Interleukin-6 (IL-6) is a proinflammatory cytokine and a key player in multiple inflammatory cascades. It is produced systemically and intraocularly by monocytes, macrophages, and T cells and binds to a number of soluble and membrane-bound receptors [1,2,3]^[1][2][3] The effects of IL-6 include inducing the differentiation of CD-4-positive T-helper cells, augmenting the effect of transforming growth factor-beta, and inducing the production of vascular endothelial growth factor (VEGF) [1,2,3]^[1][2][3].

There are currently four different IL-6 inhibitors available from two different classes of medication: monoclonal receptor antibodies and monoclonal antibodies [1,2,3]^[1][2][3]. Monoclonal antibodies are antibodies produced by a single clone of B cells, resulting in monospecific and homogenous antibodies that allow targeted and therapeutic binding to a soluble antigen, such as IL-6. In contrast, monoclonal receptor antibodies are targeted antibodies to a specific receptor, such as the IL-6 receptor (IL-6R). Monoclonal receptor antibodies include tocilizumab, sarilumab, and satralizumab, while siltuximab is currently the only IL-6 monoclonal antibody biological drug available ^[1]. Tocilizumab is approved by the Federal Drug Administration (FDA) for use in treating uveitis in the setting of juvenile idiopathic arthritis (JIA), giant cell arteritis (GCA), rheumatoid arthritis (RA), and cytokine release syndrome [1,4]^[1][4]. Sarilumab is approved by the FDA for use in treatment-resistant RA [1,5]^[1][5]. However, in the setting of ocular disease, both tocilizumab and sarilumab are used off-label for treatment-resistant macular edema in the setting of uveitic and non-uveitic pathologies ^[2]. In particular, IL-6 inhibitors have been reserved for use in treatment-resistant macular edema unresponsive to traditional therapies such as steroids, tumor necrosis factor alpha (TNF-alpha) inhibitors, or anti-VEGF inhibitors [1,6]^[1][6].

