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

IF 2.8 3区 医学 Q1 PEDIATRICS
Rashmi Sinha, Fabrizio De Benedetti, Alexei A. Grom
{"title":"Proceedings from the 4th NextGen Therapies for SJIA and MAS virtual symposium held February 13–14, 2022","authors":"Rashmi Sinha, Fabrizio De Benedetti, Alexei A. Grom","doi":"10.1186/s12969-023-00863-2","DOIUrl":null,"url":null,"abstract":"<p>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<sup>th</sup>\n<b>“</b>NextGen Therapies for SJIA and MAS” virtual symposium organized by the “SJIA Foundation” and held February 13–14, 2022<b>,</b> 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.</p><p>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<u>)</u>, 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.</p><p>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 <i>alveolar macrophages</i> with some features of pulmonary alveolar proteinosis (PAP) [15, 16]. Features of PAP typically result from dysfunction of <i>alveolar macrophages</i> leading to accumulation of pulmonary surfactant in alveolar space, and it has been suggested that there may be acquired <i>alveolar macrophages</i> dysfunction in SJIA-LD.</p><p>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 <i>alveolar macrophages</i> 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.</p><p>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.</p><p>Discussions around this topic at the 4<sup>th</sup> “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.</p><p>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.</p><p>In Part 3, Dr. Fabrizio de Benedetti summarized discussions focused on alternative designs that could be acceptable to clinicians, parents, and regulatory authorities.</p><p>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).</p><p>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.</p><p>All the data discussed during the meeting have now been published and appropriately referenced at the end of the manuscript.</p><dl><dt style=\"min-width:50px;\"><dfn>b-DMARDs:</dfn></dt><dd>\n<p>Biologic disease-modifying anti-rheumatic drug</p>\n</dd><dt style=\"min-width:50px;\"><dfn>DTH:</dfn></dt><dd>\n<p>Delayed type hypersensitivity</p>\n</dd><dt style=\"min-width:50px;\"><dfn>HSCT:</dfn></dt><dd>\n<p>Hematopoietic stem cell transplantation</p>\n</dd><dt style=\"min-width:50px;\"><dfn>IFN-γ:</dfn></dt><dd>\n<p>Interferon Gamma</p>\n</dd><dt style=\"min-width:50px;\"><dfn>IL:</dfn></dt><dd>\n<p>Interleukin</p>\n</dd><dt style=\"min-width:50px;\"><dfn>LD:</dfn></dt><dd>\n<p>Lung disease</p>\n</dd><dt style=\"min-width:50px;\"><dfn>MAS:</dfn></dt><dd>\n<p>Macrophage activation syndrome</p>\n</dd><dt style=\"min-width:50px;\"><dfn>PAP:</dfn></dt><dd>\n<p>Pulmonary alveolar proteinosis</p>\n</dd><dt style=\"min-width:50px;\"><dfn>SJIA:</dfn></dt><dd>\n<p>Systemic Juvenile Idiopathic Arthritis</p>\n</dd></dl><ol data-track-component=\"outbound reference\"><li data-counter=\"1.\"><p>Canna SW, Schulert GS, de Jesus A, Pickering A, Brunner H, Gadina M, Levine S, Goldbach-Mansky R, Boutelle J, Sinha R, DeBenedetti F, Grom AA; NextGen 2019 Participants. 