Biologic response modifiers in retinal vasculitis

Abstract

Intraocular inflammation is an important cause of blindness both in the developing and developed world. Corticosteroids play a pivotal role in the treatment of intraocular inflammation. Lately, therapy by immunosuppression has taken the center stage for patients with severe intraocular inflammation. However, the side effects of immunosuppressive drugs are oncogenic, infectious, and hematological. Recently, biologic response modifiers specifically targeting suppression of the immune effector responses have revolutionized the treatment of intraocular inflammation. Anti-tumour necrosis factor agents are etanercept, infliximab, and adalimumab. Newer drugs include certolizumab and golimumab. Infliximab has been found to be superior to corticosteroids in treating retinal vasculitis. Anti-interlenkin therapies include rituximab, daclizumab, anakinra, tocilizumab and secukinumab. Rituximab has been proven to be quite effective. Other biologics used are interferons and abatacept. However, there are several limitations and side effects associated with their use.

Key Words: Uveitis, Immunotherapy, Biologic response modifiers, Retinal vasculitis, Non-infectious uveitis

Core tip: Corticosteroids play a pivotal role in the treatment of intraocular inflammation. Lately, therapy by immunosuppression has taken the center stage for patients with severe intraocular inflammation. However, biologic response modifiers specifically targeting suppression of the immune effector responses have revolutionized the treatment of intraocular inflammation.

INTRODUCTION

Intraocular inflammation accounts for 5% to 20% of blindness in the developed world and 25% in the developing world[1]. Though the prevalence of retinal vasculitis is less, still the complexity and heterogeneity of the disease makes it unique. The etiology of most of them is unknown. Uveitogenic proteins that can incite intraocular inflammation include rhodopsin, retinal arrestin, recoverin, phosducin, retinal pigment epithelium derived (RPE-65) and inter-photoreceptor retinoid binding protein. These uveitogenic retinal antigens incite innate immunity by antigen mimicry and have been found to be associated in patients with intraocular inflammatory disease by numerous studies. Involved immunogenic pathway is similar for all types of intraocular inflammation[2,3]. Over the last two decades, laboratory diagnostic tools have entered into an era of molecular diagnostic tests. With the advent of experimental and cellular biology, several biomarkers are being identified. Many uveitic diseases are known to be strongly associated with particular human leucocyte antigen (HLA) haplotypes. It has largely been supported by continued development of experimental models of autoimmune uveitis along with improved molecular biologic techniques. Novel sophisticated technologies such as multiplex bead assays have revolutionized the management of complex refractory uveitis. Despite the varied immune etiology, intraocular inflammation poses a significant therapeutic challenge given the heterogeneity of the retinal vasculitis spectrum along with the pressing need and increasing expectations for personalised care. This review attempts to present the current concepts of immunotherapy in retinal vasculitis.

PHYSIOLOGICAL AND PATHOLOGICAL MECHANISM

Immune privilege guards the eye by mechanical sequestration behind an efficient blood-retinal barrier, local inhibition of activation and functioning of adaptive and innate immune cells, and systemic regulation by induction of T regulatory cells[2]. On the other hand, it leaves the eye vulnerable to an autoimmune attack by lymphocytes primed elsewhere in the body by chance encounter with a self or with mimic antigens.

Immunohistologically, retinal vasculitis is characterized by an infiltration of mainly cluster differentiation 4 (CD4 ⁺) T cells. Posterior uveitis in humans is considered to be a T cell-mediated autoimmune disease. Importance of T cells is highlighted by the fact that cyclosporin A can be effective in arresting the disease progression in many cases[4]. In an experimental model, the ability to adaptively transfer disease using activated retinal antigen-specific CD4 ⁺ T cells is further evidence of CD4 ⁺ T cell-mediated processes inducing the irreversible destruction of the photoreceptor cells of the retina[5]. The CD4 interacts directly with major histocompatibility complex (MHC) class II molecules on the surface of the antigen-presenting cell. Recognition of the MHC peptide complex by CD4 ⁺ T cells leads to secretion of cytokines. T Helper cells (Th) were divided into two subsets: Th1 and Th2. Th1 subset secretes Interferon-γ (IFN-γ) and Interleukin-2 (IL-2) responsible for cellular anti-viral immunity, and a Th2 subset secretes IL-4 required for blood borne parasitic responses. CD4 ⁺ Th1 cells and IFN-γ are considered to be the major effectors in the pathogenesis of experimental autoimmune uveitis[6]. Another subset of regulatory CD4 ⁺ T cells that secrete IL-10 and transforming growth factor-β (TGF-β) was added[7]. However, the presence of inflammatory diseases in IFN-γ-deficient mice indicated existence of other Th cell subsets and led to the discovery of the Th17 subset secreting IL-17 and IL-23[8]. Recently, other Th cell subsets have been assigned on the basis of the secretion of IL-9 (Th9) or IL-21 (T follicular helper)[9].

