The Lupus Book: A Guide for Patients and Their Families, Third Edition (43 page)

Abnormal liver function tests and low blood counts can be found and should

be monitored every month at the beginning of treatment and ultimately every

few months. A blood test, known popularly as “TPMT” is now available and

can predict who will have difficulty tolerating Imuran. Imuran, like all immu-

nosuppressive therapies, increases one’s susceptibility to infection. Although

Imuran can be carcinogenic after many years of use, administration of the drug

for 2 to 4 years in patients with active SLE is not associated with increased

cancer risk.

A popular rheumatoid arthritis drug,
methotrexate
, has been on the market
Big Guns and Magic Bullets: Disease-Modifying Drugs

[227]

since the 1940s. In high doses, it is a very effective agent in managing numerous types of cancer. The drug is popular because it works within weeks and is taken only once a week. Acting via its inhibition of inflammatory chemicals that are

necessary for cell growth, low doses of methotrexate decrease joint inflammation and have been used in SLE. However, several problems have been encountered.

First of all, methotrexate can make patients with lupus more sensitive to ultraviolet light. Also, it appears to have little effect on organ-threatening disease.

Additionally, the drug is handled by the kidneys. Therefore, if renal disease is present, the doses have to be drastically reduced in order to prevent a precipitous drop in blood counts. Anyone taking methotrexate must refrain from drinking

alcohol and must have blood and liver function tests made at regular intervals.

Nausea, mouth sores, and headaches are the most common side effects of meth-

otrexate, some of which can be minimized by taking daily folic acid. I restrict its use to lupus patients who have active joint inflammation without significant skin or organ-threatening disease. Folic acid supplementation to methotrexate

may minimize its toxicity.

Chlorambucil (Leukeran)
is an oral alkylating agent commonly used in Europe and developing countries, but it is prescribed in the United States only for patients who are allergic to or cannot tolerate Cytoxan. It is much better tolerated than oral Cytoxan; however, it is less effective and more dangerous than intravenous Cytoxan because its long-term use makes it a potent carcinogen.

NEWER IMMUNE SUPPRESSIVE DRUGS

Since 1990, newer approved immune suppressive drugs potentially useful for

lupus include rheumatoid arthritis drug leflunomide (Avara), mycophenolate mo-

fetil (Cell Cept), and Cyclosporin A. Preliminary studies suggest that Cell Cept may be a viable alternative to Cytoxan for patients with lupus nephritis.

Cyclosporin A
(Neoral) prevents organ transplant rejections in part by blocking the cytokine interleukin-2. Inflammatory rheumatoid-like arthritis responds to this drug, which, however, is rarely needed for this. Cyclosporin A was

avoided in lupus for a long time because it raises blood pressure, causes un-

wanted hair growth, and elevates lipid and creatinine (kidney function) blood

levels in tests. But, most lupus patients who take the drug after a kidney transplant have tolerated it surprisingly well with few adverse reactions. Some recent evidence suggests that class V (membranous) lupus nephritis responds particularly well to this agent. Cyclosporin also helps patients with suppressed bone

marrow activity who have difficulty making red blood cells or platelets and

some lupus patients with urticavia, or welts. A newer, similar agent known as

tacrolimus
(Prograf, FK506) has recently become available. A topical prepration of tacrolimus (Protopic) as well as the closely related pinecrolimus (Elidel) has been used for cutaneous lupus.

[228]

The Management of Lupus Erythematosus

Leflunomide
(Arava) inhibits pyrimidine production, one of the building blocks of DNA. As effective as methotrexate in managing rheumatoid arthritis,

our center and Johns Hopkins have suggested that this agent helps lupus arthritis as well. It probably has little effect on serious lupus. The major side effects of Arava are hair thinning and diarrhea.

Mycophenolate
mofetil (Cell Cept) is an immune suppressant developed to prevent organ transplant rejection. More powerful but more expensive than Imuran and less potent than cyclophosphamide, it is much better tolerated. Studies have suggested that Cell Cept may have a place in treating lupus nephrits. Cell Cept can be used to limit cyclophosphamide exposure and has been tried in

combination with this, and is steroid sparing.

