Advances in the Management of Non-infectious Uveitis

Uveitis may be related to systemic disease in up to 20% of patients and can be the presenting sign in many cases [1]. Ocular findings guide the workup of patients to include tests aimed at identifying related diseases. Presence of systemic disease may influence the management of the ocular inflammation, and inform the need for multidisciplinary input. Diagnostic techniques are continually advancing, establishing more exact disease etiologies and relationships to systemic diseases.

Anterior Uveitis and Spondyloarthritis

Anterior uveitis (AU) is the most common form of uveitis, accounting for up to a third of cases [1], and up to 60% are also HLA-B27 positive [14]. HLA-B27-associated acute AU (AAU) is the most common form of AU, and is strongly related to underlying systemic disease such as spondyloarthritis (SpA), [15, 16] with many patients having undiagnosed axial SpA. In a study on axial magnetic resonance imaging (MRI) of young AAU patients with chronic back pain, up to a quarter were found to have axial SpA [17]. Studies examining screening algorithms for the diagnosis of SpA among patients with AAU found that 40–50% had undiagnosed SpA [14, 18], with patients who were HLA-B27 positive more likely to be subsequently diagnosed [14]. While treatment of AU is primarily based on topical corticosteroids, systemic disease requires the involvement of rheumatologists and potentially systemic immunosuppression. This can include anti-tumor necrosis factor α (TNFα) agents, which may affect the likelihood of AU reactivation and disease control. Infliximab and adalimumab have been shown to reduce the risk of uveitis flares and the need for ocular treatment [19–25]. Conversely, etanercept is well-known to have little effect on ocular inflammation, and may actually induce intraocular inflammation and result in an increased prevalence of flares [22, 23]. Using screening algorithms to identify previously undiagnosed SpA patients would allow early treatment and disease control, while the choice of drugs can have a direct impact on uveitis control.

Sarcoidosis

Sarcoidosis is a multisystemic chronic inflammatory disorder of unknown etiology characterized by noncaseating granulomas. Between 30 and 60% of patients develop ocular signs, which can be the presenting complaint in up to 30% of patients [26]. The International Workshop on Ocular Sarcoidosis (IWOS) recently presented the revised guidelines for the diagnosis of ocular sarcoidosis [27]. Patients are considered to have definite ocular sarcoidosis with a positive biospy and compatible uveitis, and presumed or probable disease if they had a combination of ocular signs and positive laboratory findings but no suggestive biopsy (Fig. 5.2a, Table 5.1). Presumed disease requires the presence of bi-hilar lymphadenopathy and two additional intraocular signs; probable disease is defined by three intraocular signs and two other positive investigations. Other tests under consideration for inclusion in future consensus guidelines include serum levels of soluble interleukin (IL)-2 receptor and Krebs von den Lungen (KL)-6. Of note, elevated IL-2 receptor levels were reported to have 98% sensitivity and 94% specificity in ocular sarcoidosis [28].

Table 5.1

IWOS revised diagnostic criteria for ocular sarcoidosis

Clinical signs

1. Mutton-fat KPs (large and small) and/or iris nodules at pupillary margin (Koeppe) or in stroma (Busacca)

2. Trabecular meshwork nodules and/or tent-shaped PAS

3. Snowballs/string of pearls vitreous opacities

4. Multiple chorioretinal peripheral lesions (active and atrophic)

5. Nodular and/or segmental periphlebitis (± candle wax drippings) and/or macroaneurysm in an inflamed eye

6. Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule

7. Bilaterality

Systemic investigations

1. Bilateral hilar lymphadenopathy on chest X-ray and/or chest CT scan

2. Negative tuberculin test or interferon-gamma releasing assays

3. Serum angiotensin converting enzyme elevated

4. Serum lysozyme elevated

5. Bronchoalveolar lavage fluid CD4/CD8 ratio elevated (> 3.5)

6. PET positive (abnormal accumulation of gallium-67 scintigraphy or 18F-fluorodeoxyglucose)

7. Lymphopenia (< 1000 cells/uL)

8. Parenchymal lung changes consistent with sarcoidosis as determined by pulmonologists or radiologists

KP keratic precipitate; PAS peripheral anterior synechiae; CT computed tomography; PET positron emission tomography

