Dr. Daniel E. Furst
When asked to comment on this, Dr. Daniel E. Furst noted that “there could be an awfully large selection bias in this study. If you ask yourself, ‘Why do people go to subcutaneous in an observational trial?’ it is possible that they didn’t have enough response to the oral. They didn’t go to a higher dose, but, rather stopped methotrexate altogether. The result is that injection looks better. I think this study has a significant flaw, as is often unavoidable in observational studies. This study, per se, does not prove that s.c. methotrexate has an advantage over oral methotrexate in terms of delay of starting a biologic.”
The increased bioavailability of subcutaneous administration versus oral – which is about 17% – does not make it necessarily better for all patients, Dr. Furst contended, although it can certainly be a good option for those affected by gastrointestinal side effects with oral administration. “Given that a 17% increase in bioavailability with subcutaneous administration, this equals about 3-4 mg extra methotrexate. 20 mg/week s.c. methotrexate equals about 23 or 24 mg/week of oral methotrexate. My point is that if a patients tolerates it, giving a little higher dose of oral methotrexate may be the same as giving a slightly higher dose subcutaneously. It is probably true, incidentally, that subcutaneous methotrexate, when given as a generic is less expensive than the oral. A 25-mg/mL vial costs somewhere in the range of one-half to one-third of oral.”
Waiting for 6 months of treatment with oral methotrexate is ideal when a patient is having some response but may not be appropriate for all, according to Dr. Furst, the Carl Pearson Professor of Medicine in the division of rheumatology at the University of California, Los Angeles. He cited research showing 35% of patients who did not yet have an ACR 20–level response at 12 weeks of treatment with oral methotrexate alone at 7.5-20 mg/week can reach that level of response by 26 weeks (Rheumatology. 2010;49[6]:1201-3). “What I took away from that is, on a practical basis, if patients have absolutely no response, however you define it, by 12 weeks, then stop. If they’re having some response, then wait and see if they get more response before stopping,” he said.
The claims analysis that Dr. O’Dell discussed at the NCRA annual meeting gets straight to that point of whether rheumatologists are giving methotrexate a long enough time to work. What compounds the problem, according to Dr. O’Dell, is that too few people are giving oral methotrexate a long enough chance to work or trying subcutaneous dosing. The analysis of claims data from 35,640 RA patients during 2009-2014 that he originally presented at the 2015 American College of Rheumatology annual meeting showed that 44% of patients who started on oral methotrexate alone stayed on it throughout the study period and didn’t need anything else.
Prescribers, however, stopped oral methotrexate at a mean dose of 15.3 mg and moved 87% straight to a biologic without giving subcutaneous methotrexate a shot. They did that after a median of less than 6 months, and within 3 months in more than 40% of patients. Of the patients who were given subcutaneous methotrexate when their oral formulation wasn’t enough that’s all most of them needed, as 72% remained on subcutaneous methotrexate alone for the remainder of the study period. The rest moved on to a biologic, but after a median of almost a year, not a few months. When their time on oral and subcutaneous methotrexate was included, their median time to a biologic was more than 2 years. The same results applied to patients who started treatment in 2009 or 2012.
What the evidence from the claims data study does not say is why physicians are prescribing this way. Some might suggest that the influence of pharmaceutical companies might have something to do with it, although the notion is controversial. A recent systematic review and meta-analysis of randomized, controlled trials that involved a direct comparison of methotrexate monotherapy against methotrexate plus a biologic or biologic monotherapy to treat RA concluded that there is a dosing bias in the trials where methotrexate monotherapy is underdosed because none of the 13 trials that met criteria to be in the review used a methotrexate dose of 25 mg/week (Ann Rheum Dis. 2016 Apr 18. doi: 10.1136/annrheumdis-2016-209383). The investigators, led by Dr. Josefina Durán of Pontificia Universidad Católica de Chile, Santiago, said that they used 25 mg/week as the maximum recommended dose because it is recommended by EULAR and expert opinion.