eMedicine Specialties > Dermatology > Connective Tissue Diseases

Lupus Erythematosus, Drug-Induced

Author: C Lisa Kauffman, MD, FACP, Professor, Chief, Division of Dermatology, Departments of Medicine and Pathology, Georgetown University Medical Center
Coauthor(s): Arden E Fredeking, BA, Georgetown University School of Medicine
Contributor Information and Disclosures

Updated: May 24, 2007

Introduction

Background

Lupus erythematosus (LE) is an autoimmune disease that can affect the skin, joints, heart, lungs, kidneys, and brain. Drug-induced LE (DILE) is a variant of autoimmune disease that resolves within days to months after withdrawal of the culprit drug in a patient with no underlying immune system dysfunction. Care must be taken to correctly diagnose the symptoms of DILE and differentiate it from the systemic autoimmune disease, and DILE should be recognized clinically and serologically for prompt intervention.

DILE can arise months to years after exposure to drugs prescribed to treat a variety of medical conditions (eg, antihypertensives, antibiotics, anticonvulsants). The most common drugs that cause DILE are hydralazine, procainamide, quinidine, isoniazid, diltiazem, and minocycline.

Although both systemic LE (SLE) and DILE are autoimmune disorders and can have similar clinical and laboratory features, research suggests different mechanistic pathways. Although the pathogenesis of DILE is not completely understood, a genetic predisposition may play a role, as has been shown with certain drugs metabolized by acetylation, such as procainamide or hydralazine. Varying mechanisms leading to the formation of self-recognizing antibodies may explain the differential characteristics of drug effects in persons with DILE and LE. For example, whereas some drugs can cause DILE (see the list Drugs that cause DILE, below), others may cause a flare of preexisting SLE (see the list Drugs that cause flares of SLE, below).

Drugs such as procainamide, chlorpromazine, and quinidine cause the production of antinuclear antibodies against the histone dimer H2A-H2B. Hydralazine forms antinuclear antibodies to H1 and the H3-H4 complex. Drugs that cause DILE usually take months to years before the associated symptoms occur, while flares of SLE due to drugs may occur within hours to days.

DILE is characterized by improvement upon withdrawal of the offending drug or agent in a patient with a previously normal immune system. No specific criteria establish the diagnosis of DILE, and excluding underlying autoimmune disease is not a simple process. Obvious clinical or serologic evidence of DILE is not invariably present, even in rare cases of fatal DILE. Patients who have serologic and clinical findings that normally would indicate SLE might actually have DILE. The symptoms of both drug-induced flares of SLE and DILE are temporally related to drug exposure, and SLE and DILE have similar manifestations. Thus, DILE is typically diagnosed by a process of elimination to rule out SLE.

Although both LE and DILE can affect multiple organ systems, including the skin, joints, kidneys, and CNS, complications of DILE that affect the kidneys and CNS are generally considered rare. In DILE induced by certain drugs, however, the rate of kidney involvement can be significant. For example, the rate of glomerulonephritis in hydralazine-induced DILE is 5-10%. Penicillamine is also more likely to be associated with renal disease. Rare cases of death associated with DILE have been reported as a direct result of renal complications. Thus, a renal biopsy may be necessary to rule out membranous proliferative and necrotizing glomerulonephritis. Hepatic necrosis is another potential serious complication of DILE and has been documented in cases of minocycline-induced DILE.

For proper diagnosis, the following factors should be preliminarily confirmed:

• The patient has 1 or more clinical symptoms of SLE (eg, arthralgias, lymphadenopathy, rash, fever).
• Antinuclear antibodies are present.
• The patient had no history of SLE prior to using the culprit drug.
• The drug was taken anytime from 3 weeks to 2 years prior to the appearance of symptoms.
• Clinical improvement is rapid when the drug is discontinued, while antinuclear antibodies and other serologic markers slowly decrease toward more normal levels.

