Correspondence *University of Cincinnati, Division of Immunology, 231 Albert B Sabin Way, Cincinnati, OH 45267-0563, USA

Email anne.mongey@uc.edu

Introduction

Autoantibodies and autoimmune diseases such as drug-related lupus (DRL) can occur following exposure to certain drugs. An important feature of DRL is a temporal association between the ingestion of an agent and the development of lupus-like features, with remission of the features and decreased autoantibody titers following withdrawal of the offending agent. Recurrence of the lupus-like features following reintroduction of the agent would provide confirmatory evidence, although this is seldom done in clinical practice. Many patients develop autoantibodies while taking certain medications, but only a minority develop lupus-like features.¹ Hence, the development of antinuclear antibodies (ANAs) or other autoantibodies in the absence of clinical features is insufficient to make a diagnosis, and is not a sufficient cause for discontinuing the medication. Procainamide was believed to be the commonest cause of DRL, with ANAs developing in up to 90% of patients, of whom approximately 30% developed DRL;¹ however, because of the lack of prospective studies, it is difficult to predict the incidence of DRL associated with other medications. Thus far, over 90 medications have been implicated in the development of DRL (Box 1). There is no evidence that these medications precipitate flares of disease in patients with systemic lupus erythematosus (SLE), or that patients who develop DRL are at increased risk of developing SLE.

Box 1 Medications associated with drug-related lupus.

Typical features of DRL include constitutional symptoms, arthralgias or arthritis, myalgias, serositis, elevated erythrocyte sedimentation rates and ANA positivity, which is generally accepted as a requirement for the diagnosis. Features take weeks to months to develop following exposure to the medication. Apart from hydralazine-related lupus, the development of DRL seems to occur independently of drug dosage. Withdrawal of the offending agent generally leads to significant improvement in symptoms within days or, rarely, weeks, but autoantibodies tend to persist for months or even years. The staining pattern of the ANAs is typically homogeneous, which represents binding to chromatin (which consists of DNA and histones), although speckled patterns have also been reported. Antibodies to histones, and in particular to the H2A–H2B–DNA complex and chromatin, are associated with certain types of DRL.^{2, 3, 4, 5} Antibodies to double-stranded DNA (dsDNA) have been considered a rare finding in DRL and tend to favor a diagnosis of idiopathic SLE, although they are associated with the use of tumor necrosis factor (TNF) inhibitors. The autoantibody profile associated with DRL is more restrictive compared with the multitude of autoantibodies observed in SLE.⁶

Minocycline

The tetracycline antibacterial agent minocycline was first implicated as a causative agent of DRL in 1992, and over 50 further cases have been reported since then.^{7, 8, 9, 10, 11, 12, 13, 14, 15, 16} In contrast to other forms of DRL, a similar gender profile to that of idiopathic SLE has been observed; most cases have occurred in young women being treated for acne. In a case–control study of 27,688 acne patients, current users of minocycline had a relative risk of 8.5 for development of DRL compared with previous and nonusers of tetracycline combined.¹⁵ Current exposure to minocycline and a cumulative dose of over 100 defined daily doses increased the risk 16-fold. Among females, there were 17.2 cases of DRL per 100,000 prescriptions for oxytetracycline and 52.8 cases per 100,000 prescriptions for minocycline, suggesting that minocycline is more likely to induce DRL than oxytetracycline.

The most frequently reported features of minocycline-related lupus include constitutional symptoms, rash, polyarthralgias, inflammatory arthritis affecting the small joints of the hands, wrists, shoulders and ankles, and autoimmune hepatitis.^{8, 13, 14, 16} Pleuropulmonary involvement, thrombocytopenia, anemia and cutaneous involvement, such as livedo reticularis, subcutaneous nodules, erythema and urticaria, have also been noted.^{7, 9, 12, 13, 16} Autoimmune hepatitis occurs in most men who develop minocycline-related lupus.⁷

ANA titers varying from 1:80 to 1:1280 are a common finding, although they might only be transiently present in some patients.^{7, 10, 13, 16} Antibodies to cardiolipin and dsDNA occur less frequently, and antihistone antibodies are not commonly seen. Patients are often positive for perinuclear antineutrophil cytoplasmic antibodies (pANCAs) at titers of 1:160 or greater with activity directed to myeloperoxidase or elastase, or both, which might be a marker for the development of DRL in genetically susceptible individuals who are prescribed minocycline.^{10, 16}

The duration of minocycline therapy prior to the onset of symptoms varies from a few weeks to 10 years. Resolution or significant improvement of the clinical features occurs in most cases within 2–56 weeks of drug withdrawal, although some patients require steroid therapy;^{10, 11} autoimmune hepatitis tends to resolve more slowly.⁷ There is no correlation between duration of minocycline treatment and the time taken for resolution of the symptoms. Although serological features also improve, some patients might remain ANA positive.

