Tuesday, 20 Aug 2019

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Methotrexate Update

I was delighted to see that investigators presenting work at EULAR 2018 haven’t lost interest in our old friend methotrexate, with a number of abstracts examining issues of safety, dose and route of administration.

Low incidence of methotrexate induced liver abnormalities

Most rheumatologists are very comfortable using methotrexate, but many of our patients have concerns about side effects – especially where liver toxicity is concerned. Research presented by a group from Reading, UK (Abstract SAT0215) should go a long way to help us to reassure them.  The group monitored liver function tests in 1964 rheumatology patients over the course of 13 months. The patient cohort included a mix of patients with RA, PsA, and AS) of whom 775 were taking one concomitant DMARD, 82 were on triple therapy and 396 on a biologic alongside their methotrexate. 

Whereas 2.4% of patients developed an elevated ALT (35-100U/l), only 0.51% (10 patients) developed an ALT >100 U/l. Abnormalities were persistent in 8 of these patients but only resulted in one patient in the cohort discontinuing their methotrexate. Although the reported incidence of ALT abnormalities is a bit lower than that in the published literature (some data on doses of methotrexate used in the cohort would also have been useful) this is good news and echoes  the feeling amongst most rheumatologists that this drug is mostly safe where the liver is concerned The authors also suggest that based on this data, that the current BSR guidelines (which suggest monitoring each 3 months on patients on stable doses of methotrexate) are appropriate.

SC safer than Oral Methotrexate

Most rheumatologists are increasingly comfortable with the use of injectable methotrexate. It certainly appears to be better absorbed and more effective than oral methotrexate a group of researchers from the UK propose that it may be safer too (Abstract SAT0235). Using an online safety monitoring tool, FBC and LFT results were monitored from 8394 patients since 

Whereas the mean dose of MTX used in those on sc dosing was higher (21mg vs 17mg, range 5-40mg) the difference in incidence of LFT abnormalities (ALT > 80 U/l) between the two groups was not statistically significant. Patients on injectable methotrexate however (151/949) were less likely to develop neutropenia than those on oral methotrexate (491/2093) (p <0.00001 sc vs oral). Whereas the liver toxicity data is a little underwhelming, sc methotrexate may well be safer where neutropenias are concerned.

The online monitoring tool used in the study, TA Monitor, was developed by a rheumatologist (http://www.therapyaudit.com/tamonitor/) and allows web based monitoring of adverse events to medications like methotrexate. Another thing that caught my eye in that study as the dose range (up to 40mg) of Methotrexate used.

50mg of sc Methotrexate appears well tolerated

A group of Italian and US researchers have been evaluating the tolerability and safety of higher does of sc Methotrexate in RA (Abstract SAT0228). Their study protocol was an open labelled pilot study of 12 weeks duration, where 9 patients with RA were treated initially with a dose of 50mg of sc methotrexate for 4 weeks, followed by 25mg weekly for 4 weeks and the 15mg weekly for 4 weeks. Overall these higher doses were well tolerated with only AE’s occurring in 4 patients, none of which were severe. One patient developed an ALT (<2 ULN) which resolved spontaneously (the same patient also developed vertigo and subsequently withdrew). One patient developed a UTI, another short lived low back pain which resolved, and one patient developed fatigue. 

Although the numbers are small and study duration short, it will be interesting to see if this regimen proves more effective than traditionally used methotrexate doses in RA.

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