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MAUI, HAWAII – The first-ever, double-blind, randomized, controlled clinical trial evidence demonstrating that methotrexate indeed has therapeutic efficacy in psoriatic arthritis has come at an awkward time – on the heels of a basically negative Cochrane Collaboration systematic review as well as the latest American College of Rheumatology/National Psoriasis Foundation guidelines for treatment of psoriatic arthritis, which recommend anti–tumor necrosis factor therapy as first line, ahead of methotrexate.
The timing of the release of the SEAM-PsA randomized trial results was such that neither the Cochrane group nor the ACR/NPF guideline committee was able to consider the new, potentially game-changing study findings.
“I look at SEAM-PsA and have to say, methotrexate does seem to be an effective therapy. I think it calls into question the new guidelines, which were developed before the data were out. Now you look at this and have to ask, can you really say you should use a TNF inhibitor before methotrexate based on these results? I don’t know,” Eric M. Ruderman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
He also shared other problems he has with the new guidelines, which he considers seriously flawed.
The Cochrane Collaboration Systematic Review
The Cochrane group cast a net for all randomized, controlled clinical trials of methotrexate versus placebo or another disease-modifying antirheumatic drug (DMARD). They found eight, which they judged to be of poor quality. Their conclusion: “Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for 6 months; however, we are uncertain if it is more harmful” (Cochrane Database Syst Rev. 2019 Jan 18;1:CD012722. doi: 10.1002/14651858.CD012722.pub2).
“The new Cochrane Review concludes methotrexate doesn’t seem to work that well,” observed symposium director Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego.
“That’s because it’s based on published data, and there’s been very little of that,” said Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University in Chicago.
“I think most people assume, based on clinical experience, that it does work well. It’s all we had for years and years and years,” he added.
That is, until SEAM-PsA.
SEAM-PsA
SEAM-PsA randomized 851 DMARD- and biologic-naive patients with a median 0.6-year duration of psoriatic arthritis to one of three treatment arms for 48 weeks: once-weekly etanercept at 50 mg plus oral methotrexate at 20 mg, etanercept plus oral placebo, or methotrexate plus injectable placebo.
This is a study that will reshape clinical practice for many rheumatologists, according to Dr. Kavanaugh. The hypothesis was that in psoriatic arthritis, just as has been shown to be the case in rheumatoid arthritis, the combination of a TNF inhibitor plus methotrexate would have greater efficacy than either agent alone. But the study brought a couple of major surprises.
“Methotrexate didn’t do so badly,” Dr. Kavanaugh observed. “And the combination did nothing. I would have bet that the combination would have shown methotrexate had a synergistic effect with the TNF inhibitor, especially for x-ray changes. But the combination didn’t do any better than etanercept alone.”
Make no mistake: Etanercept monotherapy significantly outperformed methotrexate monotherapy for the primary endpoint, the ACR 20 response at week 24, by a margin of 60.9% versus 50.7%. Dr. Ruderman deemed that methotrexate response rate to be quite respectable, although he bemoaned the absence of a double-placebo comparator arm. And the key secondary endpoint, the minimal disease activity response rate at week 24, was also significantly better with etanercept, at 35.9% compared with 22.9%. Moreover, both etanercept arms showed significantly less radiographic progression than with methotrexate alone.
However, that was it. There were no significant differences between etanercept and methotrexate in other secondary endpoints, including the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC), the Disease Activity in PSoriatic Arthritis (DAPSA) score, the Leeds Dactylitis Instrument (LDI), and quality of life as assessed by the 36-item Short Form Health Survey total score.
“Methotrexate showed generally good efficacy across multiple domains,” the investigators concluded (Arthritis Rheumatol. 2019 Feb 12. doi: 10.1002/art.40851).
“Another intriguing thing to come out of this study for me were the enthesitis and dactylitis results. My clinical experience suggested methotrexate wasn’t so great for that, but this study suggests that’s not true,” Dr. Ruderman said.
“There are a couple of key take-home points from this study,” according to Dr. Kavanaugh. “One is that the combination is not synergistic. When you start a rheumatoid arthritis patient on methotrexate, you try to keep him on methotrexate when you add a TNF inhibitor. This study would say there doesn’t seem like there’s a reason to do that in your psoriatic arthritis patient. And the second message is that methotrexate seems to work.”
New ACR/NPF psoriatic arthritis guidelines under fire
“The new guidelines are fuzzy, aren’t they?” Dr. Kavanaugh said in lobbing the topic over to Dr. Ruderman.
