Biosimilars in Adult and Pediatric Noninfectious Uveitis

Introduction

Uveitis is a preventable, vision-threatening inflammatory disease of the uvea, presenting as redness, pain, photophobia, floaters, and blurred vision.¹ Treatment is crucial, as 10–15% of patients with uveitis in Western countries experience blindness.² Uveitis can arise from infectious or noninfectious etiologies and primarily affects adults.^1,3 The majority (67–90%) of cases are noninfectious uveitis (NIU), presumed to arise from autoimmune or autoinflammatory disorders.^3,4 Only 5–10% of uveitis cases are pediatric, with 67.2–93.8% being NIU.⁴ The pathophysiology behind NIU is theorized to involve major histocompatibility complex class II molecules, activating naïve T cells which differentiate and release a cascade of proinflammatory cytokines.¹ Cytokines then attract neutrophils and macrophages to induce vasculitis and edema.¹ In addition to primary visual disturbances, individuals with NIU have greater risks of developing glaucoma, cataract, retinal detachment and retinal disorders.⁵ Common systemic diseases associated with NIU include sarcoidosis, juvenile idiopathic arthritis (JIA), ankylosing spondylitis, multiple sclerosis, Behçet’s disease, and inflammatory bowel disease, with JIA being the most common systemic disease found in pediatric NIU.^4,6 In developed countries, sarcoidosis and spondyloarthropathies are reported to be the most common causes of NIU in the elderly.⁷ Anterior uveitis associated with HLA-B27 is known to be the most common type of NIU.⁷

Topical/local or systemic corticosteroids are the first-line therapy for NIU due to their potent and rapid anti-inflammatory effects, though long-term use is limited by well-recognized adverse effects.⁸ Disease-modifying antirheumatic drugs (DMARDs) are consequently used as steroid-sparing agents in patients with severe or refractory uveitis to maintain disease control while minimizing corticosteroid exposure.^8,9 In cases of persistent or treatment-refractory NIU, or severe sight-threatening NIU, biologic therapies targeting specific inflammatory cytokines or molecular pathways implicated in the disease pathogenesis are increasingly utilized.¹⁰ The most commonly used biologics for NIU are anti-tumor necrosis factor alpha (anti-TNF-α) agents, including adalimumab (Humira^®; AbbVie, North Chicago, IL, USA) and infliximab (Remicade^®, Janssen Biotech, Horsham, PA, USA).¹¹ Adalimumab is the only biologic approved by the United States Food and Drug Administration (FDA) for treatment of NIU.¹² Both adalimumab and infliximab show corticosteroid-sparing and anti-inflammatory effects with similar retention rates in cases of NIU.^13,14 Etanercept (Enbrel^®, Amgen, Thousand Oaks, CA, USA) is an anti-TNF-α agent known to be less effective than other anti-TNF-α agents in reducing uveitis flares and also more likely to cause paradoxical new-onset uveitis.¹⁵ Other anti-TNF-α drugs such as golimumab (Simponi^®, Janssen Biotech, Horsham, PA, USA) and certolizumab pegol (Cimzia^®, UCB, Smyrna, GA, USA) have limited but promising data showing effectiveness as anti-inflammatory treatment for NIU.^16–21 Interleukin-6 (IL-6) inhibitors tocilizumab (Actemra^®, Genentech, South San Francisco, CA, USA) and sarilumab (Kevzara^®, Sanofi-Aventis U.S. LLC, Bridgewater, NJ, USA) are reported to be off-label treatments of NIU, as well as CD-20 antibody rituximab (Rituxan^®, Genentech, South San Francisco, CA, USA) which successfully reduces corticosteroid use, contributes to disease quiescence, and increases visual acuity.^11,22–24

Biosimilars—biologic medications that are similar in structure and mechanism to the existing, original reference biologics (adalimumab, infliximab, etc.) but more affordable— are available for treatment of NIU. Biosimilars are labeled to have no clinically meaningful differences in safety or outcomes for patients compared to their reference biologic. Ten adalimumab biosimilars are FDA-approved in the United States to be used for treatment of NIU.^25,26 Additional biosimilars exist for anti-TNF-α agents, IL-6 inhibitors, and CD-20 antibody rituximab and may be used off-label for NIU. Biosimilars offer clinicians and patients less expensive, alternative medications to use for anti-inflammatory purposes, increasing access to care. Individuals or providers may choose to switch treatment of NIU from reference biologics to biosimilars due to medical (non-compliance, adverse reactions with reference, active uveitis, uncontrolled systemic disease, etc.) or non-medical reasons (insurance coverage, access, study enrollment, etc.).^27–42 Given that pediatric NIU cases are less prevalent than adult NIU, literature involving biosimilars for treatment of pediatric NIU is scarce.⁴ Several studies have compared visual acuity and disease outcomes in participants with NIU that use either originator biologics or their associated biosimilar.^25,43,44 Researchers have also tracked patients who have switched to biosimilar treatments from reference biologics or those naïve to biologics.^27–42 The purpose of this review is to summarize and compare this evidence for biosimilar therapies for NIU in both adult and pediatric populations.

