Read The Lupus Book: A Guide for Patients and Their Families, Third Edition Online
Authors: Daniel J. Wallace
Anticonvulsants (phenytoin, trimethadione, primidone, ethosuximide)
Lithium carbonate
Captopril (Capoten)
Antithyroid preparation (propylthiouracil, methimazole)
Beta-blockers (practolol, acebutolol, atenolol, labetalol, pindolol, timolol eyedrops) Lipid-lowering medicines (Mevacor, Pravachol, Lopid)
Prazosin (Minipress)
4. Drugs that can exacerbate lupus or increase the risk of allergic reactions but do not cause lupus Antibiotics (sulfa, tetracycline—rarely, penicillins or ciprofloxacins)
Nonsteroidal anti-inflammatory agents (e.g., ibuprofen)
Oral contraceptives and other hormones
Sulfa diuretics and diabetic drugs (Dyazide, Aldactone)
Cimetidine (Tagamet), alpha-interferon, and gold salts
5. Case reports have appeared implicating nearly fifty other drugs
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What Causes Lupus?
A Note of Caution
If you are a lupus patient, how do you know if you have DILE? If you are
prescribed a medication by your doctor, and after several weeks to months, start noticing a rash, fevers, pain on taking a deep breath, or swollen joints, consult your doctor immediately. Most DILE patients do not fulfill the criteria for systemic lupus. All seventy or so drugs implicated in DILE induce the formation
of antinuclear antibody to varying degrees, but the process is self-limited. In other words, once the drug is stopped, the formation of antinuclear antibody
stops as well.
Only a small percentage of these ANA-positive individuals ever develop clin-
ical lupus.
A positive ANA does not constitute grounds to discontinue treatment
with a useful drug
. Since DILE is completely reversible, the risks of not taking lifesaving heart or seizure medications, for example, are much more ominous.
Moreover, there is no evidence that a lupus-causing drug administered to a
patient who already has the disease will make the condition worse.
How Do Drugs Cause Lupus?
An exciting research challenge is presented by DILE, since investigators might
be able to use it as a model for understanding how lupus develops. Unfortu-
nately, however, DILE may come about through different chemical processes
unrelated to the evolution of the disease as it unfolds in most cases. Let’s look at some proposed mechanisms by which drugs induce lupus.
For example, the drug can bind to a part of the cell that alters DNA. This
altered DNA sets in motion an immunologic reaction, causing the body to make
anti-DNA. Similarly, drugs can activate T or B lymphocytes and, as part of the
immunologic response, lead to the formation of antibodies to white blood cells, or antilymphocyte antibodies—a common feature of lupus. Next, a drug can
induce the hypomethylation of DNA, which results in altered DNA repair and
autoantibody formation. Also, the drug may make your body so sun-sensitive
that, if you are genetically predisposed, it can turn on a lupus reaction. Finally, certain drugs are broken down into chemicals, or by-products that promote the
formation of autoantibodies—the antibodies that attack the body’s own tissue.
Several genetic factors may also increase the risk of developing DILE. For
example, the HLA-DR4 genetic marker is associated with hydralazine and D-
penicillamine-induced lupus. If your liver cannot clear these breakdown products of drugs quickly, this slow clearance system is termed ‘‘slow acetylatation.’’ If you are a
slow acetylator
and are prescribed procainamide, hydralazine, or isoniazid and if you have a certain genetic makeup, there is an increased chance
that you will develop DILE. Finally, the absence of certain HLA-derived com-
plement genes also correlates with DILE.
Drugs That May Cause Lupus or Produce Flareups
[53]
Clinical and Laboratory Features of Drug-Induced Lupus
Hydralazine
is a drug used to lower blood pressure by dilating blood vessels.
When it was introduced in the early 1950s, much higher doses were used than
are currently prescribed. Positive ANA tests seem to be related to high doses of hydralazine, as do longer treatment durations. For example, at 5 years, the risk of developing DILE at doses of 50 milligrams daily is zero, but it is 5 percent at 100 milligrams daily and 10 percent at 200 milligrams daily, even though at
this point more than half of patients will have a positive ANA.
