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CHARLOTTE, N.C. – Methotrexate’s role as the mainstay drug of choice to treat rheumatoid arthritis has never been challenged, but questions persist as to why many rheumatologists don’t seem to titrate the dose of the drug up for a long enough period to see significant improvement in disease activity, or don’t instead start with or switch to subcutaneous administration before adding a biologic.
The issue is likely to come to greater prominence soon because of the rise of value-based care, according to Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.
“Rheumatologists will ultimately be held accountable for providing value-based care. We’ll be measured on how well patients are doing, hopefully, and how expensive it is for you to take care of them. When rheumatologists are scored in that way, they will look for ways to provide quality care less expensively. And when they do that, they’ll use more methotrexate, they’ll use higher doses of methotrexate, they’ll use subcutaneous methotrexate, they’ll use more conventional therapy,” he said in an interview.
Dr. O’Dell called for rheumatologists to give methotrexate a longer time to work and to give subcutaneous methotrexate a shot before moving on to biologics, based on analyses of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial and a U.S. pharmaceutical claims database study of methotrexate-prescribing habits during 2009-2014 that he presented at the annual meeting of the North Carolina Rheumatology Association (NCRA).
Overall, 28% of the early, poor-prognosis RA patients in the TEAR trial who were randomized to receive only oral methotrexate achieved a 28-joint Disease Activity Score (DAS28) of less than 3.2 at 24 weeks. The weekly dose of methotrexate was escalated if there were any tender or swollen joints, rising from 10 mg to 15 mg at 6 weeks and from 15 mg to 20 mg at 24 weeks. Those patients who did well on methotrexate alone showed no clinically meaningful or statistically significant clinical or radiographic differences at week 48 to the end of the study at week 102, compared with patients who initially took methotrexate alone but were randomized to either triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine or combination disease-modifying antirheumatic drug (DMARD) therapy with etanercept and methotrexate after having a DAS28 of 3.2 or higher at 24 weeks, as well as patients who were initially randomized to triple therapy or combination DMARD therapy at the start of the trial (Arthritis Rheum. 2013;65:1985-94).
“The TEAR trial clearly showed that there are many individual patients who do not require anything more than methotrexate alone,” Dr. O’Dell said in an interview. “It also showed that combinations of conventional therapy – methotrexate, sulfasalazine, hydroxychloroquine – are equally efficacious both clinically and radiographically to combinations of methotrexate and etanercept. One of the messages that the TEAR trial clearly showed us is that if you have a patient that needs to step up to a biologic, you can titrate methotrexate up and wait until the 6-month time point to make that decision. And if you wait until 6 months, the patient is not going to be harmed in terms of their ultimate clinical response, and they’re not going to be harmed in terms of radiographic progression.”
However, patients using methotrexate in the TEAR trial only went up to a maximum of 20 mg/week orally, and this itself may be improved on because of evidence for greater bioavailability of oral methotrexate when it is titrated up to even higher doses by 6 months. There also is evidence, although limited, for the superior efficacy and bioavailability of subcutaneous methotrexate, Dr. O’Dell said.
Some data are beginning to indicate the usefulness of going straight to subcutaneous rather than oral methotrexate, he said. Data from the prospective, observational Canadian Early Arthritis Cohort (CATCH) have shown that 55% of patients with early RA who used subcutaneous methotrexate alone as their initial treatment needed it only during the first year of treatment, compared with 23% who were treated initially with oral methotrexate alone. Lack of efficacy was the only statistically significant difference between the two groups that was cited as a reason for failure of the initial treatment, which was the case for 72% of oral users vs. 40% of subcutaneous users.
Another analysis from the CATCH study that was reported at the 2016 Congress of the European League Against Rheumatism (EULAR) suggested that use of subcutaneous methotrexate as an initial treatment for RA could reduce the use of biologics by 53% after adjustment for confounding variables, compared with use of oral methotrexate.
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.
The contention of bias in the trial due to underdosing was met with pointed questioning from Dr. Joel Kremer of the Center for Rheumatology and Albany (N.Y.) Medical College, and founder and chief executive officer of the Consortium of Rheumatology Researchers of North America (CORRONA). The fact that the authors relied on an expert consensus statement from 2009 to use as their basis for a maximal dose recommendation of 25 mg/week is not “clinical science,” he said in a commentary accompanying the report by Dr. Durán and colleagues (Ann Rheum Dis. 2016 Apr 20. doi: 10.1136/annrheumdis-2016-209505). No trials have shown that pushing the dose from 20 to 25 mg/week gives “significant further clinical improvement without experiencing some possible clinical or laboratory toxicity,” he said, noting that it doesn’t make sense to use a one-size-fits all approach to methotrexate dosing because “the balance between maximal efficacy and toxicity is highly variable and likely to be quite different in diverse genetic populations.” Also, because 7 of the 13 studies cited by the meta-analysis were from 2010 or before, they didn’t have the opportunity to incorporate the higher doses recommended by the expert panel into their designs. Rather than having any preplanned bias, he said, “the dosages and route of administration employed by these trials reflect the common empirical practice in vogue at the time those trials were conducted.”
