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A 65-year-old woman was seen in our hypertension clinic following recovery from hydralazine-induced lupus erythematosis. She had been taking antihypertensive medication for 15 years and was evaluated by the rheumatology department a year prior to her hypertension consultation for joint pain and swelling associated with positive serologies.

A month prior to her rheumatology appointment she developed acute pain and swelling in the left fifth proximal interphalangeal joint (PIP), followed by painful swelling of the fourth and fifth PIP joints allowing minimal flexion. Subsequent joint involvement progressed to the right fifth PIP joint, bilateral wrists, right shoulder, bilateral knees, bilateral ankles, and both forefeet. Laboratory tests were significant for a diffuse pattern antinuclear antibody 1:2560 and a low positive rheumatoid factor of 17 IU/mL (normal <11 IU/mL). A complete blood cell count and renal function were normal. She denied fever, rash, pleuritic chest pain, or shortness of breath.

Rheumatology examination noted swelling and tenderness of the left third, fourth, and fifth PIP joints with dactylitis, swelling and tenderness of the right fifth PIP, and bilateral tender wrists. Additional serologies revealed antidouble stranded deoxyribonucleic acid antibody (anti-ds DNA ab) 15 IU/mL (normal <25.0 IU/mL), antihistone antibody 1.8 UOM/U (normal <1.0 UOM/U), C3 complement 153 mg/dL (normal 90–180 mg/dL), C4 complement 21 mg/dL (normal 10–40 mg/dL), and Westergren erythrocyte sedimentation rate 43 mm/h (normal 0–33 mm/h). Her 4-drug antihypertensive drug regimen included hydralazine 50 mg twice a day for 5 years.

Hydralazine was discontinued and azulfidine was initiated and advanced to 1000 mg twice a day with meloxicam 15 mg daily. Painful joints rapidly abated and 6 months later azulfidine was discontinued without a recurrence of her inflammatory arthritis. Losartan, amlodipine, and atenolol were continued. When chlorthalidone was substituted for furosemide, elevated blood pressures off of hydralazine became controlled.

Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References

Hydralazine was introduced into routine practice for treatment of hypertension in 1951 when the only alternatives were ganglionic blockers, such as hexamethonium. Case reports of long-term toxicity with presentations similar to intrinsic lupus erythematous or rheumatoid arthritis began to appear the following year.1 Clinical features prominently included those of an inflammatory polyarthropathy with arthralgias and arthritis and frequent myalgia, also with occasional fever and rash. Less commonly, symptoms of serositis, particularly pleuritis and pericarditis, associated with pleuritic pain and effusions occurred.1–4

What are the Common Clinical Features?

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References

In an early series of hydralazine patients, Perry reported on 371 individuals followed for 2 months to 20 years on hydralazine, 44 (11.9%) of whom developed late toxic reactions consistent with drug-induced lupus.5 The daily dose ranged from 100 mg to 1600 mg, with a mean of 497 mg/d. Arthropathy was the presenting complaint in 80% of patients, mostly affecting the small joints of the hands, followed by the wrists and then the elbows, ankles, knees, and toes.5 Severity ranged from minimal joint enlargement to “markedly red, hot, painful, and swollen” joints, but large synovial fluid collections were rare.5 Malaise and myalgia were occasionally “incapacitating.” Importantly, the arthritis was always nondeforming and rapidly reversible with drug discontinuation.5

Others have reported characteristic arthralgia in 90% of cases, as possibly the only clinical feature, and myalgia in 50% of cases.3 Arthralgia occurred in 19 of 21 patients in another study.6 Arthritis appears to be a more distinguishing clinical feature of hydralazine-induced lupus compared with procainamide-induced lupus, with serositis more commonly associated with procainamide-induced lupus (Table).7 However, pleuritic chest pain was a feature of 25% of 44 hydralazine-induced lupus patients in one series of patients,5 and serositis was described in 6 of 21 (29%) patients in another series.6 Fever was a solitary clinical feature in 5 of 44 patients,5 and was 105°F in one case report.8 Lymphadenopathy may be noted on physical examination5,9 as well as hepatosplenomegaly.4

Table TABLE.   Prevalence of Clinical and Laboratory Abnormalities in Hydralazine-Induced and Idiopathic Lupus
 Hydralazine-Induced Lupus, %Systemic Lupus Erythematosis, %
  1. Reproduced with permission.7

Symptoms
 Arthralgia/arthritis/myalgia8080
 Pleuritis/pleural effusion<544
 Fever/weight loss/fatigue40–50>80
 Hepatosplenomegaly155–10
 Pericarditis<520
 Rash2571
 Glomerulonephritis5–1042
 Neuropsychiatric<532
Signs
 Antinuclear antibodies>95>95
 Lupus erythematosus cells>5071
 Antihistone Abs>9554
 Antinative DNA Ab<528–67
 Anticardiolipin Ab5–1535
 Rheumatoid factor Ab2025–30
 Anemia3565
 Elevated erythrocyte sedimentation rate60>50
 Leukopenia5–2550
 Thrombocytopenia<530–50
 Hypocomplementemia<551

