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Ultrasound guidance of early RA therapy doesn’t improve outcomes
SNOWMASS, COLO. – Rheumatologists who use musculoskeletal ultrasound to help guide a treat-to-target strategy in early rheumatoid arthritis may want to reconsider that practice in light of the results of a recent randomized trial known as the TaSER study, Michael E. Weinblatt, MD, observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In TaSER, Scottish investigators randomized 111 newly diagnosed early rheumatoid arthritis patients to an intensive treat-to-target strategy guided by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) alone or in conjunction with musculoskeletal ultrasound assessment of disease activity in a limited joint set.
The stepped treatment escalation regimen began with methotrexate monotherapy, followed by the addition of sulfasalazine and hydroxychloroquine to methotrexate as triple therapy, then etanercept plus triple therapy.
The primary outcome was improvement in DAS44 at 18 months. Both groups experienced similarly robust improvements: a mean 2.69-point reduction in the ultrasound group and a 2.59-point decrease in the control arm. Nor were there any between-group differences in radiographic or MRI erosions. This was the case even though the ultrasound group received more intensive therapy (Ann Rheum Dis. 2016 Jun;75[6]:1043-50).
“This doesn’t mean that there’s not great value in ultrasound to evaluate disease activity, but I’m not convinced that using ultrasound to guide your treatment per se shows any advantages over a good clinical evaluation of the patient,” concluded Dr. Weinblatt, professor of medicine at Harvard Medical School in Boston.
He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.
SNOWMASS, COLO. – Rheumatologists who use musculoskeletal ultrasound to help guide a treat-to-target strategy in early rheumatoid arthritis may want to reconsider that practice in light of the results of a recent randomized trial known as the TaSER study, Michael E. Weinblatt, MD, observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In TaSER, Scottish investigators randomized 111 newly diagnosed early rheumatoid arthritis patients to an intensive treat-to-target strategy guided by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) alone or in conjunction with musculoskeletal ultrasound assessment of disease activity in a limited joint set.
The stepped treatment escalation regimen began with methotrexate monotherapy, followed by the addition of sulfasalazine and hydroxychloroquine to methotrexate as triple therapy, then etanercept plus triple therapy.
The primary outcome was improvement in DAS44 at 18 months. Both groups experienced similarly robust improvements: a mean 2.69-point reduction in the ultrasound group and a 2.59-point decrease in the control arm. Nor were there any between-group differences in radiographic or MRI erosions. This was the case even though the ultrasound group received more intensive therapy (Ann Rheum Dis. 2016 Jun;75[6]:1043-50).
“This doesn’t mean that there’s not great value in ultrasound to evaluate disease activity, but I’m not convinced that using ultrasound to guide your treatment per se shows any advantages over a good clinical evaluation of the patient,” concluded Dr. Weinblatt, professor of medicine at Harvard Medical School in Boston.
He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.
SNOWMASS, COLO. – Rheumatologists who use musculoskeletal ultrasound to help guide a treat-to-target strategy in early rheumatoid arthritis may want to reconsider that practice in light of the results of a recent randomized trial known as the TaSER study, Michael E. Weinblatt, MD, observed at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
In TaSER, Scottish investigators randomized 111 newly diagnosed early rheumatoid arthritis patients to an intensive treat-to-target strategy guided by 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) alone or in conjunction with musculoskeletal ultrasound assessment of disease activity in a limited joint set.
The stepped treatment escalation regimen began with methotrexate monotherapy, followed by the addition of sulfasalazine and hydroxychloroquine to methotrexate as triple therapy, then etanercept plus triple therapy.
The primary outcome was improvement in DAS44 at 18 months. Both groups experienced similarly robust improvements: a mean 2.69-point reduction in the ultrasound group and a 2.59-point decrease in the control arm. Nor were there any between-group differences in radiographic or MRI erosions. This was the case even though the ultrasound group received more intensive therapy (Ann Rheum Dis. 2016 Jun;75[6]:1043-50).
“This doesn’t mean that there’s not great value in ultrasound to evaluate disease activity, but I’m not convinced that using ultrasound to guide your treatment per se shows any advantages over a good clinical evaluation of the patient,” concluded Dr. Weinblatt, professor of medicine at Harvard Medical School in Boston.
He reported receiving research grants from half a dozen companies and serving as a consultant to more than two dozen.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
ACR guidelines on HBV screening called inadequate
SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.
