Introduction
Chronic anterior uveitis is a concern in up to 20% of children with juvenile idiopathic arthritis (JIA) and can lead to vision loss.
Early detection through regular eye screenings and timely treatment is crucial.
Risk factors for JIA-associated uveitis include female sex, young age at JIA onset, and antinuclear antibody (ANA) positivity.
About 13.9% of JIA patients develop uveitis in the first 5 years, emphasizing the need for vigilant screening.
Collaborative care between rheumatology and ophthalmology is essential. Treatment can involve topical and systemic therapies, with a focus on avoiding long-term use of topical steroids to reduce side effects.
In 2019, the American College of Rheumatology (ACR) and the Arthritis Foundation (AF) collaborated to create guidelines for JIA-associated uveitis.
Regulatory approval for therapeutics remains a challenge due to limited evidence. Canadian-specific guidelines are needed to standardize care nationwide.
The ACR/AF guidelines used the GRADE methodology and patient preferences.
Canadian guidelines were developed using the GRADE-ADOLOPMENT method, considering local factors.
This is the first set of Canadian JIA-associated uveitis guidelines and the first Canadian Rheumatology Association (CRA) guideline applying the GRADE-ADOLOPMENT framework, ensuring cost, equity, and access considerations.
Method
The literature search yielded 410 citations related to JIA-associated uveitis and 554 articles concerning equity, patient preferences, and economics after eliminating duplicates. Full-length articles were assessed, data were extracted, and evidence was graded based on 19 PICO questions from the source guideline.
Two independent reviewers conducted the screening process, with disagreements resolved by a third reviewer. An additional 22 articles were found, and SoF tables (26) for observational studies and GRADE tables (2) for clinical trials were developed, with updates to the ACR tables.
The available evidence was generally of low quality due to limited data and indirect evidence. Most articles were based on observational studies, which GRADE considers as low quality.
Results
Interpretation of strong and conditional recommendations
Results from the web survey showed agreement to adopt 13 of the source recommendations by the Canadian Uveitis Working Group.
The remaining 6 recommendations were discussed in a virtual meeting attended by 75% of the working group, along with parent/patient representatives and advisors. Of the 7 recommendations requiring significant revision, 5 were adapted, 2 were removed, and 1 was newly developed.
Feedback and comments from members who couldn’t attend the meeting were considered, and 100% consensus was reached for the discussed recommendations.
Recommendations for ophthalmic screening, ophthalmic monitoring, and treatment of children with JIA-associated uveitis
Recommendation 1
(ACR/AF recommendation 1 adapted). In children and adolescents with JIA at high risk of developing chronic anterior uveitis (CAU), ophthalmic screening at least every 3 months for the first 4 years is conditionally recommended over screening at a different frequency.
Patients with newly diagnosed disease should be screened as early as possible after diagnosis, within the first 1 to 3 months if asymptomatic (conditional recommendation, very low certainty of evidence).
Remarks:
Collaboration and communication between rheumatologists and ophthalmologists are crucial in determining the frequency of eye monitoring. The recommendation “at least every 3 months” is for individuals with vision-threatening disease, especially during the first 4 years of JIA, reflecting significant risk factors such as young age at JIA onset (<7 years), oligoarticular subtype, female sex, and a positive ANA test.
The recommendation should include the timing of the first eye examination, emphasizing its importance to caregivers.
Caregiver and patient understanding is vital due to uveitis’s asymptomatic nature, which can lead to delayed diagnosis without regular screening.
The consensus suggests the first examination should occur within 1 to 3 months of diagnosis, regardless of the patient’s location. Challenges may arise for those in rural areas or requiring travel funding for eye care access.
The discussion covered who can perform ophthalmic screening, with varying opinions and additional considerations, given geographic diversity and limited ophthalmologists in some areas. While ophthalmologists are optimal, other eyecare providers can be considered if timely access is an issue, with eventual verification by an ophthalmologist with uveitis expertise.
