The Lupus Book: A Guide for Patients and Their Families, Third Edition (40 page)

so as to minimize bleeding risks. Doctors may try as many as ten agents before

they find one that works and has no side effects. The choice of NSAID prepa-

rations is a highly individual one, and what works for one person may not work

for another.

What are Selective Cox-2 NSAIDS?

NSAIDS work by inhibiting prostaglandins via blocking the enzyme cyclo-

oxygenase. It turns out that there are two types of cyclooxygenase (called cox

for short): cox-1 and cox-2. The anti-inflammatory actions of NSAIDS are found

in cox-2, while most of their side effects are produced when cox-1 is blocked.

Selective cox-2 antagonists have been available since 1998 (see Table 26.1).

Preliminary evidence suggests they are safer for the liver, have fewer drug in-

teractions, produce less heartburn and fewer ulcers, and don’t interfere with

blood clotting. Our group has shown that celecoxib (Celebrex) is safe and ef-

fective in treating lupus symptoms, but another agent, rofecoxib, (Vioxx), was

removed from the market in 2004 due to promotion of clotting and atheroscle-

rotic disease.

Do Topical NSAIDS Work?

In the United States, compounding pharmacists are allowed to make generic

NSAIDS (especially ketoprofen and diclofenac) as topical gels. Rubbed into

painful joints twice daily, they relieve local symptoms and only very rarely

produce systemic complaints. Topical NSAIDS have been available outside of

the United States for many years. Some compounders have added cyclobenza-

prine (Flexeril) and other chemicals that relax muscles and decrease nerve irritation to their gels, with varying degrees of success. The production of these

preparations is not standardized, and some are quite expensive.

WHAT ABOUT ACETAMINOPHEN (TYLENOL)?

Acetaminophen is an analgesic medication that modestly decreases pain (e.g.,

headache) and lowers fevers. It has
no
real anti-inflammatory effects, so it is usually not recommended in lupus cases. Rheumatologists occasionally come

Taming Inflammation: Anti-inflammatory Therapies

[213]

across patients who cannot take any NSAIDs; therefore they may reluctantly

advise acetaminophen. The only other time it is used is to relieve pain for a

week prior to surgery, when NSAIDs should not be used (because they prolong

bleeding times), and when a pregnant woman has other nonlupus illnesses caus-

ing pain or discomfort such as headaches, fevers, or back sprain.

Summing Up

Salicylates have been used for more than 100 years and other nonsteroidals for

more than 40 years. They are effective in treating fevers, headaches, arthritis, arthralgia, muscle aches, and serositis. None of these agents have any disease-modifying properties in lupus and have no place in serious SLE without disease-

modifying drugs. The choice of a particular drug depends on the medical history; several agents are usually tried before one is found that is effective and safe.

Call your doctor if you encounter any problems with these drugs. All the prep-

arations listed in this section require regular blood testing and a rectal examination with a stool smear for blood at least once a year. With appropriate mon-

itoring, NSAIDs can be given concurrently with other anti-lupus medications.

27

Big Guns and Magic Bullets:

Disease-Modifying Drugs

Up to this point, we’ve covered nonmedical aspects of therapy as well as the

over-the-counter basics and prescriptions—NSAIDs—which help control symp-

toms and pain. Now we move on to other prescription drugs. Over 90 percent

of all lupus patients will be given one of these agents at some time in the course of their disease. These drugs are termed ‘‘disease-modifying’’ because they can actually alter the course of lupus. Rheumatologists have nicknames for them

such as DMARDs (disease-modifying anti-rheumatic drugs), among others. The

DMARDs for lupus fall into three general categories: antimalarials, steroids, and immune suppressives.

WHAT DOES LUPUS HAVE TO DO WITH MALARIA?

When a rheumatologist mentions to a patient that she might benefit from anti-

malarial therapy, the usual response is one of confusion. The relationship was

discovered by accident. The first use of antimalarials dates back to 1630, when the Countess Anna del Chinchon, wife of the viceroy of Peru, fell seriously ill with a high fever. In desperation, the family allowed local Indians to treat her with bark extracts from a ‘‘fever tree,’’ and she made a miraculous recovery.

