One of the biggest, costliest challenges for disease researchers is collecting accurate, diverse patient data. The Nurses’ Health Study, a cohort of 238,000 nurses with rich exposure and disease development data over the last 38 years, has been a wide-reaching, fruit-bearing tree for scientists, including those exploring the epidemiology of rheumatic diseases.
“There aren’t very many cohorts like this one,” says Elizabeth W. Karlson, MD, senior physician at Brigham and Women’s Hospital in Boston. The original study was focused on identifying cardiovascular and cancer risk factors in women. Beginning in the early 1990s, along with Matthew Liang, MD, and other colleagues in Boston, Dr. Karlson first used this stockpile of health information to explore what lifestyle habits or genetic factors may increase women’s risk of developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well.
Dr. Karlson and her colleague, Brigham and Women’s rheumatologist Karen H. Costenbader, MD, MPH, have both used the Nurses’ Health Study cohort to discover what may increase a woman’s risk for RA and SLE, as well as what may help prevent active disease. The data helped them develop and validate epidemiological testing tools for rheumatic diseases, including the Connective Tissue Disease Screening Questionnaire. They have explored what genetic biomarkers may indicate higher disease risk. They are currently examining patterns of metabolomics profiles in the blood to determine if they are connected to rheumatic disease risk or activity.
During weekly live meetings, researchers from many specialties gather at Harvard Medical School’s Channing Laboratory in Boston to discuss their new proposals for projects using the cohort, says Dr. Costenbader. “The data are very high quality. We are lucky to have this infrastructure. It’s a nice thing to have a huge cohort that has been funded and running for so many years! We wouldn’t be able to start our own enormous cohort,” she says.
Participants in the study are female nurses. Some of the women have filled out detailed questionnaires every two years since the cohort was created in 1976 by Frank Speizer, MD, with funding from the National Institutes of Health. Dr. Speizer and other investigators launched the study to examine the health effects of women taking oral contraceptives. The study’s first phase included female registered nurses aged 30–55. Participants had to be married, since at the time, taboos lingered about single woman using contraceptives, says Dr. Costenbader.
The second phase launched in 1989 and expanded to include unmarried women, women with different types of nursing jobs and broader age and racial diversity. Although the first two phases of the study involved mailed questionnaires, a third phase launched in 2010 as a Web-only study and expanded to include nurses in Canada. One of Dr. Karlson’s family friends is a nurse who has participated in the study since its launch and is now 90.
When participants noted that they had been diagnosed with a rheumatic disease, the cohort’s investigators requested their medical records and blood samples. More than 10,000 women in the cohort have reported diagnoses of RA, SLE, polymyositis, dermatomyositis, Sjögren’s syndrome, scleroderma or mixed connective tissue disease, says Dr. Karlson. With medical records, investigators have confirmed up to 1,300 RA and 300 SLE cases in the cohort. Dr. Karlson, Dr. Costenbader and their colleagues studied how lifestyle factors, such as oral contraceptive use, smoking, diet, silicone breast implants, breastfeeding, vitamin D intake and obesity, affected women’s rheumatic disease risk.
“We know that there are genetic risks. RA and lupus run in families. But what explains why one sister gets RA and another one doesn’t?” says Dr. Karlson. Because it is so detailed and long-lasting, the Nurses’ Health Study allowed them to identify possible risk factors and validate them over decades. They found that smoking cigarettes increases RA risk, and that risk is still high even 20 years after a woman quits. They found that breastfeeding reduces RA risk by 40%. They found that breast implants do not increase a woman’s RA risk and that using hair dye won’t raise her lupus risk. Early age at menarche, oral contraceptive use, as well as early menopause and use of postmenopausal hormones, all were related to increased risk of developing SLE.
[Dr. Karlson & colleagues] are currently examining patterns of metabolomics profiles in the blood to determine if they are connected to rheumatic disease risk or activity.
