{"id":71607,"date":"2024-10-10T15:04:38","date_gmt":"2024-10-10T14:04:38","guid":{"rendered":"https:\/\/www.touchophthalmology.com\/?p=71607"},"modified":"2024-10-10T15:04:38","modified_gmt":"2024-10-10T14:04:38","slug":"noninfectious-uveitis-a-review-of-ophthalmic-management-and-clinical-pearls","status":"publish","type":"post","link":"https:\/\/www.touchophthalmology.com\/ocular-immunology\/journal-articles\/noninfectious-uveitis-a-review-of-ophthalmic-management-and-clinical-pearls\/","title":{"rendered":"Noninfectious Uveitis: A Review of Ophthalmic Management and Clinical Pearls"},"content":{"rendered":"
The uvea is a vascular stratum that includes the iris, ciliary body and choroid. Uveitis is defined as inflammation of a part of the uvea or its entirety, but it is also used to describe inflammatory processes of any part of the eye, such as the vitreous or peripheral retina. The clinical taxonomy of uveitis is contingent upon the affected anatomy. Anterior uveitis, also known as iridocyclitis, is characterized by inflammation of the iris and ciliary body. Intermediate uveitis is inflammation of the vitreous or peripheral retina; it also includes pars planitis, posterior cyclitis and hyalitis. Posterior uveitis affects the retina and choroid. Panuveitis affects the entire uveal tract. Consisting of 25+ different disease characteristics, uveitides ranks fifth in the leading causes of blindness in the USA.1<\/sup><\/span>\u00a0Uveitis, along with its secondary complications and adverse effects from long-term treatment, is estimated to be the cause of 5\u201320% of cases of blindness in developed countries and 3\u201310% of such cases worldwide.2,3 <\/sup><\/span>Noninfectious uveitis (NIU), as implied by its name, arises from an underlying inflammatory or autoimmune mechanism rather than from an infectious one. Anterior uveitis is the most common manifestation of uveitis, accounting for an estimated four in five cases of all NIU.4<\/sup><\/span>\u00a0The estimated incidence of best-corrected visual acuity (BCVA) becoming 20\/400 or worse in patients affected by anterior uveitis is 2.41 per 1,000 person-years.5<\/sup><\/span>\u00a0In the USA, the estimated prevalence of NIU stands at approximately 121 per 100,000, accounting for approximately 91% of all cases of uveitis.4,6<\/sup><\/span>\u00a0The demographically most at-risk population in developing NIU is the working-age group, with ages 20\u201350 years. Within this age group, being non-Hispanic white, female sex and having concurrent autoimmune disease are also demographical risk factors.7<\/sup><\/span>\u00a0In the USA, the prevalence of the specific types of uveitis varies among different ethnic groups. Black individuals are more commonly affected by anterior uveitis, Hispanics by intermediate uveitis and white non-Hispanics by posterior uveitis.8<\/sup><\/span>\u00a0Lifestyle risk factors include smoking and vitamin D deficiency. Conditions predisposing to uveitis span a spectrum of autoimmune disorders (juvenile idiopathic arthritis [JIA], ankylosing spondylitis, psoriatic arthritis, Kawasaki disease, inflammatory bowel disease, connective tissue disorders and many more, as given in\u00a0Table 1<\/em><\/span>), trauma, cancers and adverse effects of medication. The HLA-B27-associated diseases are highly associated with acute unilateral NIU and are the leading known cause of acute anterior uveitis (AAU) in developed countries, with a 2.5:1 male-to-female predominance ratio.9<\/sup><\/span><\/p>\n Table 1: <\/span>Autoimmune aetiologies of noninfectious uveitis: Clinical presentation, uveitis type, laboratory findings and treatment<\/em><\/p>\n Condition<\/b><\/p>\n<\/td>\n Symptoms\/findings<\/b><\/p>\n<\/td>\n Typical uveitis type<\/b><\/p>\n<\/td>\n Associated laboratory\/imaging findings<\/b><\/p>\n<\/td>\n<\/tr>\n<\/thead>\n\n