|Year : 2018 | Volume
| Issue : 8 | Page : 1060-1073
Intravitreal therapeutic agents in noninfectious uveitic macular edema
Kunal Kaushik Shah1, Parthopratim Dutta Majumder2, Jyotirmay Biswas2
1 Shri Bhagwan Mahavir VitreoRetinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India
2 Department of Uvea, Medical Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
|Date of Submission||07-Jan-2018|
|Date of Acceptance||16-Apr-2018|
|Date of Web Publication||23-Jul-2018|
Dr. Jyotirmay Biswas
Department of Uveitis, Medical Research Foundation, Sankara Nethralaya, No 18, College Road, Nungambakkam, Chennai - 600 006, Tamil Nadu
Source of Support: None, Conflict of Interest: None
The management of uveitis is challenging for most treating ophthalmologists. The treatment of uveitis often requires the use of high dose of systemic corticosteroid and immunosuppressive agents, which are almost always associated with potential side effects. Intravitreal medications have become a popular mode of drug administration in uveitis patients as they provide high volume of drug to the target tissues, eliminating the risk of systemic toxicity. There has been tremendous development in the intravitreal therapeutics over the last few years. With the advent of sustained-release technique, increasing patient compliance, biodegradable nature of the implant, and introduction of newer agents with better safety profile, the intravitreal medications have become more popular in recent years. This review presents evidence in the scientific literature supporting the use of intravitreal medications for the management of uveitis and its complications.
Keywords: Anti-vascular endothelial growth factor agents, dexamethasone, fluocinolone acetonide, intravitreal agents, methotrexate, noninfectious uveitis, sirolimus, triamcinolone acetonide
|How to cite this article:|
Shah KK, Majumder PD, Biswas J. Intravitreal therapeutic agents in noninfectious uveitic macular edema. Indian J Ophthalmol 2018;66:1060-73
|How to cite this URL:|
Shah KK, Majumder PD, Biswas J. Intravitreal therapeutic agents in noninfectious uveitic macular edema. Indian J Ophthalmol [serial online] 2018 [cited 2019 Feb 16];66:1060-73. Available from: http://www.ijo.in/text.asp?2018/66/8/1060/237334
Uveitis is one of the major causes of visual morbidity, with a reported prevalence of 38–714 cases per 100,000. It is responsible for 10%–15% blindness in the developed world. It predominantly affects the younger population, and the consequent economic blindness imposes a greater burden on society and healthcare.,
Posterior uveitis is the major cause of visual morbidity among patients with uveitis. Visual loss in posterior uveitis is usually secondary to macular edema (ME), choroidal neovascularization, glaucoma, optic nerve involvement, vitreous opacification, and cataract formation., ME is the most common structural complication causing visual morbidity in about 40% of patients diagnosed with uveitis. It is more commonly seen in cases of posterior uveitis and intermediate uveitis as against anterior uveitis and may persist despite adequate control of intraocular inflammation due to prolonged damage to the blood–retinal barrier or persistent low-grade inflammatory cytokines., Cystoid ME (CME) may progressively damage the macular photoreceptors and may lead to complications such as macular ischemia, macular cyst, or hole formation.,
Pathophysiology of uveitic ME has not been fully understood, and the dysfunction of blood–retinal barrier is attributed in majority of cases. ME occurs when there is a disturbance in the balance between fluid entering the tissues and the function of metabolic pump, leading to the accumulation of fluid intra- or extra-cellularly. Chronic ME may be associated with significant vision loss.
Treatment of uveitis remains a challenge with a host of treatment options – nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressive agents, and more recently biological agents. Each agent can be administered through various drug delivery routes with each route having its own merits and demerits.
Use of topical corticosteroids, though better tolerated than systemic administration, is effective only for the treatment of anterior uveitis due to poor reach of the drug to the posterior segment of the eye.,, Periocular injection of depot corticosteroid, though minimally invasive, provides only a short-term effect with uncertain therapeutic concentration due to partial absorption of drug by highly vascular choroid before it reaches target site. Furthermore, periocular injections are associated with their own side effects – ptosis, extraocular muscle injury, globe penetration, subdermal fat atrophy, or skin depigmentation., Systemic use of corticosteroids and immunosuppressive agents may not achieve effective concentration in vitreous cavity due to physiological properties of the blood–retinal barrier, leading to the requirement of higher doses of these agents which again in turn are associated with potential side effects., Intravitreal route allows relatively lower doses of the drug to be administered while achieving high concentration in the target areas, avoiding the risk of side effects associated with systemic use of the drug  Local side effects such as cataract, glaucoma, sterile and infectious endophthalmitis, hypotony, intravitreal hemorrhage, and retinal detachment have been reported with the use of intravitreal injection although incidence of such complications is relatively low.,
Over the past few years, there has been tremendous improvement in intravitreal therapeutics – many immunomodulatory agents have been added in the armamentarium of intravitreal medications against uveitis with the development of various new formulations to attain rapid yet controlled release of drug molecule in vitreous cavity. Intravitreal drugs are now considered as a safe and effective treatment option for the management of noninfectious uveitis, especially in patients with unilateral disease without any systemic component., This article reviews the various intravitreal drugs used for the treatment of ME secondary to noninfectious uveitis.
| Literature Search|| |
A detailed review of the literature on PubMed was conducted using such terms as intravitreal [MeSH], macular edema [MeSH], cystoid macular edema [MeSH], uveitic macular edema [MeSH], corticosteroid [MeSH], anti-VEGF [MeSH], immunosuppressive [MeSH], biologicals [MeSH], intraocular injection. Additional studies were identified from the bibliographies of the retrieved articles. For non-English literature, English abstracts were reviewed when available. Foreign-language articles without English abstract were excluded.
