Drug-induced lupus

INTRODUCTION — Certain drugs may trigger an autoimmune response; most often, these drugs induce autoantibodies, which may occur in a significant number of patients, but most of these patients do not develop signs of an autoantibody-associated disease. In some patients, a clinical syndrome with features similar to systemic lupus erythematosus (SLE) may develop, which is termed drug-induced lupus. As examples, procainamide and anti-tumor necrosis factor (TNF) therapies often cause increased levels of antinuclear antibodies (ANAs) in serum, yet few patients with these antibodies develop clinical symptoms such as rash, serositis, or arthritis suggesting drug-induced disease [1].

Drug-induced lupus has similarities to spontaneous SLE, but there are some differences in clinical and immunologic features and in the frequency of such features. The clinical and serologic pattern of disease is also often drug-specific, and a single pattern is not seen across all agents. A subset of patients will have a clinical syndrome that is more consistent with drug-induced subacute cutaneous lupus erythematosus (SCLE). A few other types of drug-induced cutaneous lupus have also been described.

This topic will review causes, pathogenesis, clinical manifestations, diagnosis, and approach to management of drug-induced lupus. The clinical manifestations, diagnosis, and treatment of idiopathic SLE in adults and in children are presented elsewhere. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Overview of the management and prognosis of systemic lupus erythematosus in adults" and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

EPIDEMIOLOGY — The demographic characteristics of drug-induced lupus largely depend upon the populations most likely to receive the relevant drugs. There are an estimated 15,000 to 30,000 cases of drug-induced lupus per year in the United States [2]. It is generally equally common in males and females, and more common in older adults and White populations [2,3]. An exception is minocycline-induced lupus, which is mostly observed in young women treated for acne.

The risk for developing drug-induced lupus varies substantially between different medications, ranging from 15 to 20 percent of those taking procainamide and 7 to 13 percent of those taking hydralazine, to as low as 2 per 1000 for those taking a tumor necrosis factor (TNF) inhibitor, and 5 per 10,000 of those taking minocycline [2]. However, the relative incidence of drug-induced lupus from each of these agents will depend upon the extent to which they are prescribed.

PATHOGENESIS

Mechanisms and risk factors — The mechanism or mechanisms involved in drug-induced lupus remain uncertain. However, various theories have been developed regarding the pathogenesis of drug-induced lupus [4]. Inherited differences in drug metabolism (eg, acetylator status) and immunogenetic characteristics are genetic factors that may influence the risk of developing disease. Potential disease mechanisms include:

●Abnormalities in oxidative drug metabolism

●Drugs acting as haptens or agonists for drug-specific T cells

●Cytotoxic drug metabolites causing pathology

●Drugs nonspecifically activating lymphocytes

●Drug metabolites disrupting central immune tolerance

●Abnormalities in thymus function

●Interference with cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed cell death receptor 1 (PD-1) immune checkpoint molecules [5]

●Abnormalities in innate immune responses, particularly neutrophilic responses such as engagement and formation of the "neutrophil extracellular trap" (NET) and exposure of autoantigens [6]

●Epigenetic mechanisms, with deoxyribonucleic acid (DNA) methylation changes in particular [7]

Multiple risk factors may be involved for a given agent. As an example, risk factors for hydralazine-induced lupus include drug dose (especially doses greater than 200 mg/day and/or a cumulative dose of more than 100 g), female sex, slow hepatic acetylation, and immunogenetic factors [8-11].

Regardless of the mechanism, the result has the hallmarks of autoimmunity, and the clinical manifestations result from immune-mediated effects upon the target organs. (See 'Clinical spectrum of drug-induced lupus' below.)

Genetic factors — Although the pathogenesis of drug-induced lupus is not well understood, genetic predisposition may play a role. For certain drugs, genetically determined effects upon drug metabolism are clearly important. Immunogenetic characteristics and other factors may also play a role.

●Immunogenetics – Possible genetic risk factors include human leukocyte antigen (HLA) DR4, HLA-DR0301, and the complement C4 null allele [3,10-12]. These factors vary between different agents. As examples:

•Immunogenetic risk factors for procainamide-induced lupus, which occurs more readily in slow acetylators, may include HLA-DR6Y, but not -DR4 or -DR3 [13].

•Risk factors for hydralazine-induced lupus include female sex, slow hepatic acetylation, the HLA-DR4 genotype, and the complement C4 null allele [8-11]. In one study, lupus developed in 19 percent of women taking 200 mg of hydralazine daily, compared with 13 of 13 women who also had the HLA-DR4 genotype [10]. These factors may interact; it is possible that slow acetylation increases free drug levels, while low levels of C4 might prevent clearance of any immune complexes that are formed [10].

