Comparing Long-Term Systemic Risks of Biologic Versus Conventional Therapy in Non-Infectious Uveitis

Highlight

• Biologic therapy in non-infectious uveitis (NIU) is linked to increased risks of serious infections and hematologic cytopenias over five years compared with no systemic treatment.
• Compared to conventional immunomodulatory therapy, biologics show a broadly comparable safety profile, with some increased risks of cytopenias, psychiatric illness, and hospitalizations.
• The study supports a stepwise immunosuppressive treatment approach in NIU and emphasizes individualized risk assessment and monitoring during therapy.

Study Background

Non-infectious uveitis (NIU) represents a significant cause of ocular morbidity, potentially leading to vision loss due to chronic intraocular inflammation. The disease requires systemic immunosuppression when local therapies are inadequate. While conventional immunomodulatory therapies such as corticosteroids and antimetabolites have been mainstays, biologic agents targeting specific immune pathways have emerged as effective treatment options. However, comparative data delineating long-term systemic safety profiles of biologics versus conventional agents in NIU are limited, posing challenges in clinical decision-making regarding their risk-benefit balance.

Study Design

This investigation is a multicenter retrospective cohort study utilizing data from the TriNetX Collaborative Network, including adult patients aged 18 years and older diagnosed with NIU between January 1, 2005, and January 1, 2024. The study employed International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes to identify eligible subjects.

Three propensity score-matched cohorts were assembled to compare systemic complication risks over five years: biologic therapy versus no systemic therapy (n=6,896 per group), biologic therapy versus conventional therapy with corticosteroids (n=5,994 each), and a subgroup analysis of combination biologic plus conventional therapy versus conventional therapy alone (n=3,653 each).

The primary outcomes evaluated time-to-event incidence of systemic complications, including serious infections (e.g., pneumonia, sepsis), hematologic cytopenias, heart failure, thromboembolic events, diabetes mellitus, malignancy, psychiatric illness, all-cause hospitalization, and mortality.

Key Findings

After rigorous propensity matching ensuring balance across measured covariates (standardized mean differences <0.1), the study revealed important distinctions in systemic risk profiles.

Biologic Therapy versus No Systemic Therapy

• Patients receiving biologic therapy exhibited significantly increased five-year risks of serious infections including pneumonia (HR: 1.41, 95% CI: 1.20–1.67) and sepsis (HR: 1.43, 95% CI: 1.16–1.77).
• Hematologic cytopenias were notably elevated (HR: 1.58, 95% CI: 1.44–1.74), with a cumulative incidence of over 30% in the biologic group.
• No statistically significant differences were detected for heart failure, thromboembolic events, diabetes mellitus, psychiatric illness, or all-cause mortality when compared to no systemic treatment.

Biologic Therapy versus Conventional Immunomodulatory Therapy

• The safety profiles were largely comparable between biologic and conventional therapy groups over five years.
• Biologic therapy was associated with increased risks of hematologic cytopenias (HR: 1.28, 95% CI: 1.16–1.41), psychiatric illness (HR: 1.13, 95% CI: 1.01–1.27), and hospitalization (HR: 1.20, 95% CI: 1.07–1.35).
• Other systemic complication risks including infections, heart failure, thromboembolism, diabetes, malignancy, and mortality did not differ significantly between these groups.

Combination Therapy Subgroup Analysis

The pre-specified subgroup analysis comparing combination biologic plus conventional therapy to conventional therapy alone was consistent with the main findings, indicating that additive systemic risks may be present but require further investigation to specify magnitude and clinical implications.

Expert Commentary

This study provides valuable real-world comparative safety data derived from a large multinational collaborative database, lending strength to its generalizability and clinical relevance. The raised risk of serious infections and hematologic cytopenias with biologic therapy aligns with known immunosuppressive mechanisms affecting host defense and bone marrow function.

Importantly, the comparable overall safety to conventional immunomodulatory agents supports current clinical practice guidelines endorsing biologics in refractory or severe cases of NIU, balancing efficacy against manageable systemic risks.

Limitations inherent to retrospective observational analyses include potential residual confounding and reliance on diagnostic coding accuracy. Additionally, the study did not dissect individual biologic agents or dosing regimens, which could differ substantially in safety profiles.

Further prospective studies and randomized trials are warranted to refine patient selection criteria, optimize monitoring strategies, and elucidate mechanistic pathways underlying observed psychiatric and hematologic side effects.

Conclusion

In adult patients with non-infectious uveitis, systemic biologic therapies demonstrated a higher incidence of serious infections and hematologic cytopenias compared to no systemic therapy but exhibited largely comparable five-year systemic safety profiles to conventional immunomodulatory therapies apart from modestly increased risks of cytopenias, psychiatric illness, and hospitalization.

These findings reinforce guideline-recommended stepwise immunosuppression in NIU and underscore the critical need for personalized risk assessment, vigilant infection surveillance, and hematologic monitoring in managing patients undergoing systemic treatment.

Funding and Clinical Trials Information

The study did not report external funding sources. ClinicalTrials.gov registration was not applicable given the retrospective observational study design.

References

1. Chauhan MZ, Muayad J, Surgent-Nahay JL, Shakoor A, Thorne JE, Sallam AB. Comparative Five-Year Risks of Systemic Complications with Biologic versus Conventional Therapy in Non-infectious Uveitis. Ophthalmology. 2026 Jul 6:S0161-6420(26)00464-1. doi: 10.1016/j.ophtha.2026.06.030. Epub ahead of print. PMID: 42409178.
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3. Nguyen QD et al. Safety and efficacy of biologic agents for noninfectious uveitis. Curr Opin Ophthalmol. 2016 Jul;27(4):364-70.