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Retinal Physician

Article

The Role of TNF-α Inhibitors in Managing Wet AMD

Current literature does not support their use, but newer agents deserve further investigation.

By: Christian Akotoye, MD, Priya Shukla, BS, Rishi P. Singh, MD
Retinal Physician September 1, 2024 Vol 21, Issue September 2024

Age-related macular degeneration (AMD) is a multifactorial disease that exists in exudative (wet) and nonexudative (dry) forms, with the former accounting for 80% of the legal blindness cases despite encompassing only 15% to 20% of total AMD cases. Exudative AMD is characterized by the formation of choroidal neovascularization (CNV) with subsequent bleeding, fluid leakage, and sudden loss of central vision.1,2 Anti–vascular endothelial growth factor (anti-VEGF) agents are the first-line therapeutics for exudative AMD and act by neutralizing all the active isoforms of VEGF-A to minimize angiogenesis and thus improve vision.3,4 Despite its benefits, anti-VEGF therapy presents many limitations, including high injection burden and risk of endophthalmitis, elevations in intraocular pressure (IOP), and rhegmatogenous retinal detachment.5

Some patients may have a suboptimal or lack of response to therapy, illustrated by persistent fluid. In the Comparison of Age-related Macular Degeneration Treatment Trials (CATT), despite monthly treatment with anti-VEGF agents for two years, 51.5% of patients receiving intravitreal ranibizumab and 67.4% of patients treated with bevacizumab had evidence of persistent fluid on optical coherence tomography (OCT).6,7 Recurrence, defined as the initial appearance of a new retinal hemorrhage or intraretinal/subretinal fluid (IRF/SRF) accumulation after the initial resolution of exudative changes, can also occur. Approximately 66% to 76% of patients experience recurrence after 12 months of repeated ranibizumab and 74.8% after 24 months. Aflibercept has also shown a recurrence of 9% to 55%, half of which occurred by week 40 of bimonthly injections.8-10 This could suggest that other factors beyond VEGF are involved in the pathogenesis of exudative AMD and could be potential therapeutic targets.

The pathogenesis of AMD involves various signaling pathways, including inflammation, oxidative stress, and angiogenesis.11,12 Blockade of the angiogenic pathway via anti-VEGF therapy has also been shown to alter the prevalence of various cytokines, further suggesting that inflammatory factors are involved in the pathogenesis of exudative AMD.13,14 Inflammatory cytokines have been identified in the serum (IL-1β, IL-10, IL-13 and IL-17), aqueous humor (IL-1α, IL-6, IL-8, and TGF-β1), and vitreous (IL-1β and TGF-β1) of patients with exudative AMD.15-17 Despite the knowledge that inflammation plays a role in the pathogenesis of exudative AMD, few therapeutics have been studied that specifically target inflammatory pathways. Anti-inflammatory agents such as dexamethasone have been studied in combination with anti-VEGF injections, with conflicting results.18

Tumor necrosis factor-alpha (TNF-α) is another potential target due to its role in the pathogenesis of AMD. TNF-α is a cytokine identified as a significant regulator of inflammatory responses and is known to be involved in the pathogenesis of various inflammatory diseases.19 In the case of exudative AMD, it has been shown to act through a signaling mechanism involving NADPH oxidase-generated ROS and subsequent β-catenin transcriptional activation to increase VEGF expression in RPE cells.20 Many FDA-approved TNF-α inhibitors are readily available for treating inflammatory disorders, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. Ophthalmologists have used TNF-α inhibitors to treat noninfectious uveitis “off label.”21 Preclinical studies using an animal model have already highlighted the efficacy of intravitreal infliximab injection in reducing CNV volume.19 However, its efficacy has yet to be fully elucidated in a clinical setting. This systematic descriptive review aims to evaluate the current literature investigating the use of TNF-α inhibitors as a therapeutic in exudative AMD and comments on its potential as a therapeutic.

Methods

A systematic literature search was performed on PubMed, EMBASE, and ClinicalTrials.gov for articles published in the past 25 years (from January 1, 1999, through January 27, 2024). The search was conducted using the keywords “infliximab” or “adalimumab,” or “tumor necrosis factor alpha inhibitors,” and “neovascular age-related macular degeneration,” or “exudative age-related macular degeneration,” or “wet age-related macular degeneration.” Studies were required to report the role of intravitreal TNF-α inhibitors in the treatment of exudative AMD. Case reports/series, observational studies, and randomized controlled trials were considered for inclusion, while review articles and preclinical studies were excluded. Studies did not require randomization of a control group to be included. The full text and results of each article were extracted and reviewed.

