Synthetic triple therapy matches anti-TNF therapy in RA

MADRID – When rheumatoid arthritis patients fail initial treatment with methotrexate monotherapy, are they better served by a less expensive step-up treatment or the one that may better slow their radiographic progression and produce faster responses?

That seems to be the choice between step-up from methotrexate monotherapy by adding synthetic disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and hydroxychloroquine, or by adding a tumor necrosis factor (TNF) inhibitor such as etanercept.

Mitchel L. Zoler/IMNG Medical Media

The RACAT (Rheumatoid Arthritis: Comparison of Active Therapies) trial tested those two options in 353 rheumatoid arthritis (RA) patients at 36 U.S. or Canadian sites between July 2007 and December 2010. The study’s primary endpoint, improvement in average disease activity score in 28 joints (DAS28) from baseline to 48 weeks of treatment, was similar in both treatment arms, proving the noninferiority of the triple synthetic DMARD regimen against the etanercept, biological arm, Dr. James R. O’Dell reported in a poster at the annual European Congress of Rheumatology. The results also appeared online simultaneously with Dr. O’Dell’s poster presentation (N. Engl. J. Med. 2013 June 11 [doi: 10.1056/NEJMoal1303006]).

"We showed that starting first with a TNF inhibitor or first with triple therapy resulted in the same outcomes. But costs were not the same. We [successfully] treated another 30% of patients who did not need a biologic" with the synthetic triple therapy. "And in the patients where triple therapy doesn’t work, you can change them to a biologic and they have identical outcomes, clinically by DAS28 and radiographically," compared with patients who began on etanercept added to methotrexate from the start, he said. Dr. O’Dell is chief of rheumatology at the VA Medical Center in Omaha, Neb., and professor of medicine at the University of Nebraska.

"Nothing is lost for the patient; if they don’t do well on triple therapy they can switch to a biological. The data are persuasive and the economic case is easy to make. You absolutely ought to go with triple therapy," he concluded based on the study findings.

But "it is very difficult to get physicians to buy into this" strategy, he said in an interview. TNF inhibitors such as etanercept and other biological DMARDs are "seductive," Dr. O’Dell said, because they are effective, work quickly, and appear more "targeted" than synthetic DMARDs, and they are promoted by well-financed marketing campaigns.

Dr. O’Dell conceded that the study data showed a signal of more radiographic progression with triple synthetic DMARD treatment that could potentially, over time, accrue to more substantial differences. At 48 weeks after the onset of treatment, patients on triple therapy had an average 0.54-point increase (worsening) in their van der Heijde modified Sharp score, compared with an average 0.29-point rise in the patients who received etanercept, a 0.25-point average difference in favor of etanercept that did not reach statistical significance.

But this trend toward greater radiographic progression in patients on triple therapy was consistent with the statistically significant, roughly 1-point average additional increased radiographic progression with triple therapy, compared with patients on methotrexate plus etanercept, that was seen after 2 years of follow-up in the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial (Arthritis Rheum. 2012;64:2824-35).

The TEAR study, which enrolled patients with very early RA, included a subgroup with an inadequate response to methotrexate monotherapy, and in that subgroup, patients randomized to triple therapy and those randomized to etanercept plus methotrexate had similar clinical outcomes, consistent with the new study findings.

"It’s hard to say that 1 or 2 units on the Sharp score doesn’t matter much, even if you don’t see the difference for several years," commented Dr. Daniel Furst, professor of medicine and director of the Rheumatology Clinical Research Center at the University of California, Los Angeles.

"Triple therapy is effective clinically, but it doesn’t do so well for x-rays. There are relationships between a 1 or 2 Sharp score difference and long-term outcomes. Across the board with biologics, the difference is 1 or 2 Sharp units. If one’s philosophy is to hit the RA hard and stop it, then perhaps a biologic is better," Dr. Furst commented in an interview.

But another view was that triple therapy could play a useful and cost-effective role. The new findings, along with the TEAR results, make "initial treatment of early RA with triple therapy a reasonable approach," said Dr. Joel M. Kremer, a professor of medicine at Albany (N.Y.) Medical College and director of research at the Center for Rheumatology in Albany. The only clear downside is that if triple therapy doesn’t work, the patient loses time, but that’s true for every treatment option, he noted.

