Current trends in immunomodulatory therapy use in non-infectious uveitis

An examination of the use of immunomodulatory therapy, specifically methotrexate and adalimumab, in the treatment
of non-infectious uveitis, and exploration of the emerging role of novel biologics such as tocilizumab and anakinra

Uveitis, defined as inflammation of the uveal tract, encompasses a group of potentially sight-threatening inflammatory disorders that are often associated with systemic inflammatory diseases.¹ Anatomically classified as anterior, intermediate, posterior, or panuveitis, it describes inflammation of the middle, pigmented vascular structure of the eye.² Uveitis may involve a single site within the uveal tract or multiple uveal structures simultaneously.² Despite being uncommon, its cumulative burden on vision is substantial: It is the third most common cause of blindness in the working-age population, and according to a 2004 study, an estimated 70 per cent of patients suffer visual loss, with approximately 20 per cent meeting criteria for legal blindness over a mean follow-up of three years.³ Visual morbidity in uveitis arises secondary to glaucoma, cataract, cystoid macular oedema, or the formation of choroidal neovascular membranes.²

The objectives of treatment in non-infectious uveitis are to achieve rapid control of inflammation, prevent vision-threatening complications such as glaucoma, and obtain resolution of both ocular and extraocular manifestations.⁴ Corticosteroids have historically served as the cornerstone of uveitis management, and current expert consensus recommends initiating non-infectious uveitis treatment with systemic or local corticosteroids.⁴ However, prolonged corticosteroid use carries significant risks including cataracts, glaucoma, and osteoporosis, necessitating strategies to minimise long-term exposure.⁴ Long-term systemic steroid exposure should particularly be minimised in children, given the metabolic consequences on growth.⁴ Conventional immunosuppressive drugs and biological therapies therefore play an essential role in achieving and maintaining disease quiescence.

The use of immunomodulatory therapy

This paper discusses the use of immunomodulatory therapy, specifically methotrexate and adalimumab, in the treatment of non-infectious uveitis, and explores the emerging role of novel biologics such as tocilizumab and anakinra. To contextualise real-world practice, a global study by Branford et al involving 221 uveitis-specialised post-fellowship ophthalmologists across 53 countries examined current approaches to initiating and monitoring systemic immunomodulatory therapy.⁵

Over the past two decades, significant international efforts have shaped treatment strategies in this field. A key early milestone was the 2005 publication of standardised disease description criteria by the SUN Working Group. Subsequent landmark studies further advanced the field: The multicentre SITE Cohort Study demonstrated the efficacy of conventional immunosuppressive agents, while the VISUAL programme of trials established TNF-α blockade as an effective biological therapy. Building on these foundations, various expert groups have produced evidence-based guidelines outlining best practice for systemic immunomodulatory treatment. While such recommendations exist, real-world practice is also shaped by the practical availability of drugs, including generics, and individual clinician experience.

Findings from Branford et al revealed that oral prednisolone remains the standard first-line systemic treatment for non-infectious uveitis.⁵ Systemic immunomodulatory drugs were indicated when uveitis was not controlled with a course of oral prednisolone, for specific uveitis diagnoses, patient intolerance of prednisolone, and/or contraindication to locally delivered corticosteroid. Reported systemic immunomodulatory drugs included methotrexate, azathioprine, mycophenolate, and ciclosporin. Methotrexate was the first choice for 125 members and the most common first-line conventional drug for nine of 11 uveitides, including juvenile idiopathic arthritis (JIA)-associated uveitis, HLA-B27-positive uveitis, and sarcoid uveitis. Regarding biological therapy, 14 agents were in use, with nearly all study group members employing adalimumab for non-infectious uveitis – making it the most common first-line biological drug across 11 uveitides. Other agents used included infliximab, rituximab, and tocilizumab. The most common drug combination employed was methotrexate and adalimumab. Notably, a consistent approach was observed across the study group regarding prednisolone use, selection of conventional and biological agents, indications for treatment, pre-treatment screening, and drug monitoring.

