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JAK Inhibition in Juvenile Idiopathic Arthritis (JIA): Better Understanding of a Promising Therapy for Refractory Cases.

ABSTRACT: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases with probably differential underlying physiopathology. Despite the revolutionary era of biologics, some patients remain difficult to treat because of disease severity, drug adverse events, drug allergy or association with severe comorbidities, i.e., uveitis, interstitial lung disease and macrophagic activation syndrome. Janus Kinase (JAK) inhibitors are small molecules that target JAK/Signal Transducers and Activators of Transcription (STAT) pathways, which could then prevent the activity of several proinflammatory cytokines. They may provide a useful alternative in these cases of JIA or in patients actually affected by Mendelian disorders mimicking JIA, such as type I interferonopathies with joint involvement, and might be the bridge for haematopoietic stem cell transplantation in these disabling conditions. As these treatments may have side effects that should not be ignored, ongoing and further controlled studies are still needed to provide data underlying long-term safety considerations in children and delineate subsets of JIA patients that will benefit from these promising treatments.

SUBMITTER: Melki I

PROVIDER: S-EPMC10381267 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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JAK Inhibition in Juvenile Idiopathic Arthritis (JIA): Better Understanding of a Promising Therapy for Refractory Cases.

Melki Isabelle I Frémond Marie-Louise ML

Journal of clinical medicine 20230714 14

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases with probably differential underlying physiopathology. Despite the revolutionary era of biologics, some patients remain difficult to treat because of disease severity, drug adverse events, drug allergy or association with severe comorbidities, i.e., uveitis, interstitial lung disease and macrophagic activation syndrome. Janus Kinase (JAK) inhibitors are small molecules that target JAK/Signal Transducers and Activators of Tr ...[more]

PMID: 37510809

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Project description:ObjectivesThe International League of Associations for Rheumatology (ILAR) juvenile idiopathic arthritis (JIA) classification was revisited by the Pediatric Rheumatology International Trials Organization (PRINTO) in 2018. Classifications should establish uniform groups to assist physicians in providing optimal care. Therefore, we evaluated changes proposed by PRINTO to highlight their impact on forming consistent groups regarding uveitis and treatment responses, particularly focusing on early-onset anti-nuclear antibody (ANA)-positive JIA.MethodsPediatric patients diagnosed with JIA according to ILAR and PRINTO classification, with a minimum of 1-year of follow-up, were enrolled, excluding those meeting the exclusion criteria for both the oligoarticular JIA and the early-onset ANA-positive JIA groups.ResultsAmong the 139 enrolled patients, 110 (79.1%) had oligoarticular JIA, while 15 (10.8%) had early-onset ANA-positive JIA. The below-age-5 criterion demonstrated the strongest association with uveitis, while the below-age-7 provided similar associations without substantial exclusions (odds ratio (OR) 8.62 [2.50-29.81] vs 7.45 [2.37-26.66]). Patients with a single ANA positivity at a titer ≥ 1/160 and age of onset below 7 had a notably higher risk of new-onset uveitis and biologic DMARD requirement (OR 7.95 [2.37-26.66] and 3.6 [1.42-9.09], respectively).ConclusionThe inclusion of age of disease onset and ANA positivity with a titer ≥ 1/160 has enhanced uniformity in uveitis risk and treatment response, including failure of conventional synthetic DMARDs. Additionally, a single ANA positivity at a ≥ 1/160 titer rather than requiring two instances yields similar consistency. However, the joint count criteria failed to form consistent groups. PRINTO's classification places a significant proportion of patients into the "other JIA" group, necessitating further classification for improved clinical utility. Key Points •Inclusion of age and ANA positivity criteria increased uniformity among the subgroups. •Single ANA positivity at a ≥ 1/160 titer can be sufficient instead of twice. •Early utilization of bDMARDs may be beneficial for early-onset ANA-positive JIA group. •PRINTO classification must further classify the "other JIA" before being implemented in clinical practice.

Project description:BackgroundThe cytokine IL-10 and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in IL-10 were associated with a rare group of diseases called juvenile idiopathic arthritis (JIA). The aim of this study was to fine map genetic variants within the IL-10 cytokine family cluster on chromosome 1 using linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (tSNPs) approach with imputation and conditional analysis to test for disease associations.Methodology/principal findingsFifty-three tSNPs were tested for association between Caucasian paediatric cohorts [219 systemic JIA (sJIA), 187 persistent oligoarticular JIA (pOJIA), and 139 extended OJIA (eOJIA) patients], and controls (Wellcome Trust control cohort, WTCCC2). Significant association with sJIA was detected at rs1400986 in the promoter of IL-20 (odds ratio 1.53; 95% CI 1.21-1.93; p?=?0.0004), but in no other subtypes. Imputation analysis identified additional associated SNPs for pOJIA at IL-20 and IL-24, including a rare, functional, missense variant at IL-24 with a p?=?0.0002. Penalised logistic regression analysis with HyperLasso and conditional analysis identified several further associations with JIA subtypes. In particular, haplotype analysis refined the sJIA association, with a joint effect at rs1400986 and rs4129024 in intron 1 of MAPKAPK2 (p?=?3.2E-5). For pOJIA, a 3-SNP haplotype including rs1878672 in intron 3 of IL-10 showed evidence for association (p?=?0.0018). In eOJIA, rs10863962 (3'UTR of FCAMR) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p?=?0.0003).ConclusionsThis study supports previous association of IL-20 with sJIA. Haplotype analyses provided stronger association signals than single point analyses, while a penalised logistic regression approach also suggested multiple independent association signals. Replication studies are required to confirm or refute these findings. The results indicate that combined effects with unknown/rare variants remain to be characterised in JIA, and represent a possible example of synthetic association in this region.

Dataset Information

JAK Inhibition in Juvenile Idiopathic Arthritis (JIA): Better Understanding of a Promising Therapy for Refractory Cases.

Publications

JAK Inhibition in Juvenile Idiopathic Arthritis (JIA): Better Understanding of a Promising Therapy for Refractory Cases.

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