Table 27.2 lists the major immunosuppressive therapies available to treat SLE.

Summing Up

Antimalarials are prescribed for non-organ-threatening disease and to relieve

skin, joint, pleural, and fatigue symptoms. They take many months to work and

probably decrease the risk of lupus spreading to critical organs. I give them to all newly diagnosed lupus patients without organ-threatening disease for at least 2 to 4 years. Corticosteroids are used in high doses for critical organ disease;
Table 27.2.
Immunosuppressive Therapies Available to Treat SLE

Alkylating agents

Cyclophosphamide (Cytoxan)—The most widely used agent. It can be effective, powerful, and toxic.

Nitrogen mustard—Almost the same as cyclophosphamide but messier to give and has to be administered in a hospital.

Chlorambucil (Leukeran)—Available only orally. Very well tolerated but probably more carcinogenic than cyclophosphamide or nitrogen mustard.

Antimetabolites

Azathioprine (Imuran)—A good steroid-sparing agent. Much weaker than alkylating agents.

Methotrexate (Rheumatrex)—A good steroid sparing agent for lupus arthritis if sun sensitivity is minimal. Must be used carefully with kidney impairment; there is no evidence that it helps organ-threatening disease.

6-Mercaptopurine—Almost the same as azathioprine; rarely used because it is more toxic to the liver.

Leflunamide (Arava)—Approved for rheumatoid arthritis, helps lupus arthritis.

2-chlordeoxyadenosine (2-CDA)—A leukemia drug potentially useful for nephritis.

Transplant anti-rejection drugs

Cyclosporin A (Neoral)—Approved for rheumatoid arthritis; may help membranous lupus nephritis and sluggish bone marrows.

Tacrolimus (Prograf, FK 506)—Similar to cyclosporin, but untested in lupus.

Mycophenolate mofetil (Cell Cept)—A very promising improvement over cyclosporin and possibly azathioprine for lupus nephritis.

Big Guns and Magic Bullets: Disease-Modifying Drugs

[229]

otherwise, function in that organ might be lost. They can be prescribed for mild to moderate disease, but antimalarials, NSAIDs, and methotrexate should be

started at the same time, allowing steroids to be discontinued as soon as possible.

Chemotherapies such as cyclophosphamide or azathioprine are used for patients

with severe, active disease. They work with corticosteroids in decreasing disease activity and also allow steroid doses to be tapered. Corticosteroids and immunosuppressives are very toxic, and careful monitoring is necessary.

28

Other Options: Treatments

Occasionally Used to Manage Lupus

In addition to the disease-modifying drugs discussed in the last chapter, many

other agents have a place in managing different aspects of lupus. These drugs

or therapies ‘‘fall into the cracks,’’ or have limited uses under special circumstances. Most of them have a ‘‘bridging’’ function: they are used for short

periods of time until one of the disease-modifying agents discussed in the pre-

vious chapter becomes effective. This section offers a brief overview of these

bridge therapies.

NONCONTRACEPTIVE HORMONES

The use of estrogen-containing hormones for contraceptive purposes has been

the focus of many discussions of lupus. Far less attention has been given to

other hormones that may be useful in SLE.

Since 90 percent of lupus patients are women, rheumatologists logically

thought that male hormones might help them.
Testosterone
was given to female lupus patients without success as early as 1948, and numerous unsuccessful

findings have been published since. This might stand to reason, since males with lupus often fare worse than females. Newer formulations of testosterone patches are being studied for lupus. However, evidence that estrogen decreases the immune response and male hormones increase it suggests that certain male hor-

mone products might be useful. A male-type hormone made by the adrenal gland

known as
dehydroepiandrosterone (DHEA)
has a role in the treatment of mild to moderate lupus; it may be particularly useful in patients with cognitive dysfunction and fatigue. It may also decrease the rate of bone loss. Doses at or

above 100 mg a day are effective, high doses are associated with facial hair

growth or outbreaks of acne.

