Hydralazine-induced lupus.

Nearly 50 years after the first published case report of hydralazine-induced lupus was described, (1) scientists are still grappling with the mysteries of drug-induced autoimmunity. (2)

A drug-induced lupus-like syndrome may present with arthralgias, myalgias, fever, and serositis but is distinguished from systemic lupus erythematosus by several characteristics. Sex ratios are nearly equal in drug-induced lupus and nephritis and central nervous system features are absent, although lupus nephritis has been known to occur with hydralazine. (3) Antihistone antibodies are present in more than 90% of cases and anti-double-stranded-DNA antibodies are typically absent. More importantly, when the drug is discontinued, the patient has resolution of clinical manifestations and abnormal laboratory values revert to normal although antinuclear antibodies may persist for months.

The drug-induced lupus syndrome has been attributed to several drugs including hydralazine. Hydralazine-induced lupus may be caused in part by inducing the same extracellular signal-regulated kinase (ERK) pathway-signaling defect that occurs in idiopathic lupus. (4) Hydralazine reproduces the lupus ERK path-way, signaling abnormality and its effects on DNA methyltransferase expression, and inhibiting this pathway induces autoimmunity. (4) Scientists hope to find a cure for systemic lupus erythematosus by understanding how hydralazine causes lupus.

Although several models have been proposed to identify persons at risk for drug-induced lupus, (5) it is currently not possible to identify a specific person who is at risk for developing hydralazine-induced lupus unless the patient has a history of reaction to the drug. Most reports of hydralazine-induced lupus are limited by spontaneous reporting as case reports or small case series. The key elements in the assessment of a possible association between exposure and the development of a lupus-like syndrome include temporal association, lack of likely alternative explanations, rechallenge, and biologic plausibility. (6)

The recent publication of the A-HeFt study (7) and the FDA approval of a fixed-dose combination of hydralazine and isosorbide-dinitrate BiDil (8) for use in African-American patients with heart failure mean that clinicians will be faced with the difficult task of initiating and monitoring their African-American patients with heart failure on hydralazine. The clinician's task is further complicated by the fact that the FDA-approved prescribing information for BiDil does not recommend that patients taking the drug get routine blood tests for lupus. On the other hand, regular testing is recommended in FDA-approved prescribing information for the generic form of hydralazine before initiation of therapy and "periodically" thereafter. In the A-HeFt study, the authors described only 1 case of hydralazine-induced lupus among 1,050 patients, although four patients had myalgias, an initial manifestation of drug-induced lupus. (6) This apparent low incidence is attributed to the short duration of follow up and the fact that the authors did not measure lupus antibody levels in the study.

In this issue of the Southern Medical Journal, the authors have done a timely review of the literature on hydralazine-induced lupus. (9) The authors identify several risk factors for the development of hydralazine-induced lupus including high daily doses, slow acetylator and HLA-DRw4 phenotypes, therapy greater than 3 months, and female gender. The authors emphasize close monitoring of patients on hydralazine, including a baseline antinuclear antibody (ANA) level and recommend immediate discontinuation, rather than dose-reduction, of hydralazine therapy when symptoms develop because of the risk of fatal complications.

Our recent experience with spironolactone reminds us that the initial enthusiasm for using a new therapy in heart failure could have potentially fatal, and avoidable, side effects in patients. (10) It is therefore prudent that clinicians counsel patients appropriately about the potential side effect of hydralazine-induced lupus and monitor them closely for this disorder until we have further defined the exact magnitude and strength of this association with rigorous epidemiologic and laboratory studies.

References

1. Reinhardt DJ, Waldron JM. Lupus erythematosus-like syndrome complicating hydralazine (apresoline) therapy. J Am Med Assoc 1954;155:1491-1492.

2. Uetrecht J. Current trends in drug-induced autoimmunity. Autoimmun Rev 2005; 4:309-314. Epub 2005 Feb 15.

3. Ihle BU, Whitworth JA, Dowling JP, et al. Hydralazine and lupus nephritis. Clin Nephrol 1984; 22: 230-238.

4. Deng C, Lu Q, et al. Hydralazine may induce autoimmunity by inhibiting extra cellular signal-regulated kinase pathway signaling. Arthritis Rheum 2003; 48:746-756.

5. Adhami E. A predictive equation for drug-induced lupus. Med Hypotheses 2003; 61:473-476.

6. Yung R, Richardson B. Drug-induced rheumatic syndromes. Bulletin on the Rheumatic Diseases 2002; 51:1-5.

7. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351:2049-2057.

8. Food and Drug Administration. US FDA approves BiDil heart failure drug for African-American patients, Jun 23 2005 http://www.fda.gov/bbs/topics/NEWS/2005/NEW01190.html. Accessed September 5 2005.

9. Finks SW, Finks AL, Self TH. Hydralazine-induced lupus: Maintaining vigilance with increased use in patients with heart failure. South Med J 2006; 99:18-22.

10. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-551.</p> <pre> When the freedom they wished for most was freedom from responsibility, then Athens ceased to be free and was never free again. --Edith Hamilton </pre> <p>Sonal Singh, MD

From the Section of General Internal Medicine, Internal Medicine, Wake Forest University, Winston-Salem, NC and the MPH Program, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.

Reprint requests to Sonal Singh, MD, Department of Medicine, Wake Forest University, Medical Center Boulevard, Winston-Salem, North Carolina 27157. Email: [e-mail]

Accepted October 25, 2005.