Recommendations 2 and 3
(ACR/AF recommendations 8 and 9 adapted). For recommendation 2, in children and adolescents with JIA and CAU requiring more than 2 drops per day of prednisolone acetate 1% (or equivalent) at 3 months after the start of uveitis treatment, and not on systemic therapy, adding systemic therapy to taper topical GCs is conditionally recommended over not adding systemic therapy and maintaining on topical GCs only (conditional recommendation, very low certainty of evidence).
For recommendation 3, in children and adolescents with JIA and CAU requiring more than 2 drops per day of prednisolone acetate 1% (or equivalent) for at least 3 months and on systemic therapy for uveitis control, changing or escalating systemic therapy is conditionally recommended over maintaining current systemic therapy (conditional recommendation, very low certainty of evidence)
Remarks:
The adapted recommendations differ from ACR/AF guidelines, which suggest considering systemic therapy when using 1 to 2 drops of topical steroids per day. Reviewing the evidence, it was found that using more than 2 drops of topical steroids daily increases the risk of ocular complications. Both rheumatologists and ophthalmologists agreed that long-term use of 3 or more drops per day elevates the risk. This aligns with Australia and New Zealand’s expert consensus JIA-Uveitis Working Group recommendations.
The decision to escalate therapy should be individualized, using shared decision-making. In cases where noncompliance or significant burden is associated with topical drops, escalation may be considered when 1 to 2 drops per day are needed. The group unanimously agreed on a maximum 3-month monitoring interval for uveitis, with consideration of adding systemic therapy. The term “active” includes “steroid dependent,” encompassing controlled uveitis requiring more than 2 drops of topical steroids daily.
Recommendation 4
(developed de novo)
In children and adolescents with JIA and CAU who are initiating systemic treatment for CAU, methotrexate (MTX) is conditionally recommended as the first-line disease-modifying antirheumatic drug (DMARD; conditional recommendation, very low certainty of evidence).
Remarks:
The working group has developed a conditional recommendation for using Methotrexate (MTX) as the first-line Disease-Modifying Antirheumatic Drug (DMARD) for JIA-associated uveitis.
This differs from the ACR/AF guidelines, which implied this recommendation without explicitly stating it. The recommendation aligns with the SHARE and Australia/New Zealand groups, which both specifically recommend MTX as the first-line systemic therapy.
MTX has shown safety and efficacy in treating JIA-associated uveitis in various studies when used in doses ranging from 15 mg/m2 (or up to 1 mg/kg) to a maximum of 25 mg weekly.
These findings are supported by systematic reviews and consensus treatment guidelines. Other nonbiologic DMARDs like mycophenolate mofetil, azathioprine, and cyclosporine have been used with varying success, mainly in cases refractory to MTX.
However, the limited number of patients in these studies restricts the quality of evidence.
Overall, the evidence for MTX is more robust than for other conventional DMARDs, justifying its conditional recommendation as the first-line systemic therapy for JIA-associated uveitis.
The source guidelines conditionally recommend subcutaneous Methotrexate (MTX) over oral MTX due to data indicating increased bioavailability of the subcutaneous form at doses above 15 mg/m2. This aligns with other consensus recommendations.
However, there’s a lack of high-quality evidence showing clinical superiority of subcutaneous MTX in JIA-associated uveitis.
The initial administration route should consider factors like dose, potential complications, patient/caregiver preference, comfort with injections, and provincial health authority criteria for biologic funding after MTX failure.
ACR/AF recommendation 11 suggests dual therapy over MTX alone, but the working group favored MTX monotherapy, as there’s no direct evidence favoring one approach over the other.
Concerns were raised about limited access to tumor necrosis factor inhibitors (TNFis) as a first-line treatment in Canada for JIA-associated uveitis.
Ophthalmologists highlighted the lack of standardized definitions for severe or sight-threatening complications.
The term “severe” was removed from recommendation 11, as it doesn’t necessarily correlate with treatment difficulty, but the presence of complications like posterior synechiae or cataracts indicates a poor visual outcome in JIA-associated uveitis. Recommendation 11 was removed from the current guidelines.
