Eric B Suhler

Humanized anti-interleukin-2 (IL-2) receptor alpha therapy: long-term results in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous administration

Therapy for severe uveitis is frequently long-term immunosuppression using systemic corticosteroids and cytotoxic agents, but side effects make long-term therapy difficult. A long-term (>4 year) Phase I/II single armed interventional study using intravenous anti-IL-2 receptor alpha treatments (daclizumab) and a short-term Phase II study evaluating the use of a subcutaneous daclizumab formulation were conducted. Patients were tapered off their systemic immunosuppressive therapy and received daclizumab infusions or subcutaneous injections at intervals varying from 2 to 6 weeks. In the long-term study, seven of ten enrolled patients were tapered from their original immunosuppressive medications and maintained exclusively on repeated daclizumab infusions for control of their uveitis for over 4 years. No patient was permanently removed from therapy for an adverse event ascribed to the medication. The use of 6-week infusion intervals led to recurrence of uveitis, while 2- to 4-week intervals did not. Only one patient developed measurable anti-daclizumab antibodies but this disappeared when subcutaneous therapy was begun. In the short-term study, four of the five patients receiving the subcutaneous formulation met the study endpoints for success within the first 12 weeks. All five were successful by 26 weeks. These studies provide preliminary evidence that regularly administered long-term daclizumab therapy can be given in lieu of standard immunosuppression for years to treat severe uveitis and that subcutaneously administered daclizumab appeared to be a clinically viable treatment strategy. These studies suggest that anti-IL-2 receptor blockade could be useful in the treatment of Th1-mediated autoimmune conditions.

A Double-masked, Randomized Study to Investigate the Safety and Efficacy of Daclizumab to Treat the Ocular Complications Related to Behcet's Disease

Purpose: To investigate the safety and efficacy of daclizumab (Zenapax, humanized anti-Tac, HAT) in controlling the ocular manifestations of Behçets disease. Design: Randomized, placebo-controlled, double-masked clinical trial. Participants: Seventeen participants with Behçets disease experiencing at least two prior ocular attacks and requiring treatment with immunosuppressive agents for the ocular complications of Behçets disease. Methods: Participants received either intravenous placebo or daclizumab (1 mg/kg) infusions every two weeks for six weeks, then every four weeks while continuing their standard immunosuppressive regimens. If clinically indicated, tapering of the standard immunosuppressive medications was allowed after six months of study enrollment. Complete ocular and physical examinations and an adverse event assessment were performed at baseline and prior to each study infusion. Main Outcome Measures: Primary safety endpoints were the development of a life-threatening complication or a severe opportunistic infection. Primary efficacy outcomes were the number of ocular attacks and an assessment of systemic immunosuppressive medications required during the study, including the ability to taper concomitant immunosuppressive therapy. Results: Nine participants randomized to daclizumab and eight to placebo were followed monthly. Follow-up ranged from one to 34 months, with a median follow-up of 15 months. Two participants randomized to daclizumab discontinued study therapy prior to the end of the study for personal reasons. No participant experienced a safety endpoint, and visual acuity remained stable in all participants during the course of the study. Ten participants (six daclizumab, four placebo) experienced ocular attacks requiring therapy. The median ocular attack rate during the study was greater in the daclizumab arm than the placebo arm (median 1.27 vs. 0.17 attacks/year, respectively). Participants in the placebo arm also experienced a greater reduction in the immunosuppressive medication score compared to participants receiving daclizumab (median –4.0 vs. –1.0, respectively). Conclusions: The observed results in the placebo group demonstrate that careful follow-up and treatment with standard combination immunosuppressive therapy can be effective for the management of the ocular complications of Behçets disease. In our small study, there was no suggestion that daclizumab was beneficial in comparison with placebo. However, the low observed attack rate limited our ability to make a definitive treatment group comparison.

Mycophenolate mofetil for the treatment of scleritis

PURPOSEnTo evaluate the usefulness of mycophenolate mofetil (MMF) (CellCept, Roche, Nutley, NJ), an antimetabolite immunosuppressant with a selective antiproliferative effect on T and B lymphocytes, for the treatment of scleritis.nnnDESIGNnRetrospective, noncomparative case series.nnnPARTICIPANTSnEight patients with scleritis treated with MMF in a tertiary referral center.nnnMETHODSnReview of the clinical records of patients evaluated at the National Eye Institute and prescribed MMF for the treatment of scleritis.nnnMAIN OUTCOME MEASURESnControl of scleral inflammation, the ability to taper prednisone or other immunosuppressive medications, and adverse events were recorded for each patient. Mycophenolate mofetil was determined to be an effective steroid-sparing agent if the daily prednisone dosage could be reduced by 50% or more and was determined to be an effective adjunctive immunosuppressive agent if the scleral inflammation was controlled in patients with active scleritis.nnnRESULTSnFour patients with diffuse anterior scleritis, two with necrotizing scleritis with inflammation, one with nodular anterior scleritis, and one with nodular anterior and posterior scleritis, were identified. Mycophenolate mofetil administration was initiated as a steroid-sparing agent in 4 patients with controlled scleritis and as an additional immunosuppressive agent in 4 patients with active scleritis receiving concomitant treatment with prednisone and cyclosporine or methotrexate. In 3 of the 4 patients started on MMF as a steroid-sparing agent, the scleritis remained controlled while the prednisone dosage was tapered by more than 50%. One of the patients started on MMF as a steroid-sparing agent had recurrent scleritis, and each of the patients with active scleritis continued to have persistent scleral inflammation requiring additional immunosuppressive therapy. Adverse effects recorded in 4 of the 8 patients included a rash, gastrointestinal symptoms, paresthesias, and laboratory evidence of hepatotoxicity and renal toxicity.nnnCONCLUSIONSnAlthough MMF maybe be useful as a steroid-sparing agent, it was not effective as an adjunctive immunosuppressive agent in patients with active scleritis in our small, tertiary referral series. The adverse effects encountered with the use of MMF in this study cannot be attributed conclusively to MMF and are more likely complications of the multiagent systemic immunosuppressive therapy required for the treatment of recalcitrant scleritis.

Rituximab for treatment of ocular inflammatory disease: a series of four cases

Rituximab may be effective in the treatment of ocular inflammatory disease. Dosing is less frequent than many medications currently available. Four cases are reported, each of which appeared to have responded well to treatment with rituximab, although patient 2 was able to remain on a low dose of prednisone for only 2 months. The ongoing pilot study will hopefully provide additional insight into the benefit of rituximab for treatment of scleritis and idiopathic orbital inflammatory disease.

Serpiginous choroidopathy presenting as choroidal neovascularisation.

Serpiginous choroidopathy is an insidious, relentlessly progressive, idiopathic inflammatory disease affecting the retinal pigment epithelium and inner choroid. Choroidal neovascularisation (CNV) is a well recognised late complication of serpiginous choroidopathy in 10–25% of affected patients.1 In all previously reported cases CNV was recognised at the time of or after the diagnosis of serpiginous choroidopathy was established.2–4 We report a patient presenting with CNV who subsequently developed clinical findings characteristic of serpiginous choroidopathy.nnA 31 year old man presented with decreased vision in his right eye in July 1997. Examination revealed acuities of 20/40 right eye and 20/20 left eye with normal anterior segments. The right fundus showed subretinal fluid and haemorrhage adjacent to the disc (Fig 1A). The left eye showed an irregularity superior to the optic disc (Fig 1B). The vitreous and fundi were otherwise normal bilaterally. Fluorescein angiography (Fig 2A, B) revealed peripapillary choroidal neovascular membranes in both eyes that were treated with argon laser …