This chapter relates the notions of mutations with the concept of graphical derivatives of set-valued maps and more generally links the above results of morphological analysis with some basic facts of set-valued analysis that we shall recall.

Set-valued analysis

Background In 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and uveitis is possibly its most devastating extra-articular manifestation. Evidence-based guidelines are sparse and management is mostly based on physicians’ experience. Consequently, treatment practices differ widely, within and between nations. Objectives To provide recommendations for the diagnosis and treatment of JIA-associated uveitis. Methods Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of nine experienced paediatric rheumatologists and three experts in ophthalmology from Europe. Recommendations derived from a validated systematic literature review were evaluated by an Expert Committee and subsequently discussed at two consensus meetings using nominal group techniques. Recommendations were accepted if >80% agreement was reached (including all three ophthalmologists). Results In total, 22 recommendations were accepted (with >80% agreement among experts): 3 on diagnosis, 5 on disease activity measurements, 12 on treatment and 2 on future recommendations. Conclusions The SHARE initiative aims to identify best practices for treatment of patients suffering from JIA-associated uveitis. Within this remit, recommendations for the diagnosis and treatment of JIA-associated uveitis have been formulated by an evidence-informed consensus process to suggest a standard of care for JIA-associated uveitis patients throughout Europe.

https://ard.bmj.com/content/annrheumdis/77/8/1107.full.pdf

Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis: the SHARE initiative

New observations and emerging ideas in diagnosis and management of non-infectious uveitis: A review.

Purpose: To report a case of effective Janus kinase inhibitor treatment in a case of anterior uveitis complicated by macular edema in a patient with juvenile idiopathic arthritis.Case report: A 22-year-old woman suffering from JIA-associated anterior uveitis since the age of 2 years presented with recurrent active uveitis and macular edema in both eyes responding only to intraocular dexamethasone implants in the past while several other DMARD therapies including biologicals failed to control activity and edema. After starting treatment with tofacitinib 5 mg twice daily arthritis, uveitis, and macular edema were controlled without any further steroid implants.Conclusion: In this case, Janus kinase inhibitor represented a successful strategy for severe refractory uveitis and ME and therefore Janus kinase inhibitor may be an option in selected cases not responding properly to conventional synthetic and biologic DMARDs or to intraocular steroid implants.

Effect of Janus Kinase Inhibitor Treatment on Anterior Uveitis and Associated Macular Edema in an Adult Patient with Juvenile Idiopathic Arthritis.

Summary Background Uveitis associated with juvenile idiopathic arthritis is a cause of major ocular morbidity. A substantial proportion of children are refractory to systemic methotrexate and TNF inhibitors. Our aim was to study the safety and efficacy of tocilizumab in children with juvenile idiopathic arthritis-associated uveitis refractory to both methotrexate and TNF inhibitors. Methods This multicentre, single-arm, phase 2 trial was done following a Simon's two-stage design at seven tertiary hospital sites in the UK. Patients aged 2–18 years with active juvenile idiopathic arthritis-associated uveitis were eligible. All patients had been on a stable dose of methotrexate for at least 12 weeks and had not responded to treatment with a TNF inhibitor. Patients weighing 30 kg or more were treated with 162 mg subcutaneous tocilizumab every 2 weeks for 24 weeks, and participants weighing less than 30 kg were treated with 162 mg every 3 weeks for 24 weeks. The primary outcome was treatment response defined as a two-step decrease, or decrease to zero, from baseline in the level of inflammation (anterior chamber cells) at week 12, per the standardisation of uveitis nomenclature criteria. A phase 3 trial would be justified if more than seven patients responded to treatment. An interim analysis was planned to assess whether the trial would be stopped for futility, with futility defined as two or fewer treatment responses among ten participants. Adverse events were collected up to 30 calendar days after treatment cessation. The primary analysis was done in the intention-to-treat population and the safety analysis was done in all patients who started the treatment. This trial is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN95363507) and EU Clinical Trials Register (EudraCT 2015-001323-23). Findings 22 participants were enrolled to the trial between Dec 3, 2015, and March 9, 2018, and 21 participants received treatment. One participant was found to be ineligible immediately after enrolment and was therefore withdrawn. Seven of 21 (median unbiased estimate of proportion 34% [95% CI 25–57]) responded to treatment (p=0·11). Safety results were consistent with the known safety profile of tocilizumab. Interpretation The primary endpoint was not met, and thus the results do not support a phase 3 trial of tocilizumab in patients with juvenile idiopathic arthritis-associated uveitis. Importantly, data on the use of tocilizumab in clinical practice is now captured in national registries. Despite this trial not meeting the threshold required to justify a larger phase 3 trial, several patients responded to treatment; as such, tocilzumab might still be a therapeutic option in some children with uveitis refractory to anti-TNF drugs, given the absence of other treatment options. Funding Versus Arthritis and the National Institute for Health Research Clinical Research Network: Children.

