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Systemic Lupus-Like Syndrome Induced by Methyldopa Therapy
Systemic Lupus-Like Syndrome Induced by Methyldopa Therapy· Thomas M. Harrington, M.D.;t and Duane E. Davis, M.D.t
Pleural pericarditis, fever, and a positive reaction for antinuclear antibody developed in a 50-year-old white woman whUe she was receiving methyldopa (500 mg daDy). After withdrawal of the drug, there was complete resolution of the clinical signs and symptoms, as weD as normalization of the patient's antinuclear antibody titer. To our knowledge, this is the first reported case of a cUnical lupus-Uke syndrome induced by therapy with methyldopa. drugs, most commonly hydralazine, procainM anyamide, practolol, and penicillamine, have been 1
implicated in the development of a drug-induced lupuslike syndrome. Acute pericarditis is often a major component of this syndrome, occurring in 13 to 57 percent of the patients with systemic lupus erythematosus-like syndrome secondary to administration of procainamide. 2 t 3 Pericardial effusions and cardiac tamponade are uncommon manifestations in this syndrome.t as is constrictive pericarditis." Methyldopa, although known to induce positive reactions for antinuclear antibodies, has never been described to induce a lupus-like syndrome. We report a case of lupus-like syndrome secondary to therapy with methyldopa and presenting as pleural pericarditis and fever. CASE REPORT
A 50-year-old white woman came to the Geisinger Medical Center Rheumatology Clinic, with a three-week history of fever, chills, and malaise. The patient also noted an aching sensation in her chest, which was worsened by inspiration, coughing, or lying supine. The pain was lessened when she leaned forward. The patient had taken six tablets of acetylsalicylic acid daily for the past two weeks, with minimal relief of the pain in her chest. She denied shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, or peripheral edema. There was no history of Baynaud's phenomenon, arthralgias, photosensitivity, cutaneous rash, ulcers of the mouth, alopecia, dysphagia, muscular weakness, dry eyes, or dry mouth. She had no previous history of exposure to tuberculosis. The patient's medical history included essential hypertension and hypothyroidism secondary to surgical removal of a goiter. Her medications were methyldopa (250 mg twice daily) taken for one year prior to admission and thyroid extract (Armour); 4 grains daily. Physical examination revealed the follOwing vital signs: -From the Department of Rheumatology, Geisinger Medical Center, Danville, Pa. tFellow Deparbnent of Rheumatology. :Associate, Department of Rheumatology.
686 HARRINGTON, DAVIS
blood pressure, 130/80 mm Hg, with 14 mm Hg pulsus paradoxus; pulse rate, 120 beats per minute and regular; respiration rate, 30/min; and temperature, 38.5°C (101.3°F). No venous distention was present in the neck. Decreased breath sounds were noted at the left base. Cardiovascular examination revealed a resting tachycardia with a three-component friction rub. Findings from the remainder of the physical examination were unremarkable. A chest x-ray film showed an increased cardiac silhouette and a left-sided pleural effusion. An electrocardiogram showed sinus tachycardia and nonspecific myocardial changes. An echocardiogram revealed a moderate pericardia! effusion. The level of hemoglobin was 11.1 gm/l00 ml. The hematocrit reading was 32.5 percent, with normal indices. The serum iron level and total iron-binding capacity were both decreased. Serum levels of complement components C3 and C4 were normal at 230 mg/l00 ml and 37 mg/l00 m1, respectively. The white blood cell count was 20400/cu mm with 92 percent segmented cells, 1 percent band cells, percent lymphocytes, and 2 percent monocytes. Direct and indirect Coombs' tests were negative. Results of studies of hepatic function were normal. Westergren sedimentation rate was 121 mm/hr, The antinuclear antibody titer was I: 1,280 with a homogeneous pattern. The titer of acidtreated antinuclear antibody was less than 1:20. The titer of anti-DNA by the Crithidia luciliae method was less than 1: 10. The test for extractable nuclear antigen was negative. Reactions for cryoglobulins were also negative. The patient's temperature rose nightly to 38.5°C. Multiple cultures of blood were negative. The patient was monitored closely for further signs of tamponade; however, her hemodynamic status remained stable. On the second day of hospitalization, thoracocentesis was done, and 75 ml of serosanguineous fluid was obtained, The protein level was 4.7 gm/l00 ml, The glucose level of the pleural fluid was 90 mg/IOO ml, and the level of lactic dehydrogenase was 200 milliunits/ml, with a simultaneous serum glucose level of 130 mg/IOO ml and a serum level of lactic "dehydrogenase of 161 milliunits/ml. Levels of C3 and C4 in the pleural fluid were depressed at 84 mg/IOO ml and II mg/IOO ml, respectively. The white blood cell count was 6,800/cu mm, with 83 percent neutrophils, 11 percent monocytes, and 6 percent lymphocytes. Findings from cytologic studies were normal. Pleural biopsy revealed a nonspecific reactive pleuritis. A test with intermediate-strength purified protein derivative of tuberculin was negative. The patient was not anergic. Because of the positive reaction for antinuclear antibody, a drug-induced lupus-like syndrome was considered, and therapy with methyldopa was discontinued. Twenty-four hours later, the patient became afebrile and remained so throughout the remainder of her hospitalization. Therapy with acetylsalicylic acid (12 tablets daily) was begun for the pain in her chest, and she was discharged to be followed in the outpatient department. Follow-up examination two weeks after discharge revealed that the patient remained afebrile. Physical examination did not disclose any cardiopulmonary abnormality. A repeat chest x-ray film showed a normal cardiac silhouette and no pleural effusion. Eight months following her initial hospitalization, the patient continues to remain free of symptoms. Her antinuclear antibody reaction is now negative.
