|Year : 2017 | Volume
| Issue : 1 | Page : 3-10
Biologicals in uveitis
Priyanka, Jyotirmay Biswas
Department of Uvea and Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
|Date of Submission||19-Dec-2015|
|Date of Acceptance||30-May-2016|
|Date of Web Publication||6-Dec-2016|
Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Most noninfectious uveitis appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. Inflammatory uveitis is a difficult condition to treat. Recently, a new class of drugs obtained by a biological process and therefore defined as "biologics" has been successfully used in the treatment of immune-mediated rheumatic diseases. These drugs target different proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6 or immune effector cells including B- and T-lymphocytes. The success in rheumatology of the TNF-α inhibitors adalimumab (ADA) and infliximab (IFX) over the past several years has led to their use in uveitis, in particular in patients with Behcet's disease and for early use in patients with juvenile idiopathic arthritis who have not benefitted from methotrexate. The first experience with anti-TNF inhibitors etanercept, IFX, and ADA gave us excellent results in uveitis. Other newer biologics approved by the United States Food and Drug Administration for rheumatic diseases are emerging treatments for uveitis. These include the anti-CD20 inhibitors rituximab, the anti-TNF inhibitors certolizumab and golimumab, the IL-6 inhibitor tocilizumab, the IL-1 inhibitor anakinra, the cytotoxic T-lymphocyte antigen 4 inhibitor abatacept. Uveitis, a significant cause of ocular morbidity worldwide, is undergoing major changes as biologic therapies have entered into the field. We used PubMed and CrossRef (Google) search engine as the main source of information. In this review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging biological therapies in this context.
Keywords: Biologicals, cytokines, inflammation, tumor necrosis factor-α inhibitor, uvea
|How to cite this article:|
Priyanka, Biswas J. Biologicals in uveitis. J Clin Ophthalmol Res 2017;5:3-10
Uveitis is one of the leading causes of visual impairment and is responsible for 5-20% of legal blindness in Western countries and approximately 25% of blindness in the developing world. , Local and systemic corticosteroids constitute the first-line therapy for virtually all patients with noninfectious uveitis. Prolonged corticosteroid use can produce toxic effects, so corticosteroid-sparing immunomodulatory therapies have assumed an increasingly important role in the management of chronic ocular inflammation. However, these conventional therapies did not lead to satisfactory outcomes for some active uveitis, including the management of adverse effects.  The implication of immune-mediated inflammatory pathways in uveitis and the explosion of biologic agents to treat rheumatic and other inflammatory-mediated diseases have led to a wealth of potential therapies, systemic and local, for uveitis.
The aim of biologic therapy is to regulate the inflammatory process, potentially by offering more specific targeted suppression of immune effectors response that damage tissue. In this review, the literature is summarized, describing current assessments in the progressing fields, under headings that relate to the specific targets of these biologics. A systematic literature search was carried out using PubMed database and CrossRef (Google). Bibliographies of the retrieved literature were searched manually, and reports of randomized clinical trials preferentially were selected.
| Brief Overview of Treatment Strategies|| |
One of the most important and difficult challenges to confront the uveitis specialist is whether the inflammatory process is the result of an infectious agent. Establishing or excluding this may sometimes be possible on clinical appearance alone  but is often supplemented by battery of investigations.
For noninfectious causes, treatment involves suppression of the local immune response. It is useful to consider the concept of disease activity versus damage when treating inflammatory disease. , "Activity" refers to the ongoing immune response, which may be acute or chronic, but it is usually reversible. "Damage" refers to the effect of active inflammation on native tissues; it is usually irreversible. In simple terms, persistent activity will lead to accumulation of damage. In theory, effective therapy should suppress all activities and prevent or halt accumulation of damage.
