The Lupus Book: A Guide for Patients and Their Families, Third Edition (49 page)

Also, the onset of menopause is associated with milder disease. I occasionally

allow reluctant patients with long-standing mild lupus to avoid medicine unless they are at risk for major complications.

WHAT DO LUPUS PATIENTS DIE OF?

The natural course of SLE has been extensively studied and researchers have

come to some interesting conclusions. The concept of a ‘‘bimodal survival

curve’’ was first proposed in the 1970s and subsequently validated. This means

that some lupus patients who die from the disease do so within the first 2 to 3

years of developing it. These individuals have active, aggressive lupus that responds poorly to therapy. After the third year, however, there’s a lengthy hiatus of 10 to 15 years with few lupus-related deaths. But at 15 to 20 years, the effects of years of disease and medication seem to catch up with some patients, and a

second mortality ‘‘hump’’ is observed. For example, young women who have

active disease and are given moderate to high doses of steroids when they are

20 do well for a while, but eventually may experience complications from on-

going steroid therapy. This leads to diabetes, high blood pressure, elevated cholesterols, and obesity—which may result in heart attacks by the time they are

40, as in Bonnie’s case (Chapter 14).

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The Management of Lupus Erythematosus

More than 90 percent of lupus patients with SLE die from one of five causes:

complications of kidney disease, infections, central nervous system lupus, blood clots, or cardiovascular complications. For unknown reasons, fatal cancer is rare among lupus patients. Several trends have become evident since survival curves

were first published in the 1950s. Improved methods of dialysis and the intro-

duction of transplantation have substantially decreased kidney-related deaths.

Superior methods of detecting and managing central nervous system lupus have

also greatly decreased mortality from this complication. Unfortunately, infec-

tions are still a major cause of death, especially among patients receiving steroids or chemotherapy. The discovery of antiphospholipid antibodies in the 1980s and

the use of blood thinning to prevent serious clots and strokes in patients at risk have not yet had an impact on survival in lupus, but improvements will be

evident soon. Some types of lupus are still very difficult to treat, and insufficient progress has been made to improve survival. These subsets include those patients with pulmonary hypertension, mesenteric vasculitis, and TTP (thrombotic

thrombocytopenic purpura). Bimodal survival curves are still relevant, but many fewer lupus patients are dying in the first 2 years.

Summing Up

The outcome of SLE depends on who is treating the disease; which ethnic,

racial, or geographically defined populations have the disease; and their socioeconomic status and therefore their access to subspecialty care; and the treatment philosophy of the health-care provider. In any case, more than 90 percent of all lupus patients in the United States live more than 10 years after being diagnosed.

The survival of patients with organ-threatening disease is still an unsatisfactory 60 percent at 15 years. Patients with high blood pressure, low platelet counts, kidney disease, and severe anemia have a poorer outcome and should be managed aggressively. Mild lupus occasionally disappears spontaneously; serious

lupus may ease up but does not go away without treatment. Deaths from lupus

generally occur early on from active disease or later from continuously active

inflammation or complications of therapy. Finally, in spite of all that has been said, I have found that patients who have a positive attitude and good coping

mechanisms and employ proactive strategies with their physicians have a better

prognosis.

33

New Therapies for Lupus and

Future Directions

What advances will take place in the next 15 years? Will we be able to cure

lupus or prevent it? Is there anything to look forward to? Let’s take a look at what the future holds—and it is indeed promising!

If developments proceed at the expected rate, my crystal ball suggests that

by the year 2020, an integrated health-care system will be in place, allowing all lupus patients to receive optimal treatment regardless of socioeconomic status

or medical insurability. A national data network should reveal exactly how many lupus patients there are as well as their gender and their racial, ethnic, and

occupational background. The gene or combination of genes that predispose one

to SLE and the environmental factors (viruses, chemicals, drugs, etc.) that turn these genes on will be known. It should be possible to identify individuals at

risk for developing the disease and perhaps to vaccinate them so as to prevent

autoimmune reactions. By 2020, we will know why 90 percent of patients with

lupus are women, and we’ll be able to manipulate hormones to decrease the

disease’s severity.

Existing therapies for lupus will be fine-tuned and improved upon. An ideal

NSAID that treats mild inflammation without any adverse reactions, which may

already be on the horizon, will be marketed. New-generation antimalarials and

steroids that eliminate most of the side effects we associate with these agents should soon be available.

Our current chemotherapy approaches are very general: they suppress all types

of white blood cells and do not substantially focus on any single ‘‘bad guy’’

subset. Increased use of combinations of chemotherapies that act at different

levels of the inflammatory and immune process will be commonplace. The major

advances in lupus therapy will emphasize cellular and antibody manipulation.

HOW ARE DRUGS STUDIED FOR LUPUS?

No new drug has been approved by the Food and Drug Administration (FDA)

for lupus since the 1960s. As of this writing (November, 2004), the only drugs

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The Management of Lupus Erythematosus

approved for SLE are Plaquenil, prednisolone (Medrol, a relative of prednisone), and aspirin. To be frank, manufacturers were scared away from studying lupus

for a variety of reasons. First, there was no agreed upon guideline or index used to denote improvement in the disease. Second, lupus patients often had multisystem disease with unpredictable complications which made it hard to tell if a drug was working. Also, until recently organized lupus advocacy was weak and

fragmented. As a result, promising new immune therapies were tested in other

autoimmune conditions. In 2003, under the leadership of Lee Simon, the FDA

sponsored hearings which led to development of a guidance document which

should jump-start interest in testing new drugs for the disease. The document

recognizes the importance of a variety of disease activity and outcome measures, which are discussed below.

