Bridging the ‘vast divide’: Mistrust, bias fuel racial disparities in lupus research
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The body of data demonstrating that lupus significantly and disproportionately impacts Black, Hispanic and Asian patients is robust. It should therefore follow that these populations are appropriately represented in clinical trials for the disease.
Unfortunately, the data showing just the opposite are similarly robust.
Source: Shivani Garg, MD, MS
“This is a problem that has existed for quite some time,” Allen P. Anandarajah, MBBS, MS, of the University of Rochester Medical Center, told Healio Rheumatology.
The data support Anandarajah’s point. A 2018 systematic review published in Arthritis Care & Research by Falasinnu and colleagues presented data for 193 randomized controlled trials from 1997 to 2017. The results suggested that although Black individuals make up 43% of prevalent systemic lupus erythematosus cases, they represented only 14% of clinical trial enrollees. Meanwhile, Hispanic patients comprise 16% of prevalent SLE cases and 21% of randomized clinical trial enrollees, Asian patients comprise 13% of prevalent SLE cases but just 10% of trail enrollees, and white patients constitute 33% of prevalent cases but represent as much as 51% of trial participants.
“There is a vast divide between who is living with the disease in terms of absolute numbers and who is actually participating in clinical trials,” Joy Buie, PhD, MSCR, RN, of the Lupus Foundation of America, said in an interview.
Mistrust of the health care system among historically underrepresented populations is one explanation for this phenomenon.
“Studies have shown that patients of Black race and Hispanic ethnicity are often too wary about clinical trials,” Shivani Garg, MD, MS, an assistant professor at the University of Wisconsin School of Medicine and Public Health, told Healio Rheumatology.
However, other barriers beyond mistrust exist as well, according to Garg.
“Additionally, patients who have limited proficiency in English are often not included in studies due to language barriers,” she said. “Consent forms are not always present in translated versions in different languages.”
Garg added that there are also rheumatology- and disease-specific reasons for poor representation. Patients who mistrust the health care system are less likely to make or attend appointments, which can lead to a delayed diagnosis or misdiagnosis.
“Patients of diverse racial and social backgrounds often have severe disease presentations,” Garg said.
However, the complications in lupus do not stop there.
“These patients often require therapies that are often not allowed in clinical trials,” Garg said.
Despite the myriad obstacles to trial participation in underrepresented populations, there are solutions available, according to Buie. However, to access them, it may be necessary to begin with the basics.
“Patients need to be educated and informed about what a clinical trial is,” Buie said. “Let’s start there.”
The next consideration is who should be responsible for such patient education.
“Nurses, community health workers and other trusted healthcare paraprofessionals are needed,” Buie said. “They are on the front line when it comes to interacting with patients, forming those relationships with patients and establishing trust.”
“However, we recognize that ultimately rheumatology, nephrology and dermatology physicians will be the ones who ultimately carry the load of enrolling and treating patients in a lupus clinical trial, so trust and communication are paramount for these individuals, as well,” she added.
That said, these individuals cannot alter the status quo alone. Organizations like American College of Rheumatology and EULAR, along with advocacy groups like the Lupus Foundation of America should also play a role.
“The solutions are multilevel and multifactorial,” Buie said. “It takes all of us working together to create change.”
Making It Through the Door
In a scientific statement in ACR Open Rheumatology, Buie and colleagues addressed the social determinants of health that impact SLE, after reviewing CDC and PubMed data published between 2011 to 2023.
“Poorer neighborhoods correlate with increased damage, reduced care, and stress-induced lupus flares,” they wrote.
The results additionally revealed “large disparities” in health care affordability, accessibility, and acceptability across the United States. Meanwhile, region and insurance status impact these disparities in several “racial and minority groups,” read the findings. According to the researchers, racial and ethnic disparities in lupus are “driven” by social determinants of health, “some of which are more easily remediable than others.”
“Based on the published literature, studies show that if a patient lives too far away from an academic medical center where the clinical trial is being conducted, they may be less likely to sign up to participate,” Buie said. “In addition to that, many patients are unable risk experiencing side effects that will keep them out of work for extended periods of time or prevent them from caring for their families if they are the primary caregiver.”
