazine but not developing lupuslike symptoms had significantly lower frequencies of such histories. In early reports,21,26,30antinuclear antibodies were found only in a minority of the patients who had lupuslike syndromes. However, improved techniques for demonstrating such antibodies have resulted in the finding that most patients (54% in one series32) receiving hydralazine for long periods of time develop detectable antinuclear antibodies. It is now accepted32.36 that all patients who develop “hydralazine disease” (i.e., hydralazine-induced SLE) have circulating antinuclear antibodies-that is, antinuclear antibodies appear to be a necessary, but not a sufficient, antecedent for the development of hydralazine lupus. Hydralazine is metabolized largely by acetylation in the liver. A genetically controlled polymorphism exists in the hepatic acetyl transferase responsible for this detoxification. Analyses of enzyme activity suffice to characterize two populations-“slow acetylators” and “fast acetylators.” In a prospective study of 57 hypertensive patients on hydralazine maintenance, 22 of 33 slow acetylators de-

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SLE

veloped antinuclear antibodies during observation, while only 9 out of 24 fast acetylators did so. All 12 of the patients in this series who developed any lupuslike symptoms belonged to the group of slow acetylators.32 Attempts to reproduce hydralazine induction of SLE in experimental animals must be considered to have failed thus far. Only one worker3’ has reported complete success with a canine model. However, at least 11 negative reports have been published, using dogs, mice, rats, guinea pigs, and swine as experimental models.38-4R Antinuclear antibodies, however, have been produced regularly in mice4g and rabbitsso by injections of hydralazine. Physical complexes of hydralazine and deoxyribonucleoprotein in solution have been demonstrated.51 Since nucleoprotein is continuously being liberated from dying cells in every individual, such complexing might well be the agency which renders the nucleoprotein both less easily degradable by enzymes and more likely to induce antibody. 52 A gap remains between understanding the production of antinuclear antibodies and understanding the induction of the disease state, An attempt to bridge this gap is represented by a recent study36 in which patients with hydralazine-induced SLE were found to have circulating antibodies to hydralazine, as well as to deoxyribonucleoprotein and native deoxyribonucleic acid (DNA). The antihydralazine antibodies were unique to these patients; they were not found in patients with spontaneous SLE. Similarly, lymphocytes from patients with hydralazine-induced SLE reacted in tissue culture to the presence of hydralazine, while lymphocytes from control patients did not. These studies suggest that the full-blown syndrome of SLE in these patients depends first upon the induction of antinuclear antibodies by hydralazine and second upon the induction of antibodies to hydralazine itself; that the continuing immune reaction engendered by the simultaneous presence of hydralazine and its antibody provide sufficient stimuli to the production of symptoms in a patient already producing antinuclear (and anti-DNA) antibodies. Other Antihypertensive

Drugs

No other antihypertensive drugs have been implicated as inducers of SLE with the exception of reserpine. In a retrospective study of the hospital and clinic records of about 1200 patients with SLE, four patients were found who had been treated with reserpine for hypertension in dosages ranging up to 200 mg per day for periods of time up to 4 yr, before signs and symptoms of SLE intervened.” The inference was drawn that the disease in these patients might have been due to the reserpine. A search of the literature has failed to discover other reports implicating this drug, and it is now impossible to recover those records to examine them more critically. Alpha methyldopa (Aldomet) has been shown to induce the formation of antinuclear antibodies in some patients,, 53,54but no patient has yet been reported to have developed symptomatic SLE. PROCAINAMIOE

Procainamide (p-amino-N-(2-diethylaminoethyl) benzamide) was introduced in the treatment of cardiac arrhythmias in 195 155and in the treatment of myotonia in 1955.56The first patient to develop symptoms of systemic lupus erythematosus