•Patients with HLA-DQB1 and either HLA-DR2 or HLA-DR4 may be at increased risk of developing minocycline-induced lupus [14].

●Acetylator status – Drug-induced lupus is more likely to develop and develops sooner with certain drugs metabolized by acetylation in those patients who are slow acetylators, ie, those in whom there is a genetically mediated decrease in the hepatic synthesis of N-acetyltransferase [15-17]. Examples of such drugs include procainamide and hydralazine. (See 'Causative drugs' below.)

In contrast to the high degree of risk for drug-induced lupus with procainamide, particularly in slow acetylators, there is little or no antinuclear antibody (ANA) formation or symptomatic lupus following the administration of N-acetylprocainamide (NAPA), the major active metabolite of procainamide [18]; furthermore, remission of procainamide-induced lupus can be achieved by switching to NAPA [19]. These observations suggest an important pathogenetic role for the aromatic amino group on procainamide.

By comparison, acetylation rate is not a risk factor for idiopathic lupus [20]. Acetylation rate also seems unlikely to be related to the etiopathogenesis of disease related to other agents such as minocycline and the tumor necrosis factor (TNF) inhibitors.

CAUSATIVE DRUGS — Drugs associated with drug-induced lupus can generally be grouped in terms of their risk level or their probability of causing the disease.

The risk of drug-induced lupus varies across different medications. Drug-induced lupus-associated drugs have been classified as having a high (>5 percent), moderate (1 to 5 percent), low (0.1 to 1 percent), or very low (approximately 0.1 percent) risk of inducing drug-induced lupus [6,21,22].

●High risk – Drugs that have been associated with the highest risk of inducing drug-induced lupus in an individual patient include procainamide (15 to 20 percent incidence per year) [2] and hydralazine (5 to 10 percent incidence per year) [9].

●Moderate risk – Quinidine has been associated with a moderate risk of drug-induced lupus [23].

●Low risk – Drugs thought to be associated with a low risk include penicillamine, carbamazepine, methyldopa, sulfasalazine, minocycline, chlorpromazine, propylthiouracil, and isoniazid [24-27].

●Very low risk – Drugs associated with very low risk include statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) [28-30] and tumor necrosis factor (TNF) inhibitors (infliximab, etanercept adalimumab, golimumab, certolizumab) [31-35], as well as a variety of other miscellaneous drugs (isopropamide, propafenone, atenolol, clonidine, enalapril, labetalol, minoxidil, pindolol, prazosin, chlorpromazine, lithium carbonate, phenelzine, nitrofurantoin, ethosuximide, phenytoin, primidone, trimethadione, phenylbutazone, chlorthalidone, aminoglutethimide, levodopa, ophthalmic timolol, interferon alfa, and interleukin [IL] 2) [6].

Cases of possible drug-induced lupus secondary to trimethoprim/sulfamethoxazole have also been reported [36,37]. Rarely, cancer immunotherapy agents such as ipilimumab, nivolumab, and pembrolizumab have been associated with systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE), and lupus-like cutaneous reactions [31,38,39]. A more detailed discussion of rheumatologic complications of immune checkpoint inhibitors can be found elsewhere. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy".)

These drugs and others have also been classified in terms of probability of causing drug-induced lupus [6,15,16,21,40-44]:

●Definite – Medications identified as definitely causing drug-induced lupus include procainamide, hydralazine, minocycline, penicillamine, isoniazid, quinidine, anti-TNF therapy (most commonly with infliximab and etanercept), interferon alfa, methyldopa, chlorpromazine, and practolol [42,45,46].

●Probable – Medications identified as probable causes of drug-induced lupus include anticonvulsants (phenytoin, mephenytoin, trimethadione, ethosuximide, carbamazepine), antithyroid drugs, antimicrobial agents (sulfonamides, rifampin [47], nitrofurantoin), beta blockers, lithium, paraaminosalicylate, captopril, interferon gamma, hydrochlorothiazide, glyburide, sulfasalazine, terbinafine, amiodarone, ticlopidine, and docetaxel [45,47-52].

●Possible – Medications that are possible causes of drug-induced lupus include gold salts, penicillin, tetracycline, reserpine, valproate, statins (eg, lovastatin, simvastatin, and atorvastatin), griseofulvin, gemfibrozil, valproate, lamotrigine, ophthalmic timolol, and 5-aminosalicylate.

The drugs most likely to cause drug-induced SCLE differ from those most likely to cause typical drug-induced lupus and are discussed below. (See 'Subacute cutaneous lupus erythematosus' below.)