| Corticosteroids|| |
Corticosteroid remains the first-line therapy for the management of uveitis., Corticosteroids are effective in treating ME due to its potent anti-inflammatory properties by preventing leukocyte migration, stabilizing endothelial cell tight junctions which reduces cellular and fluid extravasation, and also inhibiting synthesis of vascular endothelial growth factor (VEGF), prostaglandins, and proinflammatory cytokines. Intravitreal administration of corticosteroids aids to circumvent a host of adverse effects which are otherwise associated with their systemic administration.
| Intravitreal Triamcinolone Acetonide Injection|| |
Triamcinolone acetonide (TA) is the most widely used corticosteroid for the treatment of uveitic CME. When injected intravitreally, TA has a mean half-life of 18.6 days in nonvitrectomized eyes and 3.2 days in postvitrectomized eyes. A single dose of 4 mg when injected as a suspension in vitreous cavity of a nonvitrectomized human eye is known to maintain a desirable drug concentration for approximately 3 months because of its decreased water solubility. It has been estimated that a single intravitreal injection of TA can yield a concentration of 0.22 ± 0.24 μg/ml.
Various studies conducted to evaluate the efficacy of intravitreal TA (IVTA) have shown that IVTA 4 mg is effective in reducing the CME and leads to improvement in visual acuity (VA) in 50%–70% of patients, but repeated injections are required to maintain the effect over a period. In their study to evaluate the outcome of IVTA in the treatment of uveitic ME, Kok et al. found that TA was effective in reducing CME with significant improvement in best-corrected VA (BCVA) (0.65–0.39 logMAR), especially in patients ≤60 years of age, but rise in intraocular pressure (IOP) was observed in 43% of subjects. Factors favoring better response to IVTA included in their study were CME of < 1-year duration, younger age, and nonvitrectomized eye. Cataract formation and increased IOP remain a concern for intravitreal corticosteroid. About 40%–70% of patients experienced rise in IOP following a single intravitreal injection of TA, but majority of these were transient and could be effectively managed by antiglaucoma medications.,,, In uveitic eyes, the risk of development and progression of cataract increases with multiple injections, almost all patients developing cataract after five injections.
Endophthalmitis following IVTA is a serious concern. Culture-positive infectious endophthalmitis following IVTA has a reported incidence of 0.45%–0.87%.,, Pseudoendophthalmitis usually occurs in pseudophakic or aphakic patients or in patients with peripheral iridectomy, when TA particles migrate into the anterior chamber and masquerade as a hypopyon. Sterile endophthalmitis occurs due to an inflammatory reaction to either TA or more likely to its preservative such as benzyl alcohol. Risk factors for developing sterile endophthalmitis following IVTA injection are pseudophakia with breached posterior capsule, CME resulting from Irvine–Gass syndrome, vitrectomized eye, and uveitic eye.,,
| Intravitreal Dexamethasone|| |
Dexamethasone (DEX) is a water-soluble, synthetic glucocorticoid that is three times more potent as compared to TA. However, being a small molecule, it is rapidly cleared from the vitreous, with an estimated vitreal half-life of 5.5 h in humans. This limitation in ocular pharmacokinetics of the drug has been overcome with advent of newer sustained-release intravitreal DEX to release corticosteroids over a prolonged duration of time in small doses. DEX was the first corticosteroid to be used as a sustained-release device.
DEX implant (Ozurdex, Allergan, Inc., Irvine, CA) is an intravitreal, biodegradable, sustained-release rod-shaped implant approved by the US Food and Drug Administration (US-FDA) in phase-wise manner for the treatment of ME secondary to retinal vein occlusion, noninfectious uveitis, and diabetic ME. It is composed of polylactic acid and polyglycolic acid polymers that slowly undergoes hydrolysis and gradually releases 700 μg of drug inside the vitreous cavity over a 6-month period, reducing the need for frequent intravitreal injections. The drug–copolymer complex comes in a preloaded applicator with a 22-gauge needle that is inserted in the eye via the pars plana approach. It can be administered in an office-based setting, in contrast to nonbiodegradable implants, which require a surgical procedure in the operating theater. There are two phases of drug release: first phase showing a high concentration of DEX reaching a peak at 2 months, followed by a second phase in which low DEX concentration were released up to 6 months, beyond which the levels fall to below limit of quantitation as most of the implant had fragmented. Subsequently, it forms glycolic acid and lactic acid which are further metabolized to water and carbon dioxide which can be easily eliminated by ocular tissue.,
It is obvious that drug diffusion and clearance from the vitreous cavity may be more rapid in vitrectomized (pars plana vitrectomy [PPV]) eyes as compared to nonvitrectomized (non-PPV) eyes, which in turn may limit the drug exposure to the retina and lead to decrease in the efficacy of the drug. However, Chang-Lin et al. in their study to understand the pharmacokinetic profile of the DEX implant found no such difference. Pelegrín et al. also showed no statistical significant difference in decrease in median central retinal thickness (CRT) and improvement in BCVA between non-PPV and PPV eyes following the implant injection.