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was not reported until 1962. 57 Other case reports soon followed,58-61 so that by 1965 a total of 12 patients had been reported. The first patient with myotonia to develop procainamide-induced SLE was reported in 1966.62 In New York City in the mid- 196Os, procainamide appeared to be responsible for more cases of lupuslike syndrome than any other drug.33 By 1970,63 over 60 patients had been reported, of whom perhaps less than half actually had manifestations completely meeting the diagnostic criteria discussed in the first segment of this review. Symptoms in most reported cases have developed only after continuous administration of the drug (in the first course) for between 3 mo to 2 yr. However, one patienF4 is reported to have noted symptoms after only 2 wk of therapy, another65 after 5 wk and anotheF6 after 2 mo; while in one patient,67 symptoms did not begin until 4yz yr after institution of procainamide therapy. Daily dosage of as little as 500 mg was sufficient in at least three patients61~68*eg to produce symptoms. The total dosage of procainamide administered before the onset of symptoms varied from only 14 g64 to 3600 g.62 Analysis of these case reports and of others has led observers to conclude that procainamide-induced SLE differs from spontaneous SLE in being milder, in having less prominent febrile and dermal manifestations, more common pulmonary involvement and, most importantly, in sparing the kidney completely.63*67,70,74 Patients with procainamide-induced SLE are approximately evenly divided between the sexes and they tend to be much older than patients with SLE.33 Most of these differences are probably explained by differences in the population at risk: Patients who are put on long-term antiarrhythmic therapy are overwhelmingly male and past middle age. Because they have heart disease and (often) pulmonary vascular congestion, pulmonary infarction and infection are common. The mildness of the disease is most probably related to the fact that it is usually diagnosed early. Discrepancies among dosages required for the development of symptoms of procainamide-induced SLE have led to speculations that certain patients might be predisposed to react unfavorably to the drug-i.e., might have a lupus diathesis. One case report75 concerns a 5 1-yr-old woman, treated for paroxysmal atria1 tachycardia with 2 g of procainamide per day, who developed arthritis, leukopenia and a positive L.E. cell test after 6 mo. Symptoms cleared slowly when the drug was stopped, and a family study revealed first-degree relatives and a first cousin with autoimmune disease and an “allergic” brother. after 1 yr Another patient,76 a 43-yr-old male physician, developed symptoms of procainamide administration. Although his symptoms cleared, antinuclear antibodies persisted. A sample of serum drawn before he started procainamide had accidentally been preserved; it showed antinuclear antibodies. Still another example of the lupus diathesis was a 51-yr-old man with known SLE who developed myotonia. After 16 mo of treatment with 4 g per day of procainamide, he experienced an exacerbation of SLE symptoms which cleared after procainamide was stopped and steroids were begun.“’ The above three case reports suggest that a possible reason for the development of SLE symptoms after procainamide administration in some patients might be an enhanced susceptibility in those patients. Procainamide is metabolized differently from hydralazine; most of an ingested dose is excreted un-

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87

changed, while smaller amounts are hydrolyzed and excreted as p-aminobenzoic acid.” Acetylation plays no role and no innate differences have yet been demonstrated in the capacity of individuals to handle the drug, despite sPeculation to that effect, expressed by the authors of one of those reports.75 Furthermore, prospective studies have shown that the administration of procainamide leads to the development of antinuclear antibodies in from 50% to 74% of patients who receive the drug for at least 2 mo.78-s’ The proportion of those who would develop symptoms if permitted to continue on the drug is not known. One studys2 suggests that the proportion may be as low as 5% but other writers74,83*84 feel that it may be high enough to warrant discarding the hypothesis of a lupus diathesis. Searches for immune reactivity to procainamide itself, in patients with procainamide-induced SLE, have yielded generally negative results, both with respect to lymphocyte transformations1 and to circulating antibodies. Nineteen to 50% of hospital patients were found to have “natural” antibodies to procainamide, but only 6% of patients with procainamide-induced SLE showed such antibodies.78 It is possible that the common presence of natural antibodies to procainamide protects those persons who possess them by hastening the elimination of the drug and thus diminishing the opportunity for procainamide-DNA complexes to develop. Natural antibodies to procainamide were not found in mice or rabbits, but were found in dogs. ‘* Although it was possible to immunize various species against procainamide,78 chronic administration of the drug to rabbits, rats, guinea pigs, and mice did not lead to the production of significant amounts of antinuclear antibodies and did not hasten the development of antinuclear antibodies in strains of mice which usually develop such antibodies spontaneously.*” However, procainamide can be complexed with DNA in vitro, in the presence of a photodynamic molecule and light in the visible range. This photochemical product has proved to be an excellent antigen in rabbits, producing high titers of antibodies which cross-react with both DNA and photo-oxidized DNA.86 The relationship of complex formation to increased antigenicity is, as is the case for hydralazine, in accord with Grabar’P hypothesis of antibody formation. If “procainamide-DNA” complexes are the actual antigens, the antinuclear antibodies in procainamide-induced SLE ought not to react primarily with pure native DNA. Indeed, the regular absence of antibodies reactive with native DNA has been noted,s7-8g in contrast to their regular occurrence in patients with SLE of spontaneous origin. ‘* The apparent total absence of antibodies to native DNA in procainamide-induced SLE contrasts with their demonstration36.9* in some patients with hydralazine-induced SLE. Since some test systems for antibodies to native DNA apparently do not always discriminate properly,g1 these apparent differences may be reconciled when technics become reliably standardized. Other Cardiac Drugs

Procainamide is, by a large margin, the most frequently used antiarrhythmia drug. Quinidine-its nearest competitor-has not been clearly implicated, although one of 19 asymptomatic patients in a prospective study, who had been receiving it for more than 2 mo, developed a positive L.E. cell test and antinuclear