The cinchona tree was named after the grateful countess, who proceeded to

corner the market and arrange for its exportation to Spain. Years later, quinine was found to be the active ingredient of cinchona bark. In addition to its ability to diminsh fever, it was noted to have anti-inflammatory and anti-infectious

properties, including beneficial activity against malaria. When the Japanese conquered Java during World War II, they effectively prevented the Allies from

obtaining natural quinine. Faced with a serious threat of malaria among their

troops in the southwestern Pacific theater, the Allies bootlegged an artificial quinine recipe from the notorious German I. G. Farbenindustrie combine (which

made the gas chambers used in the concentration camps) and called it Atabrine.

Big Guns and Magic Bullets: Disease-Modifying Drugs

[215]

In 1943, the U.S. Surgeon General declared Atabrine to be the drug of choice

to prevent malaria, and 4 million American, Canadian, Australian, New Zealand,

and British soldiers took it daily for 3 years. There were anecdotal reports that soldiers with rheumatoid arthritis or lupus experienced improvement in rashes

and joint symptoms when they took Atabrine; this led the British to conduct a

study on its efficacy in lupus. The findings were published in the English journal
Lancet
in 1951. Antimalarials have been with rheumatologists ever since. Efforts to improve upon Atabrine led to the introduction of chloroquine (Aralen) in

1953 and hydroxychloroquine (Plaquenil) in 1955. The production of Atabrine

was discontinued in 1992; it is now available from compounding pharmacists

as generic quinacrine.

How Do Antimalarials Work?

Antimalarials have remarkably different and often divergent actions. They block ultraviolet light from damaging skin; have an anti-inflammatory effect similar

to that of the NSAIDs; lower cholesterol levels by 15 to 20 percent; inhibit

clotting; block certain pro-inflammatory cytokines and, most importantly, alter the acid-base balance of the cells, which limits their ability to process antigens.

If antigens are allowed to be processed, this would lead to the creation of un-

necessary antibodies. Unlike steroids and chemotherapies, antimalarials do not

lower blood counts or make patients more susceptible to infection. They are

mild by nature, and altering the acid-base balance of cells takes time before a significant effect is noted. Plaquenil, for example, has an onset of action of 2

to 3 months, but its efficacy does not peak for several more months. Most

patients are unaware of its benefits for 4 to 6 months. These agents have no

place in the management of organ-threatening SLE.

What Symptoms and Signs of Lupus Respond Best to Antimalarials?

In patients with non-organ-threatening SLE, antimalarials benefit several sys-

tems. The skin is helped by the interruption of ultraviolet light and anti-

inflammatory actions. Discoid lesions, redness, mouth ulcers, and hair loss im-

prove in 90 percent of these patients. Joint manifestations also diminish as

swelling and aching decrease. Over time, inflammation of the pleura and peri-

cardium lessens, as do constitutional symptoms of fatigue and cognitive dys-

function. Antimalarials are mild cortical stimulants in the sense that they can give patients energy. This is particularly true with quinacrine and to a lesser extent Aralen or Plaquenil. Antimalarials are probably useful in patients with

Sjo¨gren’s syndrome (dry eyes, dry mouth, and arthritis), steroid-induced high

cholesterol, and in patients with antiphospholipid antibodies that pose a risk for blood clots.

[216]

The Management of Lupus Erythematosus

In 1991, a group of Canadian rheumatologists studied 47 patients whose mild,

non-organ-threatening lupus was under good control with Plaquenil. Half of the

patients were randomized to receive a placebo (sugar pill) and half continued

their Plaquenil. This was a double-blind study—that is, the patients had no idea which drug they were being given, nor did the reseachers. The Plaquenil group

had many fewer disease flareups and organ-threatening complications over a 6-

month period. This study confirmed previous suggestions that the institution of antimalarial therapy early in the disease course decreases the risk that lupus will spread to critical organs.

