Ophthalmology Xagena

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Infliximab, Etanercept and Adalimumab for the treatment of uveitis

All three commonly used TNF blockers ( Infliximab, Etanercept and Adalimumab ) were initially approved for the treatment of rheumatoid arthritis, and were subsequently approved for a number of other systemic indications.

Infliximab ( Remicade ) is a chimeric monoclonal antibody that binds both circulating and membrane-bound TNF-alpha. Initial reports focused on the treatment of uveitis associated with Behcet’s disease and juvenile idiopathic arthritis.
Infliximab has been reported to be a rapid and very effective therapy for the treatment of Behcet’s panuveitis, posterior uveitis, and retinal vasculitis.
One group reported in a prospective study of 25 patients with Behcet’s uveitis that the majority ( more than 90% ) of patients experienced resolution of vitritis, retinitis, retinal vasculitis and cystoid macular edema within 28 days following initiation of Infliximab therapy, and often as early as within one week.
Efficacy of Infliximab for juvenile idiopathic arthritis uveitis also has been demonstrated in several retrospective studies, with the majority of patients demonstrating rapid control of inflammation after the second infusion. Besides Behcet’s disease and juvenile idiopathic arthritis, Infliximab has been reported anecdotally to be effective for the treatment of uveitis associated with multiple conditions, including inflammatory bowel disease, ankylosing spondylitis, psoriasis, sarcoidosis, Vogt- Koyanagi-Harada disease, and Takayasu disease.
It may also be effective to treat birdshot retinochoroidopathy, recalcitrant uveitic cystoid macular edema, pars planitis, multifocal choroiditis, HLA-B27-related anterior uveitis, and idiopathic uveitis.

Etanercept ( Enbrel ) is a fusion protein of a human Fc molecule and two p75 TNF receptors that binds free TNF-alpha and -beta. A prospective pilot study in 10 patients with JIA uveitis showed no significant difference in control of anterior chamber inflammation between those who received Etanercept and controls.
Other research reported that Etanercept was not superior to placebo in preventing uveitic relapses in previously controlled patients attempting to taper Methotrexate.
In one prospective study, favorable outcomes at three months were seen in 63% of pediatric eyes treated with Etanercept.
Although a subsequent, larger, prospective, open-label, multicenter study with longer follow-up ( median of 13 months ) showed that patients with JIA may initially respond to Etanercept, only approximately half of responders had sustained improvement at one year.
The same study indicated that Etanercept was associated with a wide array of severe side effects that disappeared after discontinuation of treatment.

Based on the existing non-controlled data, Infliximab generally is believed to be more effective than Etanercept for JIA and various uveitides. However, it is important to note that no head-to-head study of the effectiveness or safety of the TNF-blockers has been prospectively performed, and Infliximab has also been reported to have significant toxicity.

Adalimumab ( Humira ) is a fully human monoclonal antibody against TNF-alpha. Due to its promising results and subcutaneous route of administration, experience in both rheumatologic and ocular indications is growing.
Several clinical studies have shown its potential for juvenile uveitis ( mainly JIA ), with data in adults relatively lacking. A prospective, non-comparative, nonrandomized study in 14 children with recalcitrant uveitis ( nine JIA and five idiopathic ) demonstrated improvement of anterior chamber inflammation in 93% of cases.
A similar retrospective study for JIA demonstrated control of uveitis and arthritis activity in more than 80% of cases, with median response time of three weeks for arthritis and six weeks for uveitis.
A more recent retrospective study for JIA uveitis revealed that Adalimumab effectively controlled inflammation in approximately one-third of patients refractory to previous treatment with Infliximab or Etanercept.
A prospective open-label study of Adalimumab in 19 adults with various uveitides reported control of inflammation in 63% of patients and complete resolution of CME in 55% of eyes at one year of therapy.
The literature for treatment of BD uveitis is less robust than that published for Infliximab; however, one group showed that Adalimumab could be an effective alternative for treatment of BD-associated panuveitis in patients already well-controlled with Infliximab wishing to avoid intravenous infusions.
Adalimumab also has been shown to reduce anterior uveitis flares in patients with ankylosing spondylitis.

Daclizumab ( Zenapax ) is a monoclonal antibody that binds the IL2-R on T lymphocytes, preventing their IL2- dependent activation. A Phase I/II open-label study of intravenous Daclizumab for the treatment of non-infectious intermediate, posterior or panuveitis demonstrated improvement of inflammation and visual acuity at one year in eight of 10 patients, which was maintained after four years of treatment. Increased uveitic recurrences were observed with reduction to six-weekly infusions compared to four-weekly infusions. After four years of intravenous infusions, some patients were transitioned to subcutaneous Daclizumab therapy, with most patients retaining good response. Ten of 15 patients in a subsequent study achieved at least a 50% reduction of concurrent immunosuppression with retained visual acuity, inflammatory control, and no significant side effects.
Daclizumab has been demonstrated effective for refractory birdshot retinochoroidopathy in one study, with seven of eight patients achieving complete resolution of vitreous inflammation and stabilization or improvement of visual acuity.
However, Daclizumab failed to demonstrate effectiveness in BD-associated uveitis in a randomized trial.
A trial of the chimeric IL-2 receptor Basiliximab was recently proposed but withdrawn, pending further studies in non-ophthalmic indications.

Other biologics of interest under current study include Efalizumab and Rituximab. Efalizumab blocks the pan-leukocyte surface marker CD11a and is under current study for non-infectious uveitis with macular edema.
The B-cell antagonist Rituximab is currently under study for treatment of scleritis and orbital inflammation and has reported effectiveness for uveitis in one case report.
Isolated reports also have suggested benefit for the IL-1 blocker Anakinra, and the T-cell costimulation inhibitor Abatacept. ( Xagena )

Pasadhika S et al, Review of Ophthalmology 2010