Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease (1). JIA includes a heterogeneous group of chronic arthritis of unknown etiology that begins before 16 years (1). Uveitis is the most frequent extra-articular manifestation of JIA (2). JIA may have an unfavorable prognosis, leading to musculoskeletal system disability or visual impairment if adequate treatment is not prescribed (3–5). There are known predictors of uveitis in JIA, such as female gender, younger-onset age, ANA-positivity, oligoarticular course, and high CRP, but data about the features of the arthritis course in patients with concomitant uveitis are scarce (6, 7). Biological treatment is an option if previous therapy with methotrexate was ineffective or intolerable and can modify the course of arthritis and uveitis and their outcomes (8–10). The question about the benefits of combined treatment with biologics and methotrexate is still open. Meanwhile, the number of patients with JIA treated with biologics alone is growing due to methotrexate side effects correlated with treatment duration.

Most current studies aim to identify predictors of the development of uveitis in patients with JIA and its course, but there are limited studies to answer whether the presence of uveitis affects the severity of arthritis.

The uveitis group has the following typical characteristics: younger age, less active joints, and ANA-positivity compared to the non-uveitis group. The female gender, ESR, CRP, and remission frequency were equal between the two groups. The patients with uveitis had more frequent flares during the observation period and a shorter time before the first significant flare (Table 1).

Uveitis might be a risk factor of more severe course of JIA. In previous studies, it was shown that the JIA category, e.g., oligoarthritis, is an independent risk factor of uveitis when combined with ANA-positivity and early age of the JIA onset (13–15). It is well-established that persistent oligoarthritis and extended oligoarthritis have the highest probability of developing uveitis, while, in systemic and RF-positive categories, uveitis occurs extremely rarely (5, 14, 15). The risk factors in acute anterior uveitis in enthesitis-related arthritis are male gender, ANA-positivity, and HLA B27 (2, 16, 17). The role of uveitis in the course of arthritis has not been previously described. Uveitis and arthritis might have similar pathogenesis related to immune cell activation and TNF-a hyperproduction (18, 19). Both arthritis and uveitis respond well to methotrexate and TNF-a inhibitors (adalimumab and infliximab) (20). Earlier prescription of methotrexate and biologics may decrease the incidence of uveitis (21–23). The combination of biologic and non-biologic DMARDs reduces the probability of active uveitis at any instance in time (22). The arthritis flare has a temporal association with uveitis flare (22). In our study, the absence of methotrexate increased the cumulative likelihood of an exacerbation rate in the subgroup of the patients receiving adalimumab. Immunogenicity of biologics, especially adalimumab, was associated with the production of antibodies against biologics. The protective role of methotrexate against the production of anti-adalimumab antibodies leads to preserving serum concentration of adalimumab and its efficacy (24, 25). The treatment efficacy of JIA-associated uveitis and arthritis with a combination of biologic and methotrexate has already been demonstrated in several studies (26–29).

According to our experience, we recommend starting methotrexate treatment early in patients with high risks of uveitis as well as continuing methotrexate in patients with JIA and uveitis, especially those who are treated with adalimumab, despite intolerance or adverse events occur.

The limitations of the study are related to its retrospective nature, the variation in times of uveitis development, and the absence of standard treatment protocol throughout the study. The use of various biologics may also influence the results. Different types of immunogenicity of adalimumab and etanercept may introduce bias into the results.

The results of our analysis indicate the need for ongoing cooperation between a pediatric rheumatologist and an ophthalmologist. Uveitis might be a hallmark of arthritis flare, and methotrexate therapy can reduce the likelihood of arthritis flare.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by The local Ethics Committee which approved the protocol of this trial of Saint-Petersburg State Pediatric Medical University (protocol # 3/11 from 04.12.2012). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

MK, EG, LSSo, and IA designed the study. MK, EG, LSSo, IA, TN, EI, IC, YK, EO, LSSn, VM, MD, OK, and VC collected and analyzed the data. MK, EG, IA, and LSSo wrote the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

This work was supported by Russian Science Foundation Grant 20-45-01005.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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