Purpose
To investigate the safety, tolerability and efficacy of subconjunctival sirolimus injections as a treatment for active, autoimmune, non-necrotizing anterior scleritis.
Design
Phase I/II, single-center, open-label, nonrandomized, prospective pilot study.
Methods
Five participants with active, autoimmune, non-necrotizing anterior scleritis with scleral inflammatory grade of ≥1+ in at least 1 quadrant with a history of flares were enrolled. A baseline injection was given, with the primary outcome measure of at least a 2-step reduction or reduction to grade zero in the study eye by 8 weeks. Secondary outcomes included changes in visual acuity and intraocular pressure, ability to taper concomitant immunosuppressive regimen, and number of participants who experienced a disease flare requiring reinjection. Safety outcomes included the number and severity of systemic and ocular toxicities, and vision loss ≥15 ETDRS letters. The study included 6 visits over 4 months with an extension phase to 1 year for participants who met the primary outcome.
Results
All participants (N = 5, 100%; 95% CI [0.60, 1.00]) met the primary outcome in the study eye by the week 8 visit. There was no significant change in mean visual acuity or intraocular pressure. Three out of 5 patients (60%) experienced flares requiring reinjection. No systemic toxicities were observed. Two participants (40%) experienced a localized sterile inflammatory reaction at the site of the injection, which resolved without complication.
Conclusions
Subconjunctival sirolimus leads to a short-term reduction in scleral inflammation, though relapses requiring reinjection do occur. There were no serious adverse events, though a local sterile conjunctival inflammatory reaction was observed.
Scleritis is a chronic, painful, and destructive inflammatory disorder that can be associated with systemic disease and, less commonly, an infectious etiology. Scleritis can lead to ocular complications such as keratitis, uveitis, glaucoma, and exudative retinal detachment. A classification scheme of scleritis was first proposed by Watson and Hayreh and is based on anatomy and appearance. They classified it as anterior or posterior and further subdivided into diffuse, nodular, and necrotizing scleritis with or without inflammation (scleromalacia perforans). Anterior scleritis is the most common form (80%–85%), with diffuse and nodular forms occurring almost equally. It is often associated with severe pain and may be associated with sight-threatening complications.
Noninfectious or autoimmune scleritis is thought to arise from immune-mediated mechanisms that are not well understood. Histopathologic studies from patients with necrotizing and recurrent non-necrotizing scleritis indicate the presence of vasculitis with fibrinoid necrosis and neutrophil invasion, as well as an increase in inflammatory cells, mainly activated T cells and macrophages.
Current treatment for scleritis is based on a stepwise approach beginning with topical corticosteroids and oral nonsteroidal anti-inflammatory drugs (NSAIDs) for mild scleritis followed by systemic corticosteroids and/or immunosuppressive treatment for more severe disease. Periocular steroid injections have been used in several studies for non-necrotizing anterior scleritis. Their use has been controversial owing to concern for scleral melting, though in recent studies there are no reported cases of scleral thinning or necrosis.
Sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, exerts its effect by a mechanism that is distinct from other immunosuppressive agents. It suppresses cytokine-driven T cell proliferation and inhibits the production, signaling, and activity of many growth factors relevant to scleritis. Sirolimus tablets and oral solution are currently approved by the Food and Drug Administration (FDA) for the prevention of transplant rejection. Subconjunctival sirolimus offers the advantage of local delivery of medication for potential control of acute scleral inflammation without the concern of scleral thinning, cataract, or glaucoma, unlike periocular corticosteroid injections.
