When counseling individuals with RA who are initiating therapy, I explain that MTX is a drug that most patients with RA can and should be taking, but there are between 25% and 50% of patients who cannot or will not take it. I try to normalize this experience because it is important that patients feel that they can be forthcoming about those bothersome symptoms. I want to know if they are feeling subpar on MTX. Additionally, while MTX is the foundation of therapy for the large majority of patients with RA, there are certain groups of individuals in which the drug should be used with caution. These are patients for whom earlier biologic monotherapy may be appropriate. Those with chronic mildly elevated alanine aminotransferase and aspartate aminotransferase that is approximately 1.5 times the upper limit of normal are a concern. Although these patients do not have dangerously elevated levels, you do not want them in that range chronically.

It is common for patients and physicians to blame MTX for such elevated liver function tests (LFTs), but there are other common reasons for this, such as nonalcoholic steatohepatitis. In patients with elevated alanine aminotransferase/aspartate aminotransferase, I will typically discontinue MTX and reassess in a few months. In my experience, approximately 50% of the time, the LFTs do not change, and then we do an ultrasound that reveals nonalcoholic steatohepatitis. Thus, it is important to discuss with patients up front that the laboratory abnormalities may or may not be the drug, and that if the LFTs do not normalize while off of MTX, then I am probably going to want them back on MTX because it is likely helpful in controlling the underlying disease. We do not want patients to be avoidant of a useful therapy for reasons that relate to laboratory abnormalities and are not due to MTX.

Older patients and those with chronic kidney disease have the potential for toxicities such as cytopenias if the MTX dose is too high. For those with renal dysfunction, which is common in older patients, the key is to adjust the dose. I have patients in their 80s on a very low dose of MTX (5 mg/week) that I would never use in a younger person. There are no models that can predict intolerability to MTX, but we will likely have algorithms that can predict the ability to successfully stop MTX or biologics in the not too distant future. An interesting discussion will be the threshold of how high your chances of staying in remission after discontinuing MTX need to be to make it attractive to patients. For some, a 70% to 80% likelihood of staying in remission or low disease activity might be enough.