In laboratory mice, giving estrogen exacerbates lupus and, depending on genetic background, augments the survival and autoreactivity of B cells.
Concern about potential effects of exogenous estrogens on lupus has deterred many doctors from prescribing oral contraceptives or hormone therapy for women with lupus. Yet there have been no placebo-controlled trials on which to base that concern, and there are situations in which estrogen might provide benefit for women with lupus.
For example, because of potential pregnancy complications and the risks of immunosuppressive drugs on a fetus, women with lupus need reliable birth control.
Hormone replacement therapy may help ease the effects of premature menopause, which can be brought on by cytotoxic drugs such as cyclophosphamide Cytoxan or help prevent post-menopausal bone loss, which can be accelerated by corticosteroid use. These potential benefits in light of the long-held concerns about estrogen in women with lupus prompted the Safety of Estrogens in Lupus Erythematosus National Assessment SELENA trial, which contained two separate randomized, placebo-controlled studies examining the risks of hormone therapy and oral contraceptives.
For both, the news was promising, for the most part. Neither showed an increased risk of severe flares in women taking estrogen-containing oral contraceptives or hormone replacement therapy; however, the risk of mild-to-moderate flares was increased significantly in women taking hormone replacement therapy. Patients enrolled in these studies were anti-phospholipid antibody negative and had stable disease for a period of 3 years prior to enrollment.
In mice, estrogen has been shown to regulate anti-DNA autoantibodies. In studies of mice transgenic for heavy chain of anti-DNA antibodies, estrogen breaks tolerance of the hyperreactive B cell and increases anti-DNA titers, which translates clinically into complex deposition in the glomeruli. In these same mice, estrogen rescued high affinity autoreactive B cells from negative selection, and interestingly Bcl-2, CD22 and SHP-1 are estrogen-responsive genes, which in paradoxical ways may perturb negative selection.
When the role of prolactin was studied in mice, the results were similar with increased anti-DNA titers and renal deposition of anti-DNA. Estrogen appears to induce autoimmunity through two distinct pathways — one affecting survival of autoreactive B cells and the other affecting maturation of autoreactive B cells. Better understanding the role of estrogen in lupus is an important goal of future research. It is also important to identify lupus patients who will be able to tolerate exogenous estrogens and those for whom estrogen may cause flares.
Researchers should also examine the relationship between hormones and coagulation and the risk of atherosclerosis. Thyroid gland inflammation is common in women with lupus and it can result in over- or under-production of thyroid hormones. A study stratifying lupus patients by comorbidities found a linkage between lupus and autoimmune thyroiditis; susceptibility genes were found for both disorders in a discrete region of human chromosome 5.
Pregnancy complications, such as preeclampsia, preterm birth, miscarriage, and low birth weight — are more frequent in lupus. These problems are especially seen in women with antiphospholipid antibodies.
Animal studies have shown that the predominant proximal and causative factor is the activation of complement. Heparin has been the treatment of choice for these pregnancy complications.
Furthermore it has been shown in studies of laboratory mice that low molecular weight heparins block the activation of complement.
Another concern for some expectant mothers is congenital heart block CHB , a condition in which the formation of fibrous tissue in the baby's heart causes interference with the electrical impulses that affect heart rhythm.
CHB carries significant mortality and morbidity. In 15 percent to 30 percent of cases, it results in fetal or prenatal death; 67 percent of children who survive require cardiac pacemakers before adulthood. An important area of research is focused on understanding these problems specifically and using the knowledge gained to better understand the disease generally. In the laboratory, CHB has been associated with autoantibodies.
But the roles of autoantibodies in mediating tissue injury are not well understood; nor are antibodies likely to be the sole cause of CHB. Scientists trying to better understand these causes suspect an interplay of genetic and environmental factors.
Women in their first pregnancy with anti-Ro and anti-La antibodies have a 2 percent chance of having a baby with CHB. If a woman has had a baby with CHB, the risk of having a subsequent child with the problem is much increased. Research also shows that heart fibrosis is the most rapid of any disease in the fetus. A fetus with a normal heart rhythm as measured by echocardiogram in utero at week 16 or 17 of gestation can progress to third-degree block within seven to 10 days.
Incomplete block can progress even after the antibody is gone. Because fetal arrhythmias can now be evaluated prenatally using echocardiographic and Doppler ultrasound techniques, atrioventricular block is more frequently identified during the fetal period. Auscultation may be misleading because the atrial rate may be mistaken for the ventricular rate. A number of groups have reported that bradycardia, as determined by fetal echocardiography, has been noted after the fetus had an initially normal heart rate.