5
DISCUSSION
Methyldopa has been used for the treatment of hyper-
CHEST, 79: 6, JUNE, 1981
tension in the United States for the past 17 years. Over the same period, multiple adverse reactions secondary to therapy with the drug have been reported. Three of the most common reactions include fever, hemolysis, and hepatitis." Methyldopa has been shown to induce the formation of antinuclear antibodies in as many as 15 percent of the patients taking the drug. 7 Case reports have documented myocarditis due to methyldopa," however, determinations of antinuclear antibody were not recorded in these cases. In fact, no clinical, symptomatic, drug-induced systemic lupus-like syndrome has been reported with therapy with methyldopa. Furthermore, no cases of pleural pericarditis, with or without positive reactions for antinuclear antibodies, have been documented. The patient developed pleural pericarditis with fever and high titers of antinuclear antibody while receiving methyldopa. Upon treatment with 0.1 N hydrochloric acid, the patient's antinuclear antibody showed a loss of nuclear staining, indicating that the antinuclear antibodies consisted of antibodies to histones. Antibodies to histones occur in 96 percent of the patients with druginduced lupus, while the frequency of antihistone antibodies in idiopathic systemic lupus erythematosus is only 35 percent." In our patient, the titer of antibody to double-stranded native DNA by the immunofluorescent method using Crithidia luciliae as a substrate was less than 1:10, providing further evidence that the patient's disease was drug-induced. Double-stranded DNA antibodies by the Crithidia method have been reported in 57 percent of the patients with idiopathic systemic lupus erythematosus but have not been reported in drug-induced lupus. to In addition, the test for extractable nuclear antigen, which includes Sm, highly specific for idiopathic systemic lupus erythematosus, and ribonucleoprotein, was negative. Following the cessation of the therapy with methyldopa, the patient's level of antinuclear antibody returned to normal, and the clinical features of fever, pleural effusion, and pericarditis resolved and have not returned over an eight-month follow-up period. Serum complement levels were determined in our patient and were normal, while levels of complement in the pleural fluid were depressed. The serum complement level is often depressed in idiopathic systemic lupus erythematosus.P In early reports of drug-induced systemic lupus erythematosus, serum complement levels were normal and were said to provide a differential diagnostic tool; however, recent reports have documented serum hypocomplementemia in drug-induced systemic lupus erythematosus.P Complement levels in the pleural fluid have been studied in idiopathic systemic lupus erythematosus and are often depressed. IS Hypocomplementemic pleural effusions have also been found in rheumatoid arthritis and in certain malignant neoplasms.P We have been unable to find reports of complement levels in the pleural fluid in drug-induced
CHEST, 79: 6, JUNE, 1981
systemic lupus erythematosus in the literature. This is the first case where complement has been measured in a drug-induced pleural. effusion, and the levels were found to be depressed. Complement levels in the pleural fluid may be normal. or depressed in idiopathic systemic lupus erythematosus and in other diseases, including drug-induced erythematosus, thus making these levels less valuable than antibody testing as a differential diagnostic tool. Some patients receiving methyldopa for hypertension may have underlying cardiac disease, with pleural pericarditis assumed to be secondary to the cardiac disease. In this group of patients, a drug-induced pleural pericarditis should also be considered because cessation of therapy with the drug may lead to resolution of the patient's symptoms. Heretofore, methyldopa has been associated with a positive reaction for antinuclear antibody but not with clinical evidence of a lupus-like syndrome. We describe a patient who developed a druginduced lupus-like syndrome secondary to therapy with methyldopa, with resolution of her symptoms and serologic abnormalities following withdrawal of this drug. REFERENCES