What Antimalarial Should Be Taken, in What Dose?

The only antimalarial currently approved by the FDA and promoted specifically

for lupus is Plaquenil. The cost of a year’s therapy is about $500. Rheumatol-

ogists vary widely in their use of this drug. I have my newly diagnosed lupus

patients without critical organ disease take Plaquenil for at least 2 years. After two weeks of 200 mg a day as a test dose, the usual maintenance dose is 400

milligrams (two tablets) once daily. During the third year of therapy, I may

reduce the dose to 200 milligrams a day (one tablet). Most of my patients are

80 to 90 percent better after 2 to 3 years. About half of them are able to dis-

continue the drug after 3 to 4 years and half need additional treatment. Some-

times, acute flareups necessitate higher doses of the drug; the FDA allows up

to 800 milligrams of Plaquenil to be given daily for short periods of time. Some lupus patients might require longer or different Plaquenil regimens. These include patients with Sjo¨gren’s syndrome. Dr. Robert Fox in La Jolla, California, has shown that it takes 2 to 3 years of therapy before dry eyes and dry mouth

show clinical improvement. Patients with critical organ disease or serious joint inflammation who require steroid therapy might benefit from the concurrent use

of Plaquenil as long as they are on corticosteroids, since the antimalarial is

steroid sparing (allows lower doses of steroids to be given), lowers cholesterol raised by steroids, and may decrease the tendency of steroids to promote clots.

What about the patient who has only a partial response to Plaquenil? After 6

months of treatment, many patients tell me that they are 50 percent better but

still have rashes or joint swelling. In these cases I first make sure they have had an adequate trial of all appropriate NSAIDs that can be given along with antimalarials. If this is the case, we can add methotrexate (discussed below), low

doses of oral steroids (discussed immediately below), or another antimalarial.

What other antimalarials are appropriate for lupus?
Chloroquine
(
Aralen
) was FDA-approved for lupus and rheumatoid arthritis and is still widely used outside the United States for these indications. But the manufacturer no longer recommends it for lupus since Plaquenil is much safer. Nevertheless, chloroquine is

readily available and is a much more potent drug. It is particularly effective for
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[217]

skin rashes and joint inflammation, and therapeutic benefits are noticeable in a month. I prescribe chloroquine when patients with severe skin or joint lupus

cannot wait 6 months for Plaquenil to work, but I switch them over to Plaquenil within 3 to 4 months to prevent serious eye toxicity. Quinacrine is still available through 2000 ‘‘compounding pharmacists’’ in the United States. These old-time

pharmacists make the drug from scratch by grinding up quinacrine powder.

Quinacrine is indicated for lupus patients who cannot risk any potential damage to their eyes, those who cannot tolerate Plaquenil (it is chemically different), and those whose main complaint is profound fatigue. Quinacrine is synergistic

with Plaquenil or chloroquine: the drugs mix together well and their combined

benefits are greater than those of both agents separately. The usual dose for

quinacrine is 100 milligrams daily, although as little as 25 milligrams a day is effective. Quinacrine works within a month, and after 2 years it can be tapered to 5 days a week, then 3 days a week, and finally once a week.

For those who remember my friend Ray Walston standing and dancing on a

box labeled Atabrine during the soldiers’ variety show in the movie
South Pacific
, it has been half-jokingly suggested that this cortical stimulant played a role in the Allies’ victory in World War II.

General Adverse Reactions and How to Handle Them

Plaquenil is generally very well tolerated. A surveillance study showed that only 8 percent of lupus patients given the drug discontinued it during the first 12

months. Approximately 10 to 15 percent of patients develop generalized com-

plaints of aching, nervousness, headache, queasiness, or nausea. When a patient relates these problems to me, I stop Plaquenil for 72 hours and then restart it at 200 milligrams daily. The body adjusts to the drug, and within a few months

the dose can be increased to 300 to 400 milligrams. Doses as low as 200 mil-

ligrams a day can be effective in lupus; they just take longer to work. Another 5 percent of patients develop a rash on Plaquenil. When this occurs, the drug