CYTOKINE PROFILE IN RETINAL VASCULITIS

Ooi et al[10] conducted a systematic review on inflammatory cytokines in uveitis of various etiologies. Few studies were conducted by us to ascertain the cytokine profile in Eales’disease. Following is a description of the cytokines involved in some of the important causes of retinal vasculitis.

Eales’ disease (retinal periphlebitis)

Eales’ disease is an idiopathic obliterative vasculopathy that primarily affects the peripheral retina of young adults. Role of tumor necrosis factor-alpha (TNF-α) in Eales’ disease was evaluated by us in several studies. In one such study, quantification of the TNF-α levels was carried out in young adults with Eales’ disease and healthy controls of similar age. TNF-α level was found to be significantly raised in cases as compared with controls. It was also observed that higher levels of TNF-α were associated with increased severity of Eales’ disease which was graded according to a new grading system based on severity of inflammation[11]. In another study, we evaluated the levels of TNF in the serum of 52 patients with proliferative stage of Eales’ disease and in 32 healthy controls to study its relation with the area of retinal capillary non-perfusion (ischemic retina). TNF levels were significantly increased in the proliferative stage of the disease as compared to controls and higher levels were associated with an increased area of retinal capillary non-perfusion on fluorescein angiography. It was concluded that increased TNF level in proliferative Eales’ disease is related to retinal cell death signaling[12]. We conducted another study in which we for the first time evaluated IL-1β, IL-6, IL-10, and TNF-α in the serum of 45 consecutive patients with Eales’ disease and in 28 healthy controls. It was found that levels of IL-1β, IL-6, IL-10, and TNF-α were significantly increased in the inflammatory stage of Eales’ disease as compared to controls. Also it was observed that IL-1β levels decreased significantly and TNF-α levels increased significantly during the proliferative stage of the disease as compared to the inflammatory stage. It was concluded that for controlling inflammatory activity and/or the associated long-term sequelae related to angiogenesis in Eales’ disease, IL-1 system and TNF- α represent novel target for immunotherapy[13].

Behcet’s disease

It is a systemic vasculitis with recurrent ocular involvement as uveitis and retinal vasculitis. HLA-B51 phenotype association has been found. Raised intraocular levels of the following immune factors have been found: IL-2, IL-6, IFN-γ and TNF-α. Recurrent episodes of Behcet’s disease-related uveitis has been found to be positively correlated with serum TNF-α levels[14].

Sarcoidosis

An acute or chronic granulomatous uveitis of unknown etiology involving the anterior, intermediate or posterior uveal layers. The aqueous immune profile of patients with sarcoidosis revealed elevated levels of IL-1α, IL-6 and IL-8[10,15].

Vogt-koyanagi-harada disease

A multisystem chronic granulomatous disorder associated with HLA-DR1 and HLA-DR4 phenotype with ocular manifestation as a chronic, bilateral panuveitis. Raised intraocular levels of the following immune factors have been identified: IL-6, IL-8 and IFN-γ[16].

Fuchs’ heterochromic iridocyclitis

A chronic typically unilateral anterior uveitis syndrome with or without associated glaucoma. One study found IFN-γ to be raised in aqueous samples of patients with FHC when compared to patients with idiopathic uveitis. Higher levels of IL-10 was found in larger number of FHC samples than of idiopathic uveitis (not statistically significant)[17].

Idiopathic uveitis

The commonest form of uveitis and has been found to be associated with increased intraocular levels of IL-1β, IL-2, TNF-α, IFN-γ, IL-6, IL-8 and MCP-1[16,18] .

Ankylosing spondylitis

A chronic inflammatory disorder of the axial skeleton with a strong association with HLA-B27 phenotype which manifests in the eye as severe acute anterior uveitis. Reports have revealed elevated intraocular levels of IL-2, IFN-γ, IL-6 and TNF-α[15].

