Why Do Women Have a Higher Risk of Developing Autoimmune Disorders?

Kristen Demoruelle, MD, PhD, associate professor of medicine at the University of Colorado School of Medicine, is working to develop new insights and novel prevention strategies that stop immune dysregulation before rheumatoid arthritis (RA) develops – a disease that affects approximately 18 million people around the world, 70% of which are women.

Demoruelle, who works in the Division of Rheumatology, spends much of her time studying the immune system at two potential sites that are likely involved in the development of RA – the lung and female genital tract mucosa.

“The work that I do attempts to find ways to better identify who will get RA so that at some point in the future, hopefully, we can prevent it. That’s the ultimate goal,” she says.

For the 50 million people in the U.S. that live with an autoimmune disease, like RA, it’s not known exactly what causes the immune system to attack the body, but researchers hypothesize it may be a combination of genetics and other factors.

Here, Demoruelle discusses what scientists know about why women face higher rates of autoimmune disease and how research is evolving and making new treatments – and possibly prevention – possible.

What defines an autoimmune disease or disorder?

We all have an immune system that's designed to do helpful things for us, like help us fight infections. Basically in all autoimmune diseases, the immune system gets mixed up for reasons that we don't totally understand and it starts to attack the person instead of attacking an infection. Depending on how and what parts of the body the immune system attacks, we label it as different types of autoimmune diseases. Rheumatoid arthritis, for example, primarily affects the joints, whereas multiple sclerosis attacks brain and spinal cord.

There are many factors that might create the right conditions for these disorders to arise. Why do women seem to have a heightened risk?

There may be a lot of factors that play into sex disparities in autoimmune diseases. The human body is complex. We know that women have two X chromosomes and men only have one. You only need one, so that second chromosome gets silenced throughout the body’s cells. Recent research findings suggest that that protein that silences the second X chromosome may contribute to higher rates of autoimmune disease in women.

Pregnancy also impacts the immune system and even a woman’s body’s ability to become pregnant has certain unique requirements of the immune system that may contribute to the disparities we see with higher rates of autoimmune diseases in women. Finally, there are features of the female immune system that can be overly protective. In terms of evolution, that can be a good thing, because you want your body to fight off infections – but it might also raise the risk for developing an autoimmune disorder.

How is research evolving in this realm?

It’s changed quite a bit over the past decade. We have seen much more research focused on women since the National Institute of Health made a policy requirement to include both sexes in the research studies they fund. Here, at the University of Colorado, the Ludeman Center for Women’s Health Research has supported the research of many young scientists who have made novel discoveries to understand sex differences across the lifespan.

There has been a huge push to ensure that studies are done with both men and women so that we can learn what's similar, and what's different to better the wellbeing in everyone.

For example, in some clinical trials, we’ve learned that medication doses should be different for men and women. Having that kind of information is crucial, so, yes, science has changed for the better over time in this area.

With that, we’re also seeing a lot more emphasis on personalized treatments.

That’s right. There are a lot of different medications available these days to treat different diseases, and we want to get to a point where we know how to choose the right medicine, for the right person and the right time. For example, in rheumatoid arthritis, we have a lot more medications to treat rheumatoid arthritis than we did 20 years ago, and it's really been a game changer for patients. That being said, there are still 20% to 25% of patients that don't respond to the treatments that we have. We want to better understand when to target which part of the immune system in each person.

In some studies that have looked at the differences between men and women and their response to these treatments for rheumatoid arthritis, we do see, in general, that women don’t respond as well as men do. This is where personalized medicine could really become helpful.

My hope is that we get to a place of personalized medicine where a variety of factors are considered. One of those needs to be sex because there are differences in treatment response. With more research, we’re getting closer to making that a possibility.