2. The Role of Interleukin-6 in Ocular Pathology

IL-6 is a protein encoded by a gene in chromosome 7p21 and functions via signal transduction after binding IL-6R [1,2,3]^[1][2][3]. The two major forms of IL-6R are the transmembrane receptor protein (IL-6R) and the soluble receptor (sIL-6R) [1,2,3]^[1][2][3]. In the classic pathway, the binding of IL-6 and IL-6R along with a transmembrane glycoprotein gp130 leads to intracellular signal transduction via activation of the Janus kinase, signal transducer, and activator of transcription 3 (STAT3) and JAK-SHP2-Ras-mitogen activated protein kinase (MAPK) pathways [1,2,3]^[1][2][3] (Figure 1). The pleiotropic effect of IL-6 is largely due to the range of cells expressing gp130, which allows pleiotropic and redundant signaling [1,2,3]^[1][2][3]. IL-6 has been shown to be a key player in protecting the host against environmental hazards by causing a signal cascade as a warning signal, with an acute increase in the IL-6 levels occurring immediately at the onset of an acute inflammatory event [1,2,3]^[1][2][3]. Due to its involvement in the protective response, IL-6 is produced by multiple cells of the innate immune system as part of the integrated defense system. Pathogenic stimulation via pathogen-associated molecular patterns (PAMPs) or non-infectious inflammatory stimulation via damage-associated molecular patterns (DAMPs) from injured cells leads to the activation of Toll-like receptors (TLR). The activation of TLR leads to the expression of inflammatory cytokines, including IL-6, TNF-alpha, and IL-1 beta (Figure 2) [1,2,3]^[1][2][3]. TNF-alpha and IL-1 beta may trigger a positive feedback loop with the additional expression of IL-6, allowing for a rapid increase in the IL-6 levels. Liver hepatocytes respond to IL-6 by producing acute-phase proteins, including C-reactive protein, serum amyloid A, haptoglobin, and fibrinogen, which are responsible for acute and chronic inflammatory processes [1,2,3]^[1][2][3]. IL-6 also induces B-cell and T-cell differentiation. IL-6 induces helper T-cell differentiation and suppresses regulatory T-cell differentiation [1,2,3]^[1][2][3]. By increasing the helper T-cell population over the regulatory T-cell population, IL-6 stimulation lowers the immunologic tolerance, resulting in a higher likelihood of developing autoimmune inflammatory disease [1,2,3]^[1][2][3]. IL-6 plays a role in immunogenicity and inflammation in both systemic and ocular immune-mediated diseases, including juvenile idiopathic arthritis and NIU. Several studies have measured elevated IL-6 levels in ocular fluids, including aqueous fluid or vitreous in patients with NIU [1,6]^[1][6]. Outside of uveitis, elevated levels of IL-6 have also been found in multiple ocular diseases, including central vein occlusion [1,6]^[1][6]. In addition to its role in inflammation, IL-6 also plays a role in the production VEGF, which results in angiogenesis and vascular permeability [1,6]^[1][6]. Two of the major causes of VEGF induction include IL-6 and hypoxia, both of which are present in ocular pathologies such as retinal vein occlusions [1,6]^[1][6]. Vitreous levels of IL-6 and VEGF have been correlated with the severity of ischemia in patients with ischemic central retinal vein occlusion (CRVO) and correlated with disease severity [1,6]^[1][6]. In a systematic review published by Minaker et al., multiple studies have shown a significant elevation of IL-6, IL-8, IL-10, and VEGF in aqueous and vitreous samples of patients with RVO compared to healthy controls ^[7]. In diabetic retinopathy, the significant elucidation of IL-6′s role has occurred. Long-term hyperglycemia-related oxidative stress and inflammation lead to diabetic retinal changes by increasing the vascular permeability and allowing fluid leakage into the retinal interstitium [8,9]^[8][9]. This blood–retinal barrier dysfunction and breakdown is a key part of pathogenesis in retinal deterioration, macular edema, and progressive vision loss [8,9]^[8][9]. IL-6 has been shown to play a role in decreasing the barrier function in retinal endothelial cells, allowing vascular leakage by downregulating tight junction proteins [8,9]^[8][9]. IL-6 normally mediates the recruitment of leukocytes by increasing Intercellular Adhesion Molecule 1 (ICAM-1) and Vascular Cell Adhesion Molecule 1 (VCAM-1) to assist adhesion to the vascular endothelium. In patients with diabetic retinopathy, elevated levels of ICAM-1 and VCAM-1 have been detected, likely due to increased IL-6 activation [8,9]^[8][9]. ICAM-1 and VCAM-1 are transmembrane proteins involved in the adhesion and migration of leukocytes and endothelial cells. In diabetic patients, increased ICAM-1 expression has been correlated to an increase in migrating neutrophils, allowing increased migration and perivascular infiltration, leading to inflammation and retinal edema [8,9]^[8][9]. In addition, elevated IL-6 and other cytokines have been demonstrated in proliferative diabetic retinopathy (PDR) and are associated with a stimulation of matrix metalloproteinase (MMP) production [1,6]^[1][6]. MMP are a family of proteinases that regulate tissue remodeling, inflammation, and injury ^[7] In particular, MMPs regulate the integrity of the blood–retinal barrier, activate inflammatory mediators, and assist in angiogenesis and neovascularization ^[10]. In a mouse model, the inhibition of IL-6 signaling was shown to reduce the diabetes-induced oxidative damage both systemically and within the retina [8,9]^[8][9]. Neovascular age-related macular degeneration (AMD) is a common cause of progressive vision loss in older patients. As with diabetic retinopathy, there is also significant evidence from in vitro and animal studies that IL-6 could play a significant role in the disease. There have been in vitro and in vivo studies published exploring the possible role of IL-6 in neovascular AMD disease. In an in vivo assay, elevated levels of IL-6 were found in mice after laser injury, with the main expression from macrophages, resulting in choroidal neovascularization and angiogenesis ^[11]. However, in IL-6 knockout mice, there was decreased choroidal neovascularization compared to the wild-type mice, indicating the role of IL-6 in stimulating choroidal angiogenesis ^[11]. Lastly, macrophages were found as the major IL-6R-positive cells present in the eye. An analysis of IL-6R-positive macrophages after laser injury revealed a transcriptional profile consistent with Signal Transducer and Activator of Transcription (STAT3) activation and angiogenesis, therefore confirming the relationship between IL-6 and STAT3 ^[12]. STAT3 activation has been shown to aid in immune cell recruitment and the promotion of choroidal neovascularization ^[12]. In a systematic review analyzing 16 studies on IL-6 levels in AMD patients, systemically elevated IL-6 levels have been correlated with late-stage neovascular AMD ^[12]. In addition, several studies have been published on aqueous humor cytokine levels in eyes with neovascular AMD compared to normal eyes after traumatic procedures such as intravitreal injection or cataract surgery ^[12]. Although these studies have found an increase in IL-6 levels in patients with neovascular AMD, the results were not statistically significant, and conclusions must be treated cautiously due to small sample sizes and imperfect control groups that also received injection or surgery ^[12]. As with the pathogenesis of diabetic retinopathy, the role of IL-6 in AMD is closely tied to the dysfunction of the endothelium, increased oxidative damage, and increased expression of VEGF, leading to angiogenesis and vascular proliferation ^[12].

