For three years after Yvonne Norton gave birth to her second son, she had a host of mysterious symptoms that left her family doctor baffled. Time and time again, she sought his advice, to no avail. In desperation, she even visited a psychiatrist who also had no answers, other than to say, "Whatever is wrong with you, it isn't in your head."

Then, one day in 1975, she landed in a hospital with complete heart failure. For three days she lay unconscious, coming around to learn that seven pints of fluid had been drained from her lungs and that she was being treated with high doses of cortisone. Six months later, the steroids were wreaking havoc on her body, without improving her symptoms. "At one point, my son got into a fight at school with a kid who called me a swollen monkey," she recalls. "I thought, 'this is serious'."

Norton, who lives near Wolverhampton in central England, then traveled down to London for an appointment with a specialist at the Hammersmith Hospital. After a month of inpatient care, she was discharged with her diagnosis written on a piece of paper: systemic lupus erythematosus. "I carried it around for weeks, until I finally managed to get my tongue around it," Norton recalls. She quickly learned that her condition was an autoimmune disease in which the immune system attacks the very body that made it. Over the years, she grew increasingly familiar with these diseases, particularly since she developed three more: Sjögren syndrome, Raynaud syndrome, and irritable-bowel syndrome.

Norton is far from alone. "Progress in Autoimmune Diseases Research," a 2004 report from the National Institutes of Health's Autoimmune Diseases Coordinating Committee (ADCC), details more than 80 chronic and often disabling diseases recognized at least in part as autoimmune. These conditions can affect any part of the body, often causing a spectrum of symptoms that make straightforward diagnosis a challenge. They include a handful of relatively common illnesses, including diabetes, rheumatoid arthritis, and multiple sclerosis (MS), plus dozens of rare conditions.

Despite diverse manifestations, many autoimmune diseases share common genetic and molecular origins, explains Virginia Ladd, founder of the American Autoimmune Related Diseases Association. The result is that many patients, such as Yvonne Norton, have more than one autoimmune disorder. In some cases, multiple autoimmune diseases cluster within the same family.

Yvonne Norton addresses a reception at the UK House of Commons at the launch of Lupus - A GP Guide to Diagnosis, which she compiled. Holding the microphone is Graham Hughes, a consultant physician at St. Thomas Hospital in London.

Courtesy of Yvonne Norton

Because autoimmune diseases can be hard to diagnose, and because many of them are rare, collecting data on their prevalence is a real challenge, says epidemiologist Glinda Cooper of the US Environmental Protection Agency. "When you talk about autoimmune diseases as a general category, it is hard to find good data to get a grasp of it," she says. The best estimates from the ADCC suggest that autoimmune diseases affect 14.7-23.5 million Americans, which represents as much as eight percent of the population. Plus, for reasons that aren't clear, the incidence of some autoimmune diseases seems to be increasing.

According to Noel Rose, director of the Center for Autoimmune Disease Research at Johns Hopkins School of Public Health and lead author of the ADCC report, the wide margin of uncertainty in that report's figures reflects a lack of solid data on autoimmune disease epidemiology in the United States. The challenge becomes even bigger globally. "The usual 'wisdom' is that autoimmune diseases are a problem mostly of developed countries," he says. "That may or may not be true; I've never been completely comfortable with the idea."

Still, scientists do know one thing about the epidemiology of autoimmune diseases: Women are affected more than men, at least in most cases. "We know that these diseases occur predominantly in women in their childbearing years, just when they have the biggest family responsibilities," says Rose.

This imbalance varies from disease to disease, says Cooper. In 2003, she coauthored a report¹ on the epidemiology of autoimmune diseases, perhaps the most detailed publication on the topic so far. That report shows that in the more common conditions, such as MS, the imbalance tilts so that affected patients are roughly two-thirds female. "In some diseases, however, the degree of disproportion is very extreme," Cooper says. For example, at least 85% of patients with thyroiditis, systemic sclerosis, systemic lupus erythematosus, and Sjögren disease are female. In data from the Centers for Disease Control and Prevention for 1995, well-defined autoimmune diseases were one of the top-10 causes of death for women under the age of 65 years.²

The struggle to track these diseases matches the pharmaceutical industry's failure to treat them. For example, drugs for rheumatoid arthritis evolved from injectable gold in the 1930s to biologics today, but treatment results remain mediocre. According to Anthony Manning, vice president and global head of inflammation, autoimmunity, and transplant research at Roche, only about one-third of patients with rheumatoid-arthritis get "significant benefit," even with today's best therapies.

