Advances in the Treatment of Intermediate and Posterior Uveitis

Samantha Fraser-Bell; Carlos Pavesio

Disclosures

Expert Rev Ophthalmol. 2008;3(4):449-456. 

In This Article

Biologicals

Inhibition of TNF-α results in a profound anti-inflammatory effect in rheumatoid arthritis[25,26] and juvenile idiopathic arthritis (JIA).[27,28] Although inflammation is characterized by multiple cytokines, the powerful effect of inhibiting this single cytokine may be explained by the position of TNF-α at the top of the cytokine cascade and its role in regulating the expression and activity of other inflammatory factors. The role of T-cell activation and TNF-α production in uveitis has also been demonstrated.[29,30,31,32] This prompted the use of medications leading to TNF blockade in the treatment of uveitis, such as monoclonal antibodies that bind to TNF-α. Biologicals, such as infliximab given intravenously, and adalimumab and etanercept administered subcutaneously, have been tried in patients with uveitis. In particular, they have been tried in refractory ocular Behçet's disease, and as rescue and maintenance therapy in refractory idiopathic posterior uveitis.

Tuberculosis (TB) must be excluded,[33] as there is a fivefold increased risk of reactivation.[34,35] The risk of TB is closely related to the risk of TB in the individual. People from endemic areas, or those with a history of contact with someone with TB deserve special attention. Exclusion can be difficult in the absence of pulmonary disease and Mantoux testing may be falsely negative due to immunosuppressive therapy, such as corticosteroids, which are usually used as initial therapy.[36] Other reported side effects include exacerbation of other infections (e.g., sepsis, pneumonia or cellulitis), hepatocellular T-cell lymphoma, hypersensitivity/allergy, lupus-like syndrome, injection-site reactions, infusion reaction, optic neuritis, seizures, demyelination or multiple sclerosis (MS).[37]

Infliximab is a monoclonal human-murine chimeric antibody. Since it is a chimeric antibody, infliximab is usually given concomitantly with a second agent, such as azathioprine or methotrexate to reduce the risk of antibodies developing against the medication itself. It is given intravenously at a dose of 3 or 6 mg/kg from once a month to every 6-8 weeks.[38]

Infliximab has been used successfully in children with noninfectious uveitis, with maintenance of visual acuity, improved control of ocular inflammation and reduced reliance on topical glucocorticoids.[39,40] There are also good results reported in adults with Behçet's associated posterior uveitis[41,42,43,44,45,46] and other causes of posterior uveitis.[33] In one study of infliximab in ocular Behçet's,[47] nine out of 12 patients (75%) at 12 months achieved complete remission having had no relapses during the treatment period. Ocular inflammation improved dramatically after the first infusion in all patients. At 24 months, seven out of nine (78%) were still in remission. Mean visual acuity improved significantly, and episodes of inflammation decreased from 40 in the year before therapy to five after infliximab cessation. Infliximab reduced macular thickness and improved visual acuity in uveitic eyes complicated by CME in one case series.[48]

Etanercept is a genetically engineered fusion protein of TNF receptor p75 given subcutaneously twice each week. There have been few favorable case series of etanercept in uveitis.[49] In a randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with JIA, there was no difference in inflammation between the treated and placebo groups.[50] In another trial, adult patients with chronic or recurrent noninfectious uveitis with inflammation controlled by low-dose methotrexate were randomized to either the etanercept or placebo in a double-masked manner, given a methotrexate taper schedule, and followed for 6 months. There was no significant difference between the treatment and placebo groups with regard to the rate of relapse and the final visual acuity.[51]

Etanercept does not appear to protect against the onset of uveitis, nor relapses of uveitis in patients prescribed etanercept for their systemic inflammatory disease,[52,53] and it has been suggested that it may induce uveitis.[54] From 70 children with a diagnosis of JIA, treated with anti-TNF-α without a prior diagnosis of uveitis, two (2.9%), both treated with etanercept, had development of new-onset uveitis during anti-TNF-α therapy.[55] When etanercept has been compared with infliximab in the treatment of uveitis, infliximab has repeatedly been found to be superior.[56,57,58]

