Methotrexate

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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.

History

In the early 1940’s, folic acid was found to cure some patients with megaloblastic anemia resistant to vitamin B12 supplementation. Because acute leukemia in children has a similar morphologic appearance, folate was used in an attempt to treat acute leukemia. Instead of decreasing the amount of neoplastic cells, folate supplementation accelerated the disease. Subsequently, folate-deficient diets were shown by Heinle and Welch to decrease cell counts in acute leukemia. This led to an effort to synthesize folate antagonists for the treatment of acute leukemias. Aminopterin, a potent folate antagonist, was shown by Farber et al. to induce remission in children with acute lymphocytic leukemia. This discovery paved the way to research for novel folate antagonists and the advent of modern chemotherapy in the 1940’s. Aminopterin was found to inhibit the enzyme dihydrofolate reductase (DHFR), which is involved in the reduction of folate to its active form. Pyrimethamine was discovered soon after, which was shown to be a selective inhibitor of parasitic DHFR, followed by the discovery of Trimethoprim, a selective bacterial DHFR inhibitor. Following this, methotrexate was discovered and was shown to have a superior therapeutic index than aminopterin in mice, and methotrexate began to replace aminopterin in clinical settings. Since then, methotrexate has been evaluated in the treatment of almost all human cancers and is still used in a variety of neoplastic conditions. It has been shown to decrease the immune response and produce remission in autoimmune diseases such as rheumatoid arthritis and psoriasis [12].

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]    

Indications and Uses

FDA-Labeled Indications (per IBM Micromedex Drug Reference)

Acute lymphoid leukemia Juvenile idiopathic arthritis Severe psoriasis Severe rheumatoid arthritis

Non-FDA Labeled Indications (per IBM Micromedex Drug Reference)

Acute myeloid leukemia Asthma Bullous pemphigoid Carcinoma of bladder Carcinoma of penis Carcinoma of stomach Chronic myeloid leukemia Crohn's disease Cutaneous lupus erythematosus Dermatomyositis Ectopic pregnancy Felty's syndrome Graft versus host disease Granulomatosis with polyangiitis Hodgkin's disease Labyrinthine disorder Lipoid dermatoarthritis Lymphomatoid papulosis Malignant epithelial tumor of ovary Malignant lymphoma of the meninges Intraocular malignant lymphoma Non-lymphomatous malignant meningitis Mantle cell lymphoma Multiple sclerosis Myasthenia gravis Polymyalgia rheumatica Primary biliary cholangitis Primary central nervous system lymphoma Psoriatic arthritis Sarcoidosis Sézary's disease Soft tissue sarcomas Systemic lupus erythematosus Systemic onset juvenile chronic arthritis Takayasu's arterits Giant Cell arteritis Termination of pregnancy Transitional cell carcinoma of the urinary tract Uveitis Cerebral Vasculitis

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].

Pregnancy

MTX is contraindicated in women who are pregnant. Care should be taken in patients who are expecting to become pregnant as MTX is a known abortifacient that can also induce congenital anomalies if taken during pregnancy. In patients who are of childbearing age, most clinicians contraceptive use in women taking MTX as well as discontinuation of therapy in both women and men (Oligospermia and chromatid breaks have been reported) at least three months prior to conception.

Drug Interactions

As many as 777 different drugs are known to interact with MTX. Non-steroid anti-inflammatory drugs (NSAIDs) and proton-pump inhibitors may increase risk of bone marrow suppression, aplastic anemia, and gastrointestinal toxicity with high doses of MTX. Drugs that are protein-bound, such as salicylates, phenylbutazone, phenytoin, and sulfonamides, may displace MTX bound to serum albumin and increase toxicity. Probenecid and penicillins can inhibit renal clearance of MTX. Some oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics may decrease intestinal absorption by inhibiting bowel flora, suppressing metabolism of MTX, Care should be taken with concomitant use of other hepatotoxic drugs as it may increase the risk of hepatotoxicity. Vitamin preparations containing folic acid may decrease the desired effects of MTX. Folate deficiency may increase methotrexate toxicity.

Contraindications

Pregnancy Nursing mothers Alcoholism, alcoholic liver disease, other chronic liver disease Pre-existing blood dyscrasia Known allergy to MTX

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]

The Systemic Immunosuppressive Therapy for Eye Diseases (SITE) study retrospectively analyzed response for anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, scleritis and ocular cicatricial pemphigoid. Gangaputra et. al. conclusion was that methotrexate was moderately effective at suppressing inflammation for greater than or equal to 1 month within six months of therapy on a dose of prednisone less than or equal to 10mg per day. Upon further review by knickelbein et al, methotrexate was found to be particularly effective at controlling inflammation in anterior (62.6%) and intermediate uveitis (68.8%)[1,15].

Dosing

MTX formulations vary: oral, subcutaneous, intramuscular, intravenous, intrathecal and intravitreal. High systemic doses should be accompanied by leucovorin (folinic acid) to reduce potential toxicity (known as leucovorin rescue).

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]

Intraocular lymphoma: Intravitreal administration of 400ug in 0.1ml 2x week for 4 weeks followed by qweek x 8 weeks followed by qmonth x 9 months [14].

Patient Assistance and Education

http://www.rasuvo.com/patient-resources/prescription-savings-2/

http://www.rasuvo.com/patient-resources/methotrexate-disposal/

https://www.otrexup.com/patients-caregivers/otrexup-totalcare-patient/co-pay-card/

https://www.otrexup.com/patients-caregivers/otrexup-totalcare-patient/

https://www.astrazeneca-us.com/medicines/Affordability.html

http://xatmep.com/co-pay-and-reimbursement/

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

12. Bertino JR (2000). "Methotrexate: historical aspects". In Cronstein BN, Bertino JR (eds.). Methotrexate. Basel: Birkhäuser. ISBN 978-3-7643-5959-1

13. IBM Micromedex Drug Reference, methotrexate, accessed from https://www-micromedexsolutions-com, 4/24/2019.

14. Frenkel S, Hendler K, Siegal T, Shalom E, Pe’er J. Intravitreal metho-trexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol. 2008;92(3):383–388.

15. Knickelbein JE, Kim M, Argon E, Nussenblatt RB, Sen NH. Comparative efficacy of steroid-sparing therapies for non-infectious uveitis. Expert Rev Ophthalmol. 2017;12(4):313–319. doi:10.1080/17469899.2017.1319762