AUTHOR INFORMATION

Section 1 of 11

Authored by C Lisa Kauffman, MD, Professor, Chief, Division of Dermatology, Departments of Medicine and Pathology, Georgetown University Medical Center

Coauthored by Arden E Fredeking, BA, Georgetown University School of Medicine

C Lisa Kauffman, MD, is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Royal Society of Medicine, Society for Investigative Dermatology, and Women's Dermatological Society

Edited by Craig A Elmets, MD, Director of Dermatology, Departments of Dermatology, Professor, Pathology, Environmental Health Sciences, The Kirklin Clinic, University of Alabama at Birmingham; Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center; Jeffrey P Callen, MD, Chief, Division of Dermatology, Professor of Medicine (Dermatology), Department of Internal Medicine, University of Louisville School of Medicine; Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital; and Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center

Author's Email:	C Lisa Kauffman, MD
Editor's Email:	Craig A Elmets, MD

eMedicine Journal, April 10 2007, VOLUME 8, Number 4

INTRODUCTION

Section 2 of 11

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, isoniazide, 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, genetic predisposition may play a role as 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 Drugs that cause DILE), others may cause a flare of preexisting LE (see Drugs that cause flares of SLE). Drugs such as procainamide, and chloropromazine, and quinidine cause the production of anti-nuclear antibodies against the histone dimer H2A-H2B. Hydralazine forms ANAs to H1 and the H3-H4 complex. Drugs that cause DILE usually take months to years to bring on the associated symptoms, while
flares of LE 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.

Drugs that cause DILE are as follows:

• Acebutolol

• Amiodarone

• Bupropione

• 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

• Olanzipine

• Ophthalmic timolol

• Oral Contraceptives

• Penicillamine

• Phenytoin

• Practolol

• Procainamide

• PTU

• Quinidine

• Reserpine

• Rifampin

• Simvastatin

• Sulfasalazine

• Tetracycline

• Ticlopidine

• Tiotropium bromide inhaler

• Trimethadione

• Tumor necrosis factor

• Valproate

• Voriconazole

Drugs that cause flares of SLE are as follows:

• 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. It is unclear exactly which characteristics of a drug cause the auto-antibody formation but there are a couple theories. One, is that the drug serves as a substrate for myeloperoxidase that is activated in PMNs. This interaction causes the formation of reactive metabolites that directly affect lymphocyte function. A second theory is that with decreased T-cell methylation there is an overexpression of LFA-1 (lymphocyte function-associated antigen). T-cells with hypomethylated DNA become autoreactive and cause antibody formation. This is the mechanism by which UV light causes flares of lupus. Thirdly, the genetic differences in a persons p450 system causes drugs to be metabolized differently causing 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.

Comparison of Findings Between DILE and SLE

Findings	SLE	DILE
Clinical	Average age of onset of 20-30 y Affects blacks more than whites Female-to-male ratio of 9:1	Average age of onset of 50-70 y Affects whites more than blacks Female-to-male ratio of 1:1
Laboratory	Antihistone antibodies in 50% Anti-dsDNA present in 80% C3/C4 levels decrease Cutaneous findings in >75% Raynaud phenomenon in 50% Antinuclear antibodies in >95%	Antihistone antibodies in >95% Anti-ssDNA present Anti-dsDNA rare C3/C4 levels normal Cutaneous findings in ~25% Raynaud phenomenon in 25% Antinuclear antibodies in >95%
Immunofluorescence Histopathology	Direct immunofluorescence reveals granular deposition of immunoglobulin G at dermoepidermal junction Lymphohistiocytic interface dermatitis Apoptosis basal vacuolization	Same as SLE Same as SLE

Frequency:

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

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

Section 3 of 11

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. This rash appears 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 Image 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)
  
  
  

DIFFERENTIALS

Section 4 of 11

Lupus Erythematosus, Discoid
Lupus Erythematosus, Subacute Cutaneous
Neonatal Lupus Erythematosus

Other Problems to be Considered:

Renal idiopathic lupus
Systemic

WORKUP

Section 5 of 11

Lab Studies:

• Test for the presence of antinuclear antibodies, which can appear in a homogeneous pattern in as many as 90% of patients with LE.


