Associate Member,
Department of Molecular & Experimental Medicine
The Scripps Research Institute
La Jolla, California
Drug-induced lupus erythematosus is a side-effect of long-term use of certain medications. Specific criteria for diagnosing drug-induced lupus have not been formally established. However, some symptoms overlap with those of SLE. These include:
* Muscle and joint pain and swelling
* Flu-like symptoms of fatigue and fever
* Serositis (inflammation around the lungs or heart that causes pain or discomfort)
* Certain laboratory test abnormalities.
Once the suspected medication is stopped, symptoms should decline within days. Usually symptoms disappear within one or two weeks. Drug-induced lupus can be diagnosed with certainty only by resolution of symptoms and their failure to recur after stopping the medication.
What Medicines Cause Drug-Induced Lupus?
Lupus-inducing drugs are typically those used to treat chronic diseases. No obvious common denominator links the drugs that are likely to cause lupus. The list includes medicines used to treat:
* Heart disease
* Thyroid disease
* Hypertension
* Neuropsychiatric disorders
* Certain anti-inflammatory agents and antibiotics.
At least 38 drugs currently in use can cause DILE. However, most cases have been associated with these three:
* procainamide (Pronestyl)
* hydralazine (Apresoline)
* quinidine (Quinaglute).
The risk for developing lupus-like disease from any of the other 35 drugs is low or very low; with some drugs only one or two cases have been reported.
What Is The Likelihood of Developing DILE?
* It usually takes several months or even years of continuous therapy with the medication before symptoms appear.
* For the high-risk drugs such as procainamide and hydralazine, only 5-20 percent of people treated for one to two years at currently used doses will develop drug-induced lupus.
* With most of the other drugs, the risk is less than 1 percent that those taking the medication will develop DILE.
Who Is Most At Risk?
* There is no evidence that people with SLE are more likely to develop drug-induced lupus.
* The use of procainamide, hydralazine, isoniazid, or various anticonvulsants has not been associated with an increase in SLE disease activity or onset of flares.
* The major risk factor for developing drug-induced lupus is chronic, long-term use of a drug known to cause this problem.
* Usually DILE occurs in males over 50 years old, because they have a higher chance of developing chronic diseases that require this type of continuous medication: procainamide or quinidine is prescribed for cardiac arrhythmias, and hydralazine is prescribed for hypertension.
* The high female-to-male ratio associated with SLE is not a distinguishing feature of drug-induced lupus.
* Some evidence suggests that whites are more likely than blacks to develop DILE.
Is Heredity A Factor In DILE?
The only well-defined genetic risk factor in DILE is the slow drug acetylation phenotype. Many medications change biochemically as they pass through the liver, and people who are "fast acetylators" more efficiently metabolize procainamide and hydralazine to a form that does not induce lupus. Therefore, people who are "slow acetylators" are at higher risk for developing lupus-like disease from these two drugs. This is a characteristic of approximately 50 percent of the North American white and black populations.
Why Does Drug-Induced Lupus Occur?
Considerable controversy and disagreement exists about the processes that lead to drug-induced autoimmunity. Drug-induced lupus was first identified almost 50 years ago and has been the subject of many research studies. However, the causes of this disorder are only beginning to be understood.
1. One view is that the offending drugs interfere with enzymes that would otherwise suppress certain genes. The result is a non-specific hyperimmune condition.
2. Considerable circumstantial evidence suggests that it is not the drug itself but the metabolic change the drug undergoes in the body that makes it able to react with the immune system.
3. One possibility is that when these drug metabolites bind to certain proteins, drug-protein complexes are produced. These then activate drug-specific lymphocytes, which damage surrounding tissue or stimulate neighboring lymphocytes.
4. In one mouse study, a drug metabolite was placed in the thymus (one of the main lymphoid organs that forms T lymphocytes). The result was production of the type of autoantibodies that are seen in drug-induced lupus. These findings point to the human thymus as the place where the DILE process begins.
5. It is possible that more than one process causes drug-induced lupus. Although most cases of SLE probably arise spontaneously, the similarities in the signs and symptoms between SLE and DILE suggest that similar immune problems are involved in both diseases.
Symptoms Of DILE
* People with drug-induced lupus most often complain of flu-like symptoms, especially muscle and joint pain.
* Sometimes the symptoms appear gradually and worsen when the person is treated with the implicated drug for many months.
* In other people, the onset of symptoms is rapid.
