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

placebo-controlled trials of 1,392 patients ≥18 years of age with active rheumatoid arthritis [82]. The most common and consistently reported treatment-related adverse event associated with Kineret is injection site reaction like redness, swelling, bruising, itching, pain and stinging. An increased rate of infections was also reported [82].

Application in Uveitis and Ocular Inflammatory Diseases. Anakinra has not been evaluated in clinical trials for noninfectious intermediate, posterior, and pan-uveitis. However, it has been used by uveitis specialists in selected cases of refractory posterior uveitis as well as cases of juvenile idiopathic arthritis-associated uveitis.

Gevokizumab

XOMA and Servier have agreed to jointly develop and commercialize the IL-1β- targeted monoclonal antibody gevokizumab (XOMA 052) for the treatment of multiple inflammatory disorders and vascular diseases [83]. In 2010, XOMA/Servier announced positive results from an open-label pilot study of XOMA 052 in BD patients with refractive uveitis. In this study, all 7 patients enrolled in the trial displayed reduction in intraocular inflammation and improvement in visual acuity. Five patients received a second infusion to blunt a developing exacerbation, and all responded to the second infusion. The drug appeared to be safe for ocular use, and no drug-related adverse events were reported [84]. Gevokizumab is currently undergoing phase II trials in diabetes type II and cardiovascular disease.

Application in Uveitis and Ocular Inflammatory Diseases. Gevokizumab has not been formally evaluated in clinical trials for noninfectious intermediate, posterior, and pan-uveitis, except for the uveitis associated with BD. Hopefully, the pilot data will be sufficiently supportive for future trials in uveitis.

Inhibitor of IL-6: Tocilizumab

IL-6 is a pleiotropic inflammatory cytokine produced by T cells, monocytes, and macrophages. IL-6, also referred to as B cell stimulatory factor-2 and interferon-β2, is a cytokine involved in a wide variety of biological functions. It plays an essential role in the final differentiation of B cells into Ig-secreting cells, as well as inducing myeloma/plasmacytoma growth, nerve cell differentiation, and, in hepatocytes, acute-phase reactants, such as hepcidin and C-reactive protein. It is essential for the differentiation of Th17 subset involved in uveitis. High levels of IL-6 in the vitreous of patients with refractory/chronic uveitis have been reported by Yoshimura et al. [85]. They have shown that systemic administration of an IL-6 antibody ameliorates EAU by suppressing both the systemic and regional Th17 response. Haruta et al. [86] and Hohki et al. [87] have also demonstrated in animal studies that inhibition of IL-6 leads to suppression of EAU via inhibition of Th17 cells.

Tocilizumab, commercialized under the name of ACTEMRA/RoACTEMRA, is a humanized IgG1 monoclonal antibody against both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R) [88]. Tocilizumab was approved by the FDA in 2010 to treat rheumatoid arthritis in patients who have been refractory to other

therapies. Clinical studies in RA patients have shown benefits in reducing joint inflammation, joint damage, and fatigue [89, 90]. This drug has also been effective in the treatment of patients with severe systemic-onset form of juvenile idiopathic arthritis and vasculitis syndromes [91–93]. It is the first monoclonal antibody which targets IL-6 and offers an alternative to 30% of arthritis patients not responding to or intolerant of TNF blockers [90, 94]. The efficacy of ACTEMRA/RoACTEMRA in alleviating the signs and symptoms of RA was assessed in five randomized, double-masked, multicenter phase III studies: the AMBITON Study, the LITHE Study, the OPTION Study, the TOWARD Study, and the RADIATE Study [88–90, 94, 95]. In total, the studies enrolled more than 4,200 patients with moderate to severe RA around the world, with the results being consistent with the effect of IL-6 on acute-phase reactants. Treatment with tocilizumab was associated with rapid decreases in C-reactive protein and increases in hemoglobin levels. A joint effort by Roche, Chugai, and Genentech has developed and commercialized the drug. The adverse drug reactions of tocilizumab are presented in table 2 and are based on the safety reported in the five studies of ACTEMRA/RoACTEMRA.

Application in Uveitis and Ocular Inflammatory Diseases. Tocilizumab is being investigated in a proof-of-concept clinical trial for noninfectious intermediate, posterior, and pan-uveitis.

