Acta Med Scand 200: 367-371, 1976
Acetylator Phenotype in Patients with Hydralazine-induced Lupoid Syndrome Inger Strandberg, Gunnar Boman, Leo Hassler and Folke Sjoqvist From the Swedish Adverse Drug Reaction Committee, the Departments of Thoracic Medicine (at Karolinska Hospitai) and Clinical Pharmacology (at Huddinge Hospital), Karolinska Institutet, Stockholm, and the Department of Chronic Diseases, Luled Hospital, Luled, Sweden
ABSTRACT. The acetylator phenotype has been determined (isoniazid half-life) in 31 patients, 25 of them women, who had exhibited a lupus erythematosus-like syndrome during treatment with hydralmine. Twenty-nine patients were slow acetylators, one was rapid (probably spontaneous SLE) and one uncertain. Only two patients had been given more than 200 mg of hydralazine daily. The mean duration of therapy was 32 months at the onset of symptoms. These were not serious but rather long-standing. Our study confirms that patients who risk developing hydralazine lupus are slow acetylators, especially females, treated with more than 100 mg daily. Rapid acetylators seem to develop this side-effect rarely, if at all.
Hydralazine (Apresolin@) was the first drug reported to induce a syndrome similar to systemic lupus erythematosus (SLE) (20). An important pathway for the metabolism of hydralazine is acetylation, which is under polymorphic genetic control (12, 26). The enzyme involved also acetylates other drugs, such as isoniazid (INH) ( I I ) , certain sulfonamides (12, 29) and procaine amide (13, 19, 27). Slow acetylators are more prone to develop side-effects on conventional doses of INH (7), phenelzine (lo), sulphapyridine ( 5 , 29) and dapsone (8). Perry (25) found that nearly all patients who developed a lupoid syndrome during treatment with hydralazine were slow acetylators and that positive antinuclear factor (ANF) preceded the clinical symptoms. By contrast, Alarc6nReprint requests to: Dr G . Boman, Thoraxmedicinska kliniken, Karolinska sjukhuset, S-104 01 Stockholm,
Sweden.
Segovia et al. (2) and Evans et al. (9) did not find a significant difference between slow and rapid acetylators in the incidence of positive ANF during long-term treatment with INH. Recent studies suggest that procaine amide may induce a lupoid syndrome not only in slow (20) but also in rapid acetylators (6, 17). In the light of these somewhat conflicting reports we have phenotyped patients in whom a lupus-like syndrome had occurred during treatment with hydralazine. A local compilation of hydralazine-induced lupus (16) initiated our study, which was enlarged to a whole-country survey, aided by the Swedish Adverse Drug Reaction Committee.
PAT1ENTS The reports to the Swedish Adverse Drug Reaction Committee on hydralazine-induced lupoid syndromes during 1%8-74 were analyzed. The reporting physicians were then contacted to obtain the clinical records. It was possible to arrange for acetylator phenotyping in 31 patients through cooperation with 17 of the reporting colleagues. Age and sex distribution, hydralazine dosage and duration of treatment The patient material consisted of 6 men and 25 women with a mean age of 58 years. All the men were under
the age of 60, while the majority of the women were older than that (Table I) when symptoms of the lupoid syndrome first appeared. The dosage of hydralazine and the duration of therapy before the onset of sjmptorns are shown in Table 11. Only two patients were given more than 200 mg of hydralazine daily and only during part of the treatment period. The mean duration of therapy at onset of sympAcra Med Scand 200
368
I . Strandberg et al.
Table I. Age and sex distribution of 31 patients with SLE during hydralazine treatment Age at onset of symptoms (y.)
Men
Women
40-49 50-59 6(M9 70-79 Total
3 3 0 0 6
5 6 10
Table 11. Dosage and duration of hydralazine therapy Duration of therapy
4 25
Hydralazine dose (mg/d.)
< 100 100-200 >200 Total
Acetylator Phenotype in Patients with Hydralazine-induced Lupoid Syndrome Inger Strandberg, Gunnar Boman, Leo Hassler and Folke Sjoqvist From the Swedish Adverse Drug Reaction Committee, the Departments of Thoracic Medicine (at Karolinska Hospitai) and Clinical Pharmacology (at Huddinge Hospital), Karolinska Institutet, Stockholm, and the Department of Chronic Diseases, Luled Hospital, Luled, Sweden
ABSTRACT. The acetylator phenotype has been determined (isoniazid half-life) in 31 patients, 25 of them women, who had exhibited a lupus erythematosus-like syndrome during treatment with hydralmine. Twenty-nine patients were slow acetylators, one was rapid (probably spontaneous SLE) and one uncertain. Only two patients had been given more than 200 mg of hydralazine daily. The mean duration of therapy was 32 months at the onset of symptoms. These were not serious but rather long-standing. Our study confirms that patients who risk developing hydralazine lupus are slow acetylators, especially females, treated with more than 100 mg daily. Rapid acetylators seem to develop this side-effect rarely, if at all.
Hydralazine (Apresolin@) was the first drug reported to induce a syndrome similar to systemic lupus erythematosus (SLE) (20). An important pathway for the metabolism of hydralazine is acetylation, which is under polymorphic genetic control (12, 26). The enzyme involved also acetylates other drugs, such as isoniazid (INH) ( I I ) , certain sulfonamides (12, 29) and procaine amide (13, 19, 27). Slow acetylators are more prone to develop side-effects on conventional doses of INH (7), phenelzine (lo), sulphapyridine ( 5 , 29) and dapsone (8). Perry (25) found that nearly all patients who developed a lupoid syndrome during treatment with hydralazine were slow acetylators and that positive antinuclear factor (ANF) preceded the clinical symptoms. By contrast, Alarc6nReprint requests to: Dr G . Boman, Thoraxmedicinska kliniken, Karolinska sjukhuset, S-104 01 Stockholm,
Sweden.
Segovia et al. (2) and Evans et al. (9) did not find a significant difference between slow and rapid acetylators in the incidence of positive ANF during long-term treatment with INH. Recent studies suggest that procaine amide may induce a lupoid syndrome not only in slow (20) but also in rapid acetylators (6, 17). In the light of these somewhat conflicting reports we have phenotyped patients in whom a lupus-like syndrome had occurred during treatment with hydralazine. A local compilation of hydralazine-induced lupus (16) initiated our study, which was enlarged to a whole-country survey, aided by the Swedish Adverse Drug Reaction Committee.
PAT1ENTS The reports to the Swedish Adverse Drug Reaction Committee on hydralazine-induced lupoid syndromes during 1%8-74 were analyzed. The reporting physicians were then contacted to obtain the clinical records. It was possible to arrange for acetylator phenotyping in 31 patients through cooperation with 17 of the reporting colleagues. Age and sex distribution, hydralazine dosage and duration of treatment The patient material consisted of 6 men and 25 women with a mean age of 58 years. All the men were under
the age of 60, while the majority of the women were older than that (Table I) when symptoms of the lupoid syndrome first appeared. The dosage of hydralazine and the duration of therapy before the onset of sjmptorns are shown in Table 11. Only two patients were given more than 200 mg of hydralazine daily and only during part of the treatment period. The mean duration of therapy at onset of sympAcra Med Scand 200
368
I . Strandberg et al.
Table I. Age and sex distribution of 31 patients with SLE during hydralazine treatment Age at onset of symptoms (y.)
Men
Women
40-49 50-59 6(M9 70-79 Total
3 3 0 0 6
5 6 10
Table 11. Dosage and duration of hydralazine therapy Duration of therapy
4 25
Hydralazine dose (mg/d.)
< 100 100-200 >200 Total
