Successful treatment of an anti-MDA5 antibody-positive Juvenile Dermatomyositis patient with refractory interstitial lung disease using tofacitinib

doi:10.21203/rs.3.rs-4973421/v1

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Successful treatment of an anti-MDA5 antibody-positive Juvenile Dermatomyositis patient with refractory interstitial lung disease using tofacitinib

https://doi.org/10.21203/rs.3.rs-4973421/v1

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Juvenile dermatomyositis (JDM) is a rare autoimmune disorder affecting children, mainly characterized by skin rash and muscle weakness (1). Anti-MDA5 antibody-positive JDM represents a distinct phenotype of disease with a high risk of developing life-threatening progressive interstitial lung disease (ILD)(2). The pivotal role of the type I interferon (IFN) pathway in the pathogenesis of anti-MDA5 positive JDM has prompted the exploration of Janus kinase (JAK) inhibitors as a therapeutic option (3). Nevertheless, while the efficacy and safety of JAK inhibitors have been established in clinical trials including adult-onset anti-MDA5-antibody positive DM (4), evidence in paediatric cases with progressive or refractory ILD is limited. In this report we describe the efficacy and safety of tofacitinib, a JAK 1/3 inhibitor, in treating an anti-MDA5-positive JDM young girl with refractory ILD, highlighting the potential of JAK inhibitors as targeted therapy in these patients.

juvenile dermatomyositis

anti-MDA5 antibodies

interstitial lung disease

tofacitinib

JAK inhibitors

type I IFN gene signature

A previously healthy 7-year-old female patient of Caucasian ethnicity presenting with a 6-month history of fatigue, weight loss, skin lesions (Figure 1A-B), and mildly impaired muscle strength was diagnosed with anti-MDA5 positive JDM. JDM-associated ILD was also detected during the initial diagnostic workup (Figure 2A). Initial treatment with methylprednisolone pulses followed by high-dose intravenous glucocorticoids, oral cyclophosphamide and monthly intravenous immunoglobulin (IVIG) infusions led to skin (Figure 1C-D) and muscle disease remission, but failed to halt lung disease progression (Figure 2B). Supported by reports on adult-onset DM (5) and the presence of elevated peripheral blood type I interferon gene signature (IGS) based on the expression of 6 type I IFN-related genes (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) in the patient (Figure 3), tofacitinib in combination with subcutaneous methotrexate and IVIG was initiated. This treatment led to a stable remission, near-complete resolution of the pulmonary involvement (Figure 2C-D), discontinuation of glucocorticoids and normalization of peripheral blood type I IGS (Figure 3). No adverse effects were observed during 2-year follow-up evaluations.

This case underscores the promising efficacy and safety of tofacitinib in managing anti-MDA5-positive JDM with ILD non-responsive to aggressive conventional immunosuppressive treatments. It also emphasizes the importance of early intervention and the potential benefits of employing targeted therapies based on specific biomarkers such as the type I IGS. Future research should focus on the design of international randomized controlled trials aimed to assess the efficacy and safety of JAK inhibitors in JDM, as to foster personalised treatment approaches and improve patient outcomes.

DM Dermatomyositis

IFN Interferon

IGS Interferon Gene Signature

ILD Interstitial Lung Disease

IVIG Intravenous Immunoglobulin

JAK Janus Kinase

JDM Juvenile Dermatomyositis

MDA5 Melanoma Differentiation-Associated protein 5

Ethics approval and consent to participate

Written informed consent for publication of their clinical details and/or clinical images was obtained from the parent of the patient. A copy of the consent form is available for review by the Editor of this journal.

The off-label use of tofacitinib was approved by the local ethics committee (“Comitato Buon Uso del Farmaco”) of the IRRCS Giannina Gaslini.

Availability of data and material

Data used during the current study are available from the corresponding author SR on reasonable request.

Competing interests

VN, SP, AIRG, PB, SR have no competing interests

CMC, SV and RP received speaker fee from SOBI

RC received speaker fee from Sobi and Novartis, consultancy from SOBI, Novartis and Eli Lilly.

AC received research support from Pfizer and speaker fee from Novartis

MG received speaker fee and consultancy from SOBI and Novartis

AR received consultancy and speaker fee from Abbvie, Alexion, Alfasigma, Angelini, BMS, Galapagos, Novartis, Pfizer, Reckitt-Benckiser, Roche, SOBI, research support from Novartis, Pfizer

Funding

No specific funding was received to carry out the here described work.

Authors' contributions

VN contributed to the conception of the study, collected clinical and radiological data, and wrote the first draft of the manuscript. SP and AIRG contributed to data collection. PB performed the type I IFN signature assays. MCC, RB, RC, SV, RP, AC, MG, AR provided critical input during the manuscript drafting and critically reviewed the final version of the manuscript. SR supervised the project, significantly contributed to the conception of the study and critically reviewed the manuscript throughtout the drafting process. All authors read and approved the final version of the manuscript.

Acknowledgements

The authors express their gratitude to the patient and her family for their cooperation and willingness to participate in this case report. We also acknowledge the exceptional care and support provided by the nursing staff, healthcare professionals, laboratory team and physicians at IRCCS Giannina Gaslini during the patient's treatment and follow-up.

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Wang Y, Luo J, Lv X, Li Y, An Q, Mo L, et al. Tofacitinib for new-onset adult patients with anti-melanoma differentiation-associated 5 gene antibody positive dermatomyositis. Clin Rheumatol. 2023 Jul;42(7):1847–53.
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Editorial decision: Minor revision
15 Nov, 2024
Reviewers agreed at journal
14 Oct, 2024
Reviewers invited by journal
10 Oct, 2024
Editor assigned by journal
03 Oct, 2024
First submitted to journal
01 Oct, 2024

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Successful treatment of an anti-MDA5 antibody-positive Juvenile Dermatomyositis patient with refractory interstitial lung disease using tofacitinib

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