In short, many patients are unable to make it through the door of the clinic to begin the process of trial enrollment. However, the struggles continue even when they make it into the room.
“There is a lack of basic health literacy among many lupus patient populations, including people from marginalized communities,” Anandarajah said. “There is so much terminology surrounding clinical trials that is poorly understood by many patients.”
In fact, many patients do not really understand what a clinical trial is, Buie added.
The language barrier Anandarajah mentioned previously is another factor.
“Many of the decisions we make in rheumatology involve patients and their families,” he said. “Even if the patient is able to speak English, if their supporting family members do not, it adds another barrier to communication.”
Age is another factor that is specific to many lupus patients, according to Buie.
“A lot of the lupus patient population is younger,” she said. “Often, their first real major, serious encounter with the health care system, that is not an annual checkup, comes when they receive a lupus diagnosis, which can take months to years for some patients.”
Young patients in this position are often fearful or uncertain about the future as a result of the diagnosis, which might preclude trial participation consideration, Buie added. However, even if they are able to participate, structural barriers can often stand in the way.
“The infrastructure for research is based on a white patient model,” Anandarajah said, adding that trials usually occur at academic centers that are easier for white patients to access. “This model still has not been adjusted or moved to incorporate minority populations.”
Organizations like the ACR and Lupus Foundation of America are, according to their leaderships, aware of the issues and are working to improve clinical trial design in lupus. In the meantime, individual rheumatologists should continue to communicate with patients in a way that will lead not only to optimal outcomes, but to increased clinical trial participation, experts said.
That starts with trust.
‘Years of Irregularities’
The history of mistrust of the health care system in Black, Hispanic and Asian communities is well-documented, according to Anandarajah.
“There have been years of irregularities in research studies among minority populations,” he said, noting that the infamous Tuskegee syphilis experiment is just one example of underrepresented populations being misled in a research setting. “This has caused Black, Hispanic and other minority populations to be afraid of participating in clinical trials.”
Evidence of this mistrust can be found in the literature.
In a paper published in Arthritis Care & Research, Sneed and colleagues conducted four focus groups with 31 total individuals in the Boston and Chicago metropolitan areas who self-identified as Black, who either had SLE or were caregivers of individuals with SLE. Candace Feldman, MD, MPH, ScD, assistant professor of medicine in the division of rheumatology, inflammation and immunity, and co-director of health equity initiatives, at Brigham and Women’s Hospital and Harvard Medical School, served as the co-senior author alongside Rosalind Ramsey-Goldman, MD, DrPH, Gallagher research professor of rheumatology and professor of medicine at the Northwestern University Feinberg School of Medicine.
“Our participants shared a number of key barriers with us, including longstanding mistrust stemming from experiences of racism, including past injustices in research, strict exclusion criteria that did not allow individuals with certain prevalent comorbid conditions to participate, and concerns about assignment to placebo groups,” Feldman said. “Several individuals also noted that they were concerned about their SLE disease activity and the effects of new medications on this.”
Rose McKeon Olson, MD, an instructor of medicine in the Division of Global Health Equity, also at Brigham and Women’s Hospital, conducts health equity research as well and has previously collaborated with Feldman. According to Olson, trust is potentially the primary issue that may ultimately decide whether or not a patient participates in a trial.
“Trusting relationships with the physicians — and the institutions they are part of — who recommend trial participation is an important motivating factor,” she said.
Although data show that most patients trust nurses more than they trust other health care professionals, Anandarajah stressed that trust must be an essential component of the rheumatologist-patient relationship.
“The most trusted information comes from physicians,” he said.
In addition, although rheumatologists may be aware of clinical trials in lupus and can advocate for participation, their patients often are under the care of several providers.
“Dermatologists, primary care providers and other physicians may not be aware of lupus trials, which presents another barrier,” Anandarajah said.
Buie stressed that all members of a multidisciplinary team share the responsibility of educating their patients.