IMMUNOTHERAPY

Corticosteroids and immunosuppressants

Corticosteroids played a pivotal role in the treatment of intraocular inflammation in the early 1950s, later on therapy by immunosuppression took the center stage for patients with severe intraocular inflammation. Now with the proteomic labeling, we can target specific cytokine pathway and deliver targeted therapy for patients with intraocular inflammation. We have now probably embarked on much specialised stratified care[4,5,18-23]. The treatment of noninfectious posterior uveitis can lead to severe vision loss, and the first-line conventional treatment includes systemic steroids. When the prednisone doses necessary to control intraocular inflammation are above 0.3 mg/d, a therapeutic association is proposed in order to lower the daily prednisone dose. The combined drugs are immunosuppressive or immunomodulative. The side effects of immunosuppressive drugs are oncogenic, infectious, hematological and can involve reproductive troubles, associated with specific toxic effects depending on the drug used. We undertook a tertiary care center-based prospective interventional study to evaluate the response time and safety profile of low-dose oral methotrexate pulsed therapy in Eales’ disease. Twenty one consecutive patients with idiopathic retinal periphlebitis were administered 12.5 mg methotrexate as a single oral dose, once per week for 12 wk. Drug safety was monitored by various laboratory tests that included twice-weekly white blood cells and differential counts, twice-weekly platelet counts, and monthly liver function tests for a mean follow-up period of 6 mo. It was found that all patients showed improvement in visual acuity. All the side effects of methotrexate were mild to moderate in severity and rapidly reversible on dose reduction or discontinuation. We concluded that low dose oral methotrexate pulse therapy (at a dose of 12.5 mg/wk) is clinically effective within 4 wk and is associated with an acceptable safety profile[24]. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. In a study conducted by us, efficacy of combined oral corticosteroid and low-dose oral methotrexate pulsed therapy in Eales’ disease was evaluated prospectively based on weighted visual morbidity scale for disease activity and visual acuity grading in 36 consecutive cases. Oral corticosteroids in a weekly tapering dose for 4 wk and 12.5 mg methotrexate as a single oral dose, once per week for 12 wk were administered simultaneously. We concluded that this combined oral therapy is clinically effective with an acceptable safety profile[25].

Biologic response modifiers

Biologics specifically target inflammatory cytokines and cause suppression of the immune effector responses that are responsible for damaging tissues. They were first used for ocular inflammation in 1990s. Commonly used biologics are anti-TNF agents and anti-interleukins. Now we have entered into an era of recombinant cytokines.

Anti TNF-α agents

TNF-α is a pleiotropic inflammatory cytokine. It plays a pivotal role in down-regulating both inflammatory and the immune response. Thus, blockade with anti-TNF agents has turned into the most important tool in the management of retinal vasculitis. The three most commonly used TNF inhibitors in the US are infliximab, etanercept and adalimumab. Newer drugs include certolizumab and golimumab.

Infliximab: Infliximab is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody with the antigen-binding region derived from a mouse antibody and the constant region from a human antibody[26]. It binds to TNF-α with high affinity thereby blocking the binding of TNF-α to its receptor. One of the considerations in giving infliximab is that it can potentially induce antinuclear antibody and anti-double stranded DNA on long term therapy[27,28]. Early monitoring and optimizing dose regimens can be useful in patients on long term infliximab therapy. Side effects are autoimmune diseases which improve on stopping the drug, blood dyscrasias, allergies secondary to infusion, fever, fatigue, upper respiratory chest infection, headache, gastrointestinal upset, headache.

Adalimumab: Adalimumab is a fully humanized recombinant IgG1 monoclonal antibody with high binding to human TNF-α. Side effects are gastrointestinal disturbances including haemorrhage, hyperlipidaemia, hypertension, chest pain, tachycardia, cough, dyspnea, mood changes, paraesthesia, haematuria, renal impairment, electrolyte disturbances, hyperuricaemia, musculoskeletal pain, eye disorders (visual impairment, conjunctivitis, blepharitis, eye swelling), rash, dermatitis.

Etanercept: Etanercept is a soluble fusion protein and prevents both TNF-α and TNF-β from interacting with receptors. It consists of 2 dimers of higher affinity type 2 TNF receptors. Side effects include headache, infection like upper respiratory tract infections, urinary tract infections, butterfly rash on cheeks, dizziness, fatigue, swelling of the arms/legs, unusual bruising/bleeding, severe headache, mental/mood changes, seizures, unexplained muscle weakness, numbness/tingling of the hands/feet, unsteadiness, vision changes, severe stomach/abdominal pain.

