Current trends of biologic therapies in uveitis and scleritis

Immunopathogenesis of uveitis and scleritis: Rationale for targeted biologics

It is crucial to understand the mechanisms underlying ocular inflammation for the selection of biologic agents. The inflammatory milieu in uveitis and scleritis is orchestrated by complex cytokine networks, prominently involving tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), interleukin-17 (IL-17), and interleukin-23 (IL-23). The cytokines drive the recruitment and activation of immune cells, disrupt the integrity of the blood-ocular barrier, promote leukocyte infiltration, and culminate in tissue damage.⁴ Multiple immune cell subsets, including T helper (Th1 and Th17) cells, B cells, macrophages, and dendritic cells, participate in this inflammatory cascade. In several immune-mediated ocular diseases, such as Behçet’s disease and juvenile idiopathic arthritis (JIA) associated uveitis, the Th17/IL-17/IL-23 axis plays a pivotal role, whereas B-cell activity, through autoantibody production and antigen presentation, is particularly relevant in vasculitis and systemic disease-associated uveitis.^5,6

Comparatively, scleritis involves inflammation of the deeper scleral and vascular structures, often driven by immune complex deposition, complement activation, and collagen degradation.⁷ The therapeutic efficacy of agents targeting TNF-α, IL-6, and B cells in both uveitis and scleritis underscores the shared immunopathogenic pathways between these entities. Moreover, the unique ocular pharmacokinetic barriers, the blood-retina and blood-aqueous barriers, significantly influence drug bioavailability and treatment response.⁸ To overcome these limitations, novel strategies such as intravitreal or periocular biologic delivery, sustained-release implants, and localized formulations are being explored to achieve higher intraocular concentrations with reduced systemic exposure.⁹

Adalimumab

Adalimumab is a fully humanized IgG1 monoclonal antibody that selectively binds to soluble TNF-α, neutralizing its interaction with p55 and p75 surface receptors.¹⁰ It was the first biologic agent to receive U.S. FDA approval (Humira®, anti-TNF-α, AbbVie) in 2016 for the treatment of non-infectious intermediate, posterior, and panuveitis.¹¹ Clinical evidence from the VISUAL I and II, study phase III trials established its efficacy in both active and inactive Non-infectious uveitis (NIU). In these multicenter, double-masked, randomized studies, adalimumab demonstrated a 50% reduction in the risk of treatment failure compared to placebo, with significant improvement in visual acuity and reduced corticosteroid dependency. The VISUAL I and II trials demonstrated that adalimumab significantly delays treatment failure in active NIU and prevents flare in quiescent disease during corticosteroid tapering.¹² The VISUAL III open-label extension further confirmed sustained disease quiescence and prolonged remission during long-term follow-up.¹³

Adalimumab is particularly effective in Behçet’s disease uveitis [Figures 1, 2a-b], JIA-associated uveitis, and HLA-B27-associated anterior uveitis [Figures 3a-b], where it reduces relapse rates.^14,15 Its superior tolerability and fully humanized composition minimize the risk of antibody formation compared with chimeric agents.

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Figure 1:

Photograph of an oral aphthous ulcer in a 28-year-old male with Behcet’s disease and a history of recurrent oral and leg ulcers.

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Figure 2:

(a) Fundus photographs of a 28-year-old male with Behcet’s disease. Pre-treatment image showing active posterior uveitis. (b) Post-treatment image after eight biweekly subcutaneous injections of adalimumab along with oral immunosuppressant and oral steroid in tapering doses, demonstrating marked resolution of vitritis and vasculitis, with clear media and a restored macular reflex. Visual acuity improved from 6/60 to 6/9, and associated oral and leg ulcers healed completely.

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Figure 3:

(a) Anterior segment photographs of a 38-year-old female with HLA-B27-positive, reactive arthritis presenting with acute anterior uveitis in the right eye. Pre-treatment image (a) shows anterior chamber inflammation. (b) Post-treatment image demonstrates significant reduction in inflammation following the first subcutaneous dose of adalimumab, topical steroids, cycloplegics & oral steroids in tapering dose. The patient showed sustained improvement, and therapy was discontinued after 6 months.

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Common adverse effects include mild injection-site reactions and headache, while serious complications such as opportunistic infections, malignancy, and tuberculosis reactivation necessitate prior screening and periodic monitoring.^16,17

Infliximab

Infliximab is a chimeric monoclonal antibody composed of human constant and murine variable regions that binds both soluble and transmembrane TNF-α.¹⁸ It is administered intravenously and exhibits a rapid onset of action, making it particularly valuable in severe or sight-threatening uveitic flares.¹⁹ Infliximab has shown robust efficacy in Behçet’s disease-associated panuveitis, sarcoidosis-related posterior uveitis, and Vogt-Koyanagi-Harada syndrome.^20-23 In a multicenter retrospective study, 82% of patients with refractory NIU achieved clinical remission following infliximab therapy. Pediatric studies further demonstrated good tolerability at high doses (10-20 mg/kg) with rapid suppression of inflammation after the second infusion.²⁴ Comparative analyses have revealed similar efficacy between infliximab and adalimumab, though infliximab may exert a more pronounced corticosteroid-sparing effect in some cohorts.¹⁹ The principal limitations include infusion reactions, immunogenicity with anti-drug antibody formation, and risk of delayed hypersensitivity. Concomitant use of methotrexate can reduce these immune responses.¹⁸