CLINICAL SPECTRUM OF DRUG-INDUCED LUPUS — Drug-induced lupus refers to a spectrum of drug-induced reactions similar to that of idiopathic systemic lupus erythematosus (SLE), but typically without the major organ-threatening complications. A subset of patients will have a clinical syndrome that is more consistent with drug-induced subacute cutaneous lupus erythematosus (SCLE). A few other types of drug-induced cutaneous lupus have also been described. Different drugs are associated with different clinical and serologic profiles for both drug-induced lupus and drug-induced SCLE.

Drug-induced lupus — Drug-induced lupus includes a spectrum of reactions characterized most commonly by a phenotype similar to that of idiopathic SLE, but usually without the major organ-threatening complications.

Clinical presentation — The most common symptoms of drug-induced lupus include fever, arthralgias/arthritis, myalgias, rash, and/or serositis. More severe manifestations, such as kidney disease and central nervous system involvement, are uncommon [2,15], although they may occur [11,53,54]. Certain drugs may be associated with different clinical and serologic profiles. As an example, pleuritis occurs in approximately half of the procainamide-induced lupus patients, 22 percent of those with quinidine-induced disease, and less than 1 percent of those with minocycline [2]. (See 'Drug-specific clinical profiles' below.)

Cutaneous manifestations are much less common in drug-induced lupus compared with idiopathic SLE, although SCLE is often drug-induced. Drug-induced discoid lupus has also been reported but appears rare [55,56]. (See 'Subacute cutaneous lupus erythematosus' below and 'Other types of drug-induced cutaneous lupus' below.)

Symptom onset generally develops after months to years of exposure, although onset may also be abrupt. Both hydralazine and procainamide have been reported as being associated with drug-induced lupus even >3 years after initiating treatment with the drug [57].

Characteristic laboratory findings and autoantibodies are discussed further below. (See 'Laboratory tests and characteristic autoantibodies' below.)

Drug-specific clinical profiles — The pattern of drug-induced lupus clinical profiles and serologies is largely drug-specific and may deviate from what has been taught based upon classical presentations of procainamide-induced and hydralazine-induced disease. The following examples illustrate the spectrum of clinical and laboratory findings that may occur with different agents implicated as causes of drug-induced lupus:

●Procainamide – Procainamide may be the most common cause of drug-induced lupus, which may be mediated by the reactive metabolite procainamide hydroxylamine. A positive antinuclear antibody (ANA) occurs in almost all patients given the drug for more than two years [8]; ANAs are more likely to develop and to develop earlier in slow acetylators [58]. Symptoms, however, develop in approximately one-third of those who have taken procainamide for more than one year [8]; the determining factors for susceptibility to symptomatic disease are not known [58,59]. Serositis typically occurs with procainamide and usually consists of pleuritis, with or without lung infiltrates, and is sometimes accompanied by pericarditis [60]. Antihistone antibodies are typically present in drug-induced lupus due to procainamide.

●Hydralazine – Clinical disease occurs in approximately 5 to 10 percent of patients receiving hydralazine [15,59]. Even low doses may not be safe, as clinical disease can develop in up to 5 percent of slow acetylators taking 100 mg/day [61]. Symptom onset may develop years later. The skin is involved in up to one-third of patients with drug-induced reactions due to hydralazine [57]. Hydralazine use can also be associated with an antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis involving the kidney, which is discussed in detail separately. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)

●Minocycline – Minocycline, unlike other tetracyclines, appears to cause a drug-induced lupus syndrome, particularly among young women being treated for acne [24,44,62-64]. The risk of developing drug-induced lupus from minocycline use is relatively low (hazard ratio 2.6 to 3.1), and the absolute risk is only approximately 1 in 1000 patients exposed [65]. Features of minocycline-induced lupus include arthralgia (73 to 100 percent), arthritis (12 to 45 percent), fever (38 percent), and rash (29 percent) [24]. Other clinical features that have been described are morning stiffness, myalgia, pneumonitis, and cutaneous vasculitis [44].

Laboratory evidence of liver involvement may be seen in 32 to 54 percent of patients with drug-induced disease [66].The autoantibody pattern differs from most other forms of drug-induced lupus. A positive ANA (including anti-double-stranded DNA [anti-dsDNA] antibodies) and perinuclear ANCA (P-ANCA) test has been found in 92 and 83 percent of tested sera, respectively; by comparison, antihistone antibodies are uncommon (0 to 13 percent) [66]. Most cases of minocycline-induced lupus resolve within a relatively short time after drug discontinuation; young children may be at increased risk for prolonged disease following minocycline exposure [67].