Golimumab: Golimumab is a novel fully humanized anti-TNFα monoclonal antibody. Side effects include body aches or pain, chills, cough, difficulty with breathing, ear congestion, fever, headache, loss of voice, muscle aches, sneezing, sore throat, stuffy or runny nose, unusual tiredness or weakness. Blurred vision, burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings, congestion cough with mucus diarrhea, dizziness, general feeling of discomfort or illness, hoarseness, joint pain, loss of appetite, muscle aches and pains, nausea, nervousness, pain or tenderness around the eyes and cheek bones, painful cold sores or blisters on the lips, pounding in the ears, shivering, shortness of breath or troubled breathing, slow or fast heartbeat, sweating, tender/swollen glands in the neck.

Anti-TNF-α agents have improved the treatment armamentarium for refractory immune-mediated uveitis particularly in Behçet disease-associated uveitis. A prospective observational study of patients with panuveitis was undertaken in which 19 eyes received an infliximab infusion, 8 eyes received high-dose methylprednisolone intravenously and 8 eyes received intravitreal triamcinolone acetonide at attack’s onset. Unchanged baseline maintenance therapy was continued for 30 d. Visual acuity, anterior chamber cells, vitreous cells and inflammation of the posterior eye segment were assessed at baseline and at days 1, 7, 14 and 29 post-treatment. Infliximab was superior to corticosteroids in treating retinal vasculitis as well as in resolution of retinitis and cystoid macular oedema[29]. A study was conducted in which anti-TNFα therapy was administered in 15 patients of chronic non-infectious uveitis when no response had been obtained with classical immunosuppressive therapies or in the presence of severe rheumatoid disease. Mean duration of ocular disease was 8 years. Treatment was initiated with infliximab, etanercept, and adalimumab. It was concluded that anti-TNF-α therapy is effective and safe[30]. Importance of TNF-α in the pathophysiology of multi-systemic sarcoidosis and refractory retinal vasculitis was emphasized in a case report in which 2 patients experienced an excellent response to infliximab[31]. A retrospective noncomparative case series was conducted on 6 pediatric patients with uveitis refractory to methotrexate, cyclosporine, mycophenolate mofetil, etanercept, daclizumab and topical steroids. These patients initially received infliximab at doses between 5 and 10 mg/kg at 2 to 4 wk interval and then were maintained at 4 to 8 wk interval at doses of 5 to 18 mg/kg. Reduction in intraocular inflammation after infliximab therapy initiation was seen in all the patients. The only adverse reactions seen were vitreous hemorrhage in 1 patient and a case of transient upper respiratory infusion reaction. It was concluded that for the treatment of refractory pediatric uveitis, infliximab seems to be an effective agent without apparent serious toxicity[32]. To evaluate the clinical response after switching from infliximab to adalimumab, a prospective, longitudinal and observational study was conducted in 69 patients with Behcet’s disease. Seventeen patients were switched to adalimumab for lack or loss of efficacy or infusion reactions to infliximab. Of the 17 treated patients, 9 showed sustained remission of the disease and 3 showed good response. No side effects were observed in any patient. They concluded that adalimumab can be used to treat patients with Behcet’s disease showing a scarce response or adverse events to infliximab[33]. A study was conducted to alert physician for timely recognition and to evaluate current treatment of recurrent hypopyon iridocyclitis or panuveitis in Behçet’s disease. It was found that for the control of acute panuveitis, a single infliximab infusion should be considered, whereas in reducing the number of episodes in refractory uveo-retinitis with faster regression and for complete remission of cystoid macular edema, repeated long-term infliximab infusions proved to be more effective[34]. Rifkin et al[35] studied current status of three of the five commercially available TNF inhibitors-etanercept, infliximab, and adalimumab for their efficacy in treatment of ocular inflammation. They found etanercept to be inadequate in controlling ocular inflammation. Infliximab and adalimumab, however, showed encouraging results in multiple trials[35]. There are only two reports in the literature about the use of golimumab in uveitis, describing four patients with juvenile idiopathic arthritis-associated uveitis and a case of idiopathic retinal vasculitis. Mesquida et al[36] first reported about the use of golimumab in Behçet’s disease. William et al[37] reported good outcomes using golimumab in three patients with juvenile idiopathic arthritis.

