Hydralazine-induced lupus: maintaining vigilance with increased use in patients with heart failure.

Objective: To review data concerning the incidence and danger of hydralazine-induced systemic lupus erythematosus (SLE) and review how best to monitor patients placed on chronic hydralazine therapy.

Data Sources: Literature was sought utilizing PUBMED (1960 to present) and MEDLINE (1966 to present). Search terms included hydralazine, drug-induced systemic lupus erythematosus, congestive heart failure, and antinuclear antibody.

Data Synthesis: A major adverse effect of hydralazine therapy is drug-induced SLE. An evaluation of case reports and review of the literature was undertaken to determine the significance of this major adverse effect and stress the importance of close monitoring of patients placed on chronic hydralazine therapy for heart failure. Risk factors are discussed including high daily doses, slow acetylator and HLA-DRw4 phenotypes, therapy longer than 3 months, and female gender.

Conclusions: Following the publication of A-HeFT, an increase in the amount of hydralazine prescribed in patients with heart failure has been noted. Patients should be closely monitored when initiating hydralazine and during chronic therapy. Although dose limitation of hydralazine reduces risk, low doses are well documented to be associated with SLE. A baseline antinuclear antibody level should be determined on initiation of hydralazine, but it is not recommended to regularly check antinuclear antibody levels because a positive result does not necessarily indicate SLE is present. Patients should be monitored at each visit for signs and symptoms of SLE, and, if any signs and symptoms of the syndrome develop while the patient is on hydralazine therapy, the drug should be discontinued immediately because complications from the syndrome can be potentially fatal.

Key Words: hydralazine-induced lupus, drug-induced lupus, hydralazine

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Hydralazine, a potent vasodilator, was first introduced as an antihypertensive agent in 1952. (1) Among the most commonly used antihypertensives of that time, hydralazine was quickly found not to be without risk. Hydralazine was one of the first medications reported to induce lupus, and many cases have appeared in the medical literature since that time. (2-15) In fact, more than 50 years have passed since the first description of the lupus syndrome associated with its use. (2) By 1972, five comprehensive reviews of this material had been published, and the problem of drug-induced lupus had been discussed in widely circulated journals. (1) A reassessment of the hydralazine-induced lupus literature is timely and important due to the recent publication of the A-HeFT trial. (16)

Although hypertension is the only FDA-approved indication, hydralazine is used today for heart failure and a few other indications. As calcium channel blockers and angiotensin converting enzyme inhibitors were introduced in the early 1980s, hydralazine's popularity as an antihypertensive agent began to diminish, given the better efficacy and outcomes associated with other medications, plus the unwanted side effects of hydralazine. (15) In part because hydralazine-induced lupus is so well documented, case reports of systemic lupus erythematosus (SLE) induced by hydralazine in the recent literature have been scarce and the last case report to be published in regard to SLE caused by hydralazine was in 1992. (7) Thus, some clinicians may not be vigilant in monitoring for this serious adverse effect in this older medication. Due to the recent publication of the A-HeFT trial, however, an increase in the prescribing of hydralazine has been noted. (16) Although this and other trials have found hydralazine plus a nitrate beneficial in heart failure, (17-19) one should be cautious when applying these results to all individuals due to the risk with this medication. (1-15)

The study, "Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure (A-HeFT)," was published in The New England Journal of Medicine, where the addition of isosorbide dinitrate plus hydralazine to standard therapy for heart failure was effective in decreasing mortality rates in black patients with New York Heart Association class III or IV heart failure. (16) A-HeFT randomly assigned 1,050 black patients to initially receive a fixed dose of isosorbide dinitrate (20 mg) plus hydralazine (37.5 mg) three times daily, with dosage increased as tolerated to a total daily hydralazine dose of 225 mg and 120 mg of isosorbide dinitrate or placebo, in addition to standard therapy for heart failure. The primary end point of the study was a composite score of death from any cause, first hospitalization for heart failure, and change in quality of life. Patients were required to have been receiving standard therapy, which included 88% receiving diuretics, 69.4% receiving ACE inhibitors, 17.2% receiving angiotensin receptor blockers, 74.1% receiving [beta]-blockers (55.2% receiving carvedilol), 58.5% receiving digoxin, and 40.2% receiving spironolactone in the treatment group. The trial was halted early secondary to a higher mortality rate in the placebo group at the end of approximately 3 years (10.2% versus 6.2% in the placebo and treatment groups, respectively, P = 0.02). The mean duration of follow up was 10 months (range, 0 to 18). Reported adverse events that were significantly greater than placebo included headache and dizziness in the hydralazine nitrate treatment arm. It is noteworthy that SLE was not reported to have occurred in this patient population at the time of first publication. (16)