Methotrexate

Methotrexate, an anti-metabolite, exerts its therapeutic effect through inhibition of dihydrofolate reductase, thereby disrupting folic acid metabolism and preventing thymidine formation required for DNA and RNA synthesis.⁵ This in turn prevents lymphocyte proliferation and reduces immune-mediated inflammation.⁵ The selection of methotrexate as a first-line agent in non-infectious uveitis is well-supported by existing literature.⁵ The First-line Antimetabolites as Steroid-Sparing Treatment Trial (FAST) demonstrated that methotrexate performed significantly better in the treatment of posterior or panuveitis compared to mycophenolate mofetil – a reversible inhibitor of inosine monophosphate dehydrogenase. The SITE Cohort Study similarly supported the efficacy of methotrexate, demonstrating effective inflammation control and successful corticosteroid tapering in a significant proportion of patients with ocular inflammatory disease. Comparative studies further suggest that methotrexate performs as well as, if not better than, other corticosteroid-sparing agents such as azathioprine and ciclosporin.⁵

Methotrexate is of particular importance in the management of JIA-associated uveitis – the most devastating extra-articular manifestation of JIA. In the European initiative, Single Hub and Access point for paediatric Rheumatology in Europe (SHARE), a committee of 12 experts in paediatric rheumatology and ophthalmology reached unanimous agreement that methotrexate is the first choice for systemic immunosuppression in this context.⁶ The overarching goal of management in JIA-associated uveitis is to minimise visual loss through early identification and treatment of ocular morbidity.⁶ While topical corticosteroids have traditionally been first-line for both acute and chronic anterior uveitis in JIA, long-term use carries an increased risk of cataract formation and glaucoma.⁶ Systemic immunosuppression with methotrexate is therefore recommended when topical steroids are insufficient to eliminate ocular inflammation, when the doses required carry unacceptable risk, or when complications are present. In cases of methotrexate inefficacy or intolerance, escalation to or addition of biological therapy, particularly adalimumab, is recommended. Once long-lasting remission has been achieved and methotrexate is withdrawn, continued monitoring remains imperative, as patients remain at risk of new-onset or recurrent uveitis, particularly in the first year following cessation.

While topical corticosteroids have traditionally been first-line for both acute and chronic anterior uveitis in JIA, long-term use carries an increased risk of cataract formation and glaucoma

Adalimumab

Adalimumab, a fully human anti-tumour necrosis factor α (TNF-α) monoclonal antibody,⁷ has proven to be highly effective in the treatment of non-infectious uveitis.⁸ TNF-α, a proinflammatory cytokine, plays a central role in mediating ocular inflammation and is elevated in the aqueous humour and serum of patients with uveitis.⁹ Targeted inhibition of TNF-α has thus become a key therapeutic strategy.¹⁰ The pivotal VISUAL I and II trials¹¹ – the most extensive randomised controlled phase 3 clinical trials of a TNF-α blocker in the uveitis field – demonstrated the effectiveness of adalimumab in controlling active uveitis and preventing flares of quiescent non-infectious intermediate, posterior, or panuveitis compared to placebo.⁸ These results led to widespread regulatory approval of adalimumab for non-infectious uveitis by both the US Food and Drug Administration and the European Medicines Agency.¹² Adalimumab monotherapy also effectively controlled several features of uveitic inflammation, reducing flare risk, and prolonging time to relapse compared to placebo,¹⁰ though it was associated with more adverse events.¹⁰ It is important to note that TNF-α blockade has been associated with demyelination, and adalimumab is therefore contraindicated in patients who have concurrent uveitis and multiple sclerosis.¹³ Nonetheless, the breadth of evidence supporting its efficacy validates adalimumab as the preferred biological drug in international real-world practice.⁵

Adalimumab monotherapy also effectively controlled several features of uveitic inflammation, reducing flare risk and prolonging time to relapse compared to placebo