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antibodiesso One other patient has been reported to have quinidine-induced SLE,g2 but the criteria for the diagnosis are not met. Diphenylhydantoin is more widely used as an anticonvulsant (see below); no cases have been reported of drug-induced SLE following its use as an antiarrhythmic, perhaps because of its relative infrequency of administration for long periods of time for this indication. Practolol (4-(2-hydroxy-3-isopropylaminopropoxy) acetanilide) is a beta-adrenergic blocking agent which was introduced to clinical use in England in 197 1.g3 Three patients with angina1 syndrome who received this drug continuously over 6-10 mo, in daily doses of 300 to 600 mg, developed SLE-like manifestations. One of these patients met the diagnostic criteria for SLE completely. In all three, the symptoms subsided promptly upon withdrawal of the drug. None of these patients had antibodies to DNA or clinical evidence of renal involvement. No evidence could be adduced in these patients of sensitization to practolol in terms of either humoral antibodies or of lymphocyte stimulation studies, although the lymphocytes of all three reacted “atypically” in response to mitogensg4 No information is available concerning the frequency of antinuclear antibodies among habitual users of practolol. ANTITUBERCULOSIS

DRUGS

Isoniazid (nicotinic acid hydrazide) was introduced for the treatment of tuberculosis in 1952.g5The first case of a syndrome possibly related to SLE, occurring after antituberculosis therapy, was not reported until 1961.g6 This patient developed L.E. cells, in association with fever, lymphadenopathy, and hepatitis. The authors attributed the syndrome to para-amino sulfonic acid, which had been administered together with isoniazid. Although only a few individual case reports at least three of thesesg-lO1 meet the crihave followed this original one, 17,g7-102 teria for drug-induced SLE. It is not certain that isoniazid is, in fact, the inducing agent in all these cases, since most patients with tuberculosis receive multiple drugs. However, at least one patient”’ was treated only with isoniazid during the critical period. Many cases, other than those individually reported, must have occurred. In two separate epidemiologic studies of different patient groups, we have encountered four6 and nine33 such patients, respectively. The daily dose of isoniazid administered to patients who developed the SLE syndrome has ranged from 300 to 900 mg; symptoms have arisen after continuous therapy of from 4 wk to 14 mo and total doses ranging from 25 to more than 1OOg. Examination of case histories raises the question as to whether some of these patients may have a lupus diathesis. An example is a 28-yr-old woman whose symptoms subsided promptly upon cessation of antituberculosis therapy but recurred 29 mo later, although no additional drug was given. That patient then had a classic presentation of SLE.gg Acetylation in the liver is, for isoniazid as for hydralazine, a major metabolic pathway,77 and it is assumed, without direct proof, that slow acetylators are more likely than fast acetylators to develop isoniazid-induced SLE.32 Both in mice4g and in humans,103*104prospective studies have shown that isoniazid is capable of inducing the formation of antinuclear antibodies. For both

DRUG-INDUCED

89

SLE

species, isoniazid appears to be less potent in this respect than is hydralazine. In patients with tuberculosis, antinuclear antibodies appeared after isoniazid administration in frequencies of 22%‘04 and 23%.lo3 As treatment continued beyond 3 mo, titers increased. lo4Of 24 patients who received isoniazid alone, ten developed antinuclear antibodies, while none of 10 patients who received other antituberculosis drugs (but not isoniazid) did so. lo4This study thus tends to confirm the impression that isoniazid, of all the antituberculosis drugs, is the one responsible for SLE-like symptoms, even though no patient in either of these prospective series developed such symptoms. The specificities of the antinuclear antibodies arising in response to isoniazid have been studied.lo5 No antibodies to native DNA were found in 214 consecutive patients, whereas 32 of 37 patients with SLE studied at the same time had such antibodies. Seventy-one per cent of patients receiving isoniazid, however, developed antibodies reactive with soluble nucleoprotein which had been denatured by contact with isoniazid. Antibodies to whole nuclei, to nucleoprotein and to soluble nucleoprotein were present in lesser frequencies. The inference to be drawn from these studies is that isoniazid induces antinuclear antibodies because it denatures and renders antigenic, in a particular way, nucleoproteins released from dying cells. Antinuclear antibodies, as detected by conventional techniques, would then in fact be cross-reacting antibodies. There remains the gap in pathogenesis, already noted for procainamide and hydralazine. Antinuclear antibody induction in a relatively high proportion of patients is a necessary, but not a sufficient precondition, for the development of lupuslike symptoms which occur in a much smaller proportion of patients. ANTICONVULSANT

DRUGS

A large number of drugs, belonging to five distinct chemical classes, have been used in the treatment of convulsive disorders. At least six of these drugs, including representatives of each of the five classes, have been implicated as inducers of symptoms resembling SLE. Many patients with convulsive disorders are treated with several of the drugs simultaneously, and so in many of the observed patients the specific guilty drug has not been identified. In some cases, the changing of these drugs has permitted such identification. The drugs which clearly have been responsible for instances of lupuslike disease are the following: Hydan toins Diphenylhydantoin, introduced into clinical medicine in 1938,1°6is one of the two most commonly used anticonvulsant drugs.77 The first case report implicating diphenylhydantoin appeared in 1953.1°7 Mephenytoin (methylethylphenylhydantoin), a close congener of diphenylhydantoin, was introduced in 1945.“’ The first case report of lupuslike disease following its administration appeared in 1957.“’ Individual case reports implicating one, the other or possibly both of these drugs have continued to appear up to the present.‘L0-~‘8 Oxazolidinediones Trimethadione, the most commonly used agent in the treatment of petit mal, was introduced in 1945.“’ At least five individuals have been described who de-