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Abu-Arja<sup>1</sup>, Edward Behrens<sup>2</sup>, Hermine Brunner<sup>3</sup>, Scott W. Canna<sup>4</sup>, Elvira Cannizzaro<sup>5</sup>, Shanmuganathan Chandrakasan<sup>6</sup>, Randy Cron<sup>7</sup>, Kyla Driest<sup>8</sup>, Yukiko Kimura<sup>9</sup>, Christopher Leptak<sup>10</sup>, Daniel J. Lovell<sup>3</sup>, Rebecca Marsh<sup>11</sup>, Bénédicte Neven<sup>12,18</sup>, Peter A. Nigrovic<sup>13,14</sup>, Nikolay Nikolov<sup>15</sup>, Karen Onel<sup>16</sup>, Sampath Prahalad<sup>6</sup>, Susan Prockop<sup>17</sup>, Pierre Quartier<sup>12,18</sup>, Johannes Roth<sup>19</sup>, Grant Schulert<sup>3</sup>, Juliana M.F. Silva<sup>20</sup>, Sebastiaan J. Vastert<sup>21</sup>, Donna Wall<sup>22</sup>, Ulrike Zeilhofer<sup>23</sup></p><p>\n<sup>1</sup>Department of BMT, Nationwide Children’s Hospital, Columbus, OH, USA</p><p>\n<sup>2</sup>Division of Rheumatology, Children's Hospital of Philadelphia, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA</p><p>\n<sup>3</sup>Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA</p><p>\n<sup>4</sup>Rheumatology &amp; Immune Dysregulation, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA</p><p>\n<sup>5</sup>Department of Rheumatology, University Children’s Hospital, Zurich, Switzerland</p><p>\n<sup>6</sup>Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA</p><p>\n<sup>7</sup>Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA</p><p>\n<sup>8</sup>Department of Rheumatology, Nationwide Children’s Hospital, Columbus, OH, USA</p><p>\n<sup>9</sup>Division of Pediatric Rheumatology, Joseph M. Sanzari Children’s Hospital, Hackensack, Meridian School of Medicine, Hackensack, NJ, USA</p><p>\n<sup>10</sup>Drugs and Biologics, Greenleaf Health, Inc., Silver Spring, MD, USA</p><p>\n<sup>11</sup>Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA</p><p>\n<sup>12</sup>Pediatric Hematology-Immunology and Rheumatology Department, Necker-Enfants-Malades University Hospital, Paris, France</p><p>\n<sup>13</sup>Division of Immunology, Boston Children’s Hospital, Boston, MA, USA</p><p>\n<sup>14</sup>Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, MA, USA</p><p>\n<sup>15</sup>Division of Rheumatology and Transplant Medicine, FDA, Washington DC, USA</p><p>\n<sup>16</sup>Department of Rheumatology, HSS, New York City, NY, USA</p><p>\n<sup>17</sup>Dana Farber/Boston Childrens Hospital Center for Cancer and Blood Disorders, Boston, MA, USA</p><p>\n<sup>18</sup>Université Paris-Cité, Paris, France</p><p>\n<sup>19</sup>Kantonsspital Luzern, University of Luzern, Luzern, Switzerland</p><p>\n<sup>20</sup>Department of BMT, Great Ormond Street Hospital for Children, London, UK</p><p>\n<sup>21</sup>Department of Pediatric Rheumatology &amp; Immunology and Center for Translational Immunology, University Medical Center Utrecht, the Netherlands</p><p>\n<sup>22</sup>Blood and Marrow Transplant/Cellular Therapy, Division of Haematology/Oncology, Hospital for Sick Children Toronto, Canada</p><p>\n<sup>23</sup>Department of BMT, University Children’s Hospital, Zurich, Switzerland</p><p><b>List of the parents</b></p><p>Pauline Acevedo<sup>1</sup>, Ronny Bachrach<sup>1</sup>, Laura Bogg<sup>1</sup>, Leah Bush<sup>1</sup>, Anna Carlson<sup>1</sup>, Cappy Culicchia<sup>1</sup>, Kari Cupp<sup>1</sup>, Vincent Delgaizo<sup>2</sup>, Zulayka Martinez<sup>1</sup>, Regina Minerva<sup>1</sup>, Luciana Peixoto<sup>1</sup>, Robyn Rivera<sup>1</sup>, Sarah Tronsdal<sup>1</sup></p><p><sup>1</sup>Systemic JIA Foundation, Cincinnati, OH, USA</p><p><sup>2</sup>Childhood Arthritis and Rheumatology Alliance (CARRA), Washington DC, USA</p>\n<h3>About this supplement</h3>\n<p>This article has been published as part of <i>Pediatric Rheumatology Volume 21 Supplement 1, 2023: Proceedings from the 4th NextGen Therapies for SJIA and MAS virtual symposium.</i> The full contents of the supplement are available online at https://ped-rheum.biomedcentral.com/articles/supplements/volume-21-supplement-1.