“To me, the Durán study is significantly overstating the data,” Dr. Furst said. He pointed out that in some of the trials the patients “were actually allowed to use higher doses, but [the meta-analysis authors] said they didn’t. The data showed that they were using 20 mg/week as a mean, but some of them went higher because the standard deviation was 4.5 mg. So to say that it wasn’t the full dosing isn’t quite legit. They actually did allow the full dosing.”
“Dr. Kremer’s point is appropriate,” Dr. O’Dell said, “but it’s not the reality. His point is that there are not a lot of trials that say methotrexate gets better when you use 25 mg/week vs. 20 mg/week, or when you use it subcutaneously vs. orally, even though we know the bioavailability is substantially greater. He’s right in a strict sense, but the whole concept, everything we know, the common sense, tells us that pushing methotrexate to higher tolerable doses and using it subcutaneously is better for our patients. All the data that have looked at that supports that.”
Dr. O’Dell serves on advisory boards for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Coherus, Antares, and Medac. Dr. Furst has received research support and has received honoraria or fees for serving as a consultant or on the speakers’ bureau for many pharmaceutical companies that manufacturer biologics.
CHARLOTTE, N.C. – Methotrexate’s role as the mainstay drug of choice to treat rheumatoid arthritis has never been challenged, but questions persist as to why many rheumatologists don’t seem to titrate the dose of the drug up for a long enough period to see significant improvement in disease activity, or don’t instead start with or switch to subcutaneous administration before adding a biologic.
The issue is likely to come to greater prominence soon because of the rise of value-based care, according to Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.
“Rheumatologists will ultimately be held accountable for providing value-based care. We’ll be measured on how well patients are doing, hopefully, and how expensive it is for you to take care of them. When rheumatologists are scored in that way, they will look for ways to provide quality care less expensively. And when they do that, they’ll use more methotrexate, they’ll use higher doses of methotrexate, they’ll use subcutaneous methotrexate, they’ll use more conventional therapy,” he said in an interview.
Dr. O’Dell called for rheumatologists to give methotrexate a longer time to work and to give subcutaneous methotrexate a shot before moving on to biologics, based on analyses of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial and a U.S. pharmaceutical claims database study of methotrexate-prescribing habits during 2009-2014 that he presented at the annual meeting of the North Carolina Rheumatology Association (NCRA).
Overall, 28% of the early, poor-prognosis RA patients in the TEAR trial who were randomized to receive only oral methotrexate achieved a 28-joint Disease Activity Score (DAS28) of less than 3.2 at 24 weeks. The weekly dose of methotrexate was escalated if there were any tender or swollen joints, rising from 10 mg to 15 mg at 6 weeks and from 15 mg to 20 mg at 24 weeks. Those patients who did well on methotrexate alone showed no clinically meaningful or statistically significant clinical or radiographic differences at week 48 to the end of the study at week 102, compared with patients who initially took methotrexate alone but were randomized to either triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine or combination disease-modifying antirheumatic drug (DMARD) therapy with etanercept and methotrexate after having a DAS28 of 3.2 or higher at 24 weeks, as well as patients who were initially randomized to triple therapy or combination DMARD therapy at the start of the trial (Arthritis Rheum. 2013;65:1985-94).
“The TEAR trial clearly showed that there are many individual patients who do not require anything more than methotrexate alone,” Dr. O’Dell said in an interview. “It also showed that combinations of conventional therapy – methotrexate, sulfasalazine, hydroxychloroquine – are equally efficacious both clinically and radiographically to combinations of methotrexate and etanercept. One of the messages that the TEAR trial clearly showed us is that if you have a patient that needs to step up to a biologic, you can titrate methotrexate up and wait until the 6-month time point to make that decision. And if you wait until 6 months, the patient is not going to be harmed in terms of their ultimate clinical response, and they’re not going to be harmed in terms of radiographic progression.”
However, patients using methotrexate in the TEAR trial only went up to a maximum of 20 mg/week orally, and this itself may be improved on because of evidence for greater bioavailability of oral methotrexate when it is titrated up to even higher doses by 6 months. There also is evidence, although limited, for the superior efficacy and bioavailability of subcutaneous methotrexate, Dr. O’Dell said.