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veloped lupuslike symptoms after receiving trimethadione as the only anticonvulsant drug4.W 110,118_ the first of these in 1960.30 Other patients’10~112~120 have developed symptoms while receiving trimethadione and hydantoin drugs. Barbiturates Phenobarbital is undoubtedly the most commonly used anticonvulsant drug. Nevertheless, no case of drug-induced SLE has been reported in a patient receiving only this drug. Primidone is a congener of phenobarbital which was introduced as an anticonvulsant in 1952. lzl At least one patient has been reported12* who developed signs and symptoms of SLE after receiving primidone as the only anticonvulsant. Acetylureas Pheneturide (phenylethylacetylurea), first suggested as an anticonvulsant drug in 1950,L23is rather widely used in Europe. At least one patientlz4 developed lupuslike symptoms while receiving this drug; the symptoms abated when pheneturide was stopped, even though she continued to receive other anticonvulsant drugs. Succinamides

This class of anticonvulsant is the most recent to reach the pharmacopeia. is considered” to be an agent of choice in petit ma1 epilepsy; it was introduced in 1958.125At least six patients have now been reported,*12~‘26-‘Zsbeginning in 1963, who have developed SLE manifestations as the result of administration of this drug. However, one of these patients*12 was receiving not only ethosuximide but also trimethadione and amino-glutethimide before symptoms developed. Another12’ is the only patient thus far to have been reported who developed the disease first on one anticonvulsant drug (trimethadione), recovered when that drug was stopped, and later again manifested symptoms of SLE while who first developed the syndrome receiving ethosuximide. One other patient 127,128 on ethosuximide was not free of symptoms as long as 2Ys yr later. Thus, only three case reports 126.128 and case 3 Of ref. 127 are convincing_ The diagnosis of SLE secondary to anticonvulsant drugs presents particular difficulty. Patients with hypertension who receive hydralazine, patients with arrhythmias who receive procainamide, and patients with tuberculosis who receive isoniazid all rather clearly do not have SLE before the drug in question has been administered. But convulsive disorders are well-recognized manifestations of SLE. Does the child who develops epileptiform seizures, is treated for them with an anticonvulsant drug and later manifests signs of SLE, have SLE or druginduced SLE? Sometimes, prolonged observation shows that what was at first thought to be a drug reaction was really the first exacerbation of underlying SLE.12’ The generally poor prognosis found in children with SLE whose early manifestations involve the central nervous system,‘2g compared with the generally good prognosis for anticonvulsant-induced SLE,l12 helps the observer to make the differential diagnosis. The picture is further complicated, however, by the evidence that patients who develop SLE manifestations after anticonEthosuximide

DRUG-INDUCED

91

SLE

vulsant drugs may have some sort of innate predisposition (the lupus diathesis) to the disease.30~1’3~127 No reliable index exists of the risk to patients with convulsive disorders of the development of drug-induced SLE from any or all anticonvulsant drugs. An epidemiologic study33 indicates that from 1957-66, in a defined population in New York City, at least 16 cases were identified related to diphenylhydantoin. This number is to be compared with nine from isoniazid, 11 from hydralazine and 18 from procainamide (17 within the second 5 yr). Patients with diphenylhydantoininduced SLE tended to be younger than those whose diseases were associated with other drugs, with a mean age of 33.4 yr (compared with 40.3 for isoniazid, 53.5 for hydralazine and 60.7 for procainamide). Fourteen of the 16 were female. Judging by the number of reported cases and estimates of the extent of drug use, the hydantoins, ethosuximide, and trimethadione represent the highest risk drugs, in the order given. Even though phenobarbital is probably the most widely used anticonvulsant, no case has been reported in which it was clearly implicated, and only one case’*’ implicated primidone, the other widely used barbiturate. Trimethadione has been involved in the causation of other quasi-immunologic syndromes-nephrotic syndrome’30.13’ and myasthenia gravis132-but no relationship has been demonstrated between these syndromes and drug-induced SLE. A series of 170 patients on anticonvulsant drugs but without SLE symptoms was tested for antibodies to various nuclear components.‘33 Patients were receiving hydantoins, primidone, carbamazepine, or succinimides, alone or in various combinations. Antinuclear antibodies, of one type or another, were found in varying frequency with all drugs. The antibody found in highest frequency was directed at soluble nucleoprotein, and it was found in from 50% to 78% of patients, depending upon the drug. Of 50 patients receiving only hydantoins, 58% had such antibodies, while 50% of ten patients receiving only primidone, 78% of nine receiving only carbamazepine, and the only patient receiving only a succinimide had antibodies to soluble nucleoprotein. Although the same authors demonstrated that in patients receiving isoniazid, antibodies appeared to react more strongly with isoniazid-denatured nucleoprotein,105 they found that antibodies of patients receiving anticonvulsant drugs did not react preferentially to isoniazid-treated nucleoprotein. ANTITHYROID