Beh\u00e7et\u2019s\u00a0<\/span>d<\/span>isease<\/span><\/p>\n<\/td>\n Oral ulcers, genital ulcers and skin lesions<\/p>\n<\/td>\n Anterior, posterior and panuveitis<\/p>\n<\/td>\n No specific serum findings<\/p>\n<\/td>\n<\/tr>\n HLA-B27<\/span>-a<\/span>ssociated\u00a0<\/span>u<\/span>veitis<\/span><\/p>\n<\/td>\n Acute anterior uveitis and asymmetric oligoarthritis<\/p>\n<\/td>\n Anterior uveitis<\/p>\n<\/td>\n Positive serum HLA-B27<\/p>\n<\/td>\n<\/tr>\n Sarcoidosis<\/span><\/p>\n<\/td>\n Granulomatous inflammation, cough and dyspnoea<\/p>\n<\/td>\n Anterior and posterior uveitis<\/p>\n<\/td>\n Elevated serum ACE, hypercalcaemia, positive serum HLA-DRB1, bilateral hilar adenopathy and reticular opacities on chest X-ray<\/p>\n<\/td>\n<\/tr>\n Juvenile\u00a0<\/span>i<\/span>diopathic\u00a0<\/span>a<\/span>rthritis<\/span><\/b><\/p>\n<\/td>\n Joint pain\/swelling, morning stiffness and antalgic gait<\/p>\n<\/td>\n Anterior uveitis<\/p>\n<\/td>\n Can be seronegative or seropositive for ANA, RF and CCP\u2014highest risk for uveitis in those who are seropositive<\/p>\n<\/td>\n<\/tr>\n Vasculitides<\/span><\/p>\n<\/td>\n Rash, joint pain and fever<\/p>\n<\/td>\n Intermediate and posterior uveitis<\/p>\n<\/td>\n Marked elevation in ESR\/CRP, stenosis, occlusion or aneurysmal dilation of affected blood vessels on CT<\/p>\n<\/td>\n<\/tr>\n Multiple\u00a0<\/span>s<\/span>clerosis<\/span><\/p>\n<\/td>\n Vision loss, weakness and numbness<\/p>\n<\/td>\n Intermediate uveitis<\/p>\n<\/td>\n Oligoclonal bands, pleocytosis on CSF and hyperintense periventricular lesions on MRI<\/p>\n<\/td>\n<\/tr>\n Vogt<\/span>\u2013<\/span><\/span>Koyanagi<\/span>\u2013<\/span><\/span>Harada<\/span><\/b>\u00a0disease<\/p>\n<\/td>\n Headache, tinnitus, alopecia and vitiligo<\/p>\n<\/td>\n Panuveitis<\/p>\n<\/td>\n Pleocytosis on CSF, delayed choroidal perfusion, peripapillary hypercyanescence and leakage on ICGA<\/p>\n<\/td>\n<\/tr>\n Kawasaki\u00a0<\/span>d<\/span>isease<\/span><\/p>\n<\/td>\n Fever, rash, conjunctivitis and coronary aneurysms<\/p>\n<\/td>\n Anterior uveitis<\/p>\n<\/td>\n Elevated ESR\/CRP, anaemia, leucocytosis, thrombocytosis, albuminaemia, elevated ALT and pyuria<\/p>\n<\/td>\n<\/tr>\n Blau\u00a0<\/span>s<\/span>yndrome<\/span><\/p>\n<\/td>\n Arthritis, rash and uveitis<\/p>\n<\/td>\n Panuveitis<\/p>\n<\/td>\n No specific serum findings; noncaseating granulomas on skin biopsy and\u00a0NOD2<\/em>\u00a0gene mutation on next-generation sequencing<\/p>\n<\/td>\n<\/tr>\n Tubulointerstitial nephritis and uveitis syndrome<\/p>\n<\/td>\n Renal symptoms, fever and rash<\/p>\n<\/td>\n Anterior uveitis<\/p>\n<\/td>\n Elevated serum BUN, creatinine and B2M; proteinuria and pyuria on UA and cortical hyperechogenicity on renal US<\/p>\n<\/td>\n<\/tr>\n Relapsing\u00a0<\/span>p<\/span>olychondritis<\/span><\/p>\n<\/td>\n Auricular\/nasal\/tracheal chondritis, arthritis and respiratory symptoms<\/p>\n<\/td>\n Anterior uveitis<\/p>\n<\/td>\n No specific serum findings; airway trapping, narrowing and collapse on CT<\/p>\n<\/td>\n<\/tr>\n Sj\u00f6gren\u2019s\u00a0<\/span>s<\/span>yndrome<\/span><\/p>\n<\/td>\n Dry eyes, dry mouth and parotitis<\/p>\n<\/td>\n Anterior and posterior uveitis<\/p>\n<\/td>\n Positive serum anti-SSA and anti-SSB<\/p>\n<\/td>\n<\/tr>\n Crohn\u2019s\u00a0<\/span>d<\/span><\/b>isease<\/span><\/b><\/p>\n<\/td>\n Abdominal pain, diarrhoea and weight loss<\/p>\n<\/td>\n Anterior uveitis<\/p>\n<\/td>\n Elevated serum CRP, ESR and ASCA; normal serum ANCA; elevated calprotectin in stool analysis and colonic abscesses and fistulas on MRE\/CT<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n ACE<\/span>\u00a0=\u00a0angiotensin\u2010converting enzyme<\/span>;<\/span>ALT<\/span>\u00a0=\u00a0alanine transaminase<\/span>;<\/span>ANA<\/span>\u00a0=\u00a0antinuclear antibody<\/span>;<\/span>ANCA<\/span>\u00a0=\u00a0antineutrophilic