• • When anti-ssDNA and anti-dsDNA are measured, the prevalence of anti-ssDNA is higher. This is a major difference from SLE; in SLE, antibodies tend to attack double-stranded DNA.
  
  
  
  • Antinuclear antibodies with homogeneous patterns are produced by procainamide, isoniazid, timolol, hydralazine, and phenytoin.
  
  
  
  • In contrast, speckled antinuclear antibody patterns are associated with anti-SSA/Ro antibodies, which can be produced in response to thiazide diuretics such as hydrochlorothiazide.
  
  
  
  • In persons with DILE, the antibodies also tend to attack histones (proteins typically found in cell nuclei); antihistone antibodies are indicated by a homogeneous pattern of antinuclear antibodies. They are present in more than 75% of patients with DILE induced by hydralazine and procainamide.
  
  
  
  • One example of an antihistone antibody that is often implicated in DILE is immunoglobulin G (anti-[H2A-H2B] DNA). Antihistone antibodies are much more likely to indicate DILE; however, they can also appear in up to 50% of patients with SLE.
  
  
  
  • In persons with DILE, anti-Sm antibodies are rare. Complement levels are within the reference range, which is not usually the case in persons with SLE.
  
  
  
• Further tests in the workup of a patient with possible DILE are as follows:


• • Urinalysis can be performed to evaluate for hematuria and proteinuria.
  
  
  
  • A BUN and creatinine evaluation is indicated.
  
  
  
  • C3 and C4 levels should be tested. Complement levels are often reduced in persons with SLE, as opposed to those with DILE; they tend to not be reduced in persons with DILE.
  
  
  
  • A complete blood cell count should be performed to evaluate for anemia, which is present in most patients with SLE but is rare in those with DILE.
  
  
  
  • Liver function tests to can be performed to evaluate for hepatic involvement.
  
  
  

Imaging Studies:

• Use chest radiography to rule out pulmonary infiltrates.



• Use echocardiography, if indicated, to rule out pericarditis.

Procedures:

• Skin biopsy



• Renal biopsy if renal involvement is suggested

TREATMENT

Section 6 of 11

Medical Care: Symptoms usually clear within weeks of stopping the culprit drug; however, residual antibodies may persist for extended periods after discontinuation of the identified causative agent. Generally, no other specific treatments are known.

• If patients with DILE are given anti-inflammatory medication, this may result in misdiagnosis because the symptoms may be masked.



• Low doses of systemic corticosteroids may be prescribed for short periods if the symptoms of DILE are severe (eg, polyarthritis resulting in debilitating inflammation in many joints simultaneously).

Activity: No specific activity restrictions are recommended. Normal activity may resume when arthralgias and myalgias resolve.

FOLLOW-UP

Section 7 of 11

Further Outpatient Care:

• Monitor antinuclear antibody levels, anti-ssDNA, anti-dsDNA, antihistone antibody levels, serum complement levels, and urinalysis findings.



• Continue to monitor cardiac, renal, and pulmonary function if any of these were initially involved.

Complications:

• In rare instances, patients may die of renal involvement.

Prognosis:

• Prognosis is excellent once the causative medication is discontinued. Recovery generally occurs within days or weeks.

Patient Education:

• For excellent patient education resources, visit eMedicine’s Blood and Lymphatic System Center and Arthritis Center. Also, see eMedicine’s patient education articles Lupus (Systemic Lupus Erythematosus) and Drug Allergy.