Such lacklustre results probably arise from rheumatoid arthritis' heterogeneity, varying in mechanism between individuals and within the same individual over time. Many other autoimmune diseases include similar variability, which thwarts effective treatment. Still, some members of the pharmaceutical community feel optimistic about improving results in the very near future. "Five years ago, we didn't have the plethora of tools that we have today," says Andrew C. Chan, vice president of research immunology and antibody engineering at Genentech. "If you only have one or two tools, it's hard to go and attack any disease and say, 'I have the answer.' It's like having a hammer, and you're walking around looking for the nail."

Source: National Institutes of Health. Progress in Autoimmune Diseases Research, 2005. (www.niaid.nih.gov/publications/pdf/ADCCFinal.pdf)

The sheer numbers of patients with autoimmune diseases places an enormous cost on health systems. In Canada, for example, "there's no doubt that we spend about 20% of our healthcare budget on the treatment of autoimmune diseases and their complications," says Bhagirath Singh, director of the Canadian Institute of Infection and Immunity. From a total healthcare budget of $120 billion, that translates to something like $25 billion, he notes, most of it spent on diabetes, multiple sclerosis, and arthritis. "There's no question we're talking about a major burden, and these costs are increasing every year."

In the United States, figures on the costs of autoimmune diseases are much more difficult to find, says Ladd. Nevertheless, overall costs are expected to increase. "In the past, most autoimmune diseases were treated with relatively cheap drugs like prednisone, which costs about $30 a month," says Ladd. "That's now changing." For example, the antitumor necrosis factor (TNF)-alpha drug Remicade (infliximab) costs about $1,250 per month, and it is prescribed for ankylosing spondylitis, Crohn disease, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. "The drug is a very good breakthrough, but the costs in the future will be enormous," Ladd says.

For the patients with autoimmune diseases, drug costs are only one part of the equation. Yvonne Norton, for example, built an extension on her home to provide a downstairs bathroom and office area, because stairs are difficult for her. Also, financial difficulties challenge many autoimmune patients, says Sharon Haffenden, director of research and services at the UK's MS Society. "We're working here with diseases that are diagnosed when people are in their 20s or 30s, so it's going to have an impact for people in the prime of their lives." Research conducted by the UK charity, Leonard Cheshire, shows that people disabled with diseases such as MS are seven times more likely to be out of work and claiming disability. "There are very, very strong correlations between MS and [people] being out of work and unable to earn a decent living," Haffenden says.

As Yvonne Norton found, the economic costs of autoimmune diseases are only one part of a complex story. These conditions, chronic and debilitating as they are for the patients, also have an impact on loved ones, such as Norton's husband Peter. "I always say that I'm the one with lupus, but Peter's the one who suffers from lupus," Norton says with a rueful laugh. "It's changed his life, too. He can't take certain jobs now because there are times when I just need him to be able to get home quickly, and that sort of thing."

This is a common experience, adds Haffenden. "In many cases, the spouse very much becomes a [caretaker]," she says. "They often have to reduce their own working hours or give up working altogether.

Source: www.mult-sclerosis.org/ms_world.html

More than 70% of the costs to society from disability are borne by informal caregivers, such as husbands or wives, according to the research of Paul McCrone and Martin Knapp from Kings College London. (The UK's MS Society funded the research.) "In MS, we've found that despite all the brouhaha over drug costs, the main cost to society is through informal care," Haffenden says. Overall, multiple sclerosis costs the United Kingdom roughly £1 billion a year, she adds.

Also, because autoimmune diseases more commonly affect young and middle-aged women, children also feel the impact. "My two sons were eight and five when I was diagnosed," says Norton. "They've grown up with a mum in a wheelchair. It was a big deal for them."

Overall, one person's autoimmunity bears on the entire family. Rheumatologist Tore Kvien from Diakonhjemmet Hospital, in Oslo, Norway, spells out the repercussions.³ "The individual and his or her family must cope with the feeling of loss of contribution to society combined with redefined social roles, and the effects of pain, fatigue, low self-esteem, mental distress, and depression," Kvien writes. He specifically describes the burden of rheumatoid arthritis, but the same thing could be said of many autoimmune diseases.

Yvonne Norton puts it this way: "It's a complete lifestyle change for those who have got it badly. We just know it's going to be there forever."

