Towards stratified treatment of JIA: machine learning identifies subtypes in response to methotrexate from four UK cohorts

Abstract

Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures.

Methods: Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year. Clusters of MTX 'response' were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment.

Findings: The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65-0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns.

Interpretation: Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis of a stratified medicine programme in early JIA.

Funding: Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and the National Institute for Health Research.

Keywords: Epidemiology; Juvenile idiopathic arthritis; Machine learning; Methotrexate; Treatment outcome.

Fig. 1

Cohort inclusion flowchart for the current study.

Fig. 2

Average log1p transformed active joint count, physician global, patient/parent global and ESR trajectories within six multivariate disease clusters over the year following MTX initiation in the discovery cohort. Shaded patterns on average trajectories are purely for visualisation and comparison with verification cohort trajectories, and are not related to underlying data. AJC: active joint count; PGA: physician’s global assessment; PGE: parental global evaluation; ESR: erythrocyte sedimentation rate.

Fig. 3

ACR Pedi 30 and 90 achievement across the 6 multivariate trajectory groups following MTX initiation in the discovery cohort: a) within 6 months, b) within 12 months. Raw numbers are presented in Supplementary Table S2.

Fig. 4

Representation of a) ILAR categories and b) oligoarticular or polyarticular joint counts at MTX initiation between the 6 multivariate trajectory clusters following MTX initiation in the discovery cohort.