Methods

A review of the literature from inception to December 2025 was conducted using Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to identify studies that included data or discussion on the use of biosimilar biologic agents for adult and/or pediatric NIU. Key terms included uveitis or retinal vasculitis, biologic or immunomodulatory therapies (including biologic disease-modifying antirheumatic drugs, specific agents and their accompanying abbreviations), and associated biosimilars to identify eligible articles.

Following removal of duplicates, 268 studies were screened, and 249 studies were excluded due to being studies of infectious uveitis, non-English publications, conference abstracts, clinical trial registrations, or having ineligible intervention, patient population, study design, or outcomes. Of these, some were still cited in the review to provide background or contextual information. In total, 19 unique original research articles specifically evaluating the efficacy or safety of biosimilar biologic agents for adult and/or pediatric NIU were identified and included in this review. Data on safety and efficacy of original and biosimilars of anti-TNF-α agents, IL-6 inhibitors and rituximab were included: improvement in best-corrected visual acuity (BCVA), uveitis activity, central retina thickness (CRT), systemic steroid burden, as well as adverse events, and retention rate of specific agents. An additional 95 references providing relevant background and discussion were also cited to contextualize the findings.

Results

Anti-Tumor Necrosis Factor-α Agents

Tumor necrosis factor-alpha is a pro-inflammatory cytokine produced by CD4+ lymphocytes linked to uveitis.^45,46 In NIU, TNF-α binds TNF-α receptors I and II on the iris, ciliary body, and retina.^45,46 A positive feedback loop of inflammation ensues; macrophages and natural killer cells are activated, and vascular endothelial growth factor (VEGF) is upregulated in its presence, contributing to edema.^45–47 Adalimumab, infliximab, golimumab, and certolizumab pegol are anti-TNF-α monoclonal antibodies, while etanercept is a fusion protein that acts as a receptor for TNF-α.^47–49 The variable region of monoclonal antibodies bind TNF-α and prevent it from interacting with its receptors, prohibiting pro-inflammatory states.^47,49

Adalimumab

Adalimumab is an anti-TNF-α humanized antibody that is the only FDA-approved biologic treatment for adults and children indicated specifically for management of NIU, including intermediate, posterior, and panuveitis. Adalimumab is offered as a self-administered subcutaneous injection. It is frequently used as a second-line treatment for NIU in adults and children two years of age and older; although, it may be used as first-line treatment in severe and sight-threatening uveitis. The VISUAL I and II double-masked, multicenter, randomized clinical trials helped establish adalimumab as a recognized treatment for NIU in adults ≥18 years old. Analysis of the VISUAL I (NCT01138657) Phase 3 study involving 217 participants with active NIU (placebo n= 107) concluded that treatment with adalimumab 80mg loading dose and 40mg injections every other week thereafter for 80 weeks was associated with fewer uveitis flares, greater improvements in anterior chamber cell grade, vitreous haze grade, and BCVA compared with placebo.^50,51 VISUAL II (NCT01124838) used the same loading and maintenance doses of adalimumab, and involved 226 patients with inactive NIU (placebo n=111). Both VISUAL I and VISUAL II trials support adalimumab lowering the risk of treatment failure in active and inactive NIU.⁵²

The SYCAMORE (ISRCTN10065623) and ADJUVITE (NCT01385826) clinical trials established efficacy of adalimumab in treating NIU in children two years of age and older.^53–55 Targeting the 20–25% of pediatric uveitis associated with JIA, the SYCAMORE study analyzed 115 eyes of 90 participants with JIA aged 2–18 years old, with 60 participants randomized to receive adalimumab for 18 months (placebo n=30).^53,55 The ADJUVITE trial was another double-blind, randomized, placebo-controlled trial including 31 patients with JIA or idiopathic uveitis aged 4 and older that were randomized to receive reference adalimumab or placebo for 2 months before receiving an open-label phase of adalimumab up to the 12 month mark.⁵⁴ Pooled analysis of the SYCAMORE and ADJUVITE studies revealed that adalimumab increases the probability of NIU treatment success compared to placebo (RR 3.11; 95% CI 1.40–6.90).⁵⁵ Research now estimates that up to 90% of children using adalimumab experience uveitis remission within three months.⁵⁶