Some data are beginning to indicate the usefulness of going straight to subcutaneous rather than oral methotrexate, he said. Data from the prospective, observational Canadian Early Arthritis Cohort (CATCH) have shown that 55% of patients with early RA who used subcutaneous methotrexate alone as their initial treatment needed it only during the first year of treatment, compared with 23% who were treated initially with oral methotrexate alone. Lack of efficacy was the only statistically significant difference between the two groups that was cited as a reason for failure of the initial treatment, which was the case for 72% of oral users vs. 40% of subcutaneous users.
Another analysis from the CATCH study that was reported at the 2016 Congress of the European League Against Rheumatism (EULAR) suggested that use of subcutaneous methotrexate as an initial treatment for RA could reduce the use of biologics by 53% after adjustment for confounding variables, compared with use of oral methotrexate.
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.
The contention of bias in the trial due to underdosing was met with pointed questioning from Dr. Joel Kremer of the Center for Rheumatology and Albany (N.Y.) Medical College, and founder and chief executive officer of the Consortium of Rheumatology Researchers of North America (CORRONA). The fact that the authors relied on an expert consensus statement from 2009 to use as their basis for a maximal dose recommendation of 25 mg/week is not “clinical science,” he said in a commentary accompanying the report by Dr. Durán and colleagues (Ann Rheum Dis. 2016 Apr 20. doi: 10.1136/annrheumdis-2016-209505). No trials have shown that pushing the dose from 20 to 25 mg/week gives “significant further clinical improvement without experiencing some possible clinical or laboratory toxicity,” he said, noting that it doesn’t make sense to use a one-size-fits all approach to methotrexate dosing because “the balance between maximal efficacy and toxicity is highly variable and likely to be quite different in diverse genetic populations.” Also, because 7 of the 13 studies cited by the meta-analysis were from 2010 or before, they didn’t have the opportunity to incorporate the higher doses recommended by the expert panel into their designs. Rather than having any preplanned bias, he said, “the dosages and route of administration employed by these trials reflect the common empirical practice in vogue at the time those trials were conducted.”
“To me, the Durán study is significantly overstating the data,” Dr. Furst said. He pointed out that in some of the trials the patients “were actually allowed to use higher doses, but [the meta-analysis authors] said they didn’t. The data showed that they were using 20 mg/week as a mean, but some of them went higher because the standard deviation was 4.5 mg. So to say that it wasn’t the full dosing isn’t quite legit. They actually did allow the full dosing.”
“Dr. Kremer’s point is appropriate,” Dr. O’Dell said, “but it’s not the reality. His point is that there are not a lot of trials that say methotrexate gets better when you use 25 mg/week vs. 20 mg/week, or when you use it subcutaneously vs. orally, even though we know the bioavailability is substantially greater. He’s right in a strict sense, but the whole concept, everything we know, the common sense, tells us that pushing methotrexate to higher tolerable doses and using it subcutaneously is better for our patients. All the data that have looked at that supports that.”
Dr. O’Dell serves on advisory boards for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Coherus, Antares, and Medac. Dr. Furst has received research support and has received honoraria or fees for serving as a consultant or on the speakers’ bureau for many pharmaceutical companies that manufacturer biologics.
CHARLOTTE, N.C. – Methotrexate’s role as the mainstay drug of choice to treat rheumatoid arthritis has never been challenged, but questions persist as to why many rheumatologists don’t seem to titrate the dose of the drug up for a long enough period to see significant improvement in disease activity, or don’t instead start with or switch to subcutaneous administration before adding a biologic.
The issue is likely to come to greater prominence soon because of the rise of value-based care, according to Dr. James O’Dell, chief of the division of rheumatology at the University of Nebraska Medical Center, Omaha.
“Rheumatologists will ultimately be held accountable for providing value-based care. We’ll be measured on how well patients are doing, hopefully, and how expensive it is for you to take care of them. When rheumatologists are scored in that way, they will look for ways to provide quality care less expensively. And when they do that, they’ll use more methotrexate, they’ll use higher doses of methotrexate, they’ll use subcutaneous methotrexate, they’ll use more conventional therapy,” he said in an interview.
Dr. O’Dell called for rheumatologists to give methotrexate a longer time to work and to give subcutaneous methotrexate a shot before moving on to biologics, based on analyses of the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial and a U.S. pharmaceutical claims database study of methotrexate-prescribing habits during 2009-2014 that he presented at the annual meeting of the North Carolina Rheumatology Association (NCRA).