Patients rechallenged with minocycline generally develop a recurrence of their symptoms within a few hours to a few days of restarting the medication.^{7, 10} Six patients who initially denied taking minocycline developed a recurrence of symptoms after a mean of 4.5 days (range 2–7 days) of restarting minocycline treatment. Thus, denial of previous minocycline use does not rule out the possibility of minocycline-related lupus, and supervised rechallenge might be helpful for confirming the diagnosis.

Sulfasalazine

There are a number of reports implicating the aminosalicylate sulfasalazine in the development of DRL, although the association is unclear. Gunnarson et al.¹⁷ reported that 4 out of 41 consecutive patients treated with sulfasalazine developed DRL. A prospective study by Gordon and colleagues,¹⁸ however, reported that although 14 (19%) of 72 patients treated with sulfasalazine who were either ANA negative or weakly ANA positive at the start of the study became strongly ANA positive during the study, no patient developed a lupus-like syndrome. Hence, although the association between sulfasalazine and DRL is unclear, one should consider the possibility of DRL in a patient with rheumatoid arthritis (RA) who develops apparent 'flare-ups' of their arthritis while receiving this drug.

Statins

Lupus-like syndromes have also been reported in association with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). There have been 12 reported cases of the development of lupus-like syndromes related to statin therapy, which have included lovastatin, simvastatin, pravastatin and fluvastatin.^{19, 20, 21, 22, 23, 24} All patients had a high titer of ANAs, varying from 1:160 to 1:1280 with both homogeneous and speckled patterns reported. Patients remained ANA-positive for many months after discontinuation of statin treatment, despite improvement in clinical symptoms. Antihistone antibodies were positive in six patients and negative in four patients; antibodies to dsDNA occurred in three patients. Clinical features included myalgias, polyarthralgias, polyarthritis, leukopenia, photosensitivity, serositis, and focal segmental glomerulosclerosis, and fibrotic lung disease in one patient. Most patients were treated with prednisone, resulting in slow resolution of their symptoms. One patient developed severe autoimmune hepatitis, rash, polyarthralgias, ANAs, antihistone antibodies, and was strongly positive for anti-dsDNA antibodies while receiving atorvastatin.²⁴ Biopsy of the rash in this patient confirmed the diagnosis of lupus, and a liver biopsy revealed highly active chronic hepatitis that did not respond initially to high-dose steroid therapy, but improved when treated with mycophenolate mofetil and tacrolimus.

There have been three cases of subacute cutaneous lupus erythematosus related to the use of pravastatin and simvastatin:²² all three patients were positive for ANAs, had interface dermatitis with perivascular and periadnexal lymphocytic infiltrates, and responded to topical steroids. The lupus band test, which is an immunofluoresence test that aids in the diagnosis of cutaneous lupus, was positive for two patients and negative for the third patient. There are also reports of 14 patients with statin-related polymyositis and dermatomyositis, of whom 11 had muscle biopsies that revealed perivascular and perifascicular T-cell inflammation. Anti-Jo-1 antibodies were present in three of these patients. Most patients required treatment with immunosuppressive agents; five patients remained positive for ANAs, despite improvement in clinical features. Statins have been demonstrated to have a number of immunomodulatory activities that might have a role in the pathogenesis of statin-induced lupus.²²

Aromatase inhibitors

Increasing numbers of patients are receiving aromatase inhibitors for the treatment or prevention of breast cancer. Clinical trial data indicate that the use of these medications is associated with a higher incidence of arthralgias and inflammatory arthropathies compared with patients treated with placebo or tamoxifen.

