Can injectable medications, such as biologics (e.g. etanercept (Enbrel)) or immunomodulators, cause lupus erythematosus (DILE) in patients with a history of chronic conditions like rheumatoid arthritis or multiple sclerosis?

Drug-Induced Lupus Erythematosus from Injectable Medications

Injectable biologics, particularly TNF-α inhibitors like etanercept (Enbrel), can cause drug-induced lupus erythematosus (DILE), but this differs substantially from classic DILE and typically does not involve renal or CNS complications. 1, 2

Key Differences Between TNF-α Inhibitor-Induced Lupus and Classic DILE

TNF-α inhibitor-induced lupus presents with distinct features that separate it from traditional drug-induced lupus 3, 4:

• Cutaneous involvement is more common with TNF-α inhibitors compared to classic systemic DILE 3
• Renal disease has been reported in several cases of anti-TNF-α DILE, whereas visceral involvement is rare in classic DILE 3
• Serologic profile differs significantly: Anti-histone antibodies (the hallmark of classic DILE) are less common with TNF-α inhibitors, while anti-dsDNA antibodies and low complement levels occur in approximately half of anti-TNF-α DILE cases 3, 4
• Anti-extractable nuclear antigen antibodies are present more frequently with TNF-α inhibitors than in classic DILE 3

Clinical Presentation

The FDA label for etanercept documents lupus-like syndrome as a postmarketing adverse reaction, with manifestations including 2:

• Arthralgia and arthritis
• Skin rashes (more frequent than classic DILE) 3
• Serositis
• Cytopenias
• Cutaneous lupus erythematosus 2

The median time from drug initiation to DILE onset is 172 days (approximately 6 months), though this can range from months to years 5.

Autoantibody Development

Etanercept induces autoantibody formation at higher rates than placebo 2:

• 15% of etanercept-treated patients developed new positive anti-double-stranded DNA antibodies by radioimmunoassay (versus 4% with placebo) 2
• 3% developed anti-dsDNA by Crithidia luciliae assay (versus 0% with placebo) 2
• Anticardiolipin antibodies increased compared to placebo 2

However, autoantibody development does not always correlate with clinical DILE 2.

High-Risk Injectable Medications

Based on the WHO pharmacovigilance database analysis of 12,166 DILE cases, the injectable biologics most strongly associated with DILE are 5:

1. Infliximab (highest number of reported cases)
2. Adalimumab
3. Etanercept

All three TNF-α inhibitors carry this risk 6, 1, 5.

Diagnostic Approach

Diagnosis requires temporal association between drug administration and symptom development, with resolution after drug cessation 7, 3. The challenge is distinguishing DILE from disease flare in patients with underlying rheumatoid arthritis or other autoimmune conditions 3.

Key diagnostic features include 3, 4:

• Onset during continuous drug exposure (months to years after initiation)
• Characteristic symptoms: arthritis/arthralgia, photosensitive rash, serositis
• Variable laboratory findings: ANA positivity common, but anti-histone antibodies less frequent than classic DILE
• Resolution within weeks to months after drug withdrawal

Management Strategy

Immediate discontinuation of the offending TNF-α inhibitor is the primary treatment 7, 4:

• Symptoms typically resolve after drug cessation without requiring additional therapy 7, 3
• Topical or systemic corticosteroids should be reserved for resistant cases with significant organ involvement 4
• Immunosuppressive agents are rarely needed and should only be considered if symptoms persist despite drug withdrawal 4

Monitoring Recommendations

For patients on TNF-α inhibitors, monitor for 1:

• Arthralgia and fever (early warning signs)
• New-onset rashes, particularly photosensitive eruptions
• Pleuritis or pericarditis symptoms
• Constitutional symptoms (fatigue, malaise)

Special Considerations for Patients with Pre-existing Autoimmune Disease

The presence of rheumatoid arthritis or multiple sclerosis does not contraindicate TNF-α inhibitor use, but complicates DILE diagnosis 6. In patients with pre-existing autoimmune conditions receiving checkpoint inhibitors (different mechanism but relevant precedent), 27-42% experienced autoimmune condition flares, though most were manageable 6.

Vaccination is not contraindicated in patients with autoimmune diseases receiving TNF-α inhibitors, and influenza or hepatitis B vaccination does not increase disease activity or trigger lupus 6.

Critical Pitfall

Do not confuse autoantibody development with clinical DILE—many patients develop positive ANA or anti-dsDNA antibodies without developing symptomatic lupus 2. Clinical correlation is essential, and asymptomatic autoantibody positivity alone does not require drug discontinuation 2.