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Rheumatoid arthritis (RA) is an autoimmune disease, meaning the immune system mistakenly attacks normal tissues, provoking inflammation that causes swelling and pain in the joints as well as their gradual erosion. The condition can also cause problems far beyond the joints, damaging the skin, eyes, lungs, heart, and blood vessels.

But researchers are also on the attack, chiseling new insights into RA's origins and developing more targeted drugs to expand the arsenal of therapies to fight back.

"This is an exciting time for RA treatment because we're learning so much more about the disease," says Dr. Devyani Misra, a geriatrician, rheumatologist, and researcher at Harvard-affiliated Beth Israel Deaconess Medical Center. "Every day there's a new option, and the paradigm shift also includes treating our patients more optimally with the options we have."

Why women are vulnerable

When one sex clearly suffers disproportionately from a health condition, it behooves scientists to figure out why. Such is the case with RA, which affects two to three times as many women as men.

Much research is focusing on RA's genetic underpinnings. A 2024 study points toward an explanation why far more women than men cope with RA and an array of other autoimmune diseases.

Published online Feb. 1, 2024, by the journal Cell, the paper revealed that a molecule known as Xist (pronounced "exist"), which is found only in women, may trigger a certain chemical response that can lead to autoimmune conditions. This type of discovery is preliminary and won't quickly lead to new treatments, but it reinforces how sex differences underlie RA development, Dr. Misra says.

Normally, cells from females contain two X chromosomes, while cells from males contain one X and one Y chromosome. "I think the X chromosome involvement may explain some of the enhanced risks," Dr. Misra says.

Given the sex disparity in RA, scientists are also zeroing in on how estrogen may be involved—especially since levels of this hormone fluctuate significantly as women move through puberty to adulthood, pregnancy, and menopause.

"Interestingly, the two- to threefold increased risk of RA in women is generally seen when RA is diagnosed in someone's 30s or 40s," Dr. Misra says. "But when it develops after 60, men and women have an equal predilection for RA. We don't know if it's something to do with menopause that makes the risk equal."

The relationship between female hormone levels and RA risk is complex. A recent study suggested that women who used hormone therapy were 46% more likely to develop RA than women who didn't. But the analysis, published online Jan. 9, 2024, by RMD Open, also found that women who have four or more children, or those who experienced menopause before age 45, could also face significantly higher risk of developing the condition. "The potential hormonal risk seems compelling in these results," Dr. Misra says.

Treatment advances

RA treatments center around an array of therapies known as disease-modifying antirheumatic drugs (DMARDs), which were first developed four decades ago. (Before that, the primary therapies were steroids like prednisone and gold injections. But these older therapies only eased pain and swelling, without reducing RA-related joint damage.)

DMARDs are broadly categorized as either conventional, biologics, or targeted synthetics. Methotrexate (Otrexup, Trexall) — a conventional DMARD that's inexpensive and taken orally or self-injected — remains the usual first go-to drug. Other conventional DMARDs include leflunomide (Arava), hydroxychloroquine (Plaquenil), and sulfasalazine (Azulfidine). Sometimes two or more DMARDs are combined.

Biologics, which are tapped in more stubborn cases, are created from living sources that target certain inflammatory pathways. The latest class, called Janus kinase (JAK) inhibitors, belong to the targeted synthetic category and resulted from research teasing out delicate differences in immune system pathways. These medications block numerous proteins that ramp up inflammation. Unlike biologics, which need to be injected or infused, JAK inhibitors can be taken orally. Those used to treat RA include tofacitinib (Xeljanz), baricitinib (Olumiant), and upadacitinib (Rinvoq). "Many patients prefer oral drugs to injectables or infusions," Dr. Misra says.

All classes of RA drugs (and indeed, all drugs in general) pose side effects, but the wide array of options now available helps doctors personalize therapies to each patient's individual needs and risk factors.

"If we need to combine drugs or use a stronger drug, we have more options to better control inflammation," she says. "With all the options we have, we're in a better position now to treat our patients."

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