The use of angiotensin converting enzyme (ACE) levels to diagnose ocular sarcoidosis is of particular interest. ACE can be elevated in many granulomatous pulmonary diseases such as tuberculosis, sarcoidosis and histoplasmosis [29], and its value in the diagnosis of these diseases is controversial. When results of elevated ACE levels were combined with abnormal levels of serum lysozyme from patients with ocular sarcoidosis they had a sensitivity of 61%, which suggests a limited role in diagnosis [30]. In a recent study that examined the value of elevated ACE levels in predicting ocular sarcoidosis from a general non-infectious uveitis population [31], ACE had a sensitivity of 78% and a specificity of 90% for ocular sarcoidosis among adults, with a negative predictive value of 97%. In children the test performed less well and had a sensitivity of 60% and a specificity of 78.5%, but still with a negative predictive value of 96.9%. These results suggest the greatest advantage of testing ACE levels would be in ruling out sarcoidosis in suspected cases, when the levels are within the normal range. It should also be noted that the normal range of ACE levels can vary between laboratories but is generally accepted to be up to 53 μL [31]. Normal ACE levels from children can be even higher and caution should be exercised in their interpretation [32].

Following diagnosis, the treatment of sarcoidosis frequently requires the use of long-term immunosuppression. Similar to other forms of uveitis, treatment is based on a drug escalation approach beginning with systemic corticosteroids [33, 34], followed by 2nd-line immunosuppressive agents and biologics as needed. Sarcoidosis appears to have a relatively good response to corticosteroids, and while these patients are seen to need more corticosteroids than other causes of uveitis, they are less likely to need 2nd-line treatment [35, 36]. The majority of patients respond to treatment and visual acuity is maintained [37], with macular edema and cataract the main causes of vision loss.

Behçet’s Disease

Behçet’s disease (BD) is a chronic inflammatory disorder of unknown etiology that predominates along the ancient ‘Silk Route’ from southern Europe, Turkey to Japan [38, 39]. The disease manifests as an immune-mediated systemic vasculitis involving small, medium, and large arteries and veins (Fig. 5.2b) [40]. Ocular involvement occurs in up to 50% of patients and ranges from a chronic panuveitis to vasculitis, resulting in vision loss in many cases [41, 42]. While the disease is classically characterized by the triad of recurrent oral and genital aphthous ulcers, ocular inflammation and skin lesions [43], many patients do not present with the full set of signs and diagnosis is based on matching diagnostic criteria. HLA-B51 has some association with the disease (sensitivity 51%, specificity 71%) but is not part of the diagnostic criteria and should mainly be used to support the diagnosis [15, 44]. Several diagnostic criteria have been proposed; the International Criteria for BD (ICBD) is currently the most commonly used [45]. These criteria comprise of a scoring system of seven items including ocular findings, genital ulcers, oral ulcers, skin lesions, neurological manifestations, vascular manifestations and a positive pathergy test [45]. The minimum score for a patient to be classified as having BD is 4. The criteria demonstrate a high sensitivity (94.8%), but a lower specificity (90.5%). Interestingly, a UK cohort study which used the newer ICBD 2014 classification in a predominantly UK population showed even lower specificity and suggested reversion to older classification systems for UK populations [46].

Behçet’s disease is a potentially blinding condition, secondary to macular ischaemia, dense vitritis, and macular edema [42, 47]. Treatment must be started immediately and maintained long-term to prevent disease progression, second eye involvement, ocular complications and vision loss. Treatment is based on the use of systemic immunosuppression, and while corticosteroids are used as the 1st-line agent, studies demonstrate that BD is particularly responsive to treatment with anti-TNFα agents [48–51]. The recent licensing of adalimumab for the treatment of refractory uveitis recognized this particular affinity and adalimumab is available in some countries for most BD-related uveitis patients immediately following treatment failure with corticosteroids, without the need of first attempting a 2nd-line agent. Other studies suggest that refractory BD-related uveitis is also highly responsive to interferon α2a [52–54], which can be considered for such cases. Treatment results in visual acuity stabilization, extended disease remission and prolonged time to relapse.