The Immune System as a Potential Target of New Drugs

Currently, several compounds targeting different molecules in the inflammatory cascades are being tested for rheumatic diseases. These agents may represent potential therapeutic options, through proper clinical trials, for ocular diseases such as uveitis and are listed in table 3.

Novel Drug Delivery Systems

Given the potential side effects associated with systemic therapies, the unmet needs in the field of uveitis and ocular inflammatory diseases are new drug delivery systems that can aid in decreasing systemic side effects, allowing rapid local delivery of high concentration of drug, and ensuring a sustained local release of the pharmacologic agents. Among the new approaches are the applications of nanoparticles and iontophoresis.

Nanoparticles

A particle ranging in size from 1 to 1,000 nm that behaves as a whole unit in terms of its physical properties is called an ultrafine or nanoparticle. From a cream that

Table 2. Systemic adverse events of ACTEMRA

releases nitric oxide gas to combat Staphylococcus infection to quantum dots that identify location of cancer cells in the body, the potential uses of nanoparticles are countless. And rightly so, nanoparticles have been a focal point of research focusing on development of better drug delivery mechanisms.

Nanoparticles are classified into nanospheres and nanocapsules depending on the spatial arrangement of the drug to the particles matrix (fig. 3). Nanospheres are solid spheres consisting of dense solid polymeric network, developing over a large specific area. Drugs can be either incorporated into the matrix of the nanospheres or adsorbed onto the surface of the colloidal carrier. Nanocapsules, on the other hand, are small containers formed of a central cavity surrounded by a polymeric membrane [96].

The use of nanoparticles has been investigated in managing conditions such as glaucoma and infectious and noninfectious uveitis [97–101]. In order to treat an anterior segment condition, the drug-loaded nanoparticles are instilled topically in the cul-de-sac of the eye, from where the drug is slowly released into the lacrimal pool by disintegration of the polymer matrix. The success of a nanoparticle drug delivery system for ophthalmic use depends upon the physical and structural properties of the polymer, which in turn dictates its rate of degradation. Currently, there is a lack

Table 3. Therapeutic agents to be considered for uveitis and ocular inflammatory diseases

Cytokines

New TNF-α blockers

Table 3. Continued

of data regarding the use of nanoparticle administration to treat a posterior segment condition. Data from animal studies by Bourges et al. [102] have shown a sustained release of the drug (tamoxifen) from nanoparticles 4 months after a single injection of nanoparticles for the treatment of experimental autoimmune uveoretinitis (EAU). The authors showed that rats injected with tamoxifen-loaded nanoparticles did not develop EAU compared to the group injected with free drug.

There is currently no nanoparticle formulation in clinical trials for uveitis and other diseases; however, animal studies have shown promising results [103]. Microspheres of PKC412 (protein C inhibitor) and inhibitors of receptors for VEGF have been successfully used in treating CNV [104]. Other investigators have shown successful reduction in development of experimental proliferative vitreoretinopathy using 5-FU and Ara-C combination nanoparticles [105–107].

The goal of therapy for uveitis is to eliminate inflammation in the eye, reduce frequency of recurrences, decrease or avoid systemic and ocular adverse events associated with therapy, and improve quality of life. Nanoparticles may have the potential to deliver on all these important goals.

Iontophoresis for Uveitis

With unique physicochemical properties, each drug will have varying abilities to penetrate ocular tissue, diffuse into the posterior chamber, and remain at therapeutic

doses before being eliminated. Iontophoresis is a noninvasive technique used to enhance the penetration of ionic drug through tissue using a low electric current (fig. 4). This mode of drug delivery provides a potential alternative to minimize the complications related to intraocular injections and increase the bioavailability of topically administered drugs. Ocular iontophoresis was studied extensively in the first half of the 20th century. However, the lack of randomized controlled trials and the paucity of toxicity data led to it being sidelined as a drug delivery mechanism. As the beginning of the 21st century saw an increased interest in development of newer efficient modes of drug delivery, iontophoresis once again came into the lime light for

safe and quick delivery of high concentration of drugs to specific sites. Iontophoresis has been most widely used to deliver transdermal local anesthetics and antibiotics. In 1908, a German scientist Wirtz used iontophoresis to treat corneal ulcers, keratitis and episcleritis, and his initial work inspired others to investigate the pharmacokinetics, penetration and efficacy of numerous antibiotics. However, the advent of newer potent topical preparation of these antimicrobials led to the demise of this approach.