• Acebutolol
• Amiodarone
• Bupropion
• Captopril
• Carbamazepine
• Chlorpromazine
• Diltiazem
• Docetaxel
• Ethosuximide
• Gemfibrozil
• Glyburide
• Gold salt
• Griseofulvin
• Hydantoins
• Hydralazine
• hydroxychloroquine
• Interferons
• Interleukins
• Isoniazid
• Leuprolide acetate
• Lithium
• Lovastatin
• Mephenytoin
• Methyldopa
• Minocycline
• Nitrofurantoin
• Olanzapine
• Ophthalmic timolol
• Oral contraceptives
• Penicillamine
• Phenytoin
• Practolol
• Procainamide
• Propylthiouracil
• Quinidine
• Reserpine
• Rifampin
• Simvastatin
• Sulfasalazine
• Tetracycline
• Ticlopidine
• Tiotropium bromide inhaler
• Trimethadione
• Tumor necrosis factor
• Valproate
• Voriconazole

• Cimetidine
• Hydralazine
• Hydrochlorothiazide
• Mesantoin
• P -Aminobenzoic acid (PABA)
• Penicillin
• Phenylbutazone
• Sulfonamides
• Terbinafine

Pathophysiology

Both SLE and DILE are autoimmune diseases that cause the immune system to manufacture autoantibodies against the patient's own tissues. Which drug characteristics cause the autoantibody formation is unclear, but several theories have been proposed.

One is that the drug serves as a substrate for myeloperoxidase, which is activated in polymorphonuclear neutrophils. This interaction causes the formation of reactive metabolites that directly affect lymphocyte function. A second theory is that with decreased T-cell methylation, an overexpression of lymphocyte function – associated antigen (LFA-1) occurs. T cells with hypomethylated DNA become autoreactive and cause antibody formation. This is the mechanism by which UV light causes flares of lupus. A third theory is that the genetic differences in an individual’s P450 system causes drugs to be metabolized differently, which results in the generation of toxic metabolites that may facilitate autoimmunity.

The medications and other exposures implicated in DILE and flares of SLE produce autoantibodies more often than systemic autoimmune symptoms. Despite these commonalities, research suggests that DILE and SLE have separate and distinct mechanistic pathways.

Molecular mimicry between antibodies directed against infectious agents (eg, bacteria, Epstein-Barr virus) and self-antigens has been implicated in SLE. These theories hold that in SLE, the immune system generates autoantibodies to foreign antigens and, in turn, these autoantibodies attack the patient's own tissues.

Autoantibodies in DILE are thought to be generated by a different mechanism than molecular mimicry. Metabolites of drugs that cause DILE are subjected to oxidative metabolism by neutrophils, creating reactive metabolites. Virtually all lupus-inducing drugs have been shown to undergo oxidative metabolism, while analogous non–lupus-inducing drugs do not undergo oxidation. The drug metabolite, in turn, is thought to trigger reactions in the thymus that prevent T cells from developing tolerance to the patient's own tissues. In a mouse model, reactive metabolites of procainamide injected into the thymus have been shown to result in lupuslike autoantibodies. Unlike in drug hypersensitivity reactions, this process takes months to years of drug exposure for symptoms to develop.

The production of autoimmune T cells is initiated in the thymus by the capacity of reactive drug metabolites to disrupt central T-cell tolerance. Both mouse model and human studies implicate thymic activity, possibly indicating the persistence of thymic activity into advanced adult life.

Predisposing factors to the development of DILE include a slow drug-acetylator phenotype and advancing patient age. Slower acetylation may play a role in the greater predisposition for elderly persons to develop DILE. Higher rates of DILE in elderly persons, however, is also likely due to decreased drug clearance and increased medication usage in these individuals.

Biologics such as interleukins (eg, interleukin 2), interferons (eg, alfa, gamma, beta), and tumor necrosis factor (TNF) (eg, TNF-alpha) inhibitors are associated with musculoskeletal symptoms and antibody production suggestive of a lupuslike autoimmune disorder. In one study, approximately 14% of rheumatoid arthritis patients treated with anti–TNF-alpha developed anti-DNA antibodies, while less than 1% developed lupuslike symptoms. In another study, TNF-alpha protected against the development of lupus nephritis in a mouse model of SLE.

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Frequency

United States

As many as 10% of the approximately 500,000 cases of LE may be DILE.

Mortality/Morbidity

Death from DILE is extremely rare and may result from renal involvement. In diagnosing DILE, first excluding the possibility of renal idiopathic lupus rather than DILE is extremely crucial.

Race

More whites than blacks develop DILE; more blacks than whites present with SLE.

Sex

In DILE, no significant statistical difference is apparent in the prevalence for males versus females. In contrast, SLE affects women with considerably higher frequency than men (female-to-male ratio of 9:1).

Age

Patients with DILE tend to be older (50-70 y) than those with SLE (average age 29 y at diagnosis). Elderly persons generally are more susceptible to DILE.

