Youthful Exuberance: The Year in Review for Pediatric Rheumatology

WASHINGTON, D.C.—It is no small task to summarize an entire year’s worth of research accomplishments in any field of medicine, let alone one as complex as rheumatology. At ACR Convergence 2024, the Pediatric Year in Review not only provided a thoughtful summary, but also grouped advances along several different themes.

Immune Health & More

Dr. Turnier

Jessica Turnier, MD, MS, assistant professor of pediatric rheumatology, University of Michigan, Saline, began her talk by discussing new tools being used to study immune health.

One article by Sparks and colleagues was meant to provide an understanding of what constitutes a healthy immune system rather than what causes immune system dysregulation. By looking at transcriptomics, serum protein, peripheral immune cell frequency and clinical data from more than 220 patients with 22 different monogenic conditions, along with 42 age- and sex-matched healthy controls, Sparks and colleagues were able to use multiple approaches (e.g., supervised machine learning and an unsupervised approach) to converge on a unified immune health metric (IHM). Dr. Turnier explained that this IHM holds promise as a biomarker of disease activity or treatment response because it is lower in patients with high disease activity, vs. low disease activity, in pediatric systemic lupus erythematosus, and it is higher in patients with rheumatoid arthritis who responded to treatment than in those who did not.¹

In a different study, Cui and colleagues sought to develop an immune dictionary to understand cell-type response to various cytokines using a murine model. This immune dictionary, which comprises single-cell transcriptomic profiles of more than 17 immune cell types in response to 86 different cytokines, can now be used to: 1) generate new hypotheses for cytokine functions; 2) illuminate pleiotropic effects of cytokines; 3) provide information about the activation states of each immune cell type; and 4) provide a framework to deduce the roles of specific cytokines in immune responses.²

The Pathogenesis of Disease

Dr. Turnier next discussed studies describing new mechanisms in the pathogenesis of rheumatic disease. The first study, by Bodansky and colleagues, looked at the link between SARS-CoV-2 infection and the development of multi-system inflammatory syndrome in children (MIS-C), a rare but serious condition that can manifest with features that look very much like toxic shock syndrome of Kawasaki disease.

In this study, the authors compared proteome-wide autoantibody profiles in nearly 200 children with MIS-C with those from 45 children convalescing after asymptomatic or mild SARS-CoV-2 infection. They found that children with MIS-C have distinct autoantibodies to the autoantigen sorting nexin 8 (SNX8) and a specific region of the SARS-CoV-2 nucleocapsid (MADS). They also found that these children have cross-reactive CD8+ T cells that bind both SNX8 and MADS, thereby implying that MIS-C is associated with these cross-reactive autoantibodies and the T cell response to them.³

Novel Diseases

Dr. Turnier went on to highlight several novel autoinflammatory diseases that are worthy of attention. Ubiquitylation—which is the addition of ubiquitylin to a protein substrate—has been recognized as a key mechanism in the regulation of immune responses. In fact, the “E” in VEXAS stands for E1 enzyme, the protein responsible for the first step in the ubiquitination pathway. Several “ubiquitinopathies” have been identified as a category of autoimmune disease, including OTULIN-related autoinflammatory syndrome (ORAS), a potentially fatal disease caused by a mutation in the OTULIN gene.

Davidson and colleagues describe the first heterozygous, dominant negative mutation that leads to loss of ubiquitinase activity in patients with ORAS. In two patients with this mutation, increased sensitivity to TNF-induced cell death was observed as was elevated type I interferon signature.⁴

In a different paper also related to a ubiquitinopathy, Oda and colleagues report on two patients with deficiency of SHARPIN, a component of the linear ubiquitin assembly complex (LUBAC). The authors found that SHARPIN loss of function mutations can lead to autoinflammatory symptoms and signs such as fevers, parotitis, arthritis, and colitis.⁵

Clinical Advances

Dr. Ruth

The second speaker in the session was Natasha Ruth, MD, MS, professor of pediatrics, division chief and program director, Pediatric Rheumatology, Medical University of South Carolina, Charleston, who provided updates in clinical advances from the past year (no small feat since by the year 2020 doubling time of medical knowledge has been estimated to be a mere 73 days).⁶

Dr. Ruth began by highlighting three clinical studies involving patients with juvenile idiopathic arthritis (JIA). The first study, carried out by the Pediatric Rheumatology InterNational Trials Organization (PRINTO) and The Pediatric Rheumatology Collaborative Study Group (PRCSG) investigators, looked at the efficacy and safety of subcutaneous tocilizumab in patients with polyarticular or systemic JIA. The investigators found that patients with these forms of JIA experienced long-term disease control with tocilizumab and that long-term safety was consistent with the known profile of this medication.⁷