Because of the relative 43% improvement in survival with hydralazine and isosorbide (hazard ratio, 0.57; P = 0.01) in the A-HeFT trial, the addition of hydralazine and nitrates may be warranted in appropriate patients with heart failure. Physicians not practicing when hydralazine was very commonly prescribed may not be familiar with the dangers of this older generation medication. An evaluation of case reports and review of the literature was undertaken to determine the significance of this major adverse effect and to stress the importance of close monitoring of patients placed on chronic hydralazine therapy for heart failure and other indications. Literature was sought using PUBMED (1960 to present) and MEDLINE (1966 to present). Search terms included hydralazine, drug-induced systemic lupus erythematosus, congestive heart failure, and antinuclear antibody.

Drug-induced Systemic Lupus Erythematosus: Clinical Presentation

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

Laboratory results that lead to the diagnosis of drug-induced SLE include antinuclear antibody (ANA) positivity in up to 90% of drug-induced cases. Although a positive ANA titer is used in conjunction with other laboratory tests and clinical findings to confirm the diagnosis of systemic lupus erythematosus, a positive ANA titer alone does not warrant a change in drug therapy, in part because some patients on hydralazine with positive ANA will not have the syndrome. (20) Other common lab findings include the presence of lupus erythematosus (LE) cells and rheumatoid factor at 47 to 80%, and 29 to 50% of patients, respectively. (4) Typical findings will include antihistone antibodies, which may be present in up to 95%. In drug-induced lupus, generally there is a higher frequency of anti-ssDNA antibodies, where anti-dsDNA antibodies are rare. Generally, complement levels are low in drug-induced disease. (21)

Although drug-induced syndromes have previously been described as mild syndromes, a timely diagnosis of drug-induced disease can be critical in life-threatening illnesses such as vasculitis, glomerulonephritis, or pulmonary failure, which underscores the importance for definitive diagnostic testing. (21)

Description of the Literature Analyzed

Only a few prospective studies have been published concerning drug-induced lupus. (5,7,12,22) Information concerning this important side effect of hydralazine is mainly found in the form of case reports reported shortly after the drug was introduced in 1952. (3) These case reports and a few reviews will be analyzed to provide information on hydralazine-induced SLE and stress the importance of close monitoring of any patient placed on chronic hydralazine therapy. Although case reports can supply valuable information, limitations exist with this type of literature review. Prospective studies, although rare on this subject, are included; however, each of these include small patient populations. (5,7,12,22) As the use of hydralazine increases because of the positive results of heart failure randomized trials, prospective reviews need to be conducted to determine the true incidence of this syndrome.

Just 3 years after hydralazine was introduced, nine cases of symptoms resembling SLE were reported in several different medical journals. (1) Shortly after these publications, more than 150 cases of hydralazine-induced SLE were reported in the literature. (3) It was reported in the early years of experience that prolonged administration (from 3 months to 5 years) of hydralazine was associated with the development of SLE, with an incidence of 8 to 13%. (1,3) Documented 20 years after its first use, hydralazine-induced SLE was estimated to occur in 10 to 20% of individuals treated with doses of 400 mg or more daily. (17) Later case reports have demonstrated that the syndrome has occurred in patients receiving as little as 50 mg daily. (5-11)

