Hydralazine-induced lupus without kidney involvement

Drug-Induced GNmedium

A 45-year-old woman with stage 3 CKD has had hypertension well controlled for 3 years on lisinopril, chlorthalidone, and hydralazine. She reports 4 months of malaise, low-grade fevers, and arthralgias. Temperature is 38.2°C. She has diffuse muscle tenderness without joint swelling and a faint maculopapular rash on her arms and torso. Creatinine is 1.4 mg/dL (1.6 two years ago); C3 120 and C4 39 mg/dL; ANA <1:80 (≤1:40); anti-dsDNA 0 IU/mL; anti-histone antibodies 1:32 (<1:16); MPO-ANCA 3 U (<1); PR3-ANCA 0.3 U (<1). Urinalysis is negative for protein and blood. What is the best next step?

  1. A.Discontinue hydralazineCorrect
  2. B.Obtain kidney biopsy
  3. C.Obtain blood cultures
  4. D.Prescribe methylprednisolone

Explanation

The next best step is to discontinue hydralazine. After 3 years of hydralazine, this woman has 4 months of malaise, low-grade fever, arthralgias, myalgias, and a rash, with a positive ANA, positive anti-histone antibodies, negative anti–double-stranded DNA antibodies, normal complements, and a low-titer positive MPO-ANCA. This is the profile of hydralazine-induced lupus. Hydralazine is metabolized by hepatic N-acetylation, and slow acetylators, cumulative doses above about 100 g, female sex, and HLA-DR4 increase risk. Hydralazine can also cause drug-induced ANCA-associated vasculitis, often with high-titer MPO-ANCA, multiple autoantibodies (ANA, anti-histone, sometimes anti-dsDNA), low complements, and pauci-immune necrotizing glomerulonephritis. Her urinalysis shows no blood or protein, and her creatinine is stable compared with 2 years ago, so there is no evidence of glomerulonephritis. The essential first step for any hydralazine-associated autoimmune syndrome is withdrawal of the drug, which leads to resolution of drug-induced lupus over weeks to months; a substitute antihypertensive can be chosen. ANCA titers and urinalysis should be monitored, because new hematuria, proteinuria, or rising creatinine would signal kidney involvement. Kidney biopsy is indicated for suspected hydralazine-associated vasculitis with active urinary sediment, proteinuria, or declining function. With a bland urinalysis and stable creatinine, a biopsy would carry risk without diagnostic benefit. Methylprednisolone or other glucocorticoids are reserved for severe drug-induced lupus that persists after withdrawal, or for hydralazine-associated vasculitis with organ-threatening disease. Mild constitutional and musculoskeletal symptoms usually resolve after stopping the drug, sometimes with NSAIDs or low-dose prednisone, which are cautious choices in CKD. Blood cultures are reasonable when fever suggests infection, particularly endocarditis, which can also produce ANCA positivity. However, her 4-month course, absence of a murmur or sick contacts, and the serologic profile point to a drug reaction, and cultures do not replace stopping the culprit drug.

Why each option

A.
Correct. Fever, arthralgia, myalgia, rash, anti-histone antibodies, negative anti-dsDNA, and normal complements after years of hydralazine indicate drug-induced lupus, treated by withdrawal.
B.
Biopsy is warranted only with hematuria, proteinuria, or declining function; her bland urinalysis and stable creatinine show no evidence of glomerulonephritis.
C.
Cultures help when fever suggests endocarditis, but a 4-month course without murmur and a classic drug-induced lupus serologic profile point to hydralazine.
D.
Glucocorticoids are reserved for drug-induced lupus persisting after withdrawal or organ-threatening hydralazine vasculitis; mild symptoms usually resolve once the drug stops.

Reference: Kumar B, Semin Arthritis Rheum 2018 (hydralazine-associated vasculitis); KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated Vasculitis

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