Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

to other disease modifying anti-rheumatic drugs. Infliximab is given by intravenous infusion at 6 to 8 weekly intervals, etancercept subcutaneously twice weekly and adalimumab subcutaneously every 1–2 weeks. Failure to respond fully to one of the anti-TNF agents does not predict resistance to other agents in this group.

The main treatment for sight threatening uveitis is corticosteroids, often in combination with immunosuppressive medications such as cyclosporin A, methotrexate or mycophenolate mofetil. However, there remains a cohort of patients who do not respond to these drugs. The literature to date on the use of infliximab in refractory posterior uveitis is limited to case series/ single case reports – there are no randomized control trials demonstrating efficacy. However, from the evidence available it seems that infliximab may have a role to play in these difficult cases of uveitis (Hale and Lightman, 2006; Joseph et al., 2003; Lanthier et al., 2005).

B. Interleukins

Interleukins are novel agents that have been evaluated as treatment in patients with severely active inflammatory diseases, such as RA and Crohn’s disease, as well as in cancer patients. These new therapies promise to improve the management of inflammatory diseases and expand our current knowledge of the underlying pathophysiologic mechanisms.

1. Interleukin-1 receptor antagonist (IL-1Ra)

IL-1Ra is a naturally occurring glycoprotein inhibitor of IL-1 that binds the high affinity cell surface IL-1 receptor but has no receptor activation activity (Arend, 1993). The agonist effects of IL-1 are therefore partially regulated by IL-1Ra. Effects of the inhibition of IL-1 include decreased prostaglandin production by synovial cells and chondrocytes, decreased matrix

metalloproteinase production by activated synovial cells and articular chondrocytes, and decreased mononuclear cell infiltration – both monocytes and tissue macrophages (Arend et al., 1990). Recombinant human interleukin 1 receptor antagonist (rHuIL1ra) has been used in clinical trials (Hannum et al., 1990); it differs from the native human protein by having an added N-terminal methionine and is not glycosylated.

Interleukin 1 has been implicated in intraocular inflammation. Rosenbaum and Boney (1992) tested the role of interleukin 1 in models of uveitis in New Zealand white rabbits. Despite the activity of interleukin 1 receptor antagonist in inhibiting interleukin 1-induced inflammation, it did not reduce inflammation in an intraocular Arthus reaction or following intravitreal injection of 125 ng of endotoxin (Rosenbaum and Boney, 1992). Lim et al. (2005) evaluated the effects of an interleukin 1 receptor antagonist (IL-1RA) on the development of immune-mediated ocular inflammation in mice and concluded that it suppressed immune-mediated ocular inflammation in mice, effecting both the afferent and efferent components of the immune response.

2. Recombinant human IL-1ra

Recombinant human IL-1ra (rHuIL1ra) has been approved for the treatment of RA by the United States Food and Drug Administration (anakinra, Kineret®). The efficacy of anakinra in RA was studied in a double-blind, placebo-controlled, 24 week multicenter trial of 472 patients with active RA (Lim et al., 2005). Transient injection site reactions were the most frequent adverse effects reported, resulting in a 5% withdrawal rate in the high dose group. Serious infections developed in 5 patients in the high dose group versus 1 patient administered a placebo. In the current literature there is only one report of a successful response of refractory posterior uveitis to recombinant human IL-1ra (Teoh et al., 2007).

3. IL-6 antagonists

Interleukin-6 (IL-6) has both proand anti-inflammatory activity (Bresnihan et al., 1998). A human recombinant anti IL-6- receptor mAb antagonizes the effects of IL-6 (atlizumab, toclizumab, MRA). Initial studies suggested some benefit without serious adverse effects (Akira et al., 1993). These results suggested that atlizumab (MRA) may become a viable addition to existing anti-cytokine therapies for RA, and possibly used in the management of uveitis patients in the future. Ohta et al. (2000) observed that IL-6 antagonized TGF beta and abolished ACAID in endotxin induced uveitis in mice, and therefore suggested that strategies to suppress the intraocular synthesis of IL-6 may reduce intraocular inflammation and restore ocular immune privilege (Akira et al., 1993).

