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

assigned to systemic therapy had more prescription-requiring infections than patients assigned to the implant therapy (0.60 vs. 0.36/person-year, p = 0.034). During the first 6 months, vision-related quality of life improved by 9.4 (of 100) units more than the systemic group (p < 0.0001); however, by 24 months both groups had improved with only a 4.6-unit advantage for the implant group. Generic health-related quality of life and health utility score were somewhat improved at the end of 24 months and favored the implant group, but the magnitude of the differences in improvement between groups was less than or equal to the threshold of previously reported minimally important differences. In their final assessment, the authors concluded that neither approach was superior over a 24-month period, particularly in view of the frequent need for additional surgery in the implant group. Specific advantages and disadvantages of either approach should guide the selection of an appropriate therapy for each individual patient. It should be noted that the low incidence of systemic side effects in patients treated systemically reflects an aggressive management approach with a rapid taper of prednisone to 10 mg or less per day and careful monitoring for systemic side effects of other immunosuppressants. The lower incidence of flare-ups in the implant group may also favor this approach after a more prolonged follow-up as recurrences are generally felt to carry a worse long-term prognosis for vision.

Treatment Paradigm in the Management of Uveitis with Steroid Implants

While the MUST trial showed that there is an equivalence in outcomes between implant and aggressive medical management with systemic medications, a number of situations can arise where the use of an ocular implant may be more appropriate than systemic therapy. The choice of implant depends on its availability, duration of action and intended use. Under no circumstances should an implant be seen as an alternative to an adequate workup and follow-up. Ruling out an infectious cause prior to the initiation of treatment cannot be overemphasized. For ophthalmologists with limited experience in uveitis, the most appropriate course of action is appropriate to refer the patient to a uveitis expert. However, the availability of implants facilitates co-management particularly in patients that must travel long distances. In each of the scenarios described below, you should consider whether you are dealing with unilateral or bilateral disease, whether uveitis is symmetrical or asymmetrical, and the expected duration of inflammation.

Uveitis with Systemic Disease

In patients with systemic disease requiring high doses of steroids or immunosuppression with bilateral uveitis requiring treatment, the most judicious course of action would call for an adjustment in systemic immunomodulation (fig. 1). In this

Uveitis with systemic disease

Fig. 1. Proposed treatment algorithm for the treatment of uveitis patients with a systemic autoimmune disease.

particular situation, management is most often carried out in conjunction with an internist or rheumatologist. A similar approach should be considered in patients with active systemic disease and unilateral uveitis requiring treatment. In the presence of bilateral active uveitis, but where the systemic disease requires only low doses of steroids/immunosuppression or is quiescent not requiring immunosuppression, the treatment of choice for the eyes could involve an increase in systemic therapy to calm the less severe of the two eyes, while implanting the more affected eye. This approach has the advantage of titrating immunomodulation based on the observed inflammatory response in an attempt to minimize both systemic and local side effects. Presence of ocular inflammation is a sign of persistent systemic activity which may require some degree of systemic immunosuppression but is likely to be much less than that required to control the ocular disease. In cases of unilateral ocular inflammation, it is clear that the most appropriate course of action will be the use of an intraocular implant with close follow-up of the noninvolved eye.

Fig. 2. Proposed treatment algorithm for the treatment of uveitis patients with no systemic autoimmune disease.

Uveitis with No Systemic Disease

Systemic therapy should be considered in cases of bilateral severe uveitis or when one eye is severely affected (fig. 2). It is likely in this scenario that systemic treatment will be aimed at a rapid reduction of inflammation by for example the use of pulsed methylprednisolone, high-dose steroids with or without the adjunct of nonsteroidal immunosuppressants. Once the inflammation is brought under control, long-term management may involve the use of an implant in one or both eyes. The aim in this case is to minimize exposure to systemic immunosuppression while providing high level immunosuppression to the eye. In cases of unilateral uveitis of moderate severity, implantation could be considered immediately.

Specific Medical Conditions

Patients intolerant to systemic steroids, with a history of diabetes, gastrointestinal tract ulceration, osteoporosis, hypertension or pregnancy even in the presence of bilateral disease may be more appropriately treated with a steroid implant. Similarly, patients requiring ocular surgery with a prior history of uveitis or with controlled uveitis on systemic immunosuppression may benefit from an implant placed at the time of surgery. Depending on the degree and type of ocular inflammation, the use of an implant may obviate the need for presurgical systemic immunosuppression.

to two-thirds of the patients [2, 3]. Conversely, posterior uveitis is usually associated with more frequent irreversible visual impairment and is more challenging to manage. The importance of this sight-threatening disease is translated in numbers. Studies have estimated that uveitis may lead to legal blindness in 30,000 patients annually [4, 5]. It is estimated that uveitis is the cause of 2.8–10% of all cases of blindness, and the annual cost associated with the disease in the United States alone hovers around USD 242.6 million [6, 7]. In the United States, uveitis has an incidence of 25–52 cases per 100,000 persons per year, although some studies have shown that it can vary worldwide, from 38 to 730 cases per 100,000 persons per year [4, 8, 9].