Methods
This was a phase I/II nonrandomized, prospective single-center study that evaluated subconjunctival sirolimus as a treatment for active, anterior, autoimmune, non-necrotizing anterior scleritis. The study protocol was reviewed and approved by the Institutional Review Board of the National Institutes of Health, a HIPAA-compliant institution, and all procedures conformed to the tenets of the Declaration of Helsinki (Clinical Trials registration: NCT01517074; NEI protocol ID: 12-EI-0057). Informed consent was obtained from all participants at the time of enrollment. All participants received subconjunctival sirolimus in the study eye at baseline. Four participants received a single 15-μL (660-μg) subconjunctival injection and 1 participant received 2 15-μL (660-μg) injections in the affected quadrants. Those who still demonstrated active inflammation, showed incomplete or no response to initial injection, or experienced a flare-up after the initial injection were eligible for repeat injections in the study eye at or after week 4 if there was a flare-up. A flare-up was defined by a ≥1-step increase in scleral inflammation.
If greater than 2 quadrants were involved, 2 15-μL (660-μg) injections were given in 2 quadrants 180 degrees apart (total dose of 30 μL or 1320 μg). The study duration was 4 months, with the option of extension to 1 year for pro re nata dosing for those who had a favorable response and met the primary outcome by 8 weeks. The study included 6 visits for the first 4 months (baseline, and weeks 2, 4, 8, 12, and 16) and additional visits every 8 weeks for the extension portion of the study (weeks 24, 32, 40, and 48), followed by a final visit at week 52. The last possible injection was allowed at 40 weeks to allow safety visits at 48 and 52 weeks.
Inclusion and Exclusion Criteria
Inclusion criteria included age ≥18 years and a diagnosis of active, anterior, autoimmune, non-necrotizing anterior scleritis. The study eye was required to have ≥1+ scleritis in at least 1 quadrant based on the NEI Scleritis Grading Scale. If taking immunosuppressive medications, the participants must have been on a stable regimen without increase, decrease, and/or start of new medications for at least 4 weeks prior to enrollment. Participants were also required to have tried therapy such as oral NSAIDs, oral or topical corticosteroids, or immunosuppressive medications in the past. Participants were required to have visual acuity (VA) of 20/640 or better in the study eye.
Important exclusion criteria included active intraocular infection in either eye, history of cancer (other than a nonmelanoma skin cancer) diagnosed within the past 5 years, or active systemic inflammation requiring immediate addition of or increase in systemic anti-inflammatory medications. Participants who were pregnant or lactating, or those who refused to use contraception during the study, were also excluded.
Ophthalmic and Medical Evaluations
At all visits, participants underwent a complete ocular examination that included visual acuity assessment using the standardized Early Treatment Diabetic Retinopathy Study (ETDRS) refraction protocol at 4 meters, vital signs, concomitant medications assessment, adverse event assessment, intraocular pressure, slit-lamp examination, dilated fundus examination, standardized scleral photographs, complete blood count with differential, basic metabolic panel, and urinalysis.
Primary, Secondary, and Safety Outcomes
The primary efficacy outcome was a 2-step reduction in scleritis grading out of a scale of 0–4+ (where 0.5+ is recognized as an ordinal step between 1+ and 0+) or reduction to grade 0 within 8 weeks, according to the standardized photographic grading system developed at NEI. Secondary outcomes included mean and median change in visual acuity via ETDRS; step changes in scleral inflammation according to the standardized photographic grading system at all follow-up visits; number of participants who experienced a disease flare, as defined by a 1-step increase in scleral inflammation at all follow-up visits; mean and median number of participants needing at least 1 additional injection; the number of days between the first injection to the second injection; and finally, the number of participants who were successfully tapered off 1 or more systemic immunosuppressive medications or tapered the dose of prednisone (≤10 mg) after week 16.
Safety outcomes were made routinely during the study, with a review of the previous visit interval performed at each scheduled visit. Safety outcomes included the number and severity of systemic and ocular toxicities and adverse events, proportion of participants with loss of ≥15 ETDRS letters at any follow-up visit, and the number of participants who experienced a substantial rise in elevated intraocular pressure at any follow-up visit.
Study Drug Administration
All participants received a subconjunctival sirolimus (15-μL, 600-μg) injection on the day of study enrollment. One participant received 2 injections (each 15-μL, 600-μg) owing to multiple nonadjacent quadrant involvement. Subconjunctival sirolimus injections were prepared for injection 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 following topical anesthesia, the needle was engaged approximately 5 mm away from the intended location. All participants 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 dose or reduced, not increased, for the study duration.