DRUGS

Following the introduction of thiourea and thiouracil for the treatment of hyperthyroidism in 1943,134a variety of thioamide drugs came into use.‘“” As in the case of the anticonvulsant drugs, most of the thioamides appear to be able to induce the appearance of symptoms of SLE in susceptible patients. At least three such patients have been reported following the administration of propylthiouraci1138-‘38 for periods of 6 wk or longer, in doses ranging from 150 to 600 mg per day. One of these13’ had tolerated 300 mg per day for 30 mo without untoward symptoms, but after the drug had been stopped for several months and then renewed, he developed fever, lymphadenopathy, arthralgia, proteinuria, and L.E. cells after only 3 mo, at only 100 mg per day. One patient was reported to have developed SLE-like symptoms after methylthiouracil administration,*“g and at least one after methimazole and propyl-

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thiouracil. I40This last patient may be still another example of an especially susceptible subject. She was one of three sisters, all of whom had thyrotoxicosis during early adolescence and all of whom had arthritic symptoms on thioamide drugs. She developed symptoms first while receiving methimazole, but they persisted and increased after propylthiouracil was substituted. Rash, fever, arthritis, and L.E. cells all subsided rapidly 8 mo later when she was treated with radioactive iodine and antithyroid drugs were stopped. One of her sisters went on, however, to develop chronic rheumatoid arthritis. All of the patients who have developed drug-induced SLE after antithyroid drugs have been adolescents. The only probable significance of this fact is that children and adolescents are the only patients with hyperthyroidism who are routinely managed over long periods of time with these drugs. No evidence has been developed concerning the frequency of this complication of the thioamide drugs, or concerning their ability to induce antinuclear antibodies. PSYCHOTROPIC

DRUGS

Chlorpromazine, introduced in the treatment of mental illness in 1952,141is probably one of the most widely used drugs in the world, having been administered to at least 50 million patients from 1955 to 1965.” A patient was reported in 1959’42 who might have developed SLE after receiving the drug, but evidence of the diagnosis or of a causal relationship in this patient was extremely weak. However, at least five additional patients have been reported,14*L43*144 of meet all the diagnostic criteria. In one of these casesI whom at least two’4~144*145 the drug had been administered continuously for 13 mo in a daily dose of 400 mg, while the other’44 received 1600 mg daily for 6 wk (but may very possibly have had previous contact with chlorpromazine). The frequency of occurrence of antinuclear antibodies in patients on long-term psychotropic drugs has been studied. 146Twenty-four per cent of patients who had been on chlorpromazine continuously were found to have antinuclear antibodies circulating, while such antibodies were demonstrated in only 5.4% of patients who had never taken chlorpromazine. Psychiatric diagnosis appeared to be irrelevant to the development of antinuclear antibodies. None of these patients had signs or symptoms referable to SLE. Other Psychotropic

Drugs

Chlorprothixene is closely related to chlorpromazine, the nitrogen in the central ring of chlorpromazine having been replaced by a carbon atom. Only three years after its introduction in 1961,‘47 a report of a case of drug-induced SLE appeared.‘4X Another case is mentioned in the course of a survey of SLE induced by psychotropic drugs, ‘43 but no details are given. In this same survey, three additional patients receiving phenothiazine derivatives, other than chlorpromazine, are reported to have developed the SLE syndrome, which remitted when the drugs were stopped. D-PENICILLAMINE

D-Penicillamine (@@dimethylcysteine) is an orally effective chelating agent for lead, mercury, and copper and has been used in the treatment of Wilson’s disease

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SLE

since 1964.L4gAt least four patients on long-term penicillamine therapy have been reported since 197 1 to have developed signs and symptoms of SLE’s~‘50-‘53which have subsided when the drug was stopped. These patients had received penicillamine for from 24 to 27 mo, in doses from 500 mg to 1600 mg per day, before symptoms appeared. Two of them’s,‘53 were able to resume the drug at lower doses (up to 500 mg per day) without prompt recurrence of symptoms, although the antinuclear antibody titer persisted. The gene for Wilson’s disease, an autosomal recessive characteristic, has been estimated to occur with a frequency of one in 500 individuals.‘“4 The disease itself is thus extremely rare. The frequency of penicillamine-induced SLE in patients with Wilson’s disease is not clear. In one series of over 200 patients treated with D-penicillamine for over 2 yr, only one case of penicillamine-induced SLE has arisen.153 On the other hand, a total of four patients with this complication of a rare disease have been reported over only a 3-yr period. Twenty-four consecutive patients with Wilson’s disease, on long-term D-penicillamine therapy, have been examined for antinuclear antibodies; none have been found.‘53 However, three patients with the Goodpasture syndrome have developed antinuclear antibodies (without SLE symptoms) after receiving D-penicillamine.153 Thus, no conclusion can yet be drawn concerning the ability of this drug to induce the formation of antinuclear antibodies. SULFONAMIDE

