Case Report: Drug-Induced Lupus & ANCA-Associated Vasculitis Overlap

A biopsy of the buccal mucosa revealed stratified squamous epithelium and underlying subepithelial connective tissue with marked acute and chronic inflammation, ulceration and necrosis. 

Stains for cytomegalovirus and herpes simplex virus were negative, and GMS and gram stains were negative for fungal elements and pathogenic bacteria. Mild perivascular inflammation was noted, but overt vasculitis was not seen. Features of Stevens-Johnson syndrome were also absent.

The renal biopsy revealed diffuse mesangial matrix expansion consistent with diabetic glomerulosclerosis class IIb (without nodular glomerulosclerosis) and very focal acute segmental necrotizing glomerulonephritis affecting 1 of 70 glomeruli in paraffin sections. 

Immunofluorescence stains were negative for IgG, IgA, kappa light chain, lambda light chain, C3 and C1q. Weak mesangial deposition of IgM was noted. Mild tubular epithelial injury was present, and there were focal red blood cell casts. Approximately 12% of glomeruli were global sclerotic (12/99 glomeruli in the specimen), and there was 10% interstitial fibrosis with tubular atrophy. 

Overall, the renal biopsy was consistent with ANCA-associated vasculitis given the presence of MPO-ANCA and the findings of pauci-immune complex deposition. However, the presence of serum anti-histone antibodies was consistent with drug-induced lupus. 

The patient was treated with 1,000 mg of intravenous methylprednisolone daily for five days, then switched to 60 mg of prednisone daily and tapered thereafter. With this treatment, her hematuria and proteinuria considerably improved, and her C3 and C4 levels normalized. 

Although hydralazine was discontinued, the patient’s condition remained active on a tapered dose of steroids. At that time, the patient was started on 375 mg/m² rituximab weekly for four doses. Following this additional immunosuppression, her renal function normalized and her anemia resolved.

1A: Glomerulus with moderate global mesangial matrix expansion consistent with moderately advanced diabetic nephropathy (without nodular glomerulosclerosis) is noted.

1B: Focal glomerulus with segmental fibrinoid necrosis with extracapillary proliferation and red blood cells casts consistent with necrotizing, pauci-immune, ANCA-associated glomerulonephritis are noted. Bar=20 μm.

Conclusion 

Hydralazine is a common medication for congestive heart failure and hyper­tension that has been associated with systemic autoimmune conditions including drug-induced lupus, ANCA-associated vasculitis and leukocytoclastic vasculitis. It is thought that hydralazine accumulates in the intra­cytoplasmic neutrophilic granules, which in turn, leads to binding of myeloperoxidase and ultimately causes release of cytotoxic products and cell death. Once these neutro­phils undergo cell death, antigens that are normally sequestered are exposed. This exposure leads to uptake by antigen-presenting cells, leading to production of ANCA.^2,3