5 Tips: Optimizing methotrexate therapy in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, progressive and painful autoimmune disease that affects the joints and other organs including the heart and lungs. Untreated, patients can suffer significant functional loss and joint damage, which can impact their quality of life (e.g., sleep, mental health, ability to remain in the labour force, overall health).1 Methotrexate (MTX), a folate metabolism inhibitor, is the recommended anchor treatment for RA.2 It can lead to low disease activity and possibly remission. However, in a U.S. study, 42% of patients reported not taking their MTX exactly as prescribed,3 and a Canadian study reported that 44% of women and 36% of men living with RA were not in remission after one year of treatment.4 This article highlights five tips for pharmacists to consider when supporting patients prescribed MTX for RA, with key points highlighted in bold print. 1. Encourage proper use of MTX MTX is administered ONCE a week for RA and should be given at the SAME TIME every week. It can be administered orally (use 2.5 mg tablets to avoid dosing errors with 10 mg tablets) or subcutaneously (SC), with a starting dose of at least 15 mg ONCE weekly (usually titrated up to 25 mg weekly).2 Several prefilled MTX syringes are available in Canada; some do NOT include needles for injecting the MTX and the pharmacist must provide them when dispensing. Educate your patients on proper administration and disposal of MTX SC syringes and provide a sharps’ disposal container. If a biologic DMARD is needed, due to the loss of benefit of the MTX or a change in disease activity, BOTH medications are continued. The biologic DMARD does not usually replace MTX, but is administered in conjunction with it. Pre-existing lung disease is not a contraindication for MTX. Use in patients with RA is recommended because of its benefit and the lack of alternatives with similar efficacy and/or superior long-term safety profiles. Patients should be informed of the risks and monitored for pneumonitis.2 2. Minimize MTX side effects Ask patients to describe any symptoms they believe are being caused by MTX. Sometimes RA symptoms can be confused with MTX side effects. For example, uncontrolled RA can cause fatigue, weight loss and a general feeling of unwellness. Common side effects of MTX include nausea, vomiting, diarrhea, mouth sores, fatigue and headache. Inform patients that switching from oral to SC MTX, especially when the dose is more than 15 mg once weekly, may improve tolerability and reduce gastrointestinal (GI) side effects.5 Instruct patients how to self-inject MTX SC; online videos are available to assist (e.g., rheuminfo.com or manufacturer websites). A family member can also be trained to give injections to a needle-averse patient. If the injection is too painful, suggest trying another brand of auto-injector. If bruising occurs at the injection site and the patient is not taking an anticoagulant or antiplatelet agent, suggest “slowing down” the injection speed. Remind patients to rotate injection sites between their abdomen and thighs. GI symptoms may be minimized by taking MTX at bedtime or splitting the weekly oral dose over a 12-hour period. Fatigue caused by MTX (for 24–48 hours after the weekly dose) usually resolves after four to six weeks of MTX therapy.2 MTX is usually prescribed with folic acid, either 5 mg once a week 24–48 hours after the weekly MTX dose, or 1 mg daily. It minimizes the elevation of liver function tests (LFTs) and reduces gastric and hematological side effects.2 Folic acid and sometimes vitamin B12 supplements may also reduce the risk of mouth sores and stomatitis. 3. Promote safe use of MTX Remind patients to get their bloodwork done as requested by their rheumatologist, preferably a day or two before their weekly dose. Bloodwork 24 hours after a MTX dose may falsely elevate LFTs. Regular bloodwork will include CBC (complete blood count), LFTs, creatinine, eGFR (estimated glomerular filtration rate) and CRP (C-reactive protein). These tests ensure that MTX is not accumulating due to reduced renal function and that it has not caused elevated LFTs (hepatic toxicity), and are also used to monitor RA activity (with CRP). MTX is not recommended in end-stage renal disease or hepatic disease.6 Remind patients that missing ONE weekly dose of MTX will not affect RA disease activity, but missing two or more consecutive doses may cause a flare in RA symptoms. Ensure there is no double dosing (e.g., dementia, forgetting they already took their weekly dose),7 by monitoring refill patterns. MTX is a teratogen; women of child-bearing age should use effective contraception while taking MTX. It should not be initiated in a woman planning to conceive in the near future. 4. Prevent potential drug interactions with MTX Trimethoprim, alone or in combination with sulfamethoxazole (co-trimoxazole), inhibits folate metabolism, like MTX. Concomitant use of MTX and trimethoprim–sulfamethoxazole can result in life-threatening myelosuppression, mucositis and nephrotoxicity.8 MTX is not contraindicated with other antibiotics (e.g., penicillins).9 Do not warn patients to avoid proton-pump inhibitors (PPIs) or nonsteroidal anti-inflammatory drugs (NSAIDs) when taking MTX.9 The low weekly dose of MTX used to treat RA is NOT contraindicated with PPIs or NSAIDs. This warning is only clinically relevant with larger, (2000–3000 mg) oncologic doses of MTX. NSAIDs are often prescribed concomitantly to manage RA symptoms. Most drug databases recommend avoiding alcohol when taking MTX. Encourage patients to discuss alcohol intake with their rheumatologist before recommending abstaining, as some physicians will allow low to moderate alcohol consumption. However, as hepatic toxicity risk is increased when MTX and alcohol