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

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I. CLINICAL DISEASE – ANTERIOR UVEITIS (IRITIS, IRIDOCYCLITIS)

A. Definition and Classification

Anterior uveitis is a common inflammatory eye disease with reported annual

incidences of between 17 and 52.4 per 100,000 person-years and prevalence of between 38 and 370 per 100,000 population (Darrell et al., 1962; Gritz and Wong, 2004). Despite the fact that most epidemiological studies on uveitis are based in tertiary

referral centers, and thus are subject to referral bias towards posterior and intermediate uveitis, anterior uveitis is the most common form of uveitis in most regions of the world (Chang and Wakefield, 2002). In the few studies based in primary care centers that were likely to better reflect true population patterns of uveitis, anterior uveitis represented up to 92% of total cases (McCannel et al., 1996).

The most widely used classification of uveitis was formulated by the International Uveitis Study Group (IUSG) in 1987, based on both the anatomical location and cause of the inflammation. The IUSG anatomic classification scheme (Bloch-Michel and Nussenblatt, 1987) defined anatomic location on the basis of the site of inflammation and not on the presence of structural complications. Hence, anterior uveitis is defined as inflammation in the anterior chamber; this includes iritis, where the inflammation is solely in the anterior chamber, and iridocyclitis, where there is also some inflammation in the anterior viterous. The term panuveitis is reserved for those situations in which there is no predominant site of inflammation, but inflammation is observed in the anterior chamber, vitreous, and retina and/or choroid (that is, retinitis, choroiditis, or retinal vasculitis).

In 2005, the Standardization of Uveitis Nomenclature (SUN) Working Group clarified other terminology for uveitis (Jabs et al., 2005). The terms “acute” and “chronic” were suggested to describe the clinical course of uveitis. Acute uveitis was characterized by sudden onset and limited duration, such as HLA-B27-associated “acute anterior uveitis” (Tay-Kearney et al., 1996). Recurrent uveitis was characterized by repeated episodes of uveitis separated by periods of inactivity without treatment, in which the periods of inactivity without treatment were at least 3 months in duration. Chronic uveitis was characterized by prompt relapse (in less than 3 months) after discontinuation of therapy (Jabs et al., 2005).

B. Signs and Symptoms

Symptoms of anterior uveitis include acute onset of pain, photophobia, redness and decreased vision, usually in one eye. A discharge is not usually present. However, if a discharge is present, it is usually watery and not mucopurulent. A previous history of iritis is of importance. Inquire about the patient’s medical history and perform a detailed review of systems. This part of the workup is important in determining the cause of iritis.

Ocular signs include limbal vascular injection (ciliary flush) with occasional chemosis. Visual acuity may range from normal to significantly reduced vision, depending on the extent of the ocular inflammation and the presence of cystoid macular edema. Intraocular pressure (IOP) is generally normal. However, IOP may be reduced in the eye with iritis due to decreased aqueous production by the inflamed ciliary body, or IOP may be elevated as a result of altered or obstructed aqueous outflow. Keratic precipitates (KPs) are found on the corneal endothelium. These are clusters of WBCs. Mutton-fat (granulomatous) KPs are large and have a greasy appearance in contrast to the fine, small KP (non-granulomatous) usually seen. They are both usually located over the lower third of the cornea. Corneal edema may be present.

C. Differential Diagnosis

In the differential diagnosis one should consider inflammation of the conjunctiva, i.e. conjunctivitis, and inflammation of the sclera, i.e. scleritis. Usually, the diagnosis of anterior uveitis is straightforward, due to the predominant involvement of the anterior chamber.

D. Non-Infectious Anterior Uveitis

1. Ocular specific

a. Autoimmune anterior uveitis – Idiopathic anterior uveitis is the most common form

of intraocular inflammation in humans. The prevalence is near 50% (i.e. 50% of uveitis patients have idiopathic uveitis) (Rodriguez et al., 1996; Weiner and BenEzra, 1991). Men and women are affected equally.

Although clinical features of acute or chronic anterior uveitis are well described, there is a lack of clear understanding about the pathogenesis and etiology of iridocyclitis in the vast majority of cases. Such cases are thought to be mediated by an autoimmune response, possibly to self-protein (e.g. the α-2 chain of type I collagen), possibly induced by an infectious agent (Smith et al., 1998).