The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.
He recommended that his fellow rheumatologists skip the ACR guidance and instead do what he does, which is to follow the American Association for the Study of Liver Diseases (AASLD) guidelines that have been in place for the past 8 years (Hepatology. 2009 Sep;50[3]:661-2).
The AASLD screening algorithm is simple and straightforward: Screen everyone who is going to go on any form of immunosuppressive therapy or cancer therapy by testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc).
The highest-risk group for HBV reactivation are patients who are HBsAg positive. They have an active infection and should be referred to a hepatologist for antiviral therapy. Depending upon the patient’s HBV DNA level and liver function test results, the antiviral therapy will be started either prior to or simultaneously with the immunosuppressive therapy.
The AASLD guidelines rank immunosuppressive agents in terms of their associated risk of HBV reactivation based upon the best available evidence. It’s a tricky business. Patients with a history of HBV are excluded from clinical trials of immunosuppressants, so the evidence is sketchy.
Nevertheless, the consensus is that among HBsAg-positive patients the risk associated with methotrexate and other antimetabolites is considered low. The tumor necrosis factor inhibitors are deemed to pose a moderate risk, as does cyclosporine. The risk of other cytokine inhibitors, including ustekinumab (Stelara) and abatacept (Orencia), is uncertain, but thought to be moderate to high. The use of corticosteroids at more than 20 mg/day for longer than 4 weeks is considered high-risk therapy. And rituximab (Rituxan), which carries a black box warning regarding HBV reactivation, is rated very-high-risk, as is cancer chemotherapy and hematopoietic stem cell transplantation.
An HBV screen that comes back HBsAg negative but anti-HBc positive indicates past HBV infection. This places a patient at intermediate risk for reactivation during immunosuppressive therapy. If Dr. Calabrese plans to put that patient on rituximab, he’ll make a referral to a hepatologist for consideration of antiviral therapy. If he’s going to use any other form of immunosuppressive therapy in a patient who is HBsAg negative/anti-HBc positive, he tests for HBV DNA every 1-3 months while the patient is on treatment. If HBV DNA becomes detectable, it’s time to start antiviral therapy.
No further action is required if a rheumatology patient’s HBV screen comes back negative for both HBsAg and anti-HBc.
“There are six approved drugs for HBV. They don’t have the power of the direct-acting antiviral agents used for hepatitis C. Cures are very infrequent. But lifelong viral suppression is readily achievable with these drugs, which are well tolerated and have low potential for drug-drug interactions. If patients have undetectable HBV DNA on antiviral therapy, I believe we can treat them with any of our rheumatologic regimens, including rituximab,” Dr. Calabrese said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.
The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.
He recommended that his fellow rheumatologists skip the ACR guidance and instead do what he does, which is to follow the American Association for the Study of Liver Diseases (AASLD) guidelines that have been in place for the past 8 years (Hepatology. 2009 Sep;50[3]:661-2).
The AASLD screening algorithm is simple and straightforward: Screen everyone who is going to go on any form of immunosuppressive therapy or cancer therapy by testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc).
The highest-risk group for HBV reactivation are patients who are HBsAg positive. They have an active infection and should be referred to a hepatologist for antiviral therapy. Depending upon the patient’s HBV DNA level and liver function test results, the antiviral therapy will be started either prior to or simultaneously with the immunosuppressive therapy.
The AASLD guidelines rank immunosuppressive agents in terms of their associated risk of HBV reactivation based upon the best available evidence. It’s a tricky business. Patients with a history of HBV are excluded from clinical trials of immunosuppressants, so the evidence is sketchy.
Nevertheless, the consensus is that among HBsAg-positive patients the risk associated with methotrexate and other antimetabolites is considered low. The tumor necrosis factor inhibitors are deemed to pose a moderate risk, as does cyclosporine. The risk of other cytokine inhibitors, including ustekinumab (Stelara) and abatacept (Orencia), is uncertain, but thought to be moderate to high. The use of corticosteroids at more than 20 mg/day for longer than 4 weeks is considered high-risk therapy. And rituximab (Rituxan), which carries a black box warning regarding HBV reactivation, is rated very-high-risk, as is cancer chemotherapy and hematopoietic stem cell transplantation.
