Ali R. Djalilian

MANAGEMENT OF ANIRIDIC KERATOPATHY WITH KERATOLIMBAL ALLOGRAFT: A LIMBAL STEM CELL TRANSPLANTATION TECHNIQUE

OBJECTIVE Aniridic keratopathy is a major cause of vision loss in patients with aniridia. Penetrating keratoplasty has been proven ineffective for the long-term treatment of this disorder because it does not address the stem cell deficiency that is the primary etiologic factor. We evaluated the role of keratolimbal allograft (KLAL), a stem cell transplantation technique, for the treatment of patients with aniridic keratopathy. DESIGN Retrospective noncomparative interventional case series. PARTICIPANTS Thirty-one eyes of 23 patients with aniridic keratopathy. INTERVENTION KLAL. MAIN OUTCOME MEASURES Ocular surface stability, visual acuity, and success of subsequent penetrating or lamellar keratoplasty. RESULTS Thirty-one eyes of 23 patients were treated with KLAL and followed up for 12 to 117 months (mean, 35.7 months). Twenty-three eyes (74.2%) achieved a stable ocular surface. Overall, the mean visual acuity improved from 20/1000 to 20/165. Twenty eyes (64.5%) underwent subsequent penetrating keratoplasty. Fourteen corneal transplant grafts (70.0%) were successful, and six (30.0%) failed. Nineteen (90.5%) of 21 eyes receiving systemic immunosuppression obtained a stable ocular surface, whereas only 4 (40.0%) of 10 eyes not receiving systemic immunosuppression achieved ocular surface stability (P < 0.01). CONCLUSIONS KLAL is effective in treating aniridic keratopathy. Patients receiving systemic immunosuppression have a greater likelihood of achieving ocular surface stability and improved visual acuity compared with those who receive only topical immunosuppression.

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.

Mycophenolate mofetil for the treatment of scleritis

PURPOSE To 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. DESIGN Retrospective, noncomparative case series. PARTICIPANTS Eight patients with scleritis treated with MMF in a tertiary referral center. METHODS Review of the clinical records of patients evaluated at the National Eye Institute and prescribed MMF for the treatment of scleritis. MAIN OUTCOME MEASURES Control 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. RESULTS Four 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. CONCLUSIONS Although 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.

Ocular surface reconstruction: limbal stem cell transplantation

In summary, the management of patients with severe ocular surface disease remains difficult. Significant progress has been made toward understanding limbal stem cell disease, and surgical treatments have been refined. Short- and long-term successes have been achieved and have improved the quality of life for patients who otherwise have had no other treatment options. Further research is needed to determine the factors leading to successful long-term stem cell transplantation and those factors associated with transplantation failure. Developments in the management of limbal stem cell disease are progressing rapidly, and the long-term outlook for patients with this challenging disease continues to improve.

Immunosuppression in uveitis

The treatment of ocular inflammatory disease continues to be a major challenge as the clinician tries to balance the risks and the benefits of immunosuppressive therapy. Currently, corticosteroids, antimetabolites, and calcineurin inhibitors are the most commonly used agents. Biologically active agents including monoclonal antibodies, however, provide a promising new form of treatment that can target the immune system more specifically and more safely. Long-term studies are needed to determine the role of biologic agents in the treatment of uveitis.