Discussion
While there have been advances in understanding disease mechanisms and treatment of cSLE in the last decade, significant needs remain, underscoring the necessity of a focused research agenda for allocation of available resources. Expanding on the findings from the ALPHA study5 6 and CARRA-LFA survey regarding cSLE research priorities,7 we elucidated approaches to address cSLE research priorities, exploring both barriers and opportunities to advancing cSLE research. Multidisciplinary experts in our study identified research priorities represented by five domains: (1) expanding disease knowledge; (2) investigator collaboration; (3) partnering with patients and families; (4) improving care to optimise research; and (5) overcoming investigator barriers. Many interviewees had difficulty selecting a single priority, and the need for a broader paradigm framework for cSLE investigation was identified. Additionally, and notably, partnership with patients emerged as a unifying factor for advancing research (figure 1).
Figure 1A visual representation of study themes. The figure proposes that research priorities for cSLE are captured by five interrelated themes, which include disease knowledge, investigator collaboration, improving care to optimise research, investigator barriers and patient partnership (depicted in the centre of the figure). Patient engagement, patient partnership and health equity in research endeavours are central to the development of any proposed research agenda, and the other four themes rely on engagement of patients and health equity for their advancement. cSLE, childhood-onset SLE.
We identified not only barriers but also numerous opportunities for progress (box 1). Our findings represent an initial step in formulating a research agenda and funding priorities for the cSLE community.
Box 1Opportunities for advancing childhood-onset SLE (cSLE) research
Collaboration
Interdisciplinary collaboration across subspecialties and scientific disciplines to engage in a team science approach.
Multicentre and multinational collaboration to develop larger representative cSLE patient cohorts with diverse disease manifestations.
Efforts to reduce regulatory barriers to collaboration (eg, Institutional Review Board, Food and Drug Administration).
Longitudinal data
Address gaps in clinical care, with attention to enhance standardised, comprehensive and longitudinal data collection.
Longitudinal patient registry data collection from paediatric disease onset through adulthood.
Data management and infrastructure support across centres/sites to share standardised electronic medical record data and link to other data sources (eg, registries, administrative data).
Patient involvement in research
Improve healthcare delivery, with particular focus on underserved populations, to empower participation in research.
Engage patients and families to determine meaningful research questions and outcomes and to enhance recruitment of diverse populations.
Include patient-reported outcomes in study design.
Include diverse staff on research teams.
Investigator support
Increase funding opportunities for early investigators to pursue cSLE-related projects.
Dedicated mentorship programming for cSLE research, including funded protected time for cSLE mentors.
Facilitated networking among senior researchers and early investigators.
Experts identified a need for a path of investigation in lupus research, described as a paradigm framework to guide ‘how’ to do the research, which would also inform ‘what’ to research. A comparison was made to the field of autoinflammatory disease research, which has seen recent significant advances due to international and interdisciplinary collaboration, and harnessing of genomic and molecular technologies to link genotype to biological pathways to phenotype.10 This has resulted in better diagnostic tools and target immunosuppressive treatment in autoinflammatory disease. A similar paradigm for lupus research, addressing the complexity and heterogeneity of the disease, would be optimal to guide lupus investigation towards improving patient care. Experts emphasised the importance of a research agenda that promotes collaboration among investigators with different expertise (immunology, genetics, basic science, translational science, etc). With regard to translating findings to the clinical setting, experts also identified biomarker and drug development as prominent priority areas, acknowledging the unique regulatory and ethical considerations that exist in studies involving paediatric patients.
One promising model of investigation is the Accelerating Medicines Partnership (AMP),11 12 which has enabled successful collaboration between the NIH, pharmaceutical companies and non-profit organisations, bringing together individuals of varying backgrounds and expertise to push the science forward. The AMP initiative has supported ‘team science’ studies in the adult SLE population, for example, with one published study using single-cell RNA sequencing technology to examine heterogeneity of lupus nephritis and skin disease, and identifying cellular changes on skin biopsy as a potential biomarker for lupus nephritis.11 A trans-NIH initiative (across specialties) could be another potential opportunity for multidisciplinary collaboration to understand lupus disease heterogeneity given the multiorgan involvement in cSLE. Fostering team science collaboration inclusive of cSLE (both within cSLE and SLE research in general) will be critical to advancing research and discovery in cSLE, furthering knowledge of potential targets for more effective and less toxic medications (box 1). Furthermore, although there has been advancement in cSLE trials in recent years,13 treatment development in cSLE will likely require innovative smaller trials with specific endpoints given the rarity and heterogeneity of the disease.14
Another potential area for collaborative research is creating purposeful synergy between existing and newly created cSLE observational registries in order to optimise the breadth and depth of the data collected. Longitudinal observational registries which capture the full breadth of patient demographics, disease manifestations, treatments and response are critical to understanding cSLE’s natural history and short-term and long-term outcomes. Harmonisation of data fields can allow for comparison or combination of related registries, which may be essential when describing less common disease manifestations or treatments. These registries are even more powerful when paired with biosample collection, allowing for determination of both clinical and biologic factors which may contribute to fluctuations in disease activity and outcomes.