Cutaneous Manifestations

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References

Dermatitis is a less common manifestation of drug-induced lupus,9 variously reported in 10% to 34%,4 33%,6 and 11%5 of patients with hydralazine-induced lupus. An important differentiating characteristic of drug-induced lupus is occasional generalized distribution with involvement of the lower extremities, which is lacking in idiopathic lupus.10 Additionally, more common nonspecific cutaneous eruptions with drug-induced lupus including purpura, erythema nodosum, and livedo reticularis are to be distinguished from the more typical idiopathic lupus presentations with malar rash, discoid lesions, mucosal ulcerations, alopecia, and Raynaud’s.2,10,11 Mild anemia, leukopenia, and enough thrombocytopenia to cause petechiae may also occur with drug-induced lupus.1,2 Drug-induced subacute cutaneous lupus with generalized annular papulosquamous lesions is a different disease than drug-induced systemic lupus and is predominantly associated with other antihypertensive agents: calcium channel blockers, angiotensin-converting enzyme inhibitors, and thiazide diuretics.3,4,10

Uncommon Clinical Features

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References

Compared with idiopathic lupus, central nervous system and renal involvement with drug-induced lupus are rare.3,9 Nonetheless, renal injury of variable prominence has been mentioned in individuals with hydralazine-induced lupus. Six of 14 (43%) patients had renal impairment in one description,11 but only 1 of 21 (5%) patients in another.6 Acute glomerulonephritis has been associated with hydralazine-induced lupus.4 A severe case of hydralazine-induced lupus and antineutrophil cytoplasmic antibody vasculitis responded to pulsed methylprednisolone, plasma exchange, and hemodialysis.12

Three of 21 patients in Speirs’ hydralazine-induced lupus report experienced central nervous system signs and symptoms,6 but this is an unusual observation. Severe organ involvement is exceedingly rare, but pericardial tamponade1,13 and fatality with pneumonitis has been reported.8 However, overall perspective should not be lost, noting that the spectrum of disease associated with drug-induced and, in particular, hydralazine-induced lupus, is decidedly mild when compared with idiopathic lupus and readily reversible with drug discontinuation.

Serologic Findings

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References

The characteristic clinical presentation of hydralazine-induced lupus with arthropathy and occasional serositis should be accompanied by a typical collection of serologic markers to make the diagnosis. The antinuclear antibody profile tends to be narrower than for idiopathic lupus.9 Positive antinuclear antigen (ANA) staining occurs in a diffuse homogenous pattern, in association with positive anti-single stranded DNA antibody and antihistone antibody, but, compared with idiopathic lupus, antibody response to native double-stranded DNA (anti-dsDNA ab), extractable nuclear antigen, and cardiolipid is usually absent in drug-induced lupus.1–3,9 Another distinction from idiopathic lupus is that serum complement levels are normal in drug-induced disease.1,4,9

Anti-dsDNA ab occurs in 50% to 70% idiopathic lupus but <5% of drug-induced lupus cases.1 However, false-positive anti-dsDNA antibody assays may occur when the crithidia assay is used due to cross reactivity with antihistone antibodies.2 Five histones, which are small DNA-binding proteins, have been identified. Antihistone antibodies have been noted to be a distinctive marker for drug-induced lupus, but the pattern of response to individual histones is not drug-specific.14 Antihistone antibodies occur in 75% of cases with either idiopathic or drug-induced lupus, and antichromatin antibodies also occur in both conditions. Chromatin is the histone-DNA macromolecular complex in the cell nucleus. Antihistone antibodies also occur in rheumatoid arthritis, scleroderma, and undifferentiated connective tissue disease.3 Anti-Smith antibodies are almost exclusive to idiopathic lupus.2

Positive rheumatoid factor occurs in 20% of patients with hydralazine-induced lupus, which may mimic rheumatoid arthritis, particularly when bilateral hand and wrist arthropathy is the sole manifestation.5,7 In the case described, a disease-modifying antirheumatic drug was used temporarily at the time of hydralazine discontinuation.

Is ANA Conversion a Disease Predictor?

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References

A prospective study of 221 patients treated with hydralazine found that positive ANA titers occurred in 54% of slow acetylators and 46% of fast acetylators after 3 years.15 Although slow acetylators accounted for most early ANA conversions, rapid acetylators eventually closed the difference, so that acetylator phenotype was no longer significant after 3 years. Cumulative drug dose was a predictor of ANA positivity, and most serologic conversions occurred between 5 and 26 months of drug exposure. Some patients experienced a significant fall in ANA titer despite drug continuation,15 and positive ANA may persist 10 years following hydralazine discontinuation.5 Only 5% patients developed hydralazine-induced lupus in the prospective study, and ANA positivity was not a predictor of clinical disease.15 Although drug-induced ANA induction is a necessary background, this process occurs commonly enough that it is not an important risk factor for the drug-induced lupus syndrome.14,15

What Are the Risk Factors for Hydralazine-Induced Lupus?

