Targeting inflammation in age-related macular degeneration through JAK-STAT pathway modulation

Introduction

Late age-related macular degeneration (AMD) is one of the leading causes of blindness globally (1). In their recent study published in JAMA Ophthalmology, Hallak et al. explore the potential of an emerging therapeutic opportunity of Janus kinase inhibitor (JAKi) in the role of systemic inflammation in AMD pathogenesis (2). This study offers a real-world examination of the relationship between JAKi and AMD, comparing the incidence of AMD in patients treated with JAKi and those receiving other immunotherapies for existing autoimmune diseases.

This retrospective cohort study utilised two extensive United States (US) administrative claims databases: MarketScan and Optum. MarketScan provided patient-level data from commercial and public insurance programs, while Optum offered longitudinal medical and pharmacy claims data. The study included individuals over 40 years old diagnosed with one or more autoimmune diseases, such as but not limited to Crohn’s disease, ulcerative colitis, and rheumatoid arthritis, who had initiated therapy with either JAKi or other immunotherapies between January 2010 and June 2021. To be eligible, patients had to have been on the databases for six months or longer.

The aim of the study was to explore potential protective effects of JAKi against AMD. Their findings demonstrate that AMD incidence was lower among patients treated with JAKi compared to those receiving alternative therapies during the initial 6–18 months of treatment (1.96 per 1,000 vs. 3.58 patient-years in MarketScan cohort, 0.86 per 1,000 vs. 2.75 per 1,000 patient-years in Optum cohort). The study revealed a relative risk reduction of 49% in AMD incidence among JAKi-treated patients in the MarketScan cohort and a 73% reduction in the Optum cohort. The absolute risk reductions were 0.36% and 0.32% in the MarketScan and Optum cohorts, respectively.

The study utilises real-world data from two large databases across different healthcare settings within the US, highlights its strengths. Propensity score matching was employed to account for baseline differences between groups, bolstering the validity of the findings. However, limitations remain. Notably, the study did not adjust for certain confounding factors, such as smoking and concurrent medication use, which are associated with development of AMD and may have influenced the results. Furthermore, the relatively short follow-up period precludes an assessment of the long-term effects of JAKi therapy on AMD risk. The findings also lack generalisability to populations without autoimmune diseases or those with a genetic predisposition to AMD. Future research must address these limitations by incorporating modifiable lifestyle factors, such as smoking, and extending follow-up periods to determine whether the observed risk reductions are sustained over time.

AMD pathophysiology

AMD is a complex, multifactorial condition influenced by genetic, environmental, and systemic factors, that requires lifelong monitoring. It is associated with systemic diseases, such as hypertension and hyperlipidaemia, and genetic variations, including those affecting complement factor H and CX3CR1 (3). Risk factors for advanced AMD include aging, Northern European ancestry, smoking, hypertension, cardiovascular disease, obesity, and poor dietary and exercise habits.

While Hallak et al. provide some insights, their analysis notably omits adjustments for smoking, a significant modifiable risk factor. Smoking increases AMD risk by two- to three-fold and represents a critical variable in understanding the disease’s pathogenesis (4). Addressing such modifiable factors in future studies will be essential to fully contextualize the impact of JAKi on AMD risk.

The role of the Janus kinase-signal transducers and signal activators of transcription (JAK-STAT) pathway

One pathway that mediates inflammation is the JAK-STAT pathway. Some diseases linked to the JAK-STAT pathway include haematological disorders, such as polycythaemia vera, myelofibrosis and essential thrombocytopaenia, through its impact on haematopoietic growth factors such as erythropoietin and thrombopoietin, which signal through this pathway. Gain-of-function mutations in JAK1 and JAK3 play a critical role in the development of solid organ malignancies including breast cancer and haematological malignancies such as T-cell acute lymphoblastic leukaemia (5-10). The Medicines and Healthcare products Regulatory Agency has issued a Drug Safety Update in 2023 for JAKis, requesting healthcare professionals to be more vigilant regarding cardiovascular risk and malignancy, particularly in older age groups where AMD is more prevalent (11).

There are currently eight approved JAKis manufactured by different pharmaceutical companies, and their therapeutic indications are summarized in Table 1. Currently there are no indications for ocular inflammatory diseases. However, there are a growing number of studies investigating JAKi use in ocular inflammatory disease (12,13).

AbbVie, the pharmaceutical company responsible for developing upadacitinib, played a significant role in funding the study, contributing to its design, data collection, analysis, interpretation, and review processes. Additionally, several authors of the study are directly or indirectly affiliated with AbbVie or other pharmaceutical companies. Repurposing approved medications can significantly accelerate drug availability to patients, should they prove to be beneficial in wider indications. Notably, AbbVie has initiated a Phase III trial evaluating upadacitinib for the treatment of giant cell arteritis (14), suggesting the company is actively exploring opportunities to expand the therapeutic applications of JAKi therapy.

