Genetic differences between mother, fetus credited with arthritis relief

August 12, 1993|By New York Times News Service

BOSTON -- For decades, doctors have been puzzled over why rheumatoid arthritis usually improves during pregnancy. The effect is often so striking that women and doctors alike call pregnancy the most powerful temporary treatment for arthritis.

Now researchers have come up with a possible answer: genetic differences between the fetus and the woman may set off maternal immune responses that ameliorate the arthritis.

In the study, being reported in today's issue of the New England Journal of Medicine, relief from rheumatoid arthritis was more likely when there was a difference in certain genes between the fetus and the pregnant woman.

Officials at the National Institutes of Health in Bethesda, say they intend to use the findings to explore new treatment strategies for rheumatoid arthritis, including a possible immunization.

More than 2 million Americans suffer from the pain and joint damage of rheumatoid arthritis, which strikes women about three times as often as men. The condition typically causes stiffness in joints on both sides of the body in the morning. But no one knows why.

Doctors consider rheumatoid arthritis an autoimmune disorder in which the body's immune system mysteriously damages its own tissues.

The ailment inflames and thickens the joint lining, or synovial membrane. As the disease process continues, it damages cartilage in joints, deforming them, causing pain and limiting movement.

For unknown reasons, the arthritis can flare up suddenly or go into remission.

For centuries, doctors debated the effect of pregnancy on rheumatoid arthritis, some saying it improved the condition, others saying it worsened it.

It was left to Dr. Philip S. Hench of the Mayo Clinic in Rochester, Minn., to do the first study documenting the frequency of remission in pregnancy. The findings, which were reported in 1938, also led Dr. Hench to discover a way to make cortisone and to win a Nobel Prize in 1950. His research led to the devel

opment of cortisone-like hormones that are used to treat severe arthritis.

Following Dr. Hench's lead, other doctors found that about three in four women with rheumatoid arthritis got substantial relief during pregnancy. Many researchers sought a hormonal connection for such improvement, but all have failed to find one.

Ten years ago, Dr. J. Lee Nelson, a rheumatologist and immunologist at the Fred Hutchinson Cancer Research Center in Seattle, read Dr. Hench's paper and concluded that cortisone and sex hormones could not explain the phenomenon.

In an interview, she said she reasoned that the answer most likely would be found in the unique challenge to the immune system that occurs in pregnancy.

During those nine months, a woman does not reject a fetus, although half of its genes come from the father and are, therefore, foreign to her immune system.

With grants from the Arthritis Foundation and the National Institutes of Health, Dr. Nelson's team studied proteins that are found on the surface of white blood cells, or leukocytes. Thus they are known as human leukocyte antigens, or HLA antigens, and they vary widely among people.

Earlier studies have linked rheumatoid arthritis and other autoimmune disorders to certain HLA antigens. But scientists do not understand the connections.

Dr. Nelson undertook a study involving 57 pregnancies in 41 women with rheumatoid arthritis. A remission or significant improvement of the arthritis occurred in 34 pregnancies. In 12 others, there was no improvement. The researchers could not be certain whether remission began during or before pregnancy in the remaining 11.

In two women, the arthritis improved in one pregnancy but remained active during another pregnancy. In each case, the children had different HLA types as a result of chance, Dr. Nelson said.

If the HLA system was important in improving rheumatoid arthritis during pregnancy, Dr. Nelson theorized before beginning the study, then the greater the genetic differences between mother and child, the greater the mother's immune response and the greater likelihood that the arthritis would improve.

Tests of the women and children found that subtypes of HLA of mother and child were often dissimilar in the pregnancies where the arthritis improved. The findings point to something in the maternal immune response that has a beneficial effect on arthritis, but discovering the precise factor is a next goal of research, Dr. Nelson said.

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