Less Recall Bias
A participant in the Nurses’ Health Study fills out questionnaires every two years, so investigators can examine her case closely after she reports a rheumatic disease diagnosis, says Dr. Costenbader. They can look at her past data to track her lifestyle habits, such as smoking or diet. This cuts down on inaccuracies rampant in studies in which patients are asked to recall things from years before.
“This is known as recall bias. When you are newly diagnosed with a disease, you may remember things you did in the past differently,” she says. “On the other hand, as we are asking a woman every two years about her lifestyle, before she is diagnosed with a rheumatic disease, there is less recall bias.”
Questionnaires are very detailed and, in past years, have included photographs of different types of cigarettes and oral contraceptives so nurses could provide specific answers about their use of these products, says Dr. Costenbader.
The study’s deep reserves of detailed information have enabled project after project for Dr. Karlson, who started using these data as a rheumatology fellow in the early ’90s. About 10 years ago, she became interested in the effects of hormonal genes on RA risk. “I wanted to find out how hormones interact with genes to give someone protection against disease. Then I got interested in predicting biomarkers in RA,” she says. She looked for blood samples from the cohort and examined levels of inflammatory cytokines, such as tumor necrosis factor alpha and interleukin 6. “We found significant elevations of these prior to the onset of RA, even up to 12 years before.”
The Nurses’ Health Study provides a map for researchers to follow throughout years of a woman’s life, so they can track what environmental triggers may happen along the way to a rheumatic disease diagnosis, says Dr. Karlson.
“A person is at risk for rheumatoid arthritis. Her immune system is activated, but not enough for her to have symptoms. At some point, a switch is flipped. She starts getting symptoms. But we don’t know what flips that switch,” she says. The cohort’s deep mine of data may help her and other investigators establish the paradigm of RA’s etiology at last, she hopes. “We need a large number of cases to show trends. There is the effect of one factor, and then we have to adjust for others.”
A woman diagnosed with RA at 50 may have reported daily smoking and coffee drinking for the previous 20 years, Dr. Karlson says. “Is caffeine a risk factor for RA? Coffee drinkers tend to be smokers also. The causal factor is smoking, not coffee.”
RA Risk Calculation
In the Nurses’ Health Study’s second phase, respondents reported more exercise, less smoking and less use of post-menopausal hormones, says Dr. Costenbader. “There are still quite a few people who smoke,” she adds.
These investigators are also looking at women’s dietary habits over the years to spot links to disease risk, says Dr. Karlson. People in Greece seem to have lower RA rates, but it’s unclear if the popular Mediterranean diet may protect North American women from RA. “Is it the high amounts of fish they eat? We have been looking at different kinds of fish, and whether omega-3 fats reduce inflammation,” she says. Eating a fish-rich diet may lower RA risk, but investigators are not yet sure the fish is the protective factor, she says. The Nurses’ Health Study’s broad range of data on diet and lifestyle may one day identify a protective amino acid or lipid, she adds.
We know that there are genetic risks. RA & lupus run in families. But what explains why one sister gets RA & another one doesn’t?
“What’s nice is that we have repeated measures in the study. It’s good to see how things change over time. We see if someone smokes and then see when she quits. We see how dietary patterns affect RA risk,” Dr. Karlson says. “These are called time-varying covariates. We can much more precisely see the effects of these factors every two years.”
In addition to RA and SLE registries and rheumatic disease diagnostic tools, the Nurses’ Health Study data are helping Dr. Karlson and her team develop an online tool to calculate RA risk among families, she says. The NIH-funded tool is currently recruiting 222 families who include someone with diagnosed RA. “People who have family members think they’re at higher risk than they actually are,” she says. A graphic thermometer shows participants their initial risk and then how they can lower it by quitting smoking or losing weight.
“It’s exciting to understand risk factors for RA, but I’ve always wanted to learn how to prevent the disease,” says Dr. Karlson. The Nurses’ Health Study may help rheumatologists complete the puzzle. “Maybe we can find a drug we could give people to prevent them from getting RA.”
Susan Bernstein is a freelance medical journalist based in Atlanta.
