Ординатура / Офтальмология / Английские материалы / New Treatments in Noninfectious Uveitis_Miserocchi, Modorati, Foster_2012

The structure of the eye is an important limiting factor. Indeed, the goal of drug delivery is to obtain and maintain drug concentration in intraocular tissues in order to have a therapeutic, but not a deleterious, effect. Due to the ocular barrier to drug penetration, it is important to carefully consider the effects of intrinsic target drugs, their distribution into the tissue and their elimination [2].

The Structure of the Eye

The choroid has a rich network of largeand small-diameter vessels. The endothelial cells of these vessels have large fenestrations that allow rapid molecular diffusion, thus permitting the treatment of choroidal diseases with systemic therapy.

The retina is separated from the blood by the blood-ocular barrier. More specifically, in the posterior segment we find the blood-retina barrier (BRB) and in the anterior segment the blood-aqueous barrier. Two parts of the BRB regulate drug diffusion from the bloodstream to the neural retina.

The outer part of the BRB is the retinal pigment epithelium (RPE) that separates the choroidal network from the neural retina. The RPE shows tight junctions that are a barrier for small molecules passing from choroidal tissue to the neural retina.

The inner part of the BRB consists of endothelial cells of the retinal vessels that are separated from the surrounding retinal tissue. Its capillaries are characterized by the thick basement membrane layer and surrounded by tight junction-linked endothelial cells. With this anatomic structure, the inner part of the BRB prevents unrestricted molecular diffusion between the vitreous-retinal compound and the bloodstream. This, however, represents a problem for the therapeutic approach to intraocular diseases, and has led scientists to bypass the BRB by means of innovative drug delivery methods [2–4].

Drug Delivery to the Posterior Segment

To obtain drug therapeutic concentration in the posterior segment of the eye, we can use various methods of administration that give very different results. Using the topical route, the posterior segment does not receive therapeutic drug concentration due to the blood-aqueous barrier, low corneal permeability and rapid drop drainage through the nasolacrimal ducts.

While systemic drug administration allows therapeutic concentration to easily reach the choroid, the BRB greatly reduces the vitreous-retinal concentration of the pharmacological agent. To improve retinal concentration, we have to use high dosages that may lead to potentially severe systemic side effects.

Periocular or subTenon injection is less invasive than intravitreal injection, but it is also less effective. Physical barriers such as the sclera, conjunctival lymphatic vessels, choroid, and the RPE (outer BRB) may reduce drug absorption into the eye and the intraocular concentration of the drug does not result constant.

Intravitreal injection of the drug therefore appears to be the ideal route to reach therapeutic concentration in the posterior segment without the risk of systemic side effects. The direct injection of drugs bypasses the blood ocular barrier and allows rapid pharmacological action into the retinal tissue. This condition might determine various pharmacological problems related to direct drug toxicity of the retinal tissue [2–7].

Intravitreal Injection

Intravitreal injection concentrates drugs into the vitreous cavity leading to rapid therapeutic drug concentration in the retinal tissue. The drug is eliminated in two ways: through the anterior chamber and the retinal tissue. The rate of elimination and tissue diffusion depends on the molecular drug dimension and vitreous consistency. Larger molecules can remain in the vitreous for several weeks, while a solution of molecules smaller than 500 Da generally has a retention half-life of 3 days. The viscoelastic gel structure of the vitreous may be seriously damaged in the elderly or following vitrectomy surgery. These conditions can influence the flow and, consequently, the concentration of the drug in the retinal tissue [2–7].

Intravitreal Injection Technique

After topical anesthesia (lidocaine) and eyelash cleaning with povidone-iodine, the lid speculum is applied. Topical antibiotics are normally used before and after intravitreal injection, but the risk of septic endophthalmitis is similar whether they are used or not. The rate of endophthalmitis after i.v. injection is low (0.02%), confirming the safety of this technique [8].

A povidone-iodine solution (5%) is applied to the eye, and the injection is carried out in the inferotemporal quadrant to reduce the risk of retinal detachment and visual axis interference.

The pharmacological agent is prepared in a 1-ml tuberculin syringe with a 30/32-gauge needle. The injection is performed through the pars plana into the middle vitreous. The injection must be carried out slowly and without interruption. The safest drug volume to inject is generally 100 μl.

After the injection, the removal of the needle must be slow, and a cotton-tipped applicator must push on the same site of the injection to reduce reflux [8, 9].

Some authors have shown that use of tunneled technique may significantly reduce reflux, and that 29/30-gauge needles guarantee less pain during injection [9].

