Juvenile idiopathic arthritis-associated uveitis (JIAU) typically takes a chronic course, frequently leading to ocular complications and often requiring long-term treatment. The present study assesses the 5-years outcome of JIAU by analyzing data from a prospective study initiated in 2010.

Data from 75 patients with onset of uveitis after study enrollment, and with a documentation at 5-years follow-up (5yFU) were available for analysis of uveitis characteristics, frequency and predictors of "inactivity on medication " (defined as inactive uveitis for ≥ 6 months) and "inactivity off medication " (defined as inactive uveitis for ≥ 6 months off medication).

At the 5yFU, visual acuity remained good in the majority of eyes (LogMAR < 0.1 in 65.5%; mean LogMAR 0.11 ± 0.31), ocular surgery was required in only 5% of patients, although complications occurred in 46.7% of patients until the 5yFU. Uveitis was inactive in 85.3% of patients, with 77.3% still receiving disease-modifying antirheumatic drugs (DMARDs). Until 5yFU, 82.7% of patients experienced ≥ one episode of "inactivity on medication " (30.7% once, 37.3% twice, 14.7% three or more times), and 17.3% ≥ one episode of "inactivity off medication ", respectively. Both "inactivity on medication " as well as "inactivity off medication " were associated with lower JIA disease activity (cJADAS10; ESR), and with an increased quality of life.

Despite intensified DMARD treatment, almost half of the children experience JIAU-related ocular complications after 5 years of disease; however, visual acuity mostly remains good. Uveitis inactivity can be achieved frequently, but is often limited in duration. Lower JIA activity appears to correlate with uveitis inactivity on and off medication.

We evaluated the impact of an Ophthalmology/Rheumatology multidisciplinary clinic for patients with anterior uveitis by comparing outcomes between those who received traditional care (TC) versus coordinated care (CC).

We conducted a retrospective cohort study of children with anterior uveitis from a pediatric tertiary care center between 2013 and 2022. Standard descriptive statistics were used; survival analyses explored differences in cohort disease activity and biologic disease-modifying antirheumatic drug (DMARD) treatment. Steroid treatment by cohort was compared using generalized estimating equation model with Poisson distribution and log link. Complications were compared using logistic regression. Number of visits in each cohort were assessed using Poisson generalized estimating equation model adjusted for complications.

We studied 215 patients with anterior uveitis; 66% were female, 53% had juvenile idiopathic arthritis, and 23% were idiopathic, with a median age at diagnosis of 8 years old (interquartile range 5-12). CC was associated with a 60% higher hazard of reaching disease control (hazard ratio 1.6; P < 0.01) when controlling for time since diagnosis and anterior chamber cell counts at the beginning of disease activity. CC was associated with starting biologic DMARDs earlier than TC (P < 0.01). Compared with the group who received TC, the group who received CC had a 96% lower rate of glucocorticoid reception per appointment within the first year (P < 0.01). The visit rate was 64% lower for the group who received CC when controlling for total complications per patient.

Patients who received multidisciplinary care had better outcomes than patients who received TC. Limitations include different cohort start times and absence of defined criteria for CC referral.

Juvenile Idiopathic Arthritis (JIA) can affect ocular structures, but choroidal involvement is not well understood. This study investigates the Choroidal Vascularity Index (CVI) in JIA patients compared to healthy controls and explores its relationship with disease activity.

In this cross-sectional study, 35 JIA patients and 40 healthy controls underwent comprehensive ophthalmic examination and swept-source optical coherence tomography (SS-OCT). CVI, central macular thickness (CMT), and subfoveal choroidal thickness (SFCT) were measured. The Juvenile Arthritis Disease Activity Score (JADAS) was calculated for JIA patients. Statistical analysis included comparison between groups and correlation analysis.

JIA patients showed significantly lower CVI compared to controls (68.3 ± 2.5% vs. 72 ± 4.6%, p < 0.001). No significant difference was found in SFCT. CVI demonstrated a moderate negative correlation with JADAS (r = -0.368, p < 0.05). However, receiver operating characteristic (ROC) analysis revealed poor diagnostic performance of CVI for detecting JIA (AUC = 0.25).

The study reveals reduced choroidal vascularity in JIA patients and a correlation between CVI and disease activity. While CVI shows limited diagnostic utility, it may serve as a potential marker for monitoring inflammatory burden and treatment response in JIA. Further research is needed to establish its clinical utility fully.

To investigate clinical features associated with lack of response to MTX in juvenile idiopathic arthritis associated uveitis (JIA-U).

Clinical records of JIA-U patients were retrospectively reviewed. Differences among variables were assessed by Mann-Whitney and χ2 or Fisher's exact tests as appropriate. Association between predictors and requirement of a biological disease-modifying antirheumatic drug (bDMARD) was evaluated by univariate Cox regression analysis and Kaplan-Meier curves. A multivariable logistic model was applied to estimate strength of association, adjusting for potential confounders.

Data from 99 JIA-U patients treated with MTX were analysed (82.8% female), with a mean follow up of 9.2 years and a mean age at uveitis onset of 5.7 years. In 65 patients (65.7%) at least one bDMARD to control uveitis was required. Children requiring a bDMARD for uveitis had lower age at JIA and uveitis onset, more frequent polyarticular course, higher frequency of bilateral uveitis at onset and higher prevalence of systemic steroids' use. Despite similar frequency of ocular damage at onset, MTX non-responders showed a higher percentage of ocular damage at last visit. Younger age at JIA onset, polyarticular course and a history of systemic steroids' use resulted independent factors associated to lack of response to MTX at Cox regression analysis. Kaplan-Meier curves and the multivariate model confirm the independent role of both polyarticular course and systemic steroids' use.

