Does this patient have drug-induced lupus?
Drug-induced lupus (DIL) has been recognized for over half a century. For practical purposes, this diagnosis signifies the development of a lupus-like illness with characteristic clinical and serological abnormalities after exposure to an offending agent. In most, though not all cases, the illness is expected to remit with discontinuation of the offending agent, though anti-inflammatory and immunosuppressive agents may be needed to reduce systemic or focal inflammation.
Moreover, once the drug induced illness remits, clinical disease does not recur unless the patient is rechallenged by the same or similar medication. Distinction between new onset SLE provoked by a drug, e.g. sulfonamides, and drug induced lupus secondary to any number of agents may be difficult or impossible unless the illness becomes chronic. While the distinction has significant prognostic implications, it does not change immediate therapy and management.
Risk factors for drug-induced lupus include slow acetylator phenotype, older age, HLA DR4 and the complement C4 null allele.
Drug-induced lupus is similar to but distinct from drug induced ANCA positive systemic necrotizing vasculitis and nephritis and from drug-induced Churg Strauss syndrome. Indeed, the same medication may lead to one or the other syndrome. Distinction is important to ensure proper therapeutic response.
Drug-induced syndromes will be reviewed below first by specific drug and then in a few circumstances by syndrome. The agents discussed below are by no means a complete listing of reported offending agents, but represent commonly encountered clinical scenarios. More complete compendia of offending agents are noted in the references section.
Drugs associated with DIL
This is the first class of medication described to cause drug-induced lupus in the 1940’s. Apart from sulfasalazine, discussed below, sulfonamide antibiotics are not frequently encountered offending agents. However, sulfa antibiotics are generally felt to induce disease flares in patients with systemic lupus.
This antihypertensive was reported to cause drug-induced lupus in the early 1950s, shortly after it was introduced into clinical practice. It leads to a lupus-like state in a dose dependent fashion. DIL rarely develops below 100mg/day, with risk increasing at higher doses. Like idiopathic lupus, it is more common and develops at lower doses in women than men.
Clinically, patients develop + ANA and anti-H1 histone antibodies. Dominant features include constitutional symptoms and arthritis. Less commonly, rash and serositis develop and less commonly still, glomerulonephritis and vasculitis may be seen.
Hydralazine was the first drug to be recognized as a clinically significant risk with frequency estimates of DIL of 10% at higher doses. As will be noted with other agents below, this medication may also present with an ANCA + (MPO) vasculitis syndrome. Both syndromes may remit with discontinuation of hydralazine but are more likely to require anti-inflammatory suppression than some of the agents noted below.
This anti-arrhythmic was associated with DIL 10 years after hydralazine. Because of the large number of patients prescribed this agent, and the approximate 20-30% risk of developing DIL, it is often viewed as the model of DIL. Indeed, 90% of patients develop isolated +ANA after one year of therapy.
Procainamide DIL manifests with +ANA, constitutional symptoms, arthritis, and serositis. Glomerulonephritis, seen with hydralazine is not typically part of this syndrome. As with most DIL syndromes, anti-DS DNA antibodies are not commonly seen and hypocomplementemia is usually absent.
Patients with this syndrome develop IgG antibody to histone (anti-H2A-H2B DNA) while most patients developing isolated +ANA are either negative or have IgM antibody to histone. While steroids may be needed to reduce inflammation, this syndrome remits with discontinuation of procainamide.
The worldwide use of INH has increased significantly as tuberculosis has become prominent in the HIV pandemic era. Long noted to induce ANA (approximately 25% of exposed patients), isoniazid presents a low risk of developing a lupus-like state (approximately 1%). Its manifestations are similar to procainamide induced LE and remits with discontinuation of INH.
Diphenylhydantoin (Dilantin) and Carbamazepine (Tegretol): recognized early as a risk for developing drug-induced lupus, there has been controversy with these drugs as to whether their original prescription was for seizure due to occult systemic lupus. These agents, particularly Carbamazepine, have been implicated in cutaneous disease, notably sub-acute lupus described below and recently with livedo racemosa.
Minocycline is a lipophilic antibiotic which penetrates sebum and is active against propionibacterium acne. It is prescribed commonly for acne and is the tetracycline most often associated with drug-induced lupus (estimated to be five times more likely to associate with DIL than other tetracyclines, such as Doxycycline, also prescribed for acne as well as Lyme disease).
Minocycline may present as a typical DIL syndrome with or without hepatitis, or as isolated autoimmune hepatitis and with livedo or vasculitis. Like idiopathic SLE, there is a female predominance. Serologies are robust and in addition to + ANA may include + DS DNA, anti-Sm and anti-histone antibodies.
Like other examples of DIL, complement levels are typically within normal limits. Positive P-ANCA (MPO) may be seen. This syndrome will be expected to remit with withdrawal of drug but may require steroid suppression.