1 Lee L, Chase PH. Drug induced systemic lupus erythematosus: a critical review. Semin Arthritis Rheum 1975; 5:83-103. 2 Blomgren E, Condemi JJ~ Vaughn JH. Procainamideinduced lupus erythematosus. Am J Med 1972; 52:338-48. 3 Swarbrick ET, Gray IR. Systemic lupus erythematosus during treatment with procainamide. Br Heart J 1972; 34:284-88. 4 Donlan J Jr, Forker AD. Cardiac tamponade in procainamide-induced erythematosus. Chest 1972; 52:685-86. 5 Sunder SK, Shah A. Constrictive pericarditis in procainamide-induced lupus erythematosus syndrome. Am J Cardioll975; 26:960-62. 6 Furhoff AK. Adverse reaction with methyldopa: a decade's report. Acta Med Scand 1978; 203:425-28. 7 Breckenridge A, Dollery CT, Worlledge SM, Holborow EJ, Johnson JD. Positive direct Coombs' test and antinuclear factor in patients treated with methyldopa. Lancet 1967; 2:1265-67. 8 Mullick FG, McAllister HA. Myocarditis associated with methyldopa therapy. JAMA 1977; 277: 1699-1701. 9 Fritzler MJ, Tan EM. Antibodies to histones in drug-induced and idiopathic lupus erythematosus. J Coo Invest 1978; 62:560-67. 10 Chubick A, Sontheimer RD, Gilliam IN, Ziff M. An appraisal of tests for native DNA antibodies in connective tissue diseases. Ann Intern Med 1978; 89:186-92. 11 Weinstein A, Bordwell B, Rothfield NF. Anti-native DNA antibodies and serum C-3 levels. Arthritis Rheum 1978; 21:602. 12 Utsinger PD, Zvaifler NJ, Bluestein HG. Hypocomplementemia in procainamide associated systemic lupus erythematosus. Ann Intern Med 1976; 84:293. 13 Hunder GG, McDuffie FC, Hepper NG. Pleural fluid complement in systemic lupus erythematosus and rheumatoid arthritis. Ann Intern Med 1972; 76:357-63.
SYSTEMIC LUPUs-LIKE SYNDROME 897
Pleural pericarditis, fever, and a positive reaction for antinuclear antibody developed in a 50-year-old white woman whUe she was receiving methyldopa (500 mg daDy). After withdrawal of the drug, there was complete resolution of the clinical signs and symptoms, as weD as normalization of the patient's antinuclear antibody titer. To our knowledge, this is the first reported case of a cUnical lupus-Uke syndrome induced by therapy with methyldopa. drugs, most commonly hydralazine, procainM anyamide, practolol, and penicillamine, have been 1
implicated in the development of a drug-induced lupuslike syndrome. Acute pericarditis is often a major component of this syndrome, occurring in 13 to 57 percent of the patients with systemic lupus erythematosus-like syndrome secondary to administration of procainamide. 2 t 3 Pericardial effusions and cardiac tamponade are uncommon manifestations in this syndrome.t as is constrictive pericarditis." Methyldopa, although known to induce positive reactions for antinuclear antibodies, has never been described to induce a lupus-like syndrome. We report a case of lupus-like syndrome secondary to therapy with methyldopa and presenting as pleural pericarditis and fever. CASE REPORT
A 50-year-old white woman came to the Geisinger Medical Center Rheumatology Clinic, with a three-week history of fever, chills, and malaise. The patient also noted an aching sensation in her chest, which was worsened by inspiration, coughing, or lying supine. The pain was lessened when she leaned forward. The patient had taken six tablets of acetylsalicylic acid daily for the past two weeks, with minimal relief of the pain in her chest. She denied shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, or peripheral edema. There was no history of Baynaud's phenomenon, arthralgias, photosensitivity, cutaneous rash, ulcers of the mouth, alopecia, dysphagia, muscular weakness, dry eyes, or dry mouth. She had no previous history of exposure to tuberculosis. The patient's medical history included essential hypertension and hypothyroidism secondary to surgical removal of a goiter. Her medications were methyldopa (250 mg twice daily) taken for one year prior to admission and thyroid extract (Armour); 4 grains daily. Physical examination revealed the follOwing vital signs: -From the Department of Rheumatology, Geisinger Medical Center, Danville, Pa. tFellow Deparbnent of Rheumatology. :Associate, Department of Rheumatology.