The ATAC (Arimidex, Tamoxifen, Alone or in Combination) Trials group reported that 27.8% of patients receiving anastrozole (1 mg/day) developed musculoskeletal disorders (no specific details were provided), which is a significantly higher frequency than is seen in patients treated with tamoxifen (20 mg/day) or placebo.²³ In a study of 5,187 women who had completed 5 years of tamoxifen (20 mg/day) for the treatment of breast cancer, 21.3% of patients subsequently treated with letrozole (2.5 mg/day) developed arthralgias and 5.6% developed arthritis, compared with 16.6% and 3.5%, respectively, of patients who received placebo.²⁴ The symptoms were generally low grade, with few women discontinuing the study because of adverse effects. Coombes et al.²⁵ reported that 33% of women receiving exemestane (25 mg/day) developed "aches or pains" and 5.4% developed arthralgias, compared with 29.4% and 3.6%, respectively, for the tamoxifen (20 mg/day) group in a double-blind, randomized trial that switched patients to either exemestane or tamoxifen after 2–3 years' therapy with tamoxifen. In a study of 77 patients with metastatic breast cancer, 12 patients (16%) developed arthralgias, primarily involving the hands, knees, hips, lower back and shoulders, within 2 months of starting anastrozole treatment (1 mg/day).²⁶ Of these patients, four (5%) discontinued anastrazole because of the severity of the arthralgias, which subsequently resolved. Bonneterre et al.²⁷ reported that 6.3% of patients developed "bone pain" while receiving anastrozole (1 mg/day), compared with 6.1% of patients receiving tamoxifen (20 mg/day) in their double-blind, multicenter, randomized study of 668 patients receiving these drugs as first-line treatment for advanced breast cancer. In a study of 551 patients with advanced breast cancer who were previously treated with antiestrogens, 8.5% of patients receiving 0.5 mg once daily of letrozole and 13.2% of those receiving 2.5 mg once daily of letrozole developed arthralgias, compared with 7.9% of those patients receiving megestrol acetate (160 mg/day).²⁸ The increased incidence of arthralgias among the patients receiving the higher dose of letrozole would suggest a possible dose-related effect. With the increased use of these agents, clinicians should be aware of the possibility of a drug-related effect in patients presenting with arthralgias or inflammatory arthritis who are receiving aromatase inhibitors.

Tumor necrosis factor inhibitors

Treatment with TNF inhibitors has been associated with the development of ANAs, antibodies to dsDNA, and lupus-like syndromes. Autoantibodies have been detected in patients with RA, Crohn's disease and spondyloarthropathy, suggesting that the development of these antibodies is independent of the disease background; however, the lupus-like syndromes have primarily been reported in patients with RA, which might be because of the relatively large number of RA patients treated with these agents compared with the other diseases. Alternatively, patients with RA might have an immunogenetic susceptibility to this syndrome.

The incidence of ANAs in patients treated with TNF inhibitors is variable, ranging from 23% to 57%, with most ANAs having activity directed against chromatin.^{29, 30} The incidence of antibodies to dsDNA varies from 9% to 33%, but antihistone antibodies, although reported, do not seem to be a common feature. In the Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) study, antibodies appeared at a mean of 6.5 weeks following initiation of treatment without any correlation with infliximab dosages.²⁹

In a placebo-controlled trial of 156 patients with RA, the incidence of ANAs increased from 30% to 53%, and anti-dsDNA antibodies from 0% to 14%, in patients treated with infliximab (Table 1).³¹ By contrast, only one patient who received placebo developed ANAs and none developed anti-dsDNA antibodies. In a prospective trial, with a mean follow-up of 20.5 months, 8 of 26 RA patients treated with infliximab developed ANAs.³² In another study (Table 1), ANAs developed in 19 of 62 patients with RA and 25 of 35 patients with spondyloarthropathy treated with infliximab; 7 of the RA patients and 6 of the spondyloarthropathy patients developed antibodies to dsDNA.³³ Haraoui and Keystone³⁴ reported a 12.6% incidence of ANAs developing in patients receiving adalimumab, compared with 7.3% of placebo-treated patients using clinical trial data. The incidence of ANAs was reported to be 11% and the incidence of anti-dsDNA antibodies was 15% in patients treated with etanercept, compared with 5% and 4%, respectively, of placebo-treated patients using data from randomized controlled trials.³⁵ Antihistone antibodies were also present.

