Tocilizumab (brand name: Actemra®) is a humanized monoclonal antibody that selectively inhibits the interleukin-6 (IL-6) receptor. IL-6 is an inflammatory cytokine involved in amplifying autoimmune responses.
It has received FDA approval for rheumatoid arthritis, systemic juvenile idiopathic arthritis (sJIA), and polyarticular juvenile idiopathic arthritis. Although its use for uveitis is off-label, multiple reports have shown efficacy in refractory cases resistant to TNF-α inhibitors. 2)
In a survey of 221 members of the International Ocular Inflammation Society (IOIS), 58.8% (130) of uveitis specialists had experience using tocilizumab. 1) It is the fourth most frequently used biologic after adalimumab (98.6%), infliximab (79.6%), and rituximab (62.9%). 1)
In Japan, tocilizumab is included among biologic options for uveitis associated with juvenile idiopathic arthritis, along with methotrexate and TNF-α receptor inhibitors (etanercept). It has insurance coverage for arthritis symptoms.
It is mainly used for refractory cases resistant to TNF-α inhibitors. Efficacy has been reported for Behçet’s disease-associated uveitis, juvenile idiopathic arthritis-associated uveitis, non-infectious retinal vasculitis, and refractory uveitic cystoid macular edema. 2) Its use for uveitis is currently off-label.
In non-infectious uveitis treated with tocilizumab, the following symptoms are the main complaints.
In non-infectious uveitis for which tocilizumab is considered, the following inflammatory findings are observed.
Anterior Segment Findings
Anterior chamber cells: Inflammatory cells floating in the anterior chamber. Evaluated using SUN grading.
Anterior chamber flare: Indicates breakdown of the blood-ocular barrier.
Keratic precipitates (KP): Mutton-fat KP suggests granulomatous inflammation.
Posterior synechiae: In chronic course, adhesions form between the iris and lens.
Posterior Segment Findings
Vitreous opacities: Observed in intermediate and posterior uveitis.
Cystoid macular edema (CME): A complication that is a major cause of vision loss.
Retinal vasculitis: Presents with perivascular sheathing and fluorescein leakage.
Optic disc leakage: Evaluated by fluorescein angiography.
In the report by Karaca et al., the mean baseline anterior chamber flare grade was 1.27 in the tocilizumab group (11 eyes), and cystoid macular edema was observed in 45.5% of cases 2).
The main etiologies of non-infectious uveitis for which tocilizumab is considered are as follows.
Non-infectious uveitis encompasses diverse pathologies based on autoimmune/autoinflammatory diseases, and vision loss due to complications such as macular edema, choroidal neovascularization, glaucoma, and hypotony is a concern 1).
Screening tests are mandatory before starting biologic therapy 1). According to an IOIS survey, almost all specialists performed the following.
The following tests are used to evaluate treatment efficacy for non-infectious retinal vasculitis.
| Test | Assessment Target | Notes |
|---|---|---|
| FA (Fluorescein Angiography) | Vascular leakage and inflammation extent | Semi-quantitative assessment using ASUWOG score2) |
| OCT | Central subfield thickness (CST) | Objective assessment of macular edema |
| Slit-lamp microscopy | Anterior chamber cells and flare | Assessment using SUN grading |
In the study by Karaca et al., the ASUWOG fluorescence angiography scoring system was shown to enable objective severity assessment of retinal vasculitis 2). This system semi-quantitatively scores fluorescein angiography findings on a 40-point scale.
It is comprehensively assessed by scoring on fluorescein angiography (FA), retinal thickness measurement on OCT, and counting of anterior chamber cells. In the report by Karaca et al., the ASUWOG FA scoring system was used, and significant improvement was confirmed at 6 months 2).
Systemic treatment for non-infectious uveitis is escalated stepwise using a step-ladder approach.
In this step-ladder, tocilizumab is positioned as the next option for cases resistant to TNF-α inhibitors (adalimumab, infliximab). 60.2% of specialists have experience using biologics without prior conventional immunosuppressants, with the reason being a specific uveitis diagnosis (91.0%) 1).
The standard administration of tocilizumab is as follows.
In the report by Karaca et al., 7 of 11 eyes (63.6%) started at 8 mg/kg, and 4 eyes (36.4%) started at 4 mg/kg and were increased to 8 mg/kg 2). Intravenous methylprednisolone (250–1000 mg/day for 1–3 days/month) was used concomitantly in 87.5% of patients 2).
