Recent Potential Treatment Approaches for the Management of Uveitis

Uveitis is an infl ammatory disease affecting the uveal tract of the eye. Non-infectious uveitis [NIU] is known to be the main cause of blindness in people of all age groups in different parts of the world. NIU can be both due to autoimmune or idiopathic responses causing severe vision-related complications leading to irreversible vision loss. Thus, the treatment of this disease after the rapid diagnosis and evaluation by eminent ophthalmologists and rheumatologists is very important. The primary goal of treatment of uveitis is to limit the infl ammation process and prevent recurring responses and hence preserving the vision. The current treatment therapies include corticosteroids as fi rst-line agents followed by more potent drugs including synthetic immunosuppressants like calcineurin inhibitors, antimetabolites, and alkylating agents. However, some patients are reported to be intolerant to these therapies, therefore, biologic agents are adopted as an effective treatment approach in such cases. Anti TNF-α agents have shown promising results in the treatment process. This review enlightens about the current effective treatment approaches that are adopted as potential therapeutic agents preventing NIU. Short Communication Recent Potential Treatment Approaches for the Management of Uveitis Nikita1 and Yasmin Sultana2* 1Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard,


Introduction
Uveitis, an infl ammatory condition of the eye affecting the uvea [blood vessel-rich middle layer of tissue] may lead to slight or complete vision loss. This disease can affect people of any age group mainly between 20 to 60 years of age. It is reported that 24.9 cases per 100,000 persons were affected in a study in the years 2006 and 2007 with a prevalence rate of 57.5 and 58 per 100,000 persons respectively [1,2]. Uveitis is classifi ed as anterior uveitis affecting the iris of the eye, intermediate uveitis affecting the ciliary body, posterior uveitis affecting choroid, and panuveitis affecting multiple areas of the eye. It can also be classifi ed on the basis of severity and progress with time, acute cases that are generally sudden and symptomatic whereas chronic cases that remain asymptomatic for a long duration and are characterized by the relapse of the disease after therapy is discontinued [3]. It can be primary or secondary to some other conditions. Generally, it is known to be associated with some systematic diseased conditions like juvenile idiopathic arthritis but it can be idiopathic too [3,4]. Treatment of uveitis should be carefully implemented after the prompt diagnosis as if it is not treated in time the chronic state of uveitis may lead to complicated conditions like glaucoma, cataract, keratopathy, macular edema, and irreversible vision loss [3,5]. Since it is known to affect people of all age groups, children diagnosed with it have more chances to develop a higher risk of complications and chronic conditions leading to severe visual impairment during the course of this medical condition. It is also reported that the quality of life of people suffering from uveitis has been noted however, these are not directly correlated with the severe infl ammation or complications associated with it [6]. The pathophysiology of ocular infl ammation is not very clear and the eye is an organ that is known to not get affected by the conventional immune response like other organs due to the presence of foreign antigens present in that tissue because of the presence of haemato-cellular barriers, immunomodulators like TGF-b, and absence of cell expression of both MHC-I & II in the eye [7]. It is thought that the infl ammation in the uveitis is due to the T cells i.e., CD4+ T cells of Th-1 Phenotype.
The exact pathogenesis of uveitis is not clearly understood but the presence of cytokines like IL-2, IL-12, IL-17, TNF-, Citation: Nikita and interferon- have been reported in uveitis patients and therefore, they are considered as key contributors in its pathogenesis [8][9][10]. Therefore, targeting these cytokines might be an effective approach for treating NIU, although it is quite challenging because of the wide range of possibilities in the pathogenesis. Treatment of uveitis is generally established on the basis of the intensity of infl ammation and the risk factors accompanied by it. The treatment is initiated using the mild therapeutic agents followed by severe therapeutic agents during the treatment process [3].

Treatment of non-infectious uveitis
The fi rst-line treatment of uveitis includes Corticosteroids that are effective in treating the infl ammation in acute conditions. However, in unrestrained conditions, immunosuppressant therapy is adopted including therapeutic agents like antimetabolites-methotrexate, azathioprine, mycophenolate; calcineurin inhibitors-cyclosporine, tacrolimus, and alkylating agents like cyclophosphamide and chlorambucil [11][12][13].

