Immunopathological Analysis of a Mouse Model of Arthritis-Associated Scleritis and Implications for Molecular Targeted Therapy for Severe Scleritis

Scleritis involves inflammation of the sclera, which constitutes 75% of the wall of the eye. This pathology is often seen as an ocular lesion associated with systemic inflammatory diseases. Severe types of scleritis such as posterior scleritis require urgent immunosuppressive treatments, including molecularly targeted therapies to avoid permanent visual impairment. Which molecules should be selected as targets has remained unclear. To clarify the pathogenesis of scleritis and propose appropriate target molecules for therapy, we have established novel animal model of scleritis by modifying the Collagen-II Induced Arthritis (CIA) model. Immunization twice with collagen II emulsified with complete Freund’s adjuvant (CFA) caused arthritis and scleritis. The clinical appearance resembled human diffuse scleritis. Histopathological analysis suggested that macrophages, plasma cells, deposition of immune complexes, and growth of blood and lymphatic vessels are involved in the pathogenesis of CIA-associated scleritis. In addition, we analysed the background diseases of posterior scleritis and responses to molecularly targeted therapies as a case series study. We inferred from both the animal model and case series study that targets should not be T cells, but factors inhibiting macrophage activity such as tumor necrosis factor (TNF) and interleukin (IL)-6, and molecules suppressing antibody-producing cells such as CD20 on B cells should be targeted by molecularly targeted therapies.

Presumed tuberculosis-related scleritis

AimsTo evaluate the clinical characteristics and therapeutic outcome of patients with recurrent scleritis of unknown demonstrable aetiology and positive QuantiFERON-TB Gold In-Tube test (QFT).MethodsRetrospective chart review of the demographic, clinical, laboratory and therapeutic outcome data of 15 patients. Clinical characteristics as well as remission rate after standard antituberculous therapy (ATT) were assessed.ResultsThere were 9 men and 6 women with a mean age of 48.9 years (range, 32–73). Scleritis was diffuse in 10 patients (66.6%) and nodular in 5 patients (33.3%), 1 of them with concomitant posterior scleritis. It was bilateral in 7 patients (46.6%) and recurrent in all of them. Scleritis appeared after prior uveitis (10 patients, 66.6%) and/or with concomitant uveitis (5 patients, 33.3%) or peripheral keratitis (5 patients, 33.3%). Previous ocular surgery was found in 7 patients (46.6%). Previous extraocular tuberculosis (TB) infection or previous TB contact was detected in 11 patients (73.3%). No radiologic findings of active extraocular TB were detected. ATT was used in 15 patients, sometimes with the addition of systemic corticosteroids (5 patients) and methotrexate (1 patient); 14 patients achieved complete remission (93.3%).ConclusionPresumed TB-related scleritis may appear in recurrent scleritis of unknown origin and positive QFT. It may occur after prior uveitis and/or concomitantly with uveitis or peripheral keratitis, and it may be triggered by previous ocular surgery. No patients had evidence of concurrent active extraocular infection, although many had previous TB infection or TB contact. ATT was effective, sometimes with the addition of systemic corticosteroids and methotrexate.

P36 A case of refractory IBD-related scleritis

Case report - Introduction Scleritis is severe vision-threatening scleral inflammation, commonly presenting with a red, painful eye and can be classified using the Watson system. Posterior scleritis may present with associated anterior uveitis in many cases. Steroid therapy is often successful initially; however, further immunomodulation is usually required to control subsequent episodes which can be challenging. We present an 18-year-old, Caucasian girl with a left eye, sight-threatening, steroid-dependent posterior uveitis who required escalation of treatment to tocilizumab before inflammation could be suppressed. Case report - Case description Our patient was diagnosed elsewhere with ulcerative colitis at the age of 12 and subsequently developed recurrent episodes of uveitis and scleritis which could be controlled with topical steroids. At the age of 16 she presented with an inflammatory arthritis and was treated with intravenous methylprednisolone before commencing sulfasalazine therapy. Due to persistent systemic and ophthalmic inflammation she was changed to adalimumab; however, this was also unsuccessful and methotrexate was added. By the age of 18 she had been steroid-dependent for 2 years and could not reduce daily prednisolone below 15mg without a deterioration in her left eye posterior scleritis with visual acuity compromise including episodes of complete visual loss causing high levels of anxiety. Due to the pain and deterioration in vision she struggled with her studies and school attendance, and withdrew from her passion for competitive sailing. With ongoing sight-threatening inflammatory changes she was referred for further tertiary assessment in 2019. During the following 4 months treatment was escalated rapidly. Methotrexate dose was increased, and adalimumab frequency reduced to weekly. There was a limited response, with further episodes of sight deterioration as a result of flares in inflammation. Response to tocilizumab treatment was seen after only two doses with good control of scleritis by 3 months of treatment when steroids were successfully weaned and stopped. Over 18 months of tocilizumab therapy the patient has only required one course of topical steroids for mild ocular inflammation which resolved without any other treatment required. She has successfully completed her degree, can complete daily gym training sessions and participate in regular sailing competitions. Case report - Discussion Posterior scleritis is the most common scleritis in children and can be associated with anterior uveitis, concurrent anterior scleritis, disc swelling or retinal striae. Posterior scleritis has a higher rate of complications therefore is treated aggressively. Refractory cases such as this require biologic therapy and rituximab is often used. Despite the preference of two adult eye units for treatment with rituximab the rationale for tocilizumab included; recent high quality studies showing successful treatment of inflammatory bowel disease, its known benefit for anterior uveitis and case studies in adults with posterior scleritis. Tocilizumab is a recombinant monoclonal antibody that causes a blockade of interleukin-6 receptors. It is currently only approved by the Food and Drug Administration (FDA) for use in children with polyarticular or systemic onset Juvenile Idiopathic Arthritis (JIA). Our patient had a very positive experience with this drug, no side effects and rapid clinical improvement seen. As a result her quality of life and mental health improved quickly. Case report - Key learning points This is a case of refractory, sight-threatening, steroid-dependent posterior scleritis on a background of inflammatory bowel disease and arthritis. As a result of this case our team reviewed current literature from other paediatric populations and adults with scleritis, informing the clinical decision to proceed with tocilizumab after control was unsuccessful with previous agents. The remarkable response demonstrated for our patient highlights the value tocilizumab can offer to the treatment options for similar refractory cases. This adds to the growing positive data published surrounding tocilizumab in children but further studies in paediatric populations are required to evaluate this in greater detail.