New therapies should therefore aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimal possible adverse events. ,
When considering the drugs currently available for use in the treatment of ocular inflammation, it is important to recognize the limitations of the evidence that supports their role in uveitis.  For many agents, there are no randomized controlled trials in uveitis; thus, justification of their use is based on open-label cohort studies, uncontrolled case series, extrapolation from their use in other inflammatory conditions, and expert opinion. As a result, it is not yet possible to provide a definitive account, of which treatment is "best" for any particular variant of uveitis. Similarly, there is no clear line between those drugs that are "established" and those that are still "in development."
[Table 1] summarizes the biologicals discussed in this review.
|Table 1: Currently available Food and Drug Administration improved biologic response modifier|
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| The Biological Revolution|| |
The initial trials of biologics in uveitis focused on patients with active disease which had failed to respond to steroids and immunosuppressant. Different systematic reviews provide varying perspectives on the value of co-prescribing steroids and/or immunosuppressant.
Tumor necrosis factor inhibitors
Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine produced by various cells including macrophages and neutrophils and exacerbates immune diseases including uveitis. ,,,, A total of five TNF inhibitors are currently available; however, the second-generation agents are not yet in general use for the management of uveitis.
Infliximab (IFX) is a chimeric monoclonal antibody that irreversibly and competitively inhibits both membranes bound and circulating TNF-α rapidly. It is to date the most commonly used biologic agent in the treatment of uveitis, and its efficacy has been particularly promising, especially in sight-threatening Behcet's uveitis. We have good quality evidence for its use as the second-line immunomodulator in vision-threatening uveitis secondary to juvenile idiopathic arthritis (JIA) or from seronegative spondyloarthropathy. Successful treatment has also been reported for sarcoidosis, birdshot chorioretinopathy, and multifocal choroiditis.
In the general protocol for uveitis, 5 mg/kg of IFX was injected at weeks 0, 2, and 6 and then every 8 weeks. Dose can be raised up to 10 mg/kg and patients with uveitis infusions are generally repeated more frequently and at a high dose up to 20 mg/kg. 
First, Sfikakis et al. reported the effectiveness of IFX on ocular inflammation in Behçet's disease (BD).  Suhler et al. assessed validity of IFX for refractory uveitis in a 2-year randomized clinical trial.  Remission of uveitis was achieved in 60% of the patients treated with IFX in the 1 st year (15 out of 23 patients), and the remission was also maintained in 60% of these patients in the 2 nd year (nine out of 15 patients).
In a recent study of Kruh et al., 88 patients with chronic, recalcitrant uveitis were treated with IFX. Of the 72 patients (81.8%) who achieved clinical remission while being treated with IFX, 42 (58.3%) required additional immunomodulatory medications. At 7, 18.1, and 44.7 weeks, 25%, 50%, and 75% of patients, respectively, achieved clinical remission off all corticosteroids. Factors associated with a higher chance to achieve clinical remission were nonidiopathic uveitis (P < 0.001), intermediate or panuveitis (P < 0.001), absence of vasculitis (P < 0.001), and a starting dose ≥5 mg/kg (P < 0.011). 
Elezoglou et al. have investigated autoantibodies in BD patients with uveitis who received long-term treatment with IFX.  Iwata et al. investigated the correlation between the reduced therapeutic effect of IFX and elevation of antinuclear antibody (ANA) titers in BD patients with uveitis who had undergone treatment with IFX for 2 years or longer.  They suggested that a serum ANA titer might be a helpful biomarker for predicting the recurrence of ocular attacks in BD patients treated with IFX therapy. Simonini et al. have described that the efficacy of IFX in the treatment of childhood chronic uveitis wanes over time.  Anti-IFX antibodies, characterized by low preinfusion serum IFX levels, have been shown to be associated with an increased risk of infusion reaction and treatment failure in rheumatoid arthritis (RA). In addition to this, early monitoring may help optimize dosing regimens for individual patients, diminish side effects, and prevent the prolonged use of inadequate IFX therapy. ,
In one study, the safety and long-term effects of intravitreal IFX on chronic noninfectious uveitis have been evaluated in 10 eyes of 7 patients.  About 1.5 mg of IFX in 0.15 ml was injected intravitreal, and the patients were followed for 6 months. Results showed that vision improved and the macular edema decreased, but the effect lasted for a short time period, suggesting the need of repeated injections to achieve the best therapeutic goal. In another study, safety and efficacy of intravitreal IFX were evaluated successfully for sight-threatening relapsing uveitis in BD.  Hence, to conclude, intravitreal IFX might be considered, especially in Behcet's whenever systemic administration is not feasible or contraindicated.