are combined, suggest avoiding alcohol on the day of their weekly MTX dose.10 Monitoring of LFTs will reveal the impact (if any) of alcohol consumption with MTX. Some rheumatologists hold MTX for one to two weeks after influenza or COVID-19 vaccination. The potential benefits of doing so (improved immune response to the vaccine) and risks (disease flare) must be considered and decisions should be individualized.11,12 Smoking can reduce the benefit/efficacy of MTX.13 Encourage patients with RA to quit smoking to improve their response to MTX and to lower their cardiovascular risks.13 5. Maximize MTX effectiveness The goal of MTX therapy is to achieve low disease activity or remission of RA, thereby preventing joint damage and improving functionality and quality of life. It takes six to 12 weeks to achieve maximal benefit from MTX. Efficacy and tolerability should be assessed six weeks after initiating MTX, and then every three months. Monitor RA activity at each MTX refill by asking patients about their pain, morning stiffness, fatigue, sleep and physical function. Any complaints in these areas are a signal to review current MTX use. Suggest ways to help manage RA flares. Flares can be triggered by stress, infection, surgery, the birth of a baby, relationship issues or the death of a loved one. Differentiating a flare from a change in RA disease activity is challenging. Help patients identify possible triggers and refer them to their rheumatologist for any significant change in their RA symptoms. Suggest icing swollen joints and the use of symptom relievers (e.g., NSAIDs) in the interim. Medication adherence is key to the successful management of RA. Pharmacists can monitor adherence as well as support patients who may not be taking their MTX. If patients say they don’t like taking MTX, remind them that the medication won’t work if they don’t take it, and that uncontrolled RA can produce permanent joint damage, pain and deformity. Stopping MTX because they feel better usually results in a RA flare in three to four weeks. Summary Ask your patients taking MTX for RA to let you help them manage any challenges they might be experiencing with this medication. Shared decision-making, when patients are informed of all their options, is key to the success of their treatment plan.2 MTX is safe and effective when used properly with ongoing monitoring for efficacy and to prevent toxicity. Working with your patients to achieve and maintain RA control with MTX will also help to reduce the use of expensive targeted synthetic DMARDs and/or biologic DMARDs, and costs to the healthcare system. Carolyn Dittmar is a pharmacist working at The Geriatric Assessment and Intervention Network (GAIN) Clinic, City of Kawartha Lakes Community Care, in Lindsay, ON. From 2006 until it was closed in 2021, she was a pharmacist at The Arthritis Program, Southlake Regional Health Centre, Newmarket, ON, where she performed patient assessments, participated in rheumatology clinics, provided medication reviews and in-person and virtual patient education on inflammatory arthritis, osteoarthritis, fibromyalgia and osteoporosis. She also provided patients with methotrexate education and SC injection instruction for many years. References 1. Badley EM, Wilfong JM, Zahid S, et al. The status of arthritis In Canada: national report. Arthritis Community Research and Evaluation Unit (ACREU), prepared for the Arthritis Society: August 2019. (accessed April 8, 2022). 2. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. (accessed April 8, 2022). 3. DiBenedetti DB, Xhou X, Reynolds M, et al. Assessing methotrexate adherence in rheumatoid arthritis: a cross-sectional survey. Rheumatol Ther 2015;2:73-84. doi: 10.1007/s40744-015-0011-1. 4. Bartlett SJ, Schieir O, Valois MF, et al. Lifestyle and MTX use are the strongest predictors of not achieving remission in the first year of rheumatoid arthritis: results from the Canadian Early Arthritis. Cohort (CATCH) [abstract]. Arthritis Rheumatol 2018; 70 (suppl 10). (accessed April 8, 2022). 5. Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration. Ann Rheum Dis 2014;73:1549-51. 6. ISMP Canada. Heightened risk of methotrexate toxicity in end-stage renal disease. ISMP Canada Safety Bulletin 2022;22(3). (accessed April 8, 2022). 7. Thompson JA, Love JS, Hendrickson RG. Methotrexate toxicity from unintentional dosing errors: calls to a poison center and death descriptions. J Am Board Fam Med 2021;34(6):1246-8.(accessed April 8, 2022). 8. Cudmore J, Seftel M, Sisler J, et al. Methotrexate and trimethoprim-sulfamethoxazole: toxicity from this combination continues to occur. Can Fam Physician 2014;60(1):53-6. (accessed April 8, 2022). 9. Hall JJ, Bolina M, Chatterley T, et al. Interaction between low-dose methotrexate and nonsteroidal anti-inflammatory drugs, penicillins, and proton pump inhibitors. Ann Pharmacother 2017;51(2):163-78. (accessed April 8, 2022). 10. Reardon J. Low-dose methotrexate—is any amount of alcohol safe? Canadian Healthcare Network Blog: Therapeutics Issues; February 21, 2021. (accessed April 8, 2022). 11. Mehta P, Sanchez E, Moraitis E, et al. Influenza vaccination and interruption of methotrexate in adult patients in the COVID-19 era: an ongoing dilemma. Lancet Rheumatol 2021;3(1):e9-10.doi: 10.1016/S2665-9913(20)30392-1. 12. Canadian Rheumatology Association. Position statement on COVID-19 vaccination. Version 6.0. March 25, 2022. (accessed August 11, 2022). 13. Safy-Khan M, de Hair MJH, Welsing PMJ, et al. Current smoking negatively affects the response to methotrexate in rheumatoid arthritis in a dose-responsive way, independently of concomitant prednisone use. J Rheumatol 2021;48:1504-7. doi: 10.3899/jrheum.200213.

5 Tips: Optimizing methotrexate therapy in rheumatoid arthritis

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