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Hydralazine-Induced Lupus: Are We Vigilant?

Timothy H. Self, PharmD, and Ryan E. Owens, PharmD, BCPS

Volume 55 - Issue 12 - December 2015

Hydralazine was one of the first drugs reported to induce SLE and has since been frequently cited in literature.2-15 Hydralazine-induced SLE continues to be an important topic due to its use in heart failure16-19 and hypertension. Soon after a landmark trial16 demonstrating the value of hydralazine combined with nitrates in African Americans with heart failure, Finks et al20 reviewed the literature regarding hydralazine-induced lupus. The purpose of this summary is to help raise awareness of the need to maintain vigilance for this drug-induced disease whether using hydralazine alone or its combination product, hydralazine/isosorbide dinitrate. Table 1 includes key points regarding hydralazine-induced SLE.

Clinical Presentation 

Hydralazine-induced lupus is characterized by onset of any or all of the following symptoms: arthralgia, fever, chest pain, anorexia, fatigue, petechiae, rash, joint pain and swelling, anemia, abnormal complete blood count, leukopenia, thrombocytopenia, positive antinuclear antibodies (ANAs), and lupus erythematosus tests. In severe cases, the syndrome may include pulmonary edema or pneumonia, pericardial tamponade, and renal failure.1-4,9,13,14 Musculoskeletal symptoms (especially arthritis in the hands and wrists) are the most common clinical manifestation.9 

Laboratory results, including positive ANA test results, lead to the diagnosis of drug-induced SLE in up to 90% of cases. While a positive ANA titer is used in conjunction with other laboratory tests and clinical findings to confirm the diagnosis of SLE, a positive ANA titer alone does not warrant a change in drug therapy as some patients on hydralazine with positive ANA will not develop the syndrome.18 Additional typical lab findings include the presence of lupus erythematosus cells in 47% to 80% and rheumatoid factor in 29% to 50% of patients.4 Importantly, antihistone antibodies may be present in up to 95% of patients. In drug-induced lupus, there is usually a higher frequency of anti-single stranded DNA antibodies, while anti-double stranded DNA antibodies are rare. Complement levels are generally low in drug-induced disease.21 

While most reviews deem the syndrome from drug-induced lupus as a milder disease than idiopathic SLE, a small number of case reports have described fatal events with hydralazine-induced SLE, thus underscoring the potential hazards of this agent.10 Fatal cases that have been reported involved doses as low as 100 mg per day and disease manifestations have included glomerulonephritis, which historically was thought not to be a consequence with the drug-induced disease.10 In addition, a study5 found that 6 of the 14 patients who developed SLE on hydralazine therapy had evidence of kidney impairment. 

Soon after hydralazine was available, 9 cases of symptoms resembling SLE were reported2 andmore than 150 cases of hydralazine-induced SLE quickly followed.3 In the early years of experience, it was described that prolonged administration (3 months to 5 years) of hydralazine was associated with the development of SLE, with an incidence of 8% to 13%.1,3 Twenty years after its initial use, hydralazine-induced SLE was estimated to occur in 10% to 20% of patients treated with doses of 400 mg or more daily.18 Subsequent case reports revealed that the syndrome has occurred in patients receiving as little as 50 mg daily.6-11 

In one study5 of 281 patients receiving hydralazine therapy, 6.7% had documented cases of hydralazine-induced SLE. Hydralazine was started for treatment of hypertension (146 male and 135 female) at 25 mg twice a day and was titrated upward as necessary to 100 mg twice daily. The maximum daily dose was 50 mg in 29%, of patients 100 mg in 26% of patients, and 200 mg in 45% of patients. Among patients diagnosed with SLE, symptoms of arthritis, fever, weight loss, and pleurisy were described. In addition, pericarditis and splenomegaly were observed, but skin rash was relatively rare. Most patients who reported these symptoms were ill enough to require hospitalization. Mean time to diagnosis of SLE was found to be 24 months after initiation of therapy (first case was after 9 months and last was after 40 months). Larger dosages were associated with an increased incidence of SLE (10.4%).5 Resolution of all manifestations was observed after hydralazine was discontinued. 

