Drug
Systemic equivalent (mg)
Potency
Cortisone
25
0.8
Hydrocortisone
20
1
Prednisone
5
4
Prednisolone
5
4
Methylprednisolone
4
5
Triamcinolone
4
5
Dexamethasone
0.75
26
Betamethasone
0.6
33
Regional: Topical, Periocular, and Intravitreal
Topical
Topically applied corticosteroids penetrate the eye through the cornea. However, studies conducted in rabbits have shown that corneal epithelium and stroma act as a barrier for hydrophilic and hydrophobic compounds, respectively. However, increasing ocular contact time by changing drug formulations as gel, microsuspension, and viscous formulation can double the corneal and aqueous concentration of steroid compared to the same in solution form [5]. A recent review article in the literature discussed the penetration of various ocular corticosteroids into aqueous humor and their therapeutic efficacy in ocular surface diseases, anterior uveitis, immune-mediated corneal diseases, and postoperative inflammation [6]. The authors conclude that prednisolone acetate 1 % and dexamethasone alcohol 0.5 % have good aqueous penetration with maximal anti-inflammatory effect in uveitis and immune related anterior segment diseases [6]. Another study evaluated the efficacy and safety of difluprednate ophthalmic solution 0.05 % (Durezol; Alcon Laboratories, Fort Worth, TX) compared with prednisolone acetate ophthalmic suspension 1 % (Pred Forte; Allergan, Inc., Irvine, CA) for endogenous anterior uveitis. Difluprednate provides effective treatment for anterior uveitis and requires less frequent dosing than prednisolone acetate [7]. Different topical corticosteroids in use are prednisolone, betamethasone, dexamethasone, flurometholone, loteprednol, and difluprednate.
Periocular [8]
Different methods for periocular steroid include subconjunctival, subtenon, transseptal, orbital floor, and retrobulbar injections where the drug penetrates through hematogenous and trans-scleral route to attain high concentration at the site of inflammation. Holland et al. studied the effect of posterior subtenon injection of triamcinolone acetonide in intermediate uveitis where they concluded that median time to visual improvement was 3 weeks and raised intraocular pressure was seen in 30 % patients at 3 weeks [9]. A recent study also described the effectiveness of periocular corticosteroid injections in noninfectious uveitis where approximately half of the treated eyes had resolution of intraocular inflammation at 3 months after corticosteroid injection [10]. Various regional corticosteroid preparations are hydrocortisone, methyl prednisolone, triamcinolone, dexamethasone, and betamethasone.
Intravitreal
Intravitreal corticosteroid treats posterior segment inflammation without adverse systemic side effects such as diabetes, osteoporosis, and cushingoid states. It bypasses the blood–retinal barrier, leading to a more concentrated dose of steroid into the vitreous cavity for a prolonged period of time. Intravitreal delivery of steroids may be carried via direct injection through the pars plana or introduction of a sustained-release or biodegradable implants.
Tricort: Triamcinolone Acetonide (TA)
It is a safe intravitreal steroid that may be given in posterior uveitis requiring long-term steroid therapy. It is minimally water soluble and injected in a suspension form. The decreased water solubility prolongs the duration of action. Beer et al. showed in a study that 4 mg TA in a non-vitrectomized human eye maintains measurable concentrations for approximately 3 months [11].
In a recent study by Habbot Wliner et al., intravitreal steroid was given in 35 eyes with chronic cystoid macular edema refractory to systemic immunosuppressive therapy. Visual acuity improved in 85 % cases at a mean time interval of 6.2 weeks with resolution of CME in 88 % of treated eyes [12].
Ozurdex (Dexamethasone Drug Delivery System DDS)
It is a sustained-release biodegradable intravitreal implant containing 0.7 mg dexamethasone in the NOVADUR® solid polymer drug delivery system which is placed in the vitreous using a 22-G applicator. The NOVADUR® system contains poly (d, l-lactide-co-glycolide) PLGA intravitreal polymer matrix without a preservative and PLGA matrix slowly degrades to lactic acid and glycolic acid.
In a study by Williams et al. [13], the effects of a dexamethasone intravitreous drug delivery system (dexamethasone DDS) in patients with persistent macular edema (ME) resulting from uveitis or Irvine–Gass syndrome were evaluated in a randomized, prospective, single-masked controlled trial. 315 patients were randomized to surgical placement of 350 or 700 μg dexamethasone DDS or observation. At day 90, a 10-letter or more BCVA improvement was seen in 41.7 % patients in the 350 μg group, in 53.8 % patients in the 700 μg group, and in 14.3 % patients in the observation group. Increase in intraocular pressure of 10 mmHg or more was seen in 5 of 13 patients in the 700 μg group, in 1 of 12 patients in the 350 μg group, and in no patients in the observation group.
