Despite their side-effects and the advent of systemic immunosuppressives and biologics, the use of corticosteroids remains in the management of patients with uveitis, particularly when inflammation is associated with systemic disease or when bilateral ocular disease is present. The use of topical corticosteroids as local therapy for anterior uveitis is well-established, but periocular injections of corticosteroid can also be used to control mild or moderate intraocular inflammation. More recently, intraocular corticosteroids such as triamcinolone and steroid-loaded vitreal inserts and implants have been found to be effective, including in refractory cases. Additional benefits are noted when ocular inflammation is unilateral or asymmetric, when local therapy may preclude the need to increase the systemic medication.Implants in particular have gained prominence with evidence of efficacy including both dexamethasone and fluocinolone loaded devices. However, an appealing avenue of research lies in the development of non-corticosteroid drugs in order to avoid the side-effects that limit the appeal of injected corticosteroids. Several existing drugs are being assessed, including anti-VEGF compounds such as ranibizumab and bevacizumab, anti-tumour necrosis factor alpha antibodies such as infliximab, as well as older cytotoxic medications such as methotrexate and cyclosporine, with varying degrees of success. Intravitreal sirolimus is currently undergoing phase 3 trials in uveitis and other inflammatory pathways have also been proposed as suitable therapeutic targets. Furthermore, the advent of biotechnology is seeing advances in generation of new therapeutic molecules such as high affinity binding peptides or modified high affinity or bivalent single chain Fab fragments, offering higher specificity and possibility of topical delivery.

Purpose To investigate whether intravitreal ranibizumab injections administered to a child alter systemic plasma levels of total and free VEGF 165. Methods A 9-year-old child sustained a choroidal rupture from blunt trauma. He subsequently developed a secondary choroidal neovascular membrane, which was treated with five ranibizumab injections over a period of 8 months. Peripheral venous blood samples were taken at each visit over a period of 12 months and plasma was extracted. Plasma VEGF 165 levels were determined using enzyme-linked immunosorbent assay and were assayed both pre-and post-immunodepletion to remove complexed VEGF. Results Plasma VEGF 165 levels proved labile following intravitreal injection of ranibizumab. Levels increased by 30% above baseline following the first intravitreal ranibizumab injection, but then returned to baseline despite two subsequent injections. There was then a rebound increase of 67% in total plasma VEGF levels following a further injection, which remained above baseline for 12 weeks despite two further intravitreal ranibizumab injections. Baseline levels were re-attained 26 weeks after the final injection. Conclusions These results suggest intravitreal ranibizumab injections can cause significant, multiphasic changes in systemic VEGF levels. This may be of particular clinical significance in children as VEGF is known to be vital in the development of major organs, in addition to its role in the maintenance of normal organ function in adults.

Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.

PurposeAdenosine‐5′‐triphosphate (ATP) functions as an important extracellular messenger and plays a critical role as a danger signalling molecule during inflammation. In pathological conditions damaged cells leak high concentrations of ATP into the extracellular milieu, activating P2 Purinergic receptors which are highly expressed on immune cells. Pathological stimulation of the P2X7 receptor may be involved in the development of autoimmune disease, so we explored the impact of P2X7R antagonist treatment on the development of Experimental Autoimmune Uveitis (EAU) in mice.MethodsEAU was induced in P2X7‐/‐ and wild‐type mice using IRBP peptide 1‐20(GPTHLFQPSLVLDMAKVLLD) with adjuvant Bordetella pertussis toxin. All procedures were performed under a Home Office License in accordance with the regulations of UK ASPA (1986). EAU was then induced in B10.rIII mice with RBP‐3 161‐180 (SGIPYIISYLHPGNTILHVD) and adjuvant Bordetella pertussis toxin. P2X7R antagonist A439079275 or vehicle were injected i.p. twice daily from day 12. p.i when clinical features of EAU manifested. Disease activity was observed through TEFI imaging and animals were treated until peak disease and termination at day 16 p.i.ResultsP2X7R deficiency protected against the development of EAU, with disease scores significantly lower in P2X7‐/‐ animals compared to control animals. P2X7R antagonist treatment with A439079 prevented development of severe EAU with disease scores in A439079 treated animals significantly lower than vehicle treated animals.ConclusionsP2X7R deficiency protects against the development of EAU in mice and P2X7R antagonist can ameliorate established disease. The P2X7R may represent a viable therapeutic target for ocular inflammatory disease.