Autoimmune disorders arise from changes in the regulation of one or more components of immune response and involve multiple genetic, epigenetic, and environmental factors that play important roles in triggering and maintaining the process.

Drug-induced autoimmune syndromes have been recognized for some time. The classic example is drug-induced lupus erythematosus (DILE).

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin, but many drugs have been seen to induce lupus-like signs and symptoms. The resulting condition has been referred to variously as DILE, lupus-like syndrome, medicine-induced lupus erythematosus, or drug-related lupus. The condition develops in patients with no history of autoimmune disease and accounts for 10% to 15% of all SLE cases.2

The incidence of drug-induced autoimmunity has risen considerably in the last 10 years, and over 90 drugs have been implicated to date. The rapid rise in the number of culprit medications may be attributable to the introduction and use of newly developed drugs in the last 10 years. For example, biologic agents created to block specific phases of the immune response can trigger significant changes in the system. That drugs such as hydralazine, procainamide, isoniazid, quinidine, and chlorpromazine can cause DILE is unquestioned. The highest risk is associated with just 2 drugs: procainamide,3 which has been linked to DILE in around 20% of treated patients, and hydralazine,4 which has caused the disorder in 5% to 8% of patients treated at least a year according to standard dosing regimens. On the basis of the low number of cases linked to other drugs, it can be inferred that they seem to involve less risk.

Although diagnostic criteria are not well established for systemic DILE, it is widely defined as a disorder that resembles SLE but develops when a drug is being taken continuously for at least a month and that disappears when treatment is discontinued. Like lupus, DILE generally causes fever, musculoskeletal pain, and serositis. This clinical picture is usually accompanied by characteristic laboratory findings, specifically serum positivity for antinuclear antibodies (ANA) and antihistone antibodies (AHA). Idiopathic SLE can be difficult to distinguish from systemic DILE given that these 2 entities have similar clinical, serologic and histologic findings. The presence of certain serum markers, and especially resolution of symptoms when treatment with the culprit drug is discontinued, assist in establishing the correct diagnosis.

The incidence of DILE in the United States has been estimated to be somewhere between 15 000 and 30 000 new cases every year, meaning that the number of patients with this form may be about 10% to 15% of the number with idiopathic SLE.1 Whereas women with idiopathic SLE outnumber men, systemic DILE affects men and women in similar proportions.5 Patients with systemic DILE also tend to be older, as patients of advanced age are often prescribed more medications. The prevalence has also been shown to be 6-fold higher in white patients than in black patients.6 To date, the drug most often associated with systemic DILE is procainamide.

The etiology and pathogenesis of DILE remains to be fully elucidated, but this disorder probably arises from a combination of features specific to the culprit drug itself and others that are patient-related.

DILE differs from drug hypersensitivity reactions in several ways. First, no evidence of drug-specific T cells or antibodies has been found, nor have target autoantigens directly affected by the culprit drug been detected. Second, DILE develops in relation to the cumulative dose taken and it can take months or even years for symptoms to appear. Finally, symptoms generally take a day or 2 to reappear after rechallenge, indicating the absence of a specific hypersensitivity immune response. It is believed that the development of DILE requires a certain degree of genetic susceptibility, given that patients with relatives who have SLE are more likely to develop the drug-induced form. An individual's acetylator status, which is determined genetically, is also known to play a role.7 Slow acetylators are homozygous for the recessive gene that controls expression of the liver enzyme acetyltransferase, which is involved in the metabolism of certain implicated drugs, such as procainamide, isoniazid, and hydralazine. Slow acetylators treated with hydralazine or procainamide have also been reported to develop ANA positivity more quickly than fast acetylators and to progress to symptomatic DILE more often. The genetic susceptibility hypothesis recently gained ground after association with certain major histocompatibility complex (HLA) phenotypes. Certain HLA haplotypes—HLA-DR2, HLA-DR4, and HLA-DR3—as well as a slow acetylator phenotype and an unexpressed or “null” allele for C4 may be linked to the development of autoimmunity.8 It is also thought that certain events must occur in sequence before DILE develops.9 The drug must first undergo biotransformation to a pharmacologically reactive form. The resulting metabolites would have the ability to form stable complexes with self-macromolecules or to directly stimulate lymphocytes, initiating changes that significantly affect the immune system. In this process, activated neutrophils in the bloodstream have been shown to take part in the oxidative metabolism of many drugs implicated in DILE, facilitating the formation of metabolites that trigger autoimmunity10; drugs biotransformed in this way include procainamide, hydralazine, quinidine, phenytoin, sulfone, propylthiouracil, penicillamine, chlorpromazine, isoniazid, and carbamazepine. A strong correlation between a drug's susceptibility to myeloperoxidase-mediated oxidative transformation and the tendency of the drug to induce lupus erythematosus has been demonstrated.10

The formation of reactive metabolites with similar characteristics could explain why chemically and pharmacologically different drugs are able to induce similar clinical manifestations and trigger autoimmunity.