In 1984, Cameron and Ramsay (5) published a prospective trial which concluded that the number of hydralazine-induced SLE cases were unacceptably high. Of 281 patients on hydralazine, 6.7% had documented cases of hydralazine-induced SLE. Hydralazine was initiated in hypertensive individuals (146 male, 135 female) at 25 mg twice a day and was increased as necessary to 100 mg twice daily. The mean age was 57 years (range, 32 to 77), and the mean (SD) blood pressure was 191 [+ or -] 27/109 [+ or -] 13 mm Hg. The mean duration of follow-up was 24.4 months (range, 5 days to 57 months). The maximum daily dose of hydralazine was 50 mg in 82 (29%) patients, 100 mg in 72 (26%), and 200 mg in 127 (45%). SLE was diagnosed on the basis of 10 predetermined clinical and laboratory features including fever, joint symptoms, rash, weight loss, splenomegaly, pleurisy, pericarditis, peak ESR, peak antinuclear factor titer, and lowest hemoglobin. The 14 patients with the syndrome had, on average, 5 of the 10 features at the time of diagnosis. Most patients described symptoms of arthritis, fever, weight loss, and pleurisy. Pericarditis and splenomegaly were also observed, but skin rash was relatively infrequent. Most patients who had these symptoms were ill enough to require hospital admission. Diagnosis time of SLE was noted to be within a mean time of 24 months (first case was after 9 months of treatment and the last was after 40 months). Higher dosages were associated with a higher incidence of SLE (10.4%). (5) All manifestations resolved rapidly after hydralazine was stopped.

Risk for Drug-induced Systemic Lupus Erythematosus

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)

Dose Ranges

The question of whether there is a safe dose with hydralazine has been raised by previous authors. (5,7,11,12) The amount of hydralazine in the serum is closely linked with its therapeutic effect, and it was once thought that this could be used to avoid drug-induced SLE and other toxic manifestations. (17) Doses of 200 mg daily or less were thought to be free from the risk of SLE, but reports have proven that the syndrome is seen at lower doses, even 50 mg daily. (5-8,11,12) Although the total daily dose of hydralazine used in A-HeFT was just above 200 mg daily, there is good evidence to suggest that these patients and those receiving lower doses are not free from the risk of development of SLE. We learn from Cameron's prospective study that there is a greater risk with higher doses of hydralazine, and this is why they suggest limiting the dose in men to 100 mg daily and 50 mg daily in women. (5) Another group of 67 patients given lower doses were followed consecutively by Hosie and Hosie (12) for a period of 32 months, without the development of a single case of hydralazine-induced lupus. Only one woman on 100 mg daily for 2 years had an antinuclear factor present at a titer of 1:256. They concur with the low doses recommended by Cameron and Ramsay. (12)

Gender

A greater percentage of females may have idiopathic SLE, with a female:male ratio of approximately 10:1, (4) although some reviews have not recognized a gender difference in drug-induced SLE. (4,9) Cameron reported the incidence of lupus in females on all doses was 11.6% and 2.8% in men at 3 years. On daily doses of 50 to 100 mg, 5.5% of females but no males had development of the syndrome. In females receiving 100 mg daily, the incidence increased to 8.0% and in those receiving 200 mg daily, the syndrome occurred in 19.4%. (5) A-HeFT's population included 45% women enrolled to receive the target of 225 mg hydralazine daily; however, only 68% of patients actually achieved target dosing. Although other prospective reports note an increase in risk in women with doses over 50 mg daily, there was no SLE reported in A-HeFT. It was only later that the authors report through correspondence that one patient was noted to have potential SLE. The authors do not report the patient's gender. (23) Clinicians should be vigilant in addressing any vague symptomatology associated with SLE, especially in women.

Genetic Factors

There are two groups of genetic factors that have been associated with the development of drug-induced SLE-HLA alleles and acetylation status in drug metabolism. It has been reported that HLA-DRW4 is present in 73% of patients with hydralazine-induced lupus, which is significantly higher than in patients with idiopathic disease. (21,22,24,25) Hydralazine is metabolized largely by acetylation in the liver. A genetic polymorphism exists in the hepatic acetyltransferase responsible for the detoxification process in metabolism. "Slow acetylators" and "fast acetylators" characterize two types of patients who differ by 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 on hydralazine, 22 of the 33 slow acetylators developed antinuclear antibodies during the study period, whereas only 9 of 24 of the fast acetylators did. Twelve patients who had lupus-like symptoms belonged exclusively to the group of slow acetylators. (22) Although drug-induced SLE is undoubtedly more common among those who are slow acetylators, rare cases in patients presenting with atypical clinical symptoms have been described in rapid acetylators and therefore does not alleviate risk from this group. (26)