Younger age at JIA onset, polyarticular course and a history of systemic steroids' use are predictors of a worse response to MTX in JIA-U.

Adalimumab is an effective treatment for juvenile idiopathic arthritis-associated uveitis. Data are scarce on the effects of discontinuing adalimumab after control of the disease had been reached. We aimed to assess efficacy and safety of discontinuing treatment in patients with juvenile idiopathic arthritis-associated uveitis.

We conducted a multicentre, double-masked, randomised, placebo-controlled trial at 20 ophthalmology and rheumatology clinics across the USA, the UK, and Australia. Patients aged at least 2 years who had controlled arthritis and uveitis for at least 1 year on adalimumab were randomly assigned in a 1:1 ratio using a web-based system to receive adalimumab or placebo, administered subcutaneously every 2 weeks until the 48-week visit or treatment failure. The primary outcome was the time to treatment failure, defined by recurrence of uveitis or arthritis; all participants were included in the primary and safety analysis. Unmasking occurred at treatment failure, and patients were offered open-label adalimumab through 48 weeks of follow-up. This trial was registered with ClinicalTrials.gov (NCT03816397).

87 patients were enrolled from March 3, 2020, to Feb 14, 2024, whereafter the prespecified interim stopping criteria were met and enrolment was stopped. One patient in each group dropped out but data were included in analyses. Six (14%) of 43 patients in the adalimumab group and 30 (68%) of 44 patients in the placebo group had treatment failure (hazard ratio 8·7, 95% CI 3·6-21·2; p<0·0001). The median time to treatment failure in the placebo group was 119 days (IQR 84-243). The median time to re-establishing sustained control of inflammation in the placebo group after restarting adalimumab was 105 days (63-196). 226 non-serious adverse events occurred in the adalimumab group (7·5 events per person-year, 95% CI 6·5-8·5), and 115 non-serious adverse events occurred in the placebo group (6·8 events per person-year, 5·6-8·1). Four serious adverse events were reported, all in the adalimumab group.

Discontinuing adalimumab led to higher rates of recurrence of uveitis, arthritis, or both in patients with previously controlled juvenile idiopathic arthritis-associated uveitis. However, all patients who had treatment failure successfully regained control of inflammation by the end of the 48-week study period after restarting adalimumab.

US National Institutes of Health (National Eye Institute).

This study aimed to identify the clinical characteristics of cases that is related to the response rate of adalimumab (ADA) treatment.

A retrospective review of medical records was conducted for pediatric patients with non-infectious uveitis undergoing ADA treatment for a minimum of six months. The patients were stratified into two groups: those with anterior segment inflammation (ASI+) and those without anterior segment inflammation (ASI-). The primary outcome was treatment success rate. Secondary outcomes including best-corrected visual acuity (BCVA), inflammation parameters [anterior chamber cell (ACC), vitreous haze (VH)], retinal nerve fiber layer (RNFL) thickness, fluorescein angiography (FA) scores, as well as systemic immunosuppression therapy (IMT) and glucocorticoid load, were assessed.

The study included 59 patients (111 eyes), with 44 patients (83 eyes, 74.58%) falling into the ASI + group and 15 patients (28 eyes, 25.42%) in the ASI- group. The treatment success rate in the ASI + group was significantly higher than in ASI- patients (93.18% vs. 20%, p < 0.001). Following 6-month of ADA treatment in the ASI + group, there was a significant improvement in BCVA (p < 0.001), inflammation parameters (p < 0.001), reduced RNFL thickness and reduced FA scores (p < 0.001). Conversely, no significant differences were observed in BCVA, inflammation parameters, RNFL thickness and FA scores in the ASI- group. There was also a significant decrease in systemic IMT and glucocorticoid dosing, comparing baseline to the 6-month follow-up visit in both the ASI+ (p < 0.001) and ASI- groups (p < 0.05). Adverse events observed during the study period included abdominal pain, skin erythema, articular symptoms and respiratory infections.

ADA demonstrates superior efficacy in the treating pediatric non-infectious uveitis with ASI + compared to ASI-.

We presented the development of a consensus guideline for managing juvenile idiopathic arthritis-associated uveitis (JIAU) in Taiwan, considering regional differences in manifestation and epidemiology. The Taiwan Ocular Inflammation Society (TOIS) committee formulated this guideline using a modified Delphi approach with two panel meetings. Recommendations were based on a comprehensive evidence-based literature review and expert clinical experiences, and were graded according to the Oxford Centre for Evidence-Based Medicine's "Levels of Evidence" guideline (March 2009). The TOIS consensus guideline consists of 10 recommendations in four categories: screening and diagnosis, treatment, complications, and monitoring, covering a total of 27 items. These recommendations received over 75% agreement from the panelists. Early diagnosis and a coordinated referral system between ophthalmologists and pediatric rheumatologists are crucial to prevent irreversible visual impairment in children with JIAU. However, achieving a balance between disease activity and medication use remains a key challenge in JIAU management, necessitating further clinical studies.

The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs).

The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM.

Four bDMARD CTPs were proposed: tumor necrosis factor α (TNFα) inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow-up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab.

CTPs for the administration of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.

Chronic anterior uveitis (CAU) carries a significant risk for eye complications and vision loss. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) introduced consensus treatment plans (CTPs) to standardize treatment for CAU and facilitate future comparative effectiveness studies. Two CTPs were developed to address: 1) initiation of methotrexate (MTX) in patients with CAU naïve to steroid-sparing therapy, and 2) initiation of a TNF inhibitor (TNFi) in patients with severe uveitis or uveitis refractory to MTX. We evaluated implementation of the uveitis CTPs using existing CARRA Registry infrastructure and assessed feasibility of the CTPs for comparative effectiveness research.