Recommendation 5
(ACR/AF recommendation 13 adapted). In children and adolescents with JIA and active CAU who have an inadequate response to one monoclonal antibody TNFi at standard JIA dosing, optimizing the dose and/or frequency of the current TNFi is conditionally recommended over switching to another monoclonal antibody TNFi.
Remarks:
No randomized controlled trials compare one monoclonal TNFi to another for treating JIA-associated chronic anterior uveitis (CAU). The working group noted that the ACR/AF wording “above standard” dosing could lead to equity concerns, as access to such dosing may vary by treatment site or reimbursement, causing anxiety for patients and caregivers.
The product monograph recommends adalimumab (ADA) dosing of 40 mg every 2 weeks for patients over 30 kg. However, for maximal clinical benefit, weekly dosing is often used without a significant increase in adverse effects.
Adjusting infliximab intervals to less than 4 weeks or increasing the dose beyond 10 mg/kg can also be considered, supported by older case series literature. Patient/caregiver advisors prefer adjusting current regimens over introducing new medications, unless clear benefits exist. This recommendation is made with very low certainty of evidence.
Recommendation 6
(ACR/AF recommendation 15 adapted). In children and adolescents with JIA and active CAU who have failed MTX and 2 monoclonal antibody TNFis at optimized doses, the use of abatacept (ABA) or tocilizumab (TCZ) as biologic DMARD (bDMARD) options are conditionally recommended over nbDMARD options (MMF, leflunomide, or cyclosporine; conditional recommendation, very low certainty of evidence).
Remark:
For patients with chronic anterior uveitis (CAU) who have failed treatment with two monoclonal TNF inhibitors, there’s no specific evidence to guide the next steps.
The ACR/AF guidelines don’t specify a preference for biologic (bDMARD) or nonbiologic (nbDMARD) options in this scenario.
The working group’s expert opinion, supported by observational data, conditionally recommends using a bDMARD like tocilizumab (TCZ) or abatacept (ABA) over an nbDMARD for refractory CAU.
Other investigated biologic agents include daclizumab, rituximab, and an alternative monoclonal TNF inhibitor (golimumab). All of these therapies offer some benefit for patients who don’t respond to conventional treatment.
Notably, there’s no direct evidence on the effects of low drug trough levels or the development of antidrug antibodies on the clinical efficacy of biologics in uveitis patients refractory to monoclonal TNF inhibitors.
The SHARE group recommends considering testing for antidrug antibodies and drug trough levels in cases where treatment loses effectiveness over time.
If a patient has no antibodies but low trough levels, increasing the dose or shortening the dosing interval may be options to explore.
Discussion
The Canadian Rheumatology Association (CRA) Uveitis Working Group’s recommendations for the treatment of juvenile idiopathic arthritis (JIA)-associated chronic anterior uveitis (CAU) differ from the 2019 ACR/AF guidelines in several aspects due to the Canadian context.
These differences include timing for initial ophthalmic screening, the threshold of topical glucocorticoids for systemic treatment escalation, the preference for a step-up approach with biologics (such as tocilizumab or abatacept) over non-biologic DMARDs as first-line therapy, removal of the recommendation for subcutaneous vs. oral methotrexate, modification of TNFi dosing recommendations, and a preference for biologics over non-biologic therapies for patients who fail methotrexate and TNFi therapies.
The ACR/AF guidelines were developed through a rigorous GRADE methodology with input from various experts and patients. The CRA Uveitis Working Group chose the GRADE-ADOLOPMENT approach to adapt the ACR/AF recommendations to the Canadian context, given the similarities in healthcare challenges and systems.
However, notable differences include varying access to biologics due to differing provincial payment models, and the scarcity of pediatric rheumatologists and ophthalmologists with expertise in uveitis across the country. Distance to urban centers can affect access, requiring the involvement of other eyecare providers for screening.
The introduction of biosimilars may improve access, and some provinces have started non-medical switching to biosimilars.
The CRA Uveitis Working Group, consisting of experts and patient representatives, adapted the ACR/AF recommendations in a relatively short time, at low cost, with updated evidence. Their judgments closely align with the source recommendations, providing Canadian-specific considerations for equitable access to uveitis care and treatment.
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