Drug-Induced Autoimmune Diseases

JANUARY 20, 2016
Anyssa Garza, PharmD
Ten percent of individuals worldwide are affected by autoimmune diseases, with systemic lupus erythematosus (SLE) being one of the most common.1 Drug-induced lupus erythematosus (DILE) was first recognized in 1945 with sulfadiazine as the offending agent.2 Since then, more than 90 medications from more than 10 drug classes have been implicated in causing lupus.1,3 DILE is estimated to affect 15,000 to 20,000 individuals each year and accounts for 10% of SLE cases.1,2 Risk factors for DILE include being a slow acetylator, having certain serologic features (eg, HLA-DR4 and HLADR0301), having complement C4 null allele, and being female.2

Drug-Induced Lupus Erythematosus
DILE is similar to idiopathic SLE. However, the prognosis of DILE is promising compared with that of SLE. DILE presents itself after exposure to the offending medication and the symptoms usually resolve within weeks of discontinuing the offending agent.2 Refer to Table 13 for a comparison of DILE and idiopathic SLE.

Patients presenting with DILE may experience fever, arthralgia, arthritis, myalgia, or serositis. In fact, 90% of affected patients present with arthralgia and 50% present with myalgia.2 After initiation of an offending medication, DILE can develop from 1 month to more than a decade after exposure to it.2

DILE can be defined by the following, according to Dipiro and colleagues4:
  • Exposure to a suspected medication
  • No history of idiopathic SLE prior to exposure to an offending medication
  • Positive antinuclear antibody (ANA) test result; usually antihistone antibodies
  • At least one clinical feature of SLE
  • Rapid improvement of symptoms after offending drug is discontinued
  • Gradual decline in ANAs after offending drug is discontinued
Associated Medications
Medications reported to have a definite relationship to DILE, based on controlled studies, include the following2:
  • Sulfadiazine 
  • Hydralazine
  • Procainamide
  • Isoniazid
  • Methyldopa
  • Quinidine
  • Minocycline
  • Chlorpromazine
Procainamide and hydralazine are associated with the highest risk for developing DILE. Procainamide carries a 15% to 20% risk and hydralazine carries a 7% to 13% risk.3 Quinidine has been classified as having a moderate risk.1 Refer to Online Table 22,3 for a list of medications and their likelihood of causing DILE.

Table 2: Drugs Implicated in the Development of Drug-Induced Lupus Erythematosus
Definite Probable Possible Recent case reports
  • Hydralazine
  • Procainamide
  • Isoniazid
  • Methyldopa
  • Quinidine
  • Minocycline
  • Chlorpromazine
  • Sulfasalazine
  • Antithyroid
  • Anticonvulsants:
    • Ethosuximide
    • Phenytoin
    • Primidone
    • Valproate
    • Zonisamide
    • Carbamazepine
  • Statins:
    • Lovastatin
    • Simvastatin
    • Fluvastatin
    • Pravastatin
    • Atorvastatin
  • Terbinafine
  • Penicillamine
  • Fluorouracil agents
  • Hydrochlorothiazide
  • Antibiotics:
    • Ciprofloxacin
    • Penicillin
    • Tetracycline
    • Nitrofurantoin
    • Cefepime
    • Cefuroxime
  • Nonsteroidal anti-inflammatory drugs:
    • Ibuprofen
    • Diclofenac
  • Antihypertensives:
    • Lithium
    • Interferons
    • Gold salts
  • Infliximab
  • Etanercept
  • Interleukin-2
  • Zafirlukast
  • Clobazam
  • Tocainide
  • Lisinopril
  • Bupropion
Adapted from references 2 and 3.

Recently, DILE has also been associated with newer medications on the market, which include tumor necrosis factor (TNF) blockers and interferons. There have been several cases of TNF-alpha antagonist–induced lupus syndrome, which is otherwise known as TAILS.3

TNF blockers include the following:
  • Remicade (infliximab)
  • Enbrel (etanercept)
  • Humira (adalimumab)
  • Cimzia (certolizumab pegol)
  • Simponi (golimumab)
According to an article published in Lupus, “Most cases of TAILS have been … due to infliximab because it is the most immunogenic based on its chimeric structure and its ability to reach high tissue concentrations, followed by etanercept and adalimumab, which is a humanized monoclonal antibody. Only one case has been described with certolizumab pegol, and we are unaware of any cases being reported following golimumab therapy.”3

The interferons that are implicated in DILE include interferons alpha and beta. However, interferon alpha carries the highest incidence of DILE.1,3 Other medications that may be linked to DILE include ticlopidine, various statins, and lisinopril.2,3

Medications that are thought to cause lupus include the following:3
  • Estrogens, oral contraceptives
  • Danazol
  • Mesalazine
  • Reserpine
  • Griseofulvin
  • Clonidine
  • Hydroxyurea
  • Gemfibrozil
  • Allopurinol
  • Quinine
  • Minoxidil
  • Calcium channel blockers
  • Amiodarone
  • Spironolactone
  • Clozapine
  • Tocainide
  • Zafirlukast
  • Omeprazole