Background: The idiopathic inflammatory myopathies (IIMs) form a rare, heterogenous group of autoimmune conditions characterised by inflammation and weakness of skeletal muscle. Elevated interferon signaling is present in IIM patients and has been linked to disease pathogenesis, highlighting the therapeutic potential of Janus kinase (JAK) inhibitors. Recently, the MYOJAK clinical trial (NCT04208464) demonstrated the efficacy of the JAK1/2 inhibitor Baricitinib in adult IIM patients, resulting in improvements in skin and muscle disease as well as physical function [1]. However, a personalised treatment approach is needed to maximise the benefits for patients which requires the identification of novel biomarkers.

Objectives: This study aimed to identify novel biomarkers for monitoring treatment response to Baricitinib in IIM in longitudinal samples collected from participants throughout the MYOJAK trial.

Methods: MYOJAK participants were randomly split into immediate-start and delayed-start trial arms. Both trial arms received Baricitinib for 24 weeks overall, but treatment start dates were staggered by 12 weeks. The immediate-start arm received treatment from week 0-24, whereas the delayed-start arm was treated from week 12-36. Biological samples and clinical measurements were collected at weeks 0, 12, 24 and 36 from all participants, regardless of trial arm. For biomarker analyses, baseline was classed as week 0 for the immediate-start arm and week 12 for delayed-start arm. Longitudinal samples of whole blood, sera, plasma and peripheral blood mononuclear cells (PBMCs) were collected from 15 UK adult IIM patients during their participation in the MYOJAK clinical trial. RNA was extracted from whole blood, and the expression of 32 interferon-related mRNAs was quantified using a custom-designed mRNA assay panel. The concentrations of 250 inflammation-related proteins were measured in sera samples with a proteomics panel assay. Concentrations and ratios of 249 metabolites were measured in plasma samples by a metabolomics panel assay. PBMC samples were subject to immunophenotyping by spectral flow cytometry. Linear mixed models with random intercepts were used to assess associations between potential biomarkers with paired clinical measurements collected across longitudinal timepoints, to account for intra-patient correlation. Physician Global Disease Activity and Myositis Disease Activity Assessment Tool (MDAAT) scores were used to assess biomarkers’ relationship with disease activity, and ACR-EULAR Myositis Response Criteria Total Improvement Score (TIS) was used to assess biomarkers’ relationship with treatment response.

Results: 15 IIM patients were enrolled in the MYOJAK clinical trial. The mean age of IIM patients was 43.5 years (range 29-65) and 73% were female. Patient ethnicities included Asian, Mixed Asian/White and White with a majority of White participants. All patients achieved the primary trial endpoint of ‘minimal response’ (TIS ≥20) after 24 weeks of Baricitinib treatment, whilst nine achieved ‘moderate’ response criteria (TIS ≥40) and two achieved ‘major’ response criteria (TIS ≥60). Blood mRNA expression analysis revealed that expression of type-I interferon-stimulated mRNAs correlated with changes in disease activity (p=0.001) and TIS (p=0.045) in IIM patients treated with Baricitinib. Furthermore, patients’ 5-gene type-I interferon score at baseline correlated with TIS achieved after Baricitinib treatment (p=0.016). Proteomic analysis showed that IIM patients presented with an elevated pro-inflammatory proteomic profile at baseline, compared with healthy controls, which tended to reduce after Baricitinib treatment. Concentrations of two pro-inflammatory proteins, IFNβ and CXCL10, correlated with changes in disease activity (p=0.016 and p=0.002, respectively). Metabolomic analysis found that IIM patients at baseline had a highly dysregulated metabolome compared to healthy controls, including decreased levels of Omega-3 fatty acids (p<0.001). Interestingly, Omega-3 tended to increase in patients after Baricitinib treatment and Omega-3 concentration negatively correlated with changes in disease activity (p=0.017). Immunophenotyping found significant increases in populations of CD28+ CD27+ CD8+ effector memory T cells (p=0.039) in peripheral blood of patients after Baricitinib treatment. Furthermore, the abundance of CD28+ CD27+ CD8+ effector memory T cells in peripheral blood positively correlated with longitudinal TIS (p<0.001) in patients throughout the trial. It is necessary to note that p-values should be interpreted with caution due to the relatively small cohort size.

Conclusions: This exploratory study identified several candidate biomarkers of disease activity and treatment response in IIM patients treated with JAK1/2 inhibitor Baricitinib. Novel findings include the identification of Omega-3 and CD28+ CD27+ CD8+ effector memory T cells as potential biomarkers of disease activity and treatment response in IIM. Additionally, this is the first study to report association between baseline type-I interferon gene expression and future response to Baricitinib, which may prove useful in the personalisation of IIM care.

REFERENCES: [1] Chinoy H, K. A., Sylvestre Y, Lilleker J, Gordon P, Tansley S, Prabu A, Aslam A, Snedden A and Lamb J (2024). ‘Baricitinib in the Treatment of Adult Idiopathic Inflammatory Myopathy: A Randomized, Treatment Delayed-Start Clinical Trial [abstract]’, ACR Conference 2024 : Arthritis Rheumatology. (Accessed: January 12, 2026).

Acknowledgments: NIL.

Disclosure of Interests: Luke Tomlinson: None declared, Sarah Sugden: None declared, Nicholas Scott: None declared, Gillian I Rice Yes, Janssen., Maria Christofi: None declared, Alexander Oldroyd: None declared, Ashma Krishan: None declared, James Lilleker JBL has received conference/travel support and speakers fees from Sanofi. He has participated in advisory boards, received conference/travel support and speakers fees from Roche. He has received speakers fees from Dyne therapeutics., Yvonne Sylvestre Garcia: None declared, Andrew Snedden: None declared, Patrick Gordon: None declared, Athiveer Prabu: None declared, Sarah Tansley: None declared, Aamir Aslam: None declared, Nicola Haupt: None declared, Helene Alexanderson: None declared, Ingrid E. Lundberg Ingrid E. Lundberg: IEL, has received speaker fees from Boehringer Ingelheim, Janssen, and has been serving on the advisory board for Argenx, Astra-Zeneca, Pfizer, Chugai Pharmaceutical Co. Ltd, Novartis and Janssen., Ingrid E. Lundberg: IEL, has stock shares in Roche and Novartis., Fionnuala McMorrow: None declared, Hector Chinoy Yes, Pfizer, Eli-Lilly, AstraZeneca and Janssen., Janine Lamb Yes, Pfizer and Eli-Lilly.