cytoplasmic antibody<\/span>;<\/span>ASCA<\/span>\u00a0=\u00a0anti-Saccharomyces cerevisiae\u00a0antibodies<\/span>;<\/span>B2M<\/span>\u00a0=\u00a0beta-2 microglobulin<\/span>;<\/span>BUN<\/span>\u00a0=\u00a0blood urea nitrogen<\/span>;<\/span>CCP<\/span>\u00a0=\u00a0cyclic citrullinated peptide<\/span>;<\/span>CRP<\/span>\u00a0=\u00a0C-reactive protein<\/span>;<\/span>CSF<\/span>\u00a0=\u00a0cerebrospinal fluid<\/span>;<\/span>CT<\/span>\u00a0=\u00a0computed tomography<\/span>;<\/span>ESR<\/span>\u00a0=\u00a0erythrocyte sedimentation rate<\/span>;<\/span>HLA<\/span>\u00a0=\u00a0human leucocyte antigen<\/span>;<\/span>ICGA<\/span>\u00a0=\u00a0indocyanine green angiography<\/span>;<\/span>MRE<\/span>\u00a0=\u00a0magnetic resonance enterography<\/span>;<\/span>MRI<\/span>\u00a0=\u00a0magnetic resonance imaging<\/span>;<\/span>NOD<\/span>\u00a0=\u00a0nucleotide-binding oligomerization domain<\/span>;<\/span>RF<\/span>\u00a0=\u00a0rheumatoid factor<\/span>;<\/span>SSA<\/span>\u00a0=\u00a0Sj\u00f6gren’s syndrome-related antigen A<\/span>;<\/span>SSB<\/span>\u00a0=\u00a0Sj\u00f6gren’s syndrome-related antigen B<\/span>;<\/span>UA<\/span>\u00a0=\u00a0uric acid<\/span>;<\/span>US<\/span>\u00a0=\u00a0ultrasound<\/span>.<\/span><\/em><\/p>\n<\/div>\n<\/div>\n<\/div>\n This article aims to provide an overview of NIU management, including current and investigative therapies, with a particular focus on ophthalmic routes, as systemic immunosuppression using antimetabolites and biologics falls beyond the scope of this review.<\/p>\n Approximately one in three uveitis cases are idiopathic, as observed in the VISUAL I (Efficacy and Safety of Adalimumab in Patients With Active Uveitis) and VISUAL II (Efficacy and Safety of Adalimumab in Subjects With Inactive Uveitis) studies (ClinicalTrials.gov\u00a0I<\/span>dentifiers:\u00a0<\/span>NCT01138657 and NCT01124838).10\u201312<\/sup><\/span>\u00a0The majority of cases of chronic anterior uveitis are also idiopathic, estimated at 39\u201372% annually.13<\/sup><\/span>\u00a0Although the exact cause of NIU remains multifactorial, aberrant immune insults against ocular tissue and cytokine imbalances play key roles. Immunologically, major histocompatibility complex (MHC) activity, T-cell activation, cytokine release and vascular changes contribute to ocular inflammation. Biochemically, prostaglandins, matrix metalloproteinases and nitric oxide are also implicated. More recently, MHC has been further elucidated through genome-wide association studies to identify genetic risk factors that are associated with ocular inflammation. Genetic studies have also highlighted the prominence of the interleukin (IL)-23R region, which is present in noninfectious uveitides associated with Beh\u00e7et\u2019s disease, ocular sarcoidosis, Vogt\u2013Koyanagi\u2013Harada disease and AAU.14<\/sup><\/span>\u00a0NIU, often arising as a complication of systemic conditions and ocular trauma, also highlights the impact of the uvea\u2019s extensive vascularization on disease progression.15,16<\/sup><\/span>\u00a0Vascular changes in posterior uveitis are especially prominent in the retina and choroid, presenting with abnormalities such as nonperfusion, occlusion, neovascularization, aneurysms and telangiectasia.16<\/sup><\/span><\/p>\n The clinical spectrum of NIU is characterized by a dichotomy in onset: acute, marked by a swift progression; and insidious, characterized by a gradual inception. The cardinal symptoms encompass a constellation of manifestations: ocular hyperaemia, pain, photophobia, blurred vision and vitreous syneresis, colloquially termed \u2018floaters\u2019. These symptoms may precipitate abruptly and escalate without expeditious therapeutic intervention, occasionally resulting in significant loss of visual acuity. Specifically in children, insidious uveitis may remain asymptomatic and elude detection, resulting in irreversible sequelae.17\u201319<\/sup><\/span><\/p>\n The evaluation of NIU is multifaceted, encompassing a detailed history, comprehensive evaluation of clinical findings, imaging modalities, initial laboratory investigations and additional tests depending on findings.