4. IL-10 agonists

IL-10 levels are increased in the serum and synovial fluids of RA patients, and IL-10 mRNA expression is increased in the peripheral blood mononuclear cells and synovial fluid cells of RA patients (Choy et al., 2002). The addition of neutralizing monoclonal antibodies to IL-10 in RA cell cultures resulted in increased production of interferon, TNF-alpha, IL1b and GM-CSF consistent with the concept that IL-10 is an endogenous inhibitor in the tissues of patients with RA (Cush et al., 1995). However, studies, including the combination of IL-10 with MTX, have been completed and failed to demonstrate significant additional clinical benefit. The agent is no longer in development for RA, but may have some benefit in the treatment of uveitis. Interestingly, gene therapy with IL-10 may offer promise in the treatment of RA. Systemic IL-10 gene therapy, consisting of intravenous injection of adenoviral vectors containing the gene, has been found to prevent the development of collageninduced arthritis in animals (Apparailly et al., 1998).

C. Oral Tolerance

Oral tolerance is the suppression of cellular and/or humoral immune responses to an antigen by prior administration of the antigen via the oral route. It is an attractive therapeutic option since it is both cheap and easy to administer. Oral tolerance presumably evolved as an analog of self-tolerance, to prevent hypersensitivity reactions to food proteins and bacterial antigens present in the intestinal mucosa. Due to their privileged access to the internal milieu, commensal bacteria and dietary antigens that continuously contact the mucosa represent a frontier between self and non-self. Thus, oral tolerance is a form of peripheral tolerance that evolved to protect intestinal bacteria and dietary antigens from destruction by the host immune response.

Three assumptions were implicit in the classical concept of tolerance. First, the primary function of the immune system was seen as a defense of the organism against pathogens or, in a broader sense, against non-self. Second, in order to perform this function, the primary type of immunologic response was thought to be inflammation. Third, since the operation of the immune system is driven by its reactions to foreign pathogens, tolerance was envisioned as the simple absence of an immune response, accomplished by the neonatal deletion of “forbidden” B- or T-cell clones which recognized self epitopes.

With a better understanding of the immune system, it is now clear that tolerance is a much more complicated and diverse process. Autoreactive immune cells, such as those against ocular antigens, are not deleted, but present in all individuals. Furthermore, immunologic tolerance does not appear to rest on a simple discrimination between self and non-self. Rather, the immune system reacts efficiently to a variety of molecular danger signals and often tolerates antigens that occur in the absence of such signals (Matzinger, 1994). Thus, immunologic tolerance cannot rely solely

on neonatal deletion, but involves an active process that functions during the entire life of the organism.

Oral tolerance is a method of inducing a state of nonor hypo-responsiveness that is antigen specific for the fed Ag. It is mediated through two main mechanisms: the generation of regulatory T-cells and clonal anergy or deletion. Active cellular suppression is induced in the gut-associated lymphoid tissue (GALT), specifically in the Peyer’s patches, leading to the induction of regulatory T-cells which then migrate throughout the systemic immune system and modulate the severity of local inflammation. One of the primary mechanisms of active cellular suppression is the secretion of downregulating or suppressive cytokines, such as TGFb, IL4 and IL10 (Toussirot, 2002).

Oral administration of S antigen (S-Ag), a retinal autoantigen that can be used to induce experimental autoimmune uveitis (EAU), prevented or markedly inhibited intraocular inflammation in EAU (Nussenblatt et al., 1990). S-Ag-induced EAU can also be suppressed by feeding a human leukocyte antigen (HLA) peptide (Wildner and Thurau, 1994). Feeding interphotoreceptor binding protein (IRBP) suppressed IRBP-induced disease and is potentiated by IL-2 (Rizzo et al., 1994). Oral feeding of retinal antigen also suppressed a second attack in chronic-relapsing EAU (Thurau et al., 1991, 1997b,a). Animal models provided the rationale for the use of oral tolerance in human autoimmune diseases. However, in man the clinical experience in recalcitrant uveitis has been disappointing. In part, it may be that feeding S-Ag is effective in preventing the induction of EAU but not when delayed until after immunization, where very high doses were required (Torseth and Gregerson, 1998; Toussirot, 2002).

Oral tolerance has been tested in other human autoimmune diseases including MS, arthritis, uveitis, diabetes and allergy (Faria and Weiner, 2006). However, clinical trials in MS showed no benefit and even turned out to have unexpectedly severe adverse

effects (Wiendl and Hohlfeld, 2002). The success of the induction of peripheral tolerance for the treatment of human disease is uncertain but its efficacy may be enhanced by variations in Ag dose, route of administration (nasal versus oral), formulation, use of adjuvants and combination therapy.

The authors would like to thank Mark Ihnen for his help with the figures.