As previously reported in a few fetuses and confirmed in this larger study, CHB is most often detected before the 30th week of gestation. Fetal echocardiogram is essential to follow the course of disease and may suggest the presence of an associated myocarditis by finding decreased contractility and secondary changes such as an increase in cardiac size, pericardial effusions, and tricuspid regurgitation. Serial fetal echocardiography at 16, 18, 22, and 24 weeks of gestation may be reasonable for all women at risk for a child with CHB; more frequent echocardiography may be reasonable if abnormalities are detected.
Dexamethasone therapy has been administered to women carrying fetuses with CHB and myocarditis in an attempt to diminish the inflammatory insult to the fetus.
Resolution of pleuropericardial effusions and ascites occurred during dexamethasone administration. Dexamethasone and betamethasone have been recommended rather than prednisone because these fluorinated steroids are not metabolized by the placenta and is available to the fetus in an active form.
Research on affected hearts in some cases has shown profound apoptosis. The potential role of apoptosis in CHB has been the focus of attention in two laboratories. This binding — called opsonization — triggers an inflammatory response by macrophages. In vitro studies using cardiac myocytes and fibroblasts from human fetal hearts provide evidence of a link between antibodies and injury. By better understanding these and other factors in CHB, scientists hope that they can predict those at greatest risk and, even more importantly, prevent this serious lupus complication.
Understanding organ-specific manifestations of lupus is likely to have implications for a better understanding of disease mechanisms in general. To advance this research field, translational research and multidisciplinary approaches are critical. The rapid application of advances in kidney research and the neurosciences will be critical to improve the diagnosis of disease subsets and disease course.
By understanding the cause s of specific manifestations, researchers can better target therapies and identify people who are at greatest risk of complications and would benefit most from new therapies and even preventive measures. Lupus is a disease that affects people of virtually every age, race, ethnic background and socioeconomic status. For example, children and adolescents under the age of 18 make up only 20 percent of lupus patients, yet the disease in children is often associated with more severe renal and hematologic involvement than it is in adults.
As many as 60 percent of children with lupus have renal involvement lupus nephritis. Lupus is believed to be three times more common in African Americans than in white women. African Americans and Hispanics also have more severe organ system involvement; that is particularly the case for lupus nephritis.
Research on these high-risk populations is a major focus of lupus investigators. By studying the factors that lead to disease or more severe disease in these populations, scientists will gain a greater understanding of these health disparities and how to address them. But even more importantly, research in one group has potential implications for all groups, by providing scientists clues into the mechanisms of and eventually treatments for the disease.
Because of their disease severity and young age, lupus is a particular burden for children. Thus, any research that leads to improved understanding, treatment and quality of life in children has significant, lifelong implications. Yet research in children has the potential to do much more than help children; more generally, studying children is valuable for a number of reasons. However, challenges to studying children do exist.
The primary drawback of studying children is the relatively low number of pediatric patients, which makes it difficult or impossible to find enough children in a single center to study.
Multi-center studies could potentially draw together more patients; however coordinating and harmonizing several centers is challenging. Additional challenges include:. It is important to increase the number of pediatric patients in adult studies to show stratification by age.
Already some clinical trials that are mainly for adult patients are accepting older children. For example, one of the trials investigating mycophenolate in adults allows enrollment of children from age It is essential to find ways to access young patients who would be appropriate for those studies and to develop ways to alert pediatric rheumatologists to the availability of those studies to appropriate patients.
Lupus occurs disproportionately in certain ethnic populations. Until recently, studies of minorities and lupus focused on African Americans as the main minority population in the United States, but an increasing Hispanic population, now the largest minority and fastest growing — not only in the Southwest or the Northeast, but in Colorado and the Southeastern United States — has brought more attention to the unique problems of that group.
The largest study of lupus in ethnic populations to date, the Lupus in Minorities: Nature vs. Nurture LUMINA study, was designed to understand why minorities are affected more frequently and more severely by lupus. Highlights of the study's findings include:. Aside from the study's ethnicity-specific findings, the LUMINA study has demonstrated that hydroxychloroquine seems to prevent the occurrence of damage in lupus and increase survival by as much as 60 percent.
This finding is particularly important because in the past hydroxychloroquine was used only in patients with mild to moderate, but not severe, disease. Studies in other ethnic minority populations have offered additional insights. For example, a study by British researchers showed that African admixture was a risk factor for the occurrence of lupus among residents of the Caribbean island of Trinidad , while the incidence of lupus in Africa itself is not that common.