Biosimilars of Adalimumab

There are over 30 biosimilars approved or being developed around the world for adalimumab.⁴⁰ As of December 2025, U.S. FDA-approved biosimilars of adalimumab include adalimumab-atto (Amjevita^®, Amgen, Thousand Oaks, CA, USA), adalimumab-adbm (Cyltezo^®, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA), adalimumab-adaz (Hyrimoz^®, Sandoz, Princeton, NJ, USA), adalimumab-bwwd (Hadlima^®, Samsung Bioepsis, Incheon, South Korea), adalimumab-afzb (Abrilada^®, Pfizer, New York, NY, USA), adalimumab-fkjp (Hulio^®, Mylan Pharmaceuticals, Canonsburg, PA, USA), adalimumab-aqvh (Yusimry^®, Coherus BioSciences, Redwood City, CA, USA), adalimumab-aacf (Idacio^®, Fresenius Kabi, Bad Homburg, Germany), adalimumab-aaty (Yuflyma^®, Celltrion USA, Jersey City, NJ, USA), and adalimumab-ryvk (Simlandi^®, Teva Pharmaceuticals/Alvotech, Parsippany, NJ, USA). Both adalimumab-aacf and adalimumab-aqvh are listed by the United States FDA as biosimilars and not interchangeable for adalimumab, while the other eight biosimilars are categorized as an interchangeable: a biological product that meets requirements as a biosimilar and can be substituted for the reference biologic without the intervention of the prescribing provider.²⁶ Biosimilars are available as subcutaneous injectables. Adalimumab biosimilars can be used for NIU in adults, but adalimumab-aaty was FDA-approved in October 2025 for pediatric NIU ages 2 and above. Other biosimilars have been approved outside the United States for the pediatric population, including adalimumab-atto in Canada. Several adalimumab biosimilars exist outside of the United States, including adalimumab-bnmn (CinnoRA^®, CinnaGen Co., Tehran, Iran).⁴⁰

Safety and Efficacy of Adalimumab Biosimilars in Adults

Several studies have characterized outcomes of NIU patients switching to adalimumab biosimilars (Table 1).^{29,33,34,37,40} Biosimilar SB5, known as adalimumab-bwwd in the United States (also known as Imraldi^®, Biogen Ltd., Maidenhead, UK and Adalloce^®, Samsung Bioepsis Co., Ltd., Incheon, Republic of Korea) has been studied extensively in the adult population. An Italian retrospective study analyzed 26 adult NIU patients (47 eyes) with active uveitis or uncontrolled systemic disease (n=3 naïve to anti-TNF-α agents) switching to SB5 from previous biologic agents, mostly reference adalimumab (69.23%).³⁵ After 14 months of treatment, at end of follow-up, the number of eyes with active retinal vasculitis significantly decreased, with inactive uveitis in 46/47 eyes.³⁵ BCVA significantly increased from 7.7±3.41 at baseline to 8.9±2.46 at the last follow-up, and mean daily glucocorticoid dosage decreased significantly from 18.33± 10.33 mg at baseline to 5.75±2.29 mg at the last follow-up.³⁵ Only one patient had an injection site reaction with SB5.³⁵ Another case series of eight adult patients with Behçet’s syndrome switching to SB5 from a variety of biologic agents also found drastic reduction of uveitis relapses and preservation of visual acuity at mean follow-up of 16 months.³⁴ A retrospective review by Fabiani et al tracked patients switching from anti-TNF-α reference biologics to SB5 and other biosimilars. Twenty patients (33 eyes) were switched to SB5 and followed up for 12 months.²⁹ At last follow up, uveitis ocular complications (epiretinal membranes, lens opacity) were present in 2 patients (3 eyes) treated with SB5. No serious adverse events post-switch was recorded, and visual acuity was maintained post-switch.²⁹

An additional retrospective study conducted in South Korea studied 15 adult patients (29 eyes) with NIU who switched from adalimumab originator to SB5 for 6 months due to non-medical reasons.³³ No clinically significant differences were reported in treatment efficacy, safety, BCVA, anterior chamber cell grades or vitreous haze compared to pre-switch. Four patients (27%) were switched back to originator adalimumab due to injection discomfort or difficulty with the new injection device, but not uveitis recurrence.³³

It is important to note that patients may still experience flares with adalimumab biosimilar use. Van Poeke et al of the Netherlands studied a subgroup of 101 adult patients with NIU that switched from reference adalimumab to biosimilar adalimumab-adaz.³⁷ Three patients had flares before switching, and five different patients developed a flare after switching. The most reported side effect was injection pain, significantly reported more frequently in the group of patients that experienced a flare during biosimilar use (p=0.001).³⁷

Researchers have also discussed the safety of adalimumab biosimilars that are approved in different countries. An Iranian retrospective cohort study by Soheilian et al evaluated the safety and efficacy of adalimumab biosimilar adalimumab-bnmn, approved in Iran since September 2016.⁴⁰ 48 patients naïve to biologics with Behçet’s uveitis were included in the study and started on adalimumab-bnmn.⁴⁰ 87.5% of the cohort was >17 years old. The patients switched from conventional immunosuppressant treatment only to receiving 40 mg adalimumab-bnmn every other week for 17.41 ± 9.07 months. Fourteen (29%) and 25 (52%) patients experienced remarkable and partial improvements in retinal vasculitis, respectively.⁴⁰ Best-corrected visual acuity (p<0.001), anterior chamber cell grade (p=0.002), and vitreous haze grade (p<0.001) showed statistically significant improvement at follow up, and the only reported side effects included abdominal pain and hepatic enzyme increase.⁴⁰