"We don’t usually have the opportunity to hear the data for generic drugs" as much as for brand-name formulations, Dr. Kremer said in an interview. "Will data like this substantially change prescribing patterns? Probably not, but what might happen is that insurers may look at these data and say that patients should fail triple therapy before starting a biologic. That would be a sea change" for rheumatology, he added.

"I have always used methotrexate first, usually in combination with hydroxychloroquine," Dr. Kremer said. He has not usually also prescribed sulfasalazine, but said he would consider adding it based on the new data.

The new study enrolled patients with a DAS28 score of 4.4 or higher despite at least 12 weeks of stable methotrexate therapy with a weekly dosage of 15-25 mg. The patients averaged about 57 years old. After the first 24 weeks on randomized treatment, patients who did not have a decrease in their DAS28 of at least 1.2 units switched to the alternate regimens. The primary outcome was change in DAS28 at week 48 according to initial treatment assignment; the researchers collected 48-week DAS28 scores from 309 enrolled patients. The mean change in DAS28 from baseline at 48 weeks was a 2.12-unit reduction in the triple-therapy patients and a 2.29-unit reduction in the etanercept patients, an average 0.17-unit difference between the two treatment arms that was not statistically significant and that fell within the study’s prespecified range for noninferiority for triple therapy.

A similar percentage of patients, 27%, in each of the treatment arms switched to the alternate therapy at 24 weeks due to lack of an adequate initial response. There were also no statistically significant differences between the treatment arms in their rate of American College of Rheumatology (ACR) 20 and 50 responses at both 24 and 48 weeks.

The results showed significant differences between the treatment arms after the first 24 weeks of treatment for higher-level responses. For example, the percentage of patients achieving an ACR 70 response was 5% in the triple-therapy patients and 16% in the etanercept patients, a statistically significant difference. The rate of patients with a DAS28 score of 2.6 points or less at 24 weeks was 13% in the triple-therapy patients and 22% in those on etanercept, a significant difference.

Based on findings like these, "I would start a biologic in a patient who failed high-dose methotrexate and had poor prognostic factors and highly active disease, because at 6 months etanercept had the edge," said Dr. Edward C. Keystone, director of the Centre for Arthritis and Autoimmune Disease at Mount Sinai Hospital in Toronto, and a coinvestigator on the new study. But for all the other patients, "why not start on triple therapy first if you can switch them later if needed and the patients do well?" he asked. "The important observation is that the same percentage of patients failed in each arm. That is a huge message."

The RACAT study received no commercial support. Dr. O’Dell said that he had no disclosures. Dr. Furst has been a consultant to or received grant support from Abbott, Amgen, Bristol-Myers Squibb, and other companies. Dr. Kremer has been a consultant to or received grant support from Pfizer, Abbott, Genentech, and other companies. Dr. Keystone said that he has been a consultant to or has received research grants from Amgen, Pfizer, Merck, and other companies.

mzoler@frontlinemedcom.com On Twitter @mitchelzoler

MADRID – When rheumatoid arthritis patients fail initial treatment with methotrexate monotherapy, are they better served by a less expensive step-up treatment or the one that may better slow their radiographic progression and produce faster responses?

That seems to be the choice between step-up from methotrexate monotherapy by adding synthetic disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and hydroxychloroquine, or by adding a tumor necrosis factor (TNF) inhibitor such as etanercept.

Mitchel L. Zoler/IMNG Medical Media

The RACAT (Rheumatoid Arthritis: Comparison of Active Therapies) trial tested those two options in 353 rheumatoid arthritis (RA) patients at 36 U.S. or Canadian sites between July 2007 and December 2010. The study’s primary endpoint, improvement in average disease activity score in 28 joints (DAS28) from baseline to 48 weeks of treatment, was similar in both treatment arms, proving the noninferiority of the triple synthetic DMARD regimen against the etanercept, biological arm, Dr. James R. O’Dell reported in a poster at the annual European Congress of Rheumatology. The results also appeared online simultaneously with Dr. O’Dell’s poster presentation (N. Engl. J. Med. 2013 June 11 [doi: 10.1056/NEJMoal1303006]).