This prospective observational cohort study was conducted at nine pilot sites between February 2020 and August 2022. Patients with JIA-associated CAU (JIA-U) were treated according to either the MTX or TNFi CTP. Uveitis activity and medication use were recorded at 0, 3, and 6 months. We assessed patient enrollment rates, CTP arm selection, uveitis control, and quality of data collection. We also evaluated CTP arm selection in a retrospective cohort of similar JIA-U patients enrolled in the CARRA Registry during the same study period.

Seventeen patients were included in the pilot cohort. Eight were treated with the MTX CTP (4 oral MTX, 4 subcutaneous MTX), and 9 with the TNFi CTP (9 received standard-dose adalimumab, none selected high-dose adalimumab or infliximab). Uveitis was controlled in 13 of 17 patients by 6 months. Query of the CARRA-wide Registry identified 42 patients with JIA-U who were treated according to the MTX or TNFi CTPs. Among these, 26 were treated with MTX (8 oral, 18 subcutaneous) and 16 with TNFi (12 standard dose adalimumab, 2 high dose adalimumab, and 2 infliximab).

Both the MTX and TNFi uveitis CTPs can practically be implemented in clinical settings and are currently being utilized across Registry sites. However, in patients starting TNFi therapy, all pilot study participants and most patients across the CARRA Registry were treated with a standard dose of adalimumab. This consensus on the treatment approach underscores its broad acceptance but also limits the applicability of the uveitis TNFi CTP for comparative effectiveness research.

Non-infectious uveitis (NIU) is an immune-mediated disorder manifesting as ocular pain, redness, floaters, and photophobia, and is a leading cause of preventable blindness. Managing NIU presents considerable challenges due to the condition's resistance to high-dose corticosteroids and various immunotherapies. This review assesses the efficacy and safety of rituximab (RTX) in the treatment of NIU, based on individual case reports and small-scale studies. A cohort of 78 patients (20 males, 58 females), with a mean onset age of 32.3 years (range 8-72), was analyzed. Juvenile idiopathic arthritis (JIA) was the most frequently associated comorbidity, affecting 28 patients, while anterior uveitis was the predominant subtype, observed in 26 of 47 cases. Prior to RTX therapy, patients had been treated with an average of 1.7 conventional immunosuppressive agents (range 0-5) and 1.1 biologics (range 0-4). RTX was introduced following the failure of high-dose corticosteroids, immunosuppressive drugs, and biologics to control the uveitis. The median time from diagnosis to RTX initiation was 7.7 years (range 0.25-21). Post-RTX, 44.2% of patients experienced improvement in visual acuity, 79.5% achieved resolution of ocular inflammation, and 8.9% showed partial improvement. Additionally, 81.1% were able to reduce their corticosteroid dosage. Overall, 88.6% (69 out of 78) demonstrated a positive response to RTX treatment. These findings indicate that RTX may serve as an effective therapeutic option for NIU unresponsive to steroids and multiple immunotherapies. It may also warrant consideration as a potential first-line treatment in certain cases.

We aimed to present the demographic, clinical, laboratory, and treatment data of children with non-infectious uveitis and to evaluate the risk factors for the development of complications and the need for biological treatment.

Patients diagnosed with non-infectious uveitis in childhood and followed up for at least 1 year were included in the study. Demographic data, including age, gender, age at diagnosis, uveitis in first-degree relatives, and rheumatologic diseases, were obtained retrospectively from medical records. The presence of complications or the need for biologic therapy was considered a composite outcome suggesting severe disease.

The study included 123 patients (female: n = 59, 48%). The mean age at diagnosis was 14.89 ± 4.86 years. Uveitis was symptomatic in 104 patients (84.6%). Approximately one-quarter of the patients had at least one rheumatic disease (n = 35, 28.5%), the most common being juvenile idiopathic arthritis. Thirty-three patients (26.8%) had anti-nuclear antibody positivity. Biologic agents were needed in 60 patients (48.8%). Complications developed in 14 patients (11.4%). Early age at disease onset (aOR, 0.875; 95% C.I. 0.795-0.965, p = 0.007) and female gender (aOR, 2.99; 95% C.I. 1.439-6.248, p = 0.003) were significantly associated with the need for biologic treatment, while Behçet's disease (BD) was strongly associated with uveitis-related complications (aOR, 14.133; 95% C.I. 2.765-72.231, p = 0.001).

We suggest that among pediatric patients with non-infectious uveitis, females, those with an early age of disease onset, and those with BD need to be closely monitored due to a significantly increased risk of severe disease. Key Points • Limited data exist on the clinical course of non-infectious uveitis in children and the associated risk factors for severe disease. • Our study reveals that nearly a quarter of pediatric patients with non-infectious uveitis also have a rheumatic disease. • Among pediatric patients diagnosed with non-infectious uveitis, we observed an increased risk of severe disease in those with an earlier onset age, in female patients, and in those diagnosed with Behçet's disease.

Pediatric uveitis poses challenges in diagnosis and treatment due to asymptomatic or oligosymptomatic presentations and high rates of intraocular complications.

This study aimed to characterize clinical manifestations and treatment approaches of pediatric uveitis patients in a northern Portuguese tertiary hospital.

A retrospective study was conducted involving 41 patients diagnosed with uveitis between 2006 and 2021. All individuals identified by the Opthalmology department were referred to Pediatric Rheumatology outpatient clinic. Demographic, clinical, treatment, and intraocular complications data were collected.

