Addressing the Need for Inclusivity and Collaboration in Lupus Research

Lupus is a highly variable disease with relevant environmental and genetic causality. Dr. Linda Hiraki sits down to discuss the issues this presents from a research perspective, focusing on the lack of genetic diversity in data and the need for scientific collaboration.

Brooke Coe, Vivian Hong, and Kajeetha Sarvananthan

The events that occur in our childhood have a stark ability to shape our adult lives. Such is the case with Dr. Linda Hiraki, a Clinician-Scientist with The Hospital for Sick Children (SickKids), who was a teenager when her sister was diagnosed with a life-altering chronic illness, Systemic Lupus Erythematosus (SLE or lupus). Dr. Hiraki was in medical school when she became impassioned to understand the complex disease that “had such a big impact on [her] sister’s life and [her] whole family.” This connection is what drove Dr. Hiraki to the top of her field as an expert in pediatric lupus. Recalling the events of her past, Dr. Hiraki acknowledges the importance of making a connection between one’s personal and professional life, stating “it [is] what gives our work meaning… And I think it [is] important to feel like our work is meaningful.” She now finds herself at the forefront of pediatric SLE research, working to understand the complex genetic differences underpinning lupus development, to improve physical and mental health experiences for patients, and to address the lack of ethnic diversity in data.

What is Lupus?

Lupus is an autoimmune disease that causes inflammation that leads to tissue damage throughout the body, affecting many organ systems¹. Lupus can affect children, adolescents, and adults, with 20% of patients diagnosed in childhood². While akin to adult SLE, pediatric SLE (also known as childhood-onset SLE or cSLE) commonly results in more severe presentations and higher levels of organ involvement². In particular, the kidneys or the brain are commonly affected with inflammation that may cause damage, leading to life-threatening complications¹.

The presentation of lupus is highly heterogeneous with Dr. Hiraki sharing that it is also known as “the disease of a thousand faces,” meaning that both its clinical manifestations and causality are highly variable. Lupus development and progression is impacted by numerous environmental factors, including hormones, UV exposure, and infection. There is also evidence that genetics play a strong role in lupus predisposition³. Over 180 lupus susceptibility genes have been identified to date, primarily in European populations⁴. Many associated genes are involved in regulating immune response³. For most people, lupus is a consequence of interactions between genetic, environmental, and epigenetic factors^3,4. This results in a wide range of clinical manifestations called lupus as some patients have life-threatening disease while for others, lupus is comparatively mild. However, Dr. Hiraki iterates that although “we call them all the same thing, practically, they [are] very different!”

Despite the variability in presentation, the interplay of lupus risk factors results in the dysregulation of the body’s immune system. This is primarily due to the overproduction of self-attacking antibodies, called autoantibodies, that target proteins on normal, healthy cells as if they were foreign pathogens^1,5. This causes a positive feedback loop of inflammation where sustained attacks from autoantibodies creates inflammation that further dysregulates autoantibody activities, creating more inflammation, and eventually tissue and organ damage (figure 1)^1,5. The involvement of other immune cell populations and inflammatory intermediaries, such as cytokines, further perpetuates the cycle and severity of inflammation⁵. Such mediators are commonly linked to lupus in gene association studies, demonstrating the complex and multifactorial nature of the disease⁵.

Using her background in genetic epidemiology, Dr. Linda Hiraki studies genetic changes associated with different SLE signs, symptoms, and complications in children and adults. At its core, she hopes her work aids our understanding of the underlying biology of SLE, hoping to gain insight into “not so much who gets lupus, but what their lupus looks like – the genetics of different manifestations of the disease.” Dr. Hiraki is currently coordinating large international studies to identify associations between common or low-frequency genetic variants and disease traits. To accomplish these goals, Dr. Hiraki acknowledges two central themes: representation and collaboration.

Issues of Representation in Lupus Research

During our discussion with Dr. Hiraki, the need for broad and representative genetic research in lupus was a recurring theme. Genetic medicine in general, is historically over-representative of white, European populations, leaving other ethnic populations greatly under-represented. This is problematic due to an unaccounted for, yet well recognized, prevalence of lupus in non-European populations⁶. Ethnicity and geography play a significant role in SLE development. For example, in North America, the prevalence of SLE for Black and Hispanic populations is 3-4 times higher compared to Caucasian populations⁶. Clinical manifestations among non-white/non-European ancestral populations are also more severe, often showing increased organ damage⁶. For Dr. Hiraki, the issue is that the under-representation of non-European populations in SLE genetic studies exacerbates disparities in our understanding of SLE across populations, and thus impedes our ability to use genetic data broadly in clinical care.

