Topical interleukin 1 receptor antagonist for treatment of dry eye disease: a randomized clinical trial

Abstract

Importance: The immunopathogenic mechanisms of dry eye disease (DED), one of the most common ophthalmic conditions, is incompletely understood. Data from this prospective, double-masked, randomized trial demonstrate that targeting interleukin 1 (IL-1) by topical application of an IL-1 antagonist is efficacious in significantly reducing DED-related patient symptoms and corneal epitheliopathy.

Objective: To evaluate the safety and efficacy of treatment with the topical IL-1 receptor antagonist anakinra (Kineret; Amgen Inc) in patients having DED associated with meibomian gland dysfunction.

Design and setting: Prospective phase 1/2, randomized, double-masked, vehicle-controlled clinical trial.

Participants: Seventy-five patients with refractory DED.

Interventions: Participants were randomized to receive treatment with topical anakinra, 2.5% (n = 30), anakinra, 5% (n = 15), or vehicle (1% carboxymethylcellulose) (n = 30) 3 times daily for 12 weeks.

Main outcomes and measures: Primary outcomes were corneal fluorescein staining (CFS), complete bilateral CFS clearance, dry eye-related symptoms as measured by the Ocular Surface Disease Index, tear film breakup time, and meibomian gland secretion quality.

Results: Topical anakinra was well tolerated compared with vehicle, with no reports of serious adverse reactions attributable to the therapy. After 12 weeks of therapy, participants treated with anakinra, 2.5%, achieved a 46% reduction in their mean CFS score (P = .12 compared with vehicle and P < .001 compared with baseline); participants treated with anakinra, 5%, achieved a 17% reduction in their mean CFS score (P = .88 compared with vehicle and P = .33 compared with baseline); and patients treated with vehicle achieved a 19% reduction in their mean CFS score (P = .11). Complete bilateral CFS clearance was noted in 8 of 28 patients (29%) treated with anakinra, 2.5%, vs in 2 of 29 patients (7%) treated with vehicle (P = .03). By week 12, treatment with anakinra, 2.5%, and treatment with anakinra, 5%, led to significant reductions in symptoms of 30% and 35%, respectively (P = .02 and P = .01, respectively, compared with vehicle); treatment with vehicle led to a 5% reduction in symptoms.

Conclusions and relevance: Treatment with topical anakinra, 2.5%, for 12 weeks was safe and significantly reduced symptoms and corneal epitheliopathy in patients with DED. These data suggest that the use of an IL-1 antagonist may have a role as a novel therapeutic option for patients with DED. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00681109.

Figure 1

Consolidated Standards of Reporting Trials flow diagram of the study. Eighty-one patients were screened, and 6 were excluded at this stage. Seventy-five patients were randomized to the 3 arms of the trial. Eight patients withdrew before the last study visit at week 16.

Figure 2

Corneal fluorescein staining (CFS) (epitheliopathy) scores. A, The mean corneal staining score during 16 follow-up weeks. B, Proportions of patients in each treatment arm who recovered from epithelial fluorescein staining in both eyes (corneal clearance). The dashed vertical line at week 12 indicates the end of the treatment period. *P < .01, †P < .05, and ‡P < .001 for the comparison of each time point value with the baseline value. The mean changes in corneal staining between anakinra, 2.5%, and anakinra, 5%, compared with vehicle at week 6 (P = .33 and P = .38, respectively) and week 12 (P = .12 and P = .88, respectively) did not reach statistical significance. At week 12, anakinra, 2.5%, attained a statistically significant difference compared with vehicle in achieving complete bilateral CFS clearance (P = .03 and P = .71, respectively).

Figure 3

Symptom scores. A, The mean Ocular Surface Disease Index (OSDI) during 16 follow-up weeks. The dashed vertical line at week 12 indicates the end of the treatment period. B, Percentage change in the Ocular Symptoms module of the OSDI questionnaire for each time point compared with baseline. C, Percentage change in the Visual Function Symptoms module of the OSDI questionnaire. D, Percentage change in the Environment-Triggered Symptoms module of the OSDI questionnaire. *P < .01, †P < .05, ‡P < .001, and §P = .05 for the comparison of each time point value with the baseline value. Both anakinra, 2.5%, and anakinra, 5%, led to a statistically significant decrease in dry eye symptom scores compared with vehicle at week 6 (P = .02 and P = .02, respectively) and week 12 (P = .02 and P = .01, respectively).