The State of Clinical Science for Pediatric Rheumatology in 2021

ACR Convergence 2021—The Pediatric Rheumatology Year in Review began with a fascinating talk by Mara Becker, MD, MSCE, a professor of Pediatrics and vice chair of faculty at Duke University School of Medicine, Durham, N.C.

Dr. Becker began by describing her search strategy to select high-yield clinical science publications in pediatric rheumatology from the past year. She queried the Medline search database, gathered content from the Pediatric Rheumatology Symposium (PRSYM), held earlier this year, and added a few of her favorite articles to identify important themes and publications. Although COVID-19 continued to dominate much of her literature search, she identified several other relevant topics, and her selections fell into these distinct themes: COVID-19 and multi-system inflammatory syndrome in children (MIS-C), disparities in pediatric rheumatology, and therapeutic optimization and innovation.

COVID-19 & MIS-C

To begin the discussion of COVID-19 and MIS-C, Dr. Becker highlighted the two clinical guidance documents developed by the ACR. These provide recommendations for recognizing and treating children with MIS-C and on managing primary COVID-19 infection in children with rheumatic disease.^1,2 She applauded the efforts of the ACR, Henderson et al. and Wahezi et al. for developing these guidance documents and for continuing to update the recommendations as new data emerge.

Dr. Becker continued by highlighting a publication by Son et al. that looked at initial therapy and outcomes in children treated with immunomodulating therapy for MIS-C. This study analyzed data from more than 500 patients from 58 hospitals in the U.S. The investigators used propensity score matching to compare outcomes between patients treated with intravenous immunoglobulin (IVIG) alone vs. those treated with IVIG plus glucocorticoids.

The researchers found that treatment with IVIG plus glucocorticoids was associated with a lower risk of adverse cardiovascular outcomes, and overall, the patients who received this combination treatment required less subsequent adjunctive immunomodulatory therapy. These results were published in the New England Journal of Medicine.³

The next COVID-19 article Dr. Becker covered was a review by Wahezi et al. discussing how the pandemic has affected the field of pediatric rheumatology.⁴ In addition to reviewing the abridged ACR guidelines, this paper also discussed advances in telerheumatology, post-COVID-19 sequelae, the impact of psychologic distress related to the pandemic and inequities that have emerged since the onset of the pandemic.

Her final selection from the COVID-19 pediatric literature was a study from Children’s Mercy Hospital, Kansas City, Mo., investigating the use of saliva to test for SARS-CoV-2. Researchers used paired testing of nasopharyngeal swabs and saliva in a small cohort of children receiving standard-of-care testing for COVID-19. Saliva samples demonstrated a high sensitivity and specificity, as well as a significant amount of viral load, suggesting that saliva testing may be a reasonable alternative to nasopharyngeal swabs for pediatric COVID-19 testing.⁵

The researchers found that treatment with IVIG plus glucocorticoids [in children with MIS-C] was associated with a lower risk of adverse cardiovascular outcomes, & overall, the patients who received this combination treatment required less subsequent adjunctive immunomodulatory therapy.

Disparities

Dr. Becker transitioned to a discussion on disparities in pediatric rheumatology. The first paper she reviewed was a study by Rubinstein et al. investigating the association of adverse childhood experiences (ACEs) with the development of juvenile idiopathic arthritis (JIA). ACEs are experiences associated with chronic stress, including abuse, neglect, violence, and household dysfunction.

Using cross-sectional data from the 2016 National Survey of Children’s Health, the investigators compared ACEs in healthy children, children with chronic arthritis and children with other acquired chronic physical disease, such as allergies, asthma, diabetes and epilepsy. The results showed children with ACEs had increased odds of having chronic arthritis when compared with both healthy peers and peers with other acquired chronic physical disease. Children with arthritis had a higher prevalence of eight of the nine specific ACE categories. Moreover, children with at least four ACEs were 9.4 times more likely to have arthritis as healthy children and 3.7 times more likely to have arthritis as children with other chronic physical disease.⁶

Another study by Chang et al. looked at the longitudinal assessment of racial disparities in JIA with a treat-to-target intervention using the clinical juvenile arthritis disease activity score (cJADAS). Data from this study show higher cJADAS scores at the index visit in Black children when compared with other racial and ethnic groups. With the treat-to-target intervention, all racial groups had statistically significant improvement in disease activity over time. Black children continued to have higher disease activity scores than other groups, but the rates of improvement were similar across all groups, suggesting treat to target may be equally effective across all racial groups.⁷

Dr. Becker then discussed a study on clinical outcome disparities among Black children with Kawasaki disease. Padilla et al. conducted a single-center retrospective study of children admitted with Kawasaki disease. In a cohort of 369 patients, the researchers found no significant difference in time to admission, time to diagnosis, time to treatment or the presence of coronary artery abnormalities in Black children versus white children. However, Black children had higher markers of inflammation, lower rates of response to IVIG therapy, received more adjunctive therapies, required longer hospital stays and exhibited a higher proportion of persistent coronary artery aneurysms on follow-up echocardiograms.