Of the patients, 78% had anterior uveitis, 17% had panuveitis, and 5% had intermediate uveitis. Uveitis associated with juvenile idiopathic arthritis (JIA) was the most common cause (43.9%), predominantly in the oligoarticular, anti-nuclear antibody-positive subgroup. Complications were identified in 80.5% of the patients. Uveitis associated with JIA was diagnosed earlier [5.0 years (3.0-10.5) vs. 9.0 years (5.5-14.0), P = .036], more frequently in asymptomatic patients (71% vs. 23%, P = .010), had a more insidious installation (71% vs. 17%, P = .004), and required more tumor necrosis factor (TNF) inhibitor treatment (70% vs. 39%, P = .027).

The high rates of intraocular complications and systemic pathology association highlight the need for a combined approach of ophthalmology and pediatric rheumatology in the diagnosis and treatment of pediatric uveitis.

Adalimumab has demonstrated efficacy in non-infectious uveitis. With the introduction of biosimilar agents such as Amgevita, we aimed to quantify efficacy and tolerability compared to Humira in a multi-centre UK cohort.

Patients identified from tertiary uveitis clinics in 3 centres, after institution-mandated switching was implemented.

Data collected for 102 patients, aged 2-75 years, with 185 active eyes. Following switch, rates of uveitis flare were not significantly different (13 events before, 21 after, p = .132). Rates of elevated intraocular pressure were decreased (32 before, 25 afterwards, p = .006) and dosing of oral and intra-ocular steroids was stable. Twenty-four patients (24%) requested to return to Humira, commonly due to pain from injection or technical difficulty with the device.

Amgevita is safe and effective for inflammatory uveitis with non-inferiority to Humira. Significant numbers of patients requested to switch back due to side effects including injection site reactions.

Since many biological drug patents have expired, biosimilar agents (BIOs) have been developed; however, there are still some reservations in their use, especially in childhood. The aim of the current study is to evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibitors BIOs as treatment for pediatric non-infectious uveitis (NIU).

Data from pediatric patients with NIU treated with TNF inhibitors BIOs were drawn from the international AutoInflammatory Disease Alliance (AIDA) registries dedicated to uveitis and Behçet's disease. The effectiveness and safety of BIOs were assessed in terms of frequency of relapses, risk for developing ocular flares, best-corrected visual acuity (BCVA), glucocorticoids (GCs)-sparing effect, drug survival, frequency of ocular complications, and adverse drug event (AE).

Forty-seven patients (77 affected eyes) were enrolled. The BIOs employed were adalimumab (ADA) (89.4%), etanercept (ETA) (5.3%), and infliximab (IFX) (5.3%). The number of relapses 12 months prior to BIOs and at last follow-up was 282.14 and 52.43 per 100 patients/year. The relative risk of developing ocular flares before BIOs introduction compared to the period following the start of BIOs was 4.49 (95% confidence interval [CI] 3.38-5.98, p = 0.004). The number needed to treat (NNT) for ocular flares was 3.53. Median BCVA was maintained during the whole BIOs treatment (p = 0.92). A significant GCs-sparing effect was observed throughout the treatment period (p = 0.002). The estimated drug retention rate (DRR) at 12-, 24-, and 36-month follow-up were 92.7, 83.3, and 70.8%, respectively. The risk rate for developing structural ocular complications was 89.9/100 patients/year before starting BIOs and 12.7/100 patients/year during BIOs treatment, with a risk ratio of new ocular complications without BIOs of 7.1 (CI 3.4-14.9, p = 0.0003). Three minor AEs were reported.

TNF inhibitors BIOs are effective in reducing the number of ocular uveitis relapses, preserving visual acuity, allowing a significant GCs-sparing effect, and preventing structural ocular complications.

ClinicalTrials.gov ID NCT05200715.

The management of refractory juvenile idiopathic associated uveitis (JIAU) or childhood-onset chronic anterior uveitis (CAU) is a challenge. There is no clear consensus or evidence base for to suggest the most appropriate therapy after primary or secondary failure of biweekly adalimumab. In this scenario, most clinicians advocate switching to another anti-tumor necrosis factor alpha inhibitor; however, there are a variety of other disease modifying agents to choose from albeit with a differing levels of evidence.

We discuss how to define nonresponse and potential treatment options for patients with JIAU and CAU refractory to biweekly adalimumab.

Uncontrolled CAU and JIAU remain one of the most challenging diseases to manage and can lead to irreversible loss of vision in a third of those affected. Amongst the possible choices, weekly adalimumab, infliximab, tocilizumab and abatacept have more evidence to support their use. JAK inhibitors seem to be a promising option. Golimumab and Rituximab has also been thought to be partially effective in some refractory cases, whereas IL-17, IL-23, and IL-12 inhibition along with apremilast seem not to be a therapeutic option currently. The route of administration should also be considered as there can be significant pros and cons for different children.

Noninfectious uveitis (NIU) in children and adolescents is a rare but treatable cause of visual impairment in children. Treatments for pediatric NIU and their side effects, along with the risks of vision loss and the need for long-term disease monitoring, pose significant challenges for young patients and their families. Treatment includes local and systemic approaches and this review will focus on systemic therapies that encompass corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARD), and biological disease-modifying antirheumatic drugs (bDMARD). Treatment is generally planned in a stepwise approach. Methotrexate is well-established as the preferential csDMARD in pediatric NIU. Adalimumab, an antitumor necrosis factor (TNF) agent, is the only bDMARD formally approved for pediatric NIU and has a good safety and efficacy profile. Biosimilars are gaining increasing visibility in the treatment of pediatric NIU. Other bDMARD with some evidence in literature for the treatment of pediatric NIU include infliximab, tocilizumab, abatacept, rituximab and, more recently, Janus kinase inhibitors. Important aspects of managing children on these systemic therapies include vaccination issues, risk of infection, and psychological distress. Also, strategies need to address regarding primary nonresponse/secondary loss of response to anti-TNF treatment, biological switching, and monitoring regimens for these drugs. Optimal management of pediatric uveitis involves a multidisciplinary team, including specialist pediatric uveitis and rheumatology nurses, pediatric rheumatologists, psychological support, orthoptic and optometry support, and play specialists.