<\/p>\n In the evaluation of uveitis, a comprehensive patient history should encompass not only ocular symptoms but also systemic manifestations that may suggest an underlying aetiology. The presence of arthralgia could indicate a rheumatological condition, while febrile episodes may suggest an ongoing infectious process. It is helpful to probe for potential exposure to sexually transmitted diseases or\u00a0Mycobacterium tuberculosis<\/em>. The absence of these systemic symptoms is equally informative as it aids in excluding certain differential diagnoses.<\/p>\n Physical examination involves a detailed slit-lamp examination, which provides a thorough assessment of the anterior segment, revealing potential findings such as keratic precipitates, anterior chamber (AC) cells and flare, iris nodules, posterior synechiae and lens changes. The Standardization of Uveitis Nomenclature (SUN) grading system, which grades inflammation from 0 to 4+ based on cell count observed on slit-lamp examination, is used on initial assessments to help tailor treatment.20<\/sup><\/span>\u00a0Dilated fundus examination is imperative for assessing posterior segment involvement, such as vitreous cells, optic disc oedema and characteristic inflammatory lesions in the retina or choroid. Advanced imaging modalities play a pivotal role in the diagnosis and management of NIU. Optical coherence tomography (OCT) and fundus fluorescein angiography offer high-resolution visualization of the retinal layers, vasculature and inflammatory changes. For anterior uveitis, anterior-segment OCT is emerging as an assessment tool adjunct to slit-lamp findings to better quantify and characterize the presence of inflammation. For uveitis involving posterior structures, OCT angiography is finding utility by delineating vasculature layers and vascular flow as well as vessel density changes that occur during the active and inactive phases of inflammation involving the choriocapillaris.21<\/sup><\/span><\/p>\n Laboratory investigations may not be needed for first-time cases of unilateral anterior uveitis or iritis; however, for bilateral cases, recurrent flares despite initial treatment or uveitis involving nonanterior structures, laboratory tests become essential for identifying underlying systemic conditions.22<\/sup><\/span>\u00a0The initial routine workup encompasses a complete blood count, erythrocyte sedimentation rate, C-reactive protein analysis, treponemal and nontreponemal assays for syphilis and a chest X-ray. QuantiFERON Gold testing should be considered in patients from an endemic area or at high risk of having tuberculosis. These initial tests will assist in ruling out infectious or cancerous aetiologies.<\/p>\n A second round of tests may overlap with the initial tests depending on practice. These should be pursued and tailored to clinical history, presentation, initial test results and differential diagnoses. These tests include syphilis\u00a0immunoglobulin G<\/span>, fluorescent treponemal antibody absorption, venereal disease research laboratory test, serum angiotensin\u2010converting enzyme and lysozyme, Lyme serology and interferon-\u03b3 release assay. For anterior uveitis, flow cytometry testing for HLA-B27 can be helpful, especially with symptoms suggestive of spondyloarthropathies.23<\/sup><\/span>\u00a0HLA-B27 testing should be omitted for intermediate and\u00a0<\/span>posterior uveitis. For posterior or panuveitis, Beh\u00e7et\u2019s disease and sarcoidosis should be suspected. One should also consider investigating parasitic infections (toxoplasmosis or toxocariasis) and viral aetiologies (herpes simplex virus, varicella zoster virus and cytomegalovirus). Infectious aetiology should also be considered for patients who are seronegative with anterior uveitis refractory to steroid treatment. Chest computed tomography should be ordered if previous tests and examinations point to sarcoidosis. Other laboratory parameters, such as rheumatoid factor, antinuclear antibody (ANA) and antineutrophilic cytoplasmic antibody (ANCA), provide little value, as the associated conditions extremely rarely manifest with uveitis. However, the presence of retinal vasculitis without significant chorioretinitis should warrant screening for ANA, ANCA and antiphospholipid antibodies.24<\/sup><\/span><\/p>\n Should the previously mentioned evaluations fail to yield a conclusive diagnosis, the pursuit of advanced examinations tailored to the presence of rarer disease entities may be necessary. Brain magnetic resonance imaging should be considered in cases of intermediate, posterior and panuveitis concurrent with neurological deficits.25<\/sup><\/span>\u00a0Such aetiologies that warrant brain imaging in these patients include multiple sclerosis, primary central nervous system lymphoma (PCNSL), neurosarcoidosis and neuroinfection.26,27<\/sup><\/span>\u00a0Systemic sarcoidosis can be uncovered using whole-body gallium scan or positron emission tomography, along with histopathological examinations of bronchial lavage fluid or biopsies from lesions, granulomas or lymph nodes.24<\/sup><\/span>\u00a0Diagnostic vitrectomy is recommended in cases where intraocular lymphoma, a type of PCNSL, is suspected. The selection of these advanced tests should be contingent upon the anatomical classification of uveitis, clinical or preclinical indicators, pertinent medical histories of patients and the exclusion of more common aetiologies.<\/p>\n The goal of treatment is to resolve local inflammation and reduce pain, photophobia and inflammation, which are mainly achieved with corticosteroids (CS). The route of delivery is dependent on the initial location of inflammation and can include topical, oral, periocular, intraocular or intravenous infusion. Oral prednisone is usually initiated at 0.5\u20131 mg\/kg\/day, with a subsequent tailored tapering regimen.28<\/sup><\/span>\u00a0Timely intervention with CS is ideal to prevent potential irreversible damage. For uveitis that continues to be poorly controlled, immunosuppressants, such as\u00a0tumour necrosis factor<\/span>-\u03b1 inhibitors, antimetabolites, calcineurin inhibitors and alkylating agents, should be considered.29,30<\/sup><\/span>\u00a0Topical CS therapy is especially effective for anterior involvement, but it has limited therapeutic effects if the affected tissues include intermediate and\/or posterior structures. In these cases, systemic CS are helpful as an adjunct therapy, but adequate stepwise treatment includes immunosuppressants and\/or biological agents, intravitreal implants, periocular steroids and even vitrectomy in extensive disease.<\/p>\n Topical CS are the first-line intervention for acute unilateral anterior uveitis, with prednisolone acetate 1% or dexamethasone 0.1% being commonly used as go-to choices for acute unilateral NIU.31<\/sup><\/span>\u00a0Strategies for steroid regimens vary by provider, but in general a typical course involves hourly or half-hourly drops while awake for 1 week, followed by a slow taper over the next few weeks.32<\/sup><\/span>\u00a0Bilateral uveitis can indicate a more chronic or systemic disease involvement and should be treated with oral prednisone as first-line therapy, dosed at least 0.2 mg\/kg\/day. If necessary, stepwise therapy with cyclosporine and antimetabolites and then biologics should be pursued for bilateral cases.