Systemic Treatment for Non-infectious Uveitis

Choice of treatment for non-infectious uveitis is influenced by the disease laterality, systemic involvement, course and natural history, and tolerability to the drugs. In many cases, long-term treatment is required to maintain disease control and issues of extended exposure and systemic side effects influence treatment choice. Oral corticosteroids are crucial for acute management while the slower acting immunosuppressive agents are important as 2nd-line treatment and as steroid-sparing agents [55]. Conventional immunosuppressants include antimetabolites (methotrexate, mycophenolate mofetil, azathioprine), calcineurin inhibitors (cyclosporine, tacrolimus), and alkylating agents (cyclophosphamide, chlorambucil). Newer biologic agents used in uveitis are the anti-TNFα inhibitors infliximab and adalimumab.

Corticosteroids are the cornerstone of uveitis management and are delivered either locally or systemically. They work quickly and effectively for most inflammatory conditions, are widely studied and generally well tolerated [55]. The aim of treatment is to achieve complete control of the disease with resolution of all intraocular inflammation, while maintaining a long-term steroid dose of ≤7.5 mg prednisolone per day, which significantly reduces the risk of systemic side effects [56]. Use of 2nd-line immunosuppressive agents and biologics is advocated as steroid-sparing treatment when inflammatory control is not achieved, maintained at low corticosteroid doses, or when the side effects are intolerable. Second-line immunosuppressive agents achieve disease control in up to 50% of cases and while none are licensed for treating uveitis, methotrexate and mycophenolate mofetil are commonly used [2, 57]. Treatment requires continual monitoring of blood counts as well as hepatic function, and side effects can restrict the use of these drugs.

The increasing understanding of the inflammatory cascade and in particular, evidence supporting Th-17 cells as mediators of uveitis, has led to the identification of cytokines that influence these cells and the development of specific biologic drugs. Current candidate molecules for treatment include pro-inflammatory cytokines such as TNFα, IL-6, IL-17 as well as vascular endothelial growth factor (VEGF) [58]. Most of the information on clinical use of biologics in uveitis focuses on anti-TNFα drugs. Infliximab is a chimeric monoclonal antibody to TNFα and adalimumab is a fully human monoclonal antibody. Both drugs appear to be effective for treating uveitis and in particular, uveitis related to juvenile idiopathic arthritis (JIA), BD, and HLA-B27-associated uveitis [20, 59]. In 2016 the results of two randomized, placebo-controlled trials resulted in the U.S. Food and Drug Administration approving adalimumab for the treatment of non-infectious, intermediate, posterior or panuveitis. The VISUAL I & II studies demonstrated that treatment with adalimumab resulted in an almost 50% reduction in relapse rates following a rapid tapering of systemic corticosteroids [60, 61]. Patients with either active uveitis (VISUAL I) and inactive uveitis (VISUAL II) had reduced rates of treatment failure and vision loss, compared to patients given placebo. A follow-up study (VISUAL III) demonstrated that 60% of patients with active uveitis at baseline were able to achieve quiescence by week 78, with 66% of them steroid-free [62]. 74% of patients who were inactive at baseline also maintained quiescence at week 78. Adalimumab was further demonstrated to be an effective adjunctive treatment to methotrexate for the management of patients with JIA-related uveitis. Those receiving adalimumab had a 27% treatment failure rate compared to 60% among placebo-treated patients [63]. Several studies have attempted to compare the effect of treating uveitis between infliximab and adalimumab and did not find a significant difference [64–66]. Adalimumab is currently indicated as a 3rd-line agent for refractory uveitis that failed corticosteroids and at least one other immunosuppressive agent, although it is licensed as 2nd-line for BD in some countries.