"We showed that starting first with a TNF inhibitor or first with triple therapy resulted in the same outcomes. But costs were not the same. We [successfully] treated another 30% of patients who did not need a biologic" with the synthetic triple therapy. "And in the patients where triple therapy doesn’t work, you can change them to a biologic and they have identical outcomes, clinically by DAS28 and radiographically," compared with patients who began on etanercept added to methotrexate from the start, he said. Dr. O’Dell is chief of rheumatology at the VA Medical Center in Omaha, Neb., and professor of medicine at the University of Nebraska.

"Nothing is lost for the patient; if they don’t do well on triple therapy they can switch to a biological. The data are persuasive and the economic case is easy to make. You absolutely ought to go with triple therapy," he concluded based on the study findings.

But "it is very difficult to get physicians to buy into this" strategy, he said in an interview. TNF inhibitors such as etanercept and other biological DMARDs are "seductive," Dr. O’Dell said, because they are effective, work quickly, and appear more "targeted" than synthetic DMARDs, and they are promoted by well-financed marketing campaigns.

Dr. O’Dell conceded that the study data showed a signal of more radiographic progression with triple synthetic DMARD treatment that could potentially, over time, accrue to more substantial differences. At 48 weeks after the onset of treatment, patients on triple therapy had an average 0.54-point increase (worsening) in their van der Heijde modified Sharp score, compared with an average 0.29-point rise in the patients who received etanercept, a 0.25-point average difference in favor of etanercept that did not reach statistical significance.

But this trend toward greater radiographic progression in patients on triple therapy was consistent with the statistically significant, roughly 1-point average additional increased radiographic progression with triple therapy, compared with patients on methotrexate plus etanercept, that was seen after 2 years of follow-up in the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial (Arthritis Rheum. 2012;64:2824-35).

The TEAR study, which enrolled patients with very early RA, included a subgroup with an inadequate response to methotrexate monotherapy, and in that subgroup, patients randomized to triple therapy and those randomized to etanercept plus methotrexate had similar clinical outcomes, consistent with the new study findings.

"It’s hard to say that 1 or 2 units on the Sharp score doesn’t matter much, even if you don’t see the difference for several years," commented Dr. Daniel Furst, professor of medicine and director of the Rheumatology Clinical Research Center at the University of California, Los Angeles.

"Triple therapy is effective clinically, but it doesn’t do so well for x-rays. There are relationships between a 1 or 2 Sharp score difference and long-term outcomes. Across the board with biologics, the difference is 1 or 2 Sharp units. If one’s philosophy is to hit the RA hard and stop it, then perhaps a biologic is better," Dr. Furst commented in an interview.

But another view was that triple therapy could play a useful and cost-effective role. The new findings, along with the TEAR results, make "initial treatment of early RA with triple therapy a reasonable approach," said Dr. Joel M. Kremer, a professor of medicine at Albany (N.Y.) Medical College and director of research at the Center for Rheumatology in Albany. The only clear downside is that if triple therapy doesn’t work, the patient loses time, but that’s true for every treatment option, he noted.

"We don’t usually have the opportunity to hear the data for generic drugs" as much as for brand-name formulations, Dr. Kremer said in an interview. "Will data like this substantially change prescribing patterns? Probably not, but what might happen is that insurers may look at these data and say that patients should fail triple therapy before starting a biologic. That would be a sea change" for rheumatology, he added.

"I have always used methotrexate first, usually in combination with hydroxychloroquine," Dr. Kremer said. He has not usually also prescribed sulfasalazine, but said he would consider adding it based on the new data.

The new study enrolled patients with a DAS28 score of 4.4 or higher despite at least 12 weeks of stable methotrexate therapy with a weekly dosage of 15-25 mg. The patients averaged about 57 years old. After the first 24 weeks on randomized treatment, patients who did not have a decrease in their DAS28 of at least 1.2 units switched to the alternate regimens. The primary outcome was change in DAS28 at week 48 according to initial treatment assignment; the researchers collected 48-week DAS28 scores from 309 enrolled patients. The mean change in DAS28 from baseline at 48 weeks was a 2.12-unit reduction in the triple-therapy patients and a 2.29-unit reduction in the etanercept patients, an average 0.17-unit difference between the two treatment arms that was not statistically significant and that fell within the study’s prespecified range for noninferiority for triple therapy.

A similar percentage of patients, 27%, in each of the treatment arms switched to the alternate therapy at 24 weeks due to lack of an adequate initial response. There were also no statistically significant differences between the treatment arms in their rate of American College of Rheumatology (ACR) 20 and 50 responses at both 24 and 48 weeks.

