Others and Daclizumab, Etanercept, Adalimumab, Infliximab, Therapies:• 35Biologicchapter

Systemic toxicity

In several studies of daclizumab for the prevention of renal allograft rejection, no difference in serious infectious complications or cancer has been observed when comparing patients receiving daclizumab or placebo. The formation of antidaclizumab antibodies has been reported in up to 15% of adult patients and on this medication, but its relationship to the medication’s efficacy has not been clearly defined.99

Of the patients treated at the National Eye Institute, one case of renal cell carcinoma was diagnosed and daclizumab was stopped. Following successful treatment of the tumor with a partial nephrectomy, the patient required prednisone, mycophenolate mofetil, and cyclosporine to treat a uveitis recurrence with cystoid macular edema (CME). Because of the severe side-effects that subsequently developed from these medications (i.e., weight gain, cushingoid body habitus, hypertension) and the equal potential risk of secondary malignancy from this immunosuppressive regimen, daclizumab infusions were reinstated without any further untoward effects.85

Drug interactions

In clinical trials evaluating the efficacy of daclizumab for solid-organ transplants, daclizumab has been used with cyclosporine, mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids with no incremental increase in adverse reactions. In renal allograft recipients treated with daclizumab and mycophenolate mofetil concomitantly, an interaction of daclizumab with the active metabolite of mycophenolate mofetil was not observed.

Summary

Prospective phase I and phase I/II trials for daclizumab for uveitis have demonstrated its efficacy for the treatment of intermediate, posterior, and panuveitis syndromes, particularly those conditions in which Th1mediated processes are thought to be instrumental. However, one randomized trial was not supportive of its use in treatment of Behçet’s disease-associated uveitis. Several retrospective trials have supported its use for the treatment of birdshot retinochoroidopathy and some cases of pediatric uveitis. The safety of daclizumab has been established in larger trials for the prevention of renal allograft rejection and the treatment of HTLV-associated T-cell lymphoma/leukemia. Further studies will be needed to determine the disease-specific efficacy of daclizumab for ophthalmic inflammatory conditions and optimal dosing strategies.

OTHER BIOLOGIC AGENTS

Other biologic agents, which have been used in several retrospective series and case reports for the treatment of uveitis, include anakinra, alemtuzumab, and interferon-α (IFN-α). Rituximab, an anti-CD20 monoclonal antibody targeting B cells, has been reported for the treatment of primary intraocular lymphoma.

Anakinra (Kineret) a is recombinant human IL-1 receptor antagonist that binds to IL-1 type 1 receptors, down-regulating the proinflammatory effects of IL-1. Its efficacy for the treatment of ocular inflammation has been demonstrated in murine models of uveitis.100 Recently, several reports have described the efficacy of anakinra for the treatment of specific uveitic syndromes thought to be IL-1-mediated. Specifically, pediatric patients with uveitis associated with chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome101 and the NOD2 gene-associated pediatric granulomatous arthritis were treated successfully with anakinra therapy.102

Alemtuzumab (Campath-1H), the anti-CD52 monoclonal antibody that targets T and B lymphocytes, has been used for a variety of hema-

tologic indications, including myelodysplastic syndrome, aplastic anemia, chronic lymphocytic leukemia, and a number of T-cell leuke- mias/lymphomas.103–105 Dick et al.106 reported the use of alemtuzumab for severe, recalcitrant ocular inflammation in 10 patients with a variety of ophthalmic inflammatory diseases, which included Wegener’s granulomatosis-associated peripheral ulcerative keratitis and pseudotumor, retinal vasculitis, sympathetic ophthalmia, and Behçet’s disease.106 All patients showed an initial improvement following Campath-1H administration; however 2 of 10 patients required retreatment. Remission was observed in 8 patients who received Campath-1H, and no opportunistic infections or malignancies were observed at shortterm follow-up.106

IFN-α has been utilized for its antineoplastic and antiviral effects; however its precise mechanism of action is unknown. Its use in the prevention of ocular relapses, as well as in the treatment of Behçet’s disease-associated ocular inflammation,16 has been reported previously.21,107 Kotter et al.107 reported that IFN-2α in combination with low-dose steroid led to remission of ocular disease in 7 patients with Behçet’s disease-associated panuveitis. A more recent report suggested a potential benefit of IFN-2α for treatment-resistant CME, with 6 of 8 patients responding to IFN-2α with resolution of CME during the first 6 months of therapy.108 Further studies into IFN-2α as a therapeutic modality are required before its implementation into routine clinical practice, however.

Rituximab, a monoclonal anti-CD20 antibody targeting B cells, has been used systemically for the treatment of a number of hematologic malignancies and lymphoproliferative disease processes, including primary central nervous system lymphoma.109,110 Recent studies have supported its use for ocular adnexal lymphomas,111,112 and limited case series have also reported its benefit for the treatment of primary intraocular lymphoma.113 While the use of rituximab has been advocated for the treatment of primary intraocular lymphoma recurrences, vigilant central nervous system surveillance, management, and treatment with a neuro-oncologist for systemic chemotherapy are highly recommended.

SUMMARY AND KEY POINTS

As the disease mechanisms underlying specific uveitic syndromes are uncovered, precisely targeted therapies will become more viable as a treatment strategy. The current biologic agents used in clinical practice include the TNF-α antagonists infliximab, adalimumab, and etanercept and the IL-2 receptor antagonist daclizumab (Table 35.3). Infliximab and adalimumab have demonstrated efficacy for uveitic syndromes in a number of retrospective case series and few prospective trials, whereas the role of etanercept for uveitis is less clear. The efficacy of daclizumab as a corticosteroid-sparing and cyclosporinesparing agent for intermediate, posterior, and panuveitis has been established in several controlled, prospective trials, as well as in several retrospective case series. Experience with other agents, including anakinra, alemtuzumab, IFN-α, and rituximab, is limited at this time.

Because the long-term side-effects of these agents are largely unknown (i.e., theoretical increased risk of malignancy, possible increase in opportunistic infection), a thorough medical evaluation and full understanding of the potential risks of each of these therapies by the patient and provider are recommended prior to their administration. These risks must be weighed against the potential benefits of biologic therapy, including improved visual acuity, better quality of life, and ability to work, and a decrease in the side-effects associated with other traditionally used immunosuppressive medications (e.g., osteoporosis, hyperglycemia associated with corticosteroid use). Thus, while judicious use of the biologics is certainly warranted, tailored therapy with these agents has tremendous promise, and the number of ophthalmic indications for which biologic therapy may be used will likely expand in the future.

Diseases Retinal in Mechanisms and Drugs • 4 section

Others and Daclizumab, Etanercept, Adalimumab, Infliximab, Therapies:• 35Biologicchapter

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