2020 Pediatric Rheumatology Research in Review

Dr. von Scheven

ACR CONVERGENCE 2020—This has been a busy year for research publications covering a number of pediatric rheumatic diseases, including the emerging multi-system inflammatory syndrome (MIS-C) associated with SARS CoV-2.

Despite the many challenges brought about by the COVID-19 pandemic, a healthy collection of publications covering a wide range of pediatric rheumatology research topics were published in 2020. These research publications advanced our knowledge of the pathophysiological basis of pediatric rheumatic diseases and treatment options and influenced the practice of pediatric rheumatology.

During the ACR Convergence 2020 session Pediatric Rheumatology: The Year in Review Emily von Scheven, MD, MAS, chief of rheumatology, director of the Child and Adolescent Chronic Illness Center, and a pediatric rheumatologist at the University of California, San Francisco, Benioff Children’s Hospital, and Grant Schulert, MD, PhD, assistant professor of pediatrics in the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center and in the Department of Pediatrics at the University of Cincinnati College of Medicine, discussed a selection of 2020 publications addressing clinical research, as well as basic and translational research in pediatric rheumatology.

Clinical Research Review

Dr. von Scheven began by describing her process for reviewing clinical pediatric rheumatology publications. She conducted a systematic PubMed review, then a manual review, identifying themes and articles. To visually illustrate common themes in 2020 pediatric rheumatology publications, Dr. von Scheven generated a word cloud with titles of papers, which revealed COVID-19 as a dominating theme, “reinforcing really what we are all feeling—that this pandemic that we are living in today seems to be dominating all aspects of our lives,” she said.

Dr. von Scheven discussed a collection of publications that investigated MIS-C in children with COVID-19. A study by Feldstein et al. investigated the epidemiology and clinical features of MIS-C through targeted surveillance between March 15 and May 20, and concluded MIS-C associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children.¹ She also discussed the ACR’s Clinical Guidance on MIS-C by Henderson et al., which provides 40 clinical guidance statements covering such key topics as MIS-C diagnosis, comparison to Kawasaki disease, management of cardiac manifestations and immunomodulatory treatment strategies.² Dr. von Scheven noted the rapid response the ACR took to release this document and stressed that it is a living document reflecting currently available evidence. The guidance document will be revised as further evidence emerges.

Dr. von Scheven’s discussion of other key themes in 2020 pediatric rheumatology research covered several papers on juvenile idiopathic arthritis (JIA) treatment modalities, including starting, switching and stopping biologics. For example, in a systematic review and meta-analysis by Cabrera et al. on the risk-benefits of using biologic agents to treat JIA, investigators found therapeutic success without serious adverse events is typical with systemic JIA patients.³

According to Dr. von Scheven, a retrospective cohort study by Mannion et al. on biologic switching found that one-quarter of JIA patients are switching biologics and noted that additional research is needed to determine optimal timing and preferred sequencing of biologics.⁴

In a treat-to-target study, Klein et al. found that many patients reached minimal disease activity or remission at 12 months and approximately half of the studies’ patients achieved target without a biologic agent.⁵ A separate commentary by Schoemaker et al. challenged readers to consider the limitations of the current treat-to-target approach, such as the absence of an agreed-upon optimal target, the need to address goals beyond disease activity, such as minimizing comorbidities, and the need to consider an individual patient’s personal targets.⁶

Several studies she discussed addressed PFAPA (i.e., periodic fever, aphthous stomatitis, pharyngitis, adenitis), including the role of tonsillectomy, which Burton et al. found beneficial but noted that patients also recover spontaneously, and medication can reduce episode severity.⁷ Regarding PFAPA treatment, Dr. von Scheven reviewed a study using the latest CARRA (Childhood Arthritis and Rheumatology Research Alliance) consensus treatment plans and emphasized that larger comparative effectiveness studies should allow us to directly compare outcomes across four treatment options—antipyretic, corticosteroid, prophylaxis and surgery—to identify best treatments for PFAPA.⁸

She described new clinical research in lupus care for pediatric patients by Sivaraman et al., which found that previsit planning and clinical pharmacist support improved vaccination rates in the rheumatology clinic.⁹ “Now their challenge is to sustain these gains, and our challenge is to do the same in our clinics,” Dr. von Scheven said.

