Pediatric Rheumatologists Discuss the Current State and Future of Precision Medicine in Juvenile Idiopathic Arthritis

The growing range of biologic disease-modifying antirheumatic drugs (DMARDs) has greatly improved the treatment landscape for juvenile idiopathic arthritis (JIA). However, certain subsets of patients with JIA remain unresponsive to these therapies and require alternate treatment strategies.¹ With the ongoing proliferation of research in the refinement of treatment in JIA, there has been increasing focus on a shift toward precision medicine in the field.^2,3 Experts have called for a revision of the JIA classification system to further improve treatment for this patient population, according to a review published in November 2021 in the Lancet Rheumatology.³

To get a deeper insight into the potential role of precision medicine in JIA, we spoke with Randy Q. Cron, MD, PhD, professor of pediatrics and medicine at the University of Alabama at Birmingham, director of the Division of Pediatric Rheumatology at Children’s of Alabama, and the Arthritis Foundation Alabama Chapter Endowed Chair in pediatric rheumatology; Mara L. Becker, MD, MSCE, professor of pediatrics and vice chair for faculty development at the Duke University School of Medicine and member of the Duke Clinical Research Institute in Durham, North Carolina; and Robert Fuhlbrigge, MD, PhD, professor of pediatric rheumatology at the University of Colorado School of Medicine and section head of pediatric rheumatology at Children’s Hospital Colorado Anschutz Medical Campus in Aurora.

What is the current state of progress on the potential role of a precision medicine-based approach in JIA?

Dr Cron: While we have made major advancements in the various beneficial therapeutic options for children with JIA, we have a long way to go in identifying which patients will benefit from which therapies. Nevertheless, in general, most children with JIA benefit from tumor necrosis factor (TNF) inhibitors, with the exception of the systemic JIA subtype, which typically benefits from therapeutics that inhibit interleukin (IL)-1 or IL-6 signaling.

Dr Becker: In some capacity, we have made great strides. Treat-to-target approaches are taking root in conjunction with shared decision-making to strive to achieve low or no disease activity in children with JIA. This approach focuses on the patients’ individual response to therapy and constantly adjusts treatment to the needs of the individual patient. We now have validated measures to set for targets of minimal disease activity in JIA, and we have data to show that these approaches work in JIA across a broad array of patients.

We have also learned that early and effective treatment is a major contributor to better long-term outcomes, so it is key to control disease activity early to optimize the chances of obtaining clinically inactive disease in the long term. We are also advancing knowledge in pharmacokinetics (PK) and pharmacodynamics (PC) in children – an area that will be necessary to advance drug development in children and to maximize safety and effectiveness. Both PK and PD also have the capacity to optimize drug exposure in children with JIA to ensure that the drug dosing they receive is the right dose for them. 

What we haven’t been able to determine at the current time is what the correct drug is for a specific patient. Although we have many more drugs at our disposal, it remains impossible to predict which drug to start and when. Several studies are currently underway to assess factors including genotype, serologic biomarkers, such as serum cytokine and metabolomic profiles, cellular drug levels, and endogenous drug targets to try to understand which patients would benefit from which medications at which timepoint in their disease course.⁴

Dr Fuhlbrigge: On the one hand, the advent of biologic DMARDs has had a transformative effect on treatment of JIA. Targeted inhibition of specific cytokines that regulate the development and progression of JIA can induce remission in many patients with JIA, preventing disability and allowing full participation in normal activities of childhood. On the other hand, 30% or more of patients with JIA do not achieve remission on the currently available medications and experience continued pain and progressive disability.⁵

Phenotypic classification structures and basic laboratories studies can inform the likelihood of response, but in the current state, we are not able to predict in advance who, specifically, will respond to one or another therapy, if any.

What are some of the key barriers toward the goal of incorporating precision medicine-based approaches in JIA, and what is needed to further advance these efforts?

Dr Cron: Compared with adults with chronic inflammatory arthritis, there are far less children with JIA and less overall infrastructure to conduct timely clinical trials of novel therapeutics as well as immunologic investigations allowing for precision medicine approaches. Rethinking the classification criteria for the various subtypes of JIA with shared features of adult rheumatic arthritides (eg, enthesitis-related arthritis/JIA and adult spondyloarthritis/ankylosing spondylitis) may allow for extrapolation of findings from studies conducted with adults to be translated for the benefit of children with related JIA subtypes.

Dr Becker: Key barriers pertain to manpower and the complexity of the disease at hand. Starting with the manpower issue, pediatric rheumatology is a small field with few providers and even fewer physician scientists to commit to these questions. The pipeline needs to be attended to, like in many small fields. There remains a dire need for both clinicians and physician scientists. Focused recruitment of students and residents to the field must occur. Programs to support and develop these individuals, such as mentored scientist development programs, loan repayment, and creative paths to streamline training in fellowship may all be ways to encourage entry into the pipeline.  

In addition, what is unique to our field of rheumatology is the amazing expansion in knowledge of our disease processes at an immunologic level and a host of new cytokine-targeting therapies that have been developed. However, this also exemplifies the complexity of the immunoinflammatory processes that drive diseases like JIA. It is not as simple as just a target to block that results in disease control in all patients, further underscoring that there is much more for us to learn.