3. Interleukin-6 Blockage in Non-Infectious Uveitis and Its Associated Macular Edema

3.1. Randomized Clinical Trials

The utility of IL-6 inhibitors for macular edema secondary to NIU has been studied for various forms of NIU. From ourthe comprehensive literature search, twelve studies were selected, highlighting the role of IL-6 inhibitors specifically on non-infectious uveitic macular edema. Most of the studies were published focusing on the use of tocilizumab, with only one study published on sarilumab. TNF-alpha inhibitors are often regarded as first-line biologic therapy in NIU refractory to steroids and conventional immunosuppressive medications such as methotrexate, mycophenolate, and cyclosporine ^[6] However, when first-line therapies fail, IL-6 inhibitors are integral in treatment-resistant NIU, particularly in the setting of uveitis secondary to JIA. As one of tocilizumab’s on-label uses, its use in treating uveitis related to JIA has been well documented in multiple studies [2,13,14,15,16]^{[2][13][14][15][16]}. In the APTITUDE study, a multicenter phase 2 single-arm trial, 21 pediatric patients with JIA-associated uveitis previously refractory to methotrexate, and TNF-alpha inhibitors were treated with subcutaneous tocilizumab over six months ^[13]. Patients were dosed according to body weight, with patients over 30 kg receiving 162 mg every two weeks and patients under 30 kg given 162 mg every three weeks ^[13]. In the APTITUDE trial, the primary endpoint, a two-step or more decrease in level inflammation based on the Standardization of Uveitis Nomenclature (SUN) criteria, was not met, with only 34% of patients responding to treatment ^[13]. Despite the overall low clinical response rate, tocilizumab proved effective in completely resolving macular edema in three out of four patients (75%) ^[13]. The medication was well tolerated, with minimal adverse effects in less than one-third of patients; these included injection site reaction, arthralgia, and headache. Although tocilizumab treatment did not meet its treatment efficacy endpoint this study, there is still evidence that it may be useful in treating JIA-related uveitis refractory to prior immunomodulatory therapy or biologics, and it may be particularly efficacious in the treatment of refractory macular edema from JIA uveitis, as per the results of the APTITUDE study [13,15,17,18]^{[13][15][17][18]}. Another randomized clinical trial, the STOP-Uveitis trial, was published investigating the safety and efficacy of tocilizumab in the treatment of NIU ^[19]. The study was conducted over a period of six months in 37 patients treated with 4 mg/kg or 8 mg/kg monthly intravenous infusions of tocilizumab ^[19]. A majority of patients had idiopathic panuveitis, with a minority of patients diagnosed with sarcoidosis, Vogt-Koyanagi-Harada syndrome, or punctate inner choroidopathy. At the baseline, 40.5% of patients were diagnosed with macular edema, with an average central foveal thickness (CFT) of 497 μm. The mean change in CFT after six months was −131.5 μm in the group treated with 4 mg/kg and −39.92 μm in the group treated with 8 mg/kg without any statistically significant difference between the two treatment groups. In addition to improvement in macular edema, patients also demonstrated improvement in best corrected visual acuity (VA) and inflammation measured as vitreous haze scores. No differences were found in treatment outcomes in the two treatment doses, although no conclusions may be drawn about ideal dosage due to the small sample size and exploratory nature of the trial. Sarilumab is less commonly used in the treatment of ocular disease. Sarilumab is a human anti-IL-6R monoclonal antibody blocking the same classic and trans-signaling pathways as tocilizumab ^[6]. The SATURN study was published in 2018 investigating the effects of sarilumab in the treatment of NIU [20,21]^[20][21]. This randomized controlled study recruited 58 eyes with NIU. Participants were divided into the treatment group, which received biweekly subcutaneous sarilumab 200 mg over the course of four months, and a group that received a placebo [20,21]^[20][21]. The trial showed a beneficial effect on macular edema as measured by optical coherence tomography (OCT), with corresponding changes in the CFT measured as −46.8 μm in the treatment group versus +2.6 μm in the placebo group [20,21]^[20][21]. In a subgroup analysis of patients with baseline CFT greater than 300 μm, the overall change was more dramatic, with −112.5 μm in the treatment group versus −1.8 μm in the placebo group [20,21]^[20][21]. This difference in change of CFT was found to be statistically significant in the cohort overall, although the difference was not significant in the subgroup analysis, likely due to the small sample size. Overall, sarilumab treatment resulted in good clinical response measured by a two or more step reduction in vitreous haze on the Miami scale or reduction of the steroid usage, with a clinical response rate of 46% versus 30% in the treatment and placebo groups, respectively [20,21]^[20][21]. Sarilumab was well tolerated with minimal reported adverse events that were clinically insignificant compared to the placebo group.