Unlike with most other agents that may cause drug-induced lupus, the author prefers to avoid use of minocycline in patients with established (idiopathic) SLE. (See 'Implications for patients with idiopathic systemic lupus erythematosus' below.)

●TNF inhibitors – Most cases of drug-induced lupus associated with the use of a tumor necrosis factor (TNF) inhibitor are characterized by skin and pleuropericardial abnormalities, along with the formation of autoantibodies such as those to dsDNA, Sm antigen, or histones. TNF inhibitor therapy with infliximab, adalimumab, and etanercept has been associated with the development of positive test results for ANAs (13 to 83 percent) and anti-dsDNA antibodies (3 to 32 percent) [43,68-70]. Such antibodies have also been reported in patients receiving golimumab and certolizumab pegol. In contrast to findings with other medications, antihistone antibodies are usually absent. Hypocomplementemia is occasionally observed [71]. The skin is involved in over 80 percent of cases induced by TNF inhibitors [34]. Renal and neurologic manifestations are extremely rare. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Systemic lupus erythematosus'.)

The proportion of patients who develop the de novo production of ANA or anti-dsDNA antibodies largely exceeds that of patients who develop drug-induced lupus; thus, the development of such antibodies should not be viewed as a sign of impending drug-induced lupus. As mentioned above, the frequency of drug-induced lupus is well below 1 percent (see 'Causative drugs' above). The high association with ANA formation often drives confusion among clinicians, resulting in withholding potentially effective therapies for patients. Anti-dsDNA antibodies induced by TNF inhibitors appear to be of predominantly immunoglobulin (Ig) M class, in contrast to primary SLE autoantibodies being predominantly of the IgG isotype [33,72]. It has been hypothesized that this may be associated with less pathogenic sequelae.

In most affected patients, drug-induced lupus associated with TNF inhibitor use resolves completely upon discontinuation of the TNF inhibitor. As an example, a case series of four patients who developed definite or probable drug-induced lupus while receiving etanercept had resolution of symptoms within two to six weeks of discontinuing therapy [45].

Subacute cutaneous lupus erythematosus — SCLE is drug-induced in a substantial proportion of patients who present with what is initially thought to be idiopathic SCLE and is distinct from the typical drug-induced lupus [73]. In one population-based case-control study involving 234 patients with SCLE, the condition appeared to be drug-induced in over one-third of patients [32]. The majority of patients with drug-induced SCLE (70 to 90 percent) were anti-Ro/SSA positive [32]. Drug-induced SCLE typically presents as an annular or psoriasiform, photodistributed cutaneous eruption. Additional information regarding drug-induced SCLE can be found separately. (See "Overview of cutaneous lupus erythematosus", section on 'Drug-induced subacute cutaneous lupus erythematosus'.)

The drugs most likely to induce SCLE include hydrochlorothiazide [74], calcium channel blockers (eg, diltiazem), and angiotensin-converting enzyme inhibitors [75]. Drugs such as statins, TNF inhibitors, and proton-pump inhibitors are also associated with drug-induced SCLE [76-79].

Additional reports suggest the following agents may also cause the syndrome: leflunomide, bupropion, acebutolol, various agents used to treat malignancies (capecitabine, uracil-tegafur, paclitaxel, docetaxel, tamoxifen, anastrozole, leuprolide, mitotane, palbociclib [80]), lamotrigine, and the antifungal agent terbinafine [2,3,6,32,49,81-84]. New onset or exacerbation of preexisting SCLE was noted after exposure to terbinafine in five patients [49]. SCLE has been associated with interferon alfa therapy in a case report [85]. Nivolumab, a cancer immunotherapy agent, has also been described as causing SCLE [86].

Other types of drug-induced cutaneous lupus

●Drug-induced chronic cutaneous lupus erythematosus – Chronic cutaneous drug-induced lupus is rare (including drug-induced discoid lupus) [55,56]. Reports have included association with tegafur, fluorouracil compounds, and TNF inhibitors [87].

●Other lupus-like cutaneous reactions – Lupus-like cutaneous reactions (in addition to SCLE) have been reported with cancer immunotherapy agents such as pembrolizumab [86,88,89]. Drug-induced lupus tumidus has also been reported in association with TNF inhibitors and other drugs [6].

DIAGNOSTIC APPROACH

Evaluation — The diagnostic evaluation of patients with suspected drug-induced lupus should be similar to that performed in patients suspected of idiopathic systemic lupus erythematosus (SLE). (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Evaluation'.)