Sulfasalazine (Azulfidine) and 5- ASA (Mesalamine)
This syndrome was originally described in 1965 in a patient with colitis treated with sulfasalazine. Since that time, it is recognized as occurring both with sulfasalazine as well as with the non-sulfa 5-ASA moieties. It may recur upon rechallenge with either agent.
This syndrome resembles other instances of DIL but may be distinctive in producing serositis syndromes. Indeed the most common lupus-like illness may be isolated pericarditis.
Similar to patients with colitis, rheumatoid arthritis patients treated with sulfasalazine may develop DIL. Approximately 10% of RA patients treated with sulfasalazine are at risk. The presence of pre-existing ANA, elevated IL-10 and HLA DRB1 0301 haplotype appear to enhance this risk.
TNF-alpha antagonists (infliximab/Remicade, etanercept/Enbrel, adalimumab/Humira, certolizumab pegol/ Cimzia and golimumab/Simponi)
The widespread use of TNF antagonists to treat inflammatory bowel disease (Crohn’s disease), rheumatoid arthritis and spondyloarthropathy has led to the recognition that autoimmunity might be enhanced as well as suppressed by these agents. In addition to the development of systemic lupus, there are numerous reports of paradoxical development or worsening of psoriasis, sarcoidosis and demyelinating disease.
Early observations with infliximab revealed development of +ANA and anti-DNA antibodies. Numerous studies have confirmed the frequent development of ANA and DNA antibodies, predominantly targeted at IgM rather than IgG DNA. DIL is considerably less common than development of autoantibodies.
Compared to other examples of DIL, hypocomplementemia is more common and antihistone antibodies less so. Clinical presentation may be similar to other DIL states with the rare occurrence of glomerulonephritis and vasculitis.
Anti-TNF antibodies may be more likely to induce autoimmunity than the receptor fusion protein (etanercept) and adalimumab may be less likely to induce DIL than infliximab. Alternatively, longer clinical experience with infliximab and etanercept may reflect more DIL with these agents simply due to greater use.
There is limited experience with use of an alternate TNF antagonist after development of DIL. Williams and Cohen recently reviewed the limited published experience of ten successful examples of rechallenge with a second agent.
Treatment of TNF antagonist-induced DIL includes withdrawal, and the use of corticosteroid, antimalarials, and immunosuppression including Rituximab. The latter successfully treated DIL as well as the underlying rheumatoid arthritis in those cases.
Interferon-alpha has been used to treat cancer as well as hepatitis C. In both groups of patients, autoimmunity has developed manifested by autoantibody production as well as clinical disease. The dominant clinical syndrome has been autoimmune thyroid disease.
In less than 1% of all treated patients, DIL has developed. Since disordered cytokine balance is increasingly appreciated in idiopathic systemic lupus erythematosus with immune complex upregulation of interferon alpha, it is perhaps surprising that the incidence of DIL is not higher than reported.
IL-2 has been available for the treatment of metastatic melanoma and renal cell cancer for 20 years. Numerous cases of autoimmune thyroid disease, vasculitis and arthritis have been reported including induction of ANA, though not full DIL.
Imiquimod is a Toll-like receptor 7 and 8 agonist in widespread use for the treatment of genital warts, actinic skin damage and basal cell carcinoma. Its reported actions include stimulation of pro-inflammatory cytokine production with enhanced TH1 immune response, and with production of interferon alpha and TNF alpha.
While reports of its activity in lupus are still few, it is worth making note of this association considering the large number of patients receiving the drug and expanding reports of efficacy in cutaneous cancer including melanoma. Like the TNF antagonists which may have dual effects on disease process, imiquimod has been reported to both improve as well as lead to cutaneous lupus.
While earlier reports suggested it was an effective treatment for resistant discoid lupus, more recent reports suggest it may induce subacute cutaneous lupus, or lupus-like interface dermatitis. Imiquimod-induced dermatitis is expected to be resolved with cessation of exposure.
Pesticides and household chemicals
Occupational and environmental histories are often overlooked in the care of patients. Coupled with susceptibility loci, environment is presumed to have a large if not necessary role in disease expression.
When a drug recognized to cause lupus has been prescribed to a patient, the association is easily seen. More difficult but important to ascertain are environmental exposures. Chemicals of concern include those with estrogenic or anti-androgen effects. Implicated chemicals include pesticides, acrylamides (bonding agents), hydrazine and phthalates.
Drug-Induced anti-phospholipid antibody syndrome
Isolated or associated with other manifestations of DIL, anti-phospholipid antibody syndrome has been associated with multiple drugs including propylthiouracil, sulfasalazine and interferon alpha-2a. Patients may experience cutaneous reaction with livedo reticularis as well as thrombotic phenomena.
Subacute cutaneous lupus
Forms of cutaneous lupus include acute, discoid, tumid, subacute and profundus. Subacute cutaneous lupus is increasingly recognized as drug-induced with a proliferation of recent reports expanding the list of offending agents. This form of lupus is characterized by a photosensitive, erythematous dermatitis, with non-scarring scaly papules and plaques often in annular form.