3.2. Comparative Retrospective Study

One multicenter retrospective observational study by Leclercq et al. sought to identify differences in clinical response in refractory uveitic macular edema, comparing tocilizumab versus anti-TNF-alpha treatment ^[22]. Two hundred and forty patients with prior treatment failure with traditional immunomodulatory therapy were included in the study with the biologic treatment chosen by the physician, resulting in 149 patients treated with infliximab or adalimumab and 55 patients treated with tocilizumab ^[22]. An improvement in CME was defined as any reduction in the baseline CFT with a lack of intraocular inflammation and less than 10 mg of corticosteroids per day. A partial response was defined as any improvement in CME, while a complete response was defined as the absence of cystic spaces on imaging and CFT measuring less than 300 μm. Overall improvement in macular edema was achieved in 46.2% of patients treated with anti-TNF alpha agents and 58.5% of patients treated with tocilizumab ^[22]. Complete or partial responses of macular edema were achieved in 21.8% of patients treated with anti-TNF alpha agents versus 35.8% of patients treated with tocilizumab ^[22]. In addition, tocilizumab improved the odds of a complete response of uveitic macular edema by more than two-fold in comparison to anti-TNF alpha agents after six months ^[22]. While 82 patients also received concomitant immunosuppressive therapy, there were no significant differences in type and distribution of concomitant treatment across the two treatment groups ^[22]. This restudyearch concluded that tocilizumab may be more effective than TNF-alpha inhibitors in treating treatment-resistant uveitic macular edema, although the findings should be confirmed ideally in a large prospective study.

3.3. Retrospective Case Series

Multiple case series have been published documenting the use of tocilizumab in treating NIU secondary to multiple etiologies, including JIA, birdshot chorioretinopathy, Bechet’s disease, and idiopathic panuveitis. The measurement of a clinical response as a primary endpoint varied by study, with most studies focusing on CFT or intraocular inflammation (IOI) as a marker for improvement. FBor this review, both thth the primary endpoint of the study and improvement in macular edema measured as a reduction in CFT (even if it was not the primary endpoint of the study) were analyzed. While the primary endpoint was not met in at least 50% of patients in one study, the majority of patients demonstrated improvement in macular edema compared to the baseline ^[22]. In the three studies that did not specify criteria for improvement in macular edema, an average of 88% of patients demonstrated an objective decrease in macular edema based on CFT measurements [15,23,24]^[15][23][24]. The remaining five studies with criteria for improvement in macular edema had different definitions for this improvement. Leclercq et al. and Vegas-Revenga et al. defined improvement as reduction of CFT to under 300 μm, with 56% and 100% of patients demonstrating improved macular edema, respectively [6,22]^[6][22]. Mesquida et al. and Adán et al. defined improvement as reduction of CFT to under 350 μm, with 100% of patients demonstrating improved macular edema in both studies ^[25]. Deuter et al. defined improvement as a reduction of CFT of at least 25% of baseline thickness, with 100% of patients demonstrating improved macular edema ^[26]. Overall, these nine selected retrospective case series demonstrated a positive response to tocilizumab treatment in treatment-resistant uveitic macular edema.