IL-6 Inhibition as a Treatment for Noninfectious Uveitis
Uveitis remains an important cause of vision loss, and its rates of legal blindness have remained relatively unchanged over the past 3 decades. Recent changes in drug availability, supply chains, therapeutic targets, and ocular drug-delivery systems have altered the treatment landscape for patients with noninfectious uveitis (NIU). This review summarizes recent advances in local and systemic therapies for NIU and highlights the persistent need for safe, effective, durable, and individualized treatment options.
Local Corticosteroids
Corticosteroids remain the cornerstone of treatment for acute ocular inflammation. Local corticosteroid therapy can deliver medication directly to the posterior segment while limiting the systemic adverse effects associated with prolonged systemic corticosteroid use.
The fluocinolone acetonide 0.59 mg intravitreal implant (Retisert; Bausch + Lomb) received US Food and Drug Administration (FDA) approval in 2005 and was the first intravitreal corticosteroid implant approved for chronic NIU. The landmark Multicenter Uveitis Steroid Treatment trial was a randomized, double-masked clinical trial comparing systemic therapy to the fluocinolone acetonide 0.59 mg intravitreal implant. At 54 months, the visual outcomes were similar in both groups, although the implant provided superior inflammation control.1-3
As newer office-based local therapies became available, the use of the surgically implanted 0.59 mg fluocinolone acetonide device declined. Retisert is no longer commercially marketed by Bausch + Lomb because of changes in product availability and supply. Its withdrawal has created a therapeutic gap, particularly for patients with unilateral disease or those who cannot tolerate systemic immunosuppressive treatment.
The fluocinolone acetonide 0.19-mg intravitreal implant (Iluvien; ANI Pharmaceuticals) is a nonbiodegradable, office-based injectable implant that provides sustained corticosteroid delivery for up to 36 months. In 2025, the FDA approved consolidation of the labeling for 2 bioequivalent fluocinolone acetonide strengths into a single prescribing information document for Iluvien, expanding its indication to include chronic posterior NIU. The fluocinolone acetonide 0.18-mg intravitreal implant (Yutiq; ANI Pharmaceuticals) is no longer commercially available.
At 3 years, patients treated with the fluocinolone acetonide implant experienced a lower frequency of recurrence (65.5%) than patients receiving sham treatment (97.6%). The median time to first recurrence was also substantially longer with the implant (657 days) than with sham treatment (70.5 days).4 Although cataract progression and intraocular pressure (IOP) elevation remain important adverse effects, rates of glaucoma surgery are lower than with the surgically implanted Retisert device.
These changes have made Iluvien an important long-duration local treatment option for selected patients. Nevertheless, there remains a need for biodegradable long-acting implants that provide durable therapy without leaving a permanent nonbiodegradable intraocular device.
Suprachoroidal triamcinolone acetonide injectable suspension 40 mg/mL (Xipere; Bausch + Lomb) was approved by the FDA in 2021 to treat uveitic macular edema. Delivered into the suprachoroidal space, it provides targeted corticosteroid therapy to the posterior segment while potentially reducing the risk of cataract progression and IOP elevation.
The PEACHTREE and MAGNOLIA trials demonstrated sustained improvement in vision compared with those receiving the sham procedure, with an excellent safety profile.5-7 Suprachoroidal administration therefore represents an innovative approach to compartment-specific ocular drug delivery. Its principal role is currently the treatment of uveitic macular edema rather than control of intraocular inflammation.
Intravitreal triamcinolone remains a useful option for rapid local control of inflammation and macular edema. It may be used as rescue therapy, as a bridge while systemic immunosuppressive treatment becomes effective, or as a therapeutic trial to assess corticosteroid responsiveness and intraocular pressure tolerance.8 Its relatively limited duration of action and risks of cataract formation and ocular hypertension restrict its suitability as a durable long-term strategy. Nevertheless, it remains accessible, familiar to clinicians, and effective in appropriately selected patients.
Systemic Immunosuppression
The stepladder approach is a structured strategy for uveitis management, escalating treatment according to disease severity, response, and side-effect risk. This strategy focuses on the rapid reduction of inflammation initially with local and systemic corticosteroids, while avoiding the associated long-term complications and adverse effects by transitioning and escalating to steroid-sparing therapies of immunosuppression once under control.
