Lupus is an autoimmune disease where the body’s immune system mistakenly attacks its own tissues and organs. Drug-induced lupus erythematosus (DILE) is a form of lupus that is triggered by certain medications. Approximately 10-15% of people diagnosed with lupus have the drug-induced form. DILE usually resolves within weeks or months after stopping the offending medication. However, symptoms can resemble systemic lupus erythematosus (SLE) and physicians must investigate a patient’s drug history when evaluating lupus. This article will review common medications known to induce DILE and provide an overview of the disease.
What is drug-induced lupus?
Drug-induced lupus erythematosus (DILE) is a form of lupus triggered by certain prescription drugs. The condition usually develops within 3 to 6 months after starting a new medication. Symptoms are similar to systemic lupus erythematosus (SLE) and can include:
– Fatigue
– Fever
– Malaise
– Joint pain or arthritis
– Muscle pain
– Rash on cheeks and arms (butterfly rash)
– Photosensitivity
– Chest pain when taking breaths
– Hair loss
– Mouth sores
– Raynaud’s phenomenon (fingers turn white or blue in cold temperatures)
However, compared to SLE, DILE generally does not affect major organs such as the kidneys, brain, nerves, or blood cells. Once the offending medication is stopped, symptoms usually resolve within weeks to months. DILE represents about 10-15% of all lupus cases.
Mechanism of drug-induced lupus
The exact mechanisms behind drug-induced lupus are not fully understood. However, research suggests medications can induce lupus through:
1. Drug metabolism forming reactive metabolites
Certain drugs are metabolized in the body into compounds called reactive metabolites. These metabolites can behave as haptens by binding to cell proteins and inducing an autoimmune response against those drug-protein adducts. The body mistakenly attacks those modified proteins as “foreign” and this leads to inflammation and symptoms of lupus.
2. Altering immune system function
Some drugs may stimulate the immune system and cause loss of normal immune tolerance. This can lead to activation of autoimmune T- and B- cells that target the body’s own tissues, resulting in lupus symptoms.
3. Cross-reaction with existing antibodies
Specific structures within a drug may cross-react with antibodies or immune complexes already circulating in susceptible individuals. This can enhance immune complex formation and complement activation, leading to inflammation and lupus symptoms.
Types of medications that can induce lupus
Over 80 medications have been associated with drug-induced lupus. Some of the more common drug classes linked to DILE include:
Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs such as ibuprofen (Advil, Motrin), naproxen (Aleve), and celecoxib (Celebrex) are very commonly associated with DILE. Symptoms generally develop within weeks or months of beginning therapy. NSAID-induced lupus usually resolves within weeks to months after stopping the medication. The most common symptoms are joint pain, fever, and rash.
Anti-hypertensives
Anti-hypertensive drugs like hydralazine, methyldopa, and calcium channel blockers can trigger DILE in slow acetylators. Symptoms tend to develop within months of starting therapy. Joint pain, fever, and rash are most common. Remission can take 1-2 months after discontinuing the anti-hypertensive.
Anti-arrhythmics
Anti-arrhythmic drugs like procainamide and quinidine have been strongly linked to DILE, with nearly 100% of slow acetylators developing symptoms. Procainamide-induced lupus generally develops within months of therapy and resolves within weeks to months of stopping the drug.
Antibiotics
Certain antibiotics can induce lupus, most notably minocycline, ciprofloxacin, and isoniazid. Symptoms tend to appear within weeks to months and include rash, arthritis, and serositis. DILE from antibiotics usually resolves slowly over months.
Antifungals
Antifungal drugs like griseofulvin and terbinafine have been associated with DILE. Lupus symptoms develop within months and disappear over weeks to months after stopping therapy. Rash, fever, and joint pain are most common.
Anticonvulsants
Some anticonvulsant drugs used to treat seizures like carbamazepine, phenytoin, and lamotrigine can trigger DILE. Symptoms generally appear within weeks to months. The lupus usually resolves within weeks to a few months of discontinuing the anticonvulsant.
Other drugs
Additional drugs with reported associations with DILE include:
– Tumor necrosis factor alpha (TNFα) inhibitors like etanercept and infliximab used for rheumatoid arthritis, Crohn’s disease
– Interferons used for hepatitis C, multiple sclerosis
– Omeprazole and other proton pump inhibitors for treating GERD
– ACE inhibitors for high blood pressure
– Chlorpromazine and other antipsychotics
– Sulfasalazine for inflammatory bowel disease
– D-penicillamine for rheumatoid arthritis
Diagnosis
Drug-induced lupus erythematosus is often suspected based on a patient’s medication history and timing of symptom onset after starting a new drug known to cause DILE. Diagnosis is usually confirmed with blood tests:
Positive ANA
>90% of DILE patients test positive for antinuclear antibodies (ANA). However, compared to SLE, ANA titers in DILE are lower, usually less than 1:1,280.
