If, like most Americans, you don’t know much about soccer, know this: Midfielder is a grueling position.

Midfielders surge forward along a 120-yard field to join offensive plays and sprint back to play defense when the opposing team takes the ball.

A midfielder runs about 7 miles in a 90-minute game, and, between sprints, engages in close combat to get and hold the ball.

Shannon Boxx is a midfielder, headed to her fourth Women’s World Cup starting this weekend as part of the United States Women’s National Team.

That Boxx can still handle this position at 37, if not quite as commandingly as she once did, is incredible enough. That she can do it with lupus, a serious autoimmune condition whose hallmark symptoms are fatigue and pain, is — simply put — dumbfounding.

“I’ve been able to play through some pain,” she laughed. “Maybe it’s because I’ve been playing at this level for this long.”

Boxx thinks she first started to develop lupus in high school in the working class Los Angeles suburb of Torrance, where she played softball, volleyball, and basketball, as well as soccer. She struggled to match her teammates in cardiovascular fitness, even though she worked just as hard. And her fingers would often go white from cold or stress, she said, a classic sign of Raynaud’s phenomenon, often seen as part of a cluster of symptoms stemming from lupus.

“I definitely had that in one finger, but I just assumed it was a dead finger — I had played catcher, and that finger gets hit all the time,” she said.

In 2002, as Boxx was tapped for the national team for the first time, she was diagnosed with Sjögren’s syndrome, an autoimmune disease similar to lupus. But the diagnosis didn’t quite fit.

In 2007, Boxx played almost every minute of the quadrennial World Cup tournament in China, leaving only when she was forced out of the semifinal on a poorly decided red card.

But she knew something was wrong.

“I was still struggling with my muscles being really tired and achy and the fatigue,” Boxx told Healthline. She got through the tournament taking one of a handful of allowed steroids.

Shortly after the World Cup, Boxx was diagnosed with lupus.

Lupus is a serious, occasionally even fatal, autoimmune disease. But, exhausted from bouncing from doctor to doctor as she traveled with her professional and national teams, Boxx felt relieved to finally get a diagnosis that made sense.

“At least I had something I could fight now. I had something I could work with the doctor on,” she said. “I think just knowing gives you a little bit of piece of mind — now I could really focus on ‘How can I stay healthy with this?’”

Three years later, blood work suggested it was time for Boxx to begin taking regular medication to keep lupus in check. Even as she started every game on the Women’s National Team, she was cycling on and off a smorgasbord of the steroids and immunosuppressants and antimalarial medications often used to treat lupus.

“I think it took through the [2011] World Cup to find something that really worked,” she said. “Some of the effects from the meds were worse than the actual illness.”

Learn More About Lupus »

Lupus Is Well Known, But Poorly Understood

It’s hard to comprehend that Boxx went through all this while continuing to play world-class soccer. But the rest of her story is pretty typical.

Most lupus patients have symptoms for several years before they get a diagnosis. Most also have to try a range of medications before they find a combination that works.

Although lupus has been diagnosed since the 1700s when it was thought to be caused by wolf bites — lupus means wolf in Latin — it remains a mysterious illness.

Scientists don’t know for certain what goes wrong in the immune system of a lupus patient.

The disease, whose full scientific name is systemic lupus erythematosus, touches every part of the body through the immune system. The most common symptoms are joint and muscle pain, unexplained fever, and rashes, especially on the face. Liver malfunction is not uncommon.

Annual Mortality for Systemic Lupus Erythematosus | HealthGrove

About half a million Americans have lupus, and, like other autoimmune diseases, it to be affecting more people over time. But just one new drug has been introduced to treat the disease in the past 50 years.

By way of comparison, another autoimmune disease, multiple sclerosis (MS), affects about 400,000 Americans. Since 2000, a half dozen new drugs have been approved to treat MS.

But while white women are most likely to develop MS, women of color are two to three times more likely to develop lupus. African Americans are at especially high risk, developing lupus earlier on average and often with more serious effects. (Most autoimmune diseases disproportionately affect women. The reasons are not clear.)

Yet, it would be overly simplistic to conclude that medical research has gone after MS more aggressively because it affects patients with more political and economic clout, according to lupus researchers and advocates, including Boxx, who is biracial.

Lupus is an unpredictable disease, researchers told Healthline. It also develops differently in different patients. Lupus manifests itself in clusters of symptoms that vary widely and its progression over time varies.

“Even though there’s very objective evidence of lupus — it’s definitely a disease — it’s not something that’s easy to diagnose or recognize,” said Emily Somers, Ph.D., an associate professor of rheumatology at the University of Michigan Medical School.  “There are rashes, fever, fatigue. These are all very general symptoms. Some types are really difficult to diagnose, where you sort of accumulate risk factors.”

Unlike other autoimmune conditions, like MS, whose effects are limited to one bodily system, lupus can affect a huge variety of bodily systems. Because lupus comes and goes in sporadic “flares,” it’s hard to track whether treatments are working.

“Take MS,” said Dr. Mary K. Crow, the chief of the rheumatology division at New York Presbyterian/Weill Cornell Medical Center. “The manifestations are related to the nervous system — movement, sensation. Rheumatoid arthritis (RA) is systemic, but the manifestations are mainly localized to the joints. But lupus involves just about every organ system, some of which are not very accessible, like the brain. It’s kind of everywhere and it’s difficult to pin down where the disease is to study it and to measure it.”

