Inflammatory Eye and Rheumatic Disease

Inflammatory eye diseases, such as uveitis, scleritis and retinal vasculitis, are among the most common extra-articular manifestations of rheumatic disease and systemic vasculitis. Uveitis is the most frequent ocular complication of rheumatic diseases and is a major cause of severe visual impairment. It affects people of all ages and varies significantly by geographic location and age of the patient. The incidence of uveitis is 25 cases per 100 000 persons with a prevalence rate of 58 per 100 000 persons.1 Uveitis is a generic term used to describe inflammation of the uvea, which is composed of the iris, ciliary body, and choroid. However, any area of the eye can be involved as the inflammatory response often spills over to involve contiguous or adjacent ocular tissues such as the cornea, anterior chamber, vitreous and retina. Uveitis can be subdivided into anterior, intermediate, posterior, and panuveitis based on the primary anatomical location of the inflammation in the eye. Anterior uveitis occurs when the anterior segment (iris and ciliary body) is the predominate site of inflammation. Intermediate uveitis is defined by inflammation of the vitreous cavity and pars plana, while posterior uveitis involves the retina and choroid. Panuveitis involves inflammation of the entire uveal tract.2 Uveitis is most commonly idiopathic or undifferentiated, although it can be associated with rheumatic, autoimmune, inflammatory or infectious systemic diseases, or be traumatic, or drug-induced (eg rifabutin, check point inhibitors and bisphosphonates). Patients with uveitis may present with concurrent systemic symptoms or infectious diseases that suggest an etiology affecting more than just the eye, or with isolated eye symptoms. Idiopathic uveitis accounts for 48% to 70% of cases.3 Uveitis is generally non-infectious (up to 85%) and anterior (80%).2 Systemic inflammatory disorders commonly associated with anterior uveitis include human leukocyte antigen (HLA)-B27-associated entities, juvenile idiopathic arthritis, inflammatory bowel disease, sarcoidosis, Behçet's disease or tubulo-interstitial nephritis (TINU). Multiple sclerosis, sarcoidosis, and TINU may be associated with intermediate uveitis, while Vogt-Koyanagi-Harada (VKH) syndrome, systemic lupus erythematosus, Behçet's disease, and sarcoidosis can cause posterior or panuveitis. Masquerade syndromes associated with lymphoma and leukemia can present with posterior or panuveitis. Infectious diseases account for approximately 15% of all cases of uveitis. These include viruses (herpes simplex, varicella zoster, cytomegalovirus), bacteria (streptococcal/ staphylococcal endophthalmitis, syphilis, tuberculosis, bartonella, Lyme borreliosis etc), or parasites/worms (toxoplasmosis, toxocara, nematodes) or other atypical infections.4 Different patterns of uveitis are encountered around the world due to the influence of many factors including genetic, ethnic, geographic and environmental factors. Such factors have a major impact on the causes and clinical phenotypes of uveitis and have been identified in a number of epidemiology studies. As examples, VKH and sarcoidosis are common in Japan, Behçet's disease in the Mediterranean and Asia, tuberculosis-associated uveitis in India5 and toxoplasmosis in South America.6-8 Over the past 15 years, the Standardization of Uveitis Nomenclature (SUN) Working Group, an international group of 79 uveitis experts from 18 countries and 62 clinical centers, has developed an anatomic classification for uveitis. This includes descriptors for uveitis, severity gradings for anterior chamber cells and flare, and definitions for uveitis activity.9 The SUN group is in the final stages of developing classification criteria for 25 clinical phenotypes of uveitis which will hopefully standardize reporting and classification of these entities.10 We conducted a retrospective chart review of adult patients with uveitis seen in 3 tertiary referral clinics, Sydney Eye Hospital, St Vincent's Clinic and Save Sight Institute, between 2009 and 2015. The total number of patients diagnosed with uveitis during the study period was 1165, consisting of 735 with anterior uveitis (63%), 234 with posterior uveitis (20%), 109 with panuveitis (9%), and 87 with intermediate uveitis (8%). Of these, 56% (650) were male, and the majority of 72% (838) were aged 17-60 years and 28% (327) were aged > 60 years. Patients with uveitis most commonly had a systemic association (679 patients; 58%), followed by no identifiable association (389 patients; 33%) and an ocular syndrome (97 patients; 8%). A specific