Immunomodulators

Immunosuppressant drugs are routinely used in place of systemic steroids in autoimmune disease and in noninfectious uveitis [1]. Intravitreal immunosuppressant drug injection helps in reducing systemic side effects, ocular hypertension and cataract formation secondary to corticosteroids.

Intraocular Methotrexate

Methotrexate (MTX) is a competitive inhibitor of dihydrofolate, and systemic MTX is chronically used to treat noninfectious uveitis, sparing systemic steroid assumption [1].

In recent years, intravitreal injection of MTX has been widely used to treat intraocular lymphoma [10]. The dose used is 400 μg in 0.1 ml, which is well tolerated by retinal tissue and remains in therapeutic concentration for 48–72 h [10].

Deng et al. [11] showed that intravitreal MTX injection in rabbit eyes was less likely to provoke bacterial endophthalmitis or ocular hypertension than intravitreal steroid injection.

Recently, various authors have reported small series of uveitis patients treated with intravitreal MTX [12–14]. Hardwig et al. [12] showed that a dose of 400 μg appears to be well tolerated and had positive effects on the preservation of visual acuity.

Taylor et al. [13] in a pilot study of 15 patients with unilateral noninfectious uveitis reactivation or macular edema showed that intravitreal MTX (400 μg in 0.1 ml) can reduce macular edema and improve visual acuity like after steroid treatment. They also obtained a reduction in systemic therapy in some patients and the relapse of inflammation, which occurred after a median of 4 months, was successfully treated with a further MTX injection. Ocular side effects were rare and acceptable (transient corneal epitheliopathy). None of these 15 patients developed endophthalmitis or ocular hypertension. Drug activity on retinal inflammation was relatively fast and visual acuity improved in one week.

Bae and Lee [14] demonstrated that increased intraocular levels of IL-6, IL-8, vascular endothelial growth factor (VEGF) and monocyte chemotactic protein 1 may be responsible for refractory retinal vasculitis in Behçet disease. Intravitreal MTX injection was effective and well tolerated even in steroid responders with refractory retinal vasculitis due to Behçet disease. Intravitreal MTX injection was associated with a significant reduction in IL-6 and IL-8 levels.

In a pilot study, Palakurthi et al. [15] evaluated the toxicity of a biodegradable microneedle implant loaded with MTX as a sustained release device in normal rabbit eyes. They demonstrated that this sustained release implant containing MTX was histopathologically nontoxic and well tolerated.

Intravitreal MTX injections might represent a therapeutic solution in those patients with unilateral posterior uveitis that cannot tolerate systemic steroid or immunosuppressant therapy, or are corticosteroid responders. In the future, further studies might clarify the role of this drug in local treatment (injection or device) of uveitis or uveitic macular edema.

Tacrolimus (FK506)

Tacrolimus (FK 506; Fujisawa Pharmaceutical Co, Japan) is a macrolide immunosuppressant that is more effective than cyclosporine in the liver, kidney and pulmonary transplantation. It also shows fewer systemic side effects than cyclosporine. Tacrolimus is effective when administered systemically in patients with refractory uveitis, but its effectiveness is limited due to the high incidence of severe adverse effects including nephrotoxicity, hypertension, hyperesthesia, muscular weakness, insomnia, tremor, photophobia, gastrointestinal symptoms and central nervous system alterations [16–19].

Many authors have evaluated the dose-related safety and efficacy of tacrolimus intravitreal injections in treating animal experimental autoimmune uveitis (EAU) [16–18].

Zhang et al. [19] treated EAU in Lewis rats with intravitreal injection of liposomes encapsulating tacrolimus (FK506). The treatment significantly reduces intraocular inflammation, and the drug remains in ocular fluids for 14 days. This study confirms that intravitreal injection of tacrolimus is highly active in controlling EAU in rats, and that liposome allowed tacrolimus to release gradually for 2 weeks, thus reducing the number of intraocular injections necessary to treat uveitis.

Anti-VEGF Drugs

Chronic intraocular inflammation is associated with increased production of inflammatory mediators, including VEGF, which are thought to disrupt the inner BRB of retinal vessels, resulting in subsequent macular edema [20].

This assumption justifies the use of intraocular anti-VEGF drugs to reduce macular edema and vascular inflammation. Intravitreal Anti-VEGF drugs are currently used to treat age-related subretinal neovascularization, diabetic macular edema, postretinal vein occlusion edema. Many authors are now using these drugs to treat uveitic macular edema with ambiguous results [21–31].