Risk Factors

Risk factors that have been linked to hydralazine-induced SLE are high daily doses, slow acetylator and HLA-DRw4 phenotypes, therapy longer than 3 months, female gender, and a family history of autoimmune disease.4,9 Although doses of 200 mg daily or less were previously thought to be free from the risk of SLE, reports have proven that the syndrome is seen at lower doses, even 50 mg daily.5-8,11,12 Therefore, while higher doses are a risk factor, patients receiving higher doses are not the only ones at risk of developing SLE.

More females have idiopathic SLE with an approximate 10:1 female-to-male ratio.4 However, some reviews have not recognized a gender difference in drug-induced SLE.4,9 Cameron and Ramsey5 reported the incidence of lupus in females on all doses was 11.6% versus 2.8% in men at 3 years. On daily doses of 50 mg to 100 mg, 5.5% of females but no males had development of the syndrome. This incidence increased to 8.0% in females receiving 100 mg daily and occurred in rates as high as 19.4% in those receiving 200 mg daily.5 

It has been reported that HLA-DRw4 is present in 73% of patients with hydralazine-induced lupus, which is notably greater than rates seen in idiopathic disease.22-25 Hydralazine is metabolized pimarily by acetylation in the liver. Slow and fast acetylators describe 2 types of patients who differ by rates of enzyme activity. Faster acetylation leads to faster elimination of the drug and is protective against reactive metabolites. In a prospective study of 57 hypertensive patients receiving hydralazine, 22 of the 33 slow acetylators developed ANAs during the study period, whereas only 9 of 24 of the fast acetylators did. Among patients who had lupus-like symptoms, 12 belonged soley to the group of slow acetylators.23 While drug-induced SLE is more common among those who are slow acetylators, rare cases have been reported in rapid acetylators as well.26 

Although there is minimal documentation of differences of drug-induced SLE in various ethnic backgrounds, one study emanating from Africa examined 58 consecutive patients receiving hydralazine for rheumatological disease over a 6-month period found a 6.9% incidence in this black population taking at least 150 mg daily, which is comparable to reported rates in white patients. This suggests that ethnicity does not appear to play a major role in hydralazine-induced SLE.7 

Table 2 summarizes the risk factors for hydralazine-induced SLE.

Monitoring 

Early detection of SLE is important and patients should be evaluated to detect early symptoms of the syndrome at each patient visit. A baseline ANA test should be determined prior to starting hydralazine therapy. Routine follow-up ANA tests are not recommended because a positive test frequently does not indicate drug-induced SLE; 50% of patients on hydralazine therapy have a positive ANA yet do not have SLE.20 

On the other hand, in patients who report common symptoms while receiving hydralazine, close monitoring and subsequent ANA levels plus antihistone antibodies and other lab workup is warranted to rule out SLE. Typical presenting symptoms include fever, weight loss, and musculoskeletal symptoms (eg, arthritis).9 If these symptoms are reported, hydralazine should be discontinued. 

In summary, clinicians should carefully assess the risk of hydralazine in each patient started on this therapy. Recent reports of this serious adverse effect demonstrate its continued occurrence and the need for vigilance in monitoring.27,28

Timothy H. Self, PharmD, is a professor of clinical pharmacy at the University of Tennessee Health Science Center and program director of PGY2 internal medicine pharmacy residency at Methodist University Hospital, both in Memphis, TN.

Ryan E. Owens, PharmD, BCPS, is a PGY2 internal medicine pharmacy resident at the Methodist University Hospital and the University of Tennessee Health Science Center, both in Memphis, TN.