While intravenous infliximab remains the gold standard for systemic therapy, intravitreal formulations have also been explored in select refractory cases with favorable short-term safety profiles.²⁰

Eternecept

Etanercept is a dimeric fusion protein composed of two extracellular domains of the human p75 TNF receptor linked to the Fc fragment of IgG1. It binds both TNF-α and TNF-β, thereby blocking receptor-mediated signaling.²⁵

Although highly effective in systemic autoimmune diseases such as rheumatoid arthritis and ankylosing spondylitis, its role in uveitis remains controversial. Several reports have documented poor ocular efficacy and even paradoxical induction or exacerbation of uveitis during treatment.^26,27

In randomized studies, etanercept failed to reduce uveitis relapse rates compared to placebo. The paradoxical inflammation is hypothesized to arise from its incomplete neutralization of membrane-bound TNF-α, and possible alterations in cytokine balance favoring Th17 activation. Thus, etanercept is not recommended as a first-line biologic in NIU and should be used cautiously or substituted with monoclonal antibodies when ocular involvement occurs.^28,29

Golimumab

Golimumab is a fully human IgG1 monoclonal antibody that binds both soluble and transmembrane TNF-α, with a longer half-life permitting monthly subcutaneous administration. Evidence supports its use in refractory cases of JIA-associated, HLA-B27-related, and Behçet’s disease-associated uveitis, particularly where previous anti-TNF therapy has failed. In a multicenter study of ankylosing spondylitis-associated uveitis, golimumab significantly reduced recurrence rates and ocular inflammation scores, with a favorable safety profile and minimal immunogenicity.³⁰ Case series have further shown sustained remission and improved best-corrected visual acuity over 12 months.³¹

Reported adverse events are mild and include injection-site reactions, upper respiratory tract infections, and antinuclear antibody positivity. Its fully human structure minimizes allergic responses, making it an attractive option for long-term biologic therapy.³²

Certolizumab

Certolizumab pegol is a PEGylated Fab’ fragment of a humanized anti-TNF-α monoclonal antibody lacking the Fc portion, which decreases complement-mediated cytotoxicity and placental transfer.³³ This unique structure makes it safer during pregnancy compared to other anti-TNF agents.³⁴

Though large uveitis-specific trials are lacking, certolizumab has demonstrated promising results in rheumatoid arthritis, Crohn’s disease, and spondyloarthropathies, with extrapolated benefit in associated ocular inflammation.³⁵

The C-VIEW trial showed significant reduction in acute anterior uveitis flares among patients with ankylosing spondylitis receiving certolizumab.³⁶ Its tolerability profile is favorable, with minimal injection reactions and low immunogenicity. Ongoing studies are expected to elucidate its role in ocular disease and expand therapeutic indications.³⁷

IL-6 pathway inhibitors

IL-6 is a pro-inflammatory cytokine implicated in the pathogenesis of several autoimmune and ocular inflammatory diseases, including uveitis. Tocilizumab, a recombinant humanized monoclonal antibody targeting IL-6 receptor (IL-6R), has demonstrated significant efficacy in refractory cases of NIU. In the STOP-Uveitis randomized clinical trial, monthly intravenous infusions of tocilizumab at doses of 4 or 8 mg/kg resulted in marked improvement in central macular thickness and visual acuity with good tolerability.³⁸

Tocilizumab has been increasingly reported for uveitic macular edema, refractory NIU, and scleritis. It may be particularly helpful when there is macular edema or when anti-TNFs are inadequate or poorly tolerated.³⁹

Sarilumab, another IL-6R monoclonal antibody, has recently been evaluated in the SATURN phase II study, which showed improvement in macular edema and visual outcomes among NIU patients refractory to corticosteroids and immunomodulatory therapy.⁴⁰

IL-1 and IL-1β inhibitors

Interleukin-1 and its subtype IL-1β are pivotal mediators of the inflammatory cascade in ocular diseases. Anakinra, a recombinant IL-1 receptor antagonist, competitively inhibits IL-1 binding and reduces cytokine-mediated inflammation. It has been used successfully in Behçet’s disease and cryopyrin-associated periodic syndromes with associated uveitis refractory to TNF-α inhibitors.⁴¹ Clinical improvement has also been documented in chronic infantile neurological cutaneous articular (CINCA) syndrome-associated posterior uveitis.⁴²

Canakinumab, a fully human monoclonal antibody specifically targeting IL-1β, has shown effectiveness in refractory Behçet’s disease-related uveitis, reducing retinal vasculitis and inflammatory recurrences. Case reports have also demonstrated remission in JIA-related uveitis with 150 mg subcutaneous dosing every 6 weeks.⁴³

Gevokizumab, another IL-1β inhibitor, demonstrated rapid resolution of inflammation and decreased vitreous haze in small-scale studies; however, larger Phase III trials (EYEGUARD series) failed to achieve primary endpoints, despite secondary benefits like reduced macular edema and corticosteroid-sparing effect.⁴⁴