“Each health care provider, paraprofessional, as well as the physician, has a role in making sure people are educated about clinical trials,” she said.
However, according to Buie, a larger concern is that Black and Hispanic patients are often simply not asked to participate in clinical trials in the first place.
“According to the literature, a major reason for this is because doctors do not believe that they will participate due to the barriers to care I previously mentioned,” she said. “Moreover, providers have often mentioned they don’t know how to broach the subject with some patients who have an increased burden of disease. When you have a patient who is on the verge of kidney failure, or if they have had multiple heart attacks or strokes, a discussion about clinical trials might be less of a priority for the provider.”
These competing priorities can materialize from both directions in the patient-physician relationship, Buie added.
“If the patient has three children at home without sufficient support and childcare, they do not really want to hear about participating in a clinical trial,” Buie said.
Ultimately, the result of this failure to communicate could be poorer real-world outcomes for individual patients and broader failures in research-adjacent areas of rheumatology care.
Underrepresentation and Harm
This failure to adjust can be observed in numerous ways, the most obvious of which is in diagnostic delays.
In one example, Garg and colleagues investigated the time to biopsy among a cohort of patients with lupus nephritis. Their findings, which they published in ACR Open Rheumatology, suggested that the presence of social factors, “such as being of a non-white race and having food insecurity,” were associated with a 54% reduction in the likelihood of a timely diagnosis (adjusted HR = 0.46; P = 0.031).
“Such delays can delay recruitment in clinical trials,” Garg said.
If poor recruitment in clinical trials was the only issue, experts could begin to tackle it more easily. However, underrepresented populations also face adjacent challenges that present barriers to effective care. In a paper published in Arthritis Care & Research, Strait and colleagues investigated 1,043 images of lupus patients in rheumatology clinical image banks. Results showed that despite the prevalence of lupus in Black patients, just 13.4% of the images were of patients with dark skin, while 84% were of patients with light skin and 2.6% were from patients of indeterminate skin color.
The researchers concluded that darker skin tones were “significantly underrepresented” in major rheumatology clinical image banks.
“Inclusion of diverse populations in research is essential to ensure that all individuals have access to new treatments and care strategies,” Olson said. “Although race is a social construct and not a biologic delineation, there are ancestral variations that can have biological impacts and may be overrepresented in certain racial and ethnic groups.”
These disparities often result in real-world outcomes.
In a paper published in Brain Behavior and Immunity, Martz and colleagues investigated the experiences of racial discrimination and changes in C-reactive protein among Black women with lupus. The analysis included 380 participants in the Black Women’s Experiences Living with Lupus (BeWELL) study, which enrolled patients between April 2015 and May 2017. Results showed that patients who reported experiencing racial discrimination demonstrated increased C-reactive protein throughout the 2-year study period (b = 0.039, SE = 0.017; 95% CI, 0.006-0.071).
According to the researchers, each incident of racial discrimination resulted in a 3.98% increase in C-reactive protein.
However, the issue is not just that these populations demonstrate increases in disease parameters like C-reactive protein, which is problematic, but also that they may be excluded from trials that can manage this and other manifestations of lupus, according to Olson.
“Populations most affected by SLE need to be included in studies of new treatments so that findings are relevant and generalizable,” she said. “Without adequate representation, novel drugs and treatments may be less effective or even harmful amongst minoritized populations.”
Faced with the documented risk for material, clinical harm for patients if nothing is done to address these concerns, advocacy organizations, professional groups and individuals alike have begun the work of reversing these trends. However, progress remains slow.
‘It’s About Relationships’
In 2019, patients, providers, clinical trialists and industry groups attended a conference entitled “Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies: Overcoming the Barriers.” Later, in a paper published in Arthritis Care & Research, Williams and colleagues summarized some of the findings and solutions discussed at this conference, highlighting “the need for changes at the societal, institutional, research team, referring physician, and patient education levels” to achieve equitable representation in SLE clinical studies.