DRUGS

Recognition of the antibacterial usefulness of sulfanilamide in 1936 was followed rapidly by the introduction of many related compounds, synthesized and tested with the aim of increasing potency and decreasing toxicity. These drugs have been used extremely widely over the world. The first report of drug-induced systemic lupus erythematosus was that of Hoffman in 1945,l titled “Sensitivity to sulfadiazine resembling acute disseminated lupus erythematosus.” A second report,‘55 involving the same drug, appeared 11 yr later. Neither of these case reports meets the diagnostic criteria for drug-induced SLE. Long-acting sulfonamide derivatives were introduced to American medicine in 1957. Over the next 8 yr, 116 cases of the Stevens-Johnson syndrome (erythema multiforme exudativum), occurring in patients (largely children) receiving these drugs, were recorded. 156 One 5-yr-old girl treated for 9 mo with suffamethoxypyridazine developed arthritis, fever, chest pain, choreiform movements, and a positive L.E. cell test, all of which disappeared after the drug was withdrawn.15’ Sulfonamide drugs have been implicated in still another way-equally inconclusive but intriguing. The records of eight patients with chronic ulcerative colitis who had been found to have positive tests for L.E. cells were studied. All eight were found to have been receiving sulfonamide drugs (administered to reduce intraluminal flora with minimal systemic effect) for periods of time before the L.E. cell tests became positive. All had some clinical manifestations suggestive of SLE. The authors suggest that the poorly absorbed sulfonamides might have triggered the SLE syndrome in a peculiarly susceptible group of patients.lsx Finally, four patients with established SLE were observed to suffer relapses after administration of sulfonamides (acetazolemide in one case, sul’soxazole in

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LEE AND CHASE

the other three). The reporting authors suggest that since increased awareness of SLE coincides in time with the advent of the sulfonamide drugs, perhaps sulfonamides are the cause of all SLE.15g No evidence has been adduced concerning the propensity of sulfonamide drugs to induce antinuclear antibodies in patients receiving them over long periods of time. However, the sulfonamide-related diuretic chlorthalidone has been studied in this way. In a series of patients with hypetension of various etiologies, 20 of 56 receiving this drug for more than 3 mo had demonstrable antinuclear factors.160 The case for sulfonamide drugs as inducers of SLE must, on the basis of all this evidence, be summed up as not proven. ALLOPURINOL

Allopurinol, a xanthine oxidase inhibitor used in the control of hyperuricemia since 1963,161has not been reported in the literature as a cause of the SLE syndrome. However, Dr. Robert Levy has been following a patient with myeloproliferative disease who showed chemical and laboratory findings of SLE after beginning allopurinol. The patient, now 53 yr of age, was first noted to have anemia, splenomegaly, leukopenia, monocytosis, and myeloblast increase in the bone marrow in 1954. Her condition remained stable, however, with only very slow growth of the spleen and liver, until 1966. At that time her physicians became aware of hyperuricemia and started her on allopurinol in a dosage of 300 mg per day. About 1 yr later, she began to complain of increasingly severe arthritis and arthralgias involving the hands, wrists, ankles, and elbows. At the same time, her spleen became much larger and progressive thrombocytopenia and purpura appeared. She became febrile, with pleuritis and pneumonitis. Antibiotic therapy was unsuccessful, but all the new symptoms responded promptly to prednisone. The L.E. cell test was positive and antinuclear antibodies were present in high titer. Arthritis, pleuritis, and thrombocytopenia became increasingly difficult to control with prednisone over the next 4 yr. Anemia became, for the first time, severe enough to require blood transfusion. Bone marrow findings, repeated at intervals, were essentially unchanged over the entire observation period of more than 20 yr. With the thought that allopurinol-the only drug, other than prednisone, which she had been taking continuously prior to the SLE manifestations-might be responsible for those manifestations, the drug was stopped in August 1973. Her arthritis subsided very promptly and the thrombocytopenia improved. However, the blood uric acid level rose rapidly and she passed some gravel in her urine. Allopurinol was resumed and arthritis recurred within a week. Allopurinol was again stopped and again arthralgias and arthritis subsided. Six months later, she was off prednisone and free of arthritic and pleuritic manifestations. However, it now appears that her myeloproliferative disease has accelerated and her general condition is worsening. ORAL CONTRACEPTIVE

AGENTS

Estrogen-progestin combinations have been widely used for the prevention of conception since the early 1960s. Three groups of patients have been reported to have developed SLE-like symptoms after their administration. Bole et al.162*163

