Non-Infectious Pediatric Uveitis

Sharma, Srilakshmi M; Dick, Andrew D.; Ramanan, Athimalaipet V

doi:10.2165/00148581-200911040-00002

Cited by 27 publications

(7 citation statements)

References 112 publications

(111 reference statements)

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“…Neither ciclosporin nor mycophenolate mofetil is very effective in controlling joint manifestations of JIA in children. 19 More recently, animal models and corroborative human evidence 23 support the role of tumour necrosis factor alpha (TNF-α) in the aetiopathogenesis of uveitis and, moreover, the potential value of its inhibition as a therapeutic intervention. 24 Studies on experimental models of autoimmune uveitis have demonstrated that TNF-α plays a pivotal role in pathogenesis of intraocular inflammation, 23 which has been borne out in treatment of adult uveitis.…”

Section: Rationale For Researchmentioning

confidence: 95%

“…Despite the scarce evidence, MTX has become the mainstay of treatment for JIA-uveitis. 19 However, up to 15-50% of children will have refractory uveitis in spite of optimal therapy with MTX. [16][17][18] In a small study, 20 some 30% of patients started on MTX for JIA-associated uveitis did not achieve disease control during the first year of therapy and, even when remission was achieved with MTX, nearly 70% of patients will later relapse, suggesting that only 4 out of 22 (18%) patients achieved total remission.…”

Section: Rationale For Researchmentioning

confidence: 99%

See 1 more Smart Citation

Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT

Ramanan

Dick

Jones

et al. 2019

Health Technol Assess

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Background Children with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira®; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined. Objective To compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA. Design This was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost–utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out. Setting The setting was tertiary care centres throughout the UK. Participants Patients aged 2–18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks). Interventions All participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months. Main outcome measures Primary outcome – time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome – incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol. Results A total of 90 participants were randomised (adalimumab, n = 60; placebo, n = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events. Conclusions Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold. Future work A clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified. Trial registration Current Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 15. See the NIHR Journals Library website for further project information. This trial was also funded by Arthritis Research UK (grant reference number 19612). Two strengths of adalimumab (20 mg/0.8 ml and 40 mg/0.8 ml) and a matching placebo were manufactured by AbbVie Inc. (the Marketing Authorisation holder) and supplied in bulk to the contracted distributor (Sharp Clinical Services, Crickhowell, UK) for distribution to trial centres.

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Section: Rationale For Researchmentioning

confidence: 95%

Section: Rationale For Researchmentioning

confidence: 99%

Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT

Ramanan

Dick

Jones

et al. 2019

Health Technol Assess

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“…Systematic review of the evidence for the effectiveness of MTX in JIA patients is restricted to joint involvement [14], but not in paediatric uveitis. Despite the scarce evidence, MTX has become the mainstay of treatment for JIA-associated uveitis [19]. However, about 15% to 50% of affected children will have refractory uveitis in spite of optimal therapy with MTX [16-18].…”

Section: Introductionmentioning

confidence: 99%

“…However, their use remains restricted because of intolerability due to adverse reactions and little evidence that they rescue MTX-refractory patients. In addition, neither ciclosporin nor MMF is very effective in controlling joint manifestations in children [19]. More recently, animal models and corroborative human evidence [23] support the role of tumour necrosis factor α (TNF-α) in the aetiopathogenesis of uveitis and, moreover, the potential value of inhibiting TNF-α as a therapeutic intervention [24].…”

Section: Introductionmentioning

confidence: 99%

A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial)

Ramanan

Dick

Benton

et al. 2014

Trials

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BackgroundJuvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy.Methods/designThis study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients <30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks.DiscussionThis is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis.Trial registrationISRCTN10065623

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“…If corticosteroids revamped the treatment of intraocular inflammation in the early 1950s, immunosuppression has ushered in a new era of therapy for patients with severe intraocular inflammation and now with targeted therapy using biologics in specific uveitic entities we are probably embarking on much specialised stratified care. [45121819202122]…”

Section: Current and Potential ‘Tailored’ Treatment Of Non-infectiousmentioning

confidence: 99%

Cytokines and Biologics in non-infectious autoimmune uveitis: Bench to Bedside

Agrawal

Iyer

Connolly

et al. 2014

Indian J Ophthalmol

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Intraocular inflammatory eye disease is one of the important causes of ocular morbidity. Even though the prevalence of uveitis is less common in relation to diabetic retinopathy, glaucoma or age related macular degeneration, the complexity and heterogeneity of the disease makes it more unique. Putative uveitogenic retinal antigens incite innate immunity by the process of antigen mimicry and have been shown to be associated in patients with intraocular inflammatory disease by numerous experimental studies. Laboratory diagnostic tools to aid the etiologic association in intraocular inflammatory disease have evolved over the last two decades and we are entering into an era of molecular diagnostic tests. Sophisticated novel technologies such as multiplex bead assays to assess biological signatures have revolutionized the management of complex refractory uveitis. Nevertheless, there is still a long way to go to establish the causal relationship between these biomarkers and specific uveitic entities. Experimental studies have shown the supreme role of infliximab in the management of Behcet's disease. Despite significant experimental and case control studies, the deficiency of randomized clinical trials using these biologic agents has handicapped us in exploring them as a front line therapy in severe refractory uveitis. Studies still need to answer the safety of these potentially life threatening drugs in a selected group of patients and determine when to commence and for how long the treatment has to be given. This review article covers some basic concepts of cytokines in uveitis and their potential application for therapy in refractory uveitis.

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Non-Infectious Pediatric Uveitis

Cited by 27 publications

References 112 publications

Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT

Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT

A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial)

Cytokines and Biologics in non-infectious autoimmune uveitis: Bench to Bedside

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