An HBV screen that comes back HBsAg negative but anti-HBc positive indicates past HBV infection. This places a patient at intermediate risk for reactivation during immunosuppressive therapy. If Dr. Calabrese plans to put that patient on rituximab, he’ll make a referral to a hepatologist for consideration of antiviral therapy. If he’s going to use any other form of immunosuppressive therapy in a patient who is HBsAg negative/anti-HBc positive, he tests for HBV DNA every 1-3 months while the patient is on treatment. If HBV DNA becomes detectable, it’s time to start antiviral therapy.
No further action is required if a rheumatology patient’s HBV screen comes back negative for both HBsAg and anti-HBc.
“There are six approved drugs for HBV. They don’t have the power of the direct-acting antiviral agents used for hepatitis C. Cures are very infrequent. But lifelong viral suppression is readily achievable with these drugs, which are well tolerated and have low potential for drug-drug interactions. If patients have undetectable HBV DNA on antiviral therapy, I believe we can treat them with any of our rheumatologic regimens, including rituximab,” Dr. Calabrese said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.
The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.
He recommended that his fellow rheumatologists skip the ACR guidance and instead do what he does, which is to follow the American Association for the Study of Liver Diseases (AASLD) guidelines that have been in place for the past 8 years (Hepatology. 2009 Sep;50[3]:661-2).
The AASLD screening algorithm is simple and straightforward: Screen everyone who is going to go on any form of immunosuppressive therapy or cancer therapy by testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc).
The highest-risk group for HBV reactivation are patients who are HBsAg positive. They have an active infection and should be referred to a hepatologist for antiviral therapy. Depending upon the patient’s HBV DNA level and liver function test results, the antiviral therapy will be started either prior to or simultaneously with the immunosuppressive therapy.
The AASLD guidelines rank immunosuppressive agents in terms of their associated risk of HBV reactivation based upon the best available evidence. It’s a tricky business. Patients with a history of HBV are excluded from clinical trials of immunosuppressants, so the evidence is sketchy.
Nevertheless, the consensus is that among HBsAg-positive patients the risk associated with methotrexate and other antimetabolites is considered low. The tumor necrosis factor inhibitors are deemed to pose a moderate risk, as does cyclosporine. The risk of other cytokine inhibitors, including ustekinumab (Stelara) and abatacept (Orencia), is uncertain, but thought to be moderate to high. The use of corticosteroids at more than 20 mg/day for longer than 4 weeks is considered high-risk therapy. And rituximab (Rituxan), which carries a black box warning regarding HBV reactivation, is rated very-high-risk, as is cancer chemotherapy and hematopoietic stem cell transplantation.
An HBV screen that comes back HBsAg negative but anti-HBc positive indicates past HBV infection. This places a patient at intermediate risk for reactivation during immunosuppressive therapy. If Dr. Calabrese plans to put that patient on rituximab, he’ll make a referral to a hepatologist for consideration of antiviral therapy. If he’s going to use any other form of immunosuppressive therapy in a patient who is HBsAg negative/anti-HBc positive, he tests for HBV DNA every 1-3 months while the patient is on treatment. If HBV DNA becomes detectable, it’s time to start antiviral therapy.
No further action is required if a rheumatology patient’s HBV screen comes back negative for both HBsAg and anti-HBc.
“There are six approved drugs for HBV. They don’t have the power of the direct-acting antiviral agents used for hepatitis C. Cures are very infrequent. But lifelong viral suppression is readily achievable with these drugs, which are well tolerated and have low potential for drug-drug interactions. If patients have undetectable HBV DNA on antiviral therapy, I believe we can treat them with any of our rheumatologic regimens, including rituximab,” Dr. Calabrese said.
He reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Perioperative infliximab does not increase serious infection risk
Administration of infliximab within 4 weeks of elective knee or hip arthroplasty did not have any significant effect on patients’ risk of serious infection after surgery, whereas the use of glucocorticoids increased that risk, in an analysis of a Medicare claims database.
“This increased risk with glucocorticoids has been suggested by previous studies [and] although this risk may be related in part to increased disease severity among glucocorticoid treated patients, a direct medication effect is likely. [These data suggest] that prolonged interruptions in infliximab therapy prior to surgery may be counterproductive if higher dose glucocorticoid therapy is used in substitution,” wrote the authors of the new study, led by Michael D. George, MD, of the University of Pennsylvania in Philadelphia.