<\/p>\n While topical CS demonstrate efficacy in treating mild cases of macular oedema (ME) associated with anterior uveitis, there is no evidence to suggest that a drop regimen is appropriate for more severe cases of uveitic ME due to penetrative limitations of ophthalmic drops. The short-acting nature of topical steroids is commonly associated with the recurrence of oedema if discontinued before at least a few weeks of treatment.33<\/sup><\/span>\u00a0Unilateral NIU with persistent ME should be treated with oral prednisone. Parabulbar or subtenon injection of triamcinolone can be considered for patients who are at low risk of glaucoma, are aphakic or have an iris-fixated lens.34<\/sup><\/span><\/p>\n The dexamethasone 0.7 mg intravitreal biodegradable implant (OZURDEX\u00ae,\u00a0Allergan, Irvine, CA, USA<\/span>), designed to last up to 3\u20136 months, is widely used to treat uveitic ME, diabetic ME refractory to anti-vascular endothelial growth factor<\/span>\u00a0and ME associated with retinal vein occlusion. It is particularly useful for patients who are elderly, are pseudophakic, are vitrectomized or have no history of ocular hypertension (OHT).34<\/sup><\/span>\u00a0The HURON trial (cHronic Uveitis evaluation of the intRavitreal dexamethasONe implant;<\/span>\u00a0ClinicalTrial.gov Identifier: NCT00333814) showed OZURDEX to be effective in treating posterior uveitis.35<\/sup><\/span>\u00a0At 26 weeks, 23% of eyes treated with 0.7 mg required\u00a0intraocular pressure<\/span>\u00a0(IOP)-lowering medications. Cataract development was 15%, but this was not statistically significantly greater than in the sham group. The study population at the time included only patients who were either previously or currently on another CS and\/or immunosuppressive therapy. Studies on OZURDEX used as monotherapy in a study population of uveitic eyes without prior or current treatment remain sparse. One study, using a small retrospective cohort without previous systemic immunomodulation therapy, showed the efficacy of the implant in improving BCVA, decreasing central subfield thickness (CST) and maintaining IOP in eyes with ME associated with nonanterior NIU.36<\/sup><\/span>\u00a0Long-term studies on OZURDEX for uveitic ME show favourable outcomes in BCVA, central retinal thickness (CRT), inflammation control and decreased need for systemic CS therapy.37\u201339<\/sup><\/span><\/p>\n Sustained-release fluocinolone acetonide implants, such as RETISERT\u00ae (Bausch & Lomb, Rochester, NY, USA), ILUVIEN\u00ae (Alimera Sciences, Alpharetta, GA, USA) and YUTIQ\u00ae (EyePoint Pharmaceuticals, Watertown, MA, USA), are available and hold advantages over OZURDEX due to their much longer-acting duration and propensity to achieve nearly a zero-order reaction. These medications are encased and delivered from a nonbiodegradable medium.<\/p>\n RETISERT<\/span>\u00a00.59 mg is designed to provide sustained release for up to 30 months. It is an intravitreal implant requiring conjunctival peritomy and full-thickness scleral incision for placement. The MUST trial (Multicenter Uveitis Steroid Treatment; ClinicalTrials.gov Identifier: NCT00132691) was a randomized study to compare the efficacy of the 0.59 mg intravitreal fluocinolone acetonide implant with that of systemic CS therapy. Results at 2 years favoured the steroid implant regarding mean visual acuity, inflammation control and macular thickness improvement.40<\/sup><\/span>\u00a0Observations at 7 years were less favourable compared with systemic CS therapy, but this was heavily influenced by attrition bias, lack of implant replacement, undertreatment and not incorporating crossover treatment in analysis.41<\/sup><\/span>\u00a0OHT was a major adverse effect, with half of the patients needing IOP-lowering medications after 34 weeks with treatment and approximately one in three patients requiring filtering surgery after 2 years.42<\/sup><\/span>\u00a0In