</p><p>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.</p><h3>Authors and Affiliations</h3><ol><li><p>Systemic JIA Foundation, Cincinnati, OH, USA</p><p>Rashmi Sinha</p></li><li><p>Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy</p><p>Fabrizio De Benedetti</p></li><li><p>Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA</p><p>Alexei A. Grom</p></li></ol><span>Authors</span><ol><li><span>Rashmi Sinha</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Fabrizio De Benedetti</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Alexei A. Grom</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Consortia</h3><h3>on behalf of the participants listed below</h3><ul><li>Rolla F. Abu-Arja</li><li>, Edward Behrens</li><li>, Hermine Brunner</li><li>, Scott W. Canna</li><li>, Elvira Cannizzaro</li><li>, Shanmuganathan Chandrakasan</li><li>, Randy Cron</li><li>, Kyla Driest</li><li>, Yukiko Kimura</li><li>, Christopher Leptak</li><li>, Daniel J. Lovell</li><li>, Rebecca Marsh</li><li>, Bénédicte Neven</li><li>, Peter A. Nigrovic</li><li>, Nikolay Nikolov</li><li>, Karen Onel</li><li>, Sampath Prahalad</li><li>, Susan Prockop</li><li>, Pierre Quartier</li><li>, Johannes Roth</li><li>, Grant Schulert</li><li>, Juliana M. F. Silva</li><li>, Sebastiaan J. Vastert</li><li>, Donna Wall</li><li>, Ulrike Zeilhofer</li><li>, Pauline Acevedo</li><li>, Ronny Bachrach</li><li>, Laura Bogg</li><li>, Leah Bush</li><li>, Anna Carlson</li><li>, Cappy Culicchia</li><li>, Kari Cupp</li><li>, Vincent Delgaizo</li><li>, Zulayka Martinez</li><li>, Regina Minerva</li><li>, Luciana Peixoto</li><li>, Robyn Rivera</li><li> &amp; Sarah Tronsdal</li></ul><h3>Contributions</h3><p>All authors participated in the meetings’ discussions and were involved in the preparation of the manuscript. The final version was reviewed by all authors.</p><h3>Corresponding author</h3><p>Correspondence to Alexei A. Grom.</p><h3>Ethics approval and consent to participate</h3>\n<p>Not applicable.</p>\n<h3>Consent for publication</h3>\n<p>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.</p>\n<h3>Competing interests</h3>\n<p>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.</p><h3>Publisher's Note</h3><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p><p><b>Open Access</b> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. 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Proceedings from the 4<sup>th</sup> NextGen Therapies for SJIA and MAS virtual symposium held February 13–14, 2022. <i>Pediatr Rheumatol</i> <b>21</b> (Suppl 1), 91 (2023). https://doi.org/10.1186/s12969-023-00863-2</p><p>Download citation<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><ul data-test=\"publication-history\"><li><p>Accepted<span>: </span><span><time datetime=\"2023-07-26\">26 July 2023</time></span></p></li><li><p>Published<span>: </span><span><time datetime=\"2024-01-05\">05 January 2024</time></span></p></li><li><p>DOI</abbr><span>: </span><span>https://doi.org/10.1186/s12969-023-00863-2</span></p></li></ul><h3>Share this article</h3><p>Anyone you share the following link with will be able to read this content:</p><button data-track=\"click\" data-track-action=\"get shareable link\" data-track-external=\"\" 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Abstract

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 4th 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 4th “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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Download references

Not applicable.