Juvenile idiopathic arthritis (JIA) is the most common cause of uveitis in children. While symptoms are usually mild, persistent eye inflammation could lead to severe complications and impaired vision. It is essential that JIA patients at risk are diagnosed with uveitis early, receive adequate treatment, and avoid developing complications, such as cataract, glaucoma, and amblyopia. The purpose of this mini-review is to summarize the screening strategies and clinical management for JIA-associated uveitis (JIA-U) as well as the current state of molecular markers linked to this condition. Because glaucoma is one of the most common causes of visual loss in JIA-U, special focus will be put on this serious complication. We conclude by describing the current evidence regarding the long-standing question of whether chronic anterior uveitis without arthritis may be the same disease entity as JIA-U.

Non-infectious chronic anterior uveitis (CAU) remains a therapeutic challenge. The purpose of this study was to analyze the effectiveness and safety of weekly dosing of adalimumab in children with non-infectious refractory CAU. Methods: Demographic and clinical data of children followed by non-infectious CAU treated with adalimumab were retrospectively reviewed.

Of the 42 children with CAU, 27/42 (64.3%) were treated with adalimumab. Escalation to weekly dosing of adalimumab was necessary for 11/27 children (40.7%). After 3 and 6 months, 7/11 children (63.6%) met the composite endpoint of inflammation control improvement. Children requiring weekly adalimumab had initially more severe uveitis: anterior chamber cells (p = 0.02), aqueous flare (p = 0.02), and presence of macular edema (p = 0.007). No children had serious systemic side effects.

Weekly adalimumab in children with refractory CAU appears to be an effective and safe treatment for inflammation control and corticosteroid sparing, and an alternative before biologic switching. Controlled studies are needed.

Sarcoidosis is a multi-system granulomatous disease that often presents with uveitis. Although sarcoidosis and sarcoid uveitis typically occur in adulthood, children also may be affected. There are two distinct clinical presentations of the pediatric disease, associated with younger and older age groups, and having different causations. "Early-onset sarcoidosis", beginning at age 5 years or less, is an autosomal dominant genetic disease, caused by a mutation in the NOD2 gene. It is also known as sporadic Blau syndrome or Jabs syndrome. "Adult-type sarcoidosis", usually beginning between the ages of 8 and 15 years, is believed to represent an excessive response to an environmental antigen. There is limited literature on the management of pediatric sarcoidosis, and treatment follows an approach applied to other forms of pediatric non-infectious uveitis. When systemic immunomodulatory therapy is indicated, methotrexate and/or adalimumab are often employed. The condition may persist into adulthood, and thus long-term follow-up is indicated.

To describe the effectiveness of leflunomide as adjunctive therapy with anti-tumor necrosis factor (anti-TNF) agents in pediatric patients with uveitis who are not able to tolerate methotrexate.

A retrospective case series was performed of pediatric patients who were receiving leflunomide in conjunction with anti-TNF agent therapy after intolerance to a combination of methotrexate with anti-TNF therapy. Dose and duration of methotrexate, leflunomide, and anti-TNF therapy were recorded. Extensive history, demographics, laboratory data, and uveitis flare rate were obtained.

A total of five children were included in the study. Most patients were initially receiving methotrexate and an anti-TNF agent was added subsequently due to inadequate response to monotherapy. After discontinuation of methotrexate, leflunomide was initiated with anti-TNF therapy. The replacement of methotrexate with leflunomide showed decreased side effects and was associated with lower flare rates and steroid-free remission.

Leflunomide was found to be well tolerated and effective at maintaining uveitis quiescence in conjunction with anti-TNF agents in pediatric patients who do not tolerate methotrexate. [J Pediatr Ophthalmol Strabismus. 2023;60(6):417-420.].

Prompt escalation to tumor necrosis factor inhibitors (TNFis) is recommended for children with juvenile idiopathic arthritis (JIA) and ongoing disease activity despite treatment with conventional disease-modifying antirheumatic drugs (cDMARDs). It is unknown whether these recommendations are equitably followed for children with different insurance types. We assessed the association of insurance coverage on the odds and timing of TNFi use.

We conducted a retrospective study of children with newly diagnosed JIA in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. We compared the odds of starting a TNFi in the first year and time from cDMARD to TNFi initiation between those with public and private insurance.

We identified 1086 children with new JIA diagnoses. Publicly insured children had significantly higher active joint counts and parent/patient global assessment scores at the enrollment visit. They were also more likely to have polyarticular arthritis compared to those with private insurance. Odds of any TNFi use in the first year did not differ between publicly and privately insured children. Publicly insured children were escalated from cDMARD to TNFi more quickly than privately insured children.

Children who were publicly insured had more severe disease and polyarticular involvement at registry enrollment compared to those who were privately insured. Whereas overall TNFi use did not differ between children with different insurance types, publicly insured children were escalated more quickly, consistent with their increased disease severity. Further research is needed to determine why insurance coverage type is associated with disease severity, including how other socioeconomic factors affect presentation to care.

Uveitis in childhood poses a distinct challenge, mainly because of the insidious onset and chronic course of intraocular inflammation in most cases, which may result in permanent visual loss due to delayed diagnosis and treatment. Although anterior uveitis, frequently associated with juvenile idiopathic arthritis, is the most common form of ocular involvement, idiopathic intermediate uveitis (pars planitis) is also a common uveitic entity in childhood. Posterior or panuveitis of a variety of noninfectious or infectious etiologies may be seen as well. Pediatric uveitis needs to be closely monitored since serious ocular complications such as intraocular pressure elevation, cataract, and macular edema may rapidly develop due to inadequately controlled inflammation and/or the use of corticosteroids. Methotrexate is generally the first- line corticosteroid-sparing agent, and adalimumab is the first-line biologic in refractory cases of noninfectious uveitis. A multidisciplinary approach is essential to monitor systemic disease associations, treatment response, and adverse events in children with uveitis.