diagnosis was established in 776/1165 (67%) of our patients. The percentage of patients with an unidentifiable or idiopathic uveitis in our series was lower than reported in other studies, most likely due to referral and selection bias (33% vs 58%). Our study was consistent with other studies in that after anterior uveitis, the next most common type of uveitis was posterior uveitis followed by panuveitis and least frequent, intermediate uveitis. While 33% of cases remain without an identifiable association (389/1165), HLA-B27-associated uveitis was seen in 264/1165 patients (22.7%) of whom 35% had anterior uveitis. The results of our retrospective review in an Australian population support previous studies of patients with uveitis seen in an outpatient setting.11 It highlights the fact that uveitis affects a significant proportion of the young working adult population and therefore has a substantial personal, social, economic and population cost. The study emphasized the key role of the ophthalmologist in the early recognition of ocular inflammation, and the diagnosis of associated systemic diseases, as their ophthalmic presentation was often the initial presentation of a systemic disorder. Accurate diagnosis of uveitis and associated systemic disease(s) can be challenging. A multidisciplinary approach improves the investigation and management of patients with either inflammatory or infectious uveitis. Close collaboration between ophthalmologists, immunologists and rheumatologists, who play a major role in diagnosing and providing treatment for patients with systemic immune disease, benefits long-term outcomes for patients with severe inflammatory eye disease. The 2018 European League Against Rheumatism guidelines12 recommended shared clinics between pediatric rheumatologists and ophthalmologists. As a result there has been a move toward multidisciplinary team clinics at adult and pediatric uveitis tertiary referral centers.13 Such clinics have been developed in most tertiary uveitis units in Australia, including the adult and pediatric uveitis clinics at Sydney Eye Hospital. In the Dublin Uveitis Evaluation Tool (DUET) study, Haroon et al found that by administering an algorithm to a validation cohort of 74 patients with idiopathic acute anterior uveitis, 40% of patients were found to have an undiagnosed spondyloarthritis (SpA).14 The SENTINEL study was initiated to increase collaboration between ophthalmologists and rheumatologists, with the aim of improving the management of patients with anterior uveitis and improving the timely diagnosis of underlying SpA. By describing and analyzing the prevalence of SpA in patients with anterior uveitis, investigators found that among the 798 patients with anterior uveitis, 50% of patients were diagnosed with axial and 18% with peripheral SpA.15 As so many of the uveitides have systemic associations, a multidisciplinary approach to care improves the coordination of pretreatment evaluation, treatment and decreases the required number of appointments, allowing management decisions in relation to both the ophthalmic and systemic disease to be made early in the course of the disease.16-20 The goals of therapy for non-infectious uveitis are to reduce ocular inflammation and attain disease remission, thereby mitigating or avoiding ocular complications (like cataract and glaucoma), permanent cumulative ocular damage, and long-term vision loss. It is also critically important to plan therapy to avoid long-term complications of corticosteroid and immunosuppressive therapy, including infections, metabolic and cardiovascular disorders and malignancy.20 Depending on the severity of the uveitis and the threat to vision, the general therapeutic progression is as follows. (a) Induction of remission and control of inflammation usually with steroids (either topical or oral). In some conditions, early administration of tumor necrosis factor (TNF) inhibitor is also recommended.21 (b) Maintenance therapy with low-dose steroid (<3 drops/d of topical steroids in cases of anterior uveitis and < 7.5 mg/d of prednisolone in non-anterior uveitis) and/or a steroid-sparing agent. (c) Relapse therapy (usually involving a burst of oral and/or locally administered therapy with peri-ocular or intravitreal corticosteroids such as triamcinolone or dexamethasone to maintain remission). (d) Cessation of therapy (gradual tapering of all immunosuppression therapy) after the disease has been in sustained long-term remission.22, 23 Topical self-administered corticosteroids are ineffective therapy in the treatment of patients with intermediate, posterior and panuveitis. Deep