History and physical examination — The history and physical examination is the same as that for SLE, with particular attention to the following symptoms and signs (see "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'History and physical examination'):

●Exposure to medications associated with drug-induced lupus (see 'Causative drugs' above)

●Constitutional symptoms such as low-grade fever, anorexia, weight loss, fatigue

●Musculoskeletal symptoms (arthralgias and/or arthritis, myalgia)

●Chest pain suggestive pericarditis

●Skin lesions

Laboratory tests and characteristic autoantibodies — Laboratory testing should include the following routine laboratory tests and antibody tests:

●Complete blood count and differential

●Complete metabolic panel

●Urinalysis with urine sediment

●Antinuclear antibody (ANA; ideally by indirect immunofluorescence testing)

●Anti-double-stranded DNA (anti-dsDNA) antibodies

●Antihistone antibodies

●Anti-Sm antibodies

●Anti-Ro/SSA and anti-La/SSB antibodies

●Anti-U1 ribonucleoprotein (RNP) antibodies

Antineutrophil cytoplasmic antibody (ANCA) should be obtained in patients who have been treated with minocycline, hydralazine, propylthiouracil, or methimazole [90]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)

Hematologic abnormalities commonly seen in idiopathic SLE such as leukopenia and thrombocytopenia are rare in drug-induced lupus. Hypocomplementemia is also uncommon in drug-induced lupus [10], except for quinidine-induced forms, in which low C3 and/or C4 levels have been described in up to one-third of cases [23]. Liver function abnormalities may occur and have been noted in 32 to 54 percent of patients with minocycline-induced lupus [2].

An important immunologic characteristic of drug-induced lupus is the presence of autoantibodies. The autoantibodies or patterns of autoantibodies that are seen largely depend upon the inciting agent:

●Antihistone antibodies – Antihistone antibodies are present in more than 95 percent of patients overall, among those taking procainamide, hydralazine, chlorpromazine, and quinidine; however, antihistone antibodies have been found in a smaller proportion of patients with drug-induced lupus associated with other medications, including minocycline, propylthiouracil, and statins (32, 42, and <50 percent, respectively) [91,92]. Importantly, antihistone antibodies are also seen in up to 80 percent of patients with idiopathic SLE [91,92]; however, patients with idiopathic SLE also form a variety of other autoantibodies, including those directed against DNA and small RNPs, which are less common in drug-induced lupus.

The antihistone antibodies in drug-induced lupus are primarily formed against a complex of the histone dimer H2A-H2B and DNA [40,58,59] and, with hydralazine, to the H1 and H3-H4 complex [91]. DNA is required either to stabilize the complex or perhaps to contribute part of the antigenic epitope [40]. Although the drugs that can cause drug-induced lupus are markedly heterogeneous, there may be a common pathway for disease induction since the antihistone antibodies produced in patients receiving procainamide, hydralazine, quinidine, acebutolol, penicillamine, isoniazid, and chlorpromazine are nearly identical in most [40], but not all, patients [59]. By contrast, the antihistone antibodies in idiopathic SLE are primarily directed against the H1 and H2B histone subunits [91].

The development of IgG antibodies to the complex of H2A-H2B and DNA soon after starting procainamide is associated with a high risk of developing drug-induced lupus; by comparison, autoantibodies to single-stranded DNA or to histones alone do not distinguish between symptomatic or asymptomatic individuals [93]. It is not known if these observations apply to other causes of drug-induced lupus.

●Anti-dsDNA antibodies – Anti-double-stranded DNA (anti-dsDNA) antibodies are typically absent in drug-induced lupus due to procainamide, hydralazine, and isoniazid, but these antibodies are associated with drug-induced disease with other agents, particularly with interferon alfa and anti-tumor necrosis factor (TNF) agents. With the latter class of anticytokine therapies, although the majority of patients may eventually develop ANAs and other autoantibodies, including anti-dsDNA antibodies, relatively few patients with any of these antibodies develop clinical manifestations of drug-induced lupus [94,95]. (See 'Drug-induced lupus' above.)

●Anti-Ro/SSA antibodies – The vast majority of patients (greater than 80 percent) with drug-induced subacute cutaneous lupus erythematosus (SCLE) have anti-Ro/SSA antibodies [96]. While not specific for drug-induced SCLE and seen in the context of other systemic autoimmune diseases, the presence of this antibody is expected in drug-induced SCLE presentations, and its absence should bring the diagnosis into question. Resolution of anti-Ro/SSA antibodies is also often observed after drug withdrawal in patients with drug-induced SCLE [82,97]. (See "Overview of cutaneous lupus erythematosus" and "Overview of cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.)