Even though there has been only one report in the world’s literature of a

lupus flare from
estrogens
given to manage menopausal symptoms (e.g., Estrace,
Other Options: Treatments Occasionally Used to Manage Lupus

[231]

estrogen patches), many physicians are needlessly reluctant to prescribe these

replacement hormones. This is partly because, unlike birth control pills (dis-

cussed in Chapter 30), replacement hormones are not associated with clinically

relevant blood clotting abnormalities, probably because they have only 20 per-

cent as much estrogen as birth control pills. These agents are generally tolerated very well by my patients and also have a place in treating
osteoporosis
. Osteoporosis is the loss of calcium in bones and is more common in lupus, due to

chronic inflammation and corticosteroid therapy. Severe bone loss leads to painful bony fractures (Chapters 13 and 29).

Danazol (Danocrine)
, marketed for endometriosis, is an antiestrogen which, for unclear reasons, can improve autoimmune hemolytic anemia and low platelet

counts associated with SLE. I use it for patients with low platelet counts who have no lupus disease activity elsewhere in the body.
Bromocriptine (Parlodel)
inhibits the secretion of breast milk by blocking the actions of prolactin, the hormone that stimulates the production of breast milk. Considerable evidence has accumulated indicating that many lupus patients have elevated prolactin levels. This, in turn, is associated with an immune dysfunction. Unfortunately, patients of mine who have taken bromocriptine have had no improvement in their clinical lupus.

RETINOIDS

Retinoids are vitamin A derivatives that block cell growth and act as anti-

inflammatories. Retinoids were not used in the past in part because they, with

the exception of beta carotene, tend to increase sun sensitivity. But recent reports indicate that retinoids are very effective in managing subacute cutaneous lupus and refractory discoid lesions if they are used with sun blocks, and this has

changed our thinking. Several of them, including
13-cis-retinoic acid (Accutane)
and
acitretin (Soriatane)
, are potent agents usually used to treat psoriasis or acne, and they also have anti-lupus effects. All these agents can raise lipid levels (especially triglycerides) and are very drying. None of these drugs should be

prescribed for women who might become pregnant, since they induce birth de-

fects. Their effects last only as long as they are taken; they do not have the

disease-modifying properties of the antimalarials. As with antileprosy drugs,

retinoids are used concurrently with antimalarials until the rashes improve to

the degree that they can be discontinued.

Beta carotene
is a nonprescription retinoid health supplement that acts as a mild sun block but has little if any effect upon lupus.

ANTILEPROSY DRUGS

Leprosy—a bacterial infection primarily involving the skin, joints, and periph-

eral nervous system—provokes a mild autoimmune reaction. Cutaneous leprosy

and discoid lupus can be difficult to tell apart.

[232]

The Management of Lupus Erythematosus

Antileprosy drugs have actions similar to those of antimalarial agents and are

useful for resistant skin and joint problems. However, they have no place in

treating serious systemic activity.
Dapsone
is the most commonly used drug in this class. It has been helpful in managing hard-to-treat skin and joint lupus, especially if a particular rash called bullous lupus is present. Bullous lupus

resembles chickenpox except that its distribution is different and the blisters tend to be larger. If it is left untreated, serious systemic complications can develop, especially dehydration. Patients taking dapsone (who have an initial negative screening blood test for an abnormality known as G6PD) should have liver

tests and blood counts monitored every few weeks. A G6PD deficiency is a

contraindication to the use of dapsone since it can cause hemolytic anemia.

Clofazimine (Lamprene)
is a relatively recent addition to the antileprosy arma-mentarium in the United States. Particularly useful for refractory discoid skin lesions, it has the advantage of being well tolerated and is taken only once a

day. Unfortunately, Lamprene can stain the skin much as quinacrine does, al-

though the pigmentation also disappears upon its discontinuation.

A third limited-use alternative,
thalidomide
, was introduced in Europe as a mild sedative in the late 1950s. A worldwide scandal exploded in the early 1960s when the agent was implicated in causing birth defects and numerous children