Janus kinase inhibitors: another potential for uveitis treatment?

Non-infectious uveitis (NIU), although a highly blinding but preventable cause of blindness around the world, has few approved pharmaceuticals for its treatment. Lack of access to effective treatment is likely a major cause of poor visual outcomes in NIU. However, despite a revolution in rheumatologic disease treatment with the advent of multiple biologic therapeutics selectively targeting the immune response, there remains a gap in the long-term management of NIU. Adalimumab remains the only systemic medication approved for the treatment of NIU by the Food and Drug Administration (FDA). All other systemic treatments, including older anti-metabolites such as methotrexate and mycophenolate, are used off-label for NIU, posing significant treatment challenges. Given the nature and rarity of the disease, there are few well designed, large, clinical trials evaluating the efficacy of novel therapeutic agents within this field. We therefore read with great interest Srivastava et al.’s randomized clinical trial on the efficacy of filgotinib, a Janus kinase inhibitor (JAKi), in active NIU (1). The early termination of the trial due to business considerations highlights the industry difficulty in FDA medication approval for NIU.

Janus kinase is a tyrosine kinase that functions to upregulate proinflammatory cytokines, interleukins, and chemokines via the signal transduction and activator of transcription (STAT) pathway (2). JAKi thus exerts immunomodulatory effects through downregulation of the inflammation cascade (3). Importantly, unlike most investigational and recently approved immunomodulatory agents, JAKi are small-molecule inhibitors chemically synthesized rather than biologic medications which require a complex living system for development and often require refrigeration for storage. Biologic medications, therefore, are not readily available worldwide in resource limited settings. To date, numerous JAKi molecules have been approved by the FDA for treatment of autoimmune conditions, including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthropathies, and atopic dermatitis (4). However, JAKi remain off-label for treatment of NIU.

The HUMBOLDT trial is the first published phase 2, placebo-controlled, double-masked randomized controlled trial of a JAKi for NIU treatment (1). Seventy-four individuals with a history of active non-infectious intermediate uveitis, posterior uveitis, or panuveitis were randomized to receive either filgotinib 200 mg daily or placebo for 52 weeks after a standardized taper course of oral prednisone. Of these 74 patients, 30 participants in the filgotinib arm and 29 participants in the placebo arm completed the study. Participants who received filgotinib had a significant 30% relative risk reduction of treatment failure by week 24 compared to placebo. Interestingly, the reduced rate of treatment failure was primarily explained by improved anterior chamber inflammation in the filgotinib group relative to placebo. Patients in the filgotinib group also had significantly reduced time to development of new inflammatory chorioretinal or retinal vascular lesions, and reduced risk of visual acuity decline by week 52. Notably, there was no difference in the rate of macular edema or improvement in vitreous haze between study groups. Taken together, these results suggest that filgotinib is a potentially promising treatment for NIU. However, it may be most beneficial to patients with predominately anterior chamber inflammation rather than those with significant vitreous haze or cystoid macular edema.

The HUMBOLDT trial builds on previous case series that have demonstrated clinical improvement in NIU with JAKi therapies. Vitale et al. reported on 12 adult patients treated with either baricitinib, tofacitinib, or upadacitinib in a prospective case series (5). Six of 18 total eyes included in the study had anterior uveitis, three had scleritis, two had intermediate uveitis, four had posterior uveitis, and four had panuveitis. At the last follow-up assessment, ranging from 3–20 months, all eyes demonstrated uveitis quiescence. All three eyes with pre-existing macular edema showed resolution. However, three patients received concomitant treatment with local corticosteroids, two patients received systemic corticosteroids, and four received conventional disease modifying anti-rheumatic drugs (cDMARDs). Miserocchi et al. described successful treatment of four patients with refractory JIA-associated anterior uveitis using baricitinib or tofacitinib (6). Two patients achieved remission of uveitis but not arthritis with baricitinib; one patient with intolerance to multiple biologic agents demonstrated continued control of uveitis and arthritis when switched to baricitinib; and one patient with end-stage, quiescent uveitis remained inactive when switched to tofacitinib for arthritis control. Finally, a case series from India demonstrated favourable results of tofacitinib in 10 children with anterior uveitis, intermediate uveitis, panuveitis or scleritis who previously failed cDMARD or adalimumab treatment (7). Eight children achieved flare-free remission on tofacitinib; one patient experienced a flare of anterior uveitis that responded to topical steroids; and one patient demonstrated breakthrough anterior uveitis that necessitated switch to adalimumab. At last follow-up, six children were controlled on tofacitinib without adjuvant topical steroids. No side effects were reported. The authors highlight the affordability of JAKi relative to adalimumab as a major advantage, particularly in low- and middle-income countries.