Recognition of self-protein involves a breakdown in tolerance and recognition of previously sequestered ocular antigens. In animal models sensitization with the ocular antigen, melanin-associated protein, produced an acute recurrent anterior uveitis with a delayed onset but an extended nature. Subsequently, it was determined that the self-antigen was the α-2 chain of type I collagen located in the iris and ciliary body. This model mimics human disease closely, with the underlying mechanism being primarily T-cell-mediated delayedtype hypersensitivity.

b. HLA-B27-related anterior uveitis – The HLA-B27-associated uveitic syndrome is the second commonest cause of anterior uveitis, following autoimmune uveitis. It accounts for 40 to 70% of cases of acute anterior uveitis in different patient populations. Like most of the other diseases associated with the B27 gene, B27-associated acute anterior uveitis also has a higher frequency in males than in females. Uveitis associated with the HLA-B27 gene may occur in the presence or absence of an associated systemic disease; some patients may present with the ocular symptoms as the first manifestation of a systemic disease that may declare itself later (Chang et al., 2005).

2. Associated with systemic disease

a. Spondyloarthropathies – Features associated with the spondyloarthropathies are the

presence of lower back pain due to sacroiliitis; an asymmetric, pauciarticular, peripheral, inflammatory large joint arthritis; the inflammation and ultimate calcification of the tendinous insertions into bones (enthesiopathy); extra-articular (bowel, skin, eye, vascular) manifestations in the absence of serum rheumatoid factor or the rheumatoid nodules classically seen in rheumatoid arthritis. Although the presence of the HLA-B27 gene is extremely helpful in the diagnosis, its absence does not exclude the presence of a spondyloarthropathy. These diseases also show considerable clinical overlap, so that sometimes it may be difficult to distinguish between them.

i. Ankylosing spondylitis (AS) – A disease present in 1 in 1000 to 1 in 2000 of the white population. A lower incidence was documented in Blacks and Asians. It varies from a relatively asymptomatic condition visible only on imaging studies (CT scan, X-ray) to a crippling disease. The typical patient is a young man with lower back pain and morning stiffness, with a progressive loss of spinal mobility. The main lesion is that of progressive spinal fusion with spinal ankylosis and sacroiliac joint involvement that results in a fixed, kyphotic spine and a restricted respiratory excursion. It may also be associated with hip and knee involvement, amyloidosis, aortitis and apical lung fibrosis. HLA-B27 is found in nearly 90% of patients with ankylosing spondylitis. Ocular involvement may take the form of conjunctivitis or acute anterior uveitis, which occurs in 20 to 30% of patients with this disease (Sieper et al., 2002).

ii. Reiter’s syndrome – A disease diagnosed on the basis of the triad of non-specific urethritis, arthritis and conjunctivitis, often with the presence of iritis. It is more common in males than in females, and tends to occur between 15 and 40 years of age. It may be post-infectious, following nongonococcal (chlamydia, ureaplasma) urethritis or infectious dysentry. Systemic

conditions associated with Reiter’s syndrome include a characteristic skin condition called keratoderma blenorrhagicum (brown aseptic abscesses on the palms and soles of the feet), mouth ulcers, circinate (serpiginous) balanitis, Achilles tendonitis and plantar fasciitis. Thirty to sixty percent of the patients have conjunctivitis, which although non-infectious, may be associated with a mild mucoid discharge. Between 3 and 12% of the patients have iridocyclitis (Kiss et al., 2003).

iii.Psoriatic arthropathy – Psoriatic arthropathy occurs in around 20% of patients with the characteristic skin and nail lesions of psoriasis, and is a usually benign arthritis involving the small joints of the hands – rarely, it may be a severe destructive arthritis known as arthritis mutilans. Twenty percent of patients with psoriatic arthropathy develop uveitis. This is usually an anterior uveitis (Queiro et al., 2002).

iv.Inflammatory bowel disease – The inflammatory bowel diseases include Crohn’s disease and ulcerative colitis. They are characterized by a recurrent, often bloody, diarrhea associated with abdominal cramping. Patients may have a non-destructive arthritis that manifests as large joint effusions. Ocular involvement in inflammatory bowel diseases may take the form of conjunctivitis, episcleritis/scleritis, peripheral ulcerative keratitis or uveitis (Kethu, 2006).