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 Neven12,18, Peter A. Nigrovic13,14, Nikolay Nikolov15, Karen Onel16, Sampath Prahalad6, Susan Prockop17, Pierre Quartier12,18, 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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  3. Alexei A. GromView 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 4th 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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2022 年 2 月 13-14 日举行的第四届下一代疗法治疗 SJIA 和 MAS 虚拟研讨会论文集
难治性系统性幼年特发性关节炎(SJIA)仍然是小儿风湿病患儿发病和死亡的主要原因[1, 2]。虽然最近发现了几个潜在的治疗靶点,但只有少数患者参加了正在进行的临床试验。由 "SJIA 基金会 "组织的第四届 "SJIA 和 MAS 的新一代疗法 "虚拟研讨会于 2022 年 2 月 13-14 日举行,SJIA 家庭、顶尖研究人员、临床医生以及制药公司和 FDA 的代表齐聚一堂,主要目的是找出该领域临床研究的障碍,并制定新的战略来推动该领域的研究。系统性特发性关节炎(SJIA;估计美国儿童发病率为 1:10,000)是慢性儿童关节病中最严重的亚型,具有明显的全身免疫激活和自身炎症特征,并发展为严重的关节损伤[2,3,4,5,6]。2012年,IL-1和IL-6阻断单克隆抗体的上市使SJIA相关关节炎和全身表现得到了很好的控制[7,8,9,10,11]。然而,尽管使用了这些生物改良抗风湿药物(b-DMARDs),仍有约 15%的 SJIA 患者出现巨噬细胞活化综合征(MAS),即可能致命的全身性高炎症发作,与嗜血细胞增多症有关[5, 6, 12, 13]。此外,自这些 b-DMARDs 获得许可以来,越来越多的 SJIA 儿童(2020 年约占 5%)被诊断出患有危及生命的慢性肺实质疾病(SJIA-LD)[14,15,16]。这促使人们猜测,阻断 IL-1 和/或 IL-6 的药物可能会导致 SJIA-LD 的发生 [16]。转化研究发现,IFN-γ 是 MAS 的关键细胞因子[6, 17, 18, 19],II 期临床试验正在进行中[20]。相比之下,SJIA 相关肺部疾病的性质仍然难以捉摸,该疾病的潜在治疗靶点仍有待确定。SJIA-LD 的典型组织病理学包括:(a) 肺间质组织中广泛的淋巴浆细胞炎症浸润;(b) 组织性肺炎;(c) 胸膜和小叶间隔胶原纤维化;(d) 与肺动脉肌肉壁增厚有关的血管病变;以及 (e) 肺泡炎症,泡沫状肺泡巨噬细胞聚集,具有肺泡蛋白沉着病(PAP)的某些特征[15, 16]。肺泡蛋白沉积症的特征通常是由于肺泡巨噬细胞功能障碍导致肺泡间隙肺表面活性物质积聚,有研究认为,SJIA-LD 患者可能存在获得性肺泡巨噬细胞功能障碍。最近的研究提出了 SJIA-LD 的潜在危险因素:(a) SJIA 发病年龄小于 2 岁,主要表现为全身性特征和局限性关节炎;(b) MAS 反复发作;(c) 对 b-DMARDs 的过敏性休克样反应;(d) 伴有外周嗜酸性粒细胞增多的高度瘙痒性皮疹;(e) 血清 IL-18 水平高度升高;(f) HLA DRB1*15 等位基因[15, 16]。SJIA-LD 肺组织中的基因表达谱分析显示了强烈的 IFN 诱导特征和大量 T 细胞活化标记(主要是 Th1)[15]。此外,小鼠实验表明,T 细胞受限过表达 T-bet(一种主转录因子,可驱动标志性 Th1 细胞因子 IFN- γ 的产生)会诱导骨髓巨噬细胞功能障碍,导致局部红细胞吞噬,并导致肺泡巨噬细胞功能障碍,出现类似 PAP 的肺部病变[21]。总之,这表明 MAS 单独或与 IL-1 或 IL-6 阻断型 b-DMARDs 合用都会导致 SJIA-LD 的发生。其他的可能性还包括感染等环境因素,而生物制剂对 IL-1 和 IL-6 的抑制作用可能有利于感染。在使用 b-DMARDs 模式相似的不同地区,SJIA-LD 的发病率存在明显差异,而在不常用 b-DMARDs 的地区(中国、印度),也有大量 SJIA-LD 病例报告,这些都支持这一假设。另外,在SJIA-LD患者中观察到的过敏性休克样反应以及瘙痒性皮疹和外周嗜酸性粒细胞增多的高发生率也指出了迟发型超敏反应(DTH)的可能性。最近报道的 SJIA LD 与 HLA DRB1*15 等位基因之间的密切关系支持了这一假设 [22]。DTH可能是由IFN- γ驱动的,是对单克隆抗体(b-DMARD)本身或这些药物共有的赋形剂(如聚山梨醇酯)的反应。这些可能性使世界各地的儿科风湿病学家和 SJIA 患儿家属对抗 IL-1 和 IL-6 的 b-DMARDs 在 SJIA 中的使用是否真正安全感到担忧。 