Diagnosis — There are no definitive tests or criteria for the diagnosis of drug-induced lupus; however, the diagnosis of drug-induced lupus is likely in the presence of the following:

●A history of taking one or more of the drugs known to be associated with this condition for at least one month, and often much longer (see 'Causative drugs' above), with the development of at least one clinical feature characteristic of SLE (see 'Drug-induced lupus' above). Patients typically exhibit some combination of arthralgia, myalgia, malaise, fever, serositis, and/or rash, but the diagnosis of drug-induced lupus does not require that a sufficient number of manifestations be exhibited to satisfy criteria for idiopathic SLE [15,98,99].

●A positive test for ANAs. Antihistone antibodies are strongly associated with some forms of drug-induced lupus but are also present in patients with idiopathic SLE. Anti-dsDNA antibodies are not found in most forms of drug-induced lupus. (See 'Laboratory tests and characteristic autoantibodies' above.)

●Resolution of the clinical manifestations of the disease, typically within several weeks but sometimes up to several months after the offending drug has been discontinued [99]. The ANAs often persist for a greater duration than the symptoms and physical findings, and in most patients, autoantibodies persist indefinitely.

The diagnosis of drug-induced SCLE can be made in patients with clinical findings characteristic of idiopathic SCLE that have developed in association with exposure to a medication known to cause this disorder, typically one to five months after initiating therapy, in whom the cutaneous changes and other associated findings resolve after discontinuation of the suspected offending agent. The presence of more widespread involvement than is typical of idiopathic SCLE should heighten suspicion of drug-induced SCLE. (See "Overview of cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.)

Differential diagnosis — The differential diagnosis of drug-induced lupus is broad; it includes the idiopathic (ie, spontaneous) forms of both SLE and SCLE and depends further upon the clinical manifestations that are present. It is thus highly similar to the differential diagnosis in patients suspected of idiopathic SLE as well as that of SCLE, which also includes other skin disorders with an annular or psoriasiform/papulosquamous morphology as well as a number of photodistributed dermatoses. Also included in the differential diagnosis is drug-induced ANCA vasculitis depending on the specific drug involved.

These differential diagnoses of SLE and SCLE are discussed in detail separately; however, we present some of the key features differentiating drug-induced lupus from the idiopathic diseases, as well as from drug-induced ANCA vasculitis, below. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Differential diagnosis' and "Overview of cutaneous lupus erythematosus", section on 'Acute cutaneous lupus erythematosus' and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)

●Idiopathic SLE – The differentiation from idiopathic systemic lupus erythematosus (SLE) may sometimes be difficult because of the number of different agents that can cause a positive ANA and may cause drug-induced lupus; and the frequent occurrence of arthralgia or arthritis, fever, and serositis with a positive ANA in both disorders. Features more suggestive of idiopathic SLE, and which are much less common in drug-induced lupus, include renal, neurologic, cutaneous, and severe hematologic involvement. Antihistone antibodies may be seen in both idiopathic and drug-induced lupus.

●Idiopathic SCLE – Several features are much more common in drug-induced than idiopathic subacute cutaneous lupus erythematosus (SCLE), although the clinical findings are not unique [97]. The cutaneous eruption in patients with drug-induced SCLE is frequently widespread in its distribution, which is uncommon in idiopathic SCLE. It is more likely to have bullous features and a vasculitic component. Additionally, anti-Ro/SSA antibodies are present in a high proportion of patients, but will disappear after resolution of the skin disease in approximately three-quarters of the patients in whom they are present. The presence of eosinophils on histopathology of the skin of SCLE does not appear to distinguish drug-induced from idiopathic forms [100].

●Drug-induced ANCA vasculitis – Drug-induced antineutrophil cytoplasmic antibody (ANCA) vasculitis can also be associated with some of the same drugs known to cause drug-induced lupus, which include hydralazine, minocycline, and propylthiouracil. In contrast to more typical drug-induced lupus, patients with hydralazine-induced vasculitis may have more severe kidney involvement and require cytotoxic or other immunosuppressive therapy as in other ANCA-positive vasculitides. Renal disease in drug-induced lupus is rare and usually due to a necrotizing glomerulonephritis with little or no immune complex deposition [54,101,102], although an immune complex-mediated glomerulonephritis can occur [53]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)

ANCA positivity can also be observed in idiopathic SLE in approximately 15 to 20 percent of patients, and occasionally in other systemic rheumatic diseases [103]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Nonvasculitic systemic rheumatic diseases'.)