v.Undifferentiated spondyloarthropathy –

This condition is diagnosed in patients with a spondyloarthropathy that does not fall clearly into one of the categories mentioned above. Anterior uveitis may occur in both eyes simultaneously in these conditions and may be chronic. Vitritis, retinal vasculitis and exudative retinal detachment may also occur (Kumar et al., 2001).

b. Other systemic diseases associated with anterior uveitis – Anterior uveitis may be associated with other non-infectious

systemic diseases such as sarcoidosis and bone marrow tumors (leukemia and lymphoma). Sarcoidosis is diagnosed when the classic clinical and radiologic findings are supported by histological evidence of widespread non-caseating epithelioid granulomata. Although best known for its thoracic involvement, the extrapulmonary, ocular, and neurologic manifestations of sarcoidosis may cause significant complications, including blindness, meningitis, arthritis, renal disease, systemic morbidity, dermatitis, and death (Bonfioli and Orefice, 2005; Kumar et al., 2001). Masquerade syndromes, including bone marrow tumefactions, can present as an anterior uveitis, but are usually part of a panuveitis with a more prominent vitriitis (Bonfioli and Orefice, 2005; Tsai and O’Brien, 2002).

E. Infectious Anterior Uveitis

1. Herpesviruses

Herpesvirus hominis, or herpes simplex virus (HSV), is one of the most common agents infecting humans of all ages. Uveitis in herpes simplex virus (HSV) ocular disease is usually associated with corneal and/ or stromal disease. It has generally been believed that herpetic uveitis in the absence of corneal disease is very rare. When seen without corneal involvement it is usually attributed to varicella zoster virus (VZV) infections (Bonfioli and Orefice, 2005; Santos, 2004). An elevated IOP may be caused by trabeculitis, inflammatory obstruction of the trabecular meshwork, and angle closure in severe keratouveitis. Treatment with systemic acyclovir when HSV or VZV cutaneous lesions are still active appears to reduce the risk of elevated IOP. Cytomegalovirus (CMV), a member of the herpes virus family, is known to be the most common cause of acquired viral retinitis in immunocompromised hosts. CMV infection can cause both an acute anterior uveitis and retinitis in immunocompromised patients, most of whom have AIDS, and is rarely seen in

immunocompetent individuals. Recently, the spectrum of CMV-related intraocular infections in immunocompetent individuals has been expanded to include apparent infections of the anterior segment with concomitant anterior uveitis, but without a typical retinitis (Bonfioli and Orefice, 2005; Markomichelakis et al., 2002).

2. Other infections

Systemic infections can cause inflammation in multiple organs and can be associated with uveitis. These include tuberculosis, spirochetal diseases such as Lyme disease and syphilis, candidiasis and HIV infection. Routine ophthalmic examination in patients with systemic infections may be indicated for several reasons: to prevent structural damage to the eye due to asymptomatic uveitis; to obtain diagnostic clues in patients with fever of unknown origin; to rule out opportunistic infections in HIV positive patients. It is clear that the information gained from routine ocular examination in systemic infections will be very variable (Bonfioli and Orefice, 2005; Kestelyn, 2005).

II.CLINICAL OBJECTIVES

A. Alleviate Symptoms

The first clinical objective in the treatment of anterior uveitis is to alleviate the patient’s symptoms. Both symptoms and complications of inflammation can be mitigated with topical cycloplegic agents. Both short-acting drops (e.g. cyclopentolate) and long-acting drops (e.g. scoploamine) can be used to decrease photophobia caused by ciliary spasm and to break up or prevent the formation of posterior synechiae.

Cyclopentolate prevents the muscles of the ciliary body and iris sphincter from responding to cholinergic stimulation. It induces mydriasis in 30–60 min and cycloplegia in 25–75 min. Its effects last up to 24 hours. Homatropine induces mydriasis in 10–30 min and cycloplegia in 30–90 min.