The SITE retrospective cohort study found that 57% of patients with NIU achieved remission within 1 month of receiving 500 to 1,000 mg of methylprednisolone daily for up to 3 days followed by an oral prednisone taper.9
Although very effective at reducing ocular inflammation, long-term systemic corticosteroids come with significant toxicity, including hyperglycemia, osteoporosis, suppression of the adrenal gland, and psychiatric symptoms. To avoid these adverse effects, systemic corticosteroids are often either used in combination with or transitioned to disease-modifying antirheumatic drugs (DMARDs) and biologics.
Conventional DMARDs are commonly used first-line steroid-sparing therapies for chronic NIU. Methotrexate and mycophenolate mofetil are the most frequently used agents, achieving inflammatory control in approximately 52% to 77% of patients with intermediate, posterior, or panuveitis.10-12 The FAST trial demonstrated comparable efficacy and safety between these agents.13 Azathioprine is considered less effective and has a higher discontinuation rate due to intolerable adverse effects.14
Overall, conventional DMARD responses vary considerably, and prolonged systemic exposure can cause hepatotoxicity, nephrotoxicity, bone marrow suppression, and infections. Limited ocular penetration may require higher systemic doses, highlighting the need for localized, targeted, and durable immunomodulatory therapies.15
Biologic agents like adalimumab, infliximab, and tocilizumab have transformed the management of NIU by allowing more selective inhibition of inflammatory pathways. They are generally used when conventional immunosuppressive therapy is ineffective, poorly tolerated, or insufficient to achieve corticosteroid-sparing disease control.
A decade after its initial approval, adalimumab (Humira; AbbVie), a tumor necrosis factor alpha (TNF) inhibitor, remains the only FDA-approved systemic therapy for intermediate uveitis, posterior uveitis, and panuveitis. The landmark VISUAL I and VISUAL II trials demonstrated that adalimumab significantly reduced the risk of treatment failure compared with placebo.16 Long-term results from the VISUAL III extension study showed sustained disease quiescence, improved visual acuity, and reduction of daily corticosteroid use, supporting its efficacy and safety as long-term treatment for chronic NIU.17,18
Infliximab (Remicade; Johnson & Johnson), delivered via intravenous infusion, represents another anti-TNF agent used in NIU treatment, although its use is off label. One retrospective study found that when given at week 0, 2, and 6 and then every 4 weeks until clinical remission at a dose of 4 to 6 mg/kg, 81.8% of patients achieved clinical remission. Adverse effects associated with anti-TNF agents include infusion reactions, gastrointestinal distress, hepatotoxicity, demyelination, and increased risk of malignancy and infection.19
Tocilizumab (Actemra; Genentech), an interleukin-6 (IL-6) receptor inhibitor, is used off-label for NIU and has shown particular efficacy in refractory uveitic macular edema. In the STOP-Uveitis trial, patients were randomized to receive intravenous tocilizumab at either 4 mg/kg or 8 mg/kg every 4 weeks. At 6 months, both groups demonstrated improvements in vitreous haze, visual acuity, and central macular thickness, along with good dose tolerance.20
A French multicenter study reported higher rates of macular edema resolution with tocilizumab than with anti-TNF agents, supporting its use in selected patients with treatment-resistant macular edema.21
Interleukin-1 inhibitors, including anakinra (Kineret; Sobi) and canakinumab (Ilaris; Novartis), have been studied in NIU with variable results. Early reports suggested potential efficacy, particularly in Behçet disease–associated uveitis. However, in a multicenter randomized clinical trial comparing adalimumab, anakinra, and tocilizumab, the anakinra treatment arm was terminated early after an interim analysis demonstrated insufficient effectiveness.22 Additional research is needed to clarify the role of interleukin-1 inhibition in specific uveitis phenotypes.
Alkylating agents such as cyclophosphamide and chlorambucil are potent immunosuppressive medications generally reserved for severe, vision-threatening disease that is refractory to safer therapies. These agents alkylate DNA and interfere with DNA replication and cross-linking, rapidly suppressing T-cell and B-cell lymphocyte activity and antibody production. In the SITE cohort, 76% of patients treated with cyclophosphamide achieved remission at 12 months. However, treatment was discontinued in 33.5% of patients because of adverse effects.23 Use of these agents therefore requires careful patient selection and close monitoring, given serious potential adverse effects and increased lifetime risk of malignancy.
Emerging Therapies and Pipeline Agents
Janus kinase (JAK) inhibitors may represent an important therapeutic shift in NIU because they can inhibit signaling from multiple proinflammatory cytokines, including IL-2, IL-6, IL-12, IL-17, and IL-23, as well as interferons.
