Positive Options for Living with Lupus (18 page)

The answers, when they come, will probably emerge little by little, because it is possible that there will turn out to be more than one trigger, and certainly more than one susceptible gene.

This chapter looks into the crystal ball to see what shapes are emerging from the mist, or more prosaically, what avenues lupus researchers are following.

New Drugs in the Pipeline

Drugs that are in the pipeline are not difficult to find on the Internet. It takes years and vast sums of money to develop a new drug, with the hope of a matching profit only if a new blockbuster makes it to the market. So every candidate’s progress is watched keenly by financial analysts as well as by the medical fraternity. However, for every drug that reaches the final stage—being tested in humans for its safety and effectiveness—nine out of ten stumble on one of the numerous hurdles along the course. Of those that reach the finish-ing line, break the tape, and go on sale, some may yet be withdrawn following a drug test, as rare side effects only emerge after a drug has been taken by tens of thousands of patients for a lengthy period.

That is what happened with the COX-2 inhibitor Vioxx, which looked so promising for arthritis patients when first launched, but turned out to damage the hearts of some patients and was subse-quently withdrawn. So the problem for drug manufacturers, doctors, patients, and authors alike is which drug in the pipeline will stay the course? And, to be honest, it’s in the lap of the gods.

Here are some of those in the race for treating lupus: Bromocriptine

This drug acts to reduce the release of a hormone called prolactin.

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in both sexes. High prolactin levels, associated with tiny tumors in the pituitary gland, where it is released, lead to infertility by preventing menstruation and ovulation in young women; bromocriptine has been used to treat this condition for some years. (Novel uses for drugs that have been approved for other therapies start at an advantage because the drugs’ safety has already been demonstrated in large numbers of patients.) The fact that lupus is a disease that predominantly strikes women of childbearing years has focused researchers’ interest on hormones. High prolactin levels seem to stimulate the production of autoreactive antibodies in lupus, hence the idea that bringing them down with bromocriptine might help. It works in laboratory mice. Work in humans suggests that it could turn out to be on a par with hydroxychloroquine as a lupus treatment.

Prasterone

We looked at the role of hormones when considering the possible causes of lupus in Chapter 3. You first met prolactin there, and a form of androgen called dehydroepiandrosterone, or DHEA, which is a precursor of both the male hormone testosterone and the female hormones that regulate fertility in women: estradiol and progesterone. DHEA levels are often lower than average in lupus patients of both sexes, which prompted the development of a synthetic version of DHEA called prasterone (Prastera). This drug has A Warning

American lupus expert Sheldon Blau alerts lupus sufferers to over-the-counter, so-called dietary supplements that profess to contain DHEA. Variously and unscientifically described as “superhormones”

or “miracle drugs,” they claim to promote weight loss, improve memory, fight infection, prevent cancer or heart disease, and generally to make you live forever with the body of a twenty-year-old.

Be advised: They won’t. Sheldon Blau speaks for medical experts everywhere when he reminds us that licensed drugs have to undergo lengthy testing for safety, purity, and effectiveness before they are let loose on the public. Supplements don’t.

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had a checkered career during clinical testing. In August 2005 the U.K. drug assessment authority, the National Institute for Clinical Excellence, announced that the application to approve it had been withdrawn.

Monoclonal Antibodies

We learned in Chapter 3, on the causes of lupus, that much of the damage in lupus is caused by antibodies, or B lymphocytes, that react to the body’s own tissues, chiefly fragments from the interior of broken-down cells in the bloodstream. Attention has therefore been focused upon reducing the proliferation of these antibodies.

On the principle of “set a thief to catch a thief,” scientists have tried to design tailor-made antibodies that will seek out and destroy those elements of the immune system that promote inflammation without reducing the parts that perform a protective function. These have worked well in laboratory mice bred to exhibit lupus-like symptoms.

“Synthetic” antibodies are constructed by cloning a single antibody-producing cell, and are called
monoclonal antibodies
(MoAbs).