In a randomized control trial, Lowder et al. in 2011 first reported the safety and efficacy of DEX implant. They found that DEX implant is relatively safe and can reduce inflammation as well as substantially improve vision in eyes with noninfectious intermediate or posterior uveitis. Since then, various studies have documented the efficacy of DEX implant in improving the BCVA and reducing the ME in patients with noninfectious uveitis. DEX implant was also found to be well tolerated in pediatric uveitis eyes and when used bilaterally., Results of various studies of DEX implant have been summarized in [Table 1].
|Table 1: Studies assessing use of dexamethasone implant in noninfectious uveitic eyes|
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DEX implant is also associated with IOP which peaks at 2 months postimplantation. However, the SAFODEX study found the raised IOP to be only transient, being effectively managed with topical antiglaucoma medications, and very rarely requiring surgical intervention (<1% eyes). Furthermore, repeated DEX implant injection was not found to be associated with any increase in IOP. Risk factors for IOP rise with DEX implant are young patients, males, type 1 diabetics, patients on 2- or 3-drug antiglaucoma therapy, and those with history of retinal vein occlusion or uveitis. It is independent of the status of the lens (phakic/pseudophakic) or vitreous (vitrectomized or not). In their study to evaluate the IOP rise following steroid injection, Kiddee et al. found that ocular hypertension developed in 32% eyes injected with IVTA, 66% and 79% eyes injected with low- and high-dose fluocinolone acetonide (FA) implant, and only 11% and 15% eyes injected with low- and high-dose DEX implant. However, migration of the implant to anterior chamber in aphakic eye, pseudophakic eye with breach of posterior capsule, or eyes with large surgical iridectomy is a major concern, and the implant is not advocated for the use in these eyes.
| Intravitreal Fluocinolone Acetonide|| |
FA is a synthetic corticosteroid which is 1/24th as soluble as DEX with an increased half-life in the vitreous even without a special delivery system. RETISERT (Bausch and Rochester, NY, USA) is a nonbiodegradable, sustained-release device available in two doses of 0.59 mg or 2.1 mg. It was approved by the US-FDA for the treatment of chronic noninfectious uveitis in 2005. The implant has an overall dimension of 3 mm × 2 mm × 5 mm and consists of a 1.5 mm central drug pellet surrounded by shells of ethyl vinyl alcohol and 98% hydrolyzed polyvinyl alcohol (PVA). The ethyl vinyl alcohol component partly coats the pellet and is impermeable to the drug restricting the amount of drug release. The 0.59 mg implant releases the drug at 0.6 μg/day initially for 1 month, following which the levels decrease to reach a steady state between 0.3 and 0.4 μg/day controlling the intraocular inflammation for 2.5–3 years. The 2.1 mg implant has a dual release orifice-releasing FA at a rate of approximately 2 μg/day initially and then decreasing to 1 μg/day for a 3-year period. Silicon adhesive is used to attach the silicone-coated drug core to a heat-treated PVA suture tab, and entire assembly is sterilized by γ-irradiation before implantation.,
The implant is surgically placed through the pars plana incision with a 20G needle and extending 3.5 mm circumferentially, 4 mm posterior to and parallel to limbus. After excising the prolapsed vitreous, the implant is sutured to the sclera. The surgical procedure is performed under local or general anesthesia, and inferior quadrant is the preferred site. An 8-0 nylon or prolene suture is passed through the hole in a suture tab and is used to anchor the implant to the sclera. In case of vitrectomized eyes, a pars plana infusion line can be used to prevent chances of globe collapse.,, Having a limited lifespan, Retisert may need re-implantation in patients with chronic uveitis to maintain disease quiescence. Such re-implantation may be done with or without exchange of the old implant. There is a high risk of dissociation of implant during removal/exchange surgery. The prospective, interventional, pilot study conducted by Jaffe et al. in 2000 showed a marked reduction in anti-inflammatory medication use and statistically significant improvement in BCVA following implantation of FA implant in seven eyes of five patients.
The Multicenter Uveitis Steroid Treatment Trial was the Phase III, randomized controlled trial conducted to study the relative effectiveness and safety of FA implant against systemic corticosteroids and immunosuppressives in 255 patients (479 eyes) with active noninfectious posterior uveitis. It showed that although eyes with ME treated with FA implant had greater decrease in macular thickness compared to those on systemic therapy, there was no statistically significant difference between two groups in regard to proportion of eyes showing resolution of CME. In addition, risk of adverse outcomes was higher in the implant group with 77.9% requiring IOP lowering medications as against 34% in those systemic therapy group after 54 weeks and nearly 4-fold higher incidence of cataract surgery in the implant group [Table 2].
|Table 2: Studies assessing use of fluocinolone acetonide (dose comparative) in noninfectious uveitic eyes|
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Retisert implant is associated with numerous complications including increase in IOP, development and progression of cataract, spontaneous dissociation or dislocation of pellet from support strut, hypotony, and cytomegalovirus endotheliitis. Due to high incidence of glaucoma, it is recommended to monitor the IOP every 6–12 weeks after Retisert implantation. Compared to DEX implant, Retisert is associated with high rate of side effects with 45% of patients requiring glaucoma filtering surgery and about 80%–100% of patients requiring cataract surgery within 3 years of implantation.,, On the other hand, a single Retisert 0.59 mg implant can control inflammation for up to 3 years reducing the need for re-implantation, whereas possibility of need for reinjection of DEX implant is 5 times more due to relatively shorter duration of action. Retisert implant may also need explantation in case of the unforeseen circumstance including uncontrolled IOP, depletion of study medication, spontaneous dissociation of implant from anchoring strut, lysis of anchoring suture, endophthalmitis, hypotony, scleral necrosis and melt, and implant protrusion.,,
Iluvien (Alimera Sciences, Alpharetta, GA, USA) is another nonbiodegradable intravitreal implant containing FA. The implant is a nonbiodegradable cylindrical tube containing a central drug–polymer matrix which releases 0.19 mg of FA into the vitreous cavity over 3 years. It is injected through a 25-gauge injector system in an office-based setting and thus requires no surgical intervention. It releases a lower dose of 0.2–0.5 μg/day for 18–36 months and is FDA approved for the treatment of diabetic ME., However, a case report has been published documenting its off-label use in a patient with ME secondary to noninfectious uveitis, in which the patient showed sustained improvement in VA with decrease in inflammatory activity and ME. Iluvien may have a potential role in future for the treatment of uveitic ME.