Research has shown that both Hispanics and African Americans have a rapid progression of kidney disease. It is not known whether this rapid progression is related to poor access to care or lack of compliance with prescribed care or whether it actually represent a less favorable response to treatment. An argument for a less favorable response to treatment is reflected in a pediatric study, looking at predominantly African American children.
Children with lupus nephritis and neuropsychiatric involvement had a higher rate of progression to end stage renal disease and a higher mortality rate than children with lupus nephritis alone despite aggressive treatment. Yet studying lupus deaths is difficult due to significant under-ascertainment of lupus in death certificates. Underreporting has been associated with certain factors such as African American ethnicity, lack of health insurance and older age.
To fully understand the role of poverty in disease in minorities, researchers must understand what aspects of poverty are related — for example, is it that they cannot get health care or that they do not take the medication? Statistically, poverty becomes such a strong variable that it overshadows everything else.
Providing the best treatment for minorities and, in fact, all patients with lupus , requires not only aggressively treating the severe manifestations such as lupus nephritis, but also not losing sight of basic lifestyle factors. For example, smoking is a major risk factor for atherosclerosis, which is already a common problem in patients with lupus , yet many lupus patients smoke.
Programs to help people with lupus stop smoking could help minimize complications of the disease. Also, it is vital to find a systematic way to inform clinicians about proven medication benefits. For example, if a treatment like hydroxychloroquine prevents the accrual of damage, it should be introduced as a therapy for everybody with lupus as close to the diagnosis as possible. Accurate estimates of the number of people who have a disease — as a whole and within specific groups — are important for a number of reasons, including understanding the disease and its impact; predicting groups and individuals who are most likely to develop lupus and, thus, are candidates for screening and preventive care; and providing care and services to people with the disease.
Getting accurate estimates and updating them periodically can also enable researchers to determine if disease incidence is increasing and if so, start taking steps to understand why. But estimates about the number of individuals with lupus vary widely, depending on the study from which the estimate was derived. Different study techniques, methodologies, populations and definitions of what constitutes lupus can lead to vastly different prevalence estimates.
The range is large and tells us little about the true magnitude of the problem. What most researchers agree on is that lupus is more common in women than men and that African Americans, Afro-Caribbeans, Hispanics, Asians, and Native Americans are affected more commonly than Caucasians. But even the degree of that discrepancy is disputable. The estimates range from a five to nine or 10 times increase among those high-risk populations. Prevalence and incidence figures for other groups and specific lupus-related problems can be even more problematic.
Following are some examples:. As with lupus in general, there are not consistent estimates of the prevalence of lupus pregnancy or neonatal lupus. Neonatal lupus is a rare, lupus -like disease in a neonate that begins during pregnancy due to the transfer of autoantibodies from mother to child through the placenta.
In neonatal lupus there are differences in incidence estimates depending on the aspect looked at — congenital heart block vs. Even so, there is more incidence data on the disease than prevalence data.
The prevalence of neonatal lupus is difficult to determine when disease presents beyond the neonatal period months and long-term follow-up of children with mothers that have lupus , to a certain extent, is lacking.
Estimates of other problems in pregnancy related to lupus are also lacking. Most figures have been of spontaneous abortion, fetal death and total losses in pregnant lupus patients.
Lupus-related problems in pregnancy may not necessarily result in a fetal loss, but rather fetal growth restriction, preeclampsia and preterm birth.
The estimates of these vary widely. All of these problems are increased in women with lupus compared to women without the disease, but studies showing the relationship between lupus and these pregnancy complications were conducted before hydroxychloroquine came into wide use as a lupus treatment and particularly throughout pregnancy.
Researchers are interested in learning how use of hydroxychloroquine in recent years may have impacted these figures. Encompassing a form of lupus referred to as drug-induced lupus DIL , exogenous agent-induced lupus is a lupus-like syndrome that occurs in response to an agent such as a drug, UV light or an infectious agent.
In some cases, agents may modify the course of lupus by unmasking or accelerating disease. Examples of such agents that have been studied but not necessarily all proven to cause or accelerate the development of lupus include silica, heavy metals, hair dye and smoking. The incidence and prevalence of this condition is not known. Given the relatively low incidence rates of lupus in the general population, classical incidence and prevalence studies of environmentally-induced lupus would be difficult to conduct, especially in the absence of widespread disease registries.