Adalimumab (ADA) is a fully humanized recombinant anti-TNF-α-specific monoclonal immunoglobulin G1 (IgG1) antibody. Like IFX, it has the ability to cause sustained neutralization of membrane-bound TNF-α. The drug blocks the interaction between TNF and the cell surface receptors p55 and p75, and being highly specific for TNF-α, it does not inhibit the lymphotoxin TNF-β.
The usual dose is 40 mg (in children 24 mg/m 2 ) subcutaneously every 2 weeks. A definitive evidence that ADA is an effective treatment in anterior uveitis has come from a study involving 1250 patients with active ankylosing spondylitis (AS) enrolled in a multinational, open-label, uncontrolled clinical study.  In a recent prospective case series, a total of 131 patients with refractory uveitis and intolerance or failure to respond to prednisone and at least one other systemic immunosuppressive were treated with ADA.  Six months after the initiation of the study, 111 patients (85%) were able to reduce at least 50% of their baseline immunosuppressant load.
In a two recent study of Zanini et al. and Simonini et al., they showed that both IFX and ADA appear to be effective and safe for treatment of refractory JIA-related uveitis, with a better performance of ADA in the medium-term period. In the first study, 48 patients were treated with IFX, 43 with ADA. A higher remission rate was observed with ADA (67.4% vs. 42.8% with IFX; P = 0.025). The second study showed a higher probability of uveitis remission on ADA (Mantel-Cox χ2 = 6.83, P < 0.001). At 40 months of follow-up, nine (60%) out of 15 children receiving ADA compared to three (18.8%) of 16 children receiving IFX were still in remission on therapy (P < 0.02). ,
In a prospective, interventional case series study by Magli et al., 21 patients (38 eyes) were treated with ADA and after a mean follow-up of 18.2 7.7 (9-41) months, resolution of anterior chamber inflammation was obtained in 29/38 eyes (76%).  Recently, multiple similar studies have shown efficacy of ADA in inflammatory uveitis. ,,,,,,
Suhler et al. conducted a prospective, multicenter, open-label phase II clinical trial to assess the effectiveness and safety of ADA, a fully human anti-TNF monoclonal antibody, in treating refractory uveitis. Twenty-one out of 31 patients (68%) were characterized as clinical responders at 10 weeks, of whom 12 patients (39%) exhibited durable response after 50 weeks. 
A first randomized controlled trial (SYCAMORE Trial) of 154 patients that will assess the clinical effectiveness, safety, and cost-effectiveness of ADA in combination with methotrexate for the treatment of JIA-associated uveitis is going on. 
Therefore, to conclude, ADA is a well-tolerated drug helpful in decreasing inflammatory activity in refractory uveitis and able to reduce steroid requirement. Interestingly, ADA has proven to be a more effective alternative in patients not responsive or allergic to IFX. ,,
Etanercept is a dimeric soluble form of the extracellular ligand-binding protein-linked p75 TNF receptor. It has the ability to bind to soluble TNF-α and TNF-β, thereby blocking binding to cell surface TNF receptors. However, the complex interaction is unstable and dissociates rapidly which may then only neutralize TNF-α transiently.
It has the same indications as ADA with the exclusion of inflammatory bowel diseases. Usual dose is 50 mg subcutaneously once weekly. In pediatric rheumatology, etanercept is used at a dose of 0.8 mg/kg given once weekly.