Current new biological therapies like Anti-Tumour Necrosis
Factor- agents have also emerged as a potential therapeutic approach for treating uveitis in children and adults targeting the immunological pathway involved in the disease [11,12,14].

Corticosteroids
These are considered as the fi rst-line treatment approach for uveitis. Depending on the severity of the diseased condition they are given via topical, periocular, intraocular, or systemic route [11,15]. Generally, 1% prednisolone is given via a topical route or 0.1% dexamethasone. Prednisolone is reported to be the most used and effective corticosteroid drug used in the treatment [16][17][18]. In severe conditions where all uvea layers including the optic nerve are affected, in such cases i.v. corticosteroids mainly methylprednisolone [30mg/kg] is given three times a week followed by oral corticosteroids [19] However, these drugs cannot be used in the long run due to the ocular and systemic side effects like cataract, glaucoma, and visual impairment associated with treatment. Treatment of the pediatric population with corticosteroids often requires attention as these drugs have reported causing a delay in growth and puberty development. Therefore, other treatment approaches should be considered [3].

Immunosuppressants based therapies
Immunosuppressant drugs are adopted for treatment to control the disease in cases when corticosteroids fail to inactivate and reduce the infl ammatory response or in cases when recurring symptoms are observed with the onset of unusual complications [3].

Methotrexate
It is often the treatment of choice in unmanageable cases of uveitis in pediatric patients [19]. It is administered either via oral route or subcutaneous route at a dose between 10 to 15mg/m 2 . Overall improvement with 95% confi dence interval [95% CI, 0.66-0.81] in ocular infl ammation in about ¾ of the total subjects has been reported for methotrexate in unmanageable cases of uveitis in pediatric patients [20].
A randomized multicentre trial on 80 patients [ [22] whereas mycophenolate mofetil is administered at a dose of 600mg twice daily via the oral route. The trial showed that the mycophenolate mofetil is effective in reducing infl ammation in uveitis but less effective when compared with methotrexate [23]. In 2007, Schatz et. al reported a follow-up study of forty children with non-infectious uveitis treated with azathioprine and mycophenolate mofetil, and it was found that when both these drugs were combined with corticosteroids the improvement of 61% and 94% were observed with azathioprine and mycophenolate mofetil respectively [24]. Limited data are reported for these drugs in childhood uveitis. The side effects associated with their treatment are usually gastrointestinal related, may enhance the risk of disrupting bone marrow, and also few malignancies are reported when used for long durations [3,25].