To evaluate the efficacy of levofolinic acid (LVF) administered 48 h before methotrexate (MTX) in reducing gastrointestinal side effects without interference with drug efficacy.

A prospective observational study was performed including patients with Juvenile Idiopathic Arthritis (JIA) reporting significant gastrointestinal discomfort after MTX despite taking a dose of LVF 48 h after MTX. Patients with anticipatory symptoms were excluded. A LVF supplemental dose was added 48 h before MTX and patients were followed every 3-4 months. At each visit data on gastrointestinal symptoms, disease activity (JADAS, ESR, CRP values) and treatment changes were collected. Friedman test for repeated measures analyzed differences between these variables over time.

Twenty-one patients were recruited and followed for at least 12 months. All patients received MTX subcutaneously (mean 9.54 mg/m2) and LVF 48 h before and after MTX (mean 6.5 mg/dose), 7 received a biological agent too. Complete remission of gastrointestinal side effects was reported in 61.9% of study patients at first visit (T1) and increased over time (85.7%, 95.2%, 85.7% and 100% at T2, T3, T4, T5, respectively). MTX efficacy was maintained as showed by significant reduction of JADAS and CRP (p = 0.006 and 0.008) from T1 to T4 and it was withdrawn for remission in 7/21.

LVF given 48 h before MTX significantly reduced gastrointestinal side effects and did not reduce drug's efficacy. Our results suggest that this strategy may improve compliance and quality of life in patients with JIA and other rheumatic diseases treated with MTX.

To determine the dose-response relationship of tumor necrosis factor (TNF) inhibition in the treatment of juvenile idiopathic arthritis (JIA).

Participants of the Childhood Arthritis and Rheumatology Research Alliance Registry were eligible for inclusion in the analyses if they started TNF inhibition treatment for JIA. The primary treatment response was determined 3 to 7 months after the start of treatment, based on the JIA American College of Rheumatology Pediatric criteria for improvement, clinical Juvenile Arthritis Disease Activity Score, and persistence of treatment after 6 months. Subsequently, pooled logistic regression models were performed to include long-term follow-up data. The models were adjusted for risk factors associated with poor treatment response. Dosing was expressed by body weight, body surface area, ideal body weight, fat free mass, and lean body mass.

Participants treated with adalimumab (n = 328) and etanercept (n = 437) were included in the analyses (median dose 0.82 mg/kg body weight [interquartile range (IQR) 0.66-1.04] and 0.83 mg/kg body weight [IQR 0.75-0.95], respectively). The majority of analyses did not show a relationship between dose and outcome. Where associations were found, results were conflicting. Alternative dosing characteristics based on ideal body weight, fat free mass, and lean body mass did not result in stronger or more consistent associations.

This study was not able to confirm our hypothesis that increased dosing of TNF inhibitors results in improved treatment outcomes. Although adjustment was performed for risk factors of impaired treatment response, residual confounding by indication likely explains the negative associations found in this study.

A significant number of children with noninfectious, chronic anterior uveitis (CAU) fail to respond to conventional therapy; however, successful alternative biologic treatments (ABT) have not been well described. This study aims to review the clinical and treatment characteristics of children with CAU who require ABT.

Retrospective, nonrandomized clinical study.

Setting: Tertiary center.

Children with noninfectious CAU.

Clinical characteristics, uveitis course, complications, and treatment were compared among patients treated with methotrexate (MTX) monotherapy, conventional TNFα inhibitors (cTNFi), and ABT for >3 months.

Success of ABT (abatacept, tocilizumab, and/or golimumab) in children failing conventional treatment.

Of the 52 children with CAU, 75% had juvenile idiopathic arthritis. CAU was controlled in 15 children receiving MTX monotherapy, 28 receiving cTNFi, and 9 receiving ABT (n = 1, abatacept; n = 3, tocilizumab; n = 5, golimumab). Patients in the ABT group had a greater number of total ocular complications per person before ABT than those in the control groups (3.4 vs 0.7 [MTX], P < .001, and 1.5 [cTNFi], P < .001, respectively). In all 9 children on ABT, treatment led to control of CAU and topical glucocorticoids tapered to ≤2 drops/d with no new ocular complications.

In this study, alternative biologics (abatacept, golimumab, and tocilizumab) were useful for treating CAU in children who fail MTX and cTNFi therapy. Patients who were controlled on ABT had more disease activity, ocular complications, and anti-cTNFi neutralizing antibodies (before ABT) than those managed with conventional therapy. Larger studies are required to confirm these findings.

Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA) and a potentially sight-threatening condition characterized by intraocular inflammation. Current treatment for JIA-associated uveitis (JIA-U) is largely based on physician experience, observational evidence and consensus guidelines, resulting in considerable variations in practice.  OBJECTIVES: To evaluate the effectiveness and safety of tumor necrosis factor (TNF) inhibitors used for treatment of JIA-U.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We last searched the electronic databases on 3 February 2022.

We included randomized controlled trials (RCTs) comparing TNF inhibitors with placebo in participants with a diagnosis of JIA and uveitis who were aged 2 to 18 years old.

We used standard Cochrane methodology and graded the certainty of the body of evidence for seven outcomes using the GRADE classification.