Several other clinical trials of JAKi for uveitis treatment are in progress, including the JUVE-BRIGHT phase 3 trial of baricitinib for juvenile idiopathic arthritis (JIA)-associated uveitis (8), and the NEPTUNE phase 2 and CLARITY phase 3 trials of brepocitinib for NIU. Clinical trials of JAKi in NIU are a critical step towards attaining FDA approval for ocular inflammatory conditions, which is important for monitoring long-term drug safety and facilitating insurance coverage.

These early studies suggest JAKi may be effective for NIU treatment. Compared to existing cDMARDS or biologic agents, JAKi hold several benefits. First, as small molecule drugs, JAKi can be administered orally in once- or twice-daily formulations with few immediate patient systemic side effects (4). In contrast, cDMARDs frequently induce gastrointestinal upset, drug-induced toxicity, or other intolerable sequelae, whereas biologics are large molecules that require subcutaneous or intravenous injection and often require refrigeration. Manufacturing of JAKi is also much cheaper compared to biologics, allowing greater patient accessibility (4). If future studies support efficacy of JAKi for NIU, clinicians may consider using JAKi as first-line immunomodulatory therapy or combining JAKi with biologics for additive effect in refractory cases. In our own clinical practice, although only anecdotal, we have noted the success of JAKi when combined with a biologic therapy in patients with refractory NIU.

The question remains as to why the HUMBOLDT trial ended early despite promising results. Filgotinib has been previously approved for the treatment of rheumatoid arthritis in the European Union and Japan. Furthermore, filgotinib is a selective JAK-1 inhibitor, unlike other FDA-approved JAKi such as tofacitinib, potentially leading to a better side effect profile. In 2020, filgotinib was notably rejected by the FDA for approval in the treatment of rheumatoid arthritis due to toxicity concerns. The FDA specifically requested more data on potential semen toxicity which was previously reported in animal studies (9). This question was later studied in a large clinical trial demonstrating no significant impact on semen parameters when taken at 200 mg daily dosing (10). Regardless, this decision from the FDA led to the scrapping of the other current trials for other filgotinib indications, including uveitis, and the termination of the HUMBOLDT trial. As such, JAKi remain off-label for treatment of NIU.

Risk and benefits of every drug need to be considered prior to approval and when prescribing. Previously approved JAKi in the United States remain with an FDA box warning of an increased risk of serious cardiovascular events including death. Furthermore, there remain concerns regarding opportunistic infections, and malignancy (11). Development of a JAK-1 specific inhibitor was thought to potentially mitigate some of these increased risks. Conclusions from the HUMBOLDT trial are limited by the study’s early termination. Only 29% of the projected sample size was recruited prior to termination, thus precluding any definite analyses regarding drug safety or efficacy. Despite this limitation, a low number of serious adverse events were reported; no participant had an arterial or venous thromboembolic event, cardiovascular event, gastrointestinal perforation, cancer, opportunistic infection or case of tuberculosis or herpes zoster. Twelve of 37 participants had infections during the study, compared to 9 of 35 in the placebo group. Therefore, safety profile overall was positive, but with a short duration and small sample size it is hard to make any conclusions.

Ultimately, given the current limited FDA-approved options for NIU, we welcome the HUMBOLDT trial as a step towards better understanding the potential role of JAKi in NIU treatment. Although the early termination of the study prevents firm conclusions about filgotinib’s efficacy, JAKi hold promise as a well-tolerated, accessible option for immunomodulation in chronic NIU. We emphasize the need for more FDA-approved “on-label” medications for NIU. Further high-quality, large-scale randomized clinical trials of JAKi molecules are needed to advance therapeutic options and ascertain long-term safety in patients with chronic uveitis.

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-25-2/prf

Funding: Unrestricted departmental grant from Research to Prevent Blindness. T.M.J. receives funding from the National Institutes of Health (K12TR005104).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-25-2/coif). T.M.J. serves as an unpaid editorial board member of Annals of Eye Science from November 2024 to December 2026. The other authors have 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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