“Where do we start?” he replied, shaking his head. “These are evidence-based guidelines in an area in which there was virtually no evidence.”
Indeed, the guidelines committee proudly employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which forces committee members to issue “conditional” recommendations when there’s not enough evidence to make a “strong” recommendation.
“You’re not allowed to say, ‘We don’t know, there’s not enough evidence to make a choice,’ ” Dr. Ruderman said. “The problem with these guidelines is virtually everything in it is a conditional recommendation except ‘stop smoking,’ which was a strong recommendation.
“A conditional recommendation is pretty much a fancy term for expert opinion. It’s basically everybody in the room saying, ‘This is what we think.’ And that makes guidelines challenging because as a rheumatologist, you’re an expert. The people in the room have perhaps looked at the data more carefully than you’ve drilled down into the studies, but ultimately they’ve taken care of these patients and you’ve taken care of these patients, so why is their opinion better than your opinion, if it’s an informed opinion?”
His other critique of the 28-page guidelines is they don’t include the reasoning behind the conditional recommendations.
“If the conditional recommendation is, ‘In this situation, a TNF inhibitor is preferred over an IL-17 inhibitor,’ that would be great if they had also said, ‘This is why we thought that.’ But that’s not in the paper,” Dr. Ruderman said.
He and Dr. Kavanaugh reported serving as consultants to numerous pharmaceutical companies.
MAUI, HAWAII – The first-ever, double-blind, randomized, controlled clinical trial evidence demonstrating that methotrexate indeed has therapeutic efficacy in psoriatic arthritis has come at an awkward time – on the heels of a basically negative Cochrane Collaboration systematic review as well as the latest American College of Rheumatology/National Psoriasis Foundation guidelines for treatment of psoriatic arthritis, which recommend anti–tumor necrosis factor therapy as first line, ahead of methotrexate.
The timing of the release of the SEAM-PsA randomized trial results was such that neither the Cochrane group nor the ACR/NPF guideline committee was able to consider the new, potentially game-changing study findings.
“I look at SEAM-PsA and have to say, methotrexate does seem to be an effective therapy. I think it calls into question the new guidelines, which were developed before the data were out. Now you look at this and have to ask, can you really say you should use a TNF inhibitor before methotrexate based on these results? I don’t know,” Eric M. Ruderman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
He also shared other problems he has with the new guidelines, which he considers seriously flawed.
The Cochrane Collaboration Systematic Review
The Cochrane group cast a net for all randomized, controlled clinical trials of methotrexate versus placebo or another disease-modifying antirheumatic drug (DMARD). They found eight, which they judged to be of poor quality. Their conclusion: “Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for 6 months; however, we are uncertain if it is more harmful” (Cochrane Database Syst Rev. 2019 Jan 18;1:CD012722. doi: 10.1002/14651858.CD012722.pub2).
“The new Cochrane Review concludes methotrexate doesn’t seem to work that well,” observed symposium director Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego.
“That’s because it’s based on published data, and there’s been very little of that,” said Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University in Chicago.
“I think most people assume, based on clinical experience, that it does work well. It’s all we had for years and years and years,” he added.
That is, until SEAM-PsA.
SEAM-PsA
SEAM-PsA randomized 851 DMARD- and biologic-naive patients with a median 0.6-year duration of psoriatic arthritis to one of three treatment arms for 48 weeks: once-weekly etanercept at 50 mg plus oral methotrexate at 20 mg, etanercept plus oral placebo, or methotrexate plus injectable placebo.
This is a study that will reshape clinical practice for many rheumatologists, according to Dr. Kavanaugh. The hypothesis was that in psoriatic arthritis, just as has been shown to be the case in rheumatoid arthritis, the combination of a TNF inhibitor plus methotrexate would have greater efficacy than either agent alone. But the study brought a couple of major surprises.
“Methotrexate didn’t do so badly,” Dr. Kavanaugh observed. “And the combination did nothing. I would have bet that the combination would have shown methotrexate had a synergistic effect with the TNF inhibitor, especially for x-ray changes. But the combination didn’t do any better than etanercept alone.”