Two main retrospective cohort studies have compared groups of adult NIU patients using either reference biologics or adalimumab biosimilars, highlighting relapse rates and discontinuation rates.^25,43 Recently, in 2025, analysis of 148 patients (260 eyes) with NIU treated with either adalimumab reference biologic (n=193 eyes) or adalimumab biosimilar (n=67 eyes, adalimumab-adaz, adalimumab-aacf, adalimumab-fkjp, or adalimumab-atto) supported the use of biosimilars for treatment of NIU. During the first 12 months, the relapse rate in the originator group was 24.2%, compared to 28.3% in the biosimilar group. In total, uveitis relapses were more predominant in the originator group (n=76) compared to the biosimilar group (n=21).²⁵ These results were published after an even larger study with a subgroup comparing adalimumab (n=509) and biosimilars adalimumab-atto, adalimumab-adaz, adalimumab-bwwd, adalimumab-fkjp, or adalimumab-aacf (n=176) for treatment of NIU.⁴³ Discontinuation rates were similar, with 35% of reference adalimumab users discontinuing treatment and 30% of the biosimilar treatment group discontinuing treatment.⁴³

These data overall show improved uveitis and similar retention rates of biosimilars for treatment of NIU in adults, compared to reference biologics. Though minimal, side effects of biosimilars should be considered before use.

Safety and Efficacy of Adalimumab Biosimilars in Pediatrics

Fewer studies analyzed pediatric populations undergoing treatment of NIU with adalimumab biosimilars. With 12.5% of the Iranian cohort study by Soheilian et al being a pediatric population, it may be presumed that adalimumab-bnmn is also safe for children, though a larger pediatric cohort in future studies is warranted.⁴⁰ Importantly, a review of the literature reveals adalimumab-atto to be one of the most studied adalimumab biosimilars in the pediatric population, apart from the more recent FDA-approved biosimilar for pediatric uveitis, adalimumab-aaty.

A retrospective study in the United Kingdom analyzed 102 patients with NIU switching from reference adalimumab to adalimumab-atto, including a larger pediatric cohort (n=67) with the majority of cases associated with JIA.³² Post-switch, 15 pediatric patients and 9 adults switched back to reference adalimumab due to painful injections or technical difficulties with the biosimilar injector, except for one patient with an allergic reaction to the biosimilar. Decreased vision was also reported in at least one patient post-switch. Of the 20 patients who reported side effects, painful injection was the most reported symptom (n=13), with 12/13 reports being from the pediatric age group. This suggests that pediatric population may have more difficulty adhering to treatment or tolerating side effects of adalimumab biosimilars.

An international registry pediatric NIU study reported results of 47 patients (majority naïve to biologics) switching/initiating to biosimilars.⁴² Most (89.4%) participants switched to either adalimumab-atto, adalimumab-adaz, or adalimumab-bwwd.⁴² Nine patients (19%) discontinued biosimilars due to inefficacy or partial efficacy on disease activity, inefficacy for extraocular manifestations, three minor adverse events, poor compliance, or other non-medical reasons.⁴² Mean BCVA was maintained, but a glucocorticoid-sparing effect was seen throughout the study.⁴² Uveitis relapses were reduced, concluding adalimumab biosimilars to be overall an effective treatment for pediatric NIU, despite side effects.⁴²

Lastly, another study from Turkey comparing 87 pediatric patients on original adalimumab and 53 on adalimumab-atto revealed similar rates of inactive disease after 3 months of treatment.⁴⁴ The authors reported 63.4% and 57.1% of patients reached inactive disease in the reference and biosimilar groups, respectively.⁴⁴ These data support the efficacy of adalimumab-atto and other biosimilars in pediatric NIU patients overall, but awareness of adverse reactions and side effects should be known before use, as several side effects were noted in children.

Infliximab

Infliximab is a chimeric mouse/human monoclonal antibody that binds to soluble and membrane-bound forms of TNF-α, preventing its inflammatory effects.⁵⁷ It is FDA-approved for inflammatory diseases ages 6 and older in the United States.²⁶ Infliximab has a murine variable region and a human IgG1 constant region.⁵⁷ Like adalimumab, infliximab is a highly efficacious treatment for rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and Crohn’s disease.⁵⁸ A systematic review of 11 clinical trials including 1459 patients with NIU has suggested that although infliximab and adalimumab have similar corticosteroid-sparing effects and therapeutic efficacy, patients using infliximab for treatment of NIU have a greater amount of adverse events.¹³ Another meta-analysis of 23 articles suggests adalimumab may result in better central macular thickness and BCVA post-treatment compared with infliximab.⁵⁹ Notably, there were not many other differences between the efficacy of adalimumab and infliximab noted. Infliximab is often used off-label for the treatment of NIU.