Dr. George and his colleagues examined data from the U.S. Medicare claims system on 4,288 elective knee or hip arthroplasties in individuals with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis who received infliximab within 6 months prior to the operation during 2007-2013 (Arthritis Care Res. 2017 Jan 27. doi: 10.1002/acr.23209).
The patients had to have received infliximab at least three times within a year of their procedure to establish that they were receiving stable therapy over a long-term period. The investigators also looked at oral prednisone, prednisolone, and methylprednisolone prescriptions and used data on average dosing to determine how much was administered to each subject.
“Although previous studies have treated TNF stopping vs. not stopping as a dichotomous exposure based on an arbitrary (and variable) stopping definition, in this study the primary analysis evaluated stop timing as a more general categorical exposure using 4-week intervals (half the standard rheumatoid arthritis dosing interval) to allow better assessment of the optimal stop timing,” the authors explained.
Stopping infliximab within 4 weeks of the operation did not significantly influence the rate of serious infection within 30 days (adjusted odds ratio, 0.90; 95% CI, 0.60-1.34) and neither did stopping within 4-8 weeks (OR, 0.95; 95% CI, 0.62-1.36) when compared against stopping 8-12 weeks before surgery. Of the 4,288 arthroplasties, 270 serious infections (6.3%) occurred within 30 days of the operation.
There also was no significant difference between stopping within 4 weeks and 8-12 weeks in the rate of prosthetic joint infection within 1 year of the operation (hazard ratio, 0.98; 95% CI, 0.52-1.87). Overall, prosthetic joint infection occurred 2.9 times per 100 person-years.
However, glucocorticoid doses of more than 10 mg per day were risky. The odds for a serious infection within 30 days after surgery more than doubled with that level of use (OR, 2.11; 95% CI, 1.30-3.40), while the risk for a prosthetic joint infection within 1 year of the surgery also rose significantly (HR, 2.70; 95% CI, 1.30-5.60).
“This is a very well done paper that adds important observational data to our understanding of perioperative medication risk,” Dr. Goodman said.
But the study results will not, at least initially, bring about any changes to the proposed guidelines for perioperative management of patients taking antirheumatic drugs that were described at the 2016 annual meeting of the American College of Rheumatology, she said.
“We were aware of the abstract, which was also presented at the ACR last fall at the time the current perioperative medication management guidelines were presented, and it won’t change guidelines at this point,” said Dr. Goodman, who is one of the lead authors of the proposed guidelines. “[But] I think [the study] could provide important background information to use in a randomized clinical trial to compare infection on [and] not on TNF inhibitors.”
The proposed guidelines conditionally recommend that all biologics should be withheld prior to surgery in patients with inflammatory arthritis, that surgery should be planned for the end of the dosing cycle, and that current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with rheumatoid arthritis, lupus, or inflammatory arthritis.
The National Institutes of Health, the Rheumatology Research Foundation, and the Department of Veterans Affairs funded the study. Dr. George did not report any relevant financial disclosures. Two coauthors disclosed receiving research grants or consulting fees from pharmaceutical companies for unrelated work.
Administration of infliximab within 4 weeks of elective knee or hip arthroplasty did not have any significant effect on patients’ risk of serious infection after surgery, whereas the use of glucocorticoids increased that risk, in an analysis of a Medicare claims database.
“This increased risk with glucocorticoids has been suggested by previous studies [and] although this risk may be related in part to increased disease severity among glucocorticoid treated patients, a direct medication effect is likely. [These data suggest] that prolonged interruptions in infliximab therapy prior to surgery may be counterproductive if higher dose glucocorticoid therapy is used in substitution,” wrote the authors of the new study, led by Michael D. George, MD, of the University of Pennsylvania in Philadelphia.
Dr. George and his colleagues examined data from the U.S. Medicare claims system on 4,288 elective knee or hip arthroplasties in individuals with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis who received infliximab within 6 months prior to the operation during 2007-2013 (Arthritis Care Res. 2017 Jan 27. doi: 10.1002/acr.23209).
The patients had to have received infliximab at least three times within a year of their procedure to establish that they were receiving stable therapy over a long-term period. The investigators also looked at oral prednisone, prednisolone, and methylprednisolone prescriptions and used data on average dosing to determine how much was administered to each subject.
“Although previous studies have treated TNF stopping vs. not stopping as a dichotomous exposure based on an arbitrary (and variable) stopping definition, in this study the primary analysis evaluated stop timing as a more general categorical exposure using 4-week intervals (half the standard rheumatoid arthritis dosing interval) to allow better assessment of the optimal stop timing,” the authors explained.
