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

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 HadchouelNaoki 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

Division of Evolution, Infection and Genomics

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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.

Original language	English
Journal	Rheumatology (Oxford, England)
Early online date	22 Nov 2019
DOIs	https://doi.org/10.1093/rheumatology/kez525
Publication status	Published - 2020

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Melki, I., Devilliers, H., Gitiaux, C., Bondet, V., Duffy, D., Charuel, J.-L., Miyara, M., Bokov, P., Kheniche, A., Kwon, T., Authier, F. J., Allenbach, Y., Belot, A., Bodemer, C., Bourrat, E., Dumaine, C., Fabien, N., Faye, A., Frémond, M.-L., ... Bader-Meunier, B. (2020). Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling. Rheumatology (Oxford, England). https://doi.org/10.1093/rheumatology/kez525

@article{70944da6db684b03b1e1e97247a0271b,

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

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.",

author = "Isabelle Melki and Herv{\'e} Devilliers and Cyril Gitiaux and Vincent Bondet and Darragh Duffy and Jean-Luc Charuel and Makoto Miyara and Plamen Bokov and Ahmed Kheniche and Theresa Kwon and Authier, {Fran{\c c}ois J{\'e}r{\^o}me} and Yves Allenbach and Alexandre Belot and Christine Bodemer and Emmanuelle Bourrat and C{\'e}cile Dumaine and Nicole Fabien and Albert Faye and Marie-Louise Fr{\'e}mond and Alice Hadchouel and Naoki Kitabayashi and Alice Lepelley and Martin-Niclos, {Maria Jos{\'e}} and Sasi Mudumba and Lucile Musset and Pierre Quartier and Rice, {Gillian I} and Luis Seabra and Florence Uettwiller and Carolina Uggenti and Sebastien Viel and Rodero, {Mathieu P} and Crow, {Yanick J} and Brigitte Bader-Meunier",

note = "{\textcopyright} The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: [email protected].",

year = "2020",

doi = "10.1093/rheumatology/kez525",

language = "English",

journal = "Rheumatology (Oxford, England)",

issn = "1462-0324",

publisher = "Oxford University Press",

}

Melki, I, Devilliers, H, Gitiaux, C, Bondet, V, Duffy, D, Charuel, J-L, Miyara, M, Bokov, P, Kheniche, A, Kwon, T, Authier, FJ, Allenbach, Y, Belot, A, Bodemer, C, Bourrat, E, Dumaine, C, Fabien, N, Faye, A, Frémond, M-L, Hadchouel, A, Kitabayashi, N, Lepelley, A, Martin-Niclos, MJ, Mudumba, S, Musset, L, Quartier, P, Rice, GI, Seabra, L, Uettwiller, F, Uggenti, C, Viel, S, Rodero, MP, Crow, YJ & Bader-Meunier, B 2020, 'Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling', Rheumatology (Oxford, England). https://doi.org/10.1093/rheumatology/kez525

TY - JOUR

T1 - Anti-MDA5 juvenile idiopathic inflammatory myopathy

T2 - a specific subgroup defined by differentially enhanced interferon-α signalling

AU - Melki, Isabelle

AU - Devilliers, Hervé

AU - Gitiaux, Cyril

AU - Bondet, Vincent

AU - Duffy, Darragh

AU - Charuel, Jean-Luc

AU - Miyara, Makoto

AU - Bokov, Plamen

AU - Kheniche, Ahmed

AU - Kwon, Theresa

AU - Authier, François Jérôme

AU - Allenbach, Yves

AU - Belot, Alexandre

AU - Bodemer, Christine

AU - Bourrat, Emmanuelle

AU - Dumaine, Cécile

AU - Fabien, Nicole

AU - Faye, Albert

AU - Frémond, Marie-Louise

AU - Hadchouel, Alice

AU - Kitabayashi, Naoki

AU - Lepelley, Alice

AU - Martin-Niclos, Maria José

AU - Mudumba, Sasi

AU - Musset, Lucile

AU - Quartier, Pierre

AU - Rice, Gillian I

AU - Seabra, Luis

AU - Uettwiller, Florence

AU - Uggenti, Carolina

AU - Viel, Sebastien

AU - Rodero, Mathieu P

AU - Crow, Yanick J

AU - Bader-Meunier, Brigitte

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1093/rheumatology/kez525

DO - 10.1093/rheumatology/kez525

M3 - Article

C2 - 31755959

SN - 1462-0324

JO - Rheumatology (Oxford, England)

JF - Rheumatology (Oxford, England)

ER -

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

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