Emerging biologics: Tocilizumab and anakinra

Despite the established efficacy of methotrexate and adalimumab, a subset of patients remains refractory to these treatments. Proteomic profiling by Velez et al revealed that patients with treatment-refractory uveitis demonstrated normal vitreous TNF-α levels, providing a mechanistic explanation for anti-TNF-α treatment failure.¹⁰ Separately, elevated IL-6 has been identified in the aqueous humour and vitreous of uveitis patients, highlighting IL-6 as a rational alternative therapeutic target in refractory disease.¹⁴ Tocilizumab, a humanised monoclonal antibody targeting the IL-6 receptor, has already demonstrated efficacy across numerous chronic inflammatory conditions, and emerging evidence supports its role in refractory non-infectious uveitis.¹⁵

A systematic review by Cao et al reported marked improvement in inflammatory markers and successful corticosteroid tapering in patients with non-infectious uveitis treated with tocilizumab, achieving a clinical remission rate of 83.3 per cent with notable improvements in both inflammation control and visual function.¹⁶ Critically, earlier initiation of tocilizumab was associated with superior outcomes; delayed treatment proved less effective at reversing irreversible visual loss.¹⁶ This finding argues compellingly for early escalation to biologics with novel mechanisms in patients refractory to conventional therapy, where cumulative tissue damage may otherwise accrue. Adverse events – including infusion reactions, elevated liver enzymes, and increased infection risk – were reported, but were generally manageable with appropriate monitoring.¹⁶

A further emerging therapeutic avenue is IL-1 blockade. Anakinra, a competitive IL-1 receptor antagonist, prevents activation of the IL-1-mediated immune response.¹⁷ IL-1β plays a crucial role in the Th17-driven inflammatory process underlying uveitis, acting via NF-κB activation in experimental models of autoimmune uveoretinitis.¹⁸ Uveitis has also been shown to improve following inhibition of IκB kinase β in endotoxin-induced animal models, particularly in disease driven by IL-1β and TNF-α oversecretion.¹⁸ Clinically, anakinra has suppressed immune-mediated ocular inflammation in patients with Blau syndrome,¹⁹ and CINCA syndrome.²⁰ Furthermore, across 19 consecutive patients with Behçet’s disease, anakinra demonstrated effectiveness in reducing ocular inflammatory flares and retinal vasculitis,²¹ with the notable reduction in intraocular flares confirming a therapeutic role for anti-IL-1 agents in Behçet’s disease-related uveitis.²¹

Conclusion

The global study by Branford et al,⁵ involving 221 uveitis-specialised ophthalmologists across 53 countries, provides a unique and contemporaneous description of real-world immunomodulatory practice in non-infectious uveitis – one that broadly reflects published guidelines while capturing the nuances of clinical experience. The management of non-infectious uveitis is undergoing significant evolution.

Methotrexate remains a robust and effective first-line conventional agent, while adalimumab has transformed outcomes for patients requiring biological therapy. Nevertheless, the persistence of treatment-refractory disease underscores the complexity of immune pathways underlying uveitis. Emerging evidence supporting tocilizumab and anakinra offers renewed hope for this difficult-to-treat population, and early initiation of targeted biological therapy may prove critical in preventing irreversible visual loss.

Ongoing evidence-based research will continue to advance and consolidate immunomodulatory therapy as a cornerstone in the future management of uveitis.