There is a need to develop carefully designed epidemiology case-controlled studies to improve the understanding of known and proposed environmental risk factors. New and improved instruments and technologies to measure environmental exposure in populations need to be developed. The current approach has relied upon recall data, and methods are needed to improve the accuracy and consistency of such data collected across different study populations.
Other methods may be used to model wide-spread environmental exposures, such as residential geocoding in conjunction with data on air contaminations and traffic patterns to study the role of pollution in lung disease. These approaches may be transferable to the study of environmental exposure in a population at risk of developing lupus. There are many different subtypes of cutaneous lupus, including chronic cutaneous, sub-acute cutaneous, acute, and non-specific lupus skin lesions.
Defining them can have prognostic significance and therefore is important, but doing so is problematic at this point. The primary problem is that current criteria and coding methods do not allow for chart abstractors to go back and get this information and to collect the proper data in this way. Variations among subtypes in different populations have not been captured. The thinking is that the best approach for future studies in cutaneous lupus will involve bringing together investigators who have dermatological expertise and an interest in lupus who can work with lupus epidemiologists to get the kind of information that is needed.
Like other problems, there is a wide range in the estimates of the frequency of APS. The data are scanty in terms of how big of a problem this really is in lupus. Also not clear is whether antiphospholipid antibodies are important in and of themselves or whether it is the APS that is important.
The bottom line is that there are not good prevalence figures for either lupus or any of these related disorders in the United States population. The reason in all cases appears to be problems with definitions, disease classification, methodological limitation and also the recruitment of special populations into studies.
Ideally, researchers would be able to look at lupus as well as some of these other disorders in adults and children and study the rate at which these patients go on to develop lupus. Such studies are probably not possible, yet it is possible that some of these conditions could be grouped together and examined. Alternatively, additional information about these diseases could be collected as part of a larger epidemiological study that would potentially be either hypothesis-generating or actually answer some other questions about risk factors and underlying pathophysiology.
The CDC is conducting one epidemiologic study of lupus in selected counties in Georgia and Michigan , using inpatient and outpatient records. While the CDC study should provide valuable information concerning lupus in these populations, there is no plan in that study, for example, to look at Native Americans, Asians or Hispanics, so important information is still lacking for those ethnic groups. However, once preliminary results of this study come out, it may be possible for other groups to analyze those results and study design and perhaps expand this study to areas where they can get the same information on lupus patients from other geographic locations and ethnicities not represented in the two study sites.
In recent years, one of the most important issues in health services research has been a radical disequilibrium in and erosion of the health care system. Research has shown that income is strongly and positively related to access to specialized care, rheumatology included. Older individuals may have more difficulty accessing health care even though they may be relatively well insured.
Understanding and disentangling the impact of all these variables on access to care and health outcomes is an area of research with the potential to help some of the most vulnerable patients and would-be patients with lupus. While most of the advances in health services research, as with that concerning the cost impact of biologics, have focused on rheumatoid arthritis, lupus-specific research has shown that the volume of services a physician provides is inversely related to mortality, particularly in lupus nephritis.
While this finding is consistent with that in other areas of medicine in recent years, what was striking was that breaks occurred at very low levels. For example, physicians who saw two patients per year had significantly better outcomes than those who treated only one patient.
The most dramatic effects were seen in physicians who saw three or more patients per year. Research shows that participatory patients achieve better outcomes in lupus. The reason for this, however, is not known, but suggests that the personal, contextual variables have a large effect on outcomes, even when biological measures are held constant for the disease.
Better understanding of disparities among all types of groups would require comprehensive epidemiological studies, yet lack of comprehensive community-based data at present makes it impossible to do sub-group analyses. Results of such studies could suggest the potential for international and perhaps interregional differences in income and outcome studies that would standardize the health care protocols and take that variable out of the system.
Given the emerging wisdom of the high prevalence of neurocognitive impairment in lupus, research is needed to determine how people are able to work and function, handle family and health care in the presence of this condition.
Current research is looking at whether there are long-term impacts in the way health care is organized, particularly as patients experience neurocognitive deficits and are in complex systems of care. In these situations, the way patients interact with these systems of care and the points at which the health care insurance system puts obstacles in their way become critical issues.
This also helps distinguish why poverty, even in people who are relatively well-insured, comes up frequently as a predictor of health care outcome. While many of the discrepancies in health care seen in lupus apply to other rheumatic diseases, in some cases the effects may be worse due to the typically younger age of lupus patients at diagnosis.
For a year-old lupus patient, for example, the loss or fraying of employment-based insurance is going to have more of an impact than it would for a year-old patient with rheumatoid arthritis who can get into the Medicare system.