In another recent study by Ozurdex Huron Study Group [14], the safety and efficacy of 2 doses of dexamethasone intravitreal implant (DEX implant) for treatment of noninfectious intermediate or posterior uveitis were evaluated. A gain of 15 or more letters from baseline best-corrected visual acuity was seen in significantly more eyes in the DEX implant groups than the sham group at all study visits. The percentage of eyes with intraocular pressure of 25 mmHg or more peaked at 7.1 % for the 0.7-mg DEX implant, 8.7 % for the 0.35-mg DEX implant, and 4.2 % for the sham. The incidence of cataract reported in the phakic eyes was 15 % with the 0.7-mg DEX implant, 12 % with the 0.35-mg DEX implant, and 7 % with the sham.
Retisert: Fluocinolone Acetonide
It is a sustained-release nonbiodegradable intravitreal implant which releases fluocinolone acetonide at an initial rate of 0.6 μg/day, decreasing over the first month to a steady state between 0.3 and 0.4 μg/day over approximately 30 months.
In a prospective multicenter randomized clinical study [15], Jaffe and colleagues reported the 34-week safety and efficacy results of a 3-year study to evaluate an investigational intravitreal fluocinolone acetonide (FA) implant in patients with noninfectious posterior uveitis. 278 were randomized to receive a 0.59-mg (n = 110) or 2.1-mg (n = 168) implant. The implant was inserted surgically into the vitreous cavity through a pars plana incision. Systemic, periocular, and topical therapies were reduced as allowed by the clinical response. FA implant reduced the rate of recurrences from 51.4 % in the 34 weeks preceding implantation to 6.1 % postimplantation in the study eyes. Comparatively, there was a significant increase in the recurrence rate in the fellow nonimplanted eyes. Visual acuity was stabilized or improved in 87 % of implanted eyes. The percentage of eyes that required systemic medications, periocular injections, and topical corticosteroids decreased from 52.9 %, 63.0 %, and 35.7 %, respectively, preimplantation to 12.1, 2.2, and 16.5 % postimplantation in all cases. 51.1 % of implanted eyes required ocular antihypertensive drops, and 5.8 % underwent glaucoma filtering surgery. 9.9 % required cataract surgery. There were no statistically significant differences in any of the parameters studied for the 0.59-mg implant, compared with the 2.1-mg implant.
In another study by Arcinue et al. group [16], a comparison was done between fluocinolone acetonide (retisert) and dexamethasone (ozurdex) intravitreal implants in uveitis. The authors concluded that both implants were comparable in preventing recurrence of noninfectious uveitis and in improving inflammation and BCVA. However, there were higher rates of cataract progression and need for glaucoma medications, laser, and surgery with the Retisert implant.
In another randomized controlled study [17], the multicenter uveitis steroid treatment trial (MUST trial), the relative effectiveness of systemic corticosteroids plus immunosuppression when indicated (systemic therapy) versus fluocinolone acetonide implant (implant therapy) for noninfectious intermediate, posterior, or panuveitis (uveitis) was compared. The authors concluded that over 24 months in 255 patients, the implant and systemic therapy groups had an improvement in visual acuity, an improvement in vision-related quality of life, and residual active uveitis in 12 % and 29 %, respectively. Over the 24-month period, implant-assigned eyes had a higher risk of cataract surgery, treatment for elevated intraocular pressure and glaucoma. Patients assigned to systemic therapy had more prescription-requiring infections. However, specific choice of treatment between implant and systemic therapy would depend on individual patients’ requirement. Systemic therapy with aggressive use of corticosteroid-sparing immunosuppression was well tolerated, suggesting that this approach is reasonably safe for local and systemic inflammatory disorders.
Side Effects
Corticosteroids cause both ocular and systemic adverse effects irrespective of the modes of delivery. Most common ocular side effects are cataract and glaucoma besides increased susceptibility to infections, poor wound healing, ptosis, and mydriasis. In a recent study by Thorne et al. [18], risk of cataract development among children with juvenile idiopathic arthritis-related uveitis treated with topical corticosteroids was studied. The authors concluded that chronic use of topical steroids at ≤3 drops daily had decreased risk of cataract formation than higher doses in chronic uveitis. Another study revealed that difluprednate, a newer corticosteroid, reduces anterior segment inflammation and cystoid macular edema in pediatric uveitis, but increased intraocular pressure and cataract progression were found in 50 % and 43 % patients, respectively [19].
Topical steroids may also cause punctate keratopathy, blurred vision, or allergy to the vehicle. Periocular injection of steroids may be associated with globe perforation, fibrosis of extraocular muscles, proptosis, and retinal and choroidal vascular occlusion. A recent case report by Shields et al. described perilymphatic linear subcutaneous fat atrophy and depigmentation after subtenon’s fascia injection of triamcinolone acetonide [20]. Central serous retinopathy has also been reported with corticosteroids [21]. Besides cataract and glaucoma, another adverse effect reported with dexamethasone DDS implant is anterior chamber migration both in aphakic and pseudophakic eyes, causing endothelial decompensation [22, 23]. Other adverse events reported in the literature are cytomegalovirus retinitis [24], herpetic necrotizing retinitis [25], CMV endothelitis [26], and spontaneous dissociation of implant device [27].
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