Its effects last 10–48 hours but duration may be less in the setting of severe anterior chamber reaction. Homatropine is the agent of choice for treating acute anterior uveitis (Bonfioli and Orefice, 2005; Hayasaka et al., 2003).

Pain in uveitis can also originate from high intra-ocular pressure (IOP). Several anti-glaucoma medications can be used to lower IOP in cases of anterior uveitis: acetazolamide (Diamox) reduces the rate of aqueous humor formation by direct inhibition of enzyme carbonic anhydrase (CA) on secretory ciliary epithelium, causing, in turn, a reduction in IOP. More than 90% of CA must be inhibited before IOP reduction can occur. Acetazolamide may reduce IOP by 40–60%. Its effects are seen in about an hour, peak in 4 hours, and wear out in 12 hours. Acetazolamide is derived chemically from sulfa drugs, so that allergic reactions to sulfa must be excluded before its instillation.Dorzolamide HCl (Trusopt) is a topical CA inhibitor which can also be used to lower IOP. Timolol (Timoptic) is a beta blocker that reduces elevated and normal IOP by reducing aqueous humor production. The use of the alpha agonist brimonidine (Alphagan) should be avoided because of reports of possible aggravation of CME (Kim and Lertsumikul, 2003). Although prostaglandin analogs, such as travoprost (Travatan), have been avoided in the treatment of ocular hypertension in uveitis, the experience of most experts in the field is that exacerbation of intraocular inflammation with this class of drugs is very rare.

B. Prevent Visual Loss

The second clinical objective in the treatment of anterior uveitis is to decrease the inflammatory process to prevent complications of inflammation. Patients with chronic anterior uveitis may need long-term treatment. Long-term topical corticosteroids are the mainstay of treatment for chronic anterior uveitis. However, periocular

corticosteroids can be given for noncompliant patients (within the anterior subTenon’s space) or macular edema (within the posterior sub-Tenon’s space) but are contraindicated in corticosteroid responders (Levin et al., 2002; Riordan-Eva and Lightman, 1994). Systemic corticosteroids are indicated for bilateral macular edema in patients who cannot tolerate or do not respond to periocular corticosteroids. They may also be needed for the management of any underlying systemic disease. Patients on chronic therapy are kept on the minimum dose of medication to control the inflammation to avoid both the systemic and ocular side effects of corticosteroids, such as posterior subcapsular cataract and ocular hypertension. If more than 10 mg of prednisone daily is required for use in the treatment of chronic anterior uveitis, supplemental therapy with vitamin D, calcium and a bisphosphonate (e.g. alendronate sodium (Fosamax)), with routine bone density scans, is recommended.

The main complications of anterior uveitis are cystoid macular edema (CME) and posterior subcapsular cataract (PSC).

1. Cystoid macular edema (CME)

The leading cause of decreased vision which may lead to permanent visual loss is the development of CME. Severe macular edema can be easily appreciated clinically. However, fluorescein angiography or optical coherence tomography is often necessary for a definitive diagnosis if the edema is subtle or if the media is hazy. Some patients with angiographic CME may have 20/20 acuity. If CME does not respond to treatment and is long standing, the photoreceptor cells in the macular area will eventually die and result in permanent visual loss. The risk of CME in posterior or intermediate uveitis is greater than in anterior uveitis (Rosenberg et al., 2004). The visual prognosis for patients with chronic anterior uveitis is generally good. CME in anterior uveitis

appears to be more likely to occur if there is an underlying associated disease (Menezo and Lightman, 2005). Although there was a trend in patients with non-idiopathic chronic anterior uveitis to develop cystoid macular edema compared with those patients with idiopathic disease, no significant differences in visual outcome were found between any of the groups after longterm follow-up (Menezo and Lightman, 2005).

2. Posterior subcapsular cataract (PSC)

Posterior subcapsular cataracts are granular opacities that occupy the polar region of the posterior cortex, just within the posterior capsule. Corticosteroid-induced cataracts are also typically posterior subcapsular in nature. Cataract development in most cases of chronic anterior uveitis is the result of several factors, including the inflammation itself and the use of steroids (Hooper et al., 1990). Smith and coauthors (1976) report that in 40% of patients with chronic iridocyclitis, lens opacities first developed in the posterior subcapsular region. Visual acuity has traditionally been the primary visual function test used to determine the need for cataract surgery. The degree of visual impairment depends on the extent of PSC formation. In one study, most eyes with PSC had a BCVA between 20/30 and 20/60 and good near vision (N8 or better) (Vasavada et al., 2004). A few studies have documented that visual acuity loss correlates with nuclear and cortical cataract and is disproportionately worse in patients with PSC (Adamsons et al., 1992).