The JAK-STAT pathway plays a central role in inflammatory signalling and has been implicated in AMD progression. Drusen, the hallmark of AMD, represents the accumulation of cellular debris within the retinal pigment epithelium (RPE). Drusen deposition disrupts Bruch’s membrane, triggering complement activation, oxidative stress, and inflammation, which can progress to neovascular AMD. The neovascular form is characterized by aberrant angiogenesis mediated by vascular endothelial growth factor (VEGF), resulting in vascular leakage, photoreceptor damage, and fibrosis (15,16).

Studies have demonstrated that JAK-STAT activation occurs in human RPE cells exposed to inflammatory cytokines such as tumour necrosis factor-α and interferon-γ. JAKi may reduce inflammation by downregulating miR-155 expression, a key modulator of RPE responses to inflammation (7). Furthermore, in mouse models STAT3 activation has been directly linked to VEGF expression, implicating this pathway in choroidal neovascularization and retinal scarring. The JAK-STAT pathway also plays a pivotal role in the formation of choroidal neovascularisation (6). Although there have been some in-vivo animal studies conducted with JAKi therapy, there is still a paucity of literature in human subjects to assess therapeutic benefits of JAKi therapy in AMD.

Interactions between different immunotherapies have the potential to confound the results of the study. For instance, certain interferon inhibitors exert regulatory effects on inflammation in rheumatic diseases characterized by chronic low-grade inflammation, indirectly modulating the JAK-STAT pathway (17). Similarly, cytokine blockers, such as interleukin-6 inhibitors commonly used in rheumatoid arthritis, inhibit upstream signalling processes that activate the JAK-STAT pathway. By reducing cytokine-induced activation, these therapies indirectly impact the JAK-STAT pathway, contributing to a reduction in inflammation (18).

Complement pathway and inflammasome activation

The complement system, a critical component of innate immunity, is heavily implicated in AMD pathogenesis, particularly in progression to late-stage disease. Dysregulation of the alternative complement pathway leads to excessive activation, resulting in chronic inflammation and tissue damage. Drusen deposits, which contain complement proteins, serve as a nidus for this inflammatory cascade, predisposing patients to geographic atrophy and choroidal neovascular membrane formation (15).

Additionally, inflammasome activation, particularly via the NLRP3 pathway, exacerbates retinal inflammation. Inflammasomes are activated by factors such as drusen, lipofuscin components, and age-related accumulation of carboxyethylpyrrole-adducted proteins, perpetuating the cycle of chronic inflammation and AMD progression (19). Previous studies to inhibit the inflammasome signalling pathways have been conducted (20). Lipofuscin also inhibits autophagy by blocking lysosomal enzymes, trigger immune cell activation in the retina further contributing to oxidative stress and retinal damage (21-23). Combining JAKi with therapies targeting inflammasomes or complement pathways could be explored as novel strategies for managing AMD.

Clinical implications and future directions

Current treatment options for non-neovascular AMD are limited to dietary antioxidant supplementation and newly approved complement factor inhibitors aimed at delaying geographic atrophy progression (15). Emerging therapies for AMD include gene and stem cell therapies (24), photobiomodulation therapy (25) and stereotactic radiotherapy (26), although their clinical efficacy is yet to be proven.

For neovascular AMD, intravitreal anti-VEGF injections remain the mainstay of therapy, although these treatments primarily regress choroidal neovascular membrane without reversing existing retinal atrophy. Photodynamic therapy has also been shown to be effective in slowing the progression of neovascular changes in AMD, but not to the same extent as anti-VEGF therapy (27). Further research on JAKi should investigate at which stage of AMD shows the highest therapeutic benefit and whether they can be used as a monotherapy or adjunctive therapy.

The findings by Hallak et al. suggest that JAKi could represent a novel therapeutic approach for AMD by targeting systemic inflammation. However, critical questions remain regarding their optimal use. Determining whether JAKi are most effective in early or intermediate stages of AMD and whether they should be used as standalone or adjunctive therapies will require further investigation, as dry AMD can take many years to progress from an early to late stage. Long-term effects of JAKis still remain unknown. Additionally, the comparative efficacy of systemic versus locally administered JAKi in terms of bioavailability and safety must be explored. Adverse effects associated with JAKi, such as increased susceptibility to infections, incidence of malignancy and thromboembolic events (28,29) also warrant consideration. While the observed absolute risk reductions in this study are modest, the potential for JAKi to address the inflammatory processes underlying AMD remains promising.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article has undergone external peer review.

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-25-5/prf

Funding: This work was supported by Health Education England/National Institute for Health Research (NIHR) (Clinical Lectureship CL-2020-18-009 for C.H.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-25-5/coif). C.H. received grants or contracts from Glaucoma UK Award (number 183772) and Health Education England/National Institute for Health Research (NIHR) (Clinical Lectureship CL-2020-18-009). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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