Results 

After screening 280 candidate publications, 87 studies were reviewed, of which 9 were included. Approximately 50 studies were eliminated as they were either review articles or preclinical studies, 21 studies did not report on TNF-α inhibitors as an intervention, 1 study reported use of TNF-α inhibitors for uveitis, 1 study assessed combined therapy, and 5 studies could not be accessed. The 9 studies examined in this review can be found in Table 1.

Markomichelakis et al were among the first to report the positive effects of systemic infliximab concerning subretinal membrane regress and BCVA improvements in exudative AMD patients.22 Van Hagen et al were unable to demonstrate BCVA improvements, but they reported nonprogression of the disease and regression of exudative lesions without marked fibrous scarring in almost half of the exudative AMD patients treated with systemic infliximab.23 However, another study, conducted by Nussenblatt et al, did not support the use of systemic infliximab as an adjunct to anti-VEGF.24

Table 1: Summary of Articles Describing the Use of TNF-a Inhibitors for Age-related Macular Degeneration.

FIRST AUTHOR*
(TRIAL NAME, NCT)

YEAR

DESIGN

INTERVENTION

SUBJECTS (EYES NO.)

RESULTS (ADVERSE EFFECTS)

Markomichelaki et al22

2005

Prospective noncomparative series

Systemic infliximab infusions (5 mg/kg) for inflammatory arthritis at weeks 0, 2, 6, and every 8 weeks thereafter).

Three patients with CNV secondary to AMD. (6)
  • CNV resolved at 6 months in the first patient. Best-corrected visual acuity (BCVA) increased from 0.05 to 0.2 and was sustained at 18 months.
  • Regression of subretinal membrane and increase of BCVA (0.1 to 0.3 and 0.05 to 0.1) was documented in the other patients.
  • No adverse effects reported.

Van Hagen et al23

2014

Open-label, nonrandomized intention-to-treat trial

Infliximab (5 mg/kg) in saline solution (0.9%) by systemic infusions administered at weeks 0, 2, 6 and 14.

Thirteen patients with neovascular AMD. (13)
  • At week 22 or last observation carried forward, 7/13 patients showed a small but not statistically significant absolute decrease in BCVA with 6/13 remaining stable.
  • No significant change in total lesion and CNV lesion area, absolute change in macular thickness and volume.
  • No adverse events reported.

Nussenblatt et al24

2010

Pilot, phase 1/2, prospective, randomized, unmasked, single-center trial
  • Patients randomized (1:1:1:1) to 1 of the 3 systemic immunosuppressive agents (intravenous daclizumab, intravenous infliximab, or oral rapamycin tablets) or observation.
  • Patients randomly assigned to infliximab received 3 mg/kg of intravenous infliximab monthly for 6 months.

Thirteen patients who were 55 year or older with CNV associated with AMD. (13)
  • Injection rates decreased in rapamycin and daclizumab arms from a median of 0.67 injections per month (prestudy) to a median of 0.34 and from 0.73 to 0.42, respectively.
  • No decrease was seen for either infliximab or control (0.83).
  • Study eyes in all groups maintained approximately stable visual acuities over the 6-month follow-up period.
  • No adverse events reported.

Fernandez-Vega et al25

2016

Observational case report

40 mg subcutaneous treatment course every 2 weeks with adalimumab.

One patient with neovascular AMD in the left eye refractory to intravitreal anti-VEGF. (1)
  • Patient did not require any new injections of ranibizumab at 25-month follow-up.
  • Vision in her left eye maintained a VA of 0.7 from the first month after initiation of therapy with adalimumab.
  • No neovascular AMD activity was apparent.
  • No adverse events reported.

Theodossiadis et al26

2009

Prospective noncomparative series

2 consecutive intravitreal injections of infliximab.

Three patients with neovascular AMD, persisting despite previous short-term anti-VEGF treatment. (3)
  • All 3 patients exhibited improvements in BVCA and central foveal thickness (CFT).
  • Improvements continued after second injection.
  • No adverse events reported.

Arias et al27

2010

Prospective, noncomparative, interventional case series

A single intravitreal injection of infliximab (2 mg/0.05 mL).

Four patients with subfoveal CNV secondary to AMD, lack of response to anti-VEGF therapy with bevacizumab and/or ranibizumab; and VA in the opposite eye ≥ 20/40. (4)
  • At Day 90, the BCVA change was -18, +3, +4, and -4 ETDRS letters from baseline.
  • Intraretinal/subretinal fluid (IRF/SRF) on SD-OCT scans was not significantly reduced in any case.
  • Two patients developed intraocular inflammation.

Wu et al28

2013

Open-label, comparative, retrospective, multicenter, interventional study

Intravitreal injections of 1 mg infliximab, 2 mg infliximab, 2 mg adalimumab, or 1.25 mg bevacizumab.