3. Secondary glaucoma

The mechanisms by which uveitis leads to elevated intraocular pressure (IOP) are numerous and poorly understood. In general, iridocyclitis affects both aqueous production and resistance to aqueous outflow, with the subsequent change in IOP representing a balance between these two factors.

Inflammation of the ciliary body usually leads to reduced aqueous production, and combined with the increased uveoscleral outflow often seen in intraocular inflammation, hypotony often develops.

Mechanisms of increased resistance to aqueous outflow, in both acute and chronic uveitis, are usually of the open-angle type and include obstruction of the trabecular meshwork by inflammatory cells or fibrin, swelling or dysfunction of the trabecular lamellae or endothelium, and inflammatory precipitates on the meshwork. However, uveitis may also cause secondary angleclosure glaucoma (Kwon and Dreyer, 1996).

Alteration of the protein content of the aqueous humor may be a cause of elevated IOP in uveitis. Increased levels of protein in the aqueous are a result of increased permeability of the blood–aqueous barrier, which leads to an aqueous that more closely resembles undiluted serum. This elevated protein content may, in fact, lead to aqueous hypersecretion and IOP elevation (Moorthy et al., 1997).

The treatment of the uveitis can lead to elevated IOP. Although corticosteroids have proven effective in relieving inflammation, prolonged administration can result in elevated IOP. Corticosteroids increase IOP by decreasing aqueous outflow. Several theories have been proposed to explain this phenomenon, including accumulation of glycosaminoglycans in the trabecular meshwork, inhibition of phagocytosis by trabecular endothelial cells, and inhibition of synthesis of certain prostaglandins (Moorthy et al., 1997).

4. Recurrent uveitis

Recurrent uveitis episodes should be avoided if possible. Each recurrent episode exposes the patient to more pain and photophobia, as well as to an increased chance of ocular complications and subsequent visual loss.

III.BASIC MECHANISMS

A. Inflammation and the Immune Response

1. Immune response

The primary task of the immune response is to recognize and dispose of invading microorganisms (viruses, bacteria, fungi, protozoa, etc.). Two different components of the immune system, namely innate and adaptive immunity, are used to accomplish this task. Innate, inborn resistance is mediated by the antigen-non-specific complement system, macrophages and natural killer cells; adaptive immunity relies on the ability of lymphocytes (T- and B-cells) to respond specifically and selectively to challenges by different antigens.

Advances in immunology have provided us with new insights about the ocular inflammatory response. Still, the etiology and pathophysiology of many uveitides remain unclear. Factors such as the blood– ocular barrier, sequestration of ocular self-antigens, local immunomodulators, and anterior chamber-associated immune deviation (ACAID) interact and render the eye an immunologically “privileged” site with a propensity to inhibit the intraocular inflammatory response. On the other hand, human leukocyte antigen complex (HLA) interactions, the immunopathology of hypersensitivity reactions and autoimmunity are associated with immunerelated ocular disease.

a. Innate immunity (TLRs, complement, MPS, NK cells) – Innate immunity comprises a large number of molecules and cells that have in common the capacity to recognize and respond immediately to pathogens. Innate immunity is a patternrecognition response to identify various offensive stimuli in an antigen-independent manner. The response is preprogrammed by pre-existing receptors for the stimulus. Unlike the adaptive immune system, the

time to response by the innate immune cells and molecules to a pathogenic insult is very short and is not enhanced by prior experience with the same stimulus.