文章 CAS PubMed PubMed Central Google Scholar Ruperto N, Brunner HI, Quartier P, Constantin T, Wulfraat N, Horneff G, Brik R, McCann L, Nistala K, Wouters C, Cimaz R, Ferrandiz MA, Flato B, Grom AA, Magnusson B, Ozen S, Abrams K, Kim D, Martini A, Lovell DJ.卡那单抗治疗系统性幼年特发性关节炎的两项随机试验。New Engl J Med.2012;367:2396-406.Article CAS PubMed Google Scholar De Benedetti F, Martini A..系统性幼年类风湿性关节炎是IL-6介导的疾病吗?J Rheumatol.1998;25:203-7.PubMed Google Scholar Yokota S, Imagawa T, Mori M, et al. Tocilizumab 对全身性发病的幼年特发性关节炎患者的疗效和安全性:随机、双盲、安慰剂对照、停药 III 期试验。柳叶刀。2008;371:998-1006.Article CAS PubMed Google Scholar De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Ravelli A, Schneider WP, Wouters C, Zemel L, Burgos-Vargos R, Dolezalova P, Grom AA, Wulffraat N, Zuber Z, Zulian F, Lovell D, Martini A. Randomized trial of tocililab for juvenile idiopathic arthritis.托西珠单抗治疗系统性幼年特发性关节炎的随机试验。新英格兰医学杂志》。2012;367:2385-95.Article PubMed Google Scholar Erkens R, Esteban Y, Towe C, Schulert G, Vastert S. Pathogenesis and treatment of refractory disease courses in systemic juvenile idiopathic arthritis: refractory arthritis, recurrent macrophage activation syndrome and chronic lung disease.Rheum Dis Clin North Am. 2021;47(4):585-606. https://doi.org/10.1016/j.rdc.2021.06.003.(Epub 2021 Aug 21 PMID: 34635293).Article PubMed Google Scholar Grom AA, Ilowite NT, Pascual V, Brunner HI, Martini A, Lovell D, Ruperto N. Paediatric rheumatology international trials organisation and the pediatric rheumatology collaborative study group; Leon K, Lheritier K, Abrams K. Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis Treated with Canakinumab.Arthritis Rheumatol.2016;68:218-28.PMID: 26314396.Kimura Y, Weiss JE, Haroldson KL, Lee T, Punaro M, Oliveira S, et al. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis.Arthritis Care Res (Hoboken).2013;65:745-52.Article CAS PubMed Google Scholar Schulert GS, Yasin S, Carey B, Chalk C, Do T, Schapiro AH, Husami A, Watts A, Brunner HI, Huggins J, Mellins ED, Morgan EM, Ting T, Trapnell BC, Wikenheiser-Brokamp KA, Towe C, Grom AA.系统性幼年特发性关节炎-肺病:特征和风险因素》(Systemic juvenile idiopathic arthritis-lung disease: characterization and risk factors.Arthritis Rheumatol.2019;71:1943-54.