We included three RCTs with 134 participants. One study conducted in the USA randomized participants to etanercept or placebo (N = 12). Two studies, one conducted in the UK (N = 90) and one in France (N = 32), randomized participants to adalimumab or placebo. All studies were at low risk of bias. Initial pooled estimates suggested that TNF-inhibitors may result in little to no difference on treatment success defined as 0 to trace cells on Standardization of Uveitis Nomenclature (SUN)-grading; or two-step decrease in activity based on SUN grading (estimated risk ratio (RR) 0.66; 95% confidence interval (CI) 0.21 to 2.10; 2 studies; 43 participants; low-certainty evidence) or treatment failure defined as a two-step increase in activity based on SUN grading (RR 0.31; 95% CI 0.01 to 7.15; 1 study; 31 participants; low-certainty evidence). Further analysis using the individual trial definitions of treatment response and failure suggested a positive treatment effect of TNF inhibitors; a RR of treatment success of 2.60 (95% CI 1.30 to 5.20; 3 studies; 124 participants; low-certainty evidence), and RR of treatment failure of 0.23 (95% CI 0.11 to 0.50; 3 studies; 133 participants). Almost all the evidence was on adalimumab and the evidence on etanercept was very limited.  For secondary outcomes, one study suggests that adalimumab may have little to no effect on risk of recurrence after induction of remission at three months (RR 2.50, 95% CI 0.31 to 20.45; 90 participants; very low-certainty evidence) and visual acuity, but the evidence is very uncertain; mean difference in longitudinal logMAR score change over six months was -0.01 (95% CI -0.06 to 0.03) and -0.02 (95% CI -0.07 to 0.03) using the best and worst logMAR measurement, respectively (low-certainty evidence). Low-certainty evidence from one study suggested that adalimumab treatment results in reduction of topical steroid doses at six months (hazard ratio 3.58; 95% CI 1.24 to 10.32; 74 participants who took one or more topical steroid per day at baseline). Adverse events, including injection site reactions and infections, were more common in the TNF inhibitor group. Serious adverse events were uncommon.

Adalimumab appears to increase the likelihood of treatment success and decrease the likelihood of treatment failure when compared with placebo. The evidence was less conclusive about a positive treatment effect with etanercept. Adverse events from JIA-U trials are in keeping with the known side effect profile of TNF inhibitors. Standard validated JIA-U outcome measures are required to homogenize assessment and to allow for comparison and analysis of multiple datasets.

Background: Treat to target (T2T) is a strategy that has been increasingly employed in the management of several chronic diseases, with demonstrated improved outcomes. The use of T2T in juvenile idiopathic arthritis (JIA), a common rheumatic disease of childhood, is still in its infancy, and the feasibility of its use in attaining drug-free clinical remission is unclear. Aims: We aim to explore the current literature of the use of T2T in JIA, and to review the potential benefits and limitations of this approach in regard to this chronic disease. Sources: A comprehensive PubMed search was conducted using relevant keywords, with full text articles in English included in the review. Content: T2T is an appealing strategy for improving outcomes of pediatric rheumatic diseases given the limited availability of therapeutics and potential cumulative effects of long-term immunosuppression. The application in a cohort of children, however, is limited by heterogeneity of disease, availability of high-quality evidence, and patient and parental preferences. Unlike adult rheumatoid arthritis, the 'window of opportunity' has not been definitively demonstrated in large scale trials, and although early studies of T2T in JIA have been favorable, the timing and means of escalation (especially with regard to biologics) need clarification. Implications: This review outlines several issues of implementing T2T in JIA, including the important extra-articular manifestations of disease and non-pharmacological management, that should be considered in future consensus guidelines.

The red eye is a common presenting complaint among patients. Although assessment may seem intimidating, clinicians who are mindful of the patient's anticipated history and physical examination findings should be able to accurately diagnose and manage common conditions, identify ocular emergencies, and expedite care.

Recent development of new medications has changed the juvenile idiopathic arthritis (JIA) treatment goal to inactive disease. With numerous options, how does a clinician choose which medication to use? Treatment options may depend on the clinical classification and a new paradigm considers the JIA subtypes in reference to categories of adult inflammatory arthritis; poligo JIA, spondyloarthritis JIA, and systemic JIA that can help guide a clinician in determining treatment options. Treatment strategies such as consensus treatment plans can provide guidance on treatment escalation. However, a treat-to-target strategy using frequent standardized disease activity measurements, shared decision making with the patient, and treatment escalation to achieve the disease activity target can provide a personalized approach to managing JIA.

Methotrexate (MTX) is included in the therapeutic armamentarium of Crohn's disease (CD), although its positioning is currently uncertain in an era in which many effective biological drugs are available. No systematic reviews or meta-analysis have stratified the clinical outcomes of MTX according to the specific clinical scenarios of its use.

Medline, PubMed and Scopus were used to extract eligible studies, from database inception to May 2021. A total of 163 studies were included. A systematic review was performed by stratifying the outcomes of MTX according to formulation, clinical indication and criteria of efficacy.

The use of MTX is supported by randomized clinical trials only in steroid-dependent CD, with similar outcomes to thiopurines. The use of MTX in patients with steroid-refractoriness, failure of thiopurines or in combination with biologics is not supported by high levels of evidence. Combination therapy with biologics can optimize the immunogenic profile of the biological drug, but the impact on long-term clinical outcomes is described only in small series with anti-TNFα. Other off-label uses, such as fistulizing disease, mucosal healing, postoperative prevention and extraintestinal manifestations, are described in small uncontrolled series. The best performance in most indications was shown by parenteral MTX, favouring higher doses (25 mg/week) in the induction phase.

Evidence from high-quality studies in favour of MTX is scarce and limited to the steroid-dependent disease, in which other drugs are the leading players today. Many limitations on study design have been found, such as the prevalence of retrospective underpowered studies and the lack of stratification of outcomes according to specific types of patients and formulations of MTX.