IL-17 pathway inhibitors

IL-17A, produced by Th17 cells, contributes to ocular inflammation by inducing chemokines and enhancing neutrophil recruitment. Secukinumab, a fully humanized monoclonal antibody against IL-17A, initially showed promise in uveitis secondary to ankylosing spondylitis and Vogt-Koyanagi-Harada syndrome. However, phase III clinical trials (SHIELD, INSURE, and ENDURE) found no significant difference in uveitis recurrence compared with placebo.⁴⁵ While secondary analyses suggested a corticosteroid-sparing effect, occasional paradoxical worsening of Behçet’s disease has been reported, warranting cautious use.⁴⁶

IL-23 and IL-12 pathway inhibitors

Ustekinumab is a monoclonal antibody targeting the shared p40 subunit of IL-12 and IL-23, both critical for Th1 and Th17 differentiation. Elevated IL-23 levels have been identified in active Behçet’s and Vogt-Koyanagi-Harada uveitis. Preliminary reports and ongoing clinical trials (STELABEC-1/2, USTEKINISU) suggest its potential in refractory NIU with acceptable safety.^47,48

Other anti-IL-23 agents, including guselkumab and risankizumab, have shown efficacy in systemic inflammatory diseases such as psoriasis and Crohn’s disease, though ocular data remain limited. Rare paradoxical worsening of ocular inflammation has been observed in isolated cases, emphasizing the need for disease-specific trials.⁴⁹

IL-2 pathway inhibitors

IL-2 signaling plays a central role in T-cell activation and proliferation. Daclizumab and basiliximab, both monoclonal antibodies directed against the IL-2 receptor α-chain (CD25), inhibit T-cell activation. Daclizumab demonstrated promising outcomes in long-term Phase I/II studies involving refractory birdshot retinochoroidopathy and JIA-associated uveitis. However, due to reports of inflammatory brain disorders and hepatic dysfunction, it was withdrawn globally in 2018.^50,51 Basiliximab has shown occasional benefit in isolated refractory uveitis cases but lacks large-scale validation.⁵²

B-cell and T-cell targeted therapies

Rituximab, a chimeric monoclonal antibody against the CD20 antigen on B lymphocytes, induces selective B-cell depletion. It has shown efficacy in refractory cases of granulomatosis with polyangiitis-associated scleritis, retinal vasculitis, and JIA-related uveitis, with several case series reporting sustained remission up to 24 months.^53,54 Comparative studies have indicated that rituximab achieves significant improvement in disease control compared with cyclophosphamide-based regimens, with fewer systemic toxicities. Common adverse events include infusion reactions, infections, and transient lymphopenia.

Abatacept, a CTLA-4-Ig fusion protein that modulates T-cell co-stimulation, has also been used in JIA-associated uveitis refractory to anti-TNF therapy. It blocks CD80/CD86-mediated T-cell activation, reducing the inflammatory cascade. Retrospective data support its utility in pediatric uveitis, though relapses may occur after withdrawal.⁵⁵

JAK inhibitors

Janus kinase (JAK) inhibitors are a newer class of small-molecule drugs that act by blocking the JAK-STAT signaling pathway, which mediates the effects of several pro-inflammatory cytokines, including IL-2, IL-6, IL-12, and interferon-γ. Since these cytokines are key drivers of ocular inflammation, JAK inhibitors offer a targeted and convenient oral alternative to biologic injections for the management of refractory noninfectious uveitis and scleritis. The most studied agent, tofacitinib, primarily inhibits JAK1 and JAK3 and has shown promising outcomes in early trials and case reports by reducing intraocular inflammation, improving visual acuity, and decreasing steroid dependence in patients unresponsive to conventional immunosuppressants or anti-TNF therapy.^56,57

Second-generation agents such as upadacitinib (JAK1-selective) and baricitinib (JAK1/JAK2) are being explored for ocular inflammation, aiming for better efficacy and fewer systemic side effects.⁵⁸ Their oral route, rapid onset, and broad cytokine blockade make them attractive options in the evolving biologic landscape. However, careful monitoring for infections, liver enzyme elevation, and thromboembolic risks is essential.^59,60

Biologics for scleritis

Scleritis, especially necrotizing and vasculitic types, often reflects systemic autoimmune disease (e.g., granulomatosis with polyangiitis). Rituximab (anti-CD20) has strong real-world evidence and series supporting efficacy and steroid-sparing remission in ANCA-associated scleritis and refractory cases.⁶¹ Anti-TNF agents (infliximab, adalimumab) also show benefit in non-necrotizing scleritis in observational cohorts.

Biosimilars

Biosimilar formulations have markedly improved access to biologic therapy worldwide. Adalimumab and infliximab biosimilars demonstrate comparable efficacy and safety in maintaining remission and reducing corticosteroid dependence, with significant cost savings.^62,63 Real-world data from India and Nepal confirm that biologic and biosimilar use is both feasible and effective in resource-limited settings, though logistical and financial barriers persist.^64,65