Despite advent of immunosuppressive therapy and biologics, corticosteroids still are the most preferred agents for treatment of non-infectious uveitic ME. However, due to the myriad of complications associated with the corticosteroid agents, the possibility of an alternate agent targeting different inflammatory pathway is continuously being explored which might be better tolerated.
| Intravitreal Anti-Vascular Endothelial Growth Factor|| |
Chronic intraocular inflammation leads to increased production of inflammatory cytokines such as interleukin (IL)-1β and IL-6 which induce VEGF production by Muller cells, which in turn may disrupt the inner and outer blood–retinal barrier and increase vascular permeability, through a protein kinase C-isoform cascade, leading to subsequent ME., Fine et al. in their study found that the aqueous VEGF concentration is significantly higher in these patients with uveitic CME than those without CME. A study done by Jeon et al. showed significant decrease in VEGF levels of aqueous humor following intravitreal injection of anti-VEGF agent. All these suggested a possible role of anti-VEGF agents in treatment of uveitic CME.
Both bevacizumab (BVZ) and ranibizumab (RBZ) have been tried in the treatment on ME associated with noninfectious uveitis. BVZ is a full-length, recombinant, humanized monoclonal antibody against all subtypes of VEGF, and despite having a potentially immunogenic property, it seems to be well tolerated in uveitic eyes with immunogenic predisposition. Available as a preservative-free solution, BVZ is free of any retinotoxic component. RBZ is a recombinant, humanized monoclonal antibody antigen-binding fragment (Fab) which neutralizes all VEGF isoforms and bioactive fragments., It has 100 times higher affinity for VEGF than bevacizumab.
Cordero Coma et al. published the first retrospective study describing the use of anti-VEGF therapy in the management of 13 patients with recalcitrant uveitic ME in 2007 with documented reduction in central macular thickness (CMT) in six patients (46.15%) and improvement in VA in nine patients (69.2%). Although the improvement in VA was not statistically significant, they encountered no ocular adverse events which are usually seen following intravitreal steroid injection. Since then, many different studies have been conducted showing variable results with anti-VEGF agents in ME associated with noninfectious uveitis. Although these drugs may lead to anatomic and visual improvement in patients with uveitic ME, they have limited potency and their effect is short-lived necessitating frequent reinjections.,, Furthermore, they are associated with a theoretical risk of systemic adverse effect such as thromboembolic events, but none of the study found any such risk associated with its use. [Table 3] highlights the results of various studies of effect of BVA and RBZ in eyes with noninfectious uveitis.
|Table 3: Studies (comparative and noncomparative) assessing use of anti-vascular endothelial growth factor agents in noninfectious uveitic eyes|
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Although anti-VEGF agents may not be as effective as various steroid agents due to limited anti-inflammatory action, they are associated with significantly lower rate of cataract progression or rise in IOP and thus can be an effective supplementary therapy in patients with persistent uveitic ME, particularly in phakic eyes and in steroid responders.
| Intravitreal Methotrexate|| |
Methotrexate (MTX) is another nonsteroidal agent which has been tried in uveitic eyes with reasonably good results. MTX is an antimetabolite which competitively inhibits the enzyme dihydrofolate reductase and thus inhibits the production of tetrahydrofolate which in turn inhibits the formation of thymidylate, resulting in the inhibition of DNA replication and RNA transcription. MTX is most commonly used for rheumatoid arthritis and cancer. Systemic MTX is now in common use for various ophthalmic diseases. Intravitreal route for MTX was first used in the management of intraocular lymphoma. Hardwig et al. were the first to evaluate the role of intraocular MTX in patients with ocular disease other than lymphoma. In their retrospective case series of 15 patients with various intraocular diseases, all four patients having intraocular inflammation showed a good response to MTX, supporting the possibility of its role in various ocular diseases. MTX exerts its anti-inflammatory action via release of adenosine into the extracellular space, where it acts through the A2A receptor to inhibit neutrophils, macrophage, and T-cell activity in a dose-dependent manner.
Taylor et al. conducted a prospective, interventional study to evaluate the use of intravitreal MTX in the treatment of uveitis and uveitic ME using a dose of 400 μg MTX in 0.1 ml in 15 eyes. They showed that 87% patients (13/15 eyes) gained at least 10 letters by the end of 3 months, improving the mean BCVA from 1.06 logMAR preinjection to 0.63 logMAR at 3 months postinjection. However, no statistically significant difference was seen between BCVA post-MTX injection compared to that after previous corticosteroid injection. Further, a statistically significant reduction in vitreous haze score, and decrease in mean CMT was noted. Five patients showed relapse after median time of 4 months and needed reinjections. The only adverse events seen were ocular pain for < 24 h duration and one case of corneal epitheliopathy who was managed symptomatically. Topical folinic acid may be used to treat corneal decompensation.