Ranibizumab

Ranibizumab (Lucentis, Biotech) intravitreal injection is widely used in the treatment of age related subretinal neovascularization [21] and has also been used recently in inflammatory choroidal neovascularization [22].

Acharya et al. [23], in a case series of 7 uveitic patients, treated refractory macular edema with monthly ranibizumab intravitreal injections for 3 months. The conclusions of this study showed visual acuity improvement and macular edema regression. The same authors [24] recently described an observed therapeutic effect of ranibizumab in the untreated contralateral eyes of patients with bilateral uveitis-related cystoid macular edema (CME). They advocate further study to evaluate ranibizumab systemic viability after intravitreal injection.

Bevacizumab

Bevacizumab (Avastin, Genentech) is a recombinant humanized anti-VEGF monoclonal antibody that is widely used to treat age-related macular degeneration subretinal neovascularization [25].

Julian et al. [26] used intravitreal bevacizumab to treat subretinal neovascularization related to inflammatory diseases with transient results. Arevalo et al. [27] demonstrated that at 24-month follow-up, intravitreal bevacizumab improved visual acuity, and reduced macular edema in OCT and fluorescein angiography images.

Cordero Coma et al. [28] treated 13 patients with intravitreal bevacizumab (2.5 mg/0.1 ml) for macular edema secondary to uveitis. Their results too showed that the treatment is well tolerated and is associated with short-term visual acuity improvement and macular thickness reduction.

Other authors have shown similar results concerning the improvement of uveitic macular edema using bevacizumab intravitreal injection [29]. Lasave et al. [30] and Soheilian et al. [31] compared intravitreal injection of bevacizumab and triamcinolone acetonide to treat refractory uveitic macular edema. These two studies, with different length follow-ups, showed opposing results regarding visual acuity improvement.

Tumor Necrosis Factor -α Blockers

Tumor necrosis factor-α (TNF-α) is implicated in the pathogenesis of many chronic inflammatory diseases. TNF-α antagonists represent a significant advance in the treatment of many inflammatory diseases. The systemic utilization of these drugs in place of steroid treatment in autoimmune diseases is well defined. To avoid the systemic side effects of these drugs, some authors proposed local utilization with intraocular injection.

Adalimumab

Adalimumab (Humira, Abbott) is an anti-TNF constructed from a fully human monoclonal antibody. It is successfully used in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, chronic psoriasis and juvenile idiopathic arthritis.

In ophthalmology, the systemic use of this drug obtained successful results in treating uveitis related to various autoimmune diseases [32–34].

Androudi et al. [35] evaluated the efficacy of a monthly adalimumab intraocular injection for refractory uveitis-related macular edema in 8 patients. The results did not show an improvement in visual acuity or CME reduction after 6 months of follow-up.

Infliximab

Infliximab (Remicade, Centocor) is a chimeric monoclonal antibody to TNF-α. It is currently used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and psoriasis.

Infliximab has shown therapeutic effects for various types of uveitis related to systemic autoimmune diseases, particularly Behçet disease [36].

Many pilot studies demonstrated the safety of intraocular infliximab in animal models [37]. Farvardin et al. [38] treated 10 eyes of 7 patients with chronic persistent noninfectious uveitis and macular edema with intravitreal infliximab injections. They injected 1.5 mg/0.15 ml, and after 4 weeks of follow-up the study showed visual acuity improvement and macular thickness reduction.

In another study, Giganti et al. [39] demonstrated that low-dose (0.5 mg/0.5 ml) intravitreal infliximab was not well tolerated. They hypothesized the immunogenetic and retinotoxic effect of intravitreal infliximab.

Corticosteroids

Topical, periocular and intravitreal steroids and systemic steroids represent the gold standard for every new anti-inflammatory drug in the treatment of uveitis. In posterior uveitis with asymmetric disease or controlled uveitis with persistent macular edema, intravitreal steroids represent an important therapeutic option for the clinician [40].

Corticosteroids are the treatment cornerstone for uveitis and secondary macular edema. Treatment with corticosteroid intravitreal injections can achieve the desired predictable intraocular therapeutic concentrations [41]. They stabilize the BRB, reducing proinflammatory mediator production [42].

Intravitreal Triamcinolone Acetonide

Intravitreal triamcinolone acetonide (IVTA) was first used by Machemer to reduce cellular proliferation after retinal detachment surgery in 1979 [43]. Triamcinolone acetonide is a water-insoluble steroid that is used in many fields of medicine. In ophthalmology, it can be administered into the subTenon or retrobulbar space, or directly into the vitreous [44].