Twenty-six consecutive patients with CNV secondary to AMD that responded suboptimally to anti-VEGF agents. (26)
  • Four eyes were injected with 2 mg of adalimumab; 8 eyes were injected with 1 mg of infliximab; 8 eyes were injected with 2 mg of infliximab; and 6 eyes with 1.25 mg of bevacizumab.
  • No significant changes from baseline in the mean BCVA and CMT throughout the follow-up in any of the groups.
  • Six of 16 eyes injected with infliximab developed severe uveitis.

Giganti et al29

2010

Prospective, interventional, noncomparative, open-label, 12-week pilot study

0.5 mg/0.05 mL intravitreal infliximab.

Second injection at 6 weeks if reinjection criteria were met.

Four patients refractory to conventional therapies and equivalent corrected visual acuity ≤ 20/70: Case 1-2 with CNV secondary to AMD and Case 3-4 with DME. (4)
  • Visual acuity declined in 3 patients (Cases 1, 3, and 4). All patients had persistence of CME on OCT.
  • Two developed panuveitis (Case 1 and 4) and 1 developed vitritis (Case 3).

Semeraro et al30

2013

Prospective interventional case series

A single intravitreal injection of 0.05 ml of reconstituted infliximab solution (20mg/ml).

Four eligible patients, affected by exudative age-related macular degeneration (2/4), retinal angiomatous proliferation (1/4), and central retinal vein occlusion (1/4), who were refractory to conventional treatments. (4)
  • Case 1 showed tomographic and angiographic improvement despite uveitis.
  • All 4 cases developed uveitis/inflammatory response.

Adalimumab is another TNF-α inhibitor distinguished from infliximab by its fully human-derived monoclonal antibody structure. Infliximab is a chimeric protein of 75% human-derived and 25% mouse-derived amino acids. To our knowledge, Fernández-Vega et al is the only study to report the effects of subcutaneous administration of adalimumab. This study showed that subcutaneous adalimumab may maintain the VA of exudative AMD patients refractory to anti-VEGF.25

Regarding intravitreal TNF-α inhibitors, Theodossiadis et al was the only study to show some clinical benefits between BCVA and central foveal thickness (CFT).26 Arias et al,27 Wu et al,28 Giganti et al,29 and Semeraro et al30 displayed no clinical benefit but highlighted the potential risk of severe noninfectious uveitis specific to intravitreal infliximab.

The Pan American Collaborative Retina Study Group assessed the effectiveness of 2 mg intravitreal adalimumab for exudative AMD refractory to anti-VEGF on 4 eyes. Results indicated no significant changes in VA and central macular thickness (CMT) from baseline to 3 months follow-up for all groups. However, no adverse inflammatory events were reported for the adalimumab cohort. Another phase 2 study (NCT01136252) completed in 2011 assessed the use of 0.05 mg adalimumab intravitreally in patients with exudative AMD. However, the results of that study were never published, because the pilot study was ineffective.

Discussion

The literature overwhelmingly illustrates the lack of benefit of intravitreal TNF-α inhibitors for exudative AMD patients. To our knowledge, Theodossiadis et al was the only study to show some clinical benefits between BCVA and CFT.26 However, the rest of the literature showed not only a lack of benefit but also the potential adverse risk of severe noninfectious uveitis in the case of intravitreal infliximab.27-30 Three of the 4 patients in the Giganti study showed human antichimeric antibodies (HACA) despite no previous exposure to infliximab. The formation of HACA is less likely with larger doses.29 Thus, the chimeric structure of infliximab may incite an inflammatory response, especially in the case of low doses of intravitreal infliximab. It is also possible that this HACA response may clear infliximab and thus reduce its overall effectiveness. This could give credence to the hypothesis that the formation of HACA may explain both the lack of benefit obtained from infliximab in exudative AMD patients and the development of severe uveitis. However, this would not explain the lack of benefit of adalimumab, which has a fully human-derived monoclonal antibody structure.