In Japan, tocilizumab is one of the treatment options for uveitis associated with juvenile idiopathic arthritis. For arthritis symptoms, biologic agents such as methotrexate, tocilizumab (anti-IL-6 antibody), and etanercept (TNF-α receptor inhibitor) are covered by insurance. For anterior uveitis, topical steroid eye drops and mydriatics are the mainstay, and systemic biologic agents aim to improve ocular inflammation primarily through control of joint symptoms.
Karaca et al. (2023) retrospectively compared the 6-month treatment effects of infliximab (IFX group: 14 patients, 24 eyes) and tocilizumab (TCZ group: 8 patients, 11 eyes) for non-infectious retinal vasculitis 2). In the TCZ group, the ASUWOG FA score significantly decreased from 11.6±4.4 at baseline to 5.8±3.9 at 6 months (p=0.001). Central subfield thickness (CST) also significantly decreased from 353.2±97.3 μm to 299.1±36.8 μm (p=0.010). Cystoid macular edema completely resolved in 4 of 5 eyes. There was no significant difference in improvement between IFX and TCZ (p=0.923).
In the TCZ group, 75% (9 eyes corresponding to 4 of 6 patients) had prior IFX use and were switched due to insufficient efficacy or side effects 2). Despite this, they showed FA improvement comparable to IFX, suggesting that TCZ may be an effective alternative for IFX-refractory cases 2).
Multiple reports have shown the efficacy of tocilizumab for uveitis refractory to adalimumab or infliximab. In the report by Karaca et al., the FA score significantly improved in the TCZ group, including cases refractory to IFX 2). Because its mechanism of action (IL-6 inhibition) differs from that of TNF-α inhibitors, switching to tocilizumab is a reasonable option for treatment-resistant cases.
Tocilizumab is a humanized monoclonal antibody against the IL-6 receptor. It binds to both membrane-bound and soluble IL-6 receptors, inhibiting IL-6 signal transduction.
IL-6 is involved in the following inflammatory cascades:
Non-infectious uveitis is intraocular inflammation caused by autoimmune or autoinflammatory mechanisms. In the conventional step-ladder approach, inflammation is first suppressed with oral steroids, followed by conventional immunosuppressants such as methotrexate or mycophenolate mofetil to taper steroids 1).
Biologic agents are used as more target-specific approaches. TNF-α is a central cytokine in the inflammatory cascade, and adalimumab or infliximab, which inhibit it, are first-line biologic agents 1). Meanwhile, IL-6 is also involved in intraocular inflammation via an inflammatory pathway independent of TNF-α, providing the rationale for IL-6 inhibition being effective in cases refractory to TNF-α inhibitors.
In non-infectious retinal vasculitis, immune cell infiltration into the vessel wall and release of inflammatory cytokines cause vascular leakage, ischemia, macular edema, and vascular occlusion 2). Tocilizumab is thought to suppress IL-6-mediated activation of vascular endothelium and reduce inflammation of the vessel wall.
A phase II clinical trial (APTITUDE; ISRCTN95363507) evaluating the efficacy and safety of subcutaneous tocilizumab for juvenile idiopathic arthritis-associated uveitis has been reported 3). Among 21 children who were refractory to methotrexate and TNF inhibitors, 7 showed treatment response, but the primary endpoint was not met 3).
The IOIS survey results indicate that while tocilizumab is increasingly used in clinical practice, it has not been standardized to the same extent as adalimumab or infliximab 1). Along with mycophenolate mofetil, it is not included in major recommendation lists 1).
In a survey by Branford et al. (2025) involving 221 specialists from 53 countries, 81.9% considered biologic therapy insufficient after 3–6 months of trial 1). Tocilizumab was the first-line choice in 1.8% of Behçet’s disease uveitis, 1.4% of birdshot chorioretinopathy, and 0.5% of multifocal choroiditis, all significantly lower than adalimumab 1). Accumulating evidence from future prospective comparative trials remains a challenge.
In biologic therapies, the production of anti-drug antibodies can contribute to reduced efficacy 2). For infliximab, cases requiring dose escalation due to the emergence of anti-IFX antibodies have been reported. Tocilizumab has a relatively favorable side effect profile, and switching to tocilizumab has been reported effective in cases with anti-IFX antibody production or those who discontinued IFX due to side effects 2).
Currently, adalimumab is the first-line biologic agent. The APTITUDE trial did not meet the criteria to support a phase III trial, but it suggested that tocilizumab may be a treatment option for some patients refractory to TNF inhibitors 3).
