New Optimism in the Treatment of Lupus

Lupus, also known by its full name: Systemic Lupus Erythematosus or SLE is a chronic and often debilitating condition. It's an autoimmune disease with many different signs and symptoms affecting all systems of the body. Autoimmune means the immune (defense) system starts to mistake your own cells as "foreign" and begins attacking them.

The destruction that takes place can affect any part of the body but especially the skin, joints, organs, the nervous system, and the blood. The body produces antibodies against itself (called autoantibodies). These immune cells go throughout the body producing an inflammatory (healing) response when it isn't needed. The result of chronic inflammation is a breakdown of tissues over time.

The patient may face serious problems like atherosclerosis (clogged arteries), osteoporosis (brittle bones), life-threatening infections, kidney failure, and fluid around the heart and lungs, to name just a few.

What can be done about this? Treatment is really more a matter of management than cure. Medications are the front runner in this area. For a long time, antiinflammatories including steroids have been used. But the long-term side effects of these medications can be very harmful.

More recently, scientists have turned toward finding better ways to target the problem rather than just treating the symptoms. Medications in a new class of drugs referred to as biologics are on the horizon. These agents treat the disease at the cellular level.

The first group of disease modifying anti-rheumatic agents found to be effective started with antimalarial drugs. Physicians found that by using antimalarial medications, patients with lupus (SLE) could manage their disease, reduce flare-ups of symptoms, and take less of the more damaging steroidal antiinflammatories.

Patients with SLE who normally have a lower life expectancy than adults without this disease were living longer with a better quality of life after taking antimalarials. Their cholesterol levels went down, too, which means fewer problems with atherosclerosis and heart disease. Steroidal antiinflammatories are still needed when the disease is severe, but antimalarials work well for mild conditions.

Another disease modifying anti-rheumatic drug (DMARD) that has worked for lupus is methotrexate (MTX). This drug seems most effective for patients who don't respond to the antimalarials and who have skin or joint problems. Like other DMARDs, methotrexate (MTX) works at the enzymatic and cellular level to alter the inflammatory process.

Other disease modifying drugs used with varying effects on lupus include cyclophosphamide (CYC), mycophenolate mofetil (MMF), and azathioprine (AZA). Each of these agents works in a slightly different way with its own benefits and disadvantages (adverse side effects).

Studies are ongoing to figure out who would benefit the most from each one and how results compare using one drug versus another. Combinations of drugs are also effective but it does take time to work through which combination is best for any individual patient.

That brings us to the most recent research focus: biologic agents. Most of the other drugs used for lupus suppress the immune system. Biologic agents stop the specific biologic steps in the pathway leading to lupus. Most of these agents are in clinical trials but close enough to be released for use soon.

There are half a dozen different biologic approaches being investigated. The first is called B-cell depletion. Specific cell-surface antigens (e.g., CD20 and CD22) are targeted. By stopping the action of these immune cells, the process of lupus can be halted.

The main biologic drug under investigation with these effects is called rituximab. It is a monoclonal antibody. It was first used and approved for non-Hodgkin lymphoma but it seems to be helpful in cases of severe lupus that does not respond to the more standard immune suppressive medications. Data from various studies around the world is being collected on the most effective dose and delivery of this drug for lupus.

Three other classes of biologic agents under investigation include costimulatory interactions, cytokine blockade, and B-lymphocyte stimulator (BlyS). As you might imagine just from their names, the way they interact with the very complex immune system isn't simple.

Each one targets a different area of the immune system in trying to stop the disease process. Some stop B- and T-cell formation (active immune cells). Others don't reduce the initiation of B-cells but keep the B-cells out of the bloodstream.

Some interfere with the signaling pathway that keeps the autoimmune cycle of self-destruction from repeating itself. There is a cascade of steps in the pathway. Each drug targets a different step along the chain of command.

Experts in the field aren't sure one drug (monotherapy) will be found to conquer lupus. We may have to be content to target patients based on their particular expression of the disease. Those with kidney disease will have one drug to stop those processes. Others with skin and joint problems will be given something else.

The use of antimalarials for mild disease and disease modifying anti-rheumatic drugs (DMARDs) early on in the disease process will remain the center of treatment. Saving steroidal antiinflammatories for severe disease manifestations may help reduce the toxic side effects of those medications. It won't be long now before biologic agents will become a routine part of the drug regimen for lupus.

Reference: Julie S. Schwartzman, MD, et al. Management of Lupus in 2010: How Close Are the Biologics? In The Journal of Musculoskeletal Medicine. November 2010. Vol. 27. No. 11. pp. 427-440.

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