Drug-induced autoimmune disease of the kidney

Drug-induced autoimmune diseases of the kidney include SLE-like disease and drug-induced vasculitis (DIV). As many as 10% of all diagnosed Lupus cases in the US may be drug-induced Lupus (DIL).


These syndromes typically develop after drug treatment for a prolonged period of time (at least 6 months and up to decades). Symptoms often include rash, fever, arthralgias, myalgias, serositis, vasculitis / glomerulonephritis and pulmonary hemorrhage. The diseases often resolve upon cessation of the drug.


Many drugs were implicated in triggering autoimmunogenicity including:

• Hydralazine
• Isoniazid
• Procainamide
• Methimazole
• Prophylthiouracil
• Etanercept
• Carbamazepine
• Phenytoin
• Methyldopa
• Minocycline
• Sulfasalazine
• Penicillamine
  

The incidence of DIL with long-term Hydralazine therapy has been reported to be as high as 5% and in some studies even higher.

1. DIL is of later onset than SLE, affects males and females equally and presents in general with less severe symptoms. Anti nuclear antibodies (ANA) are often directed against Histones and rarely against dsDNA. Some proposed drug-induced pathomechanisms are hypomethylation leading to T cell activation, change of nucleosomes by epitope liberation, macrophage inhibition causing decreased uptake of apoptotic cells and last but not least genetic predisposition. Case reports suggest that family members of affected patients are at higher risk for developing a drug-induced auto-immune response.

2. Drug-induced vasculitis (DIV) typically involves antibody formation against more than one cytoplasmic neutrophil antigen leading typically to a perinuclear staining pattern (p-ANCA). Cytoplasmic antigens identified include MPO (Myeloperoxidase), HLE (Human Leucocyte Elastase), Azurocidin, Cathepsin G and Lactoferrin.

Differences between DIV vs. idiopathic disease include significantly higher titers of anti-MPO and multi-specific ANCA (more than one target Antigen in addition to MPO). One proposed pathomechanism is that certain drugs transform into highly cytotoxic metabolites in presence of neutrophils triggering autoimmunogenicity and thereby ANCA formation.

These tables summarize the difference between drug-induced vs. idiopathic disease:

Drug-induced lupus vs. SLE

• Anti-histone Ab: common vs. rare
• Anti-dsDNA Ab: rare vs. common
• ANCA: common (multiple Antigens) vs. rare
• Anti-phospholipid Ab: common vs. common
• Immune complexes: can be seen vs. common
  

Drug-induced vasculitis vs. Idiopathic vasculitis

• Anti-histone Ab: can be seen vs. absent
• Anti-dsDNA Ab: absent vs. absent
• ANCA: common (multiple Ag) vs. common (single Ag)
• Anti-phospholipid Ab: common vs. rare
• Immune complexes: rare vs. absent