The results showed significant differences between the treatment arms after the first 24 weeks of treatment for higher-level responses. For example, the percentage of patients achieving an ACR 70 response was 5% in the triple-therapy patients and 16% in the etanercept patients, a statistically significant difference. The rate of patients with a DAS28 score of 2.6 points or less at 24 weeks was 13% in the triple-therapy patients and 22% in those on etanercept, a significant difference.

Based on findings like these, "I would start a biologic in a patient who failed high-dose methotrexate and had poor prognostic factors and highly active disease, because at 6 months etanercept had the edge," said Dr. Edward C. Keystone, director of the Centre for Arthritis and Autoimmune Disease at Mount Sinai Hospital in Toronto, and a coinvestigator on the new study. But for all the other patients, "why not start on triple therapy first if you can switch them later if needed and the patients do well?" he asked. "The important observation is that the same percentage of patients failed in each arm. That is a huge message."

The RACAT study received no commercial support. Dr. O’Dell said that he had no disclosures. Dr. Furst has been a consultant to or received grant support from Abbott, Amgen, Bristol-Myers Squibb, and other companies. Dr. Kremer has been a consultant to or received grant support from Pfizer, Abbott, Genentech, and other companies. Dr. Keystone said that he has been a consultant to or has received research grants from Amgen, Pfizer, Merck, and other companies.

mzoler@frontlinemedcom.com On Twitter @mitchelzoler

MADRID – When rheumatoid arthritis patients fail initial treatment with methotrexate monotherapy, are they better served by a less expensive step-up treatment or the one that may better slow their radiographic progression and produce faster responses?

That seems to be the choice between step-up from methotrexate monotherapy by adding synthetic disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and hydroxychloroquine, or by adding a tumor necrosis factor (TNF) inhibitor such as etanercept.

Mitchel L. Zoler/IMNG Medical Media

The RACAT (Rheumatoid Arthritis: Comparison of Active Therapies) trial tested those two options in 353 rheumatoid arthritis (RA) patients at 36 U.S. or Canadian sites between July 2007 and December 2010. The study’s primary endpoint, improvement in average disease activity score in 28 joints (DAS28) from baseline to 48 weeks of treatment, was similar in both treatment arms, proving the noninferiority of the triple synthetic DMARD regimen against the etanercept, biological arm, Dr. James R. O’Dell reported in a poster at the annual European Congress of Rheumatology. The results also appeared online simultaneously with Dr. O’Dell’s poster presentation (N. Engl. J. Med. 2013 June 11 [doi: 10.1056/NEJMoal1303006]).

"We showed that starting first with a TNF inhibitor or first with triple therapy resulted in the same outcomes. But costs were not the same. We [successfully] treated another 30% of patients who did not need a biologic" with the synthetic triple therapy. "And in the patients where triple therapy doesn’t work, you can change them to a biologic and they have identical outcomes, clinically by DAS28 and radiographically," compared with patients who began on etanercept added to methotrexate from the start, he said. Dr. O’Dell is chief of rheumatology at the VA Medical Center in Omaha, Neb., and professor of medicine at the University of Nebraska.

"Nothing is lost for the patient; if they don’t do well on triple therapy they can switch to a biological. The data are persuasive and the economic case is easy to make. You absolutely ought to go with triple therapy," he concluded based on the study findings.

But "it is very difficult to get physicians to buy into this" strategy, he said in an interview. TNF inhibitors such as etanercept and other biological DMARDs are "seductive," Dr. O’Dell said, because they are effective, work quickly, and appear more "targeted" than synthetic DMARDs, and they are promoted by well-financed marketing campaigns.

Dr. O’Dell conceded that the study data showed a signal of more radiographic progression with triple synthetic DMARD treatment that could potentially, over time, accrue to more substantial differences. At 48 weeks after the onset of treatment, patients on triple therapy had an average 0.54-point increase (worsening) in their van der Heijde modified Sharp score, compared with an average 0.29-point rise in the patients who received etanercept, a 0.25-point average difference in favor of etanercept that did not reach statistical significance.

But this trend toward greater radiographic progression in patients on triple therapy was consistent with the statistically significant, roughly 1-point average additional increased radiographic progression with triple therapy, compared with patients on methotrexate plus etanercept, that was seen after 2 years of follow-up in the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial (Arthritis Rheum. 2012;64:2824-35).