Implicated categories of drugs include diuretics, ACE inhibitors, calcium channel blockers, TNF antagonists, anti-fungals, PPI’s, chemotherapeutic agents and statins.
As in idiopathic subacute lupus, patients typically have antibody to Ro (SSa) but unlike many examples of drug-induced lupus they lack antihistone antibody. Dermatitis may resolve with discontinuation of the offending agent or require topical or systemic therapy.
What tests to perform?
Laboratory testing begins with routine studies, i.e. CBC, comprehensive metabolic chemistries, urine analysis and acute phase reactants.
Testing for rheumatic disease will follow when DIL or other rheumatic disease is suspected and should include: ANA, C3, C4, double and single stranded DNA antibody, antibodies to Sm, RNP, SSa and SSb (Ro/La), histones and ANCA.
In patients with arthritis, rheumatoid factor and anti-CCP antibodies should be obtained.
Imaging if indicated will be specific to organ involvement. Pulmonary symptoms might require chest x-ray, CT scan, and echocardiogram. Abdominal/pelvic symptoms might require CT scan, angiography or other bowel imaging.
Biopsy is largely limited to analysis of rash. Though most lesions will remit with the DIL syndrome, persistence of rash or in circumstances when DIL is uncertain will require biopsy. Isolated subacute cutaneous lupus will benefit from the clarity of a biopsy. Distinction may also be necessary between cutaneous lupus and non-lupus vasculitis.
In the patients with glomerulonephritis, the renal biopsy may alter therapy. Also, the renal biopsy may aid in the distinction between DIL and pauci-immune ANCA associated vasculitis/nephritis.
Overall interpretation of test results
Overall, most patients with DIL will be diagnosed by syndrome, recognition of offending agent and confirmatory serologies.
How should patients with drug-induced lupus be managed?
As noted above, treatment of drug-induced lupus is first and foremost recognition of and discontinuation of the offending agent. Since this syndrome is expected to remit, short term steroid may be added with the expectation of little toxicity.
Antimalarials may be added along with steroid to help maintain improvement as steroid is tapered and discontinued. In those cases that are severe, resistant to treatment as noted above or have become chronic, immunosuppressive therapy may be added. A fuller accounting of agents and treatment strategy may be found in the section on SLE.
What happens to patients with drug-induced lupus?
Fortunately, most patients will have remitting disease with little or no permanent end organ damage.
How to utilize team care?
Consultations are indicated by organ specific pathology. Cardiology, dermatology and nephrology will be most often consulted.
Are there clinical practice guidelines to inform decision making?
There are currently no guidelines.
What is the evidence?
Chang, C, Gershwin, ME. “Drug-induced lupus erythematosus”. Drug Saf. vol. 34. 2011. pp. 357-374.
Katz, U, Zandman-Goddard, G. “Drug-induced lupus: An update”. Autoimmunity Reviews. vol. 10. 2010. pp. 46-50.
Williams, VL, Cohen, PR. “TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists”. Int J Dermatol. vol. 50. 2011. pp. 619-25.
Zandman-Goddard, G, Solomon, M, Rosman, Z. “Lupus”. 2011. pp. 1-10.
Barr, KL, Konia, TH, Fung, MA. “Lupus erythematous-like imiquimod reaction: a diagnostic pitfall”. J Cutan Pathol. vol. 38. 2011. pp. 346-350.
Chan, MP, Zimarowski, MJ. “Lupus erythematosus-like reaction in imiquimod-treated skin: a report of 2 cases”. Am J Dermatopathol. vol. 33. 2011. pp. 523-527.
Callen, JP. “Drug induced subacute cutaneous lupus erythematosus”. Lupus. vol. 19. 2010. pp. 1107-1111.
Lowe, G, Henderson, CL, Grau, RH. “A systemic review of drug-induced subacute cutaneous lupus erythematosus”. Br J Dermatol. vol. 164. 2011. pp. 465-472.
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- Does this patient have drug-induced lupus?
- Drugs associated with DIL
- Hydralazine (Apresoline)
- Procainamide (Pronestyl)
- Isoniazid (INH)
- Minocycline (Minocin)
- Sulfasalazine (Azulfidine) and 5- ASA (Mesalamine)
- TNF-alpha antagonists (infliximab/Remicade, etanercept/Enbrel, adalimumab/Humira, certolizumab pegol/ Cimzia and golimumab/Simponi)
- Imiquimod (Aldara)
- Pesticides and household chemicals
- Drug-Induced anti-phospholipid antibody syndrome
- Subacute cutaneous lupus
- What tests to perform?
- How should patients with drug-induced lupus be managed?
- What happens to patients with drug-induced lupus?
- How to utilize team care?
- Are there clinical practice guidelines to inform decision making?
- What is the evidence?