The average dose of hydralazine is about 50 to 100 milligrams a day. You
should suspect hydralazine-induced lupus if you begin noticing joint swelling,
fevers, and weight loss. Rashes or anemia are found 25 percent of the time,
muscle aches and pain on taking a deep breath are less common, and organ-
threatening disease is very rare. Nearly everybody with hydralazine-induced lu-
pus has a positive ANA and specific antibodies called antihistone antibodies.
Procainamide
is an extremely effective, often lifesaving drug that treats irregular heart rhythms. As with hydralazine, the risk of procainamide-induced
lupus also depends on dose and duration of treatment. Up to 83 percent of all
individuals given long-term procainamide develop a positive ANA, but only a
small percentage ever develop full-blown DILE. Its symptoms and laboratory
results are similar to those of hydralazine-induced lupus, except that pleurisy and pericarditis are more common with procainamide and rashes almost never
occur. Organ-threatening disease is extremely rare.
Three other commonly used types of heart medicines are also culprits.
Meth-
yldopa
(Aldomet) is an antihypertensive drug that has induced lupus, although rarely. Patients with this syndrome often exhibit a marked anemia and antibodies to red blood cells. Another drug used in treating an irregular heart rhythm,
quinidine
(Quinaglute), occasionally causes positive lupus blood tests and a severe arthritis. A group of blood pressure pills known as
beta-blockers
infrequently cause a positive ANA test, but only a handful of clinical lupus cases
have been reported in connection with those drugs available in the United States (e.g., Sectral, Tenormin, Inderal, Toprol).
Anticonvulsants
prevent epileptic seizures and may result in positive ANA tests. Nearly all clinical cases of lupus attributed to phenytoin (Dilantin) occurred in children. Occasional reports have been associated with carbamazepine
(Tegretol), but phenobarbital has not been connected with DILE. Up to 15 per-
cent of patients with lupus experience epileptic seizures. None of these drugs
will cause flareups of lupus and there is no reason not to take any of them.
Isoniazid
(INH) is an antituberculosis agent similar in structure to hydralazine.
Its long-term administration may result in positive ANA tests in up to 25 percent of those taking the drug, but only a few cases of clinical lupus have been
published. Drugs that treat psychosis in the
phenothiazine
family (e.g., Thora-
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What Causes Lupus?
zine, Stelazine, Mellaril) may convert patients to ANA positivity up to 26 per-
cent of the time, but lupus-related symptoms are extremely unusual. Certain
preparations used to treat
hyperthyroidism
(e.g., propylthiouracil, or PTU) only in rare instances cause a lupus-like syndrome.
D-
penincillamine
is used to manage rheumatoid arthritis and scleroderma.
About 1 percent of the time, these patients may develop myasthenia gravis or
SLE from the drug. Since those taking D-penicillamine already have an auto-
immune disease, sorting things out can be problematic. Your doctor should
consider consulting a rheumatologist. Was the diagnosis of scleroderma or rheu-
matoid arthritis correct all along, or could the diagnosis have been lupus? D-
penicillamine has no place in the treatment of lupus and should be stopped in
anyone suspected of having SLE.
TNF blocking medicines
prescribed for rheumatoid arthritis (e.g., Remicade, Humira, Enbrel) can flare lupus if it is also present, or if a lupus patient has been misdiagnosed with rheumatoid arthritis. It rarely causes clinical lupus. TNF
blockers induce the formation of autoantibodies, particular anti-DNA in 20–40
percent of users. This is clinically relevant in a minority of patients and is not by itself a reason to stop taking it.
How Can We Tell DILE From SLE?