Anti-interleukin therapies

Rituximab: Rituximab (first used in the treatment of Non Hodgkin’s B cell lymphoma) is a recombinant chimeric monoclonal antibody with binding efficacy to CD20. It works by blocking CD20-bearing B cells. Side effects are severe stomach pain with constipation, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds, painful blistering skin rash with burning, itching, or tingly feeling, or upper stomach pain, vomiting, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes), runny or stuffy nose, sinus pain, sore throat, headache, dizziness, itching, or mild stomach cramps.

Daclizumab: Daclizumab is a recombinant monoclonal antibody of the human IgG1 isotype composed of 90% human and 10% mouse antibody sequences that bind to CD25 with high affinity and inhibit IL-2-mediated responses of activated T cells. It was withdrawn in 2009 based on a report by Wroblewski et al[38] according to which four of 39 patients developed solid malignant tumor while on daclizumab over a follow up period of 11 years. Side effects include poor wound healing, unusual growths/lumps, swollen glands (e.g., on the neck, in the armpits), unexplained weight loss, night sweats, easy bruising/bleeding, abdominal pain/swelling, unusual tiredness. A very serious allergic reaction to this drug is rare.

Anakinra: Anakinra is a recombinant non-glycosylated homologue of HuIL1Ra, a natural immunomodulating molecule, which competitively inhibits binding of IL1α and IL1β to the IL1 receptor type 1. Side effects are infections, nausea or diarrhea, headache, sinus infection, or redness, bruising, pain, or swelling at the injection site.

Tocilizumab: Tocilizumab is a recombinant humanized monoclonal antibody and inhibits IL-6 mediated responses by binding to both membrane-bound and soluble IL-6 receptors with high affinity.

Secukinumab: Secukinumab is a fully humanized IgG1k monoclonal antibody neutralizing IL-17A.

Sadreddini et al[39] reported treating a patient with visual loss due to retinal vasculitis resistant to prednisolone and azathioprine with rituximab successfully with a sustained remission of 24 mo of follow-up. Severe retinal vasculitis is a potentially blinding complication of patients with systemic lupus erythematosus (SLE). Hickman et al[40] first reported that rituximab can be used to treat severe bilateral SLE-associated retinal vasculitis. This case suggested that rituximab-induced B-cell depletion may provide an important new therapeutic option in such refractory cases. A study was conducted to evaluate the efficacy of rituximab in patients with retinal vasculitis and edema, resistant to cytotoxic drugs. Twenty patients were randomized to a rituximab group or cytotoxic combination therapy group. Rituximab was given in two 1000-mg courses (15-d interval). Subjects received methotrexate (15 mg/weekly) with prednisolone (0.5 mg/kg per day). The cytotoxic combination therapy group received pulse cyclophosphamide (1000 mg/monthly), azathioprine (2-3 mg/kg per day) and prednisolone (0.5 mg/kg per day). It was concluded that rituximab was efficient in severe ocular manifestations of Behcet’s disease as significant improvement after 6 mo was seen with rituximab, but not with cytotoxic drugs[41]. A pilot study aimed to evaluate the safety, pharmacokinetics and clinical activity of gevokizumab in Behçet’s disease patients with uveitis was conducted. Patients with acute posterior or panuveitis and/or retinal vasculitis, receiving 10 mg/d or less of prednisolone and resistant to azathioprine and/or cyclosporin were enrolled into the study. Patients received a single infusion of gevokizumab (0.3 mg/kg) and immunosuppressive agents were discontinued at baseline. On evaluation of the safety and uveitis status and pharmacokinetics of gevokizumab, it was found that no treatment-related adverse event was observed and rapid and durable clinical response was seen in all patients. Complete resolution of intraocular inflammation was achieved in 4-21 d, with a median duration of response of 49 d. Moreover, despite discontinuation of immunosuppressive agents and without the need to increase corticosteroid dosages, the effect was observed[42]. In addition, a clinical trial is underway for the use of anakinra in Behcet’s disease (clinical trial reference number NCT01441076). Muselier et al[43] showed tocilizumab to be effective in treatment of refractory uveitis. Secukinumab has proved to be quite effective in the treatment of patients with anterior and posterior uveitis with no serious adverse effects[44].

Interferons

(1) IFN α; (2) Recombinant IFN α-2a (Roferon-A); (3) Recombinant IFN α-2b (Intron A); and (4) Pegylated interferons.