Results
Five participants with active, anterior, autoimmune, non-necrotizing anterior scleritis were enrolled in this phase I/II trial. There were 3 female and 2 male participants; the average age was 50.6 years (range: 25–65). The severity of inflammation ranged from grade 1+ to grade 3+ based on the NEI Scleritis Grading Scale, and 4 out of 5 participants had multiple quadrants involved at baseline. Four out of 5 participants were on stable doses of immunosuppressive medications, and 1 was on no other therapy.
All participants (N = 5, 100%) met the primary efficacy outcome and achieved at least a 2-step reduction or reduction to grade zero inflammation in the study eye by the week 8 visit. This was achieved with only 1 injection given at baseline. Mean visual acuity at baseline was 84.6 ETDRS letters and it was 84.4 at the end of the study. No participant experienced more than 2 line changes. Three out of 5 participants experienced disease flares requiring reinjection, and mean number of days until the first reinjection was 65.3 days (range: 28–84).
No systemic toxicities were observed, and none of the patients experienced a significant rise (≥10 mm Hg) in intraocular pressure. One out of 4 participants who were on concomitant immunosuppressives was able to successfully taper off therapy during the study.
Throughout the study there were no serious adverse events attributable to the study drug. However, 2 participants experienced a localized sterile inflammatory reaction at the site of the subconjunctival injection, which resolved without complication. These are described in further detail below. One of these participants withdrew from the study during the extension phase despite resolution.
Participant 1 is a 63-year-old white man without known systemic autoimmune disease who presented with grade 3+ inflammation in the superonasal and inferonasal quadrants at the baseline visit. He was on stable doses of methotrexate and mycophenolate mofetil at the time of enrollment. After 1 injection, his inflammation improved to grade 1+ and 0.5+ in the same quadrants, respectively, after 2 weeks. At 4 weeks, his inflammation returned to grade 2+ and 2+, meeting criteria for reinjection. He was reinjected monthly for 5 months for a total of 5 injections, and by week 32 he achieved quiescence with grade 0 inflammation in all quadrants, which he maintained throughout the duration of the study (1 year) ( Figure 1 ).
Participant 2 is a 25-year-old white man without known systemic autoimmune disease who presented with grade 1+ inflammation in the superotemporal and inferotemporal quadrants at the baseline visit. He was not on systemic immunosuppressive medications and pain was not a major complaint for him. After 1 injection, he achieved quiescence with grade 0 inflammation in all quadrants, which was maintained throughout the duration of the study (1 year).
Participant 3 is a 65-year-old African-American woman with a history of rheumatoid arthritis who presented with grade 3+ inflammation in the superotemporal and inferotemporal quadrants. She was on a stable dose of adalimumab at the time of enrollment. After 1 injection, her inflammation improved to grade 1+ in the same quadrants, after 4 weeks. She remained with this level of inflammation until week 40, when she achieved complete quiescence without further treatment, with grade 0 inflammation in all quadrants, and remained without inflammation throughout the duration of the study (1 year).
Participant 4 is a 50-year-old African-American woman with a history of rheumatoid arthritis who presented with grade 2+ inflammation in the superonasal, inferotemporal, and inferonasal quadrants at the baseline visit. She was on stable doses of methotrexate and hydroxychloroquine at the time of enrollment. After 1 injection, her inflammation improved to grade 1+ in the inferonasal quadrant only and grade 0 in all other quadrants by 8 weeks. At week 12, she experienced a flare with grade 1+ in the superotemporal quadrant, 0.5+ superonasally, and 0.5+ inferonasally, meeting criteria for reinjection. She developed an inflammatory reaction at the site of injection 4 days later ( Figure 2 ). The lesion was incised and drained and sent to pathology, which confirmed noninfectious etiology. She was given oral steroids and the inflammation resolved without complication. She chose not to receive further injections and withdrew from the study after the week 32 visit.