While taking a lupus-causing drug, the DILE patient displays many of the signs
and symptoms seen in the patient with lupus. However, DILE patients rarely
have symptoms involving the many organ systems of the body. (In other words,
the central nervous system, heart, lung, and kidneys are not usually involved.) In these patients, we do find antihistone antibodies (in fact, they are found on blood testing in more than 95 percent of patients with DILE; the problem is
that 40 percent with SLE also develop these antibodies). The patient with DILE
does not have the other typical lupus antibodies reviewed in Chapter 6. Normal
complement levels are also present in DILE patients. Further, upon discontin-
uing the drug, DILE improves or resolves within days to weeks in these patients.
Even though antihistone antibodies decrease, the ANA test may remain positive
for years.
Your doctor must differentiate DILE from bacterial or viral infections, po-
lymyalgia rheumatica, SLE, rheumatoid arthritis, or Dressler’s syndrome (fever
with pericarditis in patients who have had a recent heart attack). Blood tests and cultures usually distinguish among these diseases.
How Do We Treat DILE?
If the offending drug is withdrawn as soon as symptoms present themselves, no
therapy may be necessary. Approximately one-third of the time, my patients
have benefited from several weeks to months of aspirin or other NSAID med-
Drugs That May Cause Lupus or Produce Flareups
[55]
ications (such as ibuprofen, naproxen, or indomethacin). If serious complications develop (e.g., pericardial tamponade or kidney disease) or the symptoms are
severe (e.g., disabling arthritis, pleurisy with shortness of breath), I usually prescribe several weeks to months of moderate-dose steroids (less than 40 milli-
grams of prednisone daily).
Fewer than 5 percent of patients with DILE have a complicated or unfavorable
course. These circumstances arise when the inciting drug is not withdrawn de-
spite several months of symptoms or the lupus-inducing drug is reintroduced
after being stopped. If you are a lupus patient and you have had fevers, rashes, or joint aches that you or your doctor feel may be from taking a lupus-inducing drug, stop it and
never
take the drug again.
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When rheumatologists evaluate an individual who might have lupus, they take
a complete history, perform a physical examination, obtain appropriate blood
tests, and order studies indicated by the patient’s symptoms and signs. Once this information is compiled, diagnostic possibilities other than lupus must be considered and ruled out. The fourteen chapters in this part take the reader through this diagnostic process using an approach that considers symptoms, signs, physical findings, and conditions affecting each organ, otherwise known as the
organ-system approach
. When the full evaluation is completed, the treating physician is able to formulate a comprehensive treatment plan.
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THE RHEUMATOLOGY CONSULTATION
A thorough medical evaluation is essential in order to make a diagnosis of lupus.
This consultation should be performed by a rheumatologist or qualified internist.
A rheumatologist is an internist (as are cardiologists, gastroenterologists, etc.) who has special expertise in diagnosing and managing diseases of the musculoskeletal and immune systems. The consultation includes several components.
First, a history of the patient’s complaints is taken. On the first visit to a consultant, it is helpful to present a summary of important symptoms and signs in
a concise fashion, either by making a list of them or reviewing them mentally
beforehand.
Especially when a patient has only one visit with a qualified consultant in
order to evaluate the possibility of lupus, proper preparation is essential. Copies of outside records and previous tests or workups are also helpful. Lupus is not easy to diagnose; surveys have shown that the typical lupus patient consults
three to five physicians before a correct diagnosis is made. In fact, studies have suggested that an average of 2 to 3 years elapse from the onset of symptoms
until the time lupus is diagnosed. This interval may be as short as a few weeks to months in children, who usually display more obvious symptoms, but in
patients over 60, it can be up to 4 years before a firm diagnosis is arrived at.
THE HISTORY AND REVIEW OF SYSTEMS
The lupus consultation consists of a history, physical examination, diagnostic
laboratory tests, or radiographic evaluations (x-rays, scans, etc.). A thorough initial interview is essential if the physician is to make a correct diagnosis and recommend proper treatment. After all the observations and tests are in, the
doctor will discuss the findings, perhaps at the time of the visit, at a telephone conference after the initial meeting, or in a follow-up visit.