Purpose
To evaluate the safety and possible efficacy of subconjunctival sirolimus for the treatment of chronic active anterior uveitis.
Design
Prospective, nonrandomized, open-label clinical trial.
Methods
This single-center pilot trial enrolled 5 patients with chronic active anterior uveitis. The study drug was administered as a single subconjunctival injection of 30 μL (1320 μg) sirolimus in the study eye at the baseline visit. Study visits were performed at baseline, at 2 weeks, at 4 weeks, and monthly until 4 months, and included a complete ophthalmic examination, review of systems, adverse event assessment at each visit, physical examination, and ancillary ophthalmic testing at some visits. The primary outcome measure was a 2-step reduction in the anterior chamber inflammation within 4 weeks of injection of the study drug.
Results
There were 3 female and 2 male patients; 4 patients had idiopathic anterior uveitis and 1 had psoriatic arthritis-associated anterior uveitis. Three of the 5 patients met the primary outcome criteria by showing at least a 2-step decrease in inflammation within 4 weeks; 2 patients showed a 1-step decrease in inflammation within the same time frame. No recurrence was encountered during a 4-month follow-up. There were no serious adverse events.
Conclusions
Subconjunctival sirolimus appears to be well tolerated in this pilot trial and shows promise as a treatment for active inflammation in patients with chronic anterior uveitis. Larger studies are needed to assess its usefulness in uveitis.
Uveitis is an important cause of visual loss both in adults and in children. Its prevalence and incidence appear to be much higher than initially thought, with anterior uveitis being the most common type. It is believed that over 100 000 American citizens currently require the use of systemic corticosteroids or other immunosuppressive agents as treatment for ocular inflammation. Management and prevention of iatrogenic complications of immunosuppressive therapy accounts for most of the medical resources devoted to these individuals.
Anterior uveitis is the most common form of uveitis, and it can be chronic and recurrent in up to two-thirds of cases. The recurrent episodes of anterior uveitis can ultimately lead to vision loss secondary to cataract, band keratopathy, glaucoma, and macular edema. When topical corticosteroids are insufficient, recurrences are often managed with periocular corticosteroid injections, which can cause intraocular pressure (IOP) elevation or cataracts. More severe cases require systemic corticosteroids or immunosuppressive medications, which can cause significant adverse effects, and many patients continue to experience recurrent inflammation despite systemic therapy.
Both preclinical and clinical evidence indicate that uveitis is a predominantly T cell–mediated immune disease. Drugs targeting T cells, such as cyclosporine, have been shown to be effective. Sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, exerts its effect by a mechanism that is distinct from other immunosuppressives. It suppresses cytokine-driven T-cell proliferation and inhibits the production, signaling, and activity of many growth factors relevant to uveitis. Sirolimus tablets and oral solution are currently approved by the Food and Drug Administration (FDA) for the prevention of transplant rejection. Sirolimus has been used off-label in 1 small uncontrolled case series with the suggestion of benefit for uveitis.
The purpose of this nonrandomized, open-label, prospective pilot study was to assess the safety and possible efficacy of a new subconjunctivally administered sirolimus formulation in the treatment of patients with chronic active anterior uveitis.
Methods
This was a phase 1, nonrandomized, prospective single-center study that evaluated subconjunctival sirolimus as a treatment for chronic active anterior uveitis. All participants received a single 30-μL (1320-μg) subconjunctival sirolimus injection in the study eye at baseline and were followed for 16 weeks following the study drug injection. The study duration was 16 weeks and included 6 study appointments including the baseline visit followed by visits at weeks 2, 4, 8, 12, and 16.
Inclusion and Exclusion Criteria
Inclusion criteria included age ≥18 years and a diagnosis of noninfectious chronic active anterior uveitis. The study eye was required to have ≥1+ anterior chamber (AC) cells despite treatment with topical corticosteroids. At the time of enrollment, the study eye was required to have been treated with systemic and/or topical anti-inflammatory medications (3 times daily or more frequent doses of topical corticosteroids) unless local corticosteroid treatment was contraindicated because of significant IOP elevation in the past (corticosteroid responder). Participants were required to have visual acuity (VA) of 20/400 or better in the study eye and were not anticipated to need ocular surgery during the study. If both eyes met the inclusion criteria, the eye with worse inflammation (higher grade of AC cells) was chosen as the study eye.
Important exclusion criteria included active systemic or joint inflammation requiring immediate addition of or increase in systemic anti-inflammatory medications, active anterior uveitis in the fellow eye requiring more than topical treatment, and significant active infection or history of cancer diagnosed within the past 5 years. Participants who used latanoprost within 2 weeks prior to study enrollment and those with a media opacity that precluded assessment of AC inflammation were excluded. Participants who were pregnant or lactating, or those who refused to use contraception during the study, were also not eligible.
