The method with Methotrexate.

Methotrexate in Rheumatoid Arthritis

Q: “At what stage of disease is methotrexate started in rheumatoid arthritis? Are there any criteria to start it?”

A: I shall begin answering this question with talking about the drug methotrexate.


Methotrexate


Methotrexate is a chemotherapy agent and immune system suppressant. It is used to treat various types of cancer, autoimmune diseases, ectopic pregnancy and for medical abortion.

In the context of its use in rheumatoid arthritis, it is classified as a DMARD (disease modifying antirheumatic drug). It works by inhibiting cytokinin production and purine biosynthesis with the inhibition of dihydrofolate reductase, and by stimulating adenosine release.

The purpose of using methotrexate in rheumatoid arthritis is not for symptomatic relief. The goals of treatment are as follows:


  • To control disease activity and joint pain
  • To maintain the ability to function in daily activities
  • To slow destructive joint changes
  • To delay disability.

This is why it is called a 'disease-modifying antirheumatic drug’.


The Use of Methotrexate in Rheumatoid Arthritis

Most rheumatologists today use oral methotrexate, often along with steroids (for symptomatic treatment), as the initial therapy for patients with both early (<6 months of symptoms) and established rheumatoid arthritis. Usually, it is started with a weekly dose of 7.5 - 10 mg which may be raised to 25 mg per week. The lack of uniform global guidelines on methotrexate dosage may be attributable to the highly variable absorption of oral methotrexate. The EULAR guidelines recommend administration of folic or folinic acid for patients to receive methotrexate. This significantly reduces the incidence of side effects, and improves compliance. It is recommended that folic or folinic acid be administered the day after methotrexate to avoid competition between for late and methotrexate for transport from the intestine to the bloodstream.

Treatment with oral methotrexate, with appropriate dose titration, should be continued for at least six months to accurately assess clinical response.

When oral methotrexate does not adequately control the progression of disease or is not tolerated well, the patient may be switched to subcutaneous methotrexate. This allows a greater amount of the drug to reach the circulation without increasing side effects.

If even subcutaneous methotrexate is not particularly effective, the next step in the pharmacotherapy for rheumatoid arthritis is the use of ‘combination DMARDs’ - using methotrexate in combination with other drugs like sulfasalazine and or hydroxychloroquine. Methotrexate might also be combined with biologic drugs such as abatacept and tocilizumab.


Contraindications to Methotrexate Use
  • Women who are pregnant or breastfeeding
  • Heavy alcohol users
  • Alcohol-induced or other chronic liver diseases
  • Immunodeficiency
  • Renal insufficiency
  • Anaemia, leukopenia or thrombocytopenia
  • Hypersensitivity to methotrexate
  • Certain lung diseases such as pneumonitis are interstitial lung disease of unknown cause
  • Active bacterial or herpes zoster infection
  • Active tuberculosis
  • Life-threatening fungal infection


Summary

In essence, methotrexate should be started as the initial therapy (along with steroids for symptomatic treatment) for rheumatoid arthritis, irrespective of the duration of the disease or the extent of damage, as long as its use is not contraindicated. Patients who do not tolerate oral methotrexate or do not show significant clinical improvement in 6 months may be switched to subcutaneous methotrexate. Poor disease control, even with subcutaneous methotrexate, can be ameliorated by the use of combination DMARDs and biological agents.


By Dr Anmol Dhawan


References
  1. Bello AE, Perkins EL, Jay R, Efthimiou P. [Internet]. Open Access Rheumatology : Research and Reviews. Dove Medical Press; 2017 [cited 2018Oct23]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386601/#__ffn_sectitle
  2. Singh JA, Saag KG, Bridges Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. [Internet]. Arthritis & rheumatology (Hoboken, N.J.). U.S. National Library of Medicine; 2016 [cited 2018Oct23]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26545940

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