After these biotransformations, autoimmunity can then be triggered by either the drug itself or its metabolites. Various theories to explain this process have been put forth. One hypothesis postulates that drugs can cause DILE by altering T-cell cell DNA methylation,11 which has a primordial role in the regulation and expression of genes and cell differentiation. Drugs like procainamide and hydralazine decrease methylation by inhibiting DNA methyltransferase. Impaired DNA methylation in T cells would change their genetic expression and function. A second theory is that autoreactive B cells are activated by drug-specific T cells. A final hypothesis proposes that instead of stimulating mature T cells directly, the culprit drug subverts de novo acquisition of B-cell tolerance if it is present in the thymus as these cells develop.12,13 T cells are generated in the thymus throughout life, and the injection of a metabolite of procainamide into the thymus has been shown to lead to late formation of anti-([H2A-H2B]-DNA) metabolites.14 Many drugs are also believed to have the ability to interact with nuclear proteins such as histones,15 leading to the formation of molecules that would express new antigenic products, enhancing the production of AHAs. In addition, the molecular structure of certain drugs resembles that of purine bases, favoring a DNA cross-reaction.16 Anti-tumor necrosis factor (TNF) agents appear to cause autoimmune reactions by other mechanisms. According to some hypotheses, anti-TNF antibody binding to the cell surface induces apoptosis,17 causing the release of antinucleosome antibodies and the induction of anti-double-stranded DNA (anti-dsDNA) antibodies. Another theory states that anti-TNF agents would cause a change in the helper T (TH) cell profile. TH2 cytokines are thought to play a role in SLE by activating B cells. Anti-TNF agents block the TNF TH1 cytokine, possibly driving a shift in the immune system toward a TH2 profile with production of antibodies and the development of lupus-like symptoms. The last hypothesis postulates that bacterial infections promoted by anti-TNF therapy could provide the stimulus for polyclonal B-cell activation and consequent release of antibodies.18

In discussing the etiology and pathogenesis of drug-induced subacute cutaneous lupus erythematosus (DISCLE), Sontheimer and colleagues19 recently pointed out that most of the drugs implicated in this disorder also cause photosensitivity or a lichenoid photosensitive reaction. The authors noted that this would explain a photoinduced isomorphic response in immunogenically predisposed individuals. Another possibility along the same line is that cutaneous inflammation from a photosensitive drug can change the innate immune response, leading to a local increase in type 1 interferon (IFN) production by dendritic cells. The result of dysregulation is an imbalance in the cascade (e.g., the production of CXCL9, CXCL10, and CXCL11 and consequent CXCR3-mediated recruitment of cytotoxic T cells); this process occurs in most conditions involving interface dermatitis, including SLE.

The clinical spectrum of DILE ranges from circumscribed cutaneous signs to systemic involvement, which is usually mild.2 The onset of DILE is usually insidious, and the clinical picture varies widely.

DISCLE

The clinical and laboratory findings are similar in DISCLE and the idiopathic form of subacute cutaneous lupus erythematosus. Both conditions are more prevalent in women, but patients with the drug-induced form are usually older.26 The latency period between starting the drug and the onset of symptoms ranges from 4 to 20 weeks. Cutaneous signs include an eruption of papulosquamous lesions in sun-exposed areas, such as the face, neck and throat, and the outer surface of the arms (Fig. 1); lesions may take an annular form (Figs. 2 and 3) and they resolve within weeks or months without leaving scars.27 DISCLE lesions may also be more widely disseminated, extending to unexposed skin areas such as the lower third of the back.

Figure 1.

A 29-year-old woman with a history of epilepsy and carbamazepine-induced subacute lupus erythematosus that first appeared 9 years earlier. A, Note the intense papulosquamous psoriasiform lesions on the chest and face. B, Significant eruption on the upper arm and forearm, with poikilodermal areas. C and D, Large erythematous, scaly plaques covering the back and a large portion of the abdomen. The culprit drug could not be discontinued because epileptic seizures were poorly controlled with alternatives.

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Figure 2.

A 54-year-old woman with a history of epilepsy and subacute lupus erythematosus after treatment with oxcarbazepine started 2 months earlier. A, B, and C, Scaly, erythematous annular lesions on the lumbar region of the back, shoulder, and arms, respectively. Symptoms resolved 3 months after the antiepileptic drug was discontinued.

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Figure 3.

A 79-year-old woman with a history of metastatic ovarian cancer. The back lesions are clinically and histopathologically compatible with subacute lupus erythematosus of 2 months’ duration. The patient reported having taken bisoprolol in recent months, and the lesions resolved after the drug was stopped.