One should also note that most reviews deem the syndrome from drug-induced lupus as a milder disease than idiopathic SLE. Importantly, however, a handful of case reports have described fatal events with hydralazine-induced SLE, which underscores the potential hazards of this agent. (10) One author even suggests that the drug carries an unacceptable risk and should be regarded as obsolete. (11) Fatal cases that have been reported involved doses as low as 100 mg per day and have included glomerulonephritis, which historically was thought not to be a consequence with the drug-induced disease. (10) In addition, 6 of the 14 patients in Cameron and Ramsey's study had evidence of renal impairment. (6)

Monitoring

It is likely that the classic textbook presentation of drug-induced lupus is only representative in a minority of cases. As stated previously, a timely diagnosis of drug-induced disease can be critical in life-threatening illnesses, underscoring the need for definitive diagnostic tests. Unfortunately, since drug-induced ANA patterns may overlap with idiopathic antibodies, drug-related disease and idiopathic disease may be difficult to differentiate. (20)

Four methods for patient selection when starting hydralazine were proposed by Cameron and Ramsay, namely, dose limitation, careful selection of patients, early detection, and use of alternate medications. (5) The first method would be to limit the dose used in men to 100 mg daily and 50 mg daily in women. Hosie and Hosie (12) concur with the low doses in their report of 67 patients. Second, careful assessment of acetylation status might reduce the risk if the drug were limited to fast acetylators. However, expense and practicality may limit this option that still may not prevent all cases of SLE. Third, early detection of SLE is of utmost importance. Assessment of patients to detect early symptoms of the syndrome should be conducted at each patient visit. A baseline ANA test should be determined before initiating a patient on hydralazine. Follow-up ANA tests are not recommended because positivity does not always indicate drug-induced SLE, and 50% of patients on hydralazine have a positive ANA yet do not have SLE. In patients who report suspicious symptoms, close monitoring and subsequent ANA levels plus antihistone antibodies and other lab workup is warranted. The most common presenting symptoms include fever, weight loss, and musculoskeletal symptoms, such as arthritis. (9) If these symptoms should develop, the drug should be discontinued. Last, Cameron and Ramsay recommend simply not using hydralazine and choosing an alternative drug. The final recommendation is the only option that would completely eliminate hydralazine-induced SLE. However, the recommendation of Cameron and Ramsay was obviously not made in the context of the recently published A-HeFT trial. Weighing the positive benefits of hydralazine therapy per the A-HeFT trial suggest that increased use of this drug is warranted pending further study. Close monitoring for early detection of hydralazine-induced SLE is also most certainly essential.

Discussion

Clinicians should not overlook the low incidence of SLE in the A-HeFT trial for several reasons. Hydralazine-induced SLE has occurred and been documented for more than 50 years. However, there is very little documentation of differences of drug-induced SLE in various ethnic backgrounds. The patient population in A-HeFT was black. Could the absence of SLE induced by hydralazine have been due to the fact that there is a difference in drug-induced SLE risk based on ethnicity? The East African Medical Journal documents incidence in 58 consecutive patients receiving treatment with hydralazine who were reviewed for rheumatological disease over a 6-month period. Their incidence of 6.9% in the African population taking at least 150 mg daily would be similar to reports in white individuals. (7) Further study may need to be conducted to determine the true risk of hydralazine-induced SLE among black patients.

Second, there may not have been sufficient follow-up time in A-HeFT to see the true incidence of hydralazine-induced lupus. The study was halted secondary to a higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine. The mean duration of follow up was approximately 10 months. Some case reports have noted lupus after 6 months or earlier, but, the syndrome can certainly appear later, even up to 5 years after therapy initiation. (1,3,5) Cameron and Ramsey's prospective study showed that diagnosis was within a mean time of 24 months with the first case appearing after 9 months of treatment. (5) The absence of SLE reported in A-HeFT may not be complete; the true incidence of SLE may only be apparent after further follow-up time. Other authors caution that hydralazine-induced lupus should always be considered as a possibility in any patient on hydralazine treatment lasting more than 6 months, irrespective of race, dosage, age, and acetylator phenotype. (7)

Last, the mortality difference in the A-HeFT trial was associated with a 45% relative risk reduction. The benefit from hydralazine and nitrates may outweigh the risk for some patients, due to the high mortality rate of heart failure. Caution must be exercised by each practitioner, however, to assess the risk of hydralazine in each patient started on this therapy.