Positive anti-histone antibodies
Anti-histone antibodies, especially anti-dsDNA, are present in >90% of DILE cases. This helps distinguish it from SLE where anti-histone antibodies are only found in about 10-15% of patients.
Negative antibodies
Certain antibodies common in SLE are usually absent with DILE. Negative tests help rule out SLE and confirm DILE. These include:
– Negative anti-Smith (Sm) antibodies
– Negative anti-double stranded DNA (dsDNA) antibodies
– Negative anti-ribonucleoprotein antibodies
Normal C3 and C4 levels
Unlike SLE, complement levels (C3 and C4) are usually normal in drug-induced lupus.
LE cell test
The lupus erythematosus (LE) cell test is negative with DILE. An LE cell test identifies LE cells by mixing the patient’s blood with normal blood. If the patient has SLE, LE cells form which are white blood cells that engulf the nucleus of another cell. LE cells are not seen with DILE.
Treatment
The main treatment for drug-induced lupus erythematosus is stopping the medication that triggered it. In most patients, symptoms and lab abnormalities gradually resolve within weeks to months of discontinuing the offending drug.
Drug withdrawal
Prompt withdrawal of the causative medication is key. Relapsing symptoms may occur with rechallenge or unintentional re-exposure to the drug. If the inducing drug is necessary and cannot be stopped, the lowest effective dose should be used with close monitoring.
Symptomatic therapy
Symptoms of DILE can be managed with:
– NSAIDs, analgesics: relieves joint pain, arthritis
– Antimalarials: helps fatigue, rash, arthritis
– Topical steroids: reduces skin rash and itching
– Rest, reduced sun exposure: improves fatigue, rash, arthritis
Immunosuppressants
For severe or persistent DILE symptoms, short term corticosteroids or immunosuppressants may be used such as:
– Oral prednisone or prednisolone
– Hydroxychloroquine
– Methotrexate
– Azathioprine
– Mycophenolate mofetil
However, immunosuppressants should be avoided if possible since symptoms usually resolve with drug withdrawal alone.
Prognosis
For most patients, the prognosis of drug-induced lupus erythematosus is very good. After stopping the offending medication, symptoms and lab abnormalities generally resolve completely within 1 to 6 months. Less than 10% of DILE cases persist beyond this, and <5% transition to systemic lupus erythematosus. Risk factors for developing chronic DILE include:
- Symptoms present >1 year while on the inducing drug
– High titer ANA (≥1:1,280)
– Positive anti-dsDNA antibodies
– Male gender
Since manifestations are generally mild and reversible with drug cessation, DILE has a mortality rate close to the general population. However, it’s critical to recognize and discontinue the causative medication as soon as DILE is suspected to prevent complications. Patients should be monitored long-term since certain drugs may trigger disease flares even years later.
Key Points
– Drug-induced lupus erythematosus (DILE) is triggered by certain prescription medications. Symptoms are similar to SLE but are generally reversible.
– Over 80 drugs have been implicated in DILE. Common culprits include NSAIDs, anti-hypertensives, antibiotics, and anti-arrhythmics.
– Mechanisms include formation of reactive metabolites, altering immune function, and cross-reaction with existing antibodies.
– Diagnosis is made by medication history, symptoms, and positive ANA and anti-histone antibodies. Negative antibodies help rule out SLE.
– Stopping the causative drug usually leads to resolution of symptoms within 1-6 months. Symptomatic and immunosuppressive therapies may be needed.
– Prognosis is generally good with near complete recovery after drug withdrawal. Less than 10% transition to SLE.
Conclusion
Drug-induced lupus erythematosus is an important consideration in new onset lupus. A thorough medication history and understanding of drugs that can trigger DILE aids early diagnosis. While symptoms may resemble SLE, DILE usually follows a much more benign course. Key is identifying and promptly discontinuing the offending medication, which leads to resolution of symptoms in most patients. Increased awareness of drugs capable of inducing a lupus-like illness can prevent unnecessary testing and morbidity. Patients should be monitored long-term for recurrent or persistent disease. With prompt diagnosis and drug withdrawal, the prognosis of DILE is excellent.