Stopping infliximab within 4 weeks of the operation did not significantly influence the rate of serious infection within 30 days (adjusted odds ratio, 0.90; 95% CI, 0.60-1.34) and neither did stopping within 4-8 weeks (OR, 0.95; 95% CI, 0.62-1.36) when compared against stopping 8-12 weeks before surgery. Of the 4,288 arthroplasties, 270 serious infections (6.3%) occurred within 30 days of the operation.
There also was no significant difference between stopping within 4 weeks and 8-12 weeks in the rate of prosthetic joint infection within 1 year of the operation (hazard ratio, 0.98; 95% CI, 0.52-1.87). Overall, prosthetic joint infection occurred 2.9 times per 100 person-years.
However, glucocorticoid doses of more than 10 mg per day were risky. The odds for a serious infection within 30 days after surgery more than doubled with that level of use (OR, 2.11; 95% CI, 1.30-3.40), while the risk for a prosthetic joint infection within 1 year of the surgery also rose significantly (HR, 2.70; 95% CI, 1.30-5.60).
“This is a very well done paper that adds important observational data to our understanding of perioperative medication risk,” Dr. Goodman said.
But the study results will not, at least initially, bring about any changes to the proposed guidelines for perioperative management of patients taking antirheumatic drugs that were described at the 2016 annual meeting of the American College of Rheumatology, she said.
“We were aware of the abstract, which was also presented at the ACR last fall at the time the current perioperative medication management guidelines were presented, and it won’t change guidelines at this point,” said Dr. Goodman, who is one of the lead authors of the proposed guidelines. “[But] I think [the study] could provide important background information to use in a randomized clinical trial to compare infection on [and] not on TNF inhibitors.”
The proposed guidelines conditionally recommend that all biologics should be withheld prior to surgery in patients with inflammatory arthritis, that surgery should be planned for the end of the dosing cycle, and that current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with rheumatoid arthritis, lupus, or inflammatory arthritis.
The National Institutes of Health, the Rheumatology Research Foundation, and the Department of Veterans Affairs funded the study. Dr. George did not report any relevant financial disclosures. Two coauthors disclosed receiving research grants or consulting fees from pharmaceutical companies for unrelated work.
Administration of infliximab within 4 weeks of elective knee or hip arthroplasty did not have any significant effect on patients’ risk of serious infection after surgery, whereas the use of glucocorticoids increased that risk, in an analysis of a Medicare claims database.
“This increased risk with glucocorticoids has been suggested by previous studies [and] although this risk may be related in part to increased disease severity among glucocorticoid treated patients, a direct medication effect is likely. [These data suggest] that prolonged interruptions in infliximab therapy prior to surgery may be counterproductive if higher dose glucocorticoid therapy is used in substitution,” wrote the authors of the new study, led by Michael D. George, MD, of the University of Pennsylvania in Philadelphia.
Dr. George and his colleagues examined data from the U.S. Medicare claims system on 4,288 elective knee or hip arthroplasties in individuals with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis who received infliximab within 6 months prior to the operation during 2007-2013 (Arthritis Care Res. 2017 Jan 27. doi: 10.1002/acr.23209).
The patients had to have received infliximab at least three times within a year of their procedure to establish that they were receiving stable therapy over a long-term period. The investigators also looked at oral prednisone, prednisolone, and methylprednisolone prescriptions and used data on average dosing to determine how much was administered to each subject.
“Although previous studies have treated TNF stopping vs. not stopping as a dichotomous exposure based on an arbitrary (and variable) stopping definition, in this study the primary analysis evaluated stop timing as a more general categorical exposure using 4-week intervals (half the standard rheumatoid arthritis dosing interval) to allow better assessment of the optimal stop timing,” the authors explained.
Stopping infliximab within 4 weeks of the operation did not significantly influence the rate of serious infection within 30 days (adjusted odds ratio, 0.90; 95% CI, 0.60-1.34) and neither did stopping within 4-8 weeks (OR, 0.95; 95% CI, 0.62-1.36) when compared against stopping 8-12 weeks before surgery. Of the 4,288 arthroplasties, 270 serious infections (6.3%) occurred within 30 days of the operation.