Although there was significant emphasis on research of the disease itself and its manifestations, patients’ barriers to engaging with the healthcare system (eg, transportation to clinic, reliable methods to communicate with providers) were a less expected, yet significant finding. This echoes priorities in the 2015 National Public Health Agenda for Lupus developed by a collaborative of the LFA, the Centers for Disease Control and Prevention, the National Association of Chronic Disease, and leading lupus and public health advocates,15 calling for improved lupus care coordination, self-management programmes, resources and identification of health disparities. Notably, SLE mortality risk is significantly impacted by race, with black females having increased mortality from SLE as compared with other individuals with SLE.16 17 Additionally, although individuals from racial minority groups make up a large proportion of patients with SLE in the USA, white participants are over-represented in SLE randomised control trials.18 Health equity research is therefore greatly needed to eliminate ongoing health disparities in SLE.15
To address the lack of adequate representation of racial minority groups in SLE research, a 2019 conference among patients with SLE, SLE physicians, clinical trialists, treatment developers from biotechnology, social scientists, patient advocacy groups and US government representatives explored solutions for increasing diversity in SLE research studies.19 Best practices for clinicians and researchers were developed, which included reflecting on how personal and institutional culture lead to racial bias in research questions and study design, the need to avoid making assumptions about the ‘kind’ of patient who would participate in a trial, and increasing recruitment of under-represented minorities to the field of rheumatology. Experts in our study expressed several opportunities to address these issues, including having a diverse research staff, including outcomes that are important to patients and utility of funding for patient navigators (box 1).
cSLE researchers face significant challenges—namely funding and protected time from clinical obligations—that impede their participation in multicentre studies or to procure data for registries to support longitudinal studies of diverse cohorts. As experts pointed out, this milieu discourages the number of early career faculty who pursue research careers, leading to fewer cSLE investigators and an inevitable lack of diversity in their research backgrounds. Academic institutions have created programmes to address this need,20–22 but it remains a critical issue across paediatric subspecialties and particularly in cSLE research given the small size of the paediatric rheumatology field.
As one of the smallest paediatric subspecialties, often with small institutional divisions,23 interinstitutional mentorship is crucial for trainees and early career faculty in paediatric rheumatology. The ACR/CARRA Mentoring Interest Group24 25 has established connections between individuals at different institutions for career mentorship. Even with funding (such as a mentored career development award, eg, NIH K award), the number and availability of mentors for cSLE research are limited. Grants that protect time for mentors, K24-like funding and Request for Application opportunities related to research mentorship from the LFA or Lupus Research Alliance are potential solutions to foster investigator mentoring (box 1). Patient advocacy efforts through private foundations could also fill such a role (figure 1).
There are a number of strengths in our study. To our knowledge, this is the largest qualitative study of cSLE experts regarding cSLE research priorities. The group of experts had diverse backgrounds, including their disciplines (eg, nephrology, dermatology, medicine/paediatrics rheumatology), years in practice and research backgrounds. There was also international representation. A limitation of our study is that patients were not included in our study, risking misalignment between patients’ priorities and those of experts. A follow-up study is planned to include patients’ perspectives, priorities and perceived barriers to being involved in research.
In conclusion, the findings of this study highlight the importance of a collaborative research framework and the interdependence of the essential components needed to advance cSLE research and patient care. These findings can inform an actionable research agenda that incorporates the complexity of foundational challenges that investigators in cSLE research face. Funding and limited infrastructure remain a major limitation, yet the potential solutions posited by experts should be prioritised in future request for applications for work related to cSLE.