Biologic therapies made clinical remission an achievable goal for most juvenile idiopathic arthritis (JIA) patients. Nevertheless, antirheumatic drugs have side effects and are costly. Currently, no guidelines exist for withdrawing drugs in JIA patients with clinical inactive disease (CID). Relapses following the withdrawal of antirheumatic drugs are common. To establish an optimal timeline for treatment discontinuation is a major unmet need in pediatric rheumatology.

It is hypothesized that biomarkers-guided early withdrawal of antirheumatic drugs in patients achieving clinical, imaging and biological remission is safe and more effective compared to the standard practice of maintenance of stable treatment over 12 months.

The study is designed as a multicenter, prospective, randomized, open label superiority trial of two different treatment medication withdrawal strategies (early biomarkers-guided versus conventional unguided drugs withdrawal strategy). Musculoskeletal ultrasound (MSUS) and serum biomarkers, such as the S-100 protein family, allow a more accurate assessment of remission status than clinical evaluation alone. Subclinical synovitis detected by MSUS at the joint level and increased level of S100 proteins have been associated with an increased risk of loss of clinically inactive disease after drug discontinuation. The results of this study will provide a more rational approach to treatment withdrawal in inactive JIA patients. It is expected that a risk-adapted strategy would reduce both number of disease flares and cumulative drug exposure compared with standard-of-care practice. If validated, these biomarkers will help to personalize immunosuppressant withdrawal: a therapy paradigm shift while ensuring patient and economic benefits.

Patients with inactive disease, absence of sublinical synovitis at the joint level and normal S100A8/9 and hs-CRP leves will be randomly assigned to either an early biomarker-guided drug withdrawal protocol (interventional arm) or continuation of ongoing therapy at unchanged dose for an additional 6 months and then gradual tapering (control arm).

Patients will be evaluated at baseline, then every 3 months if still on treatment and every 6 months after drug withdrawal. At each timepoint the following procedures will be performed: joint assessment, Physician's Global Assessment of Overall Disease Activity, JAMAR, Uveitis assessment (in ANA positive patients), Hematology, chemistry, CRP, ESR, urine analysis according to drug specific schedule and Good Clinical Practice (GCP). Drug Adverse Events will be collected (MedDRA).

MSUS and serum biomarkers quantification (S100A8/9, hs-CRP) will be repeated every 3 months until month 18 in patients with subclinical synovitis and pathologic values of serum biomarkers who are randomized in the intervention arm.

Blood samples for research laboratory analysis (multi Omics, characterization of immune cell populations and quantification of cytokines concentration and EV-miRNAs expression) will be collected at baseline, at drugs withdrawal and in case of disease flare.

Inclusion Criteria:

• - Children with a diagnosis of JIA according to the ILAR classification criteria
• JIA patients who satisfy criteria for inactive disease for a minimum of 6 continuous months while still taking medication.
• Patients who have been treated with cs/b/bs/ts DMARDs according to the label indication
• Ability to comply with the entire study procedures, ability to communicate meaningfully with the investigational staff, competence to give written informed consent; to be applied to the parents and/or patients, as appropriate
• Duly executed, written, informed consent obtained from the patient's parents/legal guardian
• Female of child-bearing potential must have a negative pregnancy test at the beginning of the trial. If sexually active, they must have no intention of conceiving while on treatment with antirheumatic drugs.

Exclusion Criteria:

• - Patients with systemic JIA according to ILAR criteria
• Patients with undifferentiated arthritis according to ILAR criteria
• Patients with severe disease-related ocular damage and who need systemic treatment for uveitis
• Patients who received glucocorticoid treatment 3 months prior to baseline visit
• Patients who had previously unsuccessfully attempted tapering cs/b/bs/tsDMARDs
• Patients with severe damage as per caring physician measured
• Prior or current history of other significant concomitant illness(es) that, according to the Investigator's judgment, would adversely affect the patient's participation in the study
• Any other medical condition or laboratory examination which in the opinion of the caring physician should exclude the patient from participation to the study