The second clinical trial evaluated efficacy and safety of tofacitinib in patients with JIA and found that efficacy was maintained up to month 48 of follow up and that there were no deviations from the known medication safety profile.⁸

The third trial was from CLIPPER2, an eight-year, open-label extension of the phase 3b CLIPPER study of the safety and efficacy of etanercept in patients with JIA. In this study, one case of malignancy (Hodgkin lymphoma) was reported and the relationship of this cancer to etanercept or methotrexate could not be ruled out (though the overall observed malignancy rate was within that seen in patients with JIA who had not been exposed to TNF inhibitor therapy). The authors concluded that etanercept treatment for up to 10 years was well tolerated and had durable response in the patients still on active treatment.⁹

On a different subject, Dr. Ruth highlighted a study from Jaeggi and colleagues that sought to answer the question: why are some, but not all, offspring of anti-Ro antibody-positive mothers affected by the cardiac manifestations (e.g., heart block and endocardial fibroelastosis) of neonatal lupus? The study looked at antibody-positive mothers referred for serial fetal cardiac assessment at ≤20 weeks’ gestation either for those a) at risk for cardiac manifestations of neonatal lupus (CNL) or b) with a new diagnosis of CNL. Maternal anti-Ro 52 and anti-Ro 60 were measured using a chemiluminescent immunoassay (CIA), and additional testing on diluted serum samples was used to quantify anti-Ro 60 antibody titers above the analytical measuring range (AMR) of the standard CIA. The authors found that among 27 mothers with a fetal diagnosis of CNL all displayed anti-Ro 60 antibody titers that exceeded the AMR of the CIA by at least 10-fold. In both the group of patients at risk for and with confirmed CNL in the fetus, there was a positive relationship between event rates of CNL and higher anti-Ro 60 titers.¹⁰

In Sum

The session covered many more topics beyond those described above and speaks to the pace at which new knowledge is being discovered across the world of pediatric rheumatology. Thanks to Dr. Turnier and Dr. Ruth, the audience was able to get a taste of the many advances being seen in this specialty, and much more is likely to come in 2025.

Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

References

1. Sparks R, Rachmaninoff N, Lau WW, et al. A unified metric of human immune health. Nat Med. 2024 Sep;30(9):2461–2472.
2. Cui A, Huang T, Li S, Ma A, et al. Dictionary of immune responses to cytokines at single-cell resolution. Nature. 2024 Jan;625(7994):377–384.
3. Bodansky A, Mettelman RC, Sabatino JJ Jr., et al.; Overcoming COVID-19 Network Investigators. Molecular mimicry in multisystem inflammatory syndrome in children. Nature. 2024 Aug;632(8025):622–629.
4. Davidson S, Shibata Y, Collard S, et al. Dominant negative OTULIN-related autoinflammatory syndrome. J Exp Med. 2024 Jun 3;221(6):e20222171.
5. Oda H, Manthiram K, Chavan PP, et al. Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency. Nat Immunol. 2024 May;25(5):764–777.
6. Densen P. Challenges and opportunities facing medical education. Trans Am Clin Climatol Assoc. 2011;122:48–58.
7. Brunner HI, Ruperto N, Ramanan AV, et al.; PRINTO and PRCSG Investigators. Long-term efficacy and safety of subcutaneous tocilizumab in clinical trials of polyarticular or systemic juvenile idiopathic arthritis. Rheumatology (Oxford). 2024 Sep 1;63(9):2535–2546.
8. Brunner HI, Akikusa JD, Al-Abadi E, et al.; Paediatric Rheumatology International Trials Organisation (PRINTO) and Pediatric Rheumatology Collaborative Study Group (PRCSG). Safety and efficacy of tofacitinib for the treatment of patients with juvenile idiopathic arthritis: Preliminary results of an open-label, long-term extension study. Ann Rheum Dis. 2024 Oct 21;83(11):1561–1571.
9. Vojinović J, Foeldvari I, Dehoorne J, et al. Ten-year safety and clinical benefit from open-label etanercept treatment in children and young adults with juvenile idiopathic arthritis. Rheumatology (Oxford). 2024 Jan 4;63(1):140–148.
10. Jaeggi E, Kulasingam V, Chen J, et al. Maternal anti-Ro antibody titers obtained with commercially available immunoassays are strongly associated with immune-mediated fetal heart disease. Arthritis Rheumatol. 2023 Sep;75(9):1556–1565.