Biosimilars of Infliximab

FDA-approved biosimilars of infliximab include infliximab-axxq (Avsola^®, Amgen Inc., Thousand Oaks, CA, USA), infliximab-dyyb (Inflectra^®, Pfizer Inc., New York, NY, USA), infliximab-qbtx (Ixifi^®, Pfizer Inc., New York, NY, USA), and infliximab-abda (Renflexis^®, Samsung Bioepis Co., Ltd., Incheon, Republic of Korea). Infliximab-dyyb (Zymfentra^®, Celltrion, Inc., Incheon, Republic of Korea) offers subcutaneous injection instead of intravenous injection.⁶⁰ These biosimilars are often labeled for use for rheumatoid arthritis, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and more inflammatory conditions. All biosimilars are indicated for use in children for pediatric Crohn’s disease, and, except for infliximab-qbtx, for pediatric ulcerative colitis.⁶⁰

Table 1 Summary of Patients Switching to Biosimilars from Originator Anti-TNF-α Agents for Noninfectious Uveitis

Safety and Efficacy of Infliximab Biosimilars in Adults

Many studies followed a switching cohort of NIU patients to infliximab biosimilars (Table 1).^{27–30,38,39,61} In France, a prospective observational study followed eight adult participants with NIU who systematically switched from reference infliximab to biosimilar infliximab-dyyb (CT-P13) for an average of 31.5 weeks.²⁷ Retention rate to biosimilar infliximab was 75%, with one patient switching back to reference. Retrospective studies by Deaner et al and Kumar et al analyzing adult NIU patients who switched from reference infliximab to biosimilar infliximab have shown similar retention rates of 88.2% and 82.6% with slightly larger sample sizes of 17 and 23 patients, respectively.^28,30 Of the patients that discontinued biosimilar, reasons included pregnancy, breast cancer, and fatigue.³⁰ Notably, Deaner et al reported an increase in the number of flares in patients switching to infliximab-abda, while Kumar et al concluded no significant differences in effectiveness between use of originator and infliximab-dyyb.^28,30

Small cohorts and case series add to the ideology that biosimilar infliximab is a safe alternative to originator infliximab. A subgroup of NIU patients within the Italian study discussed earlier, including five patients who switched to infliximab-dyyb and ten who switched to infliximab-abda, reported no adverse events or treatment-related side effects following the switch to infliximab biosimilars.²⁹ Another retrospective study in Japan reported similar conclusions with biosimilar infliximab-dyyb (CT-P13) in Behçet’s-related NIU patients, with three patients switching to biosimilar and four beginning treatment with biosimilar while naïve to biologics.⁶¹ Overall, 71.4% of patients achieved remission with no significant changes in visual acuity.⁶¹

In a two-phase prospective observational study over 11 adult NIU patients switching from originator infliximab to infliximab-dyyb, 2 patients discontinued biosimilar treatment: one experienced a flare while on infliximab-dyyb and another experienced severe nausea with biosimilar treatment, which persisted when switching back to originator.³⁸ This justified the nausea less likely to be a biosimilar-only side effect. An additional case series including 9 NIU patients switching to infliximab-dyyb from originator and 5 initiating infliximab-dyyb without prior biologic use cites insurance as a main factor for switching to biosimilar use.³⁹ The age range in this study was 7–66 years old, with the mean being 27 ± 16 years. No patients flared during the monitoring period of 5 to 120 months.³⁹ Cystoid macular edema remained controlled, and uveitis remained quiet with inactive vasculitis.³⁹

Throughout literature, infliximab-dyyb is widely studied in adult populations, with mostly positive results available regarding its efficacy for the treatment of NIU. Not all infliximab biosimilars are reported to have the same side effects, however. A significant increase in flares has been documented for use of infliximab-abda for NIU, and it is important that clinician supervision is available for patients who switch to biosimilars like infliximab-abda for the first time.²⁸

Table 2 Adult and Pediatric Biosimilar Evidence by Biologic Agent for Noninfectious Uveitis

Safety and Efficacy of Infliximab Biosimilars in Pediatrics

More limited data is available for pediatric NIU patients on infliximab biosimilars (Table 2). A retrospective study conducted in Turkey by Sozeri et al analyzed clinical results from 26 pediatric NIU patients aged ≤16 (mean age 9.7 years) who either switched to infliximab CT-P13 from adalimumab (n=4) or were biologic-naïve (n=22).⁴¹ Most patients had JIA associated uveitis, several with posterior synechiae and glaucoma.⁴¹ The researchers’ four-year follow concluded that infliximab CT-P13 was safe and effective for long-term pediatric NIU treatment. Biosimilar drug side effects were found to be similar in naïve and switched patients.⁴¹ Significant improvement in visual acuity was made post-initiation of infliximab biosimilar.⁴¹ However, it is important to note that despite the authors’ positive remarks, three patients discontinued biosimilar treatment due to a new-onset lupus-like syndrome.⁴¹ Seven patients also reported adverse side effects, including upper respiratory tract infection, influenza-like illness, and mild urticaria.⁴¹ These side effects should warrant caution for pediatric patients switching to infliximab biosimilar for treatment of NIU.