“These authors posited: Could there be a difference in the innate or inflammatory response in children who are Black compared to others?” she said.⁸

These studies clearly show that disparities exist in both the care and outcomes of children with rheumatic disease, Dr. Becker said, and we must seek out and address these disparities to improve our patients’ outcomes.

Optimizing Therapeutics

Dr. Becker then switched gears to discuss advances in therapeutic optimization, discussing three key papers.

In summer 2021, Kimura et al. published the first paper from the STOP-JIA (start time optimization of biologic therapy in polyarticular JIA) study. The STOP-JIA study is a multi-center, prospective, observational study using the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry that compared three consensus treatment plans (CTPs) developed for the treatment of polyarticular JIA.

The three CTPs are: 1) a step-up plan where patients were initiated on a non-biologic disease-modifying anti-rheumatic drug (DMARD) and then escalated to add a biologic DMARD if disease activity persisted; 2) an early combination treatment plan with early initiation of both biologic and non-biologic DMARDs up front; and 3) a biologic first CTP, in which patients were initiated on a biologic-only treatment plan.

Given that this is a real-world observational study, clinical differences and imbalances existed between groups, Dr. Becker explained, but the investigators found no significant differences in clinically inactive disease at 12 months. However, they did find that patients in the early combination CTP achieved a low-disease activity score by 12 months more frequently than patients treated with the other two CTPs. The patients on the early combination CTP also received less glucocorticoids during the first six months of treatment.⁹

Another study, an extension of the STOP-JIA trial, assessed the effect of biologic DMARDs on disease course. By using latent class trajectory modeling, Ong et al. found that patients could be separated into three classes of disease activity: slow, moderate and rapid improvement. These trajectories diverged by three months, and timing of biologic DMARD initiation was the most significant predictor for a favorable trajectory.

Dr. Becker also noted a subgroup within the rapid improvement group received only non-biologic DMARD therapy (rather than a biologic DMARD), but again, the most significant predictor for a rapid and favorable response was early initiation on DMARD therapy.

These results provide further evidence of the importance of early initiation of biologic DMARDs in children with polyarticular JIA and raise an additional question regarding how clinicians can identify patients who may still have favorable outcomes with non-biologic DMARD therapy.¹⁰

Continuing with the topic of therapeutics in JIA, Dr. Becker discussed a phase 3b/4, open-label, randomized study on tapering canakinumab monotherapy in children with systemic JIA in clinical remission. In this international study, investigators looked at two different methods for tapering canakinumab. Patients were randomized into either a dose-reduction arm or a dose-interval prolongation arm. On both schedules, around 40% of children maintained complete remission, but only about one-third of all patients were able to completely discontinue canakinumab.¹¹

Therapeutic Innovations

For her final theme, Dr. Becker discussed several innovative studies that are moving the field of pediatric rheumatology forward. She highlighted a study by Singh et al., that sought to examine the exposure-response relationships for biologic agents in rheumatoid arthritis and JIA. By looking at nine adult rheumatoid arthritis trials and four JIA trials, investigators found that in pediatric patients, drug exposures were generally comparable to those of adult patients. Further, for polyarticular JIA, response rates were just as favorable as adult responses.

These analyses, she explained, bridge a gap in clinical pharmacology and may allow the extrapolation of efficacy from adults with rheumatoid arthritis to children with JIA for medications with an established mechanism of action.¹²

The next innovative study she highlighted was a direct-to-family trial called iPERSONAL, in which pediatric lupus patients have access to an electronic pill bottle reminder to promote medication adherence. Impressively, this trial met enrollment within 10 days of opening and has a backup list of patients interested in participating.

