Drug-Induced LupusDz

ICD-9 Code: 710.0;
ICD-10 Code: M32.0

Definition: Drug-induced lupus is an uncommon complication of several commonly used medications. It is characterized by development of lupus-like symptoms, ANA positivity, and symptom resolution upon withdrawal of the offending drug. Drug-induced lupus differs from SLE by affecting an older population with milder symptoms and by having a different autoantibody profile (i.e., fewer autoantibodies) and a more favorable outcome.

Etiology: Numerous drugs have been implicated in causing drug-induced lupus (Table 11). Mechanisms underlying this disorder remain unclear but may involve either (a) similarities between drug and self antigens, resulting in immunologic cross-reactivity; (b) drug-induced alteration in immunogenicity of autoantigens (i.e., drugs may react with histones or deoxyribonucleoprotein); or (c) altered immunoregulation by drug or its metabolites.

Risk Factors: Other factors may contribute to the onset of drug-induced lupus. The slow acetylator phenotype clearly increases the risk of hydralazine- induced ANA positivity and drug-induced lupus but is less important in procainamide- and isoniazid-associated drug-induced lupus and does not appear to influence the risk of drug-induced lupus owing to other drugs or idiopathic SLE. There are few genetic associations with drug-induced lupus. Only HLA- DR4 has been suggested to be linked with hydralazine-induced lupus.

Pathology: CNS and renal findings are rare in drug-induced lupus. However, other lupus manifestations and pathology may occur in drug-induced lupus and be pathologically indistinguishable from SLE, including ANA positivity, LE cells, inflammatory pleuritis, pericarditis, and synovitis.

Demographics: Drug-induced lupus affects a greater percentage of males, whites, and the elderly than does idiopathic SLE (Table 12). For all implicated drugs, the incidence of drug-induced ANA positivity alone is far greater (often two- to fivefold more common) than the actual drug-induced lupus syndrome. Prevalence varies for each drug, and reliable rates have only been reported for hydralazine and procainamide, the most commonly associated drugs. The rates of drug-induced lupus are dose related for hydralazine and time dependent for procainamide. Between 60% and 90% of patients taking procainamide for >12 months develop ANA positivity, and roughly one-third of these develop drug-induced lupus. Approximately 60% or more of patients treated with TNF inhibitors will be found to have a positive ANA, and approximately 10% to 15% will have a positive anti–double-stranded DNA if these are checked on multiple occasions during the course of therapy; however, cases of drug-induced lupus related to these agents are uncommon. Rates of ANA positivity approach 50% for those taking 400 mg/day of hydralazine or more, but only 10% develop drug-induced lupus. With lower doses of hydralazine, lower percentages are seen. The incidence of ANA positivity in those treated with isoniazid, methyldopa, chlorpromazine, or quinidine ranges from 10% to 30%, yet very few develop clinical features of drug-induced lupus syndrome. Drug-induced lupus caused by minocycline has only been seen after prolonged exposure (>12 months) to the antibiotic.

Cardinal Findings: Most patients present with insidious onset of constitutional features (e.g., low-grade fever, fatigue, anorexia, weight loss, arthralgias, or myalgias). However, the pattern of organ involvement differs from that of idiopathic SLE (Table 11).
—Renal: Kidney involvement is rare in drug-induced lupus and has only been sporadically described with hydralazine-induced lupus. Such findings include sporadic proteinuria, abnormal urinary sediments, impaired creati- nine clearance, or biopsy-proven nephritis. Most of these findings tend to resolve with drug withdrawal.
—CNS: CNS involvement is very rare in drug-induced lupus. There are few reports of neuropathy.
—Skin: Lupus skin findings (e.g., malar rash, oral ulcers, photosensitivity, vasculitic skin lesions) are uncommon in most patients with drug-induced lupus, with the notable exception of drug-induced lupus related to TNF inhibitors.

—Musculoskeletal: As in SLE, articular findings are common. Myalgias, arthralgias, and synovitis tend to be symmetric and polyarticular and involve the knees and fingers. Polymyalgia rheumatica has also been described. Because most patients receiving TNF inhibitors have inflammatory arthritis, it is difficult to ascribe musculoskeletal symptoms to drug-induced lupus in such patients.
—Pulmonary: Alveolar infiltrates are common in procainamide-induced lupus but are rarely seen with other implicated drugs (Table 11). Chronic interstitial lung disease has been described, but pulmonary hemorrhage has not.
—Serositis: Symptomatic pleural or pericardial effusions are common in drug- induced lupus, especially in procainamide-induced lupus. LE cells and ANA may be found in serosal fluids.

Uncommon Findings: CNS, renal, and lupus skin disease are uncommon. There have been uncommon reports of pericardial tamponade and constrictive pericarditis.

Diagnostic Tests: Requisite findings in drug-induced lupus include lupus clinical features in association with ANA positivity (or a positive LE cell preparation). Patients with drug-induced lupus have very high titers (e.g., >1:1,280) of ANA, often in a diffuse or speckled pattern. Such ANAs are directed toward deoxyribonucleoproteins (i.e., histones). Antihistone antibodies are commonly found in drug-induced lupus but are also seen in SLE and, therefore, cannot distinguish between the two. Nonetheless, antibodies against specific histone complexes have been identified for procainamide and sulfasalazine (against H2A-H2B), hydralazine (H3-H2A), and quinidine (H1-H2B). Antibodies against double-stranded DNA and complement levels should be negative or normal with the exception of drug-induced lupus related to TNF inhibitors. Leukopenia, lymphopenia, and Coombs-positive hemolytic anemia have all been well described in drug-induced lupus. Elevated ESR may been seen during active drug-induced lupus. Lupus anticoagulants and APL antibodies have frequently been reported, but thromboses and APL syndrome are rare.

Keys to Diagnosis: This diagnosis can be suspected in older adults taking an implicated drug who develop lupus-like features described above. Development of ANA alone does not suffice for the diagnosis or for withdrawal of the drug.

Diagnostic Criteria: Most patients meet the American College of Rheumatology criteria for the diagnosis of SLE, although this is not necessary. The diagnosis of drug-induced lupus can be established if there are (a) no history of SLE before drug exposure, (b) one or more clinical features of SLE in addition to ANA positivity, and (c) resolution of symptoms and ultimately the ANA with drug withdrawal. Rechallenge with the offending agent is not necessary.

Therapy: Most patients respond promptly to drug withdrawal and symptomatic therapy. Commonly, patients benefit from rest, analgesics, and possible NSAIDs when treating constitutional, articular, or serosal manifestations. Infrequently, corticosteroids are necessary to treat refractory pleural/pericardial effusions, pericardial tamponade, moderate to severe pneumonitis, or symptomatic hemolytic anemia. Pericardiocentesis or surgery is rarely necessary for pericardial tamponade.

Course: The vast majority experience rapid resolution of their symptoms on drug withdrawal. ANA positivity may persist for 6 to 12 months after cessation.

Comment: Drugs implicated in causing drug-induced lupus (Table 11) can be safely used in patients with idiopathic SLE without risk. Identification of ANA positivity alone (without clinical features of lupus) is not a sufficient reason to withdraw potentially beneficial therapy.

BIBLIOGRAPHY

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Schlienger RG, Bircher AJ, Meier CR. Minocycline-induced lupus. A systematic review. Dermatology 2000;200:223–231.PMID:10828631