Interferon-α: Interferon α-2A and Interferon α-2B are human recombinant interferons manufactured using recombinant DNA technology with E. coli to produce human proteins. It is a type I interferon and has been used in the treatment of uveitis due to its anti-proliferative, anti-angiogenic, apoptotic effects and the ability to activate dendritic, cytolytic T and natural killer cells. A prospective, open clinical trial was conducted to study long term effects of interferon α-2A on panuveitis in seven patients with Behçet’s disease. IFN α-2A was given for a mean duration of 23.6 mo in seven patients. Initial dose of IFN α-2A was 6 × 10⁶ IU/d, followed by 3 × 10⁶ IU/d after 1 mo and 3 × 10⁶ IU every other day after 3 mo. Additionally in the beginning of the therapy, two patients received low dose prednisolone (between 0.2 and 0.4 mg/kg per body weight). In three patients complete cessation of IFN α-2A was possible (observation period was 22, 6, and 4 mo). Six patients who had ocular manifestations of Behçet’s disease for the first time or with minor damage during their course of chronic relapsing panuveitis showed marked improvement. New relapses were prevented in one patient with advanced ocular Behçet’s disease. Resolution of retinal infiltrates occured within 2 wk and retinal vasculitis within 4 wk. It was found that complete remission of retinal vasculitis occurred in all patients treated with IFN α-2A alone or in combination with low dose steroids. It was concluded that retinal or optic nerve damage due to vascular occlusion can be prevented by treatment with IFN α-2A. No severe side effects were found[45]. Evaluation of the efficacy of interferon needs to be done in other etiologies of retinal vasculitis through randomized studies[46,47]. Another study was conducted to evaluate the long-term development of visual acuity in patients with severe ocular Behcet’s disease who were treated with IFN α-2A. Fifteen eyes of 9 patients with an active panuveitis and/or retinal vasculitis due to Behcet’s disease refractory to immunosuppressive treatment were included. Visual acuity before initiation of IFN was compared to visual acuity at the end of the follow-up. Increase in visual acuity of two lines or more was seen in 10 eyes during the follow-up. In 5 eyes visual acuity remained stable. No decrease of visual acuity in any eye was seen. In the presence of macular edema, quick response to IFN α-2A was seen. It was concluded that IFN α-2A seems to be much more effective to prevent a loss or decrease of visual acuity over a long period of time in patients with severe ocular Behcet’s disease compared to conventional immunosuppressants[48].

Fusion protein of cytotoxic T- lymphocyte antigen 4

Abatacept: It is a fusion protein that prevents activation of T cells by barring antigen presenting cells from delivering the co-stimulatory signals. There are case reports and case control studies reporting on the effectiveness of abatacept in the treatment of refractory uveitis in patients with juvenile idiopathic arthritis[49].

IMPORTANT CONSIDERATION

These drugs are contraindicated in patients with tuberculosis or any active infection and in patients with pregnancy or breast feeding. Patients should be instructed to avoid pregnancy till 5 mo after stopping last dose of biologics. Before prescribing them, malignant conditions should be ruled out. Baseline blood counts, liver function tests and Glucose should be measured and subsequently at every 4 wk for three months followed by every 6 wk. If patient develops fever, sore throat or bleeding then examination by a physician needs to be done. Demyelinating diseases should be ruled out before starting these drugs as TNF-α agents can aggravate multiple sclerosis. Caution should taken as reduced immunity can lead to increased risk of infection including flare up of latent tuberculosis. Also, worsening of heart failure can occur if already present.

LIMITATIONS

There is no proven causal relationship as yet with any of these novel biomarkers, though there is association of these biomarkers with some specific uveitis entities. Whether it is the disease leading to release of a specific biomarker or is it the inflammatory cytokine causing the disease is yet to be determined in future research. In addition, biologic response modifiers are expensive and with life threatening risks. Hence, a specialist experienced with immunology and the pathophysiology of inflammatory diseases has to supervise. Strict monitoring with awareness of the adverse effects is needed in rendering this specific therapy in refractory uveitis patients.

CONCLUSION

With the advent of experimental and cellular biology, cytokines are increasingly being recognized as biological markers in intraocular inflammatory diseases. Several experimental models and improved molecular biologic techniques have supported it. Biologics provide customized ocular therapy. As shown by various studies and randomized controlled trials, they have been found to be effective in several systemic diseases. Many biologic agents have been found to be efficacious in refractory anterior and posterior uveitis, particularly Behcet’s disease. With the advent of novel and advanced sophisticated techniques, newer cytokines are being found. The efficacy of biologic therapies and their comparison with each other are being studied in various randomized controlled trials. In future, evidence based medicine will pave way for tailored treatment by specific biologic regime.