Even the root of the problem in the immune system remains a mystery. Blood work on lupus patients often turns up antigens that attack cell nuclei. Crow, who has helped develop National Institutes of Health materials on lupus, has made a persuasive case in her research that type 1 interferon is also involved.

It’s clear there is a genetic predisposition to lupus, but genes aren’t the whole story. If one identical twin has lupus, the other has only about a 1-in-3 chance of developing the disease.

Some sort of environmental exposure must trigger the disease in genetically susceptible people. Among the most agreed-upon risks are sun exposure and emotional and physical stress. Boxx, in all of her years in sports, has had plenty of both.

The statistic that matters most to Boxx, who had a daughter in February 2014, is this one: A child whose mother has lupus has just a 1-in-20 chance of getting the disease.

“I look at my family and say, ‘If this is a genetic illness, does she have it? Does she have any symptoms?’” Boxx said. “You have it in your system and something has to trigger it. We’ve been very cautious.”

Lupus Reflects Complex Social Problems

Still, medical researchers’ lack of answers when it comes to lupus can’t be entirely separated from questions of gender and ethnicity.

Alina Salganicoff, the vice president and director of women’s health policy at the Kaiser Family Foundation, participated in an Institute of Medicine forum on women’s health that concluded that autoimmune conditions were an area where medical research was “really lacking for women.”

When it comes to race and ethnicity, the question gets even more complicated. People of color, especially black people, have a historical mistrust of medical research, owing to the notorious Tuskegee experiments

Residents of smaller and poorer cities are less likely to hear about clinical trials. They often lack access to the specialists who would refer them. Lupus care falls under rheumatology, and a map of those practices shows clusters along the two coasts with wide blank swaths elsewhere.

Image source: commons.wikimedia.org/wiki/File:Raynaud%27s_Multicolor.jpg

“A lot of communities don’t have rheumatologists,” said Somers. “It’s something where the lack of significant diagnostic testing and the shortage of specialists combine into making lupus a challenging disease to study.”

It’s a catch-22 situation: A shortage of non-white research participants hamstrings efforts to figure out a disease that affects mostly non-white patients.

“There are many, many reasons that they’re not involved, and that is a factor that slows down research into the disease,” Crow said.

There is more research, much of it from Europe, on lupus among white patients than among other ethnic groups. Building on that basic research, the only drug that has gained federal approval to treat lupus, Benlysta (belimumab), in 50 years doesn’t work as well in African Americans.

“New medications could only be tested once they were developed and they were only developed once basic knowledge was advanced,” said Dr. Graciela Alarcon, M.P.H., Jane Knight Lowe Chair of Medicine in Rheumatology, emeritus, at the University of Alabama at Birmingham’s Minority Health and Health Disparities Research Center.

“It is true that once new medications were available, ethnic minorities were not enrolled in large numbers” in U.S. clinical trials, Alarcon added.

Lupus isn’t just more widespread among African Americans, though. People in every major non-white ethnic group are at elevated risk. Those findings make it hard not to at least wonder if social inequality isn’t as much at fault as genes.

Somers suspects exposure to toxic chemicals and lower quality healthcare among those groups as likely culprits. 

“It could be a common exposure, but one population could be exposed to it earlier when the immune system is more vulnerable,” Somers said. She’s researching whether mercury in fish could be a significant risk factor.

Alarcon’s research into racial groups in Texas also seems to suggest that social inequality may offer at least as good an explanation for lupus’ prevalence in non-white groups than genetics.

She has studied rates of lupus among American Caucasians, African Americans, Puerto Ricans, and Texas Hispanics.

“Worse outcomes were primarily related to poverty and socioeconomic status than to racial or ethnic group per se,” Alarcon said. 

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A Shot on Goal for Lupus Research?

Lupus patients may be next in line for medical breakthroughs, however. 

Consider RA, which also went decades without advance. In the past 10 years, the outlook has changed dramatically. Much lupus research uses that success as a model. Building on work done for RA, for example, lupus researchers have devised more complicated models for measuring patient progress in clinical trials.

“One of the things that I sometimes worry is not talked about enough is the success that has happened with RA,” Crow said. “RA was a horrendous disease 20 to 25 years ago. There has been tremendous success. Patients with RA have completely better, different lives. If we hold that up as a model, we can do the same for lupus.” 

The biggest advance in RA has been the rise of biological drugs. These drugs can selectively block certain immune processes without suppressing the whole system. Benlysta is such a drug. Others could follow. 

"I think the whole view of the disease is very different now than say 10 to 15 years ago. But I think what has lagged is drug development,” Crow said.

Basic science on lupus is narrowing down on how it works, according to Crow, and the government and patient advocacy groups have encouraged research into its effects on non-white communities in particular. 

And then there’s Boxx. Since she began playing on the national team shortly after Brandi Chastain’s famed shirtless celebration in 1999, women’s soccer has amassed a much bigger following. As her symptoms continue to advance, Boxx’s next goal is to help accomplish something similar for lupus.

In disease awareness, celebrity faces matter. They can turn a disease from an obscure Latin name to a face that’s relatable, scientists and patient advocates say. That can bring in more money for research.

After what Boxx expects to be her final World Cup this month, she will turn her attention not just to her daughter and the youth soccer camps that are the staple of retired players, but also to raising awareness of lupus through the Lupus Foundation of America.

“I’m still learning as I go,” Boxx said. “I’m learning as much as I can so I can talk about it, but also for my own sake of trying to stay as healthy as possible.”

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