Table 1 Incidence of newly induced autoantibodies in patients treated with TNF inhibitors.

Full tableFigures & Tables indexDownload Power Point slide (134K)

In a 2-year prospective study that compared TNF inhibitors, ANAs developed in 62% of infliximab-treated patients compared with 15% of etanercept-treated patients with spondyloarthropathy, and in 41% of infliximab-treated patients compared with 10% of etanercept-treated patients with RA at 1 year.³⁶ Anti-dsDNA antibodies developed in 71% of infliximab-treated patients with spondyloarthropathy and 49% of infliximab-treated patients with RA, compared with 0% among the etanercept-treated patients. Isotyping of the anti-dsDNA antibodies revealed a predominance of IgM antibodies and some IgA antibodies, but no IgG antibodies to dsDNA. The IgM antibodies developed after approximately 6 weeks of treatment with infliximab, persisted for up to 2 years without switching to the IgG isotype, and resolved rapidly after discontinuation of treatment. In another prospective study of patients with RA, the prevalence of ANAs increased from 24% to 77%, and IgG and IgM antibodies to dsDNA developed in 64% and 81% of patients, respectively, after 30 weeks of infliximab treatment.³⁷ None of the etanercept-treated patients developed autoantibodies. These studies suggest that autoantibodies are more likely to develop in patients treated with infliximab compared with etanercept. ANAs have also been reported to occur in higher titers in patients receiving higher doses of infliximab.³⁸ The increased incidence and titers of autoantibodies among patients receiving infliximab might be related to a general nonspecific B-cell activation by infliximab, the induction of apoptosis by infliximab that is not seen with etanercept, or a reduction in clearance of nuclear debris as a result of downregulation of C-reactive protein, although both infliximab and etanercept seem to have the same effect in terms of decreasing C-reactive protein levels. Both IgG and IgM anticardiolipin antibodies were detected in up to 25% of patients with RA who received TNF inhibitors, although thrombotic events occurred in only about 4% of patients.^{37, 39}

Other biologic agents

Other biologic agents, such as interferon (IFN)-, IFN-, IFN- and interleukin (IL)-2, have been associated with the development of thyroid autoantibodies, anti-dsDNA antibodies and ANAs, which might develop as early as the first month of treatment and generally disappear following discontinuation of treatment.^{51, 52, 53, 54, 55, 56, 57} Some patients develop autoimmune thyroid disease, hemolytic anemia, autoimmune thrombocytopenia, lupus-like syndromes, pernicious anemia, vitiligo and vasculitis.^{51, 55, 56, 57} Autoimmune disorders have been reported to develop in 15–30% of patients who receive IFN- therapy.^{51, 58} Reports suggest that autoimmune thyroid disease is more likely to develop in patients with pre-existing antithyroid antibodies treated with IFN-.^{51, 52, 54} IFN- and IL-2 have been associated with the induction and exacerbation of symmetric inflammatory arthropathies.^{55, 59} Three patients treated with IL-2 developed positive rheumatoid factors, ANAs and an inflammatory arthritis.⁵⁹ It has been postulated that high-dose IL-2 might enhance expression of HLA class II antigen, leading in turn to autoimmunity.

It has been suggested that the development of autoimmunity is associated with a favorable anti-tumor effect in patients who receive type 1 IFN. In one report, the risk of melanoma recurrence was reduced by a factor of 50 in patients who developed autoimmunity during treatment with IFN-2b.⁶⁰ Similarly, the development of autoimmune thyroid disease, antiphospholipid antibody syndrome and vitiligo has been reported to confer a survival benefit in patients with melanoma treated with IL-2.

Conclusion

Clinicians should consider the possibility of a drug-related effect in patients presenting with arthralgias, arthritis or lupus-like syndromes. Since arthritis is one of the manifestations of DRL, one must be cognizant of the possibility that patients with RA treated with TNF inhibitors or minocycline who present with an apparent flare of their disease might have developed DRL instead. The value of monitoring autoantibodies in patients who receive medications known to be associated with DRL is uncertain given the relatively high incidence of the development of these antibodies compared with the relatively low incidence of a resulting lupus-like syndrome.

Acknowledgments

Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Connective tissue diseases | Therapy