In a comprehensive literature review, it has been reported that ocular inflammation is paradoxically a potential adverse event following the use of etanercept in both previously uninvolved and inflamed eyes.  In a very recent study, it has been observed from data reported in the literature that 42 cases of inflammatory eye diseases believed to be associated with the use of etanercept include 33 cases of uveitis, eight scleritis, one orbital myositis.  These data have been obtained from 16 patients with RA, 10 with JIA, 14 with AS, and two with psoriatic spondyloarthropathy.
The final conclusion underlines that ocular inflammation is paradoxically a potential adverse effect of etanercept, even in previously uninvolved eyes, although it seems to involve a minority of the patients treated.
Golimumab is a fully humanized monoclonal antibody against TNF-α, with the same indications of etanercept. Compared to other anti-TNF-α antibodies, golimumab is characterized by light and heavy chains superimposed to those of humans with a consequent reduction of immunogenicity. It is administered subcutaneously once monthly. Golimumab has been approved for the treatment of RA, psoriatic arthritis, and AS.  There are a few case reports on successful use of golimumab in JIA-associated uveitis and Behcet's uveitis. ,,,, However, further studies are required to understand the long-term efficacy and safety of golimumab in the treatment of uveitis.
Interleukin-1 (IL-1) has been proven to play an important role in experimental uveitis. For this reason, antagonists of this cytokine have been tested in human uveitis. However, a few data are available to date and results are still inconclusive. It has been reported for use in the treatment of chronic infantile neurological cutaneous articular (CINCA) syndrome.  This disease may occur as a result of mutations in the cold-induced autoinflammatory syndrome 1 gene, which encodes cryopyrin. Cryopyrin regulates the apoptosis of inflammatory cells; its lack thereof upregulates levels of IL-1.
Tocilizumab is a fully humanized monoclonal antibody recognizing IL-6 receptor (IL-6 R) in both its soluble form or bound to cell membrane surface. Its indication includes moderate to severe RA. The standard dose is 8 mg/kg/month intravenously. Clinical trials have shown promising results in treating several autoimmune diseases in patients who respond inadequately to conventional immunosuppressant, including large-vessel vasculitis.  Tocilizumab may represent a treatment option for otherwise refractory JIA-associated uveitis although further prospective studies are needed to evaluate the efficacy of this new drug in comparison to other biologics. ,,
Daclizumab (Zenapax) is a monoclonal antibody that binds the IL-2 receptor on T-lymphocytes, preventing their IL2-dependent activation. A phase I/II open-label study of intravenous daclizumab for the treatment of noninfectious intermediate, posterior, or panuveitis demonstrated improvement of inflammation and visual acuity at 1 year in eight out of 10 patients, which was maintained after 4 years of treatment. Increased uveitic recurrences were observed with reduction to 6-weekly infusions as compared to 4-weekly infusions. After 4 years of intravenous infusions, some patients were transitioned to subcutaneous daclizumab therapy, with most patients retaining good response.  Ten out of 15 patients in a subsequent study achieved at least a 50% reduction of concurrent immunosuppression with retained visual acuity, inflammatory control, and no significant side effects.  Daclizumab has been demonstrated effective for refractory birdshot retinochoroidopathy in one study, with seven out of eight patients achieving complete resolution of vitreous inflammation and stabilization or improvement of visual acuity.  However, daclizumab failed to demonstrate effectiveness in BD-associated uveitis in a randomized trial. 
Anakinra competitively inhibits binding of IL-1 and is more effective in the treatment of CINCA syndrome than corticosteroids. Teoh et al. reported successful treatment of posterior uveitis associated with CINCA syndrome in a 4-year-old boy, which had responded poorly to corticosteroids, methotrexate, and etanercept.  Subcutaneous anakinra was administered at a dose of 1 mg/kg/day until remission was achieved. Inflammatory remission was achieved within the 1 st year of treatment, and his uveitis has subsequently remained quiescent, permitting the withdrawal of oral corticosteroids. No adverse side effects were reported.
