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Introduction

The first line therapy for ocular inflammation is usually corticosteroids. However, in situations that require chronic immune suppression, or in situations in which the adverse effects of corticosteroids are unsustainable, other immunomodulators are of extreme importance [1]. Immunomodulatory agents include the categories of antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), alkylating agents (cyclophosphamide, chlorambucil), T cell inhibitors (cyclosporine, tacrolimus) and cytokines inhibitors such as ☂ (interferon alfa)[2]. Of these, methotrexate is one of the most used in ocular pathology.

Mechanism of action

Methotrexate was introduced in 1948 as an antineoplastic agent [1]. In addition to being classified as an antineoplastic agent it incorporates the pharmacological classifications of antimetabolite, folic acid analogue, immunosuppressant and disease-modifying anti-rheumatic drug (DMARD) ☂.[3]

Its efficacy is attributed to the ability to inhibit key enzymes in the purine and pyrimidine biosynthesis, attenuating turnover and proliferation of malignant cells. As a potent inhibitor of dihydrofolate reductase(DHFR), the tetrahydrofolate production limiting enzyme, blocks the production of purines and pyrimidines de novo and interferes with DNA synthesis. It is understood, therefore, its application in inflammatory pathology, in which there is a high turnover and proliferation of inflammatory cells[4]. Thus, methotrexate reduces the rate of cell proliferation, increases the rate of T cell apoptosis, increases endogenous concentrations of adenosine, and alters the production of cytokines and humoral responses[5]

Side Effects

Inhibition of cell turnover is also responsible for many of the side effects of methotrexate. Although the most common side effects are nausea, vomiting and liver dysfunction, other side effects can occur as well. The potential effects of the central nervous system include headaches, fatigue, malaise and dizziness. Gastrointestinal symptoms include stomatitis, gingivitis, anorexia, diarrhea, and ulcers with or without gastrointestinal bleeding. Hepatotoxicity is a concern for patients at high doses, and with long-term use, cirrhosis may occur. At high doses, methotrexate can cause tubal toxicity, resulting in renal failure, whereas, at lower doses, it may cause severe myelosuppression[4, 6]. Folinic acid (leucovorin), a folate coenzyme, works without the need for reduction by the DHFR enzyme and restores the biosynthesis of thymidylate, purine and methionine even in the presence of methotrexate. Folinic acid is therefore used to "rescue" normal cells from toxicity during methotrexate therapy[2]. The widespread use of folic acid or folinic acid as a means of reducing these side effects is not, however, associated with any reduction in anti-inflammatory efficacy [4].

Methotrexate for ocular Inflammatory Diseases

The first use of methotrexate as a treatment for ocular inflammation was reported in 1965[1].

Several case series report that methotrexate is effective for ocular inflammation in general, as well as for specific ocular inflammatory conditions, including uveitis associated with juvenile idiopathic arthritis, sarcoidosis-related panuveitis, pemphigoid of mucous membranes, scleritis associated with rheumatoid arthritis and episcleritis, ophthalmia and corticosteroid-resistant uveitis[1, 2, 7–11].

The beneficial effects of methotrexate appeared to vary according to the type of ocular inflammation, with posterior uveitis or panuveitis responding to methotrexate less frequently than other forms of ocular inflammation on methotrexate therapy. On the other hand, it is possible that different subtypes of ocular inflammation in the same anatomical site may show heterogeneity of response to the methotrexate ☂, which was not directly addressed by this report. [1]

Dosing

Low dose methotrexate therapy is usually initiated as a 7.5 mg oral dose given once a week. The dose is usually increased to 15 mg / week for weeks to months, depending on the response[2]

References

1. Gangaputra S, Newcomb CW, Liesegang TL, Kaçmaz RO, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE (2009) Methotrexate for Ocular Inflammatory Diseases. Ophthalmology 116:2188-2198.e1 . doi: 10.1016/j.ophtha.2009.04.020

2. Okada AA (2005) Immunomodulatory Therapy for Ocular Inflammatory Disease: A Basic Manual and Review of the Literature. Ocul Immunol Inflamm 13:335–351 . doi: 10.1080/09273940590951034

3. Mager DR (2015) Methotrexate: Home Healthc Now 33:139–141 . doi: 10.1097/NHH.0000000000000203

4. Chan ESL Mechanisms of Action of Methotrexate. Bull Hosp Joint Dis 4

5. Cronstein BN (1997) THE MECHANISM OF ACTION OF METHOTREXATE. Rheum Dis Clin N Am 23:739–755 . doi: 10.1016/S0889-857X(05)70358-6

6. Mager DR (2015) Methotrexate: Home Healthc Now 33:139–141 . doi: 10.1097/NHH.0000000000000203

7. Shah SS, Lowder CY, Schmitt MA, Wilke WS, Kosmorsky GS, Meisler DM (1992) Low-dose Methotrexate Therapy for Ocular Inflammatory Disease. Ophthalmology 99:1419–1423 . doi: 10.1016/S0161-6420(92)31790-7

8. Bom S, Zamiri P, Lightman S (2001) Use of methotrexate in the management of sight-threatening uveitis. Ocul Immunol Inflamm 9:35–40 . doi: 10.1076/ocii.9.1.35.3983

9. Dev S, McCallum RM, Jaffe GJ (1999) Methotrexate treatment for sarcoid-associated panuveitis. Ophthalmology 106:111–118 . doi: 10.1016/S0161-6420(99)90011-8

10. Mccluskey P (2004) Methotrexate therapy for ocular cicatricial pemphigoid*1. Ophthalmology 111:796–801 . doi: 10.1016/j.ophtha.2003.07.010

11. Kaplan-Messas A, Barkana Y, Avni I, Neumann R (2003) Methotrexate as a first-line corticosteroid-sparing therapy in a cohort of uveitis and scleritis. Ocul Immunol Inflamm 11:131–139 . doi: 10.1076/ocii.11.2.131.15919