While describing the lack of diversity in genetic data, Dr. Hiraki also discussed the societal inequities that confound this issue. A complex matter in its own right, Dr. Hiraki simplifies the discussion, stating “disparities in health care access and health outcomes fall along ethnic and socioeconomic lines”. Not only does the link between lower socioeconomic status and ethnicity affect health at a rudimentary level, such as poorer diet, but it affects how those people are treated within the healthcare system⁷. A historic lack of adequate, accessible, and ethical healthcare based on socioeconomic and ethnic status has resulted in deep mistrust of the healthcare system by some groups. In a follow up response, Dr. Hiraki explained how this affects the ability to conduct well-represented research for lupus:

“Engaging persons of all backgrounds in research continues to be a challenge. There is a complex relationship between the medical, scientific research community and different sectors of society… it’s understandable why certain groups may mistrust the medical community and be reluctant to participate in research.”

Beyond the difficulties of getting broad ethnic participation in research, lupus presentation and progression is linked to lower socioeconomic status and ethnicity⁷. Factors associated with inequities are so heavily associated with SLE that they are often considered predictive of SLE development and progression⁷. For Dr. Hiraki, this becomes a challenge of “trying to disentangle how much of th[e] disparities are a consequence of inequity when it comes to access to health care and how much of [it] is a reflection of genetics.”

As a clinician and researcher, Dr. Hiraki has made it her mission to proactively study underrepresented and admixed populations, stating “it [is] because of that imbalance in representation that we are inclusive in our recruitment.” True to her word, in 2009, Dr. Hiraki conducted one of the largest, single centers, transethnic cSLE studies out of SickKids in Toronto⁶. This study was done with the purpose of delineating ethnic involvement in cSLE as most multiracial studies prior had focused on adult SLE⁶. In contrast to predominant American studies that comprised of Caucasian, African American, and Hispanic sample groups, Dr. Hiraki’s team took advantage of Toronto’s multiculturalism and recruited Asian and South-Asian sample groups as well. This resulted in a majority non-Caucasian cohort. Overall, this diverse study agreed with the consensus in adult SLE research that non-Caucasian populations had higher disease prevalence and younger age of diagnosis⁶. However, severity and disease progression were independent of ethnicity⁶. More recently, Dr. Hiraki has focused more on neonatal SLE (cases where the patient has lupus at birth). Dr. Hiraki and her team found that ethnicity is not associated with lupus risk or a specific disease manifestation in neonatal SLE cases, suggesting gene loci that differ among different ethnicities are involved in a gene-environment dynamic that results in specific manifestations⁸. Such studies done by Dr. Hiraki and her team allow us to move forward to fully understanding the exact role of genetics in lupus versus that of the environment. Thus, there is a demonstrated need to account for ancestry in genetic association studies for lupus, while not discounting its potential involvement.

Furthermore, Dr. Hiraki’s research also demonstrates the value of including genetically diverse data in research. Another 2009 study described autoantibody differences among different ethnic populations⁹. This was the first study suggesting autoantibody clustering was linked to different clinical outcomes in cSLE. They found that Caucasian patients predominantly associated with autoantibodies that were linked to mild SLE and minimal organ damage, while non-Caucasians clustered with more severe manifestations and complications⁹. These types of classifications can provide important clinical context, suggesting that full autoantibody profiling could help predict disease progression and potential organ involvement. In line with what she hopes to accomplish, this and subsequent work provides valuable insights into lupus pathogenesis, making data “relevant not just for certain ancestral groups but making it relevant for everybody, irrespective of what their ancestral background is.”

The Future is Collaborative

When asked to identify the biggest hurdle(s) in lupus research, Dr. Hiraki reiterated the lack of inclusivity as a major obstacle, despite the push for representation over the last couple years. She describes “still having to generalize European [data] to non-European populations because there is no information” and how she “find[s] that very frustrating.”