In another multicenter, retrospective, interventional case series by Taylor et al., 54 intravitreal injections of MTX were given in 38 eyes of 30 patients. Of 38 eyes, 30 (79%) showed effective response with decrease in intraocular inflammation and improvement in VA. None of the patient showed any serious ocular adverse effect. In addition, dosage of systemic corticosteroids could be reduced in eight of 14 patients (57%). Although eight eyes relapsed after a median of 3 months, majority (73%) entered an extended period of remission of up to 18 months. On meta-analysis of both the studies as a whole, a response rate of 80% was noted to intravitreal MTX injection. MTX and anti-VEGF agents may offer better alternative to corticosteroid in steroid responders and in phakic patients. Large-scale prospective, comparative trials are required to evaluate the same.
| Intravitreal Sirolimus|| |
Sirolimus (rapamycin) is a macrolide antibiotic and a potent immunosuppressant inhibiting mammalian target of rapamycin. Sirolimus is known to interrupt the inflammatory cascade by inhibiting the expression of the IL-2, IL-4, and IL-15, which in turn suppresses T-cell activation and proliferation. It inhibits the production, signaling, and activity of many growth factors and antibodies involved in the inflammatory cascade of uveitis. It has also been shown to downregulate the expression of a number of genes related to inflammation such as IL-8, endothelial monocyte-activating polypeptide II, granulocyte chemotactic protein 2, cyclooxygenase 1 and 2, and inducible nitric oxide synthase.
It is recently being considered for the treatment of noninfectious uveitis. Following intravitreal administration, the formulation localizes in the inferior portion of the vitreous humor as a nondispersive depot in the vitreous. The depot subsequently dissolves slowly over a period of 60 days after single intravitreal administration and diffuses through the vitreous humor to other ocular layers.
Sirolimus as a therapeutic Approach in uVEitis (SAVE) trial in 2003 was the initial study conducted in 30 patients to evaluate the efficacy of intravitreal (352 μg) and subconjunctival (1320 μg) sirolimus. Nguyen et al. showed that the drug appeared to be well tolerated via both the routes with reduced vitreous haze scores. While improvement in BCVA was seen in only 30% of the patients, remaining maintained a stable VA with only 20% showing some deterioration. Reduction in CMT was noted at 3 months compared to baseline, but benefit could not be sustained until 6 months, suggesting need for frequent repeat injections. At the end of 1 year of SAVE study, Ibrahim et al. reported reduction in vitreous haze in 70% of eyes. Although there was no statistically significant improvement in mean BCVA or change in CRT, SAVE study established that sirolimus was well tolerated in eyes when injected repeatedly. SAVE-2 study to compare the effect of 880 μg of intravitreal sirolimus as against 440 μg administered every 2 months was initiated in 2015. Interim results published by Sepah et al. have reported equal efficacy of both the dose groups in reducing vitreous haze, whereas low-dose sirolimus was more effective in reducing uveitic ME.
Systemic use of sirolimus is known to be associated with a number of cytotoxic, especially hematological, adverse effects. However, adverse events, other than those related to the procedure itself, are very rarely seen with intravitreal injections of sirolimus, with vitreous floaters being the most commonly reported adverse events.
SAKURA study was a multicenter, randomized study to evaluate the efficacy and tolerability of 3 doses of sirolimus: 44, 440, and 880 μg. The study results showed that patient using 440 μg of sirolimus demonstrated significant control of ocular inflammation with reduction in the usage of systemic corticosteroid while preserving BCVA. Thus, sirolimus appears to be well tolerated and effective in controlling active uveitic inflammation in the eye, but no significant improvement in BCVA or CMT was seen.
| Intravitreal Infliximab|| |
Infliximab is a biological agent and a chimeric monoclonal antibody drug against tumor necrosis factor, commonly being used for many systemic autoimmune diseases such as rheumatoid arthritis, spondyloarthropathy, inflammatory bowel disease, and psoriasis. It is associated with multitude of side effects on systemic administration such as congestive heart failure, reactivation of latent tuberculosis, and increased risk of infections, all of which can be minimized by administering the drug intravitreally. Markomichelakis et al. performed a prospective, noncomparative, pilot study in sight-threatening relapsing uveitis in Behçet's disease, studying the effect of single intravitreal injection of infliximab (1 mg/0.05 ml) in 15 eyes. They reported a significant improvement in BCVA by day 7, maintained until follow-up period of 30 days. Further, beneficial effects were noted in all components of intraocular inflammation, except CME. Despite decrease in mean CMT, persistent CME was noted in 80% of the eyes. No ocular or systemic side effects were documented during the study.
However, the risk of autoantibodies against the drug, known to develop after intravenous administration, was not assessed. Moreover, in another study, infliximab was found to have a significantly faster effect when administered via intravenous route as against intravitreal route. Therefore, intravitreal infliximab can be considered in cases with contraindications to systemic route or in those who manifest systemic side effects.
Although a multitude of drugs have been tried against uveitic macular edema, with new drugs being added with better understanding of the pathogenesis of disease, but very few have been statistically proven to be beneficial in treatment. [Table 4] provides the level of evidence of various intravitreal therpeutic agents discussed in this review article. Based on National Health and Medical Research Council guidelines.
|Table 4: Level of evidence of various intravitreal therapeutic agents in noninfectious uveitis based on the National Health and Medical Research Council Guidelines|
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| Conclusion|| |
Intravitreal therapeutics is slowly becoming the preferred choice of treatment for majority of ocular diseases including noninfectious uveitis due to its efficacy and better safety profile. However, this therapy has its own drawbacks with necessity to treat both eyes separately in cases of bilateral uveitis, need for more frequent follow-ups, and absence of systemic benefits in patients with extraocular manifestations. Intravitreal drugs can be used as a sole therapy or in combination with systemic therapy to treat uveitic ME secondary to noninfectious uveitis, especially in unilateral cases. With a variety of intravitreal therapeutic agents available for treatment of uveitic ME and each drug having its own advantages and disadvantages, the final treatment should be individualized based on the severity of disease, risk/benefit ratio of each therapy, patient tolerance, and choice of the patient. Sometimes, a combination of drugs may be used. In case of refractory ME not responding to any of the above therapy, PPV can be considered as a last resort.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Karim R, Sykakis E, Lightman S, Fraser-Bell S. Interventions for the treatment of uveitic macular edema: A systematic review and meta-analysis. Clin Ophthalmol 2013;7:1109-44.