Many authors used IVTA in various ocular pathologies related to systemic autoimmune disease. The main outcome of these studies was the reduction in intraocular inflammation and cystoid macular edema that were present despite systemic therapy. The results showed the efficacy, albeit temporary, of this treatment [45, 46].

Kok et al. [47] treated 54 patients with refractory CME with IVTA (4 mg) despite systemic and local treatment. After a mean follow-up of 8 months, 83% of treated eyes responded positively to the therapy with an improvement in visual acuity and a reduction of CME. After a mean of 4 weeks, 43.1% of treated eyes developed transient intraocular pressure (IOP) elevation that was greater than 10 mm Hg.

Many other studies have focused on the positive role of IVTA in the treatment of refractory CME caused by various inflammatory conditions secondary to ocular autoimmune disease, postradiation CME, immune-recovery uveitis, pseudophakic eyes and idiopathic CME [48–53]. Complications related to IVTA are well known, the most frequent being elevated IOP. Infective endophthalmitis, sterile endophthalmitis and cataract formation are less frequent [54].

Gillies et al. [55] in a double-blinded, placebo-controlled, randomized clinical trial tested the safety of a single IVTA. They described elevated IOP after IVTA as being the most common side effect. The increase in IOP occurred in about 30% of patients that require topical anti-glaucoma therapy. Eight months after the intravitreal injections, 71% of patients were able to discontinue the topical anti-glaucoma drops. Other studies showed IOP elevation in 40–50% of treated patients with most of them returning to a normal IOP after 13–17 months [56, 57]. The patients with the highest risk of IOP elevation are those under 40 years old with preexisting uveitis, higher baseline IOP or glaucoma [58].

Nonsteroidal Anti-Inflammatory Agents

Due to the numerous side effects associated with the use of corticosteroids, there is a need to identify other anti-inflammatory agents with a better safety profile. Recent studies have demonstrated the usefulness of nonsteroidal anti-inflammatory drugs (NSAIDs) as an alternative. NSAIDs are potent cyclooxygenase inhibitors and antiinflammatory agents, with potential antiproliferative and antiangiogenic effects [59]. Unlike corticosteroids, NSAIDs are not associated with cataract formation or elevated IOP. Since the topical administration of NSAIDs does not deliver appreciable

drug quantities to the posterior segment, intravitreal administration remains a viable option for treating inflammation of the posterior segment [59].

The NSAID diclofenac inhibits both the cyclooxygenase and lipoxygenase pathways. Although diclofenac has been used topically in the treatment of inflammatory conditions, intravitreal delivery has recently been under observation. Since diclofenac sodium is a low-molecular-weight drug, when in solution, as is the case with its commercial ophthalmic formulations, it is predicted to disappear rapidly from the vitreous humor, having a short half-life of 2.87 h. To maintain safe levels of diclofenac for prolonged periods in the eye, slow-release drug delivery systems, such as nanoparticles, microparticles, or implants, might be useful. Alternatively, the use of a suspension or a less soluble form of the drug might be useful in prolonging intravitreal drug delivery [59, 60].

Kim et al. reported nontoxic intraocular doses of two commercially available NSAIDs: ketorolac and diclofenac. They showed that 3,000 μg of ketorolac and 300 μg of diclofenac were nontoxic in the rabbit retina of the studied animals [61]. In another animal study, Baranano et al. [60] confirmed that a single intravitreal injection of diclofenac effectively reduces intraocular inflammation caused by lipopolysaccharide and prostaglandin production in rabbit eyes with uveitis.

Prostaglandins are one of the presumed causes of CEM in uveitis and after cataract surgery, or in diabetic macular edema. Intraocular ketorolac and diclofenac significantly inhibit prostaglandin production in animal models of uveitis. Given the established efficacy of topical NSAIDs in treating postsurgical macular edema, intraocular NSAIDs might offer a more potent treatment for this vision-threatening condition [60]. In a pilot study of intravitreal injection of diclofenac for the treatment of macular edema of various etiologies, one eye was affected by macular edema secondary to intermediate uveitis; this patient showed improved visual acuity and reduced central macular thickness during a 2-month follow up period after intravitreal injection of 500 μg/0.1 ml of diclofenac [62].

Larger studies are needed to evaluate the role of intraocular NSAIDs, including diclofenac, in different entities, to help define the ideal regimen, duration of treatment, potential of combination treatment, and the safety of long-term treatment.

References