Rates and predictors of MTX side effects

4 minute read

A large study in early RA patients could help guide patients to make informed decisions about taking the drug and potentially increase adherence.

Methotrexate side effects may be higher than first believed, with a large UK study finding three in four rheumatoid arthritis patients affected in the first year.  

The findings on prevalence rates and predictors of adverse events over the first 12 months may help patients make informed decisions about starting MTX and potentially increase adherence, the authors say. 

The large prospective cohort study, published in Rheumatology, included adult patients diagnosed with RA within the previous two years who were commencing MTX for the first time. The Rheumatoid Arthritis Medication Study (RAMS) recruited patients from 38 centres in the UK from 2008 to 2019, with just over 1000 patients included in the analysis. 

Baseline data included demographic and lifestyle data, disease-related data, co-morbidities, other medication, labs and PROs. Patients were followed up at six and 12 months after starting MTX, with a pre-defined list used to systematically capture adverse events. 

More than three-quarters of patients (77.5%) reported having at least one adverse event over the 12 months, with fewer reports in the second six-month period than the first (57% vs 64% respectively). 

The most common side effects were gastrointestinal, affecting 42% of the cohort, with nausea the single most reported event (31.2%). Fatigue was reported by around 29% of patients, and headache by 19%. Diarrhoea, dizziness and cough were also quite common, and almost one in 10 reported alopecia.  

“The percentage of patients seemed higher than I had thought,” said Queensland rheumatologist Dr Claire Barrett. 

“I am a keen MTX prescriber and do look at the dose of MTX, the dose of folic acid, the route of MTX and use of calcium folinate to try and minimise MTX adverse effects and hence improve patient compliance, said Dr Barrett. 

When looking at baseline predictors of adverse events, researchers found that women were twice as likely as men to report gastrointestinal events and mucocutaneous events, five times more likely to report alopecia and one-and-a-half times more likely to report neurological adverse events. Older patients were less likely to report gastrointestinal and haematological problems. 

In terms of potentially modifiable factors, alcohol consumption was linked with increased odds of nausea and alopecia, but reduced risk of haematological events, while higher BMI was associated with gastrointestinal and mucocutaneous events.  

“Patients have reported to me over my many years that sometimes they just can’t tolerate alcohol while on MTX,” said Dr Barrett. 

“I’ve seen the suggestion of alcohol increasing nausea published elsewhere, so I have actually added to my MTX discussion when people report nausea that it would be worth staying on MTX but cutting out alcohol for a month and see if there is any improvement,” she said. 

Strengths of the study include the large sample of real-world patients and the systematic capture of adverse events. Limitations include the observational design which restricts causal interpretation of predictors, and the lack of a comparator arm which makes it harder to attribute findings to MTX alone. 

“There is a strong ‘nocebo’ effect with methotrexate, so it is a shame there was no comparator group in the study,” said Associate Professor Sean O’Neill, who recently finished his term as chair of the ARA therapeutics committee.  

“This would be really helpful in understanding the more frequent but so-called ‘milder’ adverse events (like nausea, headaches and fatigue) that are often a reason for discontinuation. Without a comparator group it is very hard to know how much the nocebo effect may be contributing.” 

“From the rheumatologist’s point of view these symptoms were disappointingly common but not unexpected and important to acknowledge,” Professor O’Neill said.

“On the other hand, the study was otherwise reassuring from a safety perspective and that may be helpful in communicating these risks.” 

For Melbourne rheumatologist Dr Tina Racunica, the paper was a useful addition to the body of evidence but held no great surprises.  

“Most of us know about fatigue, nausea, cytopenias and abnormal LFTs – these are what we would usually discuss with our patients,” said Dr Racunica. 

When discussing the drug’s side effects, Dr Racunica said she reassured patients that these could be minimised and tried to make these patients feel supported and in control, so that they would feel comfortable explaining if and why they stopped taking the medication.  

“If they are still very worried, I also usually throw in data from studies showing that methotrexate prolongs life in those with RA.” 

Rheumatology 2022, online 25 January

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