Proceedings from the 4th NextGen Therapies for SJIA and MAS virtual symposium held February 13–14, 2022

Refractory Systemic Juvenile Idiopathic Arthritis (SJIA) remains a major source of morbidity and mortality in children with pediatric rheumatic disease [1, 2]. Although several potential therapeutic targets have been recently identified, only few patients have been enrolled in ongoing clinical trials. The 4^th “NextGen Therapies for SJIA and MAS” virtual symposium organized by the “SJIA Foundation” and held February 13–14, 2022, brought together SJIA families, leading researchers, clinicians and representatives from Pharma and FDA with the main goals to identify barriers to clinical research in this area and develop new strategies to advance it.

Systemic Idiopathic Arthritis (SJIA; estimated U.S. prevalence of 1:10,000 children) is the most severe subtype of chronic childhood arthropathy, notable for marked systemic immune activation with features of autoinflammation, and development of severe joint damage [2,3,4,5,6]. The licensing of IL-1 and IL-6-blocking monoclonal antibodies in 2012 resulted in superior control of SJIA-associated arthritis and systemic manifestations [7,8,9,10,11]. However, despite the use of these biologic disease modifying antirheumatic medications (b-DMARDs) about 15% of patients with SJIA develop macrophage activation syndrome (MAS), i.e. potentially fatal episodes of systemic hyperinflammation that are associated with hemophagocytosis [5, 6, 12, 13]. Furthermore, since the licensing of these b-DMARDs, children with SJIA (~ 5% in 2020) have increasingly been diagnosed with life-threatening chronic parenchymal lung disease (SJIA-LD) [14,15,16]. This has prompted speculations that drugs blocking IL-1 and/or IL-6 might contribute to the development of SJIA-LD [16]. Given high mortality and frequent need for hospitalization, there is an urgent need for life-saving treatments for SJIA-LD and MAS.

Translational research identified IFN-γ as the pivotal cytokine in MAS [6, 17,18,19] and Phase II clinical trials are in progress [20]. In contrast, the nature of the SJIA-associated lung disease remains elusive, and potential therapeutic targets in this disease still need to be defined. The typical histopathology of SJIA-LD includes (a) extensive lymphoplasmacytic inflammatory infiltrates in the lung interstitial tissue; (b) organizing pneumonia; (c) pleural and interlobular septal collagenous fibrosis; (d) vasculopathy associated with muscular mural thickening of the pulmonary arteries; and (e) alveolar inflammation with accumulation of foamy alveolar macrophages with some features of pulmonary alveolar proteinosis (PAP) [15, 16]. Features of PAP typically result from dysfunction of alveolar macrophages leading to accumulation of pulmonary surfactant in alveolar space, and it has been suggested that there may be acquired alveolar macrophages dysfunction in SJIA-LD.

Recent studies suggested potential risk factors for SJIA-LD: (a) SJIA onset under age 2 years with predominantly systemic features and limited arthritis, (b) recurrent MAS episodes, (c) anaphylaxis-like reactions to b-DMARDs, (d) highly pruritic rash associated with peripheral eosinophilia, (e) highly elevated serum IL-18 levels, and (f) and HLA DRB1*15 alleles [15, 16]. Gene expression profiling in SJIA-LD lung tissue revealed strong IFN-induced signature and numerous markers of T cell activation (predominantly Th1) [15]. Further, murine experiments showed that T-cell restricted overexpression of T-bet, a master transcription factor that drives production of the hallmark Th1 cytokine IFN- γ induces dysfunction of bone marrow macrophages, resulting in erythrophagocytosis locally, and alveolar macrophages dysfunction with the development of PAP-like lung pathology [21]. Together this suggests that either MAS alone or when combined with IL-1 or IL-6 blocking b-DMARDs contribute to the development of SJIA-LD. Alternative possibilities include environmental factors like infections that could be favored by inhibition of IL-1 and IL-6 with biologics. Marked differences in the prevalence of SJIA-LD in different geographic areas with similar patterns of utilization of b-DMARDS as well as large numbers of SJIA-LD cases reported in areas where b-DMARDs are not commonly used (China, India) support this hypothesis. Alternatively, high rate of anaphylaxis-like reactions as well as pruritic rash and peripheral eosinophilia observed in SJIA-LD patients point to the possibility of a delayed type hypersensitivity (DTH) reaction. The recently reported strong association between LD in SJIA and HLA DRB1*15 alleles, supports this hypothesis [22]. DTH may be driven by IFN- γ in response to either the monoclonal antibody (b-DMARD) itself or to the common excipient shared by these drugs (e.g., polysorbate). These possibilities create much apprehension among pediatric rheumatologists and families of children with SJIA worldwide whether anti-IL-1 and IL-6 b-DMARDs are truly safe for use in SJIA.