Adalimumab is a recombinant humanized IgG1 monoclonal antibody that binds specifically to TNF-α and blocks interaction with the p55 and p75 cell surface receptors. It is postulated that it may be more effective at suppressing inflammation than etanercept, which is a synthetic receptor for TNF-α and does not act against cell-bound TNF. Adalimumab is given 1-2 weekly subcutaneously at a dose of 40 mg in adults (or 40 mg/m2 in children). There are relatively few published data on the effect of adalimumab in uveitis as it is a relatively new drug. Vazquez-Cobian et al. reported a decrease in ocular inflammation in 13 out of 14 children with chronic uveitis.[59] The response was sustained at 18 months follow-up and was associated with the discontinuation or decreased dosage of other immunosuppressive agents. All of these children had been poorly responsive to conventional therapy for uveitis. Another study in children with uveitis reported adalimumab to be effective in reducing ocular inflammation in 88%.[60] It has also been used with success in adults with ocular Behçet's disease.[61]

Daclizumab is a recombinant monoclonal immunoglobulin of the human IgG-1 isotype, composed of 90% human and 10% murine antibody sequences, that recognizes the high affinity IL-2 receptor Tac protein (p55, α chain, CD25) and inhibits IL-2-mediated responses of activated lymphoid cells. It was shown to be effective in treating S-antigen-induced experimental autoimmune uveitis in nonhuman primates.[62] One double-masked, randomized, controlled trial found no benefit from daclizumab (1 mg/kg intravenously every 2 weeks for 6 weeks then every 4 weeks) in treating posterior inflammation associated with Behçet's disease compared with placebo.[63] Another prospective, multicenter, nonrandomized, noncomparative, open-label interventional trial found that daclizumab (2 mg/kg subcutaneously twice weekly for 4 weeks, then 1 mg/kg every 2 weeks for 6 months) reduced the dependence on standard systemic corticosteroids or other immunosuppressive agents in adults with intermediate or posterior uveitis while maintaining visual acuity.[64] Another case series of adults with inflammatory eye disease, which had failed conventional treatment, found that visual acuity was maintained in 21 out of 27 eyes (77%) and inflammation improved in 16 (59%) and worsened in eight (30%).

Interferon-α 2a (IFNα) is an immunomodulating cytokine with antiviral, antiproliferative and anti-angiogenic properties. It has been commonly used in the treatment of hepatitis C, myeloproliferative diseases and lymphomas. Systemic side effects are flu-like symptoms (90%), which is actually a desired effect as it indicates that the medication is producing its effect (reduced by paracetamol), mild leucopenia (30%) and alopecia (10%). Less common side effects include CNS effects (including depression, confusion, seizures and psychosis), auto-antibodies (mostly thyroid), thrombocytopenia, itching, hypotension, elevated liver enzymes, skin rash and diarrhea. Ocular side effects reported include retinal hemorrhages, cotton wool spots and vascular occlusions.

The prescribed dose is 3-6 million IU per day initially, then reducing to 3 million IU twice weekly stepwise over months before discontinuing. Immunosuppressives are usually ceased the day before starting the interferon. Autoantibodies are rare in contrast to infliximab.

Case series have reported positive clinical responses in ocular Behçet's disease[65,66,67,68] and other causes of chronic posterior uveitis refractory to conventional treatment, as measured by improvement in mean visual acuity, reduction of inflammation and reduction or resolution of CME.[69,70,71] Other case series have reported promising results in MS-related intermediate uveitis[72] and in serpiginous choroiditis.[73]

There is currently a multicenter trial comparing IFN with ciclosporin A in the treatment of ocular Behçet's (open-label, single-masked, randomized, controlled, national comparative multicenter trial).

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