JAK Inhibitors May Reduce AMD Onset in Autoimmune Diseases

A new investigation provided evidence of an association between Janus kinase inhibitor (JAKi) therapy and a lower risk of age-related macular degeneration (AMD) development among patients with autoimmune diseases.¹

Across two administrative claims databases, representing approximately 9.8 million patients in the US, JAKi therapy in those aged >40 years with autoimmune disease was linked to a notably reduced risk of incident AMD during the first 6 to 18 months of treatment.

“Our study provides evidence of an association between JAKi therapy and a reduced risk of developing AMD in patients with autoimmune diseases,” wrote the investigative team, led by Joelle A. Hallak, PhD and Nizar Smaoui, MD, PhD, AbbVie.

Despite an incomplete understanding of AMD’s etiology, previous evidence has centered on the role of inflammation in the pathogenesis and progression of the retinal disease.²

Among key inflammation mediators, the Janus Kinase/signal transducers and activators of the transcription (JAK-STAT) signaling pathway plays an important part in immune system activation, inflammation, and hematopoiesis.³ Dysregulation of the JAK-STAT pathway has been implicative across a variety of autoimmune diseases and malignancies.

Considering the potential for involvement of JAK-STAT-mediated inflammation in AMD, investigators hypothesized the use of JAKi therapy could reduce the incidence of AMD in at-risk individuals with autoimmune diseases.¹

The retrospective, observational cohort study used real-world data from the Merative MarketScan and Optum Clinformatics Data Mart research databases between January 2010 and January 2022.

These databases were screened to identify patients who had ≥1 diagnosis of Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, atopic dermatitis, psoriasis, hidradenitis suppurative, or polyarticular juvenile idiopathic arthritis, and received a first JAKi prescription or other immunotherapy. Patients were required to be continuously enrolled in the database for ≥6 months immediately before and after the date of the first prescription (index date).

After initial screening and identification, individuals with autoimmune diseases who matched study eligibility criteria in MarketScan (n = 9126) and Optum (n = 5667) were propensity-score matched 1:1 to eligible patients who received non-JAKi-based immunotherapy.

Most of the patient population treated with JAKi therapy was female in both the MarketScan (76.6%) and Optum (75.2%) databases, with >60% of the patient population ≥55 years old in both cohorts.

For the MarketScan cohort, the incidence of AMD over the first 6 to 18 months post-index was lower in JAKi therapy-treated patients (1.96 per 1000 patient-years) versus those on other immunotherapy (3.58 per 1000 patient-years). This represented a relative risk reduction of 49% among patients who received JAKi therapy (adjusted incidence rate ratio [AIRR], 0.51; 95% CI, 0.19–0.90).

In the Optum database, JAKi-treated patients had a lower AMD incidence rate (0.86 per 1000 patient-years) than patients exposed to non-JAKis (2.75 per 1000 patient-years), for a relative risk reduction of 73% (ARR, 0.27; 95% CI, 0.03 - 0.74).

Overall, the absolute percentage reductions were 0.36% in MarketScan and 0.32% in Optum, with favorable effects for individuals who received JAKi therapy. Bayesian modeling showed the probability of avoiding AMD onset in patients who received JAKi therapy was 97.6% and 98.94% in MarketScan and Optum, respectively.

“Further research is required to determine the robustness and duration of this effect in larger and/or more representative patient populations and its applicability to other diseases or indications,” Hallak and colleagues added.

In an editorial, Joseph Magagnoli, MS, University of South Carolina, highlighted the use of administrative claims database analysis as a tool for drug discovery, extending beyond finding associations.⁴

“Using large-scale database analysis provides initial assessments of drugs on human patients, complementing evidence from preclinical studies, representing an important step before initiating time-, labor-, and cost-expensive clinical trials,” Magagnoli wrote.

Magagnoli continued, noting these current findings are novel as they point to a potential new pharmacological target for AMD using patient-level administrative claims data, rather than clinical trials.

“Retrospective administrative claims analyses are a valuable tool in the arsenal of drug discovery and serve as a unique integration that can complement preclinical work facilitating drug repurposing,” he added.

References

1. _{Hallak JA, Abbasi A, Goldberg RA, et al. Janus Kinase Inhibitor Therapy and Risk of Age-Related Macular Degeneration in Autoimmune Disease. JAMA Ophthalmol. Published online July 11, 2024. doi:10.1001/jamaophthalmol.2024.2376}
2. _{Magagnoli J, Sutton SS, Ambati J. Facilitating Drug Repurposing—Using Databases for Drug Discovery in AMD. JAMA Ophthalmol. Published online July 11, 2024. doi:10.1001/jamaophthalmol.2024.251}
3. _{Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6(1):402. Published 2021 Nov 26. doi:10.1038/s41392-021-00791-1}
4. _{Arrigo A, Aragona E, Bandello F. The Role of Inflammation in Age-Related Macular Degeneration: Updates and Possible Therapeutic Approaches. Asia Pac J Ophthalmol (Phila). 2023;12(2):158-167. doi:10.1097/APO.0000000000000570}