References: 

  1. Morrow JD, Schroeder HA, Perry HM Jr. Studies on the control of hypertension by hyphex, II: Toxic reactions and side effects. Circulation. 1953;8(6):829-839. 
  2. Lee SL, Chase PH. Drug induced systemic lupus erythematosus: a critical review. Semin Arthritis Rheum. 1975;5(1):83-85. 
  3. Alarcón-Segovia D. Drug induced lupus syndromes. Mayo Clin Proc. 1969;44(9):664-681. 
  4. Skaer TL. Medication induced systemic lupus erythematosus. Clin Ther. 1992;14(4):496-506, discussion 495. 
  5. Cameron HA, Ramsey LE. The lupus syndrome induced by hydralazine: a common complication with low dose treatment. Br Med J. 1984;289(6442):410-412. 
  6. Innes A, Rennie JA, Cato GR. Drug induced lupus caused by very low dose hydralazine. Br J Rheumatol. 1986;25:225. 
  7. Yonga GO. Re: Low dose hydralazine induced lupus. East Afr Med J. 1992;69(11): 649-650. 
  8. Ramsey-Goldman R, Franz T, Solano FX, Medsger TA Jr. Hydralazine induced lupus and sweet’s syndrome report and review of the literature. J Rheumatol. 1990:17(5):682-684. 
  9. Stratton MA. Drug-induced systemic lupus erythematosus. Clin Pharm. 1985;4(6):657-663. 
  10. Sturman SG, Kumararatne D, Beevers DG. Fatal hydralazine-induced systemic lupus erythematosus. Lancet. 1988;2(8623):1304. 
  11. Kincaid-Smith P. Hydralazine—is there a safe dose? Med J Aust. 1985;142(6):337. 
  12. Hosie J, Hosie GA. The lupus syndrome induced by hydralazine. Br Med J. 1984;289(6449):923. 
  13. Bass BH. Hydralazine lung. Thorax. 1981;36(9):695-696. 
  14. Weinstein J. Hypocomplementemia in hydralazine-associated systemic lupus erythematosus. Am J Med. 1978;65(3):553-556. 
  15. Peipho RW, Beal J. An overview of antihypertensive therapy in the 20th century. J Clin Pharmacol. 2000;40(9):967-977. 
  16. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351(20):2049-2057. 
  17. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of congestive heart failure. N Engl J Med. 1991;325(5):1667-1675. 
  18. Koch-Weser J. Vasodilator drugs in the treatment of hypertension. Arch Intern Med. 1974;133(6):1020-1021. 
  19. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. N Engl J Med. 1986;314(24):1547-1552. 
  20. Finks SW, Finks AL, Self TH. Hydralazine-induced lupus: maintaining vigilance with increased use in patients with heart failure. South Med J. 2006;99(1):18-22.
  21. Mansilla-Tinoco R, Harland SJ, Ryan PJ, et al. Hydralazine, antinuclear antibodies, and the lupus syndrome. Br Med J. 1982;284(6320):936-939. 
  22. Olsen NJ. Drug-induced autoimmunity. Best Pract Res Clin Rheumatol. 2004;18(5):677-688. 
  23. Perry HM Jr, Tane EM, Carmody S, et al. Relationship of acetyl transferase activity to antinuclear antibodies and toxic symptoms in hypertensive patients treated with hydralazine. J Lab Clin Med. 1970;76(1):114-125.
  24. Batchelor JR, Welsh KI, Tinoco RM. Hydra-lazine-induced systemic lupus erythematosus: Influence of HLA-DR and sex on susceptibility. Lancet. 1980;1(8178):1107-1109. 
  25. Antonov D, Kazandjieva J, Etugov D, et al. Drug-induced lupus erythematosus. Clin Dermatol. 2004;22(2):157-166. 
  26. Harland SJ, Facchini V, Timbrell JA. Hydralazine-induced lupus erythematosus-like syndrome in a patient of the rapid acetylator phenotype. Br Med J. 1980;281(6235):273-274. 
  27. Kalra A, Yokogawa N, Raja H, et al. Hydralazine-induced pulmonary-renal syndrome: a case report. Am J Ther. 2012;19(4):e136-138.
  28. Chamsi-Pasha MA, Bassiouny M, Kim ES. Hydralazine-induced lupus syndrome presenting with large pericardial effusion. QJM. 2014;107(4):305-307.