DRUG-INDUCED

95

SLE

followed eight women who developed “rheumatic complaints” from 4 to 84 mo after beginning oral contraceptives. All showed antinuclear antibodies; six of the eight had positive L.E. cell tests. Signs and symptoms disappeared after cessation of the drugs in all but one patient. Schleicher 164followed ten patients on oral contraceptives for from 6 to 36 mo, all of whom developed positive tests for L.E. cells as well as migraine, abdominal distress, arthralgias, and menorrhagia. L.E. cell tests became negative in all within 8 wk after stopping the drugs. Elias”j” had a patient who after 6 mo on a combination of ethynodiol diacetate and ethinyl estradiol, developed erythema nodosum and a positive test for L.E. cells. All of her symptoms disappeared within I mo after stopping this combination, but recurred in milder form when only the estrogen was changed-to mestranol. To balance these instances where antinuclear antibodies and (possibly) symptoms of SLE appear to have resulted from estrogen-progestin combinations are a series of prospective studies166-168which demonstrate no tendency of these agents to induce the formation of antinuclear antibodies, while still another report legindicates that arthralgias without evidence of SLE are not uncommon in women taking these hormones. Finally, at least three patients with established diagnoses of SLE have exacerbated while taking oral contraceptive agents. 170--172 The interim verdict on these agents must, then, be the same as for sulfonamidesPnot proven. OTHER AGENTS

Gold salts,‘73-175 penicillin,‘76-17g griseofulvin,‘80 streptomycin,‘81 methysergide, lR2tetracycline, I83and phenylbutazone 184,18d have been reported to have induced manifestations of SLE to appear in individual patients. None of those reports meets the criteria of this review. One recent reportls6 suggests that a “microepidemic” of SLE in a section of Nevada, contaminated by nuclear explosions, may have been due to exposure. to gamma radiation. A writer IR7has suggested that eosin, an essential ingredient of most lipsticks and a protein denaturant, might be a cause of SLE. Evidence for or against either of these hypotheses is absent. DISCUSSION

AND CONCLUSIONS

Agents Which Induce SLE

The foregoing review permits the listing of the following drugs as definite causes of the SLE syndrome: hydralazine, procainamide, practolol, D-penicillamine, isoniazid, diphenylhydantoin, ethosuximide, propylthiouracil, methylthiouracil, trimethadione, primidone, and chlorpromazine (and other phenothiazines). Of these, hydralazine and procainamide certainly, and probably also practolol and D-penicillamine should be considered drugs of high risk:- 1% or more of patients receiving them for more than 3 mo might be expected to develop some sort of the clinical syndrome. Isoniazid, diphenylhydantoin, ethosuximide, the thiouracils and trimethadione may be considered of moderate risk. The use of primidone and chlorpromazine probably leads to a much smaller risk. Doubt remains about reserpine, quinidine, and allopurinol. Information is suggestive that they may also be low-risk SLE-inducing drugs, but the data are in-

96

LEE AND CHASE

complete. Sulfonamides and oral contraceptives-both extremely widely used classes of agents which have been implicated in reports-are probably innocent. No convincing evidence is in hand which involves any other drug. Pathogenetic

Mechanisms

In any disease, pathogenesis is a resultant of host and environmental factors. For drug-induced SLE, differences in host susceptibilities and pharmacologic and immunogenic properties of the various drugs all play roles. Each drug appears to operate under a set of circumstances which is unique to it. For hydralazine and for isoniazid, genetically determined differences in rates of detoxification (acetylation) appear to influence the appearance of drug-induced disease;32 patients in whose circulations undetoxified drugs remain longer have a higher liability to disease. For hydralazine, antibodies to the drug may be a necessary prerequisite to the appearance of disease.36 On the other hand, for procainamide, pre-existing natural antibodies may protect against the disease (perhaps by leading to rapid clearance of the drug).78 For all drugs, however, certain host factors appear to predispose certain patients to disease: female sex33 and familial clustering of rheumatic manifestations35*75*112*140 seem to be important. Furthermore, with the major drugs, convincing instances have been reported in which patients have shown an innate predisposition to the lupus syndrome.30~35*62~76*gg~111*113~’27 hydralaAlarcon-Segovia 5,7 has suggested that some drugs-procainamide, zine, isoniazid, and the anticonvulsants-lead to the development of the lupus syndrome by some pharmacologic effect, while all others operate to produce an immune reaction which has some of the manifestations of SLE. The evidence cited here is not compatible with this view. Rather, it suggests that, for all drugs, the pathogenetic pathway leads through the production of antinuclear antibodies, that these are produced because the drugs in question are able to form complexes with deoxyrinobucleoprotein released through normal catabolic processes, that the drug-nucleoprotein complexes represent “denatured” nucleoproteinnucleoprotein which resists degradation by normal enzymatic function and hence incites the formation of antibodies. 52 Why some patients of those who form antinuclear antibodies by this sequence go on to develop symptoms of immunecomplex disease while others do not is still a mystery. Drug-InducedSLE-Related

or Not Related

toSLE?