Valikodath et al retrospectively studied eight pediatric NIU patients (mean age 13.43±3.08 years) switching from adalimumab to either infliximab-dyyb (n=7) or infliximab-axxq (n=1) and two patients (mean age 10.6±8.48 years) naïve to biologic therapy were started on infliximab-dyyb.³⁶ Insurance (100%), non-compliance (37.5%), and worsening disease activity (37.5%) were listed as reasons for the switch. No adverse side-effects were reported, and no patients discontinued the biosimilar. Fewer flares per year were reported on infliximab biosimilar compared to the reference biologic; however, the length of treatment could be a confounding variable for this result, as patients were on the biosimilar for a shorter duration of time compared to the reference.³⁶

Results from Sozeri et al and Valikodath et al show similar conclusions concerning the efficacy of biosimilar infliximab for treatment of NIU but are conflicting in terms of side effects reported. Further research is needed to conclude the safety of infliximab biosimilars in pediatric NIU patients, as many cohorts reported to use infliximab biosimilars in this population are small.⁴²

Etanercept

Etanercept is a fusion protein that acts as a decoy receptor for TNF-α.⁶² Etanercept works by binding to the TNF1 and TNF2 receptors and prohibiting TNF-α’s proinflammatory effects.^47,62 It is not a monoclonal antibody like the other TNF-α inhibitors. Etanercept has a linear elimination profile with the lowest half-life of 3–5.5 days, compared to half-lives of approximately two weeks for the other anti-TNF-α medications.^47,63 It is administered subcutaneously and frequently used for rheumatoid arthritis, psoriatic arthritis, JIA, ankylosing spondylitis, and plaque psoriasis in pediatric patients.⁶²

Unlike adalimumab and infliximab, etanercept is mostly contraindicated for treatment of NIU, as many studies and cases have reported drug-induced uveitis with etanercept use.^15,64–68 A registry-based study linked 43 cases of uveitis associated with etanercept use compared to 14 associated with infliximab and two associated with adalimumab.¹⁵ The onset or recurrence of inflammatory eye disease has frequently been associated with etanercept use for rheumatic diseases.^15,68 Etanercept biosimilars etanercept-szzs (Erelzi^®, Sandoz Inc., Princeton, NJ, USA) and interchangeable etanercept-ykro (Eticovo^®, Samsung Bioepis Co., Ltd., Incheon, Republic of Korea) have limited data on their use for NIU.^29,42 Etanercept and its biosimilars are rarely used off-label for the treatment of uveitis currently, and clinicians should be aware of its adverse ocular side effects, especially if prescribed by specialists other than ophthalmologists.²⁶

Golimumab

Golimumab is a fully humanized monoclonal antibody, similar to adalimumab.⁵⁷ It has been reported that golimumab is conformationally more stable, with enhanced inhibitory ability against TNF-α-induced cytotoxicity compared to infliximab and adalimumab.^57,69 Golimumab has no FDA-approved biosimilars as of December 2025, but its originator has been studied in case series for treatment of NIU.^26,70 Biosimilars are actively being developed, with AVT05 reaching approval in Europe (Gobiaz^®, Advanz Pharma, London, United Kingdom) and Japan (Golimumab BS^®, Fuji Pharma Co., Tokyo, Japan).^71,72 Another biosimilar, BAT2506, is not yet approved for commercial use but is in review for approval, as a clinical trial (NCT04152759) including 180 healthy male subjects has concluded its pharmacokinetic similarity and biosimilarity to reference golimumab.⁷³

AVT05 is reported to be efficacious for rheumatoid arthritis. A 52-week, parallel-group, double-blind study (NCT05842213) recently analyzed participants with moderate-to-severe rheumatoid arthritis that were randomized to receive AVT05 (n=251) or reference golimumab (n=251),⁷¹ Half of the participants receiving reference product switched to AVT05 at week 16. Results described AVT05’s immunogenicity and safety profiles to be similar to reference golimumab with no clinically significant differences between treatments.⁷¹ An additional study including 336 healthy participants receiving AVT05 or U.S./E.U. originator golimumab showed similar safety, tolerability, and immunogenicity profiles between the biosimilar and reference product.⁷⁴ 6.1% of participants in the biosimilar arm experienced mild administration site reactions compared to 5.5% in the U.S. reference product arm and 10.8% in the E.U. reference product arm.⁷⁴