Conclusion

Following the publication of the A-HeFT trial, a likely increase in the amount of hydralazine used in heart failure, especially in black patients, will occur. The potential hazards of this drug have been clearly documented in the literature; however, the documents are dated on average more than 30 years ago. Practitioners who are using hydralazine in their patients for the first time in their practice may have heard of hydralazine-induced SLE but may not be familiar with the incidence, clinical presentation, and the serious risk that this agent carries. It is important for physicians to be vigilant in monitoring patients who are placed on chronic hydralazine therapy to minimize the risk of drug-induced SLE. All patients deserve careful rheumatological assessment as part of their follow up.

References

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2. Morrow JD, Schroeder HA, Perry HM Jr. Studies on the control of hypertension by hyphex, II: Toxic reactions and side effects. Circulation 1953;8:829-839.

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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;69:649-650.

8. Ramsey-Goldman FT, Solano FX, Medsger TA. Hydralazine induced lupus and sweet's syndrome report and review of the literature. J Rheumatol 1990:682-684.

9. Stratton MA. Drug-induced systemic lupus erythematosus. Clin Pharm 1985;4:657-662.

10. Sturman SG, Kumarraratine D, Beevers DG. Fatal hydralazine-induced systemic lupus erythematosus. Lancet 1988;3:1304.

11. Kincaid-Smith P. Hydralazine: Is there a safe dose? Med J Aust 1985;142:337.

12. Hosie J, Hosie GAC. The lupus syndrome induced by hydralazine. Br Med J 1984;289:923.

13. Bass BH. Hydralazine lung. Thorax 1981;36:695-696.

14. Weinstein J. Hypocomplementemia in hydralazine-associated systemic lupus erythematosus. Am J Med 1978;65:553-556.

15. Peipho RW, Beal J. An overview of antihypertensive therapy in the 20th century. J Clin Pharmacol 2000;40:967-977.

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19. 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;325:1667-1675.

20. Mansilla-Tinoco R, Harland SJ, Ryan PJ, et al. Hydralazine, antinuclear antibodies, and the lupus syndrome. Br Med J 1982;284:936-939.

21. Olsen NJ. Drug-induced autoimmunity. Best Pract Res Clin Rheumatol 2004;18:677-688.

22. 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;76:114-125. Out of Drug Induced Systemic Lupus Erythematosus: A critical review. Seminars in arthritis and rheumatism, vol 5. No 1 (August 1975).

23. Taylor AL, Cohn J. Isosorbide dinitrate and hydralazine in blacks with heart failure: Correspondence. N Engl J Med 2005;352:1043.

24. Batchelor JR, Welsh KI, Tinoco RM. Hydralazine-induced systemic lupus erythematosus: Influence of HLA-DR and sex on susceptibility. Luncet 1980;1:1107-1109.

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Shannon W. Finks, PHARMD, BCPS, A. Lloyd Finks, MD, and Timothy H. Self, PHARMD

From the Methodist University Hospital, and University of Tennessee Health Science Center, Memphis, TN.

Reprint requests to Dr. Shannon W. Finks, University of Tennessee College of Pharmacy, 25 S. Dunlap, Suite 210, Memphis, TN 38163. E-mail: [e-mail]

Accepted October 10, 2005.

RELATED ARTICLE: Key Points

* Patients should be closely monitored when initiating hydralazine and in chronic therapy.

* For systemic lupus erythematosus (SLE) induced by hydralazine, musculoskeletal symptoms are the most common clinical manifestation.

* Laboratory results that lead to the diagnosis of drug-induced lupus include antinuclear antibody (ANA), lupus erythematosus cells, rheumatoid factor, and antihistone antibodies.

* Although dose limitation of hydralazine reduces risk, low doses are well documented to be associated with SLE. A baseline antinuclear antibody (ANA) level should be determined on initiation of hydralazine, but it is not recommended to regularly check ANA levels.

* Antihistone antibody, although 50% sensitive to idiopathic SLE, has sensitivity of up to 90% in drug-induced lupus.

* Patients should be monitored at each visit, and, if any signs and symptoms of SLE develop while the patient is on hydralazine therapy, the drug should be discontinued immediately because complications from the syndrome can be potentially fatal.