Overall, 28% of the early, poor-prognosis RA patients in the TEAR trial who were randomized to receive only oral methotrexate achieved a 28-joint Disease Activity Score (DAS28) of less than 3.2 at 24 weeks. The weekly dose of methotrexate was escalated if there were any tender or swollen joints, rising from 10 mg to 15 mg at 6 weeks and from 15 mg to 20 mg at 24 weeks. Those patients who did well on methotrexate alone showed no clinically meaningful or statistically significant clinical or radiographic differences at week 48 to the end of the study at week 102, compared with patients who initially took methotrexate alone but were randomized to either triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine or combination disease-modifying antirheumatic drug (DMARD) therapy with etanercept and methotrexate after having a DAS28 of 3.2 or higher at 24 weeks, as well as patients who were initially randomized to triple therapy or combination DMARD therapy at the start of the trial (Arthritis Rheum. 2013;65:1985-94).
“The TEAR trial clearly showed that there are many individual patients who do not require anything more than methotrexate alone,” Dr. O’Dell said in an interview. “It also showed that combinations of conventional therapy – methotrexate, sulfasalazine, hydroxychloroquine – are equally efficacious both clinically and radiographically to combinations of methotrexate and etanercept. One of the messages that the TEAR trial clearly showed us is that if you have a patient that needs to step up to a biologic, you can titrate methotrexate up and wait until the 6-month time point to make that decision. And if you wait until 6 months, the patient is not going to be harmed in terms of their ultimate clinical response, and they’re not going to be harmed in terms of radiographic progression.”
However, patients using methotrexate in the TEAR trial only went up to a maximum of 20 mg/week orally, and this itself may be improved on because of evidence for greater bioavailability of oral methotrexate when it is titrated up to even higher doses by 6 months. There also is evidence, although limited, for the superior efficacy and bioavailability of subcutaneous methotrexate, Dr. O’Dell said.
Some data are beginning to indicate the usefulness of going straight to subcutaneous rather than oral methotrexate, he said. Data from the prospective, observational Canadian Early Arthritis Cohort (CATCH) have shown that 55% of patients with early RA who used subcutaneous methotrexate alone as their initial treatment needed it only during the first year of treatment, compared with 23% who were treated initially with oral methotrexate alone. Lack of efficacy was the only statistically significant difference between the two groups that was cited as a reason for failure of the initial treatment, which was the case for 72% of oral users vs. 40% of subcutaneous users.
Another analysis from the CATCH study that was reported at the 2016 Congress of the European League Against Rheumatism (EULAR) suggested that use of subcutaneous methotrexate as an initial treatment for RA could reduce the use of biologics by 53% after adjustment for confounding variables, compared with use of oral methotrexate.
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.
The contention of bias in the trial due to underdosing was met with pointed questioning from Dr. Joel Kremer of the Center for Rheumatology and Albany (N.Y.) Medical College, and founder and chief executive officer of the Consortium of Rheumatology Researchers of North America (CORRONA). The fact that the authors relied on an expert consensus statement from 2009 to use as their basis for a maximal dose recommendation of 25 mg/week is not “clinical science,” he said in a commentary accompanying the report by Dr. Durán and colleagues (Ann Rheum Dis. 2016 Apr 20. doi: 10.1136/annrheumdis-2016-209505). No trials have shown that pushing the dose from 20 to 25 mg/week gives “significant further clinical improvement without experiencing some possible clinical or laboratory toxicity,” he said, noting that it doesn’t make sense to use a one-size-fits all approach to methotrexate dosing because “the balance between maximal efficacy and toxicity is highly variable and likely to be quite different in diverse genetic populations.” Also, because 7 of the 13 studies cited by the meta-analysis were from 2010 or before, they didn’t have the opportunity to incorporate the higher doses recommended by the expert panel into their designs. Rather than having any preplanned bias, he said, “the dosages and route of administration employed by these trials reflect the common empirical practice in vogue at the time those trials were conducted.”
“To me, the Durán study is significantly overstating the data,” Dr. Furst said. He pointed out that in some of the trials the patients “were actually allowed to use higher doses, but [the meta-analysis authors] said they didn’t. The data showed that they were using 20 mg/week as a mean, but some of them went higher because the standard deviation was 4.5 mg. So to say that it wasn’t the full dosing isn’t quite legit. They actually did allow the full dosing.”
“Dr. Kremer’s point is appropriate,” Dr. O’Dell said, “but it’s not the reality. His point is that there are not a lot of trials that say methotrexate gets better when you use 25 mg/week vs. 20 mg/week, or when you use it subcutaneously vs. orally, even though we know the bioavailability is substantially greater. He’s right in a strict sense, but the whole concept, everything we know, the common sense, tells us that pushing methotrexate to higher tolerable doses and using it subcutaneously is better for our patients. All the data that have looked at that supports that.”
Dr. O’Dell serves on advisory boards for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Coherus, Antares, and Medac. Dr. Furst has received research support and has received honoraria or fees for serving as a consultant or on the speakers’ bureau for many pharmaceutical companies that manufacturer biologics.