Gevokizumab (XOMA 052)
Gevokizumab has been granted orphan drug status in the European Union for noninfectious uveitis. In a pilot study by Gül et al., seven patients with acute posterior or panuveitis, and/or retinal vasculitis, resistant to azathioprine and/or cyclosporine, and receiving 10 mg/day or less of prednisolone, were enrolled. Immunosuppressive agents were discontinued at baseline. Patients received a single infusion of XOMA 052 (0.3 mg/kg). Well-tolerated gevokizumab resulted in a rapid onset and sustained reduction in intraocular inflammation in patients with resistant uveitis and retinal vasculitis. 
Secukinumab (anti-interleukin-17A antibody)
Secukinumab is a fully humanized IgG1k monoclonal antibody neutralizing IL-17A. It has proved to be quite effective in the treatment of patients with anterior and posterior uveitis with no serious adverse effects.  Three multicenter, randomized, double-masked, placebo controlled, dose-ranging phase III studies conducted in a total of 118 patients with Behçet's uveitis (SHIELD study); 31 patients with active, noninfectious, nonBehçet's uveitis (INSURE study); and 125 patients with quiescent, noninfectious, nonBehçet's uveitis (ENDURE study) were enrolled. After completion or early termination of each trial, there were no statistically significant differences in uveitis recurrence between the secukinumab treatment groups and placebo groups in any study. 
Rituximab is a recombinant chimeric monoclonal antibody that targets CD-20, a cell surface antigen on B-cells, resulting in B-cell depletion. With the established role of B-cells in T-cell-mediated and immune complex-mediated diseases, this biologic is potentially useful in targeting the effector cells of the inflammatory cascade. The binding and clustering of CD20 by rituximab transmits a signal that causes apoptosis of B-lymphocytes. Infusions of rituximab induce the depletion of B-lymphocytes from peripheral blood for several months.
The usual dose is 1000 mg infusion on days 1 and 15 and then at months 12 and 21. Initially developed for the treatment of B-cell lymphomas, rituximab is licensed also for RA, being particularly effective in subgroups of patients, which are positive for anti-citrullinated protein antibody and/or rheumatoid factor (seropositive RA). The drug has been used in clinical trials in different autoimmune diseases including systemic lupus erythematosus, Sjogren's syndrome, antineutrophil cytoplasmic antibody-associated vasculitis. ,,
There are some case reports on successful use of rituximab in the treatment of uveitis associated with JIA. ,, Recently, Miserocchi et al. retrospectively studied eight patients (15 eyes) with severe and longstanding JIA uveitis who had an inadequate response in controlling uveitis to one or more biologic agents including TNF blockers and abatacept were treated with rituximab. All patients achieved complete control of uveitis; however, in two patients, rituximab was discontinued due to inefficacy in treating arthritis. The decrease in uveitis activity was evident 4-5 months after the first infusion. The authors conclude that rituximab may be a promising effective treatment option for refractory uveitis associated with JIA leading to long-term quiescence of uveitis, particularly for patients who have not previously responded to other biologic therapies. 
Hence, although inflammatory uveitis is believed to be a T-cell-mediated disease, B-cell depletion may be effective since these cells are efficient antigen-presenting cells (APCs) for T-lymphocytes and contribute to their activation and clonal expansion.  It has been effective for treatment of various systemic vasculitis associated uveitis, retinal vasculitis, and scleritis.
Interferon-α (IFN-α) is a type I IFN and has been used in the treatment of uveitis due to its antiproliferative, antiangiogenic, and apoptotic effects. In addition, it has the ability to modulate immune responses, specifically activating dendritic, cytolytic T- and natural killer cells. IFN α-2A and IFN α-2B are human-recombinant IFNs manufactured using recombinant deoxyribonucleic acid technology with Escherichia coli to produce human proteins. More recently, pegylated IFNs have been used which have a longer duration of action allowing weekly administration, but there are inadequate data to determine their efficacy.