MISCELLANEOUS

Section 8 of 11

Medical/Legal Pitfalls:

• Failure to diagnose renal involvement: Death from DILE is extremely rare but may result from renal involvement (eg, membranous proliferative and necrotizing glomerulonephritis)

TEST QUESTIONS

Section 9 of 11

CME Question 1: Which of the following should be preliminarily confirmed for a proper diagnosis of drug-induced lupus erythematosus (DILE)?

A: The patient has one or more clinical symptoms of systemic lupus erythematosus. No prior history of systemic lupus erythematosus is reported before the patient began using a particular isolated drug.
B: Antinuclear antibodies are present.
C: The drug was taken anytime from 3 weeks to 2 years prior to the appearance of symptoms.
D: Improvement is rapid when the patient stops taking the drug, while antinuclear antibodies and other serologic markers slowly decrease toward normal levels.
E: All of the above

The correct answer is E: Following the above diagnostic algorithm prior to diagnosing the patient with DILE, rather than systemic lupus erythematosus, is extremely important.

CME Question 2: Rare cases of fatal drug-induced lupus erythematosus (DILE) are probably due to the failure of which of the following organ systems?

A: Rheumatological
B: Dermatological
C: Renal
D: Cardiac
E: Pulmonary

The correct answer is C: Although drug-induced, rare cases of fatal DILE might more appropriately be diagnosed as renal idiopathic lupus.

Pearl Question 1 (T/F): The most common cause of drug-induced lupus erythematosus (DILE) is prescription drugs originally taken for treatments unrelated to DILE.

The correct answer is True: Other possible causes include sensitivity to insecticide compounds, certain metallic compounds, or eosin (fluorescent acid dye found in some lipsticks).

Pearl Question 2 (T/F): The most effective way to treat correctly diagnosed drug-induced lupus erythematosus (DILE) is to advise the patient to stop taking the identified drug.

The correct answer is True: Advising the patient to stop taking the identified drug is not only the most effective way, it also is the only known cure for DILE. Symptoms should clear within a few weeks or months, although tests may subsequently indicate higher levels of antibodies for longer periods. If symptoms do not clear within a few months of stopping the drug, then the disease is probably not DILE. The most likely other candidate is systemic lupus erythematosus (SLE), which may require systemic therapy. This is an important reason why SLE should be excluded before diagnosing a patient with DILE and stopping the individual drugs.

Pearl Question 3 (T/F): Drug-induced lupus erythematosus (DILE) cannot occur from anti-inflammatory medications taken to treat systemic lupus erythematosus (SLE).

The correct answer is False: As many as 10% of cases of new-onset lupus erythematosus may be DILE. SLE and DILE can occur simultaneously.

Pearl Question 4 (T/F): Drug-induced lupus erythematosus (DILE) can arise from drugs prescribed to treat medical conditions other than systemic lupus erythematosus (SLE).

The correct answer is True: DILE can arise from drugs prescribed to treat medical conditions other than SLE, such as antiarrhythmics (eg, procainamide, quinidine) and antibiotics (eg, minocycline, isoniazid).

PICTURES

Section 10 of 11

Caption: Picture 1. Erythematous macules and papules are seen on the face, upper chest, and arms in a photodistribution.
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Caption: Picture 2. The dermis contains an interface and a superficial and deep perivascular lymphohistiocytic infiltrate (100X, hematoxylin and eosin stain).
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Caption: Picture 3. Parakeratosis, apoptosis, and basal vacuolization (200X, hematoxylin and eosin stain).
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BIBLIOGRAPHY

Section 11 of 11

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• Callen, JP.: Subacute cutaneous lupus erythematous induced or exacerbated by terbinafine: a report of 5 cases. Archives of Dermatology 2001; 137: 1196.
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• Shen GQ, Shoenfeld Y, Peter JB: Anti-DNA, antihistone, and antinucleosome antibodies in systemic lupus erythematosus and drug-induced lupus. Clin Rev Allergy Immunol 1998 Fall; 16(3): 321-34[Medline].
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