Research has been conducted on the use of originator golimumab for patients with NIU. A meta-analysis of 172 NIU patients has reported that patients treated with originator golimumab for NIU achieved remission 75% of the time (95% CI 56–87%), with significant decrease in the use of glucocorticoids and improved visual acuity 42% of the time.¹⁷ Another study with 19 NIU patients (38 eyes) reported a decrease from 1.73 to 0.62 relapses of uveitis per person-years after initiation of golimumab treatment.⁷⁵ Three patients in the study discontinued golimumab due to golimumab-induced psoriasiform dermatitis, disseminated varicella-zoster infection, and resistant vitreous haze later linked to a diagnosis of B-cell lymphoma.⁷⁵ Given the data describing golimumab’s glucocorticoid sparing effects, statistically significant improvement in BCVA, as well as reduction of uveitis relapses by ~1/3 post-treatment, golimumab may be considered as a controlling agent for NIU.^70,75

Use of other anti-TNF-α agents prior to golimumab may decrease its anti-inflammatory results: a history of prior anti-TNF-α therapy in 7/30 patients analyzed by Jin et al was related to decreased golimumab’s efficacy in treatment of NIU.¹⁸ Negative side effects were reported in 13.3% of patients, including elevated liver enzymes (6.7%), fatigue (3.3%), and rash (3.3%).¹⁸ With the presumption that prior anti-TNF-α therapy may decrease the effectiveness of golimumab, it may be considered as an option for NIU treatment as a first-time biologic therapy only. Once biosimilars become FDA-approved, research is needed on their success for NIU treatment.

Certolizumab Pegol

Certolizumab pegol is a humanized, PEGylated antigen-binding fragment of a monoclonal antibody targeting TNF-α.⁷⁶ No FDA-approved biosimilars are available as of December 2025 for certolizumab pegol. Similarly, no biosimilars are available outside of the United States, but they are actively being developed.⁷⁷ Certolizumab pegol is commonly used in rheumatology for Crohn’s disease, rheumatoid arthritis, axial spondyloarthritis, and psoriatic arthritis. In cases of axial spondyloarthritis, certolizumab pegol has been reported to reduce the incidence of acute anterior uveitis and rate of uveitis flares.^78–80 It has also been concluded to be a safe short- and long-term treatment of refractory uveitis due to immune-mediated inflammatory diseases.^81,82 Other small studies and case series report preservation of visual acuity and reduction in NIU flares when undergoing treatment with certolizumab pegol for NIU.^20,83,84 Also, due to the lack of an Fc region hence minimal placental transfer, certolizumab pegol is considered safe in pregnant patients.⁸⁵

Interleukin-6-Inhibitors

Interleukin-6 (IL-6) is a cytokine produced by macrophages, monocytes, and T-lymphocytes.⁸⁶ It is a major stimulator of further production of chemokines for recruitment of neutrophils and macrophages to the retina in cases of uveitis. Its pro-inflammatory role in the intraocular immune response allows IL-6 to be a target for an anti-inflammatory treatment for NIU.⁸⁶ Tocilizumab and Sarilumab are IL-6 inhibitors studied for treatment of uveitis, though tocilizumab for NIU treatment is more common.

Tocilizumab

Tocilizumab is a humanized monoclonal antibody to IL-6 receptor, which prevents IL-6 from binding to its receptor and producing inflammation.⁸⁷ It is FDA-approved for adults with rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, and cytokine release syndrome.^70,88 Tocilizumab is also approved for patients 2 years or older with hospitalized COVID-19, polyarticular juvenile idiopathic arthritis, or systemic juvenile idiopathic arthritis.^70,88 There are several promising results concerning originator tocilizumab use for NIU and refractory uveitis.^89–92 A systematic review of NIU patients aged 4–72 years old using tocilizumab described visual improvement in 62.5% of patients, intraocular inflammation control in 83.3%, a favorable response to the drug in 83.3%, and resolution of macular edema in 90.9%.⁹³

Biosimilars of Tocilizumab

Tocilizumab biosimilars recognized by the FDA include tocilizumab-anoh (Avtozma^®, Celltrion, Incheon, Republic of Korea), tocilizumab-aazg (Tyenne^®, Fresenius Kabi USA LLC, Lake Zurich, IL, USA), and tocilizumab-bavi (Tofidence^®, Biogen MA Inc., Cambridge, MA, USA).⁸⁸ There is a lack of literature evaluating tocilizumab biosimilars specifically for uveitis as of fourth quarter 2025.