Maghsoudlou P, Epps SJ, Guly CM, Dick AD. Uveitis in adults: A review. JAMA. 2025;334(5):419-434

Tsirouki T, Dastiridou A, Symeonidis C, Tounakaki O, Brazitikou I, Kalogeropoulos C, et al. A focus on the epidemiology of uveitis. Ocul Immunol Inflamm. 2018;26(1):2-16

Durrani OM, Tehrani NN, Marr JE, Moradi P, Stavrou P, Murray PI. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol. 2004;88(9):1159-1162

Touhami S, Diwo E, Sève P, Trad S, Bielefeld P, Sène D, et al. Expert opinion on the use of biological therapy in non-infectious uveitis. Expert Opin Biol Ther. 2019;19(5):477-490

Branford JA, Bodaghi B, Ferreira LB, McCluskey PJ, Thorne JE, Matthews JM, et al. Use of immunomodulatory treatment for non-infectious uveitis: An International Ocular Inflammation Society report of real-world practice. Br J Ophthalmol. 2025;109(4):482-489

Constantin T, Foeldvari I, Anton J, De Boer J, Czitrom-Guillaume S, Edelsten C, et al. Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis: The SHARE initiative. Ann Rheum Dis. 2018;77(8):1107-1117

Mitoma H, Horiuchi T, Tsukamoto H, Ueda N. Molecular mechanisms of action of anti-TNF-α agents: Comparison among therapeutic TNF-α antagonists. Cytokine. 2018;101:56-63

Jaffe GJ, Dick AD, Brézin AP, Nguyen QD, Thorne JE, Kestelyn P, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375(10):932-943

Hale S, Lightman S. Anti-TNF therapies in the management of acute and chronic uveitis. Cytokine. 2006;33(4):231-237

Velez G, Bassuk AG, Colgan D, Tsang SH, Mahajan VB. Therapeutic drug repositioning using personalised proteomics of liquid biopsies. JCI Insight. 2017;2(24):e97818

Sheppard J, Joshi A, Betts KA, Hudgens S, Tari S, Chen N, et al. Effect of adalimumab on visual functioning in patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis in the VISUAL-1 and VISUAL-2 trials. JAMA Ophthalmol. 2017;135(6):511-518

Squires H, Poku E, Bermejo I, Cooper K, Stevens J, Hamilton J, et al. A systematic review and economic evaluation of adalimumab and dexamethasone for treating non-infectious intermediate uveitis, posterior uveitis, or panuveitis in adults. Health Technol Assess. 2017;21(68):1-170

Kaltsonoudis E, Voulgari PV, Konitsiotis S, Drosos AA. Demyelination and other neurological adverse events after anti-TNF therapy. Autoimmun Rev. 2014;13(1):54-58

Karkhur S, Hasanreisoglu M, Vigil E, Halim MS, Hassan M, Plaza C, et al. Interleukin-6 inhibition in the management of non-infectious uveitis and beyond. J Ophthalmic Inflamm Infect. 2019;9(1):17

Kang H, Wu X, Xu H, Huang Y, Zhang M. Effectiveness and safety of tocilizumab in refractory noninfectious uveitis: A systematic review and meta-analysis. Front Pharmacol. 2025;16:1694311

Cao H, Bian K, Ma C, Zhang N, Ma X. Tocilizumab for non-infectious uveitis: A systematic review. J Inflamm Res. 2025;18:13117-13138

Pasadhika S, Rosenbaum JT. Update on the use of systemic biologic agents in the treatment of noninfectious uveitis. Biologics. 2014;8:67-81

Lopalco G, Cantarini L, Vitale A, Lannone F, Anelli MG, Andreozzi L, et al. Interleukin-1 as a common denominator from autoinflammatory to autoimmune disorders: Premises, perils, and perspectives. Mediators Inflamm. 2015;2015:194864

Wu S, Zhong L, Sun Z, Zhu T, Song H, Sui R. Ocular features in Chinese patients with Blau syndrome. Ocul Immunol Inflamm. 2020;28(1):79-85

Koné-Paut I, Galeotti C. Anakinra for cryopyrin-associated periodic syndrome. Expert Rev Clin Immunol. 2014;10(1):7-18

Fabiani C, Vitale A, Emmi G, Lopalco G, Vannozzi L, Guerriero S, et al. Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behçet’s disease-related uveitis: A multicenter retrospective observational study. Clin Rheumatol. 2017;36(1):191-197