Further advancement of clinical studies focused on this patient population, however, has been hampered by the lack of agreement on whether SJIA patients with the lung disease should be classified as a separate diagnostic entity. In part, this is because arthritis is often absent in these patients while the systemic component of the disease seems more prominent compared to what has been historically seen in SJIA. As of now, the absence of arthritis in many of these patients precludes the definitive diagnosis of SJIA rendering them ineligible for existing clinical trials in this disease. Furthermore, the existing outcome measures typically used in clinical trials in SJIA are focused mainly on arthritis and do not fully capture the systemic component, specifically the lung disease.

Discussions around this topic at the 4^th “NextGen Therapies for SJIA and MAS” virtual symposium are captured by Nigrovic, et al. in Part 1 of the Proceedings. Furthermore, the existing outcome measures typically used in clinical trials in JIA are focused mainly on arthritis and do not fully capture the systemic component, particularly the lung disease.

In Part 2, Drs. Grom and Schulert summarized further discussions that defined emerging distinct clinical patterns of refractory SJIA. Considering the life-threatening nature of MAS and SJIA-LD, traditional placebo controlled/withdrawal design clinical trials may not be ethically acceptable in these patient populations.

In Part 3, Dr. Fabrizio de Benedetti summarized discussions focused on alternative designs that could be acceptable to clinicians, parents, and regulatory authorities.

Since strikingly high of serum IL-18 levels appear to be a unifying feature of various subgroups of refractory SJIA, Dr. Canna and colleagues explored the possibility of incorporation this biomarker as an inclusion criterion and measure of treatment response to a drug candidate (Part 4).

In the meantime, the patients with refractory SJIA continue to experience not only high mortality but also profound disease- and medication-related morbidities that lead to permanent tissue damage, with long lasting detrimental effects on all aspects of the child’s quality of life. The degree of immunosuppression needed in most of these patients is unlikely to be sustainable in the long term due to increased risk of infection and malignancy. As the optimal drug management of SJIA-LD remains elusive, hematopoietic stem cell transplantation (HSCT) has emerged as a potential alternative strategy in the interim. In Part 5, Dr. Silva and colleagues reviewed the growing experience with HSCT specifically for patients with SJIA and summarized the discussion about the technical aspects, optimal timing and preliminary outcomes for several patients who underwent HSCT. This description includes patients who have not been previously reported.

All the data discussed during the meeting have now been published and appropriately referenced at the end of the manuscript.

b-DMARDs:

Biologic disease-modifying anti-rheumatic drug

DTH:

Delayed type hypersensitivity

HSCT:

Hematopoietic stem cell transplantation

IFN-γ:

Interferon Gamma

IL:

Interleukin

LD:

Lung disease

MAS:

Macrophage activation syndrome

PAP:

Pulmonary alveolar proteinosis

SJIA:

Systemic Juvenile Idiopathic Arthritis

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List of the participants

Rolla F. Abu-Arja¹, Edward Behrens², Hermine Brunner³, Scott W. Canna⁴, Elvira Cannizzaro⁵, Shanmuganathan Chandrakasan⁶, Randy Cron⁷, Kyla Driest⁸, Yukiko Kimura⁹, Christopher Leptak¹⁰, Daniel J. Lovell³, Rebecca Marsh¹¹, Bénédicte Neven^12,18, Peter A. Nigrovic^13,14, Nikolay Nikolov¹⁵, Karen Onel¹⁶, Sampath Prahalad⁶, Susan Prockop¹⁷, Pierre Quartier^12,18, Johannes Roth¹⁹, Grant Schulert³, Juliana M.F. Silva²⁰, Sebastiaan J. Vastert²¹, Donna Wall²², Ulrike Zeilhofer²³

¹Department of BMT, Nationwide Children’s Hospital, Columbus, OH, USA

²Division of Rheumatology, Children's Hospital of Philadelphia, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA

³Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA

⁴Rheumatology & Immune Dysregulation, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

⁵Department of Rheumatology, University Children’s Hospital, Zurich, Switzerland

⁶Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA

⁷Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

⁸Department of Rheumatology, Nationwide Children’s Hospital, Columbus, OH, USA

⁹Division of Pediatric Rheumatology, Joseph M. Sanzari Children’s Hospital, Hackensack, Meridian School of Medicine, Hackensack, NJ, USA

¹⁰Drugs and Biologics, Greenleaf Health, Inc., Silver Spring, MD, USA

¹¹Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

¹²Pediatric Hematology-Immunology and Rheumatology Department, Necker-Enfants-Malades University Hospital, Paris, France