JIA, specifically, is a heterogeneous “umbrella” term that encompasses several subtypes of arthritis in children classified on clinical features and serologic markers, but there have been recent discussions about reclassifying JIA subtypes on a more biologic basis. Clearly, as we are continuing to unravel JIA as a disease; it is not surprising that precision medicine remains elusive.

Dr Fuhlbrigge: Key barriers include lack of awareness and access to what is known, as well as lack of research to address what is not known. There are only around 300 pediatric rheumatology providers in the US, which is approximately 6 per state on average.⁶ This workforce is insufficient to see the population of pediatric patients with rheumatic disorders, leaving many to be managed by primary care physicians or adult rheumatologists or to receive no care at all.

The speed of change in the field makes maintaining awareness of current therapeutic options and medication risks difficult for subspecialty pediatric rheumatology providers, and nearly impossible for general and adult providers. There is an even more striking deficit of investigators studying pediatric disease mechanisms, defining which medications are effective in which pediatric populations, and characterizing long-term outcomes of both disease and therapies.

Classification systems used to predict course and recommendations for treatment in both pediatric and adult rheumatology are currently based largely on clinical phenotype as opposed to biologic mechanisms of disease. This results in potential coclassification of patients with similar disease patterns (for eg, axial vs peripheral joints, large vs small joints, total number of joints, association with fever and rash, etc), but which arise from different underlying mechanisms (inborn errors of immunity, metabolic derangements, postinfections, etc) and require very different medical approaches.

Further research is required to identify various types of biomarkers that more accurately predict response to specific therapies and to clarify best treatments among the available agents for specific categories of patients. Among the large percentage of patients who do not have a response to standard therapies for their proposed category of disease, genetic screening has been shown to change the presumed diagnosis and recommended mode of treatment in a significant fraction of patients, highlighting the limitations of phenotypic classification for predicting therapeutic outcomes. These methods require rapid and low-cost access to the relevant technologies, along with the bioanalytic support needed to interpret the data sets created.

What would you recommend to other clinicians in terms of aiming for a personalized approach in practice?

Dr Cron: Early aggressive therapy with available biologic therapies will likely lower the overall disease burden and allow for more “normal” childhoods for children with JIA. Targeted therapeutics for JIA-associated comorbidities should also guide therapy. For example, children with JIA who develop granulomatous eye inflammation in the form of uveitis will better benefit from monoclonal antibodies to TNF compared with TNF-receptor hybrid therapeutics.

We have made significant progress in the [management of] children with JIA, but for some of the more difficult disease courses, we have a promising but long road ahead of us.

Dr Becker: I’d start with encouraging a treat-to-target approach in JIA in the clinic, but this needs to encompass patients and families choosing targets as well and making this an opportunity for shared goals and decision-making. This also allows for discussions of new therapies and new testing that may be considered during the treatment course.

Making a joint decision on targets is ideal, as there has yet to be a single “best” target identified, and inactive JIA does not always correlate optimally with quality of life. Pain, fatigue, disability from prior disease damage, medication side effects, and treatment burden may persist and impact outcomes, even if JIA disease activity resolves. 

I would also recommend using the knowledge we have on drug levels and antidrug antibodies for monoclonal biologic therapies to help guide treatment decisions when there is a lack of clinical response with monoclonal antibody therapies. This can help determine if dose escalation is warranted or a switch in drug class.

Dr Fuhlbrigge: Seek partnership with pediatric rheumatology resources to help with diagnosis, discuss therapeutic options, and define safe monitoring plans. Consider referral to genetics and/or immunology for patients [whose disease] does not fit the classification criteria or who do not have a response after 3 or more changes of primary therapy.

Disclosure: Dr Cron declared affiliations with biotech, pharmaceutical, and/or device companies.

References

1. Zaripova LN, Midgley A, Christmas SE, et al. Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches. Pediatr Rheumatol Online J. 2021;19(1):135. doi:10.1186/s12969-021-00629-8
2. Schoemaker CG, Swart JF, Wulffraat NM. Treating juvenile idiopathic arthritis to target: what is the optimal target definition to reach all goals? Pediatr Rheumatol Online J. 2020;18(1):34. doi:10.1186/s12969-020-00428-7
3. Reiff DD, Stoll ML, Cron RQ. Precision medicine in juvenile idiopathic arthritis—has the time arrived? Lancet Rheumatol. 2021;3(11):e808-e817. doi:10.1016/S2665-9913(21)00252-6
4. Choida V, Hall-Craggs M, Jebson BR, et al. Biomarkers of response to biologic therapy in juvenile idiopathic arthritis. Front Pharmacol. 2021;11:635823. doi:10.3389/fphar.2020.635823
5. Shoop-Worrall SJW, Kearsley-Fleet L, Thomson W, Verstappen SMM, Hyrich KL. How common is remission in juvenile idiopathic arthritis: a systematic review. Semin Arthritis Rheum. 2017;47(3):331-337. doi:10.1016/j.semarthrit.2017.05.007
6. Correll CK, Ditmyer MM, Mehta J, et al. 2015 American College of Rheumatology Workforce Study and Demand Projections of Pediatric Rheumatology Workforce, 2015-2030. Published online October 27, 2020. Arthritis Care Res (Hoboken). doi:10.1002/acr.24497