686 HARRINGTON, DAVIS
blood pressure, 130/80 mm Hg, with 14 mm Hg pulsus paradoxus; pulse rate, 120 beats per minute and regular; respiration rate, 30/min; and temperature, 38.5°C (101.3°F). No venous distention was present in the neck. Decreased breath sounds were noted at the left base. Cardiovascular examination revealed a resting tachycardia with a three-component friction rub. Findings from the remainder of the physical examination were unremarkable. A chest x-ray film showed an increased cardiac silhouette and a left-sided pleural effusion. An electrocardiogram showed sinus tachycardia and nonspecific myocardial changes. An echocardiogram revealed a moderate pericardia! effusion. The level of hemoglobin was 11.1 gm/l00 ml. The hematocrit reading was 32.5 percent, with normal indices. The serum iron level and total iron-binding capacity were both decreased. Serum levels of complement components C3 and C4 were normal at 230 mg/l00 ml and 37 mg/l00 m1, respectively. The white blood cell count was 20400/cu mm with 92 percent segmented cells, 1 percent band cells, percent lymphocytes, and 2 percent monocytes. Direct and indirect Coombs' tests were negative. Results of studies of hepatic function were normal. Westergren sedimentation rate was 121 mm/hr, The antinuclear antibody titer was I: 1,280 with a homogeneous pattern. The titer of acidtreated antinuclear antibody was less than 1:20. The titer of anti-DNA by the Crithidia luciliae method was less than 1: 10. The test for extractable nuclear antigen was negative. Reactions for cryoglobulins were also negative. The patient's temperature rose nightly to 38.5°C. Multiple cultures of blood were negative. The patient was monitored closely for further signs of tamponade; however, her hemodynamic status remained stable. On the second day of hospitalization, thoracocentesis was done, and 75 ml of serosanguineous fluid was obtained, The protein level was 4.7 gm/l00 ml, The glucose level of the pleural fluid was 90 mg/IOO ml, and the level of lactic dehydrogenase was 200 milliunits/ml, with a simultaneous serum glucose level of 130 mg/IOO ml and a serum level of lactic "dehydrogenase of 161 milliunits/ml. Levels of C3 and C4 in the pleural fluid were depressed at 84 mg/IOO ml and II mg/IOO ml, respectively. The white blood cell count was 6,800/cu mm, with 83 percent neutrophils, 11 percent monocytes, and 6 percent lymphocytes. Findings from cytologic studies were normal. Pleural biopsy revealed a nonspecific reactive pleuritis. A test with intermediate-strength purified protein derivative of tuberculin was negative. The patient was not anergic. Because of the positive reaction for antinuclear antibody, a drug-induced lupus-like syndrome was considered, and therapy with methyldopa was discontinued. Twenty-four hours later, the patient became afebrile and remained so throughout the remainder of her hospitalization. Therapy with acetylsalicylic acid (12 tablets daily) was begun for the pain in her chest, and she was discharged to be followed in the outpatient department. Follow-up examination two weeks after discharge revealed that the patient remained afebrile. Physical examination did not disclose any cardiopulmonary abnormality. A repeat chest x-ray film showed a normal cardiac silhouette and no pleural effusion. Eight months following her initial hospitalization, the patient continues to remain free of symptoms. Her antinuclear antibody reaction is now negative.