Two MoAbs are being investigated for the treatment of lupus. One, called rituximab, was approved some years ago for the treatment of a form of cancer called non-Hodgkin’s lymphoma in which B lymphocytes multiply beyond control. The MoAb attacks a marker on the surface of B lymphocytes, which grow up to produce the autoimmune antibodies, which in turn cause the inflammation that does all the harm in conditions like rheumatoid arthritis and lupus.

So it seems logical to explore whether it would be effective in these conditions. In September 2004 researchers at the University of Rochester Medical Center reported that a single injection of rituximab gave eleven lupus patients, out of a total of seventeen, relief from a range of symptoms for a year or more. The improvement coincided with a drop in the number of B cells circulating in the patients’ bloodstream. This was a very small trial and not randomly controlled (see Chapter 6, “Randomized Clinical Trials (RCT): The Therapeutic Gold Standard”), so judgment must be provisional.

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Another monoclonal antibody currently being studied in patients with lupus or rheumatoid arthritis strikes even earlier in the antibody-producing process. Its target is a recently discovered protein that stimulates B lymphocytes, which grow up to produce the autoimmune antibodies . . . and so on. A MoAb known provisionally as LymphoStat-B latches onto this B-lymphocyte stimulator (BlyS for short) and inhibits the development of harmful antibody-producing B cells. So far this particular MoAb has been shown to be side-effect free.

Selective Immunomodulators

Lupus is an autoimmune disease, but the autoimmune system plays a vital protective role in the body, so even if you could, you wouldn’t want to suppress it entirely. The goal is to find a drug that will be selective: a rapier rather than a bludgeon, a drug that will remove the autoimmune antibodies causing the trouble while leaving the good antibodies to carry on with the positive work, vanquishing infection. Such drugs modify, or modulate, the immune system, hence the name immunomodulators. One such drug, code-named “LJP

394” (trade name Riquent), targets an antibody to a particular kind of DNA known as double-stranded DNA (hence its title of anti-dsDNA antibody) that shows up in the blood of lupus patients, especially when they have bouts of nephritis. So far it appears that the catchily named LJP 394 does reduce the quantity of anti-dsDNA antibodies and may also reduce the risk of nephritis.

Experimental Treatments for

Kidney Damage

The most serious manifestation of lupus is kidney inflammation (nephritis). If it proves impossible to “head it off at the pass,” there may come a stage when the only solution is a kidney transplant, and donor organs are in very short supply. A number of treatments short of replacement are being investigated.

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A healthy body has built-in mechanisms for repairing damaged organs. One of the substances that stimulates this process has been identified and goes under another of those catchy pharmaceutical code names: BMP7. This stands for “bone
morphogenetic
(form-generating) protein number 7,” and a synthetic version of it has in fact been used successfully to speed the process of recovery in broken bones. Natural BMP7 is found in the kidneys. Inflammation such as occurs in severe lupus produces scar tissue known as renal fibro-sis, and researchers have discovered that BMP7 can reverse this process and stimulate the production of new, healthy tissue. So far it’s only been done in laboratory mice.

Two nondrug treatments have been tried for severe or unre-sponsive lupus. Although not surgical, these therapies might be considered heroic. One is the use of targeted radiation, which is successful in preventing the recurrence of some cancers. A procedure called
total lymphoid irradiation (TLI)
targets the lymph nodes and other tissues where the lymphocytes—including the cells that grow up into the B cells that produce the antibodies, etc.—congregate. TLI appears to suppress some of the antibodies overproduced in lupus. It has been used successfully for some years to treat a potentially fatal form of lymphoma (cancer of the lymphatic system).

Less frequently it has been tried for multiple sclerosis and rheumatoid arthritis. Its long-term safety and efficacy have not been established, and, like some drug treatments, it makes patients more susceptible to infection. It is uncertain whether it will ultimately prove useful in severe and refractory lupus, which is only infrequently life-threatening.