Lowder C, Belfort R Jr., Lightman S, Foster CS, Robinson MR, Schiffman RM, et al.
Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129:545-53.
Pleyer U, Klamann M, Laurent TJ, Mänz M, Hazirolan D, Winterhalter S, et al.
Fast and successful management of intraocular inflammation with a single intravitreal dexamethasone implant. Ophthalmologica 2014;232:223-9.
Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Kempen JH, Altaweel MM, Holbrook JT, Jabs DA, Louis TA, et al.
Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: The multicenter uveitis steroid treatment trial. Ophthalmology 2011;118:1916-26.
Callanan DG, Jaffe GJ, Martin DF, Pearson PA, Comstock TL. Treatment of posterior uveitis with a fluocinolone acetonide implant: Three-year clinical trial results. Arch Ophthalmol 2008;126:1191-201.
Tan HY, Agarwal A, Lee CS, Chhablani J, Gupta V, Khatri M, et al.
Management of noninfectious posterior uveitis with intravitreal drug therapy. Clin Ophthalmol 2016;10:1983-2020.
Bansal P, Agarwal A, Gupta V, Singh R, Gupta A. Spectral domain optical coherence tomography changes following intravitreal dexamethasone implant, ozurdex® in patients with uveitic cystoid macular edema. Indian J Ophthalmol 2015;63:416-22.
] [Full text]
Cordero Coma M, Sobrin L, Onal S, Christen W, Foster CS. Intravitreal bevacizumab for treatment of uveitic macular edema. Ophthalmology 2007;114:1574-9.e1.
Acharya NR, Hong KC, Lee SM. Ranibizumab for refractory uveitis-related macular edema. Am J Ophthalmol 2009;148:303-9.
Lasave AF, Zeballos DG, El-Haig WM, Díaz-Llopis M, Salom D, Arevalo JF, et al.
Short-term results of a single intravitreal bevacizumab (avastin) injection versus a single intravitreal triamcinolone acetonide (kenacort) injection for the management of refractory noninfectious uveitic cystoid macular edema. Ocul Immunol Inflamm 2009;17:423-30.
de Smet MD. Insights into the physiopathology of inflammatory macular edema. Dev Ophthalmol 2017;58:168-77.
Fardeau C, Champion E, Massamba N, LeHoang P. Uveitic macular edema. Eye (Lond) 2016;30:1277-92.
Yap YC, Papathomas T, Kamal A. Results of intravitreal dexamethasone implant 0.7 mg (Ozurdex®) in non-infectious posterior uveitis. Int J Ophthalmol 2015;8:835-8.
Modorati G, Miserocchi E. Intravitreal injection therapy in the treatment of noninfectious uveitis. Dev Ophthalmol 2012;51:110-21.
Frère A, Caspers L, Makhoul D, Judice L, Postelmans L, Janssens X, et al.
Single dexamethasone intravitreal implant in the treatment of noninfectious uveitis. J Ocul Pharmacol Ther 2017;33:290-7.
Tsang AC, Virgili G, Abtahi M, Gottlieb CC. Intravitreal dexamethasone implant for the treatment of macular edema in chronic non-infectious uveitis. Ocul Immunol Inflamm 2017;25:685-92.
Tomkins-Netzer O, Taylor SR, Bar A, Lula A, Yaganti S, Talat L, et al.
Treatment with repeat dexamethasone implants results in long-term disease control in eyes with noninfectious uveitis. Ophthalmology 2014;121:1649-54.
Beer PM, Bakri SJ, Singh RJ, Liu W, Peters GB 3rd
, Miller M, et al.
Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology 2003;110:681-6.
Ciulla TA, Walker JD, Fong DS, Criswell MH. Corticosteroids in posterior segment disease: An update on new delivery systems and new indications. Curr Opin Ophthalmol 2004;15:211-20.
Inoue M, Takeda K, Morita K, Yamada M, Tanigawara Y, Oguchi Y, et al.
Vitreous concentrations of triamcinolone acetonide in human eyes after intravitreal or subtenon injection. Am J Ophthalmol 2004;138:1046-8.
Kok H, Lau C, Maycock N, McCluskey P, Lightman S. Outcome of intravitreal triamcinolone in uveitis. Ophthalmology 2005;112:1916.e1-7.
Park UC, Park JH, Yu HG. Long-term outcome of intravitreal triamcinolone acetonide injection for the treatment of uveitis attacks in Behçet disease. Ocul Immunol Inflamm 2014;22:27-33.
Tuncer S, Yilmaz S, Urgancioglu M, Tugal-Tutkun I. Results of intravitreal triamcinolone acetonide (IVTA) injection for the treatment of panuveitis attacks in patients with Behçet disease. J Ocul Pharmacol Ther 2007;23:395-401.
Sallam A, Taylor SR, Habot-Wilner Z, Elgohary M, Do HH, McCluskey P, et al.
Repeat intravitreal triamcinolone acetonide injections in uveitic macular oedema. Acta Ophthalmol 2012;90:e323-5.
Moshfeghi DM, Kaiser PK, Scott IU, Sears JE, Benz M, Sinesterra JP, et al.
Acute endophthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol 2003;136:791-6.
Ozkiriş A, Erkiliç K. Complications of intravitreal injection of triamcinolone acetonide. Can J Ophthalmol 2005;40:63-8.
Nelson ML, Tennant MT, Sivalingam A, Regillo CD, Belmont JB, Martidis A, et al
. Infectious and presumed noninfectious endophthalmitis after intravitreal triamcinolone acetonide injection. Retina 2003;23:686-91.