Iontophoresis enhances drug delivery via electrophoresis (enhanced movement of ionic species by the applied electric field), electro-osmosis (transport of both neutral and charged species by an electric field-induced convective solvent flow) and electroporation (alteration of the tissue barrier that increases the intrinsic permeability of the membrane) [108–111]. Based on the site of treatment, iontophoresis is classified into transcorneal and transscleral. Transcorneal iontophoresis has mainly been used to deliver drugs to the anterior segment across the corneal layers while transscleral iontophoresis overcomes lens-iris barrier and delivers drugs directly into the vitreous and retina through the choroid or indirectly through systemic circulation or anterior chamber.

Evaluations in animal models of drugs delivered via transscleral iontophoresis reveal differential pharmacokinetic profiles, particularly when ITV drug concentration and duration are the measured parameters [103]. For example, using a current of 2.0 mA/0.5 cm2 and duration of 10 min, methyl-prednisolone reached a peak concentration of 45 μg/ml 2 h after application, maintaining greater tissue concentration than the same dose delivered intravenously [112]. In anti-infectious control, the antibiotic gentamicin saw a peak concentration of 53.5 μg/ml in the vitreous at 16 h following transscleral iontophoresis, still significantly higher than levels achieved with SCJ injection [108]. Administration for 10 min at 1 mA of foscarnet, used to treat cytomegalovirus infection, resulted in a peak concentration after only 4 h, but maintenance of therapeutic levels for up to 60 h following iontophoresis, indicating a slower elimination rate than other drugs delivered via the same method [113]. These results suggest that different drugs behave differently in the same electromagnetic environment. Early-phase studies employing iontophoresis as the method of drug delivery in patients with various forms of ocular inflammation have shown encouraging results. In a phase II clinical trial, Chauvaud et al. [114] has shown that methylprednisolone hemiscuccinate (SoluMedrol) was well tolerated, safe, and reduced the need of systemic corticosteroids. Patients with acute corneal graft rejection have also received corticosteroids once daily for 3 consecutive days (1.5 mA 3 min) via the same mechanism in addition to topical steroids and have shown improvement in visual acuity and elimination of need for analgesics [115, 116].

Although iontophoresis is a relatively safe technique of drug delivery, one should be aware that at high current densities of 100–700 mA/cm2, adverse reactions such as retinal and choroidal burns, hemorrhagic necrosis, edema, and infiltrations have been observed. Tissue damage can also occur with an increased duration of the procedure. The extent of such damage depends on the site of the application and current density.

Application in Uveitis and Ocular Inflammatory Diseases

Iontophoresis technology has been evaluated for uveitis. The early study using dexamethasone as the index drug delivered via iontophoresis has demonstrated safety and bioactivity in patients’ anterior uveitis. Such success has led to the multicenter phase 3 study evaluating dexamethasone phosphate delivered by ocular iontophoresis [4.0 mA-min at 1.5 mA compared to iontophoresis with sodium citrate buffer solution (100 mm) 4.0 mA-min at similar current] for noninfectious anterior uveitis currently being conducted in the United States.

Conclusions

Patients with uveitis and ocular inflammatory diseases are in desperate need of effective therapeutic agents which not only eliminate inflammation and prevent recurrences but also protect the patients from potential side effects. In addition, we believe that all currently available drugs should be approved by the regulatory bodies as soon as possible so that they can be of benefit to all patients.

The horizon currently appears very bright, given the many therapeutic agents and approaches for uveitis and ocular inflammatory diseases. Different classes of agents, from calcineurin inhibitors to mTOR inhibitors and IL inhibitors, among others, are being evaluated. In addition, delivery systems such as iontophoresis will also allow novel methods of safe and effective administration of pharmacologic agents. Hopefully, such efforts will lead to therapeutic options for our patients in the near future.