Potential advantages include oral administration, relatively short half-lives, reduced risk of antidrug antibody formation, and potentially lower manufacturing costs than injectable biologic therapies.
Small retrospective case series have described successful remission of NIU in patients receiving tofacitinib (Xeljanz; Pfizer), a preferential JAK1 and JAK3 inhibitor, or upadacitinib (Rinvoq; AbbVie), a selective JAK1 inhibitor. These observations remain preliminary and require confirmation in prospective controlled studies.24
The HUMBOLDT trial was a double-masked, placebo-controlled phase 2 randomized clinical trial evaluating oral filgotinib, a selective JAK1 inhibitor, at a dose of 200 mg daily. The study was terminated prematurely for business reasons. Analysis of the available data nevertheless demonstrated a lower treatment-failure rate among patients receiving filgotinib than among those receiving placebo, at 37.5% vs 67.6%.25 Although the study did not proceed to full completion, its results provide proof of concept for targeting the JAK pathway in NIU.
Brepocitinib (Priovant Therapeutics) is an investigational oral inhibitor of TYK2 and JAK1. Through JAK1 inhibition, it affects signaling from several inflammatory cytokines. TYK2 inhibition additionally interferes with interleukin-12 and interleukin-23 signaling.
Its oral administration and lack of biologic immunogenicity make it an attractive candidate for chronic inflammatory diseases. Brepocitinib is being evaluated in the phase 3 CLARITY clinical trial in patients with NIU. The results of this trial may help determine whether oral targeted small-molecule therapy can provide effective, durable control of ocular inflammation while reducing dependence on corticosteroids and injectable biologic agents.26
Future Directions
Despite the increasing number of available treatments, major unmet needs remain in the management of NIU. Safer, sustained, targeted anti-inflammatory therapies are needed to reduce corticosteroid exposure and prevent irreversible structural damage from recurrent inflammation.
The discontinuation of Retisert has highlighted the need for durable local therapy, particularly for patients with severe unilateral disease and those who cannot tolerate systemic immunosuppression. An ideal replacement would provide prolonged, controlled corticosteroid or immunomodulatory delivery through a biodegradable platform, minimizing the need for repeated injections or permanent intraocular devices.
Novel drug classes and innovative delivery systems represent complementary strategies for improving long-term outcomes. Future therapies may target multiple components of the inflammatory cascade, improve penetration into posterior-segment tissues, and reduce systemic exposure.
Validated biomarkers are also needed to predict disease course, treatment response, and the risk of relapse. Current treatment selection remains largely empirical and is not routinely guided by molecular profiling. Individual differences in immune responses, pharmacokinetics, environmental exposures, and genetic background further limit treatment predictability.
Nanomedicine-based delivery may permit targeted and sustained ocular drug release, reduce dosing frequency, and limit systemic exposure. Such systems could potentially carry corticosteroids, conventional immunosuppressive agents, biologic therapies, small interfering RNA, or other pathway-specific treatments.
The ultimate objective is to transition from broadly suppressive, empirically selected therapy toward precision treatment guided by disease phenotype, molecular mechanisms, biomarkers, and individual risk factors.
Early referral to tertiary centers with expertise in uveitis remains important, particularly for patients with severe, atypical, recurrent, or treatment-resistant disease. Specialized centers may provide access to multidisciplinary care, advanced diagnostic testing, clinical trials, and emerging therapies that are not widely available.
Conclusions
The treatment landscape for NIU continues to evolve. Conventional antimetabolites and biologics remain central to systemic management, although JAK and TYK2 inhibitors represent promising oral alternatives that may allow simultaneous modulation of several inflammatory pathways.
Despite these advances, important therapeutic gaps remain. Current regimens are frequently empirical, systemic therapies lack ocular specificity, and durable local treatments continue to carry substantial risks of cataract and glaucoma. The loss of previously available long-acting implants has further emphasized the need for sustained, biodegradable, and targeted ocular drug-delivery systems. Future progress will depend on integrating novel therapeutic targets with precision medicine, validated biomarkers, and innovative delivery technologies. These advances may ultimately allow more individualized and durable control of ocular inflammation while minimizing local and systemic toxicity. RP
William R. Bloom, MD, is a PGY4 resident at The Ohio State University in Columbus, Ohio. He reports no financial disclosures.
Ana M. Suelves, MD, PhD, is an assistant professor in the vitreoretinal and uveitis service at The Ohio State University, and codirector of the multidisciplinary uveitis clinic. She reports no financial disclosures. Reach her at ana.suelvescogollos@osumc.edu.
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