Although there is little individual rheumatologists can do about societal or institutional changes, the rest of that list — regarding the research-team, referring-physician and patient-education levels — is well within their reach. For example, Feldman encouraged rheumatologists to ensure that the materials advertising a trial, and the strategies employed, are culturally sensitive and community engaged.
“In general, promoting active community engagement early in a study’s development and throughout the process — including, ultimately, engaging partners in the dissemination of results — is critical,” she said. “Inclusion and exclusion criteria must be considered to ensure that they do not systematically exclude certain populations that may experience disproportionate burden. For example, this includes patients who have certain comorbid conditions.”
The makeup of the group conducting the trial also can help the study population more accurately reflect real-world patient populations, Olson added.
“Ensuring diverse study teams that include racially, ethnically and socioeconomically diverse patient representatives would also be beneficial,” she said.
Meanwhile, guideline development committees within ACR and EULAR should consciously avoid race-based recommendations derived from trials that lack diverse populations, according to Feldman.
“The main journals of the ACR and EULAR can consider requiring demonstration of diverse participation in studies in order to consider the trial for publication,” she said. “Clear explanation of strategies employed for diverse recruitment should also be required in all publications. Ensuring that the work of ACR and EULAR, and the publications, can reach diverse audiences is also essential in order to disseminate the information learned from all research studies to all populations.”
Garg concurred with this sentiment, stating that researchers leading clinical trials should aim to recruit diversely, “rather than aiming to complete the recruitment.”
According to Buie, the FDA has, to this end, made a “strong push” for patient-focused drug development.
“This in large part includes making sure that the people who are living with the disease, or those who are most adversely affected, are influencing how processes are being created, how protocols are written and how trials are being executed,” she said. “We are happy to see that they are moving in the right direction.”
Anandarajah’s group, meanwhile, is developing materials pertaining to clinical trial participation in lupus with colleagues at the University of North Carolina, Chapel Hill, and the ACR.
“We are hoping to educate patients, primary care providers, advanced practice practitioners and community health workers,” he said. “We have been funded by the ACR and are lucky to have this opportunity to build bridges between patients, providers and lupus research experts.”
The Lupus Foundation of America is similarly seeking to connect patients, physicians and researchers, with education, outreach and peer-to-peer programs all targeting clinical trial representation.
For Buie, it will be these relationships — patient and physician, physician and researchers, researcher and patient — their strengths and their weaknesses, that will govern how successful any other these initiatives prove to be.
“It is about relationships,” Buie said. “We have to come together as a community to do the work to make people understand why research is so necessary and so important.”
- References:
- Buie J, et al. ACR Open Rheum. 2023;doi:10.1002/acr2.11590.
- Falasinnu T, et al. Curr Rheumatol Rep. 2018;doi:10.1007/s11926-018-0728-2.
- Garg S, et al. ACR Open Rheum. 2022;doi:10.1002/acr2.11435.
- Martz CD, et al. Brain Behav Immun. 2023;doi:10.1016/j.bbi.2023.06.004.
- Sneed RS, et al. Arthritis Car Res. 2021;doi:10.1002/acr.24635).
- Strait A, et al. Arthritis Care Res. 2021;doi:10.1002/acr.24602.
- Williams J, et al. Arthritis Care Res (Hoboken). 2022;doi:10.1002/acr.24474.
- For more information:
- Allen P. Anandarajah, MBBS, MS, can be reached at 400 Red Creek Drive, Suite 240 Rochester, NY 14623; email: allen_anandarajah@urmc.rochester.edu.
- Joy Buie, PhD, MSCR, RN, can be reached at 1779 Massachusetts Ave., Suite 500, Washington, DC 20036; email: buie@lupus.org.
- Candace Feldman, MD, MPH, ScD, can be reached at 75 Francis Street, Boston, MA 02115; email: cfeldman@bwh.harvard.edu.
- Shivani Garg, MD, MS, can be reached at 1685 Highland Ave., MFCB #4122, Madison, WI 53705; email: sgarg@medicine.wisc.edu.
- Rose McKeon Olson, MD, can be reached at 75 Francis Street, Boston, MA 02115; email: rolson@bwh.harvard.edu.
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