文章 CAS PubMed PubMed Central Google Scholar Saper VE、Chen G、Deutsch GH、Guillerman RP、Birgmeier J、Jagadeesh K、Canna S、Schulert G、Deterding R、Xu J、Leung AN、Bouzoubaa L、Abulaban K、Baszis K、Behrens EM、Birmingham J、Casey A、Cidon M、Cron RQ、De A、De Benedetti F、Ferguson I、Fishman MP、Goodman SI、Graham TB、Grom AA、Haines K、Hazen M、Henderson LA、Ho A、Ibarra M、Inman CJ、Jerath R、Khawaja K、Kingsbury DJ、Klein-Gitelman M、Lai K. Lapidus S、Lin C. Lapidus S、Lin C. Lapidus S、Lin C. Lapidus S、Lin C. Lapidus S、Lin C、Lapidus S、Lin C、Lin J、Liptzin DR、Milojevic D、Mombourquette J、Onel K、Ozen S、Perez M、Phillippi K、Prahalad S、Radhakrishna S、Reinhardt A、Riskalla M、Rosenwasser N、Roth J、Schneider R、Schonenberg-Meinema D、Shenoi S、Smith JA, Sönmez HE, Stoll ML, Towe C, Vargas SO, Vehe RK, Young LR, Yang J, Desai T, Balise R, Lu Y, Tian L, Bejerano G, Davis MM, Khatri P, Mellins ED, Childhood Arthritis and Rheumatology Research Alliance Registry Investigators.全身性幼年关节炎的高致死率肺部疾病。Ann Rheum Dis.2019;78:1722-31 (PMID:31562126).Article CAS PubMed Google Scholar Bracaglia C, de Graaf K, PiresMarafon D, Guilhot F, Ferlin W, Prencipe G, Caiello I, Davì S, Schulert G, Ravelli A, Grom AA, De Benedetti F. Rheum Dis.循环中干扰素-γ和干扰素-γ诱导的趋化因子水平升高是全身性幼年特发性关节炎并发巨噬细胞活化综合征患者的特征。Ann Rheum Dis.2017;76:166-72 (PMID: 27296321).Article CAS PubMed Google Scholar De Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA.在炎症亢进中靶向γ干扰素:机遇与挑战。Nature Rev Rheumatology.2021;17(11):678-91 (PMID: 34611329).Article Google Scholar Schulert GS, Pickering AV, Do T, Dhakal S, Fall N, Schnell D, Medvedovic M, Salomonis N, Thornton S, Grom AA.系统性幼年特发性关节炎的单核细胞和骨髓巨噬细胞转录表型显示 TRIM8 是 IFN-γ 高反应性和巨噬细胞活化综合征风险的介质。Ann Rheum Dis.2020;80:617-25.PMID: 33277241.De Benedetti F, Grom AA, Quartier P, Schneider R, Antón J, Bracaglia C, et al.大剂量糖皮质激素治疗失败的系统性幼年特发性关节炎并发巨噬细胞活化综合征(mas)患者的γ干扰素(IFN-γ)中和与依马帕单抗和反应时间摘要。Arthritis Rheumatol.2019;71(10):5229-30. Google Scholar Iriguchi S, Kikuchi N, Kaneko S, Noguchi E, Morishima Y, Matsuyama M, Yoh K, Takahashi S, Nakauchi H, Ishii Y.T细胞受限的T-bet过表达诱导髓系细胞异常造血并损害肺部巨噬细胞的功能。Blood.2015;125(2):370-82.Saper VE, Ombrello MJ, Tremoulet AH, Montero-Martin G, Prahalad S, Canna S, et al. IL-1和IL-6抑制剂的严重迟发性超敏反应与常见的HLA-DRB1*15等位基因有关。Ann Rheum Dis.2022;81:406-15.Download referencesNot applicable.List of the participantsRolla 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 J. Rheum Dis.Lovell3、Rebecca Marsh11、Bénédicte Neven12,18、Peter A. Nigrovic13,14、Nikolay Nikolov15、Karen Onel16、Sampath Prahalad6、Susan Prockop17、Pierre Quartier12,18、Johannes Roth19、Grant Schulert3、Juliana M.F. Silva20、Sebastiaan J.Vastert21、Donna Wall22、Ulrike Zeilhofer231美国俄亥俄州哥伦布市全国儿童医院 BMT 部2美国宾夕法尼亚州费城佩雷尔曼大学医学院费城儿童医院风湿病部3美国俄亥俄州辛辛那提市辛辛那提大学辛辛那提儿童医院医疗中心风湿病部4美国俄亥俄州辛辛那提市辛辛那提儿童医院风湿病与免疫失调研究室免疫调节,费城儿童医院,费城,宾夕法尼亚州,美国5风湿病学系,苏黎世大学儿童医院,苏黎世,瑞士6儿科系,埃默里大学医学院,亚特兰大,佐治亚州,美国7儿科系,阿拉巴马大学伯明翰分校,伯明翰,阿拉巴马州,美国8风湿病学系,全国儿童医院,哥伦布,俄亥俄州,美国9儿科风湿病学部,约瑟夫 M. 