Younger workers with lupus in the United States may also be less likely to secure employment that provides insurance than an older person would. Children affected with lupus may never get insurance as they transition into adulthood. Better understanding how those factors influence outcomes can help in planning health services for all people.
As with any disease, early diagnosis of lupus often leads to the most successful treatment. Yet with lupus, diagnosis is often difficult, in part because the disease evolves over time. Particularly in its early stages, lupus can resemble any number of diseases, many of which require different courses of treatment. Moreover, the manifestations can be staggered and often are not all present at once.
Therefore the accumulation of enough signs and symptoms to fulfill the diagnostic criteria for lupus takes time. Treating lupus can be difficult as well. Kahlenberg has developed a model in which lupus-prone female mice develop a rapid flare of kidney disease following skin injury.
In this project, Dr. Kahlenberg is studying the mechanisms by which skin injury can lead to a rapid flare of kidney inflammation. She will study the inflammatory cell populations present in the kidney and relate this to simultaneous changes in the skin and blood of the mice.
Additionally, she will target the cytokine IL to determine whether induction of flares of kidney inflammation by skin injury requires this cytokine. She anticipates this work will show that skin injury rapidly increases the inflammatory cell populations in the kidney and that blocking IL may modulate this. Potential: This work will benefit the scientific community by increasing knowledge of how the skin and kidney may cross-talk in lupus, thus leading to development of novel therapies that may help to prevent flares of lupus nephritis and reduce the need for immunosuppressive medications in lupus patients.
Courtney Gray-McGuire, PhD at Oklahoma Medical Research Foundation, Oklahoma City has identified that the genes that make patients more susceptible to lupus are producing soluble molecules that appears to be involved in causing lupus.
Result: This research could lead to development of drugs that block the gene products and prevent getting the disease. Zia Rahman, MD, PhD of Thomas Jefferson University in Philadelphia, Pennsylvania is examining the mechanism of how lupus genes and their products induce the immune system to attack self tissues in the mouse. Result: These results could lead to the development of drugs which block these steps to stop the disease process.
Elaine Lourenco, PhD at UCLA is examining the mechanism involved in the finding that regulatory cells that control the immune response in lupus can be controlled by the hormone leptin. Belimumab was already an approved drug for treating lupus. Voclosporin, a pill, works by binding to a protein called calcineurin and preventing it from activating immune-system T cells also involved in kidney inflammation. People with lupus face a higher risk for heart disease and stroke.
In a press release from the American College of Rheumatology , the lead study author, Shivani Garg, MD , an assistant professor of medicine at the University of Wisconsin School of Medicine and Public Health in Madison, noted that this information can help people with lupus and their doctors take steps to protect cardiovascular health sooner.
Garg noted in the press release. The LRA funded the research, but Dr. Staeva was not involved in the study. In one clinical trial of anifrolumab, participants were able to use lower steroid doses. A study from the University of Leeds published December 3, , in the journal PLoS Medicine , for instance, found that steroid use was associated with a two- to fourfold higher risk for heart attacks, heart failure , and offbeat heart rhythms called atrial fibrillation over five years.
Researchers looked at 87, people with a variety of inflammatory conditions involving the immune system — including 3, with lupus. Two recent studies illustrate that new mothers with lupus can safely and successfully nurse their new babies, but reluctance remains. In a study of pregnant women with rheumatic conditions including lupus, published in April in the journal Lupus , researchers from Duke University in Durham, North Carolina, found that while 80 percent of the women with lupus planned to breastfeed, the number who were nursing their babies seven and a half weeks after birth was 57 percent.
By reducing flares, the medication may simply make it easier to continue nursing, the researchers note. Now, a study of cancer partly funded by the Lupus Research Alliance may explain how these macrophages promote lupus. Douglas Green, PhD, of St. A recent review article about key discoveries on the role of the microbiome in lupus includes two researchers funded by the Lupus Research Alliance who may have discovered how some of these microbial passengers promote lupus by […] READ MORE.
Aker BioMarine and Lupus Research Alliance launch a new clinical study, investigating how phospholipid-rich krill oil can benefit people with lupus, with the aim to lessen the severity of symptoms associated with the disease. July 26, By uncovering how some killer viruses beat our immune system, scientists partly funded by the Lupus Research Alliance have identified a potential new way to treat lupus.
The viruses that cause Lassa fever and other similar diseases kill thousands of people every year. June 5, The Lupus Research Alliance is driven by one central goal — to improve the lives of people living with the disease, today and in the long term.
0コメント