Most autoimmune diseases affect women more than men. In most of the disease shown here, women get them four or more times more often than men. Only two of the diseases show roughly equal gender percentages, and just one - ankylosing spondylitis - occurs more often in men.

Source: Randall Stevens of Roche, presentation in a 6 November 2006 Teleconference

The breadth of autoimmune diseases resembles the variation in prevalence. As shown here, some autoimmune diseases such as psoriasis and rheumatoid arthritis, occur much more often than others, such as scleroderma and Wegener's granulomatosis.

Source: Randall Stevens of Roche, presentation in a 6 November 2006 Teleconference

One of the few things that can be said with certainty about the burden of autoimmune diseases: Policymakers have not yet realized the size of the issue, says Rose. "The US and most developed countries have overlooked the significance of autoimmune diseases," he says. "Partly, this is because historically they have been looked at one at a time, which means they look quite small. It's only when you begin to look at them inclusively that you appreciate the scale of the problem."

Patient groups play a crucial role in raising consciousness, pushing for more funding, and lobbying for provision of new treatments. "I think that really is an extremely important part of the whole equation," says Rose, who is involved with the American Autoimmune Related Disease Association (AARDA), which played a key role in convincing the NIH to establish a coordinating committee on autoimmune disease research. Ladd, the association's president, is proud of the role that AARDA played in getting congress to ask NIH for a report on the autoimmune disease research it was funding.

"It was very obvious at that time [in the late 1990s] that autoimmune diseases were underfunded, and that 90% of the research was on just one or two of the 80 or so diseases," Ladd says. In 1998, NIH established the ADCC, and, says Ladd, "with the formation of the committee about $30 million was made available that served as a kind of springboard for a lot of work." The money helped establish, for example, a blood registry for families with clustering of autoimmune diseases.

Across the Atlantic, patient groups generated their own successes. Since 2000, for example, Norton has served on a parliamentary working group with Lupus UK, a group that includes Janet Dean, a member of parliament. In recent years, the group managed to initiate discussions in Westminster and has been in direct communication with health ministers. "We've drawn in a lot of members of Parliament," Norton says. "I think they're beginning to understand about it."

Beyond raising awareness, disease-specific groups help patients obtain their medications. The MS Society, for example, fought a sustained battle to get the UK's health-spending watchdog, the National Institute for Clinical Excellence (NICE), to fund new MS drugs through the National Health Service. For a while, it looked as if beta-interferon would not be available under the state-health system, but in 2002, a deal was brokered in which costs were shared between the government and drug firms.

Other battles lie ahead. For example, NICE is considering whether Tysabri (natalizumab), a new MS drug from Biogen Idec, should be available on the National Health Service. This drug is administered by infusion and will involve significant costs to the healthcare system. The MS Society, among others, is pushing hard for a positive decision.

Meanwhile, the struggle to raise awareness among physicians continues. "So many patients come to me and say, 'I've been to my GP time after time with my various symptoms, and he doesn't know what's wrong with me, or who to refer me to,'" says Norton. "It's hard, because when you're ill, you don't want to have to bang the table at your GP's surgery just to get him to refer you to the right specialist." The situation is improving, partly thanks to the work of Lupus UK. This organization hangs posters in hospitals and produced a book for general practitioners, which genuinely seems to be raising awareness, Norton says.

It isn't all heartbreak, though, because lobbying benefits patients. The US National MS Society's Web site, for example, carries this comment from Scott Hansen, who has lived with MS for eight years: "Engaging in advocacy gives me optimism. My doctor believes that I'm actually getting healthier with age, and I think that's because I'm involved in fighting for myself and others."

Despite the significant victories that autoimmune-patient groups have achieved, Ladd says more could be achieved with a more united front. "Disease-specific groups on their own do good advocacy work, but we need collective numbers to really get the job done," she says. The trouble is that the general public, and some of those who form policy, still think of these diseases singularly, she says. Only five percent of Americans can name an autoimmune disease, Ladd says, and some 29% think AIDS is one. "Just having that awareness among the public would be great," Ladd says.

Meanwhile, Norton remains positive, despite everything that lupus has cost her. "I do think we're getting there," she says. "I think awareness is growing. To me, you can't cope with something unless you get out and face up to it."

Correction (posted April 25, 2007): When originally posted, this story incorrectly reported the Nobel Prize that Gertrude Elion and George Hitchings won in 1988. The Scientist regrets the error.