Studies on tocilizumab, an IL-6 receptor antagonist, suggest that repeat infusions can result in effective control of intraocular inflammation over 6–12 months [67–70]. Currently, treatment with tocilizumab is not licensed for uveitis and is considered only in cases that failed anti-TNFα agents. Sarilumab, another IL-6 receptor antibody, demonstrated less efficacy at controlling intraocular inflammation, though it demonstrated a more pronounced effect on macular edema [71]. Secukinumab, an anti IL-17A antibody, has demonstrated mixed results. Three randomized controlled studies failed to demonstrate a significant effect for subcutaneous drug administration [72], while a trial examining intravenous infusions *resulted in* showed improved inflammatory control and remission rates [73].

Use of Local Treatment for Non-infectious Uveitis

Local treatment for uveitis includes the use of topical drops as well as periocular and intraocular injections. Intraocular steroids are used as monotherapy or as an adjunctive to systemic immunosuppression [74, 75]. Intravitreal injections of triamcinolone acetate (2–4 mg) are routinely used for controlling posterior uveitis, vitritis, and macular edema [76]. The injections are effective in controlling the intraocular inflammation, reducing macular edema, and improving vision, with few systemic side effects. A single injection can last up to three months and can be repeated as needed. However ocular side effects are common, predominantly raised intraocular pressure and cataract progression [76, 77]. The bioerodible dexamethasone implant Ozurdex (Allergan, Irvine, CA) is licensed for use in non-infectious non-anterior uveitis to control intraocular inflammation, reduce vitreous haze and macular edema, and improve vision [78].

Long-term corticosteroid implants are also used for controlling uveitis and there are currently two commercially available intravitreal fluocinolone acetonide implants (0.59 mg), a surgically inserted implant (Retisert; Bausch & Lomb, Bridgewater, NJ) and an injectable insert (Iluvien; Alimera Sciences, Aldershot, UK). These implants continually release a steady dose of steroids into the vitreous up to 2.5 years. The Multicenter Uveitis Steroid Treatment (MUST) trial and follow-up study (MUST-FS) was a prospective, randomized, multicenter study designed to compare conventional systemic therapy with oral corticosteroids and immunosuppression against the surgically inserted fluocinolone acetonide implant [79]. The study randomized 255 patients (479 eyes with uveitis) to either treatment arm and by 2 years found there was no difference with regards to visual acuity, though the implant was superior in inflammatory control [80]. Patients who completed the study were followed up to 7 years with the results remaining steady for an additional 30 months and only lost at the 7 years timepoint, when the group receiving systemic treatment achieved an average visual benefit of 7.1 letters [79]. It is thought that inflammatory relapses once the steroid implant wears out results in chorioretinal scarring and visual penalty. Ocular side effects were greater in the implant group, with 45% of eyes requiring glaucoma surgery and 90% requiring cataract surgery. However, visual function improved following cataract surgery and remained comparable [81], with many patients remaining disease free for many years, without the need for additional systemic treatment. The injectable fluocinolone acetate insert is currently under investigation as a treatment for non-infectious uveitis and preliminary results form a prospective, randomized, multicenter study comparing it to sham injections suggest that by 12 months the risk of disease recurrence was significantly reduced (38% vs. 98%), though the risk of cataract development was higher (33% vs. 12%) [82].

To identify the preferred local treatment approach to uveitic macular edema, the Periocular and Intravitreal Corticosteroids for Uveitis Macular Edema (POINT) trial compared the relative efficacy of periocular triamcinolone, intravitreal triamcinolone and the intravitreal dexamethasone implant [83]. The study randomized 192 patients (235 eyes with uveitic macular edema) to one of the three treatment arms and followed them for 6 months. The primary endpoint was the change in central subfield thickness (CST) at 8 weeks. The study found that while all treatment arms resulted in improved CST, for those receiving intravitreal triamcinolone injections or the dexamethasone implant the change was greater than for those receiving periocular triamcinolone (39%, 46% and 23%, respectively). Both intravitreal treatment arms were superior in resolving macular edema and improving visual acuity, though there was no difference between them.