* Features of drug-induced lupus are essentially the same regardless of the implicated medication. (However, there is some suggestion that certain symptoms are more common with particular drugs.)
* Symptoms are mild in most people, but can become debilitating if the individual continues to take the offending medication.
* By the time a diagnosis is made, most people will have one or more of these symptoms:
- joint pain
- muscle pain
- fever
- arthritis
- inflammation of the heart and lung.
DILE Should Not Be Confused With Medication Side Effects
Drug-induced lupus should not be confused with the drug side-effects that often occur after short-term therapy for gastrointestinal, neurologic, or allergic symptoms. These problems usually occur within a few hours to days of taking the medication.
Drug-induced lupus typically comes after many months or years of continuous therapy with the causative drug.
Laboratory Testing For DILE
As with SLE, most people with drug-induced lupus develop antinuclear antibodies, or ANAs, although those with a form of drug-induced lupus related to quinidine often are ANA-negative. The ANAs in drug-induced lupus are primarily autoantibodies that are able to react with a histone-DNA complex, which is the major component of the nucleus of all cells.
A special laboratory test to detect certain antibodies to this histone-DNA complex is a sensitive marker for lupus-like disease brought on by many drugs. Hydralazine is the exception, as only about one-third of people with DILE have this type of anti-histone antibody.
* Although the ANA or anti-histone test can help to confirm a diagnosis of DILE, it is not useful to periodically test people who have no symptoms.
* Most medications with a tendency to induce lupus-like disease also produce (at a much higher frequency) a mild type of anti-histone antibody not associated with symptoms.
* There is no evidence that people who develop only ANA without symptoms are at increased risk for future development of DILE symptoms.
The Process Of DILE
In most people who develop drug-induced lupus, the symptoms and ANA appear at about the same time. After discontinuing the offending medication, drug-induced ANA should gradually disappear. If the ANA is truly drug-induced, its gradual decline after the medication is discontinued can confirm that the diagnosis was correct. A return to normal can take many months and sometimes years.
How Is Drug-Induced Lupus Different From SLE?
* Acute onset SLE, especially in young women, is usually not confused with drug-induced lupus, due to the general lack of skin disease, kidney disease, and the milder symptoms.
* Oral ulcers, photosensitivity, hair loss, and central nervous system disease are also very rare in DILE.
* However, the onset of SLE in elderly people often fails to show the disease's classical features:
- Sometimes the symptoms can be just like the symptoms of drug-induced lupus.
- However, many elderly people take several medications.
- Therefore, knowing that one of these drugs has a risk for producing lupus-like side-effects should raise suspicion.
Laboratory tests can also be used to distinguish these two diseases. People with SLE usually have more abnormal immunological features (although both people with SLE and people with DILE have ANA and anti-histone-DNA antibodies).
If possible, the suspected medication should be discontinued or replaced with one that is similar. Symptoms that go away within a week or two without additional treatment are likely to be from drug-induced lupus, rather than due to SLE.
Treatment Of DILE
The most important aspect of treating drug-induced lupus is to recognize the medication that is likely to be causing the problems. Its use can then be discontinued. This step is often sufficient to improve the symptoms within a few days, which will indicate that symptoms were drug-induced.
Individuals will probably improve more quickly if non-steroidal anti-inflammatory drugs (NSAIDs) are then used.
* These medications can also reduce symptoms of other rheumatic diseases and therefore may confuse diagnosis.
Corticosteroids may be appropriate for individuals with severe symptoms of drug-induced lupus, which would include:
* severe inflammation of several joints
* inflammation of the sac around the heart
* in rare cases, kidney disease.
Prognosis
By definition, drug-induced lupus is "cured" merely be stopping the offending medication. However, the complete disappearance of symptoms can sometimes take months, and the disappearance of abnormal autoantibodies may take a few years.
After recovering from DILE, some people may develop this syndrome again if not enough time has passed before they again begin to take the same medication. It would be best to avoid a medicine that has previously caused drug-induced lupus.
DILE With SLE?
There is often the desire to attribute a spontaneous disease to environmental factors. In cases of SLE it seems especially justified to implicate drugs shown to induce lupus-like disease. The medical literature mentions that selected cases of true SLE might have been "triggered" by a lupus-inducing drug. It is not possible to prove or disprove this idea.
Researchers continue to search for environmental factors that might cause and sustain systemic lupus and other autoimmune diseases, based on the phenomenon of drug-induced lupus. However, the vast majority of people with DIL are fully cured simply by discontinuing use of the responsible medicine.