More than 60% of patients with RA, PsA report side effects in days after methotrexate dose
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Approximately 61% of patients with rheumatoid arthritis or psoriatic arthritis who use methotrexate report side effects following weekly dosing, including fatigue and nausea, according to data published in Rheumatology and Therapy.
“Currently, a gap exists in patient-centric studies that focus on the patient experience with MTX, including beliefs regarding its benefits and behavioral distress and anxiety experienced by patients in anticipation of their upcoming dose,” W. Benjamin Nowell, PhD, of the Global Healthy Living Foundation, in Upper Nyack, New York, and colleagues wrote. “An important feature of MTX use is that some symptoms may be temporally related to its weekly administration.”
“For example, patients may experience nausea, fatigue, or malaise within a few days after MTX dosing, which may subsequently improve over time until the next weekly dose is given,” they added. “This pattern is particularly difficult to study in clinical trials or with traditional study designs (eg, a cohort study) because it would require multiple study visits within the same week, which is something that may be infeasible from a participant burden perspective.”
According to the Nowell and colleagues, an online, app-based method for obtaining patient data between visits may improve accessibility and participation in a study or remote patient monitoring system requiring multiple data collection points within the same week.
Designed in part to establish digital data collection for remote patient monitoring, Nowell and colleagues conducted a proof-of-concept study to analyze methotrexate side effects in patients with RA or PsA. In part one of the study, the researchers recruited adults aged 19 years and older with either disease, who were past or current MTX users, from the ArthritisPower Patient-Powered Research Network Registry, a collaboration between the nonprofit Global Healthy Living Foundation and the University of Alabama at Birmingham. These participants were invited via email to complete an online, cross-sectional survey.
Among the 20,359 invited patients, a total of 671 agreed to participate and completed the survey, among whom 79% had RA. In part two of the study, the 353 participants who were current MTX users were enrolled in a longitudinal study in which they completed another brief online survey and completed Patient-Reported Outcomes Measurement Information System (PROMIS) 1-day nausea/vomiting and fatigue measures. Among these patients, 175 completed the survey, while 123 provided any electronic PROMIS data.
Nowell and colleagues used mixed models to compare the within-person change in PROMIS scores between the risk — defined as 6 to 36 hours after the dose — and control — 96 to 144 hours post-dose — time periods.
According to the researchers, 61% of current MTX users reported side effects, with the most common being fatigue. In all, 46% of MTX users reported fatigue symptoms. In part two of the study, among the 39 participants with baseline nausea and the 84 without, the mean increases in PROMIS-reported nausea were 5.1 (P<.0001) and 0.7 units (P=.135), respectively. Among the 51 patients with baseline fatigue, and the 72 without, the mean increases in PROMIS fatigue were 3.9 (P=.0003) and 0.4 units (P=.554), respectively.
“The entirely virtual nature of this longitudinal study is promising for future research with RA and PsA patients adopting remote patient monitoring as an essential component of digital health, where out-of-office data capture from patients is critical,” Nowell and colleagues wrote. “We would anticipate a framework such as that used in this study, deployed as part of routine clinical care, can improve patient–physician communication and subsequent medication adherence and has the potential to significantly impact clinical outcomes.”
The researchers added that their findings suggest that health care practitioners should consider the burden of MTX use in patients who may be bothered by weekly side effects, but nonetheless do not disclose them.
“These [adverse events (AEs)] associated with chronic medication use are often combined with preexisting fatigue, which is an important symptom experienced by patients with rheumatic diseases such as RA and PsA,” Nowell and colleagues wrote. “Based on this study’s findings, only half to two-thirds of patients taking MTX acknowledge its role in achieving optimal disease control yet were nevertheless still taking it.”
They added: “While only patients with intolerable side effects with MTX should be switched to alternative [conventional synthetic disease-modifying antirheumatic drugs]] or [biologic/targeted synthetic DMARDS (b/tsDMARDs)], if their clinician is able to have insights into tolerability problems, it allows dose adjustments or alteration in the route of administration (eg, to SQ injection) if needed.”
Perspective
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As the gold standard treatment for psoriatic arthritis and rheumatoid arthritis, methotrexate is all too familiar to rheumatology health care providers, as well as the patient-reported “blahs” that often come with its use. The fatigue and nausea are often associated with the timing of the weekly dosing; however, patients don’t always report these side effects and may not even notice the correlation initially.
This study is a great reminder to have upfront discussions with our patients regarding these common side effects and the timing in which they may experience them. However, what is unique, and perhaps more promising about this particular study, is its stray from the use of traditional research methods with the ability for patients to participate completely remotely via a digital platform and in real-time. As we continue to adapt to our new normal in a virtual health care space, this is promising for the future of research participation among our immunocompromised patients.
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Methotrexate is an effective medication for rheumatoid arthritis as well as other diseases such as psoriatic arthritis. However, like every medication, there are negatives to methotrexate. In this present proof of concept evaluation of remote patient monitoring, nausea and fatigue were found to be significant with MTX use.
Previous studies have shown that as many as 50% of RA and PsA patients discontinue MTX within 6 months to 2 years of treatment due to intolerance and gastrointestinal symptoms. Not mentioned in the list of adverse events is hair loss. My female patients report hair loss frequently and while this may be considered a “minor” problem from a medical standpoint, this is often significant to them. Over the years, we have used leucovorin 5 mg orally 12 hours after methotrexate to try to prevent hair loss, but even with this and the use of biotin, we have patients who refuse to take MTX.
Recent Healio Honoree Jack Cush, MD, has discussed the “blahs” with methotrexate for years. Patients often tell me that they have to take methotrexate on the weekend because they feel so bad for several days afterwards. Cush offered these suggestions for combating methotrexate toxicity:
- Use lower doses; higher dose equals more toxicity and oral ulcerations respond to lower methotrexate doses, folate, or vitamin A 8,000 units/day.
- For the post-MTX funk, use dextromethorphan 20-50 mg weekly, and give with methotrexate and then 8-12 hours later (as Mucinex DM).
For my patients, I have had success with leflunomide at 10 mg per day as a substitute for methotrexate. As with much of what we do in clinical practice, there are no double-blind, placebo-controlled trials to prove what is the best course of action, and trials of this sort will probably never be done.
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