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Some authors note that blistering lesions are more common in DISCLE than in the idiopathic form of subacute cutaneous lupus.28 Noncutaneous manifestations, such as arthritis, serositis, and visceral organ involvement are not normally seen in DISCLE.29 Anemia and low white blood cell or platelet counts are very rarely found. Symptoms improve in most patients 8 weeks after withdrawal of the drug and anti-Ro antibodies disappear by 8 months.26

Chronic Cutaneous DILE

The clinical manifestations of chronic cutaneous DILE are the classic discoid lesions in sun-exposed areas like the face, upper trunk, and arms (Fig. 4). As in the idiopathic form of this disease, systemic manifestations are usually absent. The literature indicates that some 8 months pass between initiating treatment with the culprit drug and the onset of symptoms. Clinical manifestations typically resolve about 5 weeks after withdrawal of the drug.30

Figure 4.

A and B, An 82-year-old man with scaly, erythematous lesions on the face and arms that appeared 9 months earlier. Histopathology was compatible with chronic discoid lupus. The patient had been treated with hydrochlorothiazide. The lesions resolved several months after treatment was discontinued.

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Systemic DILE should be suspected whenever a patient on continuous therapy for months or years becomes ANA positive and develops at least one of the characteristic symptoms of idiopathic SLE. A diagnosis of DILE must be made in a patient without a history of SLE and without serious kidney or neurologic disease. Suspicion is confirmed if clinical and immunologic changes disappear once the drug is withdrawn. Most patients with systemic DILE do not fulfill the 4 diagnostic criteria of the American Association of Rheumatology for SLE. Serology is also an important diagnostic tool. Circulating AHA, particularly antibodies to the (H2A-H2B)-DNA complex are typically detected; anti-dsDNA, anti-smooth muscle, anti-RNP, anti-Ro, and anti-La antibodies are absent. Unlike idiopathic SLE, systemic DILE does not usually present with low complement levels. Standard diagnostic criteria have not been established, but a series of characteristic findings that aid diagnosis of systemic DILE have been proposed, as follows:

• 1.

  Ongoing treatment (of at least 1 month) with a drug.

• 2.

  No prior history of SLE before the drug was started.

• 3.

  Fever, arthritis, general malaise, and muscle pain.

• 4.

  Positive findings for AHAs (especially IgG antibodies to the [H2A-H2B]-DNA complex) and for anti-single-stranded DNA antibodies. Negative findings for anti-extractable nuclear antigen antibodies.

Antigen positivity tends to have resolved months after the culprit drug is discontinued. ANA-positive seroconversion in a patient being treated with a drug that can potentially trigger systemic DILE does not necessarily mean treatment must stop, as only a small percentage of cases progress to lupus. Diagnostic criteria for the subacute and chronic cutaneous forms are not well defined. Skin lesions after a challenge test with the suspected drug is a strong indicator, but this finding has seldom been reported in the literature. These diagnoses are more likely to be made if the lesions have developed for the first time and are clinically and histologically similar to those of cutaneous lupus in middle-aged or elderly patients, if they coincide with taking a medication that has been prescribed recently, and if they improve following discontinuation of the drug. The immunologic work-up in some of the DISCLE cases we have reviewed shows that anti-Ro antibodies are more prominent than AHA antibodies, whose role is more doubtful in this type of lupus.

Although the usefulness of epidermal (patch) tests in diagnosing DILE has not been evaluated, they can be helpful in differential diagnosis to rule out other early-stage toxicodermal diseases, such as Stevens-Johnson syndrome (toxic epidermal necrolysis) or DRESS syndrome (drug reaction with eosinophilia and systemic symptoms). One recent study found these tests to be useful in cases caused by carbamazepine, a drug that can also cause DILE.90

DILE is managed by discontinuing the drug that triggered the condition. Pharmacotherapy should be reserved for refractory cases, which are usually seen in patients who actually had pre-existing lupus that became exacerbated on exposure to a drug. Although cutaneous manifestations normally disappear within weeks of discontinuing the culprit drug, complete resolution can take several months, making it necessary to provide medical treatment. The cutaneous lesions, such as vasculitis, can be temporarily treated in either DISCLE or systemic DILE by prescribing systemic corticosteroids at the doses indicated for idiopathic lupus; topical corticosteroids and hydroxychloroquine can also be used. Refractory cases can be managed with immunosuppressant agents such as thalidomide, azathioprine, cyclophosphamide, or mycophenolate-mofetil. The chronic cutaneous form can also be treated with topical corticosteroids and hydroxychloroquine, a combination that is usually effective. Further treatment with systemic corticosteroids and thalidomide should be reserved for cases that remain refractory.

DILE is similar to idiopathic lupus but occurs as a result of exposure to an increasing number of drugs. As new therapies are developed for a multitude of diseases, the incidence of this autoimmune disorder is expected to rise significantly, especially as immunomodulators gain ground in the market. Clinical and serologic manifestations normally resolve after withdrawal of the culprit medication. In addition to systemic DILE, there are 2 cutaneous forms of the disease—one chronic and the other subacute (i.e., DISCLE). Whereas the chronic form is rare, the subacute form is considered the most prevalent DILE.

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Confidentiality of data. The authors declare that they have followed the protocols of their hospital concerning the publication of patient data, and that all the patients mentioned were appropriately informed and gave their written informed consent.

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The authors declare that they have no conflicts of interest.