This paper, by Randell et al., discusses how the researchers have implemented the study, including their use of in-home visits, how they navigated the direct-to-patient implementation and other lessons they learned during the trial. Dr. Becker applauded their unique and innovative approach, explaining that innovative strategies help advance the field.¹³

For her last three studies, Dr. Becker reviewed new therapies for children with rheumatic disease. Li et al. provided preliminary evidence on the safety and efficacy of abatacept in children with refractory juvenile localized scleroderma.¹⁴

A report by Zulian and colleagues discussed the researchers’ positive experience with rituximab for children with rapidly progressive systemic sclerosis involving the heart and/or lung.¹⁵

Dr. Becker concluded by highlighting a study by Li et al. showing significant and rapid improvement in global disease, skin manifestations, muscle strength and magnetic resonance imaging findings in four children with refractory juvenile dermatomyositis when treated with baricitinib, a Janus kinase inhibitor.¹⁶

She thanked the investigators for providing evidence to support the use of newer medications in children with refractory rheumatic diseases and expressed her hope for continued innovative therapies and future studies.

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Elizabeth Sloan, MD, is an instructor in the Division of Pediatric Rheumatology, UT Southwestern Medical Center, Dallas, where she also completed her rheumatology fellowship. Dr. Sloan has served on the ACR’s Special Committee on Pediatric Rheumatology, as well as the Fellows-in-Training Subcommittee of the Committee on Rheumatology Training and Workforce Issues.

References

1. 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 2. Arthritis Rheumatol. 2021 Apr;73(4):e13–e29.
2. Wahezi DM, Lo MS, Rubinstein TB, et al. American College of Rheumatology guidance for the management of pediatric rheumatic disease during the COVID-19 pandemic: Version 2. Arthritis Rheumatol. 2021 Aug;73(8):e46–e59.
3. Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children—initial therapy and outcomes. N Engl J Med. 2021 Jul 1;385(1):23–34.
4. Wahezi DM, Peskin M, Tanner T. The impact of the COVID-19 pandemic on the field of pediatric rheumatology. Curr Opin Rheumatol. 2021 Sep 1;33(5):446–452.
5. Banerjee D, Sasidharan A, Abdulhamid A, et al. Diagnostic yield of saliva for SARS-CoV-2 molecular testing in children. J Pediatric Infect Dis Soc. 2021 Nov 11; 10(10):967–969.
6. Rubinstein TB, Bullock DR, Ardalan K, et al. Adverse childhood experiences are associated with childhood-onset arthritis in a national sample of US youth: An analysis of the 2016 National Survey of Children’s Health. J Pediatr. 2020 2020 Nov;226:243–250.e2.
7. Chang JC, Xiao R, Burnham JM, Weiss PF. Longitudinal assessment of racial disparities in juvenile idiopathic arthritis disease activity in a treat-to-target intervention. Pediatr Rheumatol Online J. 2020 Nov 13;18(1):88.
8. Padilla LA, Collins JL, Idigo AJ, et al. Kawasaki disease and clinical outcome disparities among Black children. J Pediatr. 2021 Feb;229:54–60.e2.
9. Kimura Y, Schanberg LE, Tomlinson GA, et al. Optimizing the start time of biologics in polyarticular juvenile idiopathic arthritis: A comparative effectiveness study of Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans. Arthritis Rheumatol. 2021 Oct;73(10):1898–1909.
10. Ong MS, Ringold S, Kimura Y, et al. Improved disease course associated with early initiation of biologics in polyarticular juvenile idiopathic arthritis: Trajectory analysis of a Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans study. Arthritis Rheumatol. 2021 Oct;73(10):1910–1920.
11. Quartier P, Alexeeva E, Constantin T, et al. Tapering canakinumab monotherapy in patients with systemic juvenile idiopathic arthritis in clinical remission: Results from a phase IIIb/IV open-label, randomized study. Arthritis Rheumatol. 2021 Feb;73(2):336–346.
12. Singh R, Ivaturi VD, Penzenstadler J, et al. Response similarity assessment between polyarticular juvenile idiopathic arthritis and adult rheumatoid arthritis for biologics. Clin Pharmacol Ther. 2021 Jul;110(1):98–107.
13. Randell RL, Singler L, Cunningham A, et al. Delivering clinical trials at home: Protocol, design and implementation of a direct-to-family paediatric lupus trial. Lupus Sci Med. 2021 May;8(1):e000494.
14. Li SC, Torok KS, Ishaq SS, et al. Preliminary evidence on abatacept safety and efficacy in refractory juvenile localized scleroderma. Rheumatology (Oxford). 2021 Aug;60(8):3817–3825.
15. Zulian F, Dal Pozzolo R, Meneghel A, et al. Rituximab for rapidly progressive juvenile systemic sclerosis. Rheumatology (Oxford). 2020 Dec 1;59(12):3793–3797.
16. Kim H, Dill S, O’Brien M, et al. Janus kinase (JAK) inhibition with baricitinib in refractory juvenile dermatomyositis. Ann Rheum Dis. 2021;80(3):406–408.