Safety and Efficacy in Adults

A crucial study on originator tocilizumab in adults was the STOP-uveitis study, a Phase 2 multicenter, randomized, interventional trial with administration of tocilizumab in NIU eyes for six months.⁹⁴ Analysis of 37 NIU patients found positive clinical responses in 83.8% of patients.⁹⁴ Other clinical trials have established tocilizumab an effective treatment for systemic sclerosis, giant-cell arteritis, and graves orbitopathy.^95–97 Biosimilars have undergone clinical trials for rheumatoid arthritis and deemed comparable to originator for their immunogenicity and safety profiles.^98,99

Safety and Efficacy in Pediatrics

In children, originator tocilizumab has been studied mostly in cases of JIA.^100,101 The APTITUDE trial, a multicenter, phase 2 trial conducted on NIU patients less than 18 years old, found only 34% of children responded to tocilizumab.¹⁰² Further studies are warranted on the efficacy of tocilizumab in pediatrics, as well as biosimilars.¹⁰²

Sarilumab

Sarilumab is a monoclonal antibody that blocks the IL-6 receptor. It is FDA-approved for adult patients with moderate to severe rheumatoid arthritis with an inadequate response or intolerance to one or more DMARDs.¹⁰³ Sarilumab is administered subcutaneously and has no biosimilars that are FDA-approved as of fourth quarter 2025.¹⁰³ The literature is limited concerning sarilumab use for NIU. The SATURN study was a randomized, double-masked, placebo-controlled, phase 2 study involving 58 adult patients with NIU receiving sarilumab or placebo for 16 weeks.¹⁰⁴ Results showed significant vitreous haze reduction and mean BCVA improvement with sarilumab compared to placebo. Within the group receiving sarilumab, three patients (10.71%) experienced worsening of uveitis.¹⁰⁴ This study provides evidence for efficient treatment of NIU with sarilumab, but further research including pediatric age groups is needed to understand its clinical outcomes. There are no biosimilars currently available for sarilumab.

CD20 Antibody

The B-cell differentiation membrane antigen CD20 promotes B-cell activation and proliferation.^105,106 Rituximab is the primary CD20 antibody which has been studied and used off-label for treatment of NIU, but other CD20 antibodies exist: Ocrelizumab, Ofatumumab, Obinutuzumab, Ublituximab, and Ibritumomab are used to target B-cell malignancies or other auto-immune conditions.¹⁰⁷ B-cell infiltrate has been associated with several conditions that are correlated to NIU. Particularly, Juvenile idiopathic arthritis has been described as a primarily B-cell mediated disease, allowing for CD20 antibody to be considered an off-label treatment option for JIA associated NIU.¹⁰⁸

Rituximab

Rituximab is a chimeric monoclonal antibody targeting the CD20 antigen to prohibit proliferation of pro-inflammatory B-cells.¹⁰⁸ It is also presumed to restore the quantity and function of regulatory B-cells in NIU.¹⁰⁸ Rituximab is indicated by the FDA for treatment of adult patients with Non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia, rheumatoid arthritis, moderate-to-severe pemphigus vulgaris, and adults and children with mature B-cell NHL, B-cell acute leukemia, or granulomatosis with polyangiitis.¹⁰⁹ It is often used off label for second- or third-line treatment of NIU.¹¹⁰ It has been reported that rituximab induces and maintains disease quiescence, reduces glucocorticoid use, and significantly improves visual acuity in NIU and scleritis patients.²⁴

Biosimilars of Rituximab

Rituximab biosimilars include rituximab-arrx (Riabni^®, Amgen, Inc., Thousand Oaks, CA, USA), rixtuximab-pvvr (Ruxience^®, Pfizer, Puurs, Belgium), and rituximab-abbs (Truxima^®, Celltrion, Inc., Incheon, South Korea).¹⁰⁹ While originator rituximab has been reported in multiple case series and small observational studies to be effective for refractory NIU, scleritis and retinal vasculitis, there are no randomized clinical trials or prospective uveitis-specific studies of rituximab biosimilars to date.^24,111 Efficacy and safety of rituximab biosimilars may be inferred by the regulatory approvals for rituximab biosimilars such as DRL_RI and CT-P10 in clinical trials of rheumatologic and hematologic indications, but there is a need for scientific justification for extrapolation to an indication for uveitis.^112,113 An isolated 2025 case series describing occlusive retinal vasculitis after intravitreal biosimilar rituximab-arrx for primary vitreoretinal lymphoma provides evidence that rituximab biosimilars may have some adverse ocular side effects.¹¹⁴ Studies are needed for conclusions to be drawn on the efficacy of rituximab biosimilars for NIU.

Conclusions

The available evidence regarding biosimilar use in NIU is heterogenous, with some studies demonstrating comparable effectiveness and safety to reference biologics, while others remain limited or inconclusive (Table 2). Adalimumab and infliximab biosimilars possess the most robust evidence base, specifically in adult cohorts, whereas data supporting other biologics are comparatively sparse. Gaps in the literature are more pronounced in pediatric NIU populations compared to adults (Table 2). There remains an urgent need for well-designed, uveitis-specific studies, particularly in children, to better define the role of biosimilars in clinical practice and guide evidence-based treatment decisions.