a follow-up study of the MUST trial, the risk of the\u00a0RETISERT<\/span>\u00a0pellet dislodging or separating from its original structure, causing visual disturbances, becomes more significant around the 5\u20136-year mark postimplantation.43<\/sup><\/span>\u00a0However, this issue appears preventable with timely replacement of the implant.44,45<\/sup><\/span><\/p>\n ILUVIEN was approved by the US\u00a0Food and Drug Administration<\/span>\u00a0(FDA) for the treatment of diabetic ME and by the UK National Institute for Health and Clinical Excellence for managing NIU of the posterior segment. The 0.19 mg implant consists of a 3.5 mm-long nondegradable case containing the active compound designed to last 36 months. It is administered via intravitreal injection using a proprietor injector, with repeated injections expected to leave behind the small encasement. ILUVIEN offers a smaller dosage and compact size and does not necessitate surgical administration, making it highly favoured for the prevention of posterior uveitic flares. At the time in which this review was written, ILUVIEN has not been approved for treating uveitis in the USA. Multiple studies have shown its effectiveness in achieving both visual and anatomical endpoints in eyes with NIU.46\u201352<\/sup><\/span>\u00a0One study suggests that the factors associated with effectiveness include female sex and a thicker retinal nerve fibre layer.52<\/sup><\/span>\u00a0One randomized trial (ClinicalTrials.gov\u00a0I<\/span>dentifier: NCT01694186) showed that at 3 years, 42.5% of eyes treated with 0.19 mg of fluocinolone acetonide required IOP-lowering medications and 5.7% required IOP-lowering surgery, displaying a more favourable side-effect profile than what was seen for\u00a0RETISERT<\/span>.53<\/sup><\/span>\u00a0A retrospective case review of 13 eyes with posterior NIU through 3 years shows significant, sustained improvement in BCVA, CRT decrease and vitritis resolution with stable IOP.54<\/sup><\/span><\/p>\n YUTIQ<\/span> is an injectable therapy, similar to ILUVIEN, containing 0.18 mg of fluocinolone acetonide encased in a 3.5 mm form factor intended to provide a 36-month duration of action. This was also designed to supersede RETISERT<\/span>\u00a0by delivering a smaller dosage with a reduced burden of adverse effects. FDA approval was secured based on initial findings from two randomized, double-blinded, multicentre clinical trials comparing the efficacy and safety of 0.2 mg fluocinolone acetonide (designed to be released 0.2 \u03bcg\/day) with sham control (ClinicalTrials.gov Identifiers: NCT01694186 and NCT02746991).53,55<\/sup><\/span>\u00a0Three-year outcomes favoured the implant over sham injection, showing reductions in uveitis recurrence, adjunctive therapy usage and central foveal thickness and improvements in BCVA. Similar outcomes were observed when comparing treated eyes with their untreated fellow eyes.56<\/sup><\/span><\/p>\n More recently, triamcinolone acetonide (TA) (XIPERE\u00ae, Bausch + Lomb, Laval, Canada) can be administered via suprachoroidal injection. XIPERE is the first FDA-approved therapy to be administered through the suprachoroidal space (SCS) and is indicated for ME associated with noninfectious uveitis. Delivery through the SCS allows for substantial concentration, targeted tissue exposure and higher bioavailability in posterior structures than other injection routes.57<\/sup><\/span>\u00a0The molecular size of the drug prevents it from being cleared through the sclera and choriocapillaris, resulting in limited exposure to the anterior segment and other body systems. The PEACHTREE trial (Suprachoroidal Injection of CLS-TA in Subjects With Macular Edema Associated With Non-infectious Uveitis; ClinicalTrials.gov\u00a0Id<\/span><\/span>entifier: NCT02595398) showed greater efficacy compared with sham in