regional corticosteroid therapy with orbital floor injections or intravitreal triamcinolone and intravitreal bio-erodible dexamethasone implants are often used in patients with uniocular posterior segment uveitis which needs therapy. Patients with bilateral involvement usually need high doses of 1-1.5 mg/kg of prednisolone to induce remission, tapering to a maintenance dose of ≤7.5 mg/d to minimize longer-term complications. High-dose methylprednisolone can be administered intravenously at doses of 500 mg to 1000 mg/d, for 3 days, when a rapid response is essential, in rapidly progressing vision-threatening diseases like VKH and Behçet's disease. The use of high-dose systemic steroids is critical for achieving rapid control of inflammation, but immunosuppressive agents are usually required to attain remission in severe or chronic vision-threatening uveitis and to allow corticosteroid dose reduction to doses that minimize adverse effects and long-term complications. Pneumocystis prophylaxis should be considered for all patients receiving more than 30 mg prednisone for 4 weeks, particularly when combined with a conventional or biologic immunosuppressive agent.24 Complete corticosteroid-free remission is the desired outcome, but is often difficult to achieve, and a major role for immunosuppressant drugs is to reduce and minimize corticosteroid exposure. In patients taking oral systemic corticosteroids to control uveitis, a daily dose > 7.5 mg/d contributes to long-term adverse effects. Combination immunosuppressive therapy is used as a steroid-sparing approach when inflammation cannot be controlled with oral systemic steroids ≤ 7.5 mg/d within 3 months. Conventional immunosuppressive therapy used to supplement systemic corticosteroid and help reduce the steroid burden include antimetabolites (methotrexate, mycophenolate, azathioprine), T-cell inhibitors (cyclosporine, tacrolimus), and alkylating agents (cyclophosphamide, chlorambucil), although the latter are rarely used because of higher risk of serious complications and infertility, especially in young patients.25-27 We typically use methotrexate or mycophenolate as first-line agents.28 Local corticosteroid treatments such as intravitreal injection or intraocular implants have also been developed. These offer an alternative for those patients requiring a top-up to their systemic treatment to control inflammation in one eye. The MUST Trial Research Group directly compared slow-release intravitreal fluocinolone acetonide implants to systemic therapy for management of intermediate uveitis, posterior uveitis, and panuveitis in a 2-year randomized clinical trial. At the primary 2-year time point and at the subsequent observational cohort analysis at 4.5 years after randomization, the 2 strategies reviewed visual acuity and inflammation, and found significantly more local adverse outcomes, with implant therapy.29 It is important to note that 62% of the patients in the systemic arm of the MUST study needed additional local therapy to maintain control of their uveitis. The anti-TNF agents have provided an alternative or concurrent option to immunomodulators as steroid-sparing therapies to treat patients with non-infectious uveitis. Adalimumab, a human monoclonal antibody that blocks TNF-α signaling, has been approved by the Food and Drug Administration for the treatment of non-infectious intermediate, posterior, and panuveitis.30, 31 The efficacy and safety of adalimumab has been assessed in randomized, controlled clinical trials.32, 33 The multi-center placebo-controlled VISUAL I trial assessed efficacy and safety of adalimumab as a steroid-sparing therapy in adult patients with active non-infectious intermediate, posterior, and panuveitis (n = 223). Patients were randomized 1:1 to receive subcutaneous placebo or adalimumab. Adalimumab therapy reduced the risk of treatment failure by 50% (hazard ratio, 0.50; P < .001) and resulted in longer median time to treatment failure (TTF) (24 vs 13 weeks in patients receiving adalimumab vs placebo, respectively). Additionally, adalimumab significantly reduced the worsening of the anterior chamber cell grade, vitreous haze grade, and best corrected visual acuity compared with placebo (P ≤ .01). The VISUAL II clinical trial addressed efficacy and safety of adalimumab as a steroid-sparing therapy for preventing reactivation of uveitis in adults with inactive non-infectious intermediate, posterior, or panuveitis (n = 229) who received steroid doses higher than the recommended maintenance therapy. Based on the exploratory analyses, patients receiving adalimumab had significantly increased TTF