There also was no significant difference between stopping within 4 weeks and 8-12 weeks in the rate of prosthetic joint infection within 1 year of the operation (hazard ratio, 0.98; 95% CI, 0.52-1.87). Overall, prosthetic joint infection occurred 2.9 times per 100 person-years.
However, glucocorticoid doses of more than 10 mg per day were risky. The odds for a serious infection within 30 days after surgery more than doubled with that level of use (OR, 2.11; 95% CI, 1.30-3.40), while the risk for a prosthetic joint infection within 1 year of the surgery also rose significantly (HR, 2.70; 95% CI, 1.30-5.60).
“This is a very well done paper that adds important observational data to our understanding of perioperative medication risk,” Dr. Goodman said.
But the study results will not, at least initially, bring about any changes to the proposed guidelines for perioperative management of patients taking antirheumatic drugs that were described at the 2016 annual meeting of the American College of Rheumatology, she said.
“We were aware of the abstract, which was also presented at the ACR last fall at the time the current perioperative medication management guidelines were presented, and it won’t change guidelines at this point,” said Dr. Goodman, who is one of the lead authors of the proposed guidelines. “[But] I think [the study] could provide important background information to use in a randomized clinical trial to compare infection on [and] not on TNF inhibitors.”
The proposed guidelines conditionally recommend that all biologics should be withheld prior to surgery in patients with inflammatory arthritis, that surgery should be planned for the end of the dosing cycle, and that current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with rheumatoid arthritis, lupus, or inflammatory arthritis.
The National Institutes of Health, the Rheumatology Research Foundation, and the Department of Veterans Affairs funded the study. Dr. George did not report any relevant financial disclosures. Two coauthors disclosed receiving research grants or consulting fees from pharmaceutical companies for unrelated work.
FROM ARTHRITIS CARE & RESEARCH
Key clinical point:
Major finding: Subjects on glucocorticoids had an OR of 2.11 (95% CI 1.30-3.40) for serious infection within 30 days and an HR of 2.70 (95% CI 1.30-5.60) for prosthetic joint infection within 1 year.
Data source: Retrospective cohort study of 4,288 elective knee and hip arthroplasties in Medicare patients with rheumatoid arthritis, inflammatory bowel disease, psoriasis, psoriatic arthritis, or ankylosing spondylitis during 2007-2013.
Disclosures: The National Institutes of Health, the Rheumatology Research Foundation, and the Department of Veterans Affairs funded the study. Dr. George did not report any relevant financial disclosures. Two coauthors disclosed receiving research grants or consulting fees from pharmaceutical companies for unrelated work.
Hydroxychloroquine dosing guidelines have little impact in clinical practice
A substantial number of rheumatology patients are receiving excess starting and maintenance doses of hydroxychloroquine despite the existence of dosing guidelines, a group of ophthalmologists has reported.
The report raises some concerns because hydroxychloroquine has well-established ocular side effects and toxicities that makes screening by a ophthalmologist necessary for all patients on long-term therapy.
Rebekah A. Braslow, MD, and her colleagues in the division of ophthalmology at NorthShore University HealthSystem in Illinois conducted a retrospective review of the records of 554 rheumatology patients who were prescribed hydroxychloroquine during 2009-2016 and seen by a NorthShore ophthalmologist. They found that about half of the patients were on excess initial doses of the disease-modifying antirheumatic drug, according to retinal toxicity guidelines published by the American Academy of Ophthalmology (AAO) in 2011. There was no difference in the percentage of patients on an excess starting dose before the 2011 guidelines were published (54% of 92 patients) or after (49% of 462). The maintenance dose 1 year after beginning treatment was the same as the starting dose in 84% of patients, with reductions in 7% and increases in 9% (Ophthalmology. 2017 Jan 30. doi: 10.1016/j.ophtha.2016.12.021).
The AAO revised the guidelines in 2016 to define excess doses of hydroxychloroquine as greater than 5.0 mg/kg of actual body weight (Ophthalmology. 2016;123:1386-94). Based on these new guidelines, the investigators found that 56% of 527 patients who were currently receiving hydroxychloroquine were taking excess doses, and 43% of the 527 patients were still receiving doses that are more than 50 mg in excess of the calculated target dose that is recommended by the guidelines.
“The published ophthalmology screening guidelines have had no appreciable impact on clinical practice, highlighting a persistent deficiency in patient care and a significant medico-legal risk,” they concluded.
