Methotrexate for Ocular Inflammatory Diseases

Abstract

Purpose To evaluate the outcome of treatment with methotrexate for noninfectious ocular inflammation. Design Retrospective cohort study. Participants Patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to add methotrexate as a single, noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007, inclusive. Methods Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage, route of administration of methotrexate, and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. Main Outcome Measures Control of inflammation, corticosteroid-sparing effects, and incidence of and reason for discontinuation of therapy. Results Among 384 patients (639 eyes) observed from the point of addition of methotrexate to an anti-inflammatory regimen, 32.8%, 9.9%, 21.4%, 14.6%, 15.1%, and 6.3%, respectively, had anterior uveitis, intermediate uveitis, posterior or panuveitis, scleritis, ocular mucous membrane pemphigoid, and other forms of ocular inflammation. In these groups, complete suppression of inflammation sustained for ≥28 days was achieved within 6 months in 55.6%, 47.4%, 38.6%, 56.4%, 39.5%, and 76.7%, respectively. Corticosteroid-sparing success (sustained suppression of inflammation with prednisone ≤10 mg/d) was achieved within 6 months among 46.1%, 41.3%, 20.7%, 37.3%, 36.5%, and 50.9%, respectively. Overall, success within 12 months was 66% and 58.4% for sustained control and corticosteroid sparing ≤10 mg), respectively. Methotrexate was discontinued within 1 year by 42% of patients. It was discontinued owing to ineffectiveness in 50 patients (13%); 60 patients (16%) discontinued because of side effects, which typically were reversible with dose reduction or discontinuation. Remission was seen in 43 patients, with 7.7% remitting within 1 year of treatment. Conclusions Our data suggest that adding methotrexate to an anti-inflammatory regimen not involving other noncorticosteroid immunosuppressive drugs is moderately effective for management of inflammatory activity and for achieving corticosteroid-sparing objectives, although many months may be required for therapeutic success. Methotrexate was well tolerated by most patients, and seems to convey little risk of serious side effects during treatment. Financial Disclosure(s) The authors have no proprietary or commercial interests in any of the materials discussed in this article.

Ocular Involvement in Sjögren’s Syndrome: Advances in Therapy

“…By targeting mammalian dihydrofolate reductase (an enzyme important for purine and thymidylate synthesis), methotrexate abrogates the growth and division of rapidly dividing cells, which in the case of autoinflammatory conditions includes inflammatory cells. Methotrexate is a mainstay for steroid-sparing control of ocular inflammation, including uveitis and scleritis [38]. In a small case series, two patients with intractable keratoconjunctivitis sicca (one patient with Sjögren's syndrome and the other with rheumatoid arthritis and, thus, perhaps secondary Sjögren's syndrome) responded well to methotrexate alone or methotrexate used in combination with a biologic [39].…”

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…Methotrexate was used initially as an antineoplastic agent in 1948 and for treatment of rheumatoid arthritis four decades later (Farber et al 1948;Gangaputra et al 2009). It was first implemented in the treatment of ocular inflammation in 1965 (Wong and Hersh 1965).…”

“…While methotrexate is most commonly administered orally, it can also be given via subcutaneous or intravitreal injections. When given orally, up to 35% of the dose is metabolized by intestinal flora prior to absorption; however, when parenterally administered, it is fully absorbed (Gangaputra et al 2009;Larson et al 2011). Gangaputra and colleagues retrospectively reviewed the records of 384 patients identified from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Study and found no significant difference in the effectiveness of subcutaneous versus oral routes of administration (Gangaputra et al 2009).…”

“…When given orally, up to 35% of the dose is metabolized by intestinal flora prior to absorption; however, when parenterally administered, it is fully absorbed (Gangaputra et al 2009;Larson et al 2011). Gangaputra and colleagues retrospectively reviewed the records of 384 patients identified from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Study and found no significant difference in the effectiveness of subcutaneous versus oral routes of administration (Gangaputra et al 2009). Among patients with anterior uveitis, intermediate uveitis, posterior or panuveitis, complete suppression of inflammation sustained for !28 days was reached in 55.6%, 47.4% and 38.6%, respectively, and corticosteroid-sparing success was achieved in 6 months among 46.1%, 41.3%, and 20.7%, respectively.…”

“…Intravitreal administration of methotrexate was first used in the treatment of uveitis in 2006 and was found to achieve a faster onset of action than systemic administration (Hardwig et al 2006;Taylor et al 2009), which typically takes up to 6 months to reach its full effect (Gangaputra et al 2009). When given intravitreally, the mechanism of action is thought to be primarily mediated by the release of adenosine into the extracellular space, ultimately inhibiting the activity of neutrophils, macrophages, and T lymphocytes (Cronstein et al 1993;Chan and Cronstein 2002;Bouma et al 1994;Constantin et al 1998).…”