5
DISCUSSION
Methyldopa has been used for the treatment of hyper-
CHEST, 79: 6, JUNE, 1981
tension in the United States for the past 17 years. Over the same period, multiple adverse reactions secondary to therapy with the drug have been reported. Three of the most common reactions include fever, hemolysis, and hepatitis." Methyldopa has been shown to induce the formation of antinuclear antibodies in as many as 15 percent of the patients taking the drug. 7 Case reports have documented myocarditis due to methyldopa," however, determinations of antinuclear antibody were not recorded in these cases. In fact, no clinical, symptomatic, drug-induced systemic lupus-like syndrome has been reported with therapy with methyldopa. Furthermore, no cases of pleural pericarditis, with or without positive reactions for antinuclear antibodies, have been documented. The patient developed pleural pericarditis with fever and high titers of antinuclear antibody while receiving methyldopa. Upon treatment with 0.1 N hydrochloric acid, the patient's antinuclear antibody showed a loss of nuclear staining, indicating that the antinuclear antibodies consisted of antibodies to histones. Antibodies to histones occur in 96 percent of the patients with druginduced lupus, while the frequency of antihistone antibodies in idiopathic systemic lupus erythematosus is only 35 percent." In our patient, the titer of antibody to double-stranded native DNA by the immunofluorescent method using Crithidia luciliae as a substrate was less than 1:10, providing further evidence that the patient's disease was drug-induced. Double-stranded DNA antibodies by the Crithidia method have been reported in 57 percent of the patients with idiopathic systemic lupus erythematosus but have not been reported in drug-induced lupus. to In addition, the test for extractable nuclear antigen, which includes Sm, highly specific for idiopathic systemic lupus erythematosus, and ribonucleoprotein, was negative. Following the cessation of the therapy with methyldopa, the patient's level of antinuclear antibody returned to normal, and the clinical features of fever, pleural effusion, and pericarditis resolved and have not returned over an eight-month follow-up period. Serum complement levels were determined in our patient and were normal, while levels of complement in the pleural fluid were depressed. The serum complement level is often depressed in idiopathic systemic lupus erythematosus.P In early reports of drug-induced systemic lupus erythematosus, serum complement levels were normal and were said to provide a differential diagnostic tool; however, recent reports have documented serum hypocomplementemia in drug-induced systemic lupus erythematosus.P Complement levels in the pleural fluid have been studied in idiopathic systemic lupus erythematosus and are often depressed. IS Hypocomplementemic pleural effusions have also been found in rheumatoid arthritis and in certain malignant neoplasms.P We have been unable to find reports of complement levels in the pleural fluid in drug-induced
CHEST, 79: 6, JUNE, 1981
systemic lupus erythematosus in the literature. This is the first case where complement has been measured in a drug-induced pleural. effusion, and the levels were found to be depressed. Complement levels in the pleural fluid may be normal. or depressed in idiopathic systemic lupus erythematosus and in other diseases, including drug-induced erythematosus, thus making these levels less valuable than antibody testing as a differential diagnostic tool. Some patients receiving methyldopa for hypertension may have underlying cardiac disease, with pleural pericarditis assumed to be secondary to the cardiac disease. In this group of patients, a drug-induced pleural pericarditis should also be considered because cessation of therapy with the drug may lead to resolution of the patient's symptoms. Heretofore, methyldopa has been associated with a positive reaction for antinuclear antibody but not with clinical evidence of a lupus-like syndrome. We describe a patient who developed a druginduced lupus-like syndrome secondary to therapy with methyldopa, with resolution of her symptoms and serologic abnormalities following withdrawal of this drug. REFERENCES
1 Lee L, Chase PH. Drug induced systemic lupus erythematosus: a critical review. Semin Arthritis Rheum 1975; 5:83-103. 2 Blomgren E, Condemi JJ~ Vaughn JH. Procainamideinduced lupus erythematosus. Am J Med 1972; 52:338-48. 3 Swarbrick ET, Gray IR. Systemic lupus erythematosus during treatment with procainamide. Br Heart J 1972; 34:284-88. 4 Donlan J Jr, Forker AD. Cardiac tamponade in procainamide-induced erythematosus. Chest 1972; 52:685-86. 5 Sunder SK, Shah A. Constrictive pericarditis in procainamide-induced lupus erythematosus syndrome. Am J Cardioll975; 26:960-62. 6 Furhoff AK. Adverse reaction with methyldopa: a decade's report. Acta Med Scand 1978; 203:425-28. 7 Breckenridge A, Dollery CT, Worlledge SM, Holborow EJ, Johnson JD. Positive direct Coombs' test and antinuclear factor in patients treated with methyldopa. Lancet 1967; 2:1265-67. 8 Mullick FG, McAllister HA. Myocarditis associated with methyldopa therapy. JAMA 1977; 277: 1699-1701. 9 Fritzler MJ, Tan EM. Antibodies to histones in drug-induced and idiopathic lupus erythematosus. J Coo Invest 1978; 62:560-67. 10 Chubick A, Sontheimer RD, Gilliam IN, Ziff M. An appraisal of tests for native DNA antibodies in connective tissue diseases. Ann Intern Med 1978; 89:186-92. 11 Weinstein A, Bordwell B, Rothfield NF. Anti-native DNA antibodies and serum C-3 levels. Arthritis Rheum 1978; 21:602. 12 Utsinger PD, Zvaifler NJ, Bluestein HG. Hypocomplementemia in procainamide associated systemic lupus erythematosus. Ann Intern Med 1976; 84:293. 13 Hunder GG, McDuffie FC, Hepper NG. Pleural fluid complement in systemic lupus erythematosus and rheumatoid arthritis. Ann Intern Med 1972; 76:357-63.
SYSTEMIC LUPUs-LIKE SYNDROME 897