Tocilizumab in patients with anti-TNF refractory juvenile idiopathic arthritis-associated uveitis (APTITUDE): a multicentre, single-arm, phase 2 trial.

Objectives To assess the efficacy and safety of adalimumab on uveitis in patients with early onset, chronic, juvenile idiopathic arthritis (JIA)-associated or idiopathic anterior uveitis and an inadequate response to topical steroids and methotrexate (MTX). Methods Patients aged 4 years or more with ocular inflammation quantified by laser flare photometry (LFP) ≥30 photon units/ms were double-blindly randomised (1:1) to 2 groups, one treated with placebo and one with adalimumab subcutaneously at a dose of 24 mg/m 2 in patients aged Results At M2, among 31 patients included in intention-to-treat analysis, there were 9/16 responders on adalimumab and 3/15 on placebo (P=0.038, Χ 2 test; relative risk=2.81, 95% CI 0.94 to 8.45; risk difference: 36.3%, 95% CI 2.1 to 60.6); there was no significant difference using the Standardised Uveitis Nomenclature classification criteria of improvement. Thirty patients continued the trial after M2 and received adalimumab (open-label phase), 29 reached M12. There were seven serious adverse events none related to study treatment. Conclusions This trial is in favour of using adalimumab in patients with early onset, chronic anterior uveitis, which is in most cases associated with JIA, in case of inadequate response to topical therapy and MTX. LFP could be a valuable tool to assess early treatment efficacy. Trial registration number NCT01385826.

https://ard.bmj.com/content/annrheumdis/early/2017/12/23/annrheumdis-2017-212089.full.pdf

ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis

https://hal-ensta-bretagne.archives-ouvertes.fr/hal-01560817/document

A global optimization approach to H infinity synthesis with parametric uncertainties applied to AUV control

This paper presents a global optimization approach to the structured H ∞ sensitivity problem. The problem is formulated as a min/max optimization problem, and is solved with a branch and bound algorithm based on interval arithmetic. The method is compared with other existing H ∞ synthesis methods and results are discussed.

https://hal.archives-ouvertes.fr/hal-01416977/document

A global optimization approach to structured regulation design under H ∞ constraints.

The viability kernel corresponds to the set of all state vectors of a controlled dynamic system that are viable, i.e., such that there exists an input such that the system will not enter inside a forbidden zone. In this paper, we propose a method which computes an inner and an outer approximation of the viability kernel in a guaranteed way. Our method is based on interval analysis and uses the notions of V-viability and capture basin. We illustrate our approach on the car on the hill problem. A software package has been developed to solve any 2D-problem.

https://hal.archives-ouvertes.fr/hal-01366752/document

Computing an Inner and an Outer Approximation of the Viability Kernel

In this paper, a new technique to compute a synthesis structured Robust Control Law is developed. This technique is based on global optimization methods using a Branch-and-Bound algorithm. The original problem is reformulated as a min/max problem with non-convex constraint. Our approach uses interval arithmetic to compute bounds and accelerate the convergence.

https://hal.archives-ouvertes.fr/hal-01236171/document

Dominique Monnet

Papers

ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis

A global optimization approach to H infinity synthesis with parametric uncertainties applied to AUV control

A global optimization approach to structured regulation design under H ∞ constraints.

Computing an Inner and an Outer Approximation of the Viability Kernel

Global Optimization of $$H_\infty $$ Problems: Application to Robust Control Synthesis Under Structural Constraints