Managing interactions and enhancing safety in patients taking low-dose methotrexate

Low-dose methotrexate (LD-MTX) is recommended first line for the management of rheumatoid arthritis (RA) and is commonly used for other conditions including psoriasis (PsO) and inflammatory bowel disease (IBD).1-3These autoimmune inflammatory conditions put patients at higher risk for common infections due to the diseases themselves and potentially the immunomodulating therapies (e.g., LD-MTX) being used to manage them.4-8 The Infectious Diseases Society of America defines LD-MTX as ≤ 0.4 mg/kg/week and causing only low-level immunosuppression; however, MTX has a complex immunomodulatory mechanism of action that affects all immune cells involved in vaccine response.9,10 Patients taking LD-MTX are at the lowest risk for infectious complications when in remission and fully vaccinated, yet vaccine uptake in these patients is suboptimal.11 Causes of patient vaccine hesitancy include conflicting information on the safety of vaccines during LD-MTX therapy as well as healthcare provider uncertainty regarding the timing and safety of vaccine administration. Pharmacists can provide key information on vaccine use and safety for patients taking LD-MTX.Pharmacists are also best positioned with their knowledge of pharmacokinetics to assess drug interactions and other factors that might impact the appropriate dose or safety of LD-MTX in a given patient.These five tips should help pharmacists gain confidence in supporting patients using LD-MTX, including making decisions regarding vaccine administration and potential drug interactions.1. Realize that inactivated vaccine response may not be as strong or last as long, but vaccination is still worth it!Patients with autoimmune conditions like RA, PsO and IBD are at higher risk for vaccine-preventable infections including influenza, pneumococcal disease, COVID-19 and herpes zoster. A patient’s immunization history should be reviewed at diagnosis and at regular intervals thereafter.12Inactivated vaccines are considered safe and effective for patients using LD-MTX. They are ideally provided (at least 2 weeks) before the initiation of immunomodulating therapy, including LD-MTX, to maximize immunogenicity; however, treatment should not be delayed or held to provide vaccines.5,6,8While data on vaccine response in patients receiving LD-MTX are limited, available studies suggest seroconversion rates (short-term antibody response) are similar to that of the general population or somewhat attenuated, but adequate protection is still provided.4,5,10,12-14One way to improve the immunogenicity of influenza vaccine, specifically, is to hold LD-MTX for two weeks following vaccination.5,15 In a study investigating this approach, patients did not experience higher rates of RA disease flare; however, holding LD-MTX should only be considered when disease activity allows (e.g., patients in remission) and after shared decision-making with the patient.52. Be aware that live vaccines require an individualized approachLive attenuated vaccines are generally considered contraindicated in patients using LD-MTX due to the hypothetical risk of infection.4,5 While the need for live vaccines is rare in adults (e.g., yellow fever vaccine for travel to endemic areas), live vaccine use is increasing due to the resurgence of measles and need for MMR vaccine.Live vaccines are ideally administered four or more weeks before LD-MTX initiation or three or more months after discontinuation.16 However, cohort studies and a randomized controlled trial have demonstrated the efficacy and safety of MMR booster doses in children using various immunomodulatory therapies, including LD-MTX.17-20 European guidelines recommend an MMR booster without interruption of LD-MTX therapy in children with autoimmune inflammatory rheumatic diseases.21 North American guidance is more cautionary, recommending consideration of risk versus benefit and ideally interruption of therapy.4,5,7,22 The American College of Rheumatology states that MMR vaccine administration may be considered safe four or more weeks after stopping LD-MTX, with LD-MTX therapy resumed four weeks post-vaccination, in line with the Canadian Immunization Guide.5,163. Recognize that LD-MTX is very different than HD-MTX . . . but your computer doesn’t know that!LD-MTX use can pose other challenges in practice, given its potential adverse effects and drug interactions, which are confounded in dispensing and prescribing software by the use of high-dose MTX (HD-MTX) to treat malignant diseases. Dispensing software and drug information databases alert pharmacists to several potential drug interactions with MTX, with variable recommendations and often insufficient information to enable a quick clinical decision. Interactions between HD-MTX and nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs) or penicillins are real; however, these