Research from Li et al. on a pilot study using CARRA consensus treatment plans for localized scleroderma found that patients improved in all three consensus treatment plans—methotrexate monotherapy, methotrexate with supplemental intravenous (IV) methylprednisolone for three months, and methotrexate with daily oral steroids—with over 75% having a major or moderate improvement compared to baseline.¹⁰

She also highlighted findings from a retrospective, single-site study by Do et al., which found that publication of CARRA consensus treatment plans have led to a change in treatment for pediatric morphea.¹¹

Several 2020 papers Dr. von Scheven discussed addressed therapeutics for Kawasaki disease, including a comparative study by Crayne et al. that found infliximab monotherapy should be considered as second-line treatment for patients who fail to respond to initial intravenous immunoglobulin.¹² A separate study by Miura et al. on infliximab for Kawasaki disease found it was well tolerated and effective for acute Kawasaki disease refractory to conventional therapies.¹³

Dr. von Scheven also presented a group of papers addressing healthcare disparities in pediatric rheumatology patients, including a study by Rubinstein et al. on disparities in childhood-onset lupus that reported Black children with end-stage renal disease are half as likely to receive renal transplants as white children and almost twice as likely to die.¹⁴ She reiterated the words of the authors that “some patients remain largely invisible in the literature,” and stressed that this is a call to action, with more studies on health disparities in pediatric rheumatology desperately needed.

Basic & Translational Research

In his presentation, Dr. Schulert focused on basic and translational pediatric rheumatology research. He said COVID-19 was a dominating trend in research, with a PubMed search revealing 433 articles on JIA and 3,851 articles on pediatric COVID-19. One of these papers he described, by Consiglio et al., addressed SARS CoV-2-associated MIS-C immunology. The investigators found a distinct, overall serum inflammatory profile in MIS-C that differed from severe acute COVID-19 and Kawasaki disease, and included uniquely elevated interleukin (IL) 17α.¹⁵

Dr. Schulert

Dr. Schulert highlighted several other publications he found significant in 2020 that have the potential to change the way pediatric rheumatologists think about and treat pediatric rheumatic diseases going forward. These fall into six themes: pyrin, familial Mediterranean fever (FMF) and the plague; ENCODE: Encyclopedia of DNA Elements; molecular heterogeneity of pediatric lupus; pre-inflammatory mesenchymal (PRIME) cells; genetics of PFAPA; and dissecting the interferon (IFN) signature.

Considering the current pandemic and covering the topics of pyrin, FMF and the plague, he highlighted a study by Park et al. on ancient FMF mutations in human pyrin and resistance to Yersinia pestis (the Black Plague).¹⁶ FMF is caused by recessively inherited mutations in the MEFV gene, encoding the pyrin inflammasome. Because heterozygous carrier frequencies are very high in some Mediterranean populations, it has been suggested this is a selective advantage involving resistance to Yersinia pestis infection. By studying historical data, the researchers found Yersinia pestis mutations rapidly increased around Black Plague epidemics, and that Yersinia virulence factor YopM inhibits pyrin inflammasome formation and YopM binding to pyrin substantially reduced FMF mutation pyrin. Dr. Schulert said these findings together suggest an evolutionary and functional link between the prototypical FMF variant pyrin autoimmune disease with one of the most important pathogens in human history.

Moving from microbiology to “the biggest of big data,” Dr. Schulert described several papers on ENCODE: Encyclopedia of DNA Elements. Van Nostrand et al. introduced a large dataset of RNA elements that are bound by RNA-binding proteins (RBP) across the genome and identified RBP binding sites on RNA and chromatin in vivo, which provides “an incredible resource for our emerging understanding of genomics in rheumatic diseases,” he said.¹⁷

Staying with the theme of big data as it relates to lupus, Dr. Schulert discussed a study by Nehar-Belaid et al. examining molecular heterogeneity in pediatric lupus by mapping expression of genes from lupus-related monogenic disorders to distinct cell clusters, including mostly monocytes and dendritic cells. The researchers found that combining cell cluster enrichment yielded six patient cellular clusters, which provides a “tremendous resource for lupus immunology to lay the groundwork for understanding the heterogeneity of pediatric lupus,” he said.¹⁸

Another interesting cell population with relevance to pediatric rheumatic diseases are PRIME cells, Dr. Schulert noted. In recent research using PRIME cells to predict rheumatoid arthritis flares, he discussed a paper by Orange et al. that used a unique method of obtaining three drops of blood once per week remotely from study patients, paired with a weekly remote clinical assessment, to identify the unique gene expression characteristics of patients experiencing a flare, characterized by circulating PRIME cells.¹⁹ Dr. Schulert said this approach raises an interesting question regarding the identification of similar PRIME cells in childhood arthritis.

