Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling

Isabelle Melki; Hervé Devilliers; Cyril Gitiaux; Vincent Bondet; Darragh Duffy; Jean-Luc Charuel; Makoto Miyara; Plamen Bokov; Ahmed Kheniche; Theresa Kwon; François Jérôme Authier; Yves Allenbach; Alexandre Belot; Christine Bodemer; Emmanuelle Bourrat; Cécile Dumaine; Nicole Fabien; Albert Faye; Marie-Louise Frémond; Alice Hadchouel; Naoki Kitabayashi; Alice Lepelley; Maria José Martin-Niclos; Sasi Mudumba; Lucile Musset; Pierre Quartier; Gillian I Rice; Luis Seabra; Florence Uettwiller; Carolina Uggenti; Sebastien Viel; Mathieu P Rodero; Yanick J Crow; Brigitte Bader-Meunier

doi:10.1093/rheumatology/kez525

Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling

Rheumatology (Oxford). 2020 Aug 1;59(8):1927-1937. doi: 10.1093/rheumatology/kez525.

Authors

Isabelle Melki^{1

2

3}, Hervé Devilliers⁴, Cyril Gitiaux^{5

6

7}, Vincent Bondet^{8

9}, Darragh Duffy^{8

9}, Jean-Luc Charuel¹⁰, Makoto Miyara¹⁰, Plamen Bokov^{11

12}, Ahmed Kheniche¹³, Theresa Kwon¹⁴, François Jérôme Authier^{7

15}, Yves Allenbach^{16

17}, Alexandre Belot^{18

19

20}, Christine Bodemer^{21

22

23}, Emmanuelle Bourrat², Cécile Dumaine², Nicole Fabien^{19

24}, Albert Faye^{2

12}, Marie-Louise Frémond^{1

3}, Alice Hadchouel^{25

26}, Naoki Kitabayashi¹, Alice Lepelley¹, Maria José Martin-Niclos¹, Sasi Mudumba²⁷, Lucile Musset¹⁰, Pierre Quartier^{3

23}, Gillian I Rice²⁸, Luis Seabra¹, Florence Uettwiller^{3

29}, Carolina Uggenti^{1

30}, Sebastien Viel^{19

20

24}, Mathieu P Rodero^{1

31}, Yanick J Crow^{1

30}, Brigitte Bader-Meunier^{3

23}

Affiliations

¹ Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Paris.
² General Paediatrics, Infectious Disease and Internal Medicine Department, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Hôpital Robert Debré, AP-HP, Paris.
³ Paediatric Hematology-Immunology and Rheumatology Department, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Hôpital Necker-Enfants Malades, AP-HP, Paris.
⁴ Centre Hospitalier Universitaire de Dijon, Hôpital François-Mitterrand, Service de Médecine Interne 2 et Centre d'Investigation Clinique, Inserm CIC 1432, Dijon.
⁵ Reference Centre for Neuromuscular Diseases, Necker-Enfants Malades Hospital, AP-HP.5, Paris.
⁶ Department of Paediatric Neurophysiology, Necker-Enfants Malades Hospital, AP-HP.5, Paris University, Paris.
⁷ INSERM U955-Team 10 'Biology of the Neuromuscular System', Paris Est-Creteil University, Creteil.
⁸ Immunobiology of Dendritic Cells, Institut Pasteur, Paris.
⁹ INSERM U1223, Paris.
¹⁰ Department of Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris.
¹¹ Paediatric Physiology Department, Hôpital Robert Debré, AP-HP, Paris.
¹² Université Paris Diderot, Paris.
¹³ Paediatric Radiology Department, Hôpital Robert Debré, AP-HP, Paris.
¹⁴ Nephrology Department, Hôpital Robert Debré, AP-HP, Paris.
¹⁵ Reference Centre for Neuromuscular Diseases, Henri Mondor University Hospital, Paris.
¹⁶ Département de médecine Interne et Immunologie Clinique, Centre de Référence Maladies Neuro-Musculaires, DHUi2B, AP-HP, GH Pitié-Salpêtrière, Paris.
¹⁷ Centre de Recherche en Myologie, UMRS 974 UPMC - INSERM, Paris.
¹⁸ Service de néphrologie, rhumatologie et dermatologie pédiatriques, Reference centre for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Filière des maladies autoimmunes et autoinflammatoires rares (FAI2R), Hôpital Femme Mère-Enfant, hospices civils de Lyon, Lyon.
¹⁹ Université de Lyon, Bron cedex, France.
²⁰ Inserm U1111, Lyon.
²¹ National Reference Centre for Genodermatosis and Rare Diseases of the Skin (MAGEC).
²² Department of Dermatology, Necker-Enfants Malades Hospital, APHP5, Paris.
²³ Imagine Institute, Inserm U 1163, Paris University, Paris.
²⁴ Department of Immunology, Reference centre for Rheumatic, AutoImmune and Systemic diseases in children (RAISE) Filière des maladies autoimmunes et autoinflammatoires rares (FAI2R), Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon.
²⁵ Paris University, Paris.
²⁶ Paediatric Pulmonology, University Hospital Necker-Enfants Malades, AP-HP, Paris, France.
²⁷ Genalyte Inc, San Diego, CA, USA.
²⁸ Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
²⁹ Transversal Unit of Allergology and Rheumatology, CHRU Tours, Tours, France.
³⁰ Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
³¹ Chimie & Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes, CNRS, UMR8601, Paris, France.

PMID: 31755959
DOI: 10.1093/rheumatology/kez525

Abstract

Objectives: JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2).

Methods: This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes.

Results: Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported.

Conclusion: This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.

Keywords: Simoa; anti-MDA5 autoantibodies; interferon alpha; interstitial lung disease (ILD); juvenile idiopathic inflammatory myopathies (JIIM).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Autoantibodies / immunology*
Child
Child, Preschool
Female
Humans
Interferon-Induced Helicase, IFIH1 / immunology*
Interferon-alpha / metabolism*
Male
Muscle, Skeletal / immunology
Muscle, Skeletal / metabolism*
Muscle, Skeletal / pathology
Myositis / immunology
Myositis / metabolism*
Myositis / pathology
Prospective Studies
Retrospective Studies
Signal Transduction / physiology*

Substances

Autoantibodies
Interferon-alpha
IFIH1 protein, human
Interferon-Induced Helicase, IFIH1