Pathogenesis

Understanding the pathogenesis of uveitis is complicated by the fact that it encompasses a wide range of underlying etiologies. The inflammation present in uveitis can be triggered by an infectious agent, a traumatic insult to the eye, or by an imbalance between the ocular immune privilege and an autoimmune response. The noninfectious uveitis of a putative autoimmune nature, also known as endogenous uveitis, affects patients of different age groups, and can be limited to the eye or be part of a systemic syndrome. The autoimmune causality is supported by strong human leukocyte antigen (HLA) association and by the demonstration of errant responses to retinal antigens in animals models [10, 11]. Two principal models have been used to study autoimmune uveitis: the endotoxin-induced uveitis (EIU), representing a nonspecific, innate efferent immune response (inflammation), and the experimental autoimmune uveitis (EAU), which includes the afferent arm (antigen-specific activation of T cells) and the subsequent ocular inflammation [12]. These two models have shown that during the effector phase of uveitis, humoral and cellular components of the immune system trigger a cascade of events that ultimately lead to tissue destruction. The cells involved in EIU are monocytes/macrophages and polymorphonuclear neutrophils, the key players of inflammation. Thereafter, the tumor necrosis factor-α (TNF-α) cytokine is essential for the induction of EIU, and along with the interleukin (IL)-6 produced in the eye, plays a major role in the development of ocular inflammation [13, 14]. Two different types of T helper cells, the Th1 type and/or the Th17 type, are able to drive the ocular autoimmune activity, as demonstrated by the EAU model [15] (fig. 1). The Th1 response has been related to R14-specific T cell and with more relapsing disease than seen in the Th17 response [16]. During the autoimmune activity, T cells release cytokines including various ILs (IL-1, IL-2, IL-4, IL-6, IL-17, IL-21 and IL-22) [17], interferon-γ (INF-γ) and TNF-α that work as signaling molecules towards the amplification and sustenance of the inflammatory process [18–20]. IL-10 is also involved in the autoimmune process and the increase in IL-10 mRNA expression in late disease may reflect its role in the disease resolution [18]. Complement also plays an important role in the induction of antigenspecific T cell responses in EAU. Complement activation products such as C3b and C4b

+CD4

Fig. 1. Illustrative scheme of the CD4 T cell activation by antigen-presenting cells (APCs), differentiation and recruitment to the chorioretinal tissue. The cytokine network associated with uveitis is illustrated based on currently available information from the literature and role(s) of each subset in the animal models of EAU. The naïve CD4 T cells recognize a complex of class II MHC and peptide present on the surface of APCs. This results in signaling via the T cell receptor (TCR) which combined with a specific cytokine profile leads to a specific Th cell subset differentiation (Th1, Th17, Th2, Th9 and Tregs). TCR engagement in the absence of costimulatory (CD28) signals is thought to produce tolerance by inducing nonresponsiveness to specific antigens and promoting apoptotic deletion of the activated cells (activation-induced cell death). AG = Antigen.

have been demonstrated to increase during the active phase of the disease [21]. Major histocompatibility complex (MHC class I and II) and adhesion molecules (ICAM-1 and LECAM-1) are some other molecules upregulated by the cytokine release, facilitating the migration of leukocytes to the inflamed eye and contributing to the inflammatory cascade, consequently leading to a chronic uveitis [22–24].

The rationale of targeting the etiologic agent of any pathology is the ideal way to stop its progression and sequelae. However, this rationale is not applicable to uveitis. The etiologic triggers of the vigorous immunologic and inflammatory responses against ocular antigens are poorly understood, and the mechanism by which the immune privilege is lost is yet to be described. Thus, targeting the inflammatory pathway is the only available way to manage this sight-threatening disease and to avoid further sequels as cataract, glaucoma, proliferative vitreoretinopathy, cystoid macular edema (CME), vascular occlusion and blindness [25]. A better understanding of the immunologic process in the last few decades has made possible the identification of key points in the inflammatory chain that can be targeted to stop the pathology. These potential targets are described in table 1.

Standard Therapies

Since its first use in 1951, corticosteroids remain as the first line therapy in the armamentarium against uveitis. This is the only class of drug approved by the United States Food and Drug Administration (FDA) to treat uveitis and ocular inflammatory diseases

[26].Different routes of administration and different formulations are available. Topical corticosteroids penetrate well only into the anterior chamber of the eye, and are useful in the management of anterior uveitis and episcleritis. Periocular injections of steroids offer the benefit of a local high-dose and great penetration into the posterior segment, making them a good choice to treat intermediate uveitis, CME and posterior uveitis

[27].Intravitreal (ITV) injection provides the most direct route to posterior segment, thus potentially greater efficacy for posterior uveitis and CME than oral or periocular injection. However, ITV delivery of steroid is also most likely to be associated with ocular side effects, including cataract, high intraocular pressure and endophthalmitis [28]. Steroid implants have the benefit of sustained corticosteroid delivery to the eye while avoiding complications of systemic therapy. Fluocinolone acetonide and dexamethasone are the two corticosteroid compounds in the FDA-approved intraocular implants Retisert® and Ozurdex®, respectively. A multicenter randomized clinical trial comparing 0.59to 2.1-mg fluocinolone acetonide implant for uveitis has shown improvement and stabilization of visual acuity in patients with noninfectious uveitis. No significant difference in mean LogMAR VA at the 1- or 3-year postimplantation visit compared to the baseline for either the 0.59-mg group or the 2.1-mggroup was observed. However, there was a significant improvement in LogMAR VA at the 2-year postimplantation visit for both dose groups and a deterioration in mean LogMAR VA in fellow nonimplanted eyes at all 3 postimplantation visits (p < 0.01). The one-year postimplantation recurrence rates in the 0.59 mg group dropped from 62 to 4%, and in the 2.1 mg group from 58 to 7% in 3 years. During the course of the 3-year study, 78% (both groups combined) of the patients required intraocular pressure-lowering drops, 40% required glaucoma surgery and 93% of eyes required cataract extraction. While the frequency of IOP-

Table 1. Potential immune targets