Ophthalmic and Medical Evaluations
At the baseline and close-out visits patients underwent an ophthalmic examination that included grading of AC cells/flare and vitreous cells/haze according to Standardization of Uveitis Nomenclature (SUN) criteria, manifest refraction, review of systems, physical examination, fundus photography, optical coherence tomography (OCT), and intravenous fluorescein angiography (FA). Ophthalmic examinations (including visual acuity assessment using the standardized Early Treatment Diabetic Retinopathy Study [ETDRS] refraction protocol at 4 meters, inflammation grading, and dilated fundus examinations), review of systems, adverse event assessment, concomitant medication assessment, complete blood count with differential (CBC/diff), chemistry panel (chem20), and serum sirolimus levels were done at each visit.
Primary and Secondary Outcome Assessment
The primary efficacy outcome was a 2-step reduction in AC inflammation out of a scale of +0 to +4 (where 0.5+ is recognized as an ordinal step between 1+ and 0) according to SUN criteria within 4 weeks from the time of study drug administration in the absence of an increase in concomitant treatments (topical or systemic). AC cell grading, as the primary outcome measure, was assessed by 2 investigators independently. Any difference in observation was adjudicated by a third examiner. Secondary efficacy outcomes included changes in VA, FA, or retinal thickening as measured by OCT.
Study Drug Administration
All patients received a single injection of subconjunctival sirolimus (30 μL, 1320 μg) on the day of study enrollment. Subconjunctival sirolimus injections were done according to the manufacturer’s guidelines. Briefly, the study drug was thawed immediately prior to use, drawn into the syringe using sterile technique (0.3-cc insulin Becton Dickinson [BD] syringe), and injected within 2 hours. Following topical anesthesia, the needle was engaged approximately 5 mm away from the intended location in the inferior bulbar conjunctiva. Following slow advancement of the needle, the drug was injected into the subconjunctival space. Immediately following needle withdrawal, a sterile, cotton-tipped applicator was placed over the conjunctival entry site for approximately 1 minute. All patients received 0.3% ofloxacin drops immediately following the procedure and 3 times daily for 2 days.
Topical treatments and systemic immunosuppressives, including corticosteroids, were maintained at the baseline doses or reduced, but not increased, for the study duration. The non-study eye, if active, was treated with topical corticosteroids, and the participant was instructed to apply punctal pressure for 2 minutes in an attempt to prevent systemic absorption of topical corticosteroids.
Safety Assessment and Adverse Event Reporting
Safety assessments were made routinely during the study, with a review of the previous visit interval performed at each scheduled visit. Each participant was contacted 1 day after the injection for safety, and participants were encouraged to report any apparent adverse events between scheduled visits. Serum sirolimus levels were checked at each visit.
Results
Five patients with chronic active anterior uveitis were enrolled in this pilot trial. There were 3 female and 2 male patients; the average age was 46 (range: 36–52). Four patients had idiopathic anterior uveitis and 1 had psoriatic arthritis-associated anterior uveitis. The median duration of uveitis was 27 months, and the median duration of active inflammation despite topical therapy was 8 weeks immediately prior to enrollment. The severity of inflammation ranged from 1+ to 3+ AC cells despite topical corticosteroids 3 times daily or more (prednisolone acetate 1% in 4 patients and difluprednate 0.005% in 1 patient). One patient was using systemic methotrexate in addition to topical therapy. Four of the 5 patients were known corticosteroid responders or had the diagnosis of glaucoma suspect in the study eye, which limited a higher frequency of corticosteroids (Patients 1, 2, 4, 5). Three of these patients were on topical IOP-lowering medications in the study eye at the baseline visit ( Table ).
| Patient | Age/Sex/Race | Duration of Uveitis (Months) | Etiology of Uveitis | Glaucoma Status | Medications in the Study Eye a | AC Cells | Vision | Ocular AEs c | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | 4 Weeks | 16 Weeks | Baseline | 4 Weeks | 8 Weeks | 16 Weeks | Baseline | 4 Weeks | 16 Weeks | ||||||
| 1 | 54/F/W | 258 | Idiopathic | Glaucoma | Alphagan BID Cosopt BID PF QID | Alphagan TID Cosopt TID PF QID | Alphagan BID Cosopt BID PF TID | +1 | +0.5 | 0 | +0.5 | 20/25 | 20/32 | 20/20 | Chemosis, redness, ocular irritation |
| 2 | 51/M/A | 13 | Psoriatic arthritis | Steroid responder Glaucoma suspect | PF OD QID MTX 15 mg | PF TID MTX 15 mg | Timolol BID b MTX 15 mg | +2 | 0 | 0 | 0 | 20/50 | 20/20 | 20/16 | — |
| 3 | 43/M/W | 27 | Idiopathic | None | PF TID | PF BID | PF BID | +1 | +0.5 | +0.5 | 0 | 20/16 | 20/16 | 20/16 | Mild ocular irritation |
| 4 | 36/F/AA | 182 | Idiopathic | Steroid responder | Combigan BID Durezol TID | Cosopt BID Durezol BID | Combigan BID | +3 | 0 | 0 | +0.5 | 20/25 | 20/25 | 20/20 | Mild ocular irritation |
| 5 | 52/F/W | 3 | Idiopathic | Steroid responder | Timolol BID PF ×6/day | Timolol BID PF QID | Timolol BID PF BID | +2 | +0.5 | 0 | 0 | 20/25 | n/a | 20/20 | Mild foreign body sensation |
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