Abatacept is a fusion protein composed of the Fc region of the IgG1 fused to the extracellular domain of cytotoxic T-lymphocyte antigen 4 molecule. Abatacept is a selective co-stimulation modulator as it inhibits the co-stimulation of T-cells, preventing APCs from delivering the co-stimulatory signal to T-cells to fully activate them. It is usually administered intravenously at a dose ranging from 500 to 1000 mg every 4 weeks.
There are a few case reports on successful use of abatacept in refractory uveitis associated with uveitis. ,, In a study of seven patients with JIA-related uveitis refractory to immunosuppressive and anti-TNF-α agents were treated with abatacept.  All patients responded to abatacept and six maintained a clinical remission after a mean of 9.2 months of treatment.
| Things to Remember for Patients on Biologics|| |
- It is contraindicated in patients with tuberculosis (TB), chronic hepatitis B or C, or any active infection
- IFX, etanercept, and ADA, all have been categorized as the United States Food and Drug Administration category B for use in pregnancy (animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women). Avoid pregnancy till 5 months after stopping the last dose of biologics
- Rule out malignant conditions before starting biologics
- Patient to be advised to see a doctor if he develops fever, sore throat, bleeding
- As TNF-α agents can aggravate multiple sclerosis, rule out demyelinating disease before starting these agents in those set of patients
- Common side effects:
- Reduced immunity leading to increased risk of infection including flare-up of latent TB
- Worsening of heart failure if already present, so contraindicated in the New York Heart Association Class III/IV heart failure.
| Key Points for Initiating and Monitoring Patients on Biological Therapies|| |
- Before starting biologics, a careful clinical examination is important to rule out previous cardiac diseases, malignancy, neurological disorders, or infections
- The patient who will be treated with biologics should know the main signs and symptoms ("red flags") of the adverse effects associated with their use
- Laboratory tests
- Annual TB skin test; alternatives include the QuantiFERON; -TB gold blood test and chest X-ray if indicated
- Complete metabolic panel with liver function tests for each IFX infusion and with any sign of hepatic injury
- Complete metabolic panel (renal function test, electrolyte, liver function test, and glucose) every 3-6 months on all biological therapies
- Complete blood counts every 3-6 months on all biological therapies
- Hepatitis screen and human immunodeficiency virus testing when risk factors present on all biological therapies.
- Patients initiating anti-TNF therapy should be up-to-date for pneumococcal, influenza (nonlive virus), and hepatitis B vaccines. Patients receiving anti-TNF therapy should not have live virus vaccine, including varicella zoster, oral polio, or rabies vaccination.
| Conclusion|| |
Biologics are potent medications and very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications, such as those with RA, JIA, AS, BD, and inflammatory bowel disease.
IFX and ADA can be considered as the first-line immunomodulator for the treatment of ocular manifestations of Behcet's disease and as the second-line immunomodulatory agent for the uveitis associated with juvenile arthritis and seronegative spondyloarthropathy with good quality evidence. The literature for ADA is less developed than for IFX, but these agents seem to show similar efficacy in most studies. Until more comparative data are available, no recommendation can be made as to preferred agent although numerous studies have suggested that ADA may be effective in patients who have become intolerant to or have developed reduced clinical responsiveness to IFX. Evidence suggests that etanercept may not be as effective for uveitis as IFX and ADA and it has been associated with development of uveitis in JIA patients and development of sarcoid-like disease in others. Other agents, such as golimumab, abatacept, gevokizumab, and tocilizumab, may have great future promise for the treatment of noninfectious uveitis. An ophthalmologist should seek to treat the patient, rather than simply suppress the uveitis. As such, it is important to take a holistic approach to treatment.
Due to limited data from randomized clinical trials on biologic agents for uveitis, many studies are currently underway. Because the pool of patients with uveitis is not that large, it is not easy to do clinical trials. A major unanswered question is whether biologic therapies will be effective if delivered locally to the eye. New drugs and innovative drug delivery systems will pave the way for future treatments in uveitis.
It is crucial that we continue to develop new therapies for use in uveitis that aims to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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