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In its precise (albeit narrow) definition, uveitis refers to inflammatory conditions of the uveal tract: the iris, ciliary body, and choroid. As it is more commonly used, uveitis refers to any non-corneal inflammatory ocular condition, including retinitis and sometimes scleritis. These diseases constitute a significant public health problem. Uveitis is relatively common. Recent studies have suggested an incidence of 52 per 100,000 person-years for all forms of uveitis, and a prevalence of approximately 150 cases per 100,000 person-years. Many cases of uveitis are associated with poor ocular outcomes. Uveitis is considered the fifth leading cause of blindness in the United States. Retrospective studies estimate that as many as 25% of eyes with any form of uveitis will permanently lose some vision, while nearly 15% will become blind because of the condition. Many uveitic diseases affect young patients in their school

or working years. This compounds the societal problem of uveitic disease; many years of lost productivity can be attributed to these conditions.

This chapter will discuss the spectrum of uveitic disease as it affects the posterior segment (i.e. those structures posterior to the ciliary body). It will then discuss the objectives in treatment, concentrating on both systemic and locally applied modalities. The chapter will conclude with a brief discussion of future therapy for posterior segment uveitis.

I. THE CLASSIFICATION OF

UVEITIS

Recently, an international working group convened to standardize the classification of uveitis. Anatomically, anterior uveitis was defined as having a primary site of inflammation in the anterior chamber; intermediate

uveitis as having the primary site of inflammation in the vitreous cavity; posterior uveitis as having the primary site of inflammation in the choroid or retina; and panuveitis as having inflammation in all three sites. Descriptors of the course of uveitis were also agreed upon (Tables 13.1 and 13.2). A schema for grading anterior segment inflammation (on a scale of 0 to 4 ) for cell and flare was also agreed upon. The National Eye Institute scheme for grading vitreous haze (based on standardized photographs) was also adopted, but unfortunately the group could not reach consensus on grading schema for vitreous cell.

II.TYPES OF POSTERIOR

SEGMENT UVEITIS

In general terms, there are three etiologic categories of uveitis: infectious, “autoimmune”, and masquerade syndrome. All

three types may be observed in posterior segment uveitis. A summary of different posterior segment uveitic entities is given in Table 13.3.

The most common infectious cause of posterior segment ocular inflammation in the immunocompetent host is ocular toxoplasmosis. This parasite is most typically associated with cats, which are the obligate host for sexual reproduction; however, the parasite can also be acquired from contaminated water sources or meat. The organism can form a cyst, or bradyzoite, which can persist in the retina for decades, reactivating and dividing when stimulated by an as- yet-unidentified stimulus. Toxoplasmosis is frequently identified in the posterior segment by the presence of hyperand hypo-pigmented chorioretinal scars. Active toxoplasmosis generally produces a creamy retino-choroiditis with substantial vitritis.

The most common form of infectious posterior segment uveitis in the immunocompromised host is cytomegalovirus (CMV) retinitis. This opportunistic viral infection reactivates in the setting of the suppressed immune system of AIDS patients and others with severe immunocompromised status (for example, solid organ transplant patients), and causes a severe necrotizing retinitis. Findings include intraretinal hemorrhage, retinal whitening and thinning, and frequently rhegamatogenous retinal detachment secondary to retinal holes in atrophic regions.

Herpetic disease can also cause retinitis in the immunocompetent individual. Acute retinal necrosis syndrome (ARN) is a necrotizing retinitis associated with an occlusive arteriolitis that may occur unilaterally or bilaterally. The disease typically spreads in a circumferential manner. It may be caused by varicella zoster virus, or herpes simplex virus type 1 or type 2. Vision loss

from ARN syndrome can occur secondary to direct necrosis of central retina, optic nerve involvement with secondary atrophy, or late rhegamatogenous or tractional retinal detachment (from thin retina postinfection). Approximately 30% of unilateral cases will become bilateral if the disease is not adequately treated.

Other, less common, forms of infectious posterior segment uveitis include disease from syphilis, tuberculosis, Lyme disease, fungal disease (particularly Candida), endogenous endophthalmitis, late onset endophthalmitis (usually associated with

Propionibacterium acnes), and the canine ascarid worm Toxocara canis.

The canonical autoimmune posterior segment uveitis is sympathetic ophthalmia. In this disease, penetrating injury to one eye (called the exciting eye) exposes uveal antigens to the immune system, which then precipitates an autoimmune attack of the fellow (sympathizing) eye. Very closely