Furthermore, Giganti et al did not measure baseline HACA levels. Pulido et al suggest that because these patients were treated with anti-VEGF agents before infliximab, anti-VEGF could have induced the formation of HACA and potentially cross-reacted with the HACA test in this study.31 An alternative theory is that infliximab may act as haptens, binding some unknown extracellular or intracellular protein components or receptors that could trigger an inflammatory response.32

Surprisingly, systemic TNF-α inhibitors showed more promise as a therapeutic than intravitreal TNF-α inhibitors.22,23,25 This seems contradictory to the literature, which suggests AMD is a disease of local inflammatory pathway dysregulation instead of systemic.33 Serum samples of TNF-α have not demonstrated significant differences in concentration between exudative AMD patients and healthy controls.34 Thus, one would suspect that intravitreal injections would be the optimum method of drug administration. However, due to the nature of these studies as case reports, the discrepancy in results among studies examining systemic vs intravitreal TNF-α inhibitors is likely due to the small sample size and heterogenicity in patient characteristics. This is highlighted by the fact that the studies in which there was an improvement or stabilization of disease consisted of less than 3 patients being treated for a concomitant inflammatory condition.22,25 Recent studies have demonstrated a potential causal link between some autoimmune diseases and the development of AMD.35,36 These studies do not highlight whether some autoimmune diseases may exacerbate exudative AMD progression. However, they may suggest systemic TNF-α inhibitors may have a place in AMD therapy when simultaneously targeting autoimmune conditions for specific patient populations.

It is also important to note that systemic TNF-α inhibitors are not void of potential adverse effects with chronic use. Surprisingly, no adverse effects were reported in the studies assessed in this review. However, systemic TNF-α inhibitors can potentially increase the risk of serious infections such as bacteremia, pneumonia, and tuberculosis.37 The New York Heart Association (NYHA) also recommends against the use of TNF-α inhibitors for patients with class III and IV heart failure due to worsening mortality.38 In addition, an increased incidence of melanoma and lymphoma has been observed in patients taking TNF-α inhibitors.39 These are generally rare, but vigilant follow-up periods and careful patient selection must be considered before undergoing further clinical research on the efficacy and safety of systemic TNF-α inhibitors.

The lack of benefit associated with TNF-α inhibitors remains unclear. In animal models, TNF-a plays a role in the development of early CNV.40 Thus, it is possible that most of its benefits would be achieved earlier in the disease process, while many of the patients in the reviewed studies have advanced disease and were previously treated with multiple injections of intravitreal anti-VEGF with minimal improvements. Alternatively, it is quite possible that TNF-α inhibitors have not been able to penetrate the blood-retina barrier in humans effectively, and thus, enough may have been administered to cause an inflammatory reaction in the case of infliximab but not enough to effectively block TNF-α. This theory has not been purported in the literature as baseline and post-therapy vitreous samples were not obtained in many studies to determine the extent of TNF-α blockade. Considering that rabbit models have shown that intravitreal adalimumab doses of up to 5 mg are safe,41 it is possible that larger doses of adalimumab could be beneficial in treating exudative AMD. Lastly, though animal models do provide valuable insights, it should be considered that the mechanisms and mediators involved in AMD pathogenesis and progression might be different and may explain the discrepancy between preclinical suppression of CNV and lack of clinical results.42 This is especially true considering that murine models, which are heavily used to study AMD, lack a macula.43

In summary, the current literature does not support using TNF-α inhibitors for exudative AMD treatment. Many current studies are case reports/studies with small sample sizes of heterogeneous patients, lack of randomization, controls, and consistent primary outcomes. Considering the consistent presentation of adverse inflammatory reactions associated with infliximab, it would not be recommended to pursue further research regarding this agent as a therapeutic for exudative AMD.

Alternatively, implementing more extensive randomized controlled trials to investigate the efficacy of TNF-α inhibitors beyond infliximab and adalimumab, such as certolizumab, pegol, and golimumab for treating exudative AMD, could be explored. The PEGylation of certolizumab pegol allows for significant tissue distribution compared to infliximab and adalimumab, while golimumab has a higher affinity and potency for neutralizing TNF-α.19 Thus, these agents are exciting prospects for exudative AMD therapy. To our knowledge, there have not been any previous or current observational studies or clinical trials that have explored the use of certolizumab, pegol, and golimumab. Thus, further preclinical/clinical research is needed to assess the potential adverse effects and efficacy of these TNF-α inhibitors and adalimumab either solely or in tandem with current anti-VEGF therapy. Once the potential safety concerns are addressed, clinical trials with large sample sizes and clear endpoints can be considered.

Christian Akotoye, MD

Christian Akotoye, MD, is an ophthalmology resident at Indiana University School of Medicine in Indianapolis, Indiana. He reports no disclosures.

Priya Shukla, BS

Priya Shukla, BS, is a medical student at Cleveland Clinic Lerner College of Medicine in Cleveland, Ohio. She reports no disclosures.

Rishi P. Singh, MD

Rishi P. Singh, MD, is president of Cleveland Clinic Martin Hospitals, a staff surgeon at the Cole Eye Institute, Cleveland Clinic, and professor of ophthalmology at the Lerner College of Medicine in Cleveland. He reports no disclosures. Reach Dr. Singh at singhr@ccf.org.

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