Systemic lupus erythematosus is, by and large, a disease of young women, with a prolonged course characterized by remissions and exacerbations, with 60% of patients who show clinical evidence of renal involvement and with a very high proportion of patients who have antibodies to native DNA during periods of disease activity. Drug-induced systemic lupus erythematosus differs in all these particulars. The population affected depends on the epidemiology of the disease for which the drug is used-but within these limits, women still tend to be affected much more often than men.33 The course of drug-induced SLE depends almost entirely on how long the drug is administered after symptoms first appear. In general, symptoms increase in variety and severity with continuation of the inducing agent (but exceptions to

DRUG-INDUCED

97

SLE

In general, symptoms disappear when the drug is this rule have been noted). 1R*L53 withdrawn (exceptions which may occur cannot, by definition, be proved to be examples of drug-induced SLE). Renal lupus, with proteinuria, cylinduria, microscopic hematuria, and azotemia, is indeed rare in drug-induced SLE. However, instances which are conin_ vincingly related to drug administration and some of which 18,110,118,137,IR8,189 elude biopsy demonstration of immune complex nephritis, have been recorded with hydralazine,25~31~*g0 anticonvulsant drugs,110-“2*‘18propylthiouracil,‘37 peni18g,1g1 Thus, it appears likely that drugcillaminelR and even procainamide. I883 induced SLE can lead to renal lesions, indistinguishable from those of SLE, irrespective of the particular drug administered. Antibodies to native (double-stranded) DNA may have been demcnstrated in patients with hydralazine-induced SLE. 36,g3However, it is possible that such apparent demonstration has resulted from technical errors in the assay methods.“’ It appears more likely that antibodies to native DNA really are specific for SLE of nondrug origin, and that they may reflect a response of the immune system to the etiologic agent of that condition-possibly a DNA virus.*g2 In drug-induced SLE, evidence suggests that antinuclear antibodies arise in response to drugaltered DNA.5’*86.105 Thus, differences between manifestations of SLE and of drug-induced SLE appear to be differences in degree rather than in kind; the only exception is the specificities of the antinuclear antibodies. A working hypothesis might be that induction of antinuclear antibodies may, in certain persons susceptible by reason of sex and genetic makeup, lead (by steps yet unknown) to the formation of other autoantibodies and to antigen-antibody complex disease. In the terms of this hypothesis, the clinical and pathologic manifestations of SLE and of druginduced SLE represent a final common pathway. The elucidation of the mechanisms by which drug-induced antinuclear antibodies lead to disease may then be of great value in an understanding of the pathogenesis of SLE. ACKNOWLEDGMENT The authors

aregrateful

to Mrs. Annette

Finigan for her expert secretarial

assistance.

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in immu-

53. Sherman JD, Love DE, Harrington JF: Anemia, positive lupus and rheumatoid factors with methyldopa. A report of 3 cases. Arch Intern Med 120:321-326, 1967 54. Feltkamp TEW, Dorhout EJ, Nieuwehnuis MG: Autoantibodies related to treatment with chlorthalidone and Lu-methyldopa. Acta Med Stand 187:219-223, 1970 55. Berry K, Garlett EL, Bellet S, et al: Use of pronestyl in the treatment of ectopic rhythms; treatment of ninety-eight episodes in seventyeight patients. Circulation 4:13-22, 195 1 56. Geschwind N, Simpson JA: Procaine amide in the treatment of myotonia. Brain 78:81-91, 1955 57. Ladd AT: Procainamide-induced lupus erythematosus. N Engl J Med 267: 1357, 1962 58. Hahn AL: Systemic lupus erythematosus associated with procainamide therapy. Missouri Med61:19-23, 1964 et

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LEE AND CHASE

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to four

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101

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Arch

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Psychiatr

63:235-

248, 1950 109. Lindqvist T: Lupus erythematosus disseminatus after administration of mesantoin: Report of two cases. Acta Med Stand 158:131138, 1957 110. Rallison MJ, Carlisle JW, Lee RE Jr, et al: Lupus erythematosus and the StevensJohnson syndrome. Am J DisChild 101:7255738, 1961 I1 I. Benton JW, Tynes B, Register HB Jr, et al: Systemic lupus erythematosus occurring during anticonvulsive drug therapy. JAMA 180:115- 118, 1962 112. Jacobs JC: Systemic lupus erythematosus in childhood. Pediatrics 32:257-264, 1963 113. Holley HL: Evidence for a predisposition to rheumatic disease in families of patients developing drug-induced SLE. Arthritis Rheum 7:684-686, 1964 114. Vossen R: Neheuwirkungen der medikamentosen epilepsiebehandlung. Ther Umsch 24~527-529, 1967

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119. Lennox Their treatment 1073,1945

WG: The petit mal epilepsies: with tridione. JAMA 129:1069-

120. Beernink DH, Miller JJ III: Anticonvulsant-induced antinuclear antibodies and lupus-like disease in children. J Pediatr 82: I1 3~117, 1973 121. Handley R, Stewart new drug in the treatment 11742-744, 1952

ASR: Mysoline: A of epilepsy. Lancet

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phenylacetylureas.

J

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