compared with placebo (hazard ratio, 0.33; P = .002). Long-term efficacy and safety of adalimumab in adult patients with inactive non-infectious intermediate, posterior, or panuveitis (n = 424) were also addressed in a multi-center, open-label clinical trial extension (VISUAL III). Results were analyzed at 78 weeks of follow-up, and adalimumab was assessed as a steroid-sparing therapy. Overall, 80% of patients were quiescent at week 78 with no or low-dose uveitis-related corticosteroid therapy. Additionally, adalimumab therapy improved best corrected visual acuity in patients with active uveitis and maintained stable best corrected visual acuity in patients with inactive uveitis throughout follow-up. In a study of 90 pediatric patients with juvenile idiopathic arthritis (JIA)-associated uveitis receiving concomitant methotrexate, adalimumab was highly effective therapy in controlling the ocular inflammation (SYCAMORE trial).34 Adalimumab therapy resulted in a significantly longer TTF, reducing the risk of treatment failure by 75% in the adalimumab group compared with the placebo group (hazard ratio, 0.25; P < .0001) and a reduction in the daily dose of glucocorticoids (P = .04). Another prospective, randomized, multi-center study (ADJUVITE; n = 32) has shown adalimumab efficacy in patients with early-onset idiopathic or JIA-associated chronic anterior uveitis.35 The use of adalimumab as steroid-sparing systemic therapy was supported and received recommendation level A in a recently published guidance for the treatment of non-infectious uveitis provided by the Fundamentals of Care for Uveitis (FOCUS) initiative.25 Infliximab received recommendation level B/C. Importantly, the FOCUS initiative reported there was no evidence to support etanercept therapy in patients with non-infectious uveitis. Other biologics that are being used in patients with non-infectious uveitis include IL–6 receptor inhibitors such as tocilizumab. In the phase 1/2 STOP-Uveitis randomized clinical trial (n = 37), patients receiving 4 or 8 mg/kg intravenous tocilizumab for 6 months showed improvements in visual acuity and a reduction in vitreous haze; tocilizumab was well tolerated.36 Additionally, a multi-center, randomized controlled study using filgotinib, a small molecule selective Janus-activated kinase 1 inhibitor, to treat patients with non-infectious uveitis, is ongoing at present. Adalimumab is our first-line biologic agent. We institute it in combination with high-dose corticosteroids for aggressive Behçet's uveitis. We also use it in patients who remain active despite the combination of a conventional steroid-sparing agent and low-dose corticosteroid. Due to the risk of reactivation of latent infections, we screen and treat all patients for latent tuberculosis and hepatitis B and C before initiating TNF inhibitor therapy. Screening is particularly important in endemic regions in the Asia-Pacific region and clinicians must be vigilant that active tuberculosis may mimic non-infectious uveitis. We also screen all patients with intermediate uveitis with a magnetic resonance imaging of the brain due to its higher association with multiple sclerosis prior to commencing adalimumab. Uveitis is a group of more than 25 different diseases with complex etiologies and a range of clinical symptoms that may include eye pain, redness, floaters, and light sensitivity. There is a spectrum of clinical signs that allow ophthalmologists to identify the pattern of uveitis and often make a specific diagnosis or develop a potential differential diagnosis. Ophthalmologists play a critical role in the early diagnosis, therapy and long-term management of patients with severe or recurrent uveitis. Collaboration between ophthalmologists and rheumatologists/immunologists improves the management of patients with non-infectious uveitis and helps identify previously undiagnosed systemic disease associated with uveitis, as demonstrated in the SENTINEL and DUET studies. Although conventional steroid-sparing agents have been the mainstay therapy for patients with non-infectious uveitis, biologic agents such as adalimumab are utilized for aggressive forms of disease and in refractory patients. These agents appear safe and effective in reducing the daily steroid dose in both adult and pediatric patients while significantly increasing TTF and enabling most patients with non-anterior non-infectious uveitis to achieve or maintain remission of their uveitis. The complex nature of uveitis and its treatment highlights the collaborative role which ophthalmologists and rheumatologists/immunologists play in treating these challenging conditions.