TNF-α inhibitors
The next therapeutic approach for the treatment of NIU is biological response modifi ers i.e., Tumour necrosis factor - inhibitors as these TNF- is a proinfl ammatory cytokine that is released in the infl ammation process of NIU and hence it has become the signifi cant target for the treatment [26,27].
TNF- is the cytokine that gets binds to the Tumour Necrosis Adalimumab, an entire human anti-TNF- monoclonal antibody approved for the treatment of various immunemediated infl ammatory diseases including non-infectious uveitis [30]. Various clinical trials including randomized placebo-controlled trails VISUAL-I, VISUAL-II & III, and SYCAMORE [31] and ADJUVITE [32] were performed. VISUAL-I study, a phase-III multinational trial where adalimumab was given to treat non-infectious uveitis showed that the extent of treatment failure was declined to 50%. The VISUAL-II, a multicentre randomized trial showed that the adalimumab was effective in reducing the relapsing of uveitis in patients and the treatment failure was observed in 55% patients in the placebo group whereas 39% in the adalimumab group [33]. SYCAMORE trial involved the patients [2 to 18 years] with active juvenile idiopathic arthritis induced uveitis, these patients were kept in the placebo and adalimumab group and were treated with stable methotrexate followed up for 2 years. Results of this trial showed that treatment failure was found to be in 27% of patients receiving adalimumab and methotrexate whereas 60% in patients receiving methotrexate only [3]. In ADJUVITE randomized trial, patients were given adalimumab and methotrexate for two months and it was found that ocular infl ammation was decreased in 56% patients and laser fl are photometry examination showed improvement in 30% patients with anterior uveitis. The results of these clinical trials showed that adalimumab is effective in treating ocular infl ammation and preventing relapses [34,35].
Infl iximab, a chimeric monoclonal antibody [25% murine and 75% human] have undergone clinical trials for evaluating its effectiveness in NIU and it has been found that although it shows a sudden onset of action it is of less therapeutic importance as compared to adalimumab as some studies showed its failure after 12 months i.e., 60% of the treatment process [36,37].
A retrospective case study carried out by Maleki et. al showed a reduction in infl ammation in 19 out of 23 patients with NIU [38]. Baughman, et al. carried out a study on patients with ocular infl ammation and showed improvement in 13 out of 14 patients when treated with infl iximab after the failure with usual immunosuppressant therapy [39]. A noncomparative trial conducted by Suhler et. al involved patients with unmanageable uveitis and were treated with infl iximab and the results showed clinical improvement in 18 out of 23 patients in the 10 th week of the treatment [40].
Golimumab, a complete humanized monoclonal antibody. Tosi. et. al conducted a study on 21 uveitis patients and it has been found that ocular fl ares were signifi cantly decreased from 128.6 events per 100 patients-year to 24.9 events per 100 patients-year although all patients in that group had received another anti-TNF drug previously [41]. Also, results from Palmou-Fontana, et al. study showed improvement in 4 out of 7 patients when treated with golimumab [42].
Etanercept is a dimeric protein and is known to have a different mechanism of action than other TNF- inhibitors [43]. There is not much evidence about the effectiveness of this agent and also, it is no longer prescribed for uveitis due to its low ocular distribution and low effectiveness when compared with adalimumab and infl iximab [44].
Certolizumab, a recombinant humanized monoclonal antibody administered at an initial dose of 400mg for one month [4 weeks] and followed by 200mg per week. It is reported having improved distribution in the infl amed ocular tissues than adalimumab and infl iximab [45]. A recent study has specifi ed that both golimumab and certolizumab can be effective and safe options for patients with uveitis even if the result with other TNF- inhibitors have not been effi cacious [41].

Anti-IL-6 therapy
Interleukin-6 is a proinfl ammatory cytokine produced by monocytes, macrophages, B and T cells, and are involved in several immune-mediated diseases. The intraocular concentration of IL-6 is found to be increased in uveitis and retinal vein obstruction [46]. An IL-6 receptor blocker,

Tocilizumab [a recombinant human monoclonal antibody] is
reported to be effective for the treatment of NIU [47]. The side effects associated with its treatment generally include chest tightness, nausea, fatigue, blisters on limbs and hands, and mild bronchitis [48,49].

Anti-IL-1 therapy
It includes IL-1 receptor antagonist Anakinra, Kineret®, and Canakinumab [Ilaris®], an anti-IL-b antibody. The effects of both these anti-IL-1 molecules were examined in a multicentre retrospective study that involved 19 patients with Behcet's disease-associated uveitis. The results showed that both these anti-IL therapies were effective in reducing infl ammation in long-lasting and obstinate cases of uveitis [50]. Few mild side effects like headaches and arthralgias have been reported in the case of Kineret® with no major problems, hence these can be considered safe to be used in uveitis [50,51].

Anti-CD25 therapy
Daclizumab is a monoclonal antibody that blocks the immune response generated by the activated T-cells by binding to the 2a subunit of the IL-2 receptor of these T cells.
Few mild side effects are reported with its use mainly rashes, herpes zoster infections, palpitations, and some liver-related disorders [35,54].

Anti-IL-17A therapy
Secukinumab is a humanized monoclonal antibody that binds to the IL-17A receptor and neutralizes the immune response [55]. Side effects reported are usually nasopharyngitis and headache. Some cases of recurring uveitis are also reported with its use [56].

Conclusions
The treatment strategies for the management of uveitis follow a stepladder approach starting with corticosteroids, immunosuppressants therapy followed by the biological therapies including anti TNF- agents. However, acute conditions can be very well treated with the corticosteroids but the severe conditions and long-term therapies cannot be treated with these fi rst-line agents, and hence, a new therapeutic agent is to be adopted. With the available clinical data on the biological therapies and their effectiveness in reducing the recurring infl ammatory events and reduction of ocular infl ammation, it can be concluded that they may be considered as the new fi rst-line treatment approach for some cases of uveitis. Also, various other therapeutic approaches are likely to emerge as potential treatment therapies for NIU.