The innate immune response is the first line of defense against microbial infection. Since the discovery of the Drosophila protein Toll, which induces an effective immune response to Aspergillus fumigatus

(Lemaitre et al., 1996), the importance of the innate immune system in protection from infection with microorganisms has been recognized. The targets of innate immune recognition are the conserved molecular patterns (pathogen-associated molecular patterns, PAMPs) of microorganisms. Receptors in innate immunity are therefore called pattern recognition receptors (PRRs) (Medzhitov and Janeway, 1997). PAMPs are generated by microbes, and not by the host, suggesting that PAMPs are good targets for innate immunity to discriminate between self and non-self. Furthermore, PAMPs are essential for microbial survival and are conserved structures among many pathogens, which allow innate immunity to recognize a multitude of microorganisms with a limited numbers of PRRs.

Toll-like receptors (TLRs), i.e. mammalian homologs of Toll, were identified as the key recognition structures of the innate immune system in the past few years (Akira et al., 2006). TLRs are capable of identifying bacteria, fungi, protozoa, and viruses. The TLR family now consists of 13 mammalian members, with each TLR having an intrinsic signaling pathway and inducing a specific biological response against a microorganism(s). Recognition of microbial components by TLRs triggers the activation of signal transduction pathways, which then induces dendritic cell (DC) maturation and cytokine production, resulting in the development of adaptive immunity (Akira et al., 2006).

The cellular component of the innate immune response in large part relies on phagocytic and granulocytic cells that express germline-encoded invariant receptors that

recognize pathogen-associated molecular patterns (Medzhitov and Janeway, 2002). These pattern-recognition receptors mediate killing of the recognized microbe by triggering phagocytosis. Apart from the prototypic Toll-like receptors, there has been an increasing appreciation of the importance of other types of pattern-recognition receptors (Brown et al., 2002). Soluble patternrecognition receptors can contribute to pathogen clearance via activation of the complement system.

The complement system is a class of over 20 soluble and cell-surface proteins that, when activated, form a cascade of biologically active molecules important in the clearance of pathogenic microorganisms (Figure 12.1). There are three major pathways of complement activation – the classical, mannan binding lectin (MBL), and alternative pathways. Each of the pathways is activated by a different stimulus, with the alternative pathway primarily serving for amplification of the complement casacade. For example, binding of MBL to a microbial surface activates the complement cascade directly, whereas immune complex formation (antigen–antibody) activates the classical pathway. All three pathways converge at complement C3 (a component of one of the heteromultimeric enzyme complexes). Even though the complement system evolutionarily predates the adaptive immune response, it has evolved to mediate crosstalk between the adaptive and innate immune responses. Although the three pathways are activated independently, it is becoming increasingly apparent that they interact at numerous levels.

Polymorphonuclear leukocytes, macrophages, dendritic cells, and NK cells are the major cellular response elements of the innate immune system. The mononuclear phagocyte system (MPS) is of hematopoietic lineage derived from progenitor cells in the bone marrow. Committed myeloid progenitor cells differentiate to form blood monocytes, circulate in the blood and enter tissues to become resident tissue

macrophages (Hume et al., 2002). Mononuclear phagocytes in tissues share several features (Hume, 2006):

1.Stellate morphology and ultrastructural evidence of endocytic activity observed by light and electron microscopy.

2.Expression of certain enzymes that can be detected by histochemical staining (notably non-specific esterases, lysosomal hydrolases and ecto-enzymes).

3.Non-specific uptake of particles such as latex or colloidal carbon, and specific endocytic receptors especially for the Fc portion of immunoglobulin and for complement-coated particles.

Natural killer (NK) cells through surface recognition structures can identify pathogenic cells and kill them directly. NK cells were originally characterized as cytolytic effector lymphocytes with the ability to kill

targets without the requirement of prior exposure, in contrast to cytolytic T-cells (Kiessling et al., 1975). NK cells are a conserved subpopulation of lymphocytes that recognize glycolipid antigens in a CD1d context. Upon activation through their semiinvariant T-cell receptor, these cells rapidly release large amounts of immunomodulating Th1 and Th2 cytokines (Kiessling et al., 1975).

Recent data shows that circulating NK cells are not steady state killers unless they have gone through a process of functional maturation that involves self MHC class I recognition via inhibitory receptors, but also some still unidentified factors are involved (Vivier, 2006). This means that NK cells have the potential to attack normal self cells, but there are regulatory mechanisms to ensure this does not usually occur. Self-tolerance is acquired by NK cells during their development, but the underlying molecular and cellular mechanisms remain