This issue is demonstrated in one of Dr. Hiraki’s recent studies investigating the genetic link between schizophrenia and SLE in a multiethnic cohort. Here, the data on schizophrenia susceptibility genes was primarily from populations of European ancestry which affected the ability of the study to truly assess the link for non-Europeans¹⁰. This example demonstrates the sacrifices that are still being made in lupus research that potentially alter the conclusions made and subsequent clinical treatments.

Further discussing the issues in lupus research, Dr. Hiraki addressed the need for standardization and “speaking the same language” when it comes to the definition of lupus across research. Due to the variability in clinical presentation, lupus can be commonly misdiagnosed and misclassified (for example, lupus is commonly misdiagnosed as rheumatoid arthritis). Additionally, she explained “lupus is not only heterogeneous between people but it’s heterogeneous within a person over time.” That is, lupus involves periods of active inflammation and followed by periods of inactivity. Also, lupus manifestations can fluctuate over time, creating potential for new organ involvement years after the initial diagnosis.

To address these challenges, Dr. Hiraki urges collaboration, expressing:

“Science has evolved in such a way that we’re increasingly collaborative …By expanding [our] circle[s], not only [are we] connecting with people who have very different skill sets but again have different perspectives.”

The challenges of lupus, like the disease itself are complex and require unique troubleshooting that truly only arises from effective collaboration. On her end, Dr. Hiraki involves herself in international groups of lupus researchers aiming to ensure that data is being collected with consistent methods and definitions. By standardizing how research is done and data is collected, it will be easier to centralize and harmonize globally. Overall, this affords lupus researchers access to more diverse and usable data.

Much of her current work focuses on using these connections to coordinate large-scale, long-term, transethnic studies to delineate immunological profiles of individual patients. She is working to characterize single cell populations within lupus patients to distinguish inflammation over the course of a disease. In doing this, “the hope is as we have better characterization of each individual person’s disease and trajectory, [and] we’ll be able to treat them more effectively,” explains Dr. Hiraki. At the end of the day, Dr. Hiraki wants her research to provide broadly applicable data that translates to more personalized patient experiences.

Dr. Hiraki has established herself as a reputable powerhouse at the forefront of lupus research. Her research affords invaluable genetic context for a disease that is incredibly multifaceted and difficult to understand. Furthermore, her actions as an advocate for diversity in lupus research will have profound effects for patients worldwide. As the scientific community continues towards the trend of individualized medicine, Dr. Hiraki’s work will shine as a key driver of progression, exemplifying the need and value of inclusive and collaborative research.

References:

1. Pathak, S. & Mohan, C. Cellular and molecular pathogenesis of systemic lupus erythematosus: Lessons from animal models. Arthritis Research Therapy 13, 241 (2011).
2. Knight, A. M., Trupin, L., Katz, P., Yelin, E. & Lawson, E. F. Depression risk in young adults with juvenile- and adult-onset lupus: Twelve years of followup. Arthritis Care & Research 70, 475–480 (2018).
3. Kwon, Y., Chun, S., Kim, K., & Mak, A. Update on the genetics of systemic lupus erythematosus: Genome-wide association studies and beyond. Cells 8, 1180 (2019).
4. Elghzaly, A. A. et al. Genome-wide association study for systemic lupus erythematosus in an Egyptian population. Frontiers in Genetics 13, (2022).
5. Dema, B. & Charles, N. Autoantibodies in SLE: Specificities, isotypes and receptors. Antibodies 5, 2 (2016).
6. Hiraki, L. et al. Ethnic differences in pediatric systemic lupus erythematosus. The Journal of Rheumatology 36, 2539–2546 (2009).
7. Demas, K. L. & Costenbader, K. H. Disparities in lupus care and outcomes. Current Opinion in Rheumatology 21, 102–109 (2009).
8. Diaz, T. et al. Ethnicity and neonatal lupus erythematosus manifestations risk in a large multiethnic cohort. The Journal of Rheumatology 48, 1417–1421 (2021).
9. Jurencak, R. et al. Autoantibodies in pediatric systemic lupus erythematosus: Ethnic grouping, cluster analysis, and clinical correlations. The Journal of Rheumatology 36, 416–421 (2009).
10. Ulloa, A. C. et al. Schizophrenia genetics and neuropsychiatric features in childhood-onset systemic lupus erythematosus. The Journal of Rheumatology 49, 192–196 (2021).