Make no mistake: Etanercept monotherapy significantly outperformed methotrexate monotherapy for the primary endpoint, the ACR 20 response at week 24, by a margin of 60.9% versus 50.7%. Dr. Ruderman deemed that methotrexate response rate to be quite respectable, although he bemoaned the absence of a double-placebo comparator arm. And the key secondary endpoint, the minimal disease activity response rate at week 24, was also significantly better with etanercept, at 35.9% compared with 22.9%. Moreover, both etanercept arms showed significantly less radiographic progression than with methotrexate alone.
However, that was it. There were no significant differences between etanercept and methotrexate in other secondary endpoints, including the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC), the Disease Activity in PSoriatic Arthritis (DAPSA) score, the Leeds Dactylitis Instrument (LDI), and quality of life as assessed by the 36-item Short Form Health Survey total score.
“Methotrexate showed generally good efficacy across multiple domains,” the investigators concluded (Arthritis Rheumatol. 2019 Feb 12. doi: 10.1002/art.40851).
“Another intriguing thing to come out of this study for me were the enthesitis and dactylitis results. My clinical experience suggested methotrexate wasn’t so great for that, but this study suggests that’s not true,” Dr. Ruderman said.
“There are a couple of key take-home points from this study,” according to Dr. Kavanaugh. “One is that the combination is not synergistic. When you start a rheumatoid arthritis patient on methotrexate, you try to keep him on methotrexate when you add a TNF inhibitor. This study would say there doesn’t seem like there’s a reason to do that in your psoriatic arthritis patient. And the second message is that methotrexate seems to work.”
New ACR/NPF psoriatic arthritis guidelines under fire
“The new guidelines are fuzzy, aren’t they?” Dr. Kavanaugh said in lobbing the topic over to Dr. Ruderman.
“Where do we start?” he replied, shaking his head. “These are evidence-based guidelines in an area in which there was virtually no evidence.”
Indeed, the guidelines committee proudly employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which forces committee members to issue “conditional” recommendations when there’s not enough evidence to make a “strong” recommendation.
“You’re not allowed to say, ‘We don’t know, there’s not enough evidence to make a choice,’ ” Dr. Ruderman said. “The problem with these guidelines is virtually everything in it is a conditional recommendation except ‘stop smoking,’ which was a strong recommendation.
“A conditional recommendation is pretty much a fancy term for expert opinion. It’s basically everybody in the room saying, ‘This is what we think.’ And that makes guidelines challenging because as a rheumatologist, you’re an expert. The people in the room have perhaps looked at the data more carefully than you’ve drilled down into the studies, but ultimately they’ve taken care of these patients and you’ve taken care of these patients, so why is their opinion better than your opinion, if it’s an informed opinion?”
His other critique of the 28-page guidelines is they don’t include the reasoning behind the conditional recommendations.
“If the conditional recommendation is, ‘In this situation, a TNF inhibitor is preferred over an IL-17 inhibitor,’ that would be great if they had also said, ‘This is why we thought that.’ But that’s not in the paper,” Dr. Ruderman said.
He and Dr. Kavanaugh reported serving as consultants to numerous pharmaceutical companies.
MAUI, HAWAII – The first-ever, double-blind, randomized, controlled clinical trial evidence demonstrating that methotrexate indeed has therapeutic efficacy in psoriatic arthritis has come at an awkward time – on the heels of a basically negative Cochrane Collaboration systematic review as well as the latest American College of Rheumatology/National Psoriasis Foundation guidelines for treatment of psoriatic arthritis, which recommend anti–tumor necrosis factor therapy as first line, ahead of methotrexate.
The timing of the release of the SEAM-PsA randomized trial results was such that neither the Cochrane group nor the ACR/NPF guideline committee was able to consider the new, potentially game-changing study findings.
“I look at SEAM-PsA and have to say, methotrexate does seem to be an effective therapy. I think it calls into question the new guidelines, which were developed before the data were out. Now you look at this and have to ask, can you really say you should use a TNF inhibitor before methotrexate based on these results? I don’t know,” Eric M. Ruderman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
He also shared other problems he has with the new guidelines, which he considers seriously flawed.
The Cochrane Collaboration Systematic Review
The Cochrane group cast a net for all randomized, controlled clinical trials of methotrexate versus placebo or another disease-modifying antirheumatic drug (DMARD). They found eight, which they judged to be of poor quality. Their conclusion: “Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for 6 months; however, we are uncertain if it is more harmful” (Cochrane Database Syst Rev. 2019 Jan 18;1:CD012722. doi: 10.1002/14651858.CD012722.pub2).