¹³Division of Immunology, Boston Children’s Hospital, Boston, MA, USA

¹⁴Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, MA, USA

¹⁵Division of Rheumatology and Transplant Medicine, FDA, Washington DC, USA

¹⁶Department of Rheumatology, HSS, New York City, NY, USA

¹⁷Dana Farber/Boston Childrens Hospital Center for Cancer and Blood Disorders, Boston, MA, USA

¹⁸Université Paris-Cité, Paris, France

¹⁹Kantonsspital Luzern, University of Luzern, Luzern, Switzerland

²⁰Department of BMT, Great Ormond Street Hospital for Children, London, UK

²¹Department of Pediatric Rheumatology & Immunology and Center for Translational Immunology, University Medical Center Utrecht, the Netherlands

²²Blood and Marrow Transplant/Cellular Therapy, Division of Haematology/Oncology, Hospital for Sick Children Toronto, Canada

²³Department of BMT, University Children’s Hospital, Zurich, Switzerland

List of the parents

Pauline Acevedo¹, Ronny Bachrach¹, Laura Bogg¹, Leah Bush¹, Anna Carlson¹, Cappy Culicchia¹, Kari Cupp¹, Vincent Delgaizo², Zulayka Martinez¹, Regina Minerva¹, Luciana Peixoto¹, Robyn Rivera¹, Sarah Tronsdal¹

¹Systemic JIA Foundation, Cincinnati, OH, USA

²Childhood Arthritis and Rheumatology Alliance (CARRA), Washington DC, USA

About this supplement

This article has been published as part of Pediatric Rheumatology Volume 21 Supplement 1, 2023: Proceedings from the 4th NextGen Therapies for SJIA and MAS virtual symposium. The full contents of the supplement are available online at https://ped-rheum.biomedcentral.com/articles/supplements/volume-21-supplement-1.

Funding for the symposium was provided by the SJIA Foundation. Publication costs have been covered by the SJIA Foundation. The SJIA Foundation did not have any direct influence on the research and results being presented.

Authors and Affiliations

1. Systemic JIA Foundation, Cincinnati, OH, USA

   Rashmi Sinha

2. Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy

   Fabrizio De Benedetti

3. Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA

   Alexei A. Grom

Authors

1. Rashmi SinhaView author publications

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2. Fabrizio De BenedettiView author publications

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Consortia

on behalf of the participants listed below

• Rolla F. Abu-Arja
• , Edward Behrens
• , Hermine Brunner
• , Scott W. Canna
• , Elvira Cannizzaro
• , Shanmuganathan Chandrakasan
• , Randy Cron
• , Kyla Driest
• , Yukiko Kimura
• , Christopher Leptak
• , Daniel J. Lovell
• , Rebecca Marsh
• , Bénédicte Neven
• , Peter A. Nigrovic
• , Nikolay Nikolov
• , Karen Onel
• , Sampath Prahalad
• , Susan Prockop
• , Pierre Quartier
• , Johannes Roth
• , Grant Schulert
• , Juliana M. F. Silva
• , Sebastiaan J. Vastert
• , Donna Wall
• , Ulrike Zeilhofer
• , Pauline Acevedo
• , Ronny Bachrach
• , Laura Bogg
• , Leah Bush
• , Anna Carlson
• , Cappy Culicchia
• , Kari Cupp
• , Vincent Delgaizo
• , Zulayka Martinez
• , Regina Minerva
• , Luciana Peixoto
• , Robyn Rivera
•  & Sarah Tronsdal

Contributions

All authors participated in the meetings’ discussions and were involved in the preparation of the manuscript. The final version was reviewed by all authors.

Corresponding author

Correspondence to Alexei A. Grom.

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have reviewed the manuscript and provided their consent to publish. All the patients mentioned in the manuscript gave their permissions to use full names.

Competing interests

RS has no conflicts of interest or competing interests to declare. FDB has received research grants from SOBI, Novartis, Roche, Sanofi, consultancies from Sobi, Novartis, Roche. AAG received research grants from Novartis and SOBI; consulting fees from Novartis and SOBI; royalties from UpToDate Inc. and payment for development of CME slide presentation on MAS from Clinical Viewpoints.

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Sinha, R., De Benedetti, F., Grom, A.A. et al. Proceedings from the 4^th NextGen Therapies for SJIA and MAS virtual symposium held February 13–14, 2022. Pediatr Rheumatol 21 (Suppl 1), 91 (2023). https://doi.org/10.1186/s12969-023-00863-2

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• Accepted: 26 July 2023

• Published: 05 January 2024

• DOI: https://doi.org/10.1186/s12969-023-00863-2

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