Elsevier

Ophthalmology

Volume 125, Issue 2, February 2018, Pages 193-202
Ophthalmology

Original article
Immunosuppression for the Uveitides

Presented in part at: the First C. Stephen and Frances Foster Lecture on Uveitis and Immunology at the Meeting of the American Academy of Ophthalmology, October 15–18, 2016, Chicago, Illinois.
https://doi.org/10.1016/j.ophtha.2017.08.007Get rights and content

The uveitides are a collection of more than 30 diseases characterized by intraocular inflammation. Many cases of juvenile idiopathic arthritis–associated uveitis, many cases of intermediate uveitis, and most cases of posterior and panuveitides requiring treatment are treated with corticosteroids and immunosuppression. Disease-specific, time-updated modeling of clinical data for several uveitides suggests superior prevention of ocular complications and visual outcomes with immunosuppression. These studies also suggest that oral corticosteroids at doses low enough for safe long-term therapy (i.e., <7.5 mg/day) are ineffective, implying that immunosuppression should be part of the initial regimen. The Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study was a randomized comparative effectiveness trial comparing systemic therapy with oral corticosteroids and immunosuppression with regional corticosteroid treatment. It demonstrated that, when used properly, oral corticosteroids and immunosuppression can be given safely for up to 7 years with no evident increased risk of systemic side effects compared with regional corticosteroid therapy, except for greater antibiotic use for infections. The Systemic Treatment for Eye Diseases (SITE) Cohort Study suggested long-term safety for this approach, when the immunosuppressive agents were antimetabolites or calcineurin inhibitors. Thus, oral corticosteroids and immunosuppression may be a preferred initial therapy for many noninfectious, intermediate, posterior, and panuveitides. Nonalkylating-agent immunosuppression has a low rate of sustained, drug-free remissions, <10%/year. Nonalkylating-agent immunosuppression for >3 years with control of the inflammation for >2 years is associated with a decreased risk of relapse after discontinuing immunosuppression. Alkylating agents can induce sustained drug-free remissions but likely increase the lifetime risk of cancer. Biologics, which target specific cytokines and pathways, hold promise for the future. Monoclonal antibodies directed against tumor necrosis factor (TNF)-α have been studied most often, and one, adalimumab, is U.S. Food and Drug Administration approved for the treatment of noninfectious, intermediate, posterior, and panuveitides.

Section snippets

Treatment Target

The decision to treat an individual patient and the choice of therapy always represent risk–benefit decisions. Not every case of uveitis needs treatment. In Fuchs' uveitis syndrome (also known as “Fuchs' heterochromic iridocyclitis”), treatment appears not to have beneficial effects and typically is not given. Some 25% to 35% of patients with pars planitis have mild disease, no macular edema or other complications, and good vision, and do not need treatment; these patients maintain good vision

Oral Corticosteroids

Oral corticosteroids are critical for the initial control of ocular inflammation, even when immunosuppression is used. Studies of patients with sarcoid uveitis have shown that oral corticosteroid therapy is associated with a 93% reduction in the odds of visual impairment.28 The initial dose of prednisone should be 1 mg/kg/day up to a maximum of 60 mg/day.12, 13 Doses >60 mg/day are associated with an increased risk of ischemic necrosis of bone and should be avoided.29 After 2 to 4 weeks,

Evidence for the Effectiveness of Immunosuppression

There are a limited number of randomized clinical trials demonstrating the efficacy of immunosuppression in the treatment of the uveitides. Azathioprine was shown to be effective for Behçet disease uveitis, but 22% of treated patients had uveitis relapses.35 Cyclosporine was superior to colchicine (which is ineffective for uveitis) for Behçet disease, but only 48% of patients on cyclosporine had good control of the uveitis.36 In a small single-center, randomized trial, cyclosporine was

Conventional Immunosuppressive Drugs

Conventional immunosuppressive drugs are classified as antimetabolites, calcineurin inhibitors, or alkylating agents (Table 3).13 The antimetabolites used most often are azathioprine (Imuran, Prometheus Labs, Inc, San Diego, CA), methotrexate (Rheumatrex, Dava Pharmaceuticals, Inc, Newark, DE, and others), and mycophenolate (Cellcept, Genentech, Inc, San Francisco, CA). The calcineurin inhibitors are cyclosporine (Neoral, Novartis Pharmaceuticals Corp, New York, NY) and tacrolimus (Prograf,

Remission Induction

The SITE Cohort Study suggested that sustained, drug-free remissions (i.e., inactive disease off all treatment) were uncommon with nonalkylating agent immunosuppression. In intermediate uveitis, the incidence of a sustained, drug-free remission was 0.089/PY.55 For nonalkylating agent conventional immunosuppressive drugs, the estimated remission incidence was <0.10/PY for each drug.43, 44, 45, 46 In JIA uveitis, the median time to a drug-free remission is approximately 10 years for mild disease;

Safety of Immunosuppression

The MUST Trial and Follow-up Study evaluated the safety of systemic therapy for the uveitides.27, 58, 59, 60, 61, 62 The trial randomized patients with noninfectious, intermediate, posterior, and panuveitides to treatment with the fluocinolone acetonide implant (Retisert, Bausch & Lomb, Rochester, NY) or systemic therapy with oral corticosteroids and immunosuppression. The fluocinolone acetonide implant is surgically placed in the eye and releases corticosteroids over a period of 2.5 to 3 years.

Biologics for the Uveitides

Biologics have transformed the field of rheumatology and are widely used. In uveitis, most of the data on biologics are on the use of agents directed against tumor necrosis factor (TNF)-α and involve infliximab (Remicade, Janssen Biotech, Inc, Titusville, NJ), a chimeric monoclonal antibody to TNF-α given as an intravenous infusion, or adalimumab (Humira, AbbVie, Inc, North Chicago, IL), a fully human monoclonal antibody given every other week as a subcutaneous injection.72, 73, 74, 75, 76

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    Financial Disclosure(s): The author has no proprietary or commercial interest in any materials discussed in this article.

    Supported in part by Cooperative Agreement U10 EY014655 to the Icahn School of Medicine from the National Eye Institute, National Institutes of Health, Bethesda, Maryland. Bausch & Lomb, Inc, donated a limited supply of fluocinolone acetonide implants to the Multicenter Uveitis Steroid Treatment (MUST) Trial.

    Off-label Drug Use: azathioprine, methotrexate, mycophenolate, cyclosporine, tacrolimus, cyclophosphamide, chlorambucil, infliximab, abatacept, tocilizumab, and rituximab.

    HUMAN SUBJECTS: This article discusses multiple human studies, all of which had IRB approval, and followed the tenets of the Declaration of Helsinki.

    Author Contributions:

    Conception and design: Jabs

    Data collection: Jabs

    Analysis and interpretation: Jabs

    Obtained funding: Not applicable

    Overall responsibility: Jabs

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