medications are generally considered safe in patients using LD-MTX.23-25The mechanism for drug interactions with MTX is mostly likely inhibition of renal tubular secretion, but genetic polymorphisms in transport proteins may also play a role. The risk for LD-MTX adverse effects is greatest in elderly patients and those with reduced renal function, low albumin, and/or folate deficiency, and with dosing errors (e.g., daily instead of weekly dosing).23,26-28 Use your knowledge of pharmacology and pharmacokinetics to make patient-specific decisions. For example, a patient who is > 75 years of age with poor nutrition and an eGFR of ~50 mL/min who is using an NSAID short-term for RA flare management should be monitored more closely for adverse effect symptoms and with their usual interval lab work.4. Help ensure LD-MTX safety and manage adverse effectsLD-MTX is associated with several nuisance adverse effects that contribute to reduced adherence or discontinuation. Pharmacists with access to laboratory information can help ensure ongoing safety of therapy by monitoring CBC/differential, ALT, eGFR (measured every 1–3 months) and albumin (measured annually); those without access can inquire about blood work adherence at each refill. Trends are important to follow, with LD-MTX dose adjustment or discontinuation considered when WBC 2x upper limit of normal, along with MCV > 105, serum creatinine increase > 30% over one year or eGFR < 50 mL/min, and/or albumin < 30 g/L.29,30 A rash, new/worsening dyspnea or dry cough, and severe sore throat are additional reasons to refer a patient for specialist reassessment.30A modestly elevated MCV may signal LD-MTX effectiveness and adherence,31 but may also be a sign of folate or vitamin B12 deficiency (which put patients at higher risk of toxicity, including pancytopenia).26,28 Folic acid supplementation (at least 1 mg daily or 5 mg weekly, but up to 10 mg daily) reduces nuisance adverse effects such as nausea, hair loss and mouth sores, as well as transaminitis, and improves adherence.32,33 Vitamin B12 supplementation may also be beneficial as patients on LD-MTX may have masked deficiency.34 Fortunately, with the short half-life of LD-MTX, nuisance adverse effects such as fatigue, ‘brain fog’, and malaise are short-lived (lasting 1–2 days after each weekly dose); they may be reduced with the use of dextromethorphan (30 mg bid on the day of and day following MTX) if deemed otherwise safe.35,365. Take responsibility for supporting specialist carePharmacists are ideally positioned to support their patient’s achievement of remission and reduce the incidence of autoimmune inflammatory disease-associated complications, such as cardiovascular disease, infections and certain types of cancer. We can support patient adherence and assess signs and symptoms by asking questions about their ability to perform activities of daily living, pain and quality of life (perhaps using validated tools37,38), and refer patients to their specialist for reconsideration of disease-modifying therapies if needed. You could ask a patient with RA, “Is there anything you’re not doing right now because of your joints?” You can also measure and manage modifiable cardiovascular risk factors (dyslipidemia, hypertension, diabetes, tobacco cessation), regularly assess for and update recommended vaccinations, and encourage screening for disease-associated malignancies at recommended ages and intervals.39,40SummaryLD-MTX is a complicated medication commonly used across a spectrum of autoimmune inflammatory disorders. The five tips presented in this article should help pharmacists understand how to best manage vaccine and drug interactions with LD-MTX and enable patients to get the most out of this important therapy with the fewest adverse outcomes.Jill Hall (Jill.Hall@ualberta.ca) is the Director of the PharmD Program and a Clinical Professor at the Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta in Edmonton. She works clinically as a pharmacist providing care to patients with inflammatory arthritis.References:Bykerk VP, Akhavan P, Hazlewood GS, et al. Canadian Rheumatology Association recommendations for pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs. J Rheumatol 2012;39:1559-82.Panaccione R, Steinhart AH, Bressler B, et al. Canadian Association of Gastroenterology clinical practice guideline for the management of luminal Crohn’s disease. J Can Assoc Gastroenterol 2019;2:e1-e34.Papp K, Gulliver W, Lynde C, et al. Canadian guidelines for the management of plaque psoriasis: overview. J Cut Med Surg 2011;15(4):210-9.Papp KA, Haraoui B, Kumar D, et al. Vaccination guidelines for patients with immune-mediated disorders taking immunosuppressive therapies: executive summary. 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Managing interactions and enhancing safety in patients taking low-dose methotrexate

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