桑扎里儿童医院,约瑟夫 M. 桑扎里儿童医院,约瑟夫 M. 桑扎里儿童医院,约瑟夫 M. 桑扎里儿童医院,约瑟夫 M. 桑扎里儿童医院,约瑟夫 M. 桑扎里儿童医院,美国Sanzari 儿童医院小儿风湿科,哈肯萨克,子午线医学院,哈肯萨克,新泽西州,美国10Drugs and Biologics, Greenleaf Health, Inc、美国马萨诸塞州波士顿市布里格姆妇女医院风湿病、炎症和免疫科15 美国华盛顿特区 FDA 风湿病学和移植医学部16 美国纽约州纽约市 HSS 风湿病学部17 美国马萨诸塞州波士顿市丹娜法伯/波士顿儿童医院癌症和血液疾病中心18 法国巴黎巴黎市立大学19 瑞士卢塞恩卢塞恩大学卢塞恩医院20 英国伦敦大奥蒙德街儿童医院 BMT 部21 小儿风湿病学&amp;荷兰乌得勒支大学医学中心免疫学和转化免疫学中心22 加拿大多伦多病童医院血液/肿瘤科血液和骨髓移植/细胞疗法23 瑞士苏黎世大学儿童医院 BMT 部父母名单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 Tronsdal11系统性 JIA 基金会,美国俄亥俄州辛辛那提市2儿童关节炎和风湿病学联盟 (CARRA),美国华盛顿特区关于本增刊本文已作为《儿科风湿病学》第 21 卷第 1 号增刊(2023 年)的一部分发表:第四届SJIA和MAS新一代疗法虚拟研讨会论文集》的一部分。该增刊的全部内容可通过 https://ped-rheum.biomedcentral.com/articles/supplements/volume-21-supplement-1.Funding 在线查阅,研讨会由 SJIA 基金会提供。出版费用由 SJIA 基金会承担。作者和单位系统性 JIA 基金会(Systemic JIA Foundation),美国俄亥俄州辛辛那提市ARashmi SinhaDivision of Rheumatology, Ospedale Pediatrico Bambino Gesù,罗马,意大利Fabrizio De BenedettiDivision of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USAAlexei A. Grom作者Rashmi Sinha是美国俄亥俄州辛辛那提市系统性 JIA 基金会的成员。GromAuthorsRashmi SinhaView author publications您也可以在PubMed Google Scholar中搜索该作者Fabrizio De BenedettiView author publications您也可以在PubMed Google Scholar中搜索该作者Alexei A. GromView author publications您也可以在PubMed Google Scholar中搜索该作者Consonsortiaon behalf of the participants listed belowRolla F. Abu-Arja, Edward Behhavi.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.
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来源期刊
Pediatric Rheumatology
Pediatric Rheumatology PEDIATRICS-RHEUMATOLOGY
CiteScore
4.10
自引率
8.00%
发文量
95
审稿时长
>12 weeks
期刊介绍: Pediatric Rheumatology is an open access, peer-reviewed, online journal encompassing all aspects of clinical and basic research related to pediatric rheumatology and allied subjects. The journal’s scope of diseases and syndromes include musculoskeletal pain syndromes, rheumatic fever and post-streptococcal syndromes, juvenile idiopathic arthritis, systemic lupus erythematosus, juvenile dermatomyositis, local and systemic scleroderma, Kawasaki disease, Henoch-Schonlein purpura and other vasculitides, sarcoidosis, inherited musculoskeletal syndromes, autoinflammatory syndromes, and others.
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