Review explores reducing corticosteroid use with immunomodulatory therapies.
Noninfectious uveitis (NIU) is a critically underserved disease with regard to the number of medications approved by the US Food and Drug Administration (FDA) for its treatment, according to C. Stephen Foster, MD (pictured) and colleagues at the Ocular Immunology and Uveitis Foundation in Weston, Massachusetts.
In a recent review, they point out that the paucity of randomized, controlled clinical trials of immunomodulatory therapy (IMT) drugs for NIU, the heterogeneity of the disease, and the rarity of some types of NIU have contributed to the current unapproved status of many IMTs useful for NIU.
Although ocular inflammation can occur alone, it often accompanies systemic inflammatory diseases such as juvenile idiopathic arthritis (JIA) or systemic lupus erythematosus (SLE). Many IMTs approved for use in treating these systemic diseases are also appropriate for treating NIU. But because the FDA has not approved them for NIU, they are used for this indication off-label.
Although current guidelines recommend corticosteroids as first-line therapy for active uveitis, long-term steroid treatment can cause hypertension, diabetes, cataract, and glaucoma. IMTs can be used to reduce the steroid dose needed and can treat both systemic and ocular inflammatory disease and preserve vision in many patients. The goal is remission without the need for continued steroid therapy. Aggressive treatment may minimize complications and recurrences. And recurrent or refractory NIU often requires IM monotherapy or a combination of agents to control inflammation.
Conventional IMTs typically are used before biologic response modifiers and include antimetabolites like methotrexate (Rheumatrex/Dava) and calcineurin inhibitors like tacrolimus (Prograf/Astellas).
Methotrexate is often considered the first-line IMT for NIU because it is easy to use and has a long record of success in treating ocular inflammation. It is the most commonly used IMT in children with JIA-associated uveitis and is an agent of choice for recurrent anterior uveitis because it concentrates preferentially in the aqueous humor.
Tacrolimus was effective in treating 62 NIU patients for 4 years and posed a low cardiovascular risk. It can control inflammation in posterior NIU and reduce or eliminate the need for steroids.
Biologic response modifiers used for NIU include the tumor necrosis factor-α (TNF-α) inhibitor infliximab (Remicade/Janssen) and the lymphocyte inhibitor rituximab (Rituxan/Roche).
Infliximab can treat human leukocyte antigen (HLA)-B27-related anterior uveitis and Vogt—Koyanagi–Harada (VKH) uveitis, among other types of NIU. It is also a rapid, effective therapy for panuveitis related to Behçet’s disease and controls JIA-associated uveitis in most patients after the second infusion. However, like all TNF-α inhibitors, infliximab may cause sarcoidosis, psoriasis, and lupus.
Rituximab treats uveitis associated with JIA, particularly the oligoarthritic type, and can produce long-term remissions in these patients. It also treats refractory ocular SLE.
Specific receptor antagonists used for NIU include alemtuzumab (Campath/Genzyme), anakinra (Kineret/Sobi), canakinumab (Ilaris/Novartis), and tocilizumab (Actemra/Roche).
Alemtuzumab is not FDA approved but can be obtained through a restricted distribution program. Case reports indicate it can treat uveitis related to Behçet’s disease. In four such cases treated with a single course of alemtuzumab at escalating daily doses for 5 days, this IMT produced complete or partial remission of uveitis at a 6-month follow-up visit.
In another case series, anakinra completely resolved intraocular inflammation in three of four patients with recurrent uveitis related to Behçet’s disease, but NIU relapsed after a mean of 6 months. And canakinumab, indicated for the treatment of systemic JIA, has treated several refractory cases of uveitis related to Behçet’s disease successfully.
Tocilizumab is FDA-approved for JIA refractory to other biologic response modifiers and can treat refractory uveitis related to JIA or Behçet’s disease. It is the focus of two early-phase clinical trials in several types of NIU. However, in one case, uveitis developed for the first time in a patient after he received tocilizumab for HLA-B27-positive ankylosing spondylitis.
In addition, interferon-α 2a (Roferon-A/Roche) and 2b (Intron A/Merck) are used for posterior uveitis. Interferon-α 2a was studied most often in patients with uveitis related to Behçet’s disease but is also used to treat VKH, intermediate uveitis, and idiopathic panuveitis. But interferon therapy can cause sarcoidosis and should not be used to treat sarcoidosis-related uveitis.
To reduce the risk of NIU recurrence, the reviewers recommend continuing IMTs for 2 years before tapering the dose. They also recommended additional studies of the utility of IMTs for NIU and encourage more rapid FDA approval of their use for NIU to facilitate coverage of their costs by insurers and expand access to them.
“A review and update on orphan drugs for the treatment of noninfectious uveitis” was published online by Clinical Ophthalmology in late January.