“The new Cochrane Review concludes methotrexate doesn’t seem to work that well,” observed symposium director Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego.
“That’s because it’s based on published data, and there’s been very little of that,” said Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University in Chicago.
“I think most people assume, based on clinical experience, that it does work well. It’s all we had for years and years and years,” he added.
That is, until SEAM-PsA.
SEAM-PsA
SEAM-PsA randomized 851 DMARD- and biologic-naive patients with a median 0.6-year duration of psoriatic arthritis to one of three treatment arms for 48 weeks: once-weekly etanercept at 50 mg plus oral methotrexate at 20 mg, etanercept plus oral placebo, or methotrexate plus injectable placebo.
This is a study that will reshape clinical practice for many rheumatologists, according to Dr. Kavanaugh. The hypothesis was that in psoriatic arthritis, just as has been shown to be the case in rheumatoid arthritis, the combination of a TNF inhibitor plus methotrexate would have greater efficacy than either agent alone. But the study brought a couple of major surprises.
“Methotrexate didn’t do so badly,” Dr. Kavanaugh observed. “And the combination did nothing. I would have bet that the combination would have shown methotrexate had a synergistic effect with the TNF inhibitor, especially for x-ray changes. But the combination didn’t do any better than etanercept alone.”
Make no mistake: Etanercept monotherapy significantly outperformed methotrexate monotherapy for the primary endpoint, the ACR 20 response at week 24, by a margin of 60.9% versus 50.7%. Dr. Ruderman deemed that methotrexate response rate to be quite respectable, although he bemoaned the absence of a double-placebo comparator arm. And the key secondary endpoint, the minimal disease activity response rate at week 24, was also significantly better with etanercept, at 35.9% compared with 22.9%. Moreover, both etanercept arms showed significantly less radiographic progression than with methotrexate alone.
However, that was it. There were no significant differences between etanercept and methotrexate in other secondary endpoints, including the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC), the Disease Activity in PSoriatic Arthritis (DAPSA) score, the Leeds Dactylitis Instrument (LDI), and quality of life as assessed by the 36-item Short Form Health Survey total score.
“Methotrexate showed generally good efficacy across multiple domains,” the investigators concluded (Arthritis Rheumatol. 2019 Feb 12. doi: 10.1002/art.40851).
“Another intriguing thing to come out of this study for me were the enthesitis and dactylitis results. My clinical experience suggested methotrexate wasn’t so great for that, but this study suggests that’s not true,” Dr. Ruderman said.
“There are a couple of key take-home points from this study,” according to Dr. Kavanaugh. “One is that the combination is not synergistic. When you start a rheumatoid arthritis patient on methotrexate, you try to keep him on methotrexate when you add a TNF inhibitor. This study would say there doesn’t seem like there’s a reason to do that in your psoriatic arthritis patient. And the second message is that methotrexate seems to work.”
New ACR/NPF psoriatic arthritis guidelines under fire
“The new guidelines are fuzzy, aren’t they?” Dr. Kavanaugh said in lobbing the topic over to Dr. Ruderman.
“Where do we start?” he replied, shaking his head. “These are evidence-based guidelines in an area in which there was virtually no evidence.”
Indeed, the guidelines committee proudly employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which forces committee members to issue “conditional” recommendations when there’s not enough evidence to make a “strong” recommendation.
“You’re not allowed to say, ‘We don’t know, there’s not enough evidence to make a choice,’ ” Dr. Ruderman said. “The problem with these guidelines is virtually everything in it is a conditional recommendation except ‘stop smoking,’ which was a strong recommendation.
“A conditional recommendation is pretty much a fancy term for expert opinion. It’s basically everybody in the room saying, ‘This is what we think.’ And that makes guidelines challenging because as a rheumatologist, you’re an expert. The people in the room have perhaps looked at the data more carefully than you’ve drilled down into the studies, but ultimately they’ve taken care of these patients and you’ve taken care of these patients, so why is their opinion better than your opinion, if it’s an informed opinion?”
His other critique of the 28-page guidelines is they don’t include the reasoning behind the conditional recommendations.
“If the conditional recommendation is, ‘In this situation, a TNF inhibitor is preferred over an IL-17 inhibitor,’ that would be great if they had also said, ‘This is why we thought that.’ But that’s not in the paper,” Dr. Ruderman said.
He and Dr. Kavanaugh reported serving as consultants to numerous pharmaceutical companies.
REPORTING FROM RWCS 2019