O28 A rare sight-threatening complication of a rare disease

Case report - Introduction Relapsing polychondritis (RP) is a rare autoimmune disorder characterised by inflammation of cartilaginous structures throughout the body. It usually presents in the fourth and sixth decade, and commonly affected areas include the nasal and respiratory tracts, external ears and joints. Ocular involvement is reported in around 65% of RP patients during their lifetime but is rarely sight-threatening. However, we present an unusual case of recurrent ocular inflammation due to RP that resulted in unilateral posterior scleritis with sub-retinal exudation, and posed a high risk of retinal detachment. Prompt escalation of immunosuppressive treatment was required to prevent this. Case report - Case description A 48-year-old man of south-east Asian descent presented to rheumatology in December 2020 with a typical history of new inflammatory arthritis of 4 weeks duration. He was known to have bilateral episcleritis and ocular hypertension for 3 years and took Brinzolamide and Latanoprost eye drops, as well as metformin for type 2 diabetes mellitus. The only other relevant history was treatment with antibiotics as an inpatient for bilateral pinna cellulitis 2 months prior, which was suspected to be related to his diabetes. Examination revealed mildly reduced hand grips but no definite synovitis. The most remarkable finding was bilateral painless red eyes. Both pinnae appeared inflamed on close inspection without obvious auricular lobe involvement. Blood tests showed raised C-Reactive Protein (38 mg/L), and Erythrocyte Sedimentation Rate (62 mm/hr), with normochromic normocytic anaemia but other blood counts were normal. Renal and liver function was normal. Detailed immunology was negative. Relapsing Polychondritis was suspected and confirmed following multidisciplinary team (MDT) discussions with the Ear Nose and Throat and ophthalmology teams. At the next visit, his disease progressed to florid polyarthritis in a rheumatoid distribution. This responded well to low-dose prednisolone and methotrexate. However, the patient attended eye casualty on multiple occasions over the next 6 weeks with alternating acute eye pain and redness, mildly reduced visual acuity and raised intraocular pressures. He developed sub-retinal fluid pockets suggestive of posterior scleritis in the right eye and retinal tomography demonstrated extensive pigment clumping especially in the macula with outer retinal disruption. Urgent pulses of intravenous methylprednisolone were given, followed by high-dose prednisolone tapering. The case was discussed with the regional uveitis MDT, and treatment was escalated to adalimumab. He is currently 1 month into treatment and has preserved visual acuity and stable intraocular pressures, with no other systemic involvement of his RP. Case report - Discussion The diagnosis of RP requires a high index of clinical suspicion given the lack of diagnostic markers. The clinical features are multisystem and might not occur simultaneously as in this case, where the eye disease preceded the ear and joint manifestations by a couple of years. Perichondritis might be more difficult to appreciate in patients with darker skin and can further delay diagnosis. The average time to diagnosis from the initial symptoms has been reported as 14 months from a case series of 158 patients with RP in China. Ocular complications are usually bilateral and the commonest are episcleritis and scleritis (over 50% of cases have one of these), followed by uveitis and retinopathy. Eyelid oedema, proptosis and optic neuritis can also occur but are rarer, and exudative retinal detachment has only been noted in a small number of case reports. Unfortunately, no current treatment guidelines exist for RP due to a lack of randomised controlled trials but treatment is usually guided by the severity of manifestations in conjunction with trends from case series and expert opinion. The aim is to halt or slow disease progression and glucocorticoids are often used first-line for moderate to severe disease, with or without the addition of steroid-sparing agents such as methotrexate, ciclosporin and azathioprine. A meta-analysis of biologics in RP conducted by Kemta et al. in 2012 has suggested anti-TNF (particularly Infliximab) might be beneficial as second-line treatment for severe or refractory cases of organ involvement due to RP such as central nervous system, nasal or pulmonary involvement. However, due to the extreme rarity of both RP and associated severe retinal disease, the optimum therapeutic choice in this setting is currently not known. Case report - Key learning points

LA SCLERITEPOSTERIEURE UNE GRANDE SIMULATRICE: UN CAS RARE DE SCLERITEPOSTERIEURE DEGUISEE SOUS FORME DUNE CELLULITE ORBITAIRE

Posterior scleritis, is a rare form of eye inflammation, affecting the part of the sclera behind the Oraserrata. It is a rare condition, often underdiagnosed due to its unspecific, protean clinical symptomatology. B-mode ultrasound is a key examination for confirmation of the diagnosis. The causes are varied and multiple. The visual prognosis is involved in the event of diagnostic and therapeutic delay.