Wang LC, Yang CM. Sterile endophthalmitis following intravitreal injection of triamcinolone acetonide. Ocul Im- munol Inflamm 2005;13:295–300.
Roth DB, Chieh J, Spirn MJ, Green SN, Yarian DL, Chaudhry NA, et al.
Noninfectious endophthalmitis associated with intravitreal triamcinolone injection. Arch Ophthalmol 2003;121:1279-82.
Taban M, Singh RP, Chung JY, Lowder CY, Perez VL, Kaiser PK, et al.
Sterile endophthalmitis after intravitreal triamcinolone: A possible association with uveitis. Am J Ophthalmol 2007;144:50-4.
Chan A, Leung LS, Blumenkranz MS. Critical appraisal of the clinical utility of the dexamethasone intravitreal implant (Ozurdex) for the treatment of macular edema related to branch retinal vein occlusion or central retinal vein occlusion. Clin Ophthalmol 2011;5:1043-9.
Chang-Lin JE, Attar M, Acheampong AA, Robinson MR, Whitcup SM, Kuppermann BD, et al.
Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci 2011;52:80-6.
Khurana RN, Porco TC. Efficacy and safety of dexamethasone intravitreal implant for persistent uveitic cystoid macular edema. Retina 2015;35:1640-6.
Pelegrín L, de la Maza MS, Molins B, Ríos J, Adán A. Long-term evaluation of dexamethasone intravitreal implant in vitrectomized and non-vitrectomized eyes with macular edema secondary to non-infectious uveitis. Eye (Lond) 2015;29:943-50.
Tomkins-Netzer O, Talat L, Seguin-Greenstein S, Bar A, Lightman S. Outcome of treating pediatric uveitis with dexamethasone implants. Am J Ophthalmol 2016;161:110-50.
Ryder SJ, Iannetta D, Bhaleeya SD, Kiss S. Efficacy and tolerability of bilateral sustained-release dexamethasone intravitreal implants for the treatment of noninfectious posterior uveitis and macular edema secondary to retinal vein occlusion. Clin Ophthalmol 2015;9:1109-16.
Malclès A, Dot C, Voirin N, Vié AL, Agard É, Bellocq D, et al.
SAFETY OF Intravitreal Dexamethasone Implant (Ozurdex): The Safodex study. Incidence and risk factors of ocular hypertension. Retina 2017;37:1352-9.
Kiddee W, Trope GE, Sheng L, Beltran-Agullo L, Smith M, Strungaru MH, et al.
Intraocular pressure monitoring post intravitreal steroids: A systematic review. Surv Ophthalmol 2013;58:291-310.
Sangwan VS, Pearson PA, Paul H, Comstock TL. Use of the fluocinolone acetonide intravitreal implant for the treatment of noninfectious posterior uveitis: 3-year results of a randomized clinical trial in a predominantly Asian population. Ophthalmol Ther 2015;4:1-9.
Jaffe GJ, Martin D, Callanan D, Pearson PA, Levy B, Comstock T, et al.
Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: Thirty-four-week results of a multicenter randomized clinical study. Ophthalmology 2006;113:1020-7.
Jaffe GJ, McCallum RM, Branchaud B, Skalak C, Butuner Z, Ashton P, et al.
Long-term follow-up results of a pilot trial of a fluocinolone acetonide implant to treat posterior uveitis. Ophthalmology 2005;112:1192-8.
Jaffe GJ, Ben-Nun J, Guo H, Dunn JP, Ashton P. Fluocinolone acetonide sustained drug delivery device to treat severe uveitis. Ophthalmology 2000;107:2024-33.
Jaffe GJ. Reimplantation of a fluocinolone acetonide sustained drug delivery implant for chronic uveitis. Am J Ophthalmol 2008;145:667-75.
Tomkins-Netzer O, Lightman S, Drye L, Kempen J, Holland GN, Rao NA, et al.
Outcome of treatment of uveitic macular Edema: The multicenter uveitis steroid treatment trial 2-year results. Ophthalmology 2015;122:2351-9.
Bollinger K, Kim J, Lowder CY, Kaiser PK, Smith SD. Intraocular pressure outcome of patients with fluocinolone acetonide intravitreal implant for noninfectious uveitis. Ophthalmology 2011;118:1927-31.
Nobre-Cardoso J, Champion E, Darugar A, Fel A, Lehoang P, Bodaghi B, et al.
Treatment of non-infectious uveitic macular edema with the intravitreal dexamethasone implant. Ocul Immunol Inflamm 2017;25:447-54.
Pavesio C, Zierhut M, Bairi K, Comstock TL, Usner DW; Fluocinolone Acetonide Study Group, et al.
Evaluation of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious posterior uveitis. Ophthalmology 2010;117:567-75, 575.e1.
Kane FE, Burdan J, Cutino A, Green KE. Iluvien: A new sustained delivery technology for posterior eye disease. Expert Opin Drug Deliv 2008;5:1039-46.
Reddy AK, Burkholder BM, Khan IR, Thorne JE. Iluvien implantation for uveitis and uveitic macular edema. Ocul Immunol Inflamm 2018;26:315-6.
Taylor SR, Habot-Wilner Z, Pacheco P, Lightman SL. Intraocular methotrexate in the treatment of uveitis and uveitic cystoid macular edema. Ophthalmology 2009;116:797-801.
Kozak I, Shoughy SS, Stone DU. Intravitreal antiangiogenic therapy of uveitic macular edema: A Review. J Ocul Pharmacol Ther 2017;33:235-9.