improving BCVA, decreasing CST and decreasing the need for rescue therapy with a CS or a nonsteroidal anti-inflammatory drug (NSAID).58<\/sup><\/span>\u00a0IOP increase and cataract formation through 24 weeks were comparable between the two groups. No studies have compared the efficacy of suprachoroidal TA and intravitreal TA in the treatment of uveitic ME; however, studies comparing the two routes for diabetic macular oedema show comparable results, with a preference for suprachoroidal administration due to decreasing posterior thickness and having longer-lasting therapeutic effects.59,60<\/sup><\/span><\/p>\n Despite therapeutic efficacy, steroid therapy is not without challenges, notably for its proclivity for elevated IOP and the development of cataracts. CS are thought to decrease uveoscleral outflow by inhibiting the degradation of extracellular matrix material in the trabecular meshwork (TM) through inhibition of proteases and phagocytosis, thus leading to the aggregation of material and increased outflow resistance.61<\/sup><\/span>\u00a0The response may involve the alteration of mucopolysaccharide metabolism, causing their accumulation in the TM. Glucocorticoid receptors are concentrated in ocular tissue, and steroids induce structural and functional changes in TM cells, affecting nuclear size, DNA content and extracellular matrix deposition.62<\/sup><\/span>\u00a0Approximately one in three of the general population are \u2018steroid responders\u2019, in which IOP significantly increases (5\u201315+ mmHg) secondary to CS treatment.63<\/sup><\/span>\u00a0Eyes with prior history of glaucoma are more likely to be steroid responders, develop secondary OHT earlier and require additional pressure-lowering drops.64,65<\/sup><\/span>\u00a0Studies have shown a positive correlation between CS potency and both severity and speed of onset of OHT.66,67<\/sup><\/span>\u00a0Risk factors for developing OHT in untreated eyes with NIU include previous history of OHT, systemic hypertension and AC structural irregularities, while bilateral presentation and prior hypotony are associated with diminished risk of OHT. Spontaneous normalization of IOP can be achieved post-treatment cessation.68,69<\/sup><\/span>\u00a0For patients with high susceptibility of being steroid responders, potent steroid alternatives with less risk of elevated IOP, such as fluorometholone 0.1%, although typically more expensive than prednisolone or dexamethasone formulations, can be a favourable choice.66,70<\/sup><\/span><\/p>\n It is well acknowledged that uveitic eyes have an appreciable risk of developing cataracts due to CS treatment and\/or chronic inflammation. Glucocorticoids bind to proteins in the lens, causing structural instability and damage in the setting of oxidation.71<\/sup><\/span>\u00a0It is estimated that the incidence in which a cataract develops in eyes with anterior uveitis is 5.4%.72<\/sup><\/span>\u00a0For intermediate uveitis, the incidence was calculated to be 7.6%.73<\/sup><\/span>\u00a0Topical CS were associated with an increased risk of developing cataracts only in mild cases with cell grades of \u22640.5 but not in eyes with cell grades of \u22651+.72<\/sup><\/span>\u00a0Steroid therapy was highly associated with cataract development if the regimen was 2+ drops per day, 4+ periocular injections or >7.5 mg oral tablet per day, whereas regimens below those dosages posed greater risk but not to statistical significance.\n\n
\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n Pathogenesis<\/h1>\n
Presentation and evaluation<\/span><\/h1>\n
Current medical therapies<\/span><\/h1>\n
Topical corticosteroids<\/span><\/h2>\n
Intravitreal corticosteroid implants<\/span><\/h2>\n
Suprachoroidal delivery of\u00a0<\/span>triamcinolone acetonide<\/span><\/h2>\n
Addressing ophthalmic adverse effects of steroids<\/span><\/h2>\n