Galectin-9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation.

Judith Wienke,Jessica E Hoogendijk,Anneke J Van Der Kooi,Joo Guan Yeo,Thaschawee Arkachaisri,Wilco De Jager,Annet Van Royen‐Kerkhof,Timothy R D J Radstake,Luuk L Van Den Hoogen,Femke Van Wijk,Camiel A Wijngaarde,Felicitas Bellutti Enders,W Ludo Van Der Pol,Claire T Deakin,Alain Meyer,Lucy R Wedderburn,Jorre S Mertens,Janneke Tekstra,Kiran Nistala,Clarissa Pilkington,Johan Lim,Stefan Nierkens,Wineke Armbrust,Henny G Otten,Esther P A H Hoppenreijs ,Joël A G Van Roon ,Sylvia Kamphuis ,P Müller ,Ruth Fritsch-Stork ,Marjolein Visser ,Van Den Berg M

doi:10.1002/art.40881

Abstract

ObjectiveObjective evaluation of disease activity is challenging in patients with juvenile dermatomyositis (DM) due to a lack of reliable biomarkers, but it is crucial to avoid both under‐ and overtreatment of patients. Recently, we identified 2 proteins, galectin‐9 and CXCL10, whose levels are highly correlated with the extent of juvenile DM disease activity. This study was undertaken to validate galectin‐9 and CXCL10 as biomarkers for disease activity in juvenile DM, and to assess their disease specificity and potency in predicting the occurrence of flares.MethodsLevels of galectin‐9 and CXCL10 were measured by multiplex immunoassay in serum samples from 125 unique patients with juvenile DM in 3 international cross‐sectional cohorts and a local longitudinal cohort. The disease specificity of both proteins was examined in 50 adult patients with DM or nonspecific myositis (NSM) and 61 patients with other systemic autoimmune diseases.ResultsBoth cross‐sectionally and longitudinally, galectin‐9 and CXCL10 outperformed the currently used laboratory marker, creatine kinase (CK), in distinguishing between juvenile DM patients with active disease and those in remission (area under the receiver operating characteristic curve [AUC] 0.86–0.90 for galectin‐9 and CXCL10; AUC 0.66–0.68 for CK). The sensitivity and specificity for active disease in juvenile DM was 0.84 and 0.92, respectively, for galectin‐9 and 0.87 and 1.00, respectively, for CXCL10. In 10 patients with juvenile DM who experienced a flare and were prospectively followed up, continuously elevated or rising biomarker levels suggested an imminent flare up to several months before the onset of symptoms, even in the absence of elevated CK levels. Galectin‐9 and CXCL10 distinguished between active disease and remission in adult patients with DM or NSM (P = 0.0126 for galectin‐9 and P < 0.0001 for CXCL10) and were suited for measurement in minimally invasive dried blood spots (healthy controls versus juvenile DM, P = 0.0040 for galectin‐9 and P < 0.0001 for CXCL10).ConclusionIn this study, galectin‐9 and CXCL10 were validated as sensitive and reliable biomarkers for disease activity in juvenile DM. Implementation of these biomarkers into clinical practice as tools to monitor disease activity and guide treatment might facilitate personalized treatment strategies.

Highlights

Juvenile dermatomyositis (DM) is a rare, chronic systemic immune-mediated disease with a high disease burden
The Dutch Juvenile Dermatomyositis (DM) cohort was supported by the Princess Beatrix Fund and the De Bas Stichting and the Healthcare Insurers Innovation Fund
The Singaporean Juvenile DM cohort was supported by the National Research Foundation Singapore (National Medical Research Council grant NMRC/CG/M003/2017) and the Singapore Ministry of Health’s National Medical Research Council

Summary

Introduction

Juvenile dermatomyositis (DM) is a rare, chronic systemic immune-mediated disease with a high disease burden. In children with juvenile DM, the disease is characterized by inflammation of the skeletal muscles and skin, leading to muscle weakness and a pathognomonic skin rash. Vital organs such as the lung and heart can be involved. 50% of patients do not respond to initial treatment or present with disease flares during follow-u p, resulting in additional tissue damage and impaired physical recovery [13,14,15]. Of the other 50% of patients, some could likely benefit from a shorter treatment duration, taking into account that overtreatment with steroids can result in serious side effects in children, such as Cushing’s syndrome, osteoporosis, and growth delay [16,17,18]

Results

Discussion

Conclusion