MTX is a valid option as steroid-sparing agent in steroid-dependent CD. Numerous other clinical scenarios require well-designed clinical studies in terms of patient profile, drug formulation and dosage, and criteria of efficacy.

Subtenon triamcinolone acetonide (Kenalog®; Bristol Myers Squibb) (STA) injections are commonly used in the treatment of adults in an outpatient setting. However, publications on detailing its outpatient use, safety, and efficacy in the pediatric population are scarce.

We reviewed STA injections performed in children in the outpatient clinics at two tertiary centers from 2014 to 2020. All children were aged ≤ 18 years and had a diagnosis of non-infectious uveitis. STA injections were done using 0.5 cc (20 mg) triamcinolone injected superotemporally with only topical anesthesia. Data on the efficacy and safety of STA in treating inflammation and compiled data on visual acuity improvement and incidence of ocular complications were evaluated.

Forty-eight eyes in 30 patients were included. The mean age of patients was 13.1 (range 7-18) years. There were no immediate complications observed in all injections performed. At the 3-month follow-up, inflammation had improved in 85.4% of eyes, macular edema had resolved in 77.8% of eyes, and there was significant vision improvement after STA. At 6 months after STA, the incidence of ocular hypertension was 12.5% and no new cataracts had developed.

STA injection with topical anesthesia was a well-tolerated, reasonable alternative for short-term treatment of uveitis among this pediatric population.

Childhood noninfectious uveitis leads to sight-threatening complications. Idiopathic chronic anterior uveitis and juvenile idiopathic arthritis-associated uveitis are most common. Inflammation arises from an immune response against antigens within the eye. Ophthalmic work-up evaluates anatomic involvement, disease activity, ocular complications, and disease course. Local and/or systemic glucocorticoids are initial treatment, but not as long-term sole therapy to avoid glucocorticoids-induced toxicity or persistent ocular inflammation. Children with recurrent, refractory, or severe disease require systemic immunosuppression with methotrexate and/or anti-tumor necrosis factor monoclonal antibody medications (adalimumab, infliximab). Goals of early detection and treatment are to optimize vision in childhood uveitis.

The Childhood Arthritis & Rheumatology Research Alliance (CARRA) launched in 2000 as a small network of pediatric rheumatologists and investigators dedicated to promoting collaborative research to improve the care and outcomes of childhood-onset rheumatic diseases. Over the past 2 decades, CARRA has grown to become a major driver of advances in evidence-based medicine and career development in pediatric rheumatology. Its research approach has transformed pediatric rheumatology. CARRA is a vibrant organization that will continue to facilitate impactful research in the care of children, adolescents, and young adults with rheumatic disease in the years to come.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in pediatric population, with uveitis as the most common and severe extra-articular manifestation. Eye damage (bilateral in 70-80% of cases) is usually anterior, chronic and asymptomatic. Young age, female gender, oligoarticular form and ANA positivity are risk factors for chronic anterior uveitis (CAU). Acute anterior uveitis (AAU) frequently occurs in HLA-B27 positive boys with enthesitis-related arthritis. The onset is on average 1.8 years after the onset of JIA, but it may also precede the articular manifestations. Ophthalmological screening for JIA is recommended every 3 or 6-12 months depending on the combination of risk factors for associated uveitis. The major purpose of the treatment is to minimize the loss of visual acuity. The treatment is topical (corticosteroids, cycloplegics) and systemic (short-term glucocorticoids, methotreexate, biological drugs). Biological therapy (indicated if previous treatments are ineffective) is using anti-TNF drugs as first choice (most studies are indicating sup erior efficiency for Adalimumab). Usually AAU is treated promptly and no systemic treatment is needed. In some cases the evolution of CAU can lead to severe complications (synechiaes, cataract, glaucoma, even blindness). Interdisciplinary approach involving the pediatric rheumatologist and ophthalmologist is essential for correct monitoring of this disease.

Essential medicines lists (EMLs) are intended to reflect the priority health care needs of populations. We hypothesized that biologic disease-modifying antirheumatic drugs (DMARDs) are underrepresented relative to conventional DMARDs in existing national EMLs. We aimed to survey the extent to which biologic DMARDs are included in EMLs, to determine country characteristics contributing to their inclusion or absence, and to contrast this with conventional DMARD therapies.

We searched 138 national EMLs for 10 conventional and 14 biologic DMARDs used in the treatment of childhood rheumatologic diseases. Via regression modelling, we determined country characteristics accounting for differences in medicine inclusion between national EMLs.

Eleven countries (7.97%) included all 10 conventional DMARDs, 115 (83.33%) ≥5, and all countries listed at least one. Gross domestic product (GDP) per capita was associated with the total number of conventional DMARDs included (β₁1.02 [95% CI 0.39, 1.66]; P = 0.00279). Among biologic DMARDs, 3 countries (2.2%) listed ≥10, 15 (10.9%) listed ≥5, and 47 (34.1%) listed at least one. Ninety-one (65.9%) of countries listed no biologic DMARDs. European region (β₁ 1.30 [95% CI 0.08, 2.52]; P = 0.0367), life expectancy (β₁-0.70 [95% CI -1.22, - 0.18]; P = 0.0085), health expenditure per capita (β₁ 1.83 [95% CI 1.24, 2.42]; P < 0.001), and conventional DMARDs listed (β₁ 0.70 [95% CI 0.33, 1.07]; P < 0.001) were associated with the total number of biologic DMARDs included.

Biologic DMARDs are excluded from most national EMLs. By comparison, conventional DMARDs are widely included. Countries with higher health spending and longer life expectancy are more likely to list biologics.