Other options for local treatment include the use of intravitreal methotrexate injections (400 μg/0.1 mL), which may be effective for up to 4 months in refractory cases [84, 85], or intravitreal biologic agents such as sirolimus. A study examining the effect of an intravitreal injection of 440 μg of sirolimus demonstrated a significant improvement in intraocular inflammation and vitreous haze, while maintaining visual acuity and allowing up to 77% of patients to taper their systemic immunosuppression [86]. The follow-up study did not reach primary outcomes and was therefore not approved by the FDA. Other small cohort studies suggest that while visual acuity may improve, in some eyes the treatment induced inflammation [87, 88]. The current available data is not sufficiently robust to conclude about the role of intravitreal anti-TNFα agents for the treatment of non-infectious uveitis.

Anti-vascular endothelial growth factor agents are routinely used for the treatment of macular edema secondary to diabetic retinopathy and retinal vein occlusions [89, 90]. While its role in these diseases is well established, the evidence in ocular inflammation is less clear and relies mainly on small case series. A recent study of uncommon causes of macular edema compared monthly injections of ranibizumab to sham treatment and included 21 patients with uveitis-related macular edema. At two months, the treated group had a greater gain in visual acuity and CST, however by 12 months the effect on CST was lost [91]. A second study comparing repeated monthly injections of bevacizumab to intravitreal triamcinolone for the treatment of refractory CME in eyes with inactive uveitis found that by 24 months, both treatments resulted in improvement in CST and visual acuity [92]. The study suggests bevacizumab may have a role in the management of refractory CME in quiescent eyes. The Macular Edema Ranibizumab vs. Intravitreal Anti-inflammatory Therapy (MERIT) trial is currently recruiting and will attempt to compare the efficacy of ranibizumab and intravitreal steroids in treating uveitic macular edema.

Acute Retinal Necrosis

Acute retinal necrosis (ARN) is a retinal infection occurring in either immunocompetent or immunocompromised patients caused by viruses from the herpesviridae family, particularly herpes simplex virus and varicella zoster virus. The infection results in extensive retinal necrosis, typically beginning in the retinal periphery and progressing towards the posterior pole (Fig. 5.1d). Patient visual outcome is generally poor and early, aggressive treatment is warranted to prevent vision loss and retinal complications, such as retinal detachment [102]. Treatment includes the use of systemic antivirals, particularly intravenous (IV) aciclovir with systemic corticosterois and adjunctive intravitreal injections of antiviral drugs. Alternatively, intravenous aciclovir can be substituted with oral valaciclovir, a prodrug of aciclovir, which has good bioavailability and results in comparable intravitreal concentrations of the active drug. Pharmacokinetic modeling predicted equivalent vitreal concentrations between valaciclovir 1.5/2.0 g three times a day and IV aciclovir 700 mg every 8 h. Intravitreal drug levels exceeded the 50% inhibitory concentration for varicella zoster virus [103]. Using oral drugs allows patients to be managed in an outpatient setting, though strict monitoring is still required. While severe vision loss still occurs in up to 50% of eyes [104, 105], a study comparing both treatment approaches found no difference in final visual acuity [106]. Vision loss is most commonly related to the development of retinal detachment that occurs in up to 60% of eyes [98, 106, 107]. The concurrent use of intravitreal injections, either foscarnet 2.4 mg/0.1 mL or ganciclovir 2–5 mg/0.05–0.1 mL, may have a greater therapeutic effect and several case series suggest that rates of retinal detachment and vision loss may be reduced [108, 109]. The value of early prophylactic barrier laser remains unclear with conflicting results from retrospective case series. The American Academy of Ophthalmology recently concluded that initial oral or IV antiviral treatment with adjunctive intravitreal foscarnet is an effective therapeutic approach, and that the role of prophylactic laser retinopexy remains unclear [98].