The other nondrug treatment is
plasmapheresis
. This is a mechanical procedure rather like kidney dialysis, in which the blood is circulated outside the body and harmful elements filtered out before the blood is returned. Plasma is the fluid in which various sorts of blood cells swim around. Pheresis (from the Greek for “removal”) is the process of filtering out substances circulating in the blood. In the case of autoimmune diseases it can be used to remove some of the inflammatory antibodies and antigen-antibody complexes in the POL text Q6 good.qxp 8/12/2006 7:39 PM Page 117

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blood of lupus patients. So far it has only been used experimentally for rheumatoid arthritis, and although it removed harmful antibodies and improved some symptoms, the results are not long-lasting. It doesn’t appear to provide any improvement in the kidney problems that are the most severe manifestations of lupus.

And Now for Something

Completely Different

On several occasions we have commented that the human body is, by and large, if not infallibly, a self-healing organism. Self-healing is what the autoimmune system, among others, is all about. In recent years, scientists have asked whether the processes the body uses to grow and develop, as well as to heal, could be adapted to treat diseases that have so far outfoxed them. This is a step beyond making a drug in the laboratory that mimics a substance that is naturally active in the body, such as a steroid. This is using the body’s own cells as a cure (see box “Chameleon Stem Cells,” on the next page).

Stem cells may come from a donor, like a transplanted kidney, but preferably they are harvested from the patient’s own blood. After the harvest the patient’s abnormal mature cells are destroyed by use of a powerful immunosuppressant. This is the tricky stage, because at that moment, having no functional immune system, the patient is extremely vulnerable to infection. Needless to say the procedure is carried out with the patient in the hospital, in protective isolation. Once the abnormal cells are cleansed, the stem cells are reintroduced. Hopefully they mature, thrive, and produce new, normally functioning cells for the patient. This procedure is called
autologous
(self-sourced)
hematopoietic
(blood-making) stem-cell transplantation.

Used experimentally since 1997 in specially selected patients, it has been successful for some cases of another disease of the immune system, non-Hodgkin’s lymphoma. It is also under consideration for rheumatoid arthritis. Because it is so risky it is only offered to patients with severe, drug-resistant, organ-threatening disease. At this POL text Q6 good.qxp 8/12/2006 7:39 PM Page 118

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moment that applies to very few lupus patients. However, it is almost certainly a form of therapy that has a very promising future.

Chameleon Stem Cells

Most adult body cells are specialists; as mature cells they are either specialist blood cells, muscle cells, brain cells, etc. They cannot switch and do a different job once they are mature. But cells start life as simpler nonspecialists known as stem cells. The most versa-tile stem cells are those in the embryo; they are the basis for the very beginning of life. Basic, dividing embryonic stem cells have the capacity to develop into all the different specialist cells a mature human body requires. Some embryonic stem cells are still present in the umbilical cord, and that is why the United Kingdom has set up a unit to bank cord blood harvested during birth. But even mature specialist cells, which are continually replacing themselves, start as immature forms and, in this state, can be encouraged to diversify if cleverly handled. It means harvesting immature stem cells from the site where they are produced; in the case of blood cells—white and red cells or platelets—this is in the bone marrow. Although blood cells are produced in the bone marrow, they can be harvested from blood by giving the patient something that encourages them to pro-liferate so that they spill out into, and can be picked up from, the bloodstream. They are then frozen in plastic bags with preservative until they are needed.

Fundamental Research in Progress

The research discussed in this chapter is mostly about potential treatments being investigated in the clinic. But what guides new treatments is fundamental research into the disease process that goes on in laboratories, behind the scenes. Several studies are looking at ways of reducing the number of autoimmune B cells produced in lupus, and similar diseases, and also looking at understanding how they are different from B cells in people without lupus. Studies are also going on to identify the genes that make people susceptible to lupus and other autoimmune diseases.