Fine HF, Baffi J, Reed GF, Csaky KG, Nussenblatt RB. Aqueous humor and plasma vascular endothelial growth factor in uveitis-associated cystoid macular edema. Am J Ophthalmol 2001;132:794-6.
Jeon S, Lee WK, Jung Y. Changes in the intraocular cytokine levels after intravitreal bevacizumab in uveitic macular edema. Ocul Immunol Inflamm 2012;20:360-4.
Bae JH, Lee CS, Lee SC. Efficacy and safety of intravitreal bevacizumab compared with intravitreal and posterior sub-tenon triamcinolone acetonide for treatment of uveitic cystoid macular edema. Retina 2011;31:111-8.
Mackensen F, Heinz C, Becker MD, Heiligenhaus A. Intravitreal bevacizumab (avastin) as a treatment for refractory macular edema in patients with uveitis: A pilot study. Retina 2008;28:41-5.
Hardwig PW, Pulido JS, Erie JC, Baratz KH, Buettner H. Intraocular methotrexate in ocular diseases other than primary central nervous system lymphoma. Am J Ophthalmol 2006;142:883-5.
Taylor SR, Banker A, Schlaen A, Couto C, Matthe E, Joshi L, et al.
Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis. Retina 2013;33:2149-54.
Nguyen QD, Ibrahim MA, Watters A, Bittencourt M, Yohannan J, Sepah YJ, et al.
Ocular tolerability and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis: Primary 6-month results of the SAVE study. J Ophthalmic Inflamm Infect 2013;3:32.
Ibrahim MA, Sepah YJ, Watters A, Bittencourt M, Vigil EM, Do DV, et al.
One-year outcomes of the SAVE study: Sirolimus as a therapeutic approach for UVEitis. Transl Vis Sci Technol 2015;4:4.
Sepah YJ, Sadiq MA, Soliman MK, Ibrahim M, Hanout MS, Sarwar S, et al
. Interim analyses of the SAVE-2 study: Sirolimus as a therapeutic approach for UVEitis: A phase 2, open-label, randomized study to assess the safety, tolerability, and bioactivity of two doses of intravitreal injection of sirolimus in patients with non-infectious uveitis. Invest Ophthalmol Vis Sci 2015;56:5775.
Nguyen QD, Merrill PT, Clark WL, Banker AS, Fardeau C, Franco P, et al.
Intravitreal sirolimus for noninfectious uveitis: A Phase III sirolimus study assessing double-masKed uveitis TReAtment (SAKURA). Ophthalmology 2016;123:2413-23.
Sfikakis PP. The first decade of biologic TNF antagonists in clinical practice: Lessons learned, unresolved issues and future directions. Curr Dir Autoimmun 2010;11:180-210.
Markomichelakis N, Delicha E, Masselos S, Sfikakis PP. Intravitreal infliximab for sight-threatening relapsing uveitis in Behçet disease: A pilot study in 15 patients. Am J Ophthalmol 2012;154:534-41.
Markomichelakis N, Delicha E, Masselos S, Fragiadaki K, Kaklamanis P, Sfikakis PP, et al.
A single infliximab infusion vs. corticosteroids for acute panuveitis attacks in Behçet's disease: A comparative 4-week study. Rheumatology (Oxford) 2011;50:593-7.
Adán A, Pelegrín L, Rey A, Llorenç V, Mesquida M, Molins B, et al.
Dexamethasone intravitreal implant for treatment of uveitic persistent cystoid macular edema in vitrectomized patients. Retina 2013;33:1435-40.
Khurana RN, Bansal AS, Chang LK, Palmer JD, Wu C, Wieland MR, et al.
Prospective evaluation of a sustained-release dexamethasone intravitreal implant for cystoid macular edema in quiescent uveitis. Retina 2017;37:1692-9.
Zarranz-Ventura J, Carreño E, Johnston RL, Mohammed Q, Ross AH, Barker C, et al.
Multicenter study of intravitreal dexamethasone implant in noninfectious uveitis: Indications, outcomes, and reinjection frequency. Am J Ophthalmol 2014;158:1136-45.e5.
Cao JH, Mulvahill M, Zhang L, Joondeph BC, Dacey MS. Dexamethasone intravitreal implant in the treatment of persistent uveitic macular edema in the absence of active inflammation. Ophthalmology 2014;121:1871-6.
Arcinue CA, Cerón OM, Foster CS. A comparison between the fluocinolone acetonide (Retisert) and dexamethasone (Ozurdex) intravitreal implants in uveitis. J Ocul Pharmacol Ther 2013;29:501-7.
Palla S, Biswas J, Nagesha CK. Efficacy of ozurdex implant in treatment of noninfectious intermediate uveitis. Indian J Ophthalmol 2015;63:767-70.
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Ziemssen F, Deuter CM, Stuebiger N, Zierhut M. Weak transient response of chronic uveitic macular edema to intravitreal bevacizumab (Avastin). Graefes Arch Clin Exp Ophthalmol 2007;245:917-8.
Reddy AK, Cabrera M, Yeh S, Davis JL, Albini TA. Optical coherence tomography-guided ranibizumab injection for cystoid macular edema in well-controlled uveitis: Twelve-month outcomes. Retina 2014;34:2431-8.
Mirshahi A, Namavari A, Djalilian A, Moharamzad Y, Chams H. Intravitreal bevacizumab (Avastin) for the treatment of cystoid macular edema in Behçet disease. Ocul Immunol Inflamm 2009;17:59-64.
Lott MN, Schiffman JC, Davis JL. Bevacizumab in inflammatory eye disease. Am J Ophthalmol 2009;148:711-7.
[Table 1], [Table 2], [Table 3], [Table 4]