Tuberculosis-Related Uveitis

Tuberculosis (TB) is a worldwide problem caused by Mycobacterium tuberculosis, and results in extensive morbidity and mortality [110]. The majority of people exposed to tuberculosis remain asymptomatic and the disease is described as latent TB. Diagnosis relies on positive testing, such as the Mantoux test or interferon gamma release assays, amongst other investigations [111]. Ocular involvement classically presents as choroidal granulomas, chronic panuveitis, and/or occlusive retinal vasculitis (Fig. 5.1a, b). The mechanism of ocular disease in latent TB remains unclear. Serpiginous choroiditis accounts for up to half the cases associated with TB [112, 113], particularly in endemic regions (Fig. 5.1c). While anti-TB treatment is clearly indicated in patients with signs of active pulmonary or extrapulmonary TB infection, treatment of those with latent TB is inconsistent, particularly if the ocular phenotype is atypical. While the ocular inflammation is managed with local and systemic immunosuppressive drugs, several studies have suggested that systemic anti-TB treatment may reduce uveitis recurrence rates [114–118]. If the ophthalmologist suspects the uveitis to be related to latent TB and decides to initiate immunosuppressive treatment, a full six month anti-TB course is advocated and therapy should be given in coordination with infectious disease specialists. In particular, patients should be treated for latent TB prior to commencing anti-TNFα immunosuppression given the increased risk of infection.

Toxoplasmosis

Toxoplasma gondii, an intracellular protozoan parasite, is a common pathogen infecting approximately 30% of the global population [119]. The life cycle of the parasite is linked to that of cats, and in regions where cats are common up to 90% of the population are seropositive (e.g. Brazil, Paris) [120]. Ocular infection is common and primary infection may be either congenital or following ingestion of contaminated food or drink. Most primary infections are asymptomatic and cases that are brought to clinical attention are typically reactivations along the border of an old chorio-retinal scar (Fig. 5.1e). Active infection can appear as a chorioretinitis with vitritis and occasionally AU. While diagnosis is based on clinical presentation and positive serum serology for Toxoplasma gondii, identifying the retinal lesions in the presence of severe inflammation and dense vitritis may be difficult and a high level of suspicion is needed [121]. Although toxoplasmosis in an immunocompetent patient is a self-limiting disease, treatment is considered when active inflammation is located near structures that are important for visual function (optic disc, macula and main retinal blood vessels) or when symptoms affect visual function. Treatment is based on a combination of anti-parasitic agents and anti-inflammatory drugs [122], and while the classic triad of pyrimethamine, sulfadiazine and folinic acid is commonly used, other treatment protocols are also suggested. Alternative treatment approaches include the use of oral or intravitreal clindamycin or oral trimethoprim and sulfamethoxazole [123, 124]. The latter is given twice a day and is considerably easier for patients to follow. Several studies examined the efficacy of these different treatment options though none demonstrated a clear advantage [123]. In a recent statement, the American Academy of Ophthalmology concluded there was no clinical evidence to support an advantage to using any particular treatment and choice of protocol should be based on clinical experience [125]. The use of prophylactic treatment following reactivation continues to be debated and several studies demonstrated that antibiotic treatment for up to a year could reduce the risk of reactivation by as much as 90% [126–129]. The risk of reactivation may continue to be reduced after stopping treatment for up to three years [130], though there is no clear recommendation for continuing prophylactic treatment [125, 127]. Long-term prophylactic treatment should be considered in patients with increased risk of reactivation, immunocompromised patients, or those with multiple previous recurrences [125, 131].

The last decade has seen an exponential increase in diagnostic and treatment tools available to the ophthalmologist, with the ensuing advancement in research, knowledge, and management. Precise imaging methods, utilizing wide-angle imaging and combined techniques, will help identify active inflammation even in the retinal periphery and will distinguish it from other retinal lesions, such as neovascularization. The increasing use of biologic agents and intravitreal drugs will also result in better control of intraocular inflammation and less systemic side effects related to systemic corticosteroids. Longer acting agents, with less ocular and systemic side effects will help manage the disease in these otherwise healthy patients and promote their continued independence and productivity.