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References

Risk factors for hydralazine-induced lupus have been studied extensively since the disease was first described in 1953, and 6 well-recognized risk factors have been identified: (1) cumulative dose (150 vs 76 g), (2) female sex, (3) white race, (4) slow acetylation, (5) human leukocyte antigen (HLA) DR4, and (6) C4 null.9 When first introduced in the 1950s, hydralazine doses up to 3 g/d were prescribed15 and the mean daily dose in Perry’s series of patients was nearly 500 mg.5 After 20 years of use of hydralazine ≥400 mg/d, drug-induced lupus is estimated to occur in 10% to 20% of patients.1

In a longitudinal study of 281 patients treated with hydralazine for a mean of 51 months, the incidence of drug-induced lupus was 5.4% on 100 mg/d and 10.4% on 200 mg/d.11 Hydralazine-induced lupus occurred in 2.8% men and 11.6% women. When dose and sex risks occurred in combination, lupus occurred in 19.4% of women taking 200 mg/d.11 Although no cases were observed on hydralazine 50 mg/d in this study, case reports have appeared documenting hydralazine-induced lupus on a dose as little as 50 mg/d with longer exposures.1 In case reports, drug exposure ranged from 6 months to 5 years.1

There is a 10:1 female:male predilection for idiopathic lupus, usually occurring in younger women.1 Although hydralazine exposure occurs in an older population with a higher male proportion, the female sex risk factor persists for hydralazine-induced lupus, though not as striking.1,2,9 African American patients appear to be more resistant to the development of hydralazine-induced lupus.3,5,8,9 Concern was raised that following the results of the African American heart failure trial showing survival benefit of hydralazine/isosorbide using hydralazine up to 225 mg/d,16 that there would be large numbers of black patients developing drug-induced lupus.1,17 Only one patient developed this disease during the trial, but the trial was terminated at 10 months due to significant benefit in the treatment group.17 The lack of such follow-up reports may reflect relative racial protection or clinical inertia and intolerance for the target dose in black patients with low systolic function.

In 1964, a genetic dimorphism in the activity of an enzyme acetylating hydralazine was discovered such that patients were either fast or slow acetylators of the drug with first-pass hepatic metabolism. The fast N-acetyl transferase isotype represents the dominant expression.6 Shortly thereafter, slow acetylation was recognized as an important risk factor for the development of hydralazine-induced lupus.5 In one series, 25 of 26 cases of hydralazine-induced lupus were slow acetylators.18 HLA-DR haplotypes exert genetic control of immune responsiveness: idiopathic lupus is associated with HLA-DR3 and rheumatoid arthritis is associated with HLA-DR4. Batchelor undertook a search for abnormal HLA-DR frequencies associated with hydralazine-induced lupus and discovered a significant concordance with HLA-DR4.18 Most hydralazine-induced lupus could be avoided by excluding slow acetylator women with HLA-DR4.18 C4A and C4B generate complement, which inhibits the formation of insoluble immune complexes. Null alleles of C4A and C4B result in nonexpression of these proteins, another risk factor for the development of hydralazine-induced lupus.6

How Common is Hydralazine-Induced Lupus?

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References

Although more than 80 drugs have been associated with drug-induced lupus, the “definite” associations have been limited to a small group: procainamide, hydralazine, isoniazid, methyldopa, chlorpromazine, quinidine, and minocycline.2,7,9 Of that small group, the especially high-risk drugs are procainamide with an estimated incidence of 20% per year and hydralazine at 5% to 8% per year.7 A recent nested case-control study using data from the UK general practice research database representing a cohort of 6% of the UK population discovered 875 incident cases of drug-induced lupus.19 Hydralazine was the drug most frequently implicated, with an odds ratio of 6.62 and a 95% confidence interval of 1.03–42.74.19

Case Summary

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References

The case presented illustrates a typical presentation of hydralazine-induced lupus with bilateral finger and wrist inflammatory polyarthropathy in a patient who had been taking hydralazine 50 mg twice a day for 5 years. Risk factors included white race and female sex as well as cumulative dose >150 g. The serologic profile was high titer homogenous ANA, positive antihistone antibody, and negative anti-dsDNA antibody. Serum complement levels were normal. Following drug discontinuation, disease remission described in the literature occurs in a time frame ranging from days, to weeks, to months.7,9,10 In this case, symptoms completely resolved after 6 months.

Doses of hydralazine above 200 mg/d are not recommended for the treatment of hypertension because of the risk of drug-induced lupus,11 as well as the lack of additional antihypertensive efficacy.

References

  1. Top of page
  2. Case Discussion: Recognition of Drug-Induced Lupus Occurred Soon After Hydralazine Introduction
  3. What are the Common Clinical Features?
  4. Cutaneous Manifestations
  5. Uncommon Clinical Features
  6. Serologic Findings
  7. Is ANA Conversion a Disease Predictor?
  8. What Are the Risk Factors for Hydralazine-Induced Lupus?
  9. How Common is Hydralazine-Induced Lupus?
  10. Case Summary
  11. References