The TEAR study, which enrolled patients with very early RA, included a subgroup with an inadequate response to methotrexate monotherapy, and in that subgroup, patients randomized to triple therapy and those randomized to etanercept plus methotrexate had similar clinical outcomes, consistent with the new study findings.

"It’s hard to say that 1 or 2 units on the Sharp score doesn’t matter much, even if you don’t see the difference for several years," commented Dr. Daniel Furst, professor of medicine and director of the Rheumatology Clinical Research Center at the University of California, Los Angeles.

"Triple therapy is effective clinically, but it doesn’t do so well for x-rays. There are relationships between a 1 or 2 Sharp score difference and long-term outcomes. Across the board with biologics, the difference is 1 or 2 Sharp units. If one’s philosophy is to hit the RA hard and stop it, then perhaps a biologic is better," Dr. Furst commented in an interview.

But another view was that triple therapy could play a useful and cost-effective role. The new findings, along with the TEAR results, make "initial treatment of early RA with triple therapy a reasonable approach," said Dr. Joel M. Kremer, a professor of medicine at Albany (N.Y.) Medical College and director of research at the Center for Rheumatology in Albany. The only clear downside is that if triple therapy doesn’t work, the patient loses time, but that’s true for every treatment option, he noted.

"We don’t usually have the opportunity to hear the data for generic drugs" as much as for brand-name formulations, Dr. Kremer said in an interview. "Will data like this substantially change prescribing patterns? Probably not, but what might happen is that insurers may look at these data and say that patients should fail triple therapy before starting a biologic. That would be a sea change" for rheumatology, he added.

"I have always used methotrexate first, usually in combination with hydroxychloroquine," Dr. Kremer said. He has not usually also prescribed sulfasalazine, but said he would consider adding it based on the new data.

The new study enrolled patients with a DAS28 score of 4.4 or higher despite at least 12 weeks of stable methotrexate therapy with a weekly dosage of 15-25 mg. The patients averaged about 57 years old. After the first 24 weeks on randomized treatment, patients who did not have a decrease in their DAS28 of at least 1.2 units switched to the alternate regimens. The primary outcome was change in DAS28 at week 48 according to initial treatment assignment; the researchers collected 48-week DAS28 scores from 309 enrolled patients. The mean change in DAS28 from baseline at 48 weeks was a 2.12-unit reduction in the triple-therapy patients and a 2.29-unit reduction in the etanercept patients, an average 0.17-unit difference between the two treatment arms that was not statistically significant and that fell within the study’s prespecified range for noninferiority for triple therapy.

A similar percentage of patients, 27%, in each of the treatment arms switched to the alternate therapy at 24 weeks due to lack of an adequate initial response. There were also no statistically significant differences between the treatment arms in their rate of American College of Rheumatology (ACR) 20 and 50 responses at both 24 and 48 weeks.

The results showed significant differences between the treatment arms after the first 24 weeks of treatment for higher-level responses. For example, the percentage of patients achieving an ACR 70 response was 5% in the triple-therapy patients and 16% in the etanercept patients, a statistically significant difference. The rate of patients with a DAS28 score of 2.6 points or less at 24 weeks was 13% in the triple-therapy patients and 22% in those on etanercept, a significant difference.

Based on findings like these, "I would start a biologic in a patient who failed high-dose methotrexate and had poor prognostic factors and highly active disease, because at 6 months etanercept had the edge," said Dr. Edward C. Keystone, director of the Centre for Arthritis and Autoimmune Disease at Mount Sinai Hospital in Toronto, and a coinvestigator on the new study. But for all the other patients, "why not start on triple therapy first if you can switch them later if needed and the patients do well?" he asked. "The important observation is that the same percentage of patients failed in each arm. That is a huge message."

The RACAT study received no commercial support. Dr. O’Dell said that he had no disclosures. Dr. Furst has been a consultant to or received grant support from Abbott, Amgen, Bristol-Myers Squibb, and other companies. Dr. Kremer has been a consultant to or received grant support from Pfizer, Abbott, Genentech, and other companies. Dr. Keystone said that he has been a consultant to or has received research grants from Amgen, Pfizer, Merck, and other companies.

mzoler@frontlinemedcom.com On Twitter @mitchelzoler