Shifting gears back to pediatric rheumatology and the genetics of PFAPA, Dr. Schulert shared findings from a study by Manthiram et al. that looked at common genetic susceptibility loci links between PFAPA syndrome, Behçet’s disease and recurrent aphthous stomatitis.²⁰ The investigators examined three large cohorts of PFAPA patients using a target gene approach to identify genetic risk alleles and found both Behçet’s and PFAPA most significantly associate with interleukin 12α, especially during PFAPA flares.

In a separate study looking at autoinflammation, de Jesus et al. measured distinct interferon signatures and cytokine patterns to define additional systemic autoinflammatory diseases among four distinct groups of patients and found that the interferon-stimulated gene score can be used to identify and subdivide patients with undifferentiated systemic autoinflammatory diseases, Dr. Schulert explained.²¹

Carina Stanton is a freelance science journalist based in Denver.

References

1. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020 Jul 23;383(4):334–346.
2. Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS–CoV‐2 and hyperinflammation in pediatric COVID‐19: Version 1. Arthritis Rheumatol. 2020;72(11):1791–1805.
3. Cabrera N, Avila-Pedretti G, Belot A, et al. The benefit-risk balance for biological agents in juvenile idiopathic arthritis: A meta-analysis of randomized clinical trials. Rheumatology (Oxford). 2020 Sep 1;59(9):2226–2236.
4. Mannion ML, Xie F, Horton DB, et al. Biologic switching among non-systemic juvenile idiopathic arthritis patients: A cohort study in the Childhood Arthritis and Rheumatology Research Alliance Registry. J Rheumatol. 2020 Sep 15;jrheum.200437.
5. Klein A, Minden K, Hospach A, et al. Treat-to-target study for improved outcome in polyarticular juvenile idiopathic arthritis. Ann Rheum Dis. 2020 Jul;79(7):969–974.
6. 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 Apr 16;18(1):34.
7. Burton MJ, Pollard AJ, Ramsden JD, et al. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev. 2019 Dec 30:12(12):CD008669.
8. Amarilyo G, Rothman D, Manthiram K, et al. Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): A framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group. Pediatr Rheumatol Online J. 2020 Apr 15;18(1):31.
9. Sivaraman V, Wise KA, Cotton W, et al. Previsit planning improves pneumococcal vaccination rates in childhood-onset SLE. Pediatrics. 2020 Jan;145(1):e20183141.
10. Li SC, Torok KC, Rabinovich CE, et al. Initial results from a pilot comparative effectiveness study of three methotrexate-based consensus treatment plans for juvenile localized scleroderma. J Rheumatol. 2019 Oct;jrheum.190311.
11. Do N, Ringold S, Sullivan E, et al. A retrospective study: Impact of consensus treatment plans on systemic therapy of pediatric morphea. Pediatr Dermatol. 2020 Mar;37(2):278–283.
12. Crayne CB, Mitchell C, Beukelman T. Comparison of second-line therapy in IVIg-refractory Kawasaki disease: A systematic review. Pediatr Rheumatol Online J. 2019 Nov 27;17(1):77.
13. Miura M, Kobayashi T, Igarashi T, et al. Real-world safety and effectiveness of infliximab in pediatric patients with acute Kawasaki disease: A postmarketing surveillance in Japan (SAKURA Study). Pediatr Infect Dis J. 2020 Jan;39(1):41–47.
14. Rubinstein TB, Knight AM. Disparities in childhood-onset lupus. Rheum Dis Clin North Am. 2020 Nov;46(4):661–672.
15. Consiglio CR, Cotugno N, Sardh F, et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell. 2020 Nov;183(4):968–981.e7.
16. Park YH, Remmers EF, Lee W, et al. Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis. Nat Immunol. 2020 Aug;21(8):857–867.
17. Van Nostrand EL, Freese P, Pratt GA, et al. A large-scale binding and functional map of human RNA-binding proteins. Nature. 2020 Jul;583(7818):711–719.
18. Nehar-Belaid D, Hong S, Marches R, et al. Mapping systemic lupus erythematosus heterogeneity at the single-cell level. Nat Immunol. 2020 Sep;21(9):1094–1106.
19. Orange DE, Yao V, Sawicka K, et al. RNA identification of PRIME cells predicting rheumatoid arthritis flares. N Engl J Med. 2020 Jul 16;383(3):218–228.
20. Manthiram K, Preite S, Dedeoglu F, et al. Common genetic susceptibility loci link PFAPA syndrome Behçet’s disease, and recurrent aphthous stomatitis. Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14405–14411.
21. De Jesus AA, Hou Y, Brooks S, et al. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. J Clin Invest. 2020 Apr 1;130(4):1669–1682.