MANAGEMENT

Discontinuation of offending medication — The initial step in management is to discontinue the offending medication. Drug-induced lupus typically resolves after discontinuation of the medication, but complete resolution may require weeks to months. Factors influencing the time to resolution include the type of drug, the extent of clinical manifestations, and patient characteristics [6]. Some experts suggest that lack of resolution of symptoms suggests the presence of preexisting systemic lupus erythematosus (SLE) that was unmasked by the medication.

Medical management in selected cases — Specific manifestations of drug-induced systemic or cutaneous lupus may be treated temporarily until they resolve using the same approaches as those used in patients with idiopathic SLE and subacute cutaneous lupus erythematosus (SCLE). There are no randomized trials that have examined the optimal treatment approach to drug-induced lupus, and the management is based upon the observational data and the experience of the authors and other experts that medications that are effective in idiopathic SLE and SCLE are also effective in patients with drug-induced illness [2,92,104], and that symptoms gradually resolve after drug discontinuation in most patients. The duration of treatment is guided by the clinical response, and the decision to discontinue or taper therapy is based on clinical improvement after cessation of the offending agent over weeks to months.

Examples of treatment approaches for drug-induced lupus include the following:

●Arthralgia and arthritis may be treated with nonsteroidal antiinflammatory drugs (NSAIDs). (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Treatment of arthritis'.)

●Hydroxychloroquine can be used temporarily if constitutional, cutaneous, and musculoskeletal symptoms do not clear within four to eight weeks. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Treatment of arthritis' and "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Treatment of specific SLE manifestations'.)

●Systemic glucocorticoids are infrequently required; however, they may be of benefit if used temporarily for patients with more severe pleurisy or pericarditis, for which they can usually induce quick resolution. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults", section on 'Course and treatment' and "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Treatment'.)

●Cutaneous lesions from drug-induced SCLE typically respond to topical therapies such as topical corticosteroids. (See "Initial management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus", section on 'Overview'.)

The evolution of the autoantibody profile should not be used as a guide to tailor therapy, since autoantibody titers typically remain positive long after the clinical remission of drug-induced lupus. (See "Initial management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus" and "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Approach to drug therapy'.)

We do not rechallenge patients with a medication that has been identified as a likely cause of drug-induced lupus in that individual.

PROGNOSIS

Outcomes — The prognosis of drug-induced lupus is generally quite favorable in most case series and in our experience, with disease typically resolving after drug withdrawal, even though management of specific manifestations (eg, with nonsteroidal antiinflammatory drugs [NSAIDs] or hydroxychloroquine) may be needed for up to several months in some patients [2,92,104]. Occasional patients require glucocorticoid therapy, but life-threatening disease is infrequent and may suggest idiopathic systemic lupus erythematosus (SLE)-like presentation [3]. (See 'Management' above.)

Implications for patients with idiopathic systemic lupus erythematosus — The safe use of drugs associated with drug-induced lupus in the patient with idiopathic SLE remains unclear, and there is little evidence to support the avoidance of these medications in the setting of SLE. The increasing use of tumor necrosis factor (TNF) inhibitors may offer some relevant insight into this dilemma. TNF inhibitor use is associated with a high rate of antinuclear antibody (ANA) induction, including anti-double-stranded DNA (dsDNA) antibody production, with reports of a positive ANA in greater than 50 percent of patients with prolonged exposure to anti-TNF therapy [105]. Despite this high rate of antibody induction, most are of the IgM subclass (seemingly less pathogenic), and clinical manifestations are rare and/or mild when they occur. Transient autoantibody formation in the setting of medication use does not seem to correlate with SLE flares acutely [106]. Rare lupus nephritis has been reported in the setting of anti-TNF use.

A conservative approach to the SLE patient receiving any medications previously reported to cause drug-induced lupus is to observe for clinical evidence of increased disease activity, including novel organ manifestations, as well as with appropriate laboratory monitoring (see "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Laboratory evaluation'). More data are needed to compare the safety of short-term medication exposure in this group with longer-term exposure risk.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic lupus erythematosus".)

SUMMARY AND RECOMMENDATIONS

●Definition and epidemiology – Certain drugs may trigger an autoimmune response, which in some patients may result in a clinical syndrome with features similar to systemic or cutaneous lupus erythematosus, termed drug-induced lupus. Most commonly, these drugs induce autoantibodies without causing a clinical disorder. Drug-induced lupus has similarities to spontaneous (idiopathic) systemic lupus erythematosus (SLE), but there are some differences in clinical and immunologic features and in the frequency of such features. (See 'Introduction' above and 'Epidemiology' above.)