Classification of Lupus

Any patient participating in a clinical SLE trial will have to fulfill the ACR

criteria for lupus. Although flawed (see Chapter 2) and though revision attempts are underway, they are still 90 percent sensitive and specific for diagnosing the disease.

Clinical Activity Indices

Since the mid-1980s, several centers have developed indices which assess dis-

ease activity. By giving points for specific symptoms, signs and laboratory ab-

normalities, these indices allowed investigators to follow improvement or wors-

ening of the disease through a composite score. The most thorough and accurate

index is the BILAG (British Isles Lupus Assessment Group), but it requires

considerable time to compile and expensive software to be run on. It should

only be used in performing complicated clinical trials. Any investigator can

calculate a SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) or

SLAM (Systemic Lupus Activity Measure) in a couple of minutes, and these

indices complement BILAG. The SLEDAI is more weighted to measure serious,

organ threatening activity, while SLAM includes more laboratory determinations

and subjective factors. The ECLAM (European Consensus Lupus Activity Mea-

surement) and National Institutes of Health derived SIS are also useful.

Response Measures

Determining whether or not a drug leads to worsening, no change, a partial

response, or resolution of a particular aspect of lupus has been the focus of

intense investigation recently. An example of such an instrument is the RIFLE

(Responder Index for Lupus Erythematosus).

New Therapies for Lupus and Future Directions

[263]

Quality of Life

Several instruments which have been validated for other diseases have been

shown to be helpful in lupus as well. These include measuring health related

quality of life using the SF-36 (which evaluates physical functioning, physical role, bodily pain, general health, vitality, social functioning, emotional roles, and mental health), HAQ (Health Assessment Questionnaire) score, patient and

physician assessments of the disease, disability, and Krupp Fatigue Severity

Scale Index.

Drug Safety

A new agent must not only be effective, but it also must be safe. Adverse events from a drug’s administration must be outweighed by its potential benefits.

Damage Indices

The ACR and SLICC have developed and validated a Damage Index. Prior

inflammation can scar the kidneys, heart, lung, kidney, or liver, producing ir-

reversible changes. If a drug can prevent new damage by slowing the rate of

increase of a damage index, it is potentially useful.

Biomarker or Surrogate Markers

In the past, clinicians used sedimentation rates, C3 complement, and anti-DNA

levels to assess disease activity and adjusted medication based on these values.

It turns out that some of these markers, or a combination of these markers

correlates with long-term outcome. If a new drug can improve these markers, it

may decrease the time necessary to test it since it often takes 10 years of ob-

servation to know if a treatment protocol for the kidneys, for example, prevents one from needing dialysis. The FDA is studying the use of traditional and newly developed markers in its lupus drug testing evaluations.

The Bottom Line

In order for a new drug to be approved for lupus, it should ideally decrease

clinical disease activity by clinical indices or biomarkers, prevent damage, be safe, and improve one’s quality of life.

WHAT DRUGS ARE BEING TESTED FOR LUPUS?

Only a handful of lupus drug trials were conducted in the 1990s. This section

provides a brief review of agents which are undergoing testing around the world.

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The Management of Lupus Erythematosus

Refractory skin disease:
Ultraviolet A-1 light, newer vehicles (polar solvents, liposomal encapsulation, enthosmoal systems, iontophoresis, electro-

poration, sonophoresis), epidermal grafting, cryotherapy, lasers (argon, carbon dioxide, erbium: YAG), topical immunophylles (tacrolimus, pinecrolimus).

Nonsteroidal anti-inflammatory drugs (NSAIDs:
Celecoxib (Celebrex)

Antimalarials:
isomeric forms of Plaquenil and quinacrine may be studied in the next few years

Corticosteroids:
budesonide

Hormones:
testosterone patches, leuprolide for fertility sparing purposes
Traditional immune suppressives:
newer insights into methotrexate and azathioprine metabolism will result in studies of measuring blood levels and

genetic factors which can predict response; intrathecal methotrexate for central nervous system lupus

Immunophylles:
transplant patients receiving cyclosporine A, tacrolimus and rapamycin with lupus will be followed and trials with cycylosporine are ongoing

Newer immune suppressive:
several mycophenolate mofetil trials are on-

going

Apheresis:
columns which remove specific components (e.g., anti-DNA,

staph protein A, C1q) are being evaluated

Vasodilators:
prostaglandin derivatives and bosentan for Raynaud’s and pulmonary hypertension

WHAT ABOUT BIOLOGICS?

Most drugs traditionally used for serious lupus are immune suppressives. In

other words, they lower blood counts and kill cells. However, these agents kill good cells as well as bad cells. In the early 1990s, a group of drugs known as

TNF (tumor necrosis factor) blockers was shown to be effective and approved

for managing rheumatoid arthritis. TNF blockers are known as biologics since

they do not lower blood counts and target a specific chemical interaction. Some patients with lupus have been treated with TNF blockade. Those with lupus

arthritis who do not have anti-DNA have generally done well, but this agent

can cause a drug induced lupus in rheumatoid and inflammatory bowel disease

patients since they stimulate the formation of autoantibodies such as anti-DNA, ANA, and anticardiolipin antibody. Most of the time this is of little significance, but sometimes clinical lupus evolves which goes away with the drug’s discontinuation. Most lupologists generally avoid the use of these agents in SLE unless the clinical presentation is one of primary rheumatoid arthritis.

New Therapies for Lupus and Future Directions

[265]

Biologics have recently begun to be studied for lupus and are reviewed below.

Biologics tested for lupus no longer under study:
anti-CD4, anti-CD5 ricin A im-munoconjugate, human recombinant DNAse, IDEC anti-CD40-L (all ineffective),