Clinical

History

• Most patients have 1 or more clinical symptoms of SLE (eg, arthralgias, lymphadenopathy, rash, fever) and have had no prior history of autoimmune disease. If a rash is present, it often manifests as a polycyclic, scaling, erythematous rash in sun-exposed areas.
• • Approximately 50% of patients have constitutional symptoms of fever, weight loss, and fatigue.
  • As many as 90% of patients with DILE have severe but usually noninflammatory joint pain; however, synovitis may be present.
  • Arthralgia is often the only clinical manifestation of DILE.
• As many as 50% of patients with DILE experience muscle pain (myalgia).
• The drug was taken anytime from 3 weeks to 2 years prior to the appearance of symptoms. Importantly, note that drug-associated exacerbations of SLE and typical drug hypersensitivities can also be temporally related to drug exposure.
• Clinical improvement is usually rapid when the drug is discontinued, while antinuclear antibodies and other serologic markers slowly decrease toward more normal levels.
• Generally, the absence of CNS and renal involvement is more suggestive of DILE than SLE. High rates (ie, 5-10%) of glomerulonephritis, however, occur in hydralazine-induced DILE, and rare cases of death from renal involvement in DILE have been reported.

Physical

• Extracutaneous physical findings can include the following:
• • Splenomegaly
  • Hepatomegaly
  • Inflammation of the serous membranes that surround the lungs and pleural cavity walls (pleurisy)
  • Fever
  • Inflammation of the fibroserous membranes that cover the heart and the initial part of the great vessels (ie, pericarditis)
  • Cerebritis (rarely)
  • Nephritis (rarely)
• Skin findings are apparent in approximately 25% of all patients diagnosed with DILE. Importantly, note that certain manifestations typical in persons with SLE are not usually observed in persons with DILE. Patients with DILE (unlike patients with SLE) typically do not have the following:
• • Mucosal ulcers
  • Hair loss (alopecia)
  • Circular (discoid) plaques
  • Photosensitivity (with the exception of thiazide-induced subacute lupuslike syndrome)
• Compared with SLE patients, patients with DILE present with a higher prevalence of the following:
• • Purpura
  • Erythema nodosum (painful nodules, usually on the extremities)
  • Erythematous papules (typically on sun-exposed areas; see Media File 1)
• Lymphadenopathy or Raynaud phenomenon is present in approximately 35-50% of patients with SLE but in less than 25% of those with DILE.
• More than 75% of patients with SLE also have cutaneous findings, versus an average of less than 25% in patients with DILE. However, in both SLE and DILE, approximately 75% of patients have arthritis or arthralgia.
• Patients with DILE also occasionally exhibit skin findings that are analogous to those manifested in patients with subacute cutaneous LE, such as erythematous annular or scaly plaques.

Causes

DILE may be induced by medications or caused by other compounds in the environment. The most common drugs that cause DILE are hydralazine (rate roughly 20%), procainamide (rate roughly 20%, 5-8% if taken for 1 y), quinidine, and minocycline.

• Several broad drug categories have been linked to DILE.
• • Antiarrhythmics - Procainamide and quinidine
  • Antibiotics - Minocycline and isoniazid
  • Antifungals - Griseofulvin and voriconazole
  • Anticonvulsants - Valproate, ethosuximide, carbamazepine, and hydantoins
  • Hormonal therapy - Leuprolide acetate
  • Antihypertensives - Hydralazine, methyldopa, and captopril
  • Anti-inflammatories - Penicillamine and sulfasalazine
  • Antipsychotics - Chlorpromazine
  • Cholesterol-lowering agents - Lovastatin, simvastatin, and gemfibrozil
  • Biologics - Interleukins (eg, interleukin 2), interferons (eg, alfa, beta, gamma), and TNF inhibitors (eg, TNF-alpha)
  • Inhalers - Tiotropium bromide inhaler
  • Other drug categories - Ophthalmic timolol
• A genetic predisposition may play a role. Hydralazine-induced DILE has been observed with increased frequency in association with HLA-DR4.
• Intrinsic genetic susceptibility may help explain why some patients experience DILE as a reaction to drug therapies, while others do not. For example, the rate of acetylation is genetically predetermined. In the United States, the population is almost evenly divided between those who are fast acetylators and those who are slow acetylators. Those with slow acetylation rates have a higher prevalence of DILE than those with faster acetylation rates. In contrast, SLE affects individuals with slow and fast acetylation rates approximately equally.
• Other causes may induce DILE in certain individuals for no apparent reason, such as sensitivity to the following:
• • Insecticide compounds
  • Certain metallic compounds
  • Eosin (a fluorescent acid dye found in some lipsticks)

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