Flash back to 1993 ... I was one of a few high school seniors in the first-ever class of the Cotter Schools Academy of Math and Science in Winona. Human genetics was my particular fascination. Just four years before, scientists had made an unprecedented discovery: For the first time, a gene that causes a human disease had been discovered without the help of any prior clues to its whereabouts. Although we were just kids, we were also budding scientists. We couldn't help but get swept up in the buzz about the implications of this discovery. With the advent of gene therapy, this disease - cystic fibrosis (CF) - could now be cured. We were sure of it.
Fast forward to today ... Turns out, a cure for CF never did materialize the way we had predicted. It took 23 years for scientists to learn enough about the CF gene and its particular quirks to yield an FDA-approved drug that specifically targets the faulty gene product. But that drug, initially approved in 2012, can only help about 8% of CF patients in the US. You see, nearly 2000 variations in the CF gene sequence have been identified. Granted, some of these are much more common than others, and there is some overlap in faulty behaviors exhibited by the gene product because of these variations. But, as is often the case in science, the problem was much more difficult than it appeared.
Last year, the FDA approved a new drug combination that can help about one-third of CF patients. While these drugs are welcome advances, they are not a cure. In clinical trials, the drug combination approved last year improved one measurement of lung function by only 3-4% on average, and the rate of acute lung problems was reduced by about one-third. Scientists are on the right track, but they have a lot of territory left to cover.
As a scientist and clinical researcher, I remain fascinated by CF, and I've never forgotten the excitement I felt as a high school student in the wake of the discovery of the CF gene. But now it's also personal. On May 22nd, we'll participate in Great Strides St. Paul, walking in support of Anna's friend Mason to raise money for the Cystic Fibrosis Foundation and its commitment to finding a cure. Nearly every CF drug available today was made possible because of the Cystic Fibrosis Foundation's support. Please join us in making a donation to help sustain their support of life-saving research.
Ask a Doctor: Lupus in African Americans
Q: Why are African-American women three times more likely to get lupus than white women, and why do African-American women tend to develop lupus at a younger age and have more severe symptoms than white women?
- Joleen, Sauk Rapids
A: We don’t fully know the answers to these questions yet, but researchers are working hard to discover them. They believe that the answers will go beyond race, and they hope they will reveal modifiable risk factors; that is, factors that patients and/or their caregivers could potentially take action to change. These could be keys to reducing such disparities.
One likely culprit is genetics. There are many genetic factors that can put individuals at a greater risk of developing lupus. It’s possible that some genetic risk factors are specific to African-Americans and might put individuals at risk for a more severe form of lupus. However, genetic factors can’t completely explain the increase in lupus incidence and severity in African-Americans. And since you can’t take action to change your genes, these genetic factors don’t make easy targets for interventions aimed at reducing disparities in lupus.
Studies have shown that socioeconomic factors, such as income, education, medical insurance, and access to quality healthcare are correlated with lupus activity and severity. Sadly, race and socioeconomic factors often overlap, making it extremely difficult to identify what truly causes lupus to be more severe in African-Americans. Fortunately, researchers have recently developed tools to help adjust for the overlap. Here are a few of their conclusions:
(1) Lower socioeconomic status, not race, is a predictor of diminished survival in lupus patients. Researchers made this conclusion because after they adjusted for socioeconomic factors, there was no significant difference in mortality between African-American and Caucasian lupus patients.
(2) The increased frequency of renal disease in African-American patients seems to be due more to genetic factors than socioeconomic factors. This is based on the observation that African-American patients were more likely to have renal disease even after they adjusted for socioeconomic factors.
(3) Overall lupus severity and survival are influenced more by socioeconomic factors like poverty, education, and medical insurance. So, there may indeed be modifiable risk factors that could be targeted to improve long-term outcomes in lupus. Some interventions that have already shown some success were aimed at increasing patient participation in their clinic visits and boosting social support.
A new drug is approved, what's next?
We finally get to ask that question about lupus, after the FDA approved Benlysta, the first new drug approved for SLE in over 50 years, in March 2011. Patients and researchers alike are asking questions … Who needs to take this drug? How is it different from the medicines that doctors were already using? How do we know it’s going to work? How do we know that it’s going to work better than those other medications?
Fortunately, many researchers have ideas about where to look for answers, because we know that Benlysta works by reining in a type of immune cells called B cells. B cells play an important role in the normal immune response, but when inappropriately activated in a lupus patient, they produce harmful elements that cause the damaging effects seen in SLE. Researchers think that measuring these may provide clues to help us determine whether an individual patient is likely to respond to this particular drug.
So where exactly might these clues be found? One place to look is among the autoantibodies that doctors routinely test for in lupus patients. B cells also make an arsenal of other factors that they release into the environment around them, boosting the fight against invading germs but also waging war against a lupus patient’s own tissues and organs. Finally, B cells display tell-tale markers on their outside surface when they are in attack mode.
A number of outstanding scientists have built their careers upon studying B cells and how they contribute to autoimmune disease. They are now poised to study these factors in the context of Benlysta treatment, with the hope of answering our questions. The approval of this drug is a major milestone, but it is not the end of its story. The next chapter will hold answers that will allow doctors to use this medication to its greatest benefit in treating patients with SLE.
Increased severity of lupus in African-American women
Researchers who seek new biomarkers for human diseases may have many goals. In the field of lupus research, we would like to find biomarkers that could make the disease easier to diagnose, improve the management of disease activity, predict when a flare is likely to occur, and help physicians decide which medications to use (or avoid) in a particular patient.
Thanks to advances in genomic and proteomic technologies over the past 10 years, lupus researchers have been successful in identifying many candidate biomarkers in human SLE. Many of these studies have been focused on patients of European descent. However, African Americans are disproportionately affected with SLE. Not only is the incidence of SLE in African American women higher than in Caucasian women, but African Americans also tend to have more severe disease compared with white SLE patients. We would like to gain a better understanding of the biology that leads to the increased severity of lupus in African American women, so that we may have a chance to improve patient care and reveal new targets for therapy.
Our goal in this study, funded by the Lupus Foundation of Minnesota, is to detect patterns of gene expression in the blood that can be biomarkers for SLE in African Americans. So far, we have discovered several gene expression patterns that are unique to African Americans with lupus, in addition to patterns that are found in both African American and Caucasian patients. Our next step is to study these patterns in patients who have been followed over time, so that we can determine whether they change as patients experience flares of their lupus. In doing so, we may uncover biological clues to help explain the increased susceptibility to and severity of SLE in African American patients.
Ultimately, we hope that this study will provide a foundation for improving clinical management of lupus patients. These biomarkers may also point us toward new therapeutic targets that may be particularly effective in African Americans.