●Causative drugs – Drugs associated with drug-induced lupus can generally be grouped in terms of their risk level or their probability of causing the disease. The drugs associated with the highest risk of inducing lupus in an individual patient are procainamide, hydralazine, and penicillamine. Other medications identified as definitely causing drug-induced lupus include minocycline, diltiazem, isoniazid, quinidine, tumor necrosis factor (TNF) inhibitors, interferon alfa, methyldopa, chlorpromazine, and practolol. A variety of agents have been implicated as probable or possible, but not definite, causes of drug-induced lupus, including anticonvulsants, antithyroid drugs, antimicrobials, and others. (See 'Causative drugs' above.)

●Clinical spectrum

•Drug-induced lupus – The most common manifestations include fever, myalgias, arthralgias, arthritis, and serositis. The frequency of these manifestations vary with the drug. Hematologic abnormalities and more severe manifestations, such as kidney disease and central nervous system involvement, are uncommon, although they can occur. Liver function abnormalities have been noted, especially in patients with minocycline-induced lupus. Cutaneous manifestations are much less common in drug-induced (systemic) lupus compared with idiopathic SLE, although subacute cutaneous lupus erythematosus (SCLE) is often drug-induced. (See 'Drug-induced lupus' above.)

•Subacute cutaneous lupus erythematosus – SCLE may be drug-induced in a substantial proportion of patients, and drug-induced SCLE is distinct from the typical drug-induced lupus syndrome. The majority of patients with drug-induced SCLE are anti-Ro/SSA-positive. Drug-induced SCLE typically presents as an annular or psoriasiform, photodistributed cutaneous eruption. Medications most often associated with SCLE include hydrochlorothiazide, calcium channel blockers, angiotensin-converting enzyme inhibitors, statins, TNF inhibitors, and proton-pump inhibitors. (See 'Subacute cutaneous lupus erythematosus' above.)

●When to suspect drug-induced lupus – Drug-induced lupus should be suspected when a patient taking one or more of the suspect drugs for at least one month, and usually much longer, presents with some combination of arthralgias/arthritis, myalgia, malaise, fever, rash, and/or serositis. At least one feature typical of SLE should be present, but patients with drug-induced lupus often do not exhibit a sufficient number of manifestations to satisfy criteria for idiopathic SLE. (See 'Evaluation' above.)

●Evaluation – The diagnostic evaluation of patients with suspected drug-induced lupus should be similar to that performed in patients suspected of idiopathic SLE. (See 'Evaluation' above.)

•History and physical examination – The history and physical examination should include attention to exposure to medications associated with drug-induced lupus; constitutional symptoms (eg, low grade fever, weight loss, fatigue); arthralgias/arthritis or myalgia; chest pain suggestive of pericarditis; skin lesions. (See 'History and physical examination' above.)

•Laboratory tests and characteristic autoantibodies – The autoantibodies or patterns of autoantibodies that are seen largely depend upon the inciting agent, but for certain drugs may include antinuclear antibodies (ANAs) that have specificity for histone proteins, while with disease due to other drugs, antibodies that are more often associated with idiopathic SLE (eg, anti-double stranded [anti-dsDNA] antibodies) or with systemic vasculitis (eg, antineutrophil cytoplasmic antibodies [ANCAs]) may be present. (See 'Laboratory tests and characteristic autoantibodies' above.)

●Diagnosis – There are no definitive tests or criteria for the diagnosis of drug-induced lupus; however, the diagnosis of drug-induced lupus is likely in the presence of the following (see 'Diagnosis' above):

•A history of taking one or more of the drugs known to be associated with this condition for at least one month, and often much longer, with the development of at least one clinical feature characteristic of SLE. Patients typically exhibit some combination of arthralgia, myalgia, malaise, fever, serositis, and/or rash.

•A positive test for ANAs. Antihistone antibodies are strongly associated with some forms of drug-induced lupus but are also present in patients with idiopathic SLE. Anti-dsDNA antibodies are not found in most forms of drug-induced lupus.

•Resolution of the clinical manifestations of the disease, typically within several weeks but sometimes up to several months after the offending drug has been discontinued. The ANAs often persist for a greater duration than the symptoms and physical findings, and in most patients, autoantibodies persist indefinitely.

●Management – The initial management of drug-induced systemic or cutaneous lupus requires discontinuation of the offending medication. Drug-induced lupus typically resolves after discontinuation, but complete resolution may require weeks to months. Specific manifestations of drug-induced systemic or cutaneous lupus may be treated temporarily until they resolve using the same approaches as those used in patients with idiopathic SLE and SCLE. (See 'Medical management in selected cases' above.)

●Prognosis – The prognosis is generally quite favorable, with disease typically resolving after drug withdrawal, even though treatment may be needed for up to several months in some patients. (See 'Outcomes' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.