“Our findings are particularly concerning given that choosing a proper starting dose is the single safest, simplest, and most cost-effective measure available,” they wrote.
According to the authors, there were several reasons for the widespread inaccurate dosing. Firstly, the guidelines were published in ophthalmology literature and were therefore unlikely to be seen by rheumatologists. Secondly, the formulation of the drug, currently available only in 200-mg tablet form, made it difficult to adjust doses according to a patient’s weight.
This particular issue could be addressed if the drug manufacturers expanded formulation options, or by alternating daily dosing regimens or involving compound pharmacies, they suggested.
System-wide education and prompts via electronic medical records would also go some way toward ensuring that patients are prescribed the correct dose, they added.
The study was supported by intramural research funds within the division of ophthalmology in NorthShore University Health System.
A substantial number of rheumatology patients are receiving excess starting and maintenance doses of hydroxychloroquine despite the existence of dosing guidelines, a group of ophthalmologists has reported.
The report raises some concerns because hydroxychloroquine has well-established ocular side effects and toxicities that makes screening by a ophthalmologist necessary for all patients on long-term therapy.
Rebekah A. Braslow, MD, and her colleagues in the division of ophthalmology at NorthShore University HealthSystem in Illinois conducted a retrospective review of the records of 554 rheumatology patients who were prescribed hydroxychloroquine during 2009-2016 and seen by a NorthShore ophthalmologist. They found that about half of the patients were on excess initial doses of the disease-modifying antirheumatic drug, according to retinal toxicity guidelines published by the American Academy of Ophthalmology (AAO) in 2011. There was no difference in the percentage of patients on an excess starting dose before the 2011 guidelines were published (54% of 92 patients) or after (49% of 462). The maintenance dose 1 year after beginning treatment was the same as the starting dose in 84% of patients, with reductions in 7% and increases in 9% (Ophthalmology. 2017 Jan 30. doi: 10.1016/j.ophtha.2016.12.021).
The AAO revised the guidelines in 2016 to define excess doses of hydroxychloroquine as greater than 5.0 mg/kg of actual body weight (Ophthalmology. 2016;123:1386-94). Based on these new guidelines, the investigators found that 56% of 527 patients who were currently receiving hydroxychloroquine were taking excess doses, and 43% of the 527 patients were still receiving doses that are more than 50 mg in excess of the calculated target dose that is recommended by the guidelines.
“The published ophthalmology screening guidelines have had no appreciable impact on clinical practice, highlighting a persistent deficiency in patient care and a significant medico-legal risk,” they concluded.
“Our findings are particularly concerning given that choosing a proper starting dose is the single safest, simplest, and most cost-effective measure available,” they wrote.
According to the authors, there were several reasons for the widespread inaccurate dosing. Firstly, the guidelines were published in ophthalmology literature and were therefore unlikely to be seen by rheumatologists. Secondly, the formulation of the drug, currently available only in 200-mg tablet form, made it difficult to adjust doses according to a patient’s weight.
This particular issue could be addressed if the drug manufacturers expanded formulation options, or by alternating daily dosing regimens or involving compound pharmacies, they suggested.
System-wide education and prompts via electronic medical records would also go some way toward ensuring that patients are prescribed the correct dose, they added.
The study was supported by intramural research funds within the division of ophthalmology in NorthShore University Health System.
A substantial number of rheumatology patients are receiving excess starting and maintenance doses of hydroxychloroquine despite the existence of dosing guidelines, a group of ophthalmologists has reported.
The report raises some concerns because hydroxychloroquine has well-established ocular side effects and toxicities that makes screening by a ophthalmologist necessary for all patients on long-term therapy.
Rebekah A. Braslow, MD, and her colleagues in the division of ophthalmology at NorthShore University HealthSystem in Illinois conducted a retrospective review of the records of 554 rheumatology patients who were prescribed hydroxychloroquine during 2009-2016 and seen by a NorthShore ophthalmologist. They found that about half of the patients were on excess initial doses of the disease-modifying antirheumatic drug, according to retinal toxicity guidelines published by the American Academy of Ophthalmology (AAO) in 2011. There was no difference in the percentage of patients on an excess starting dose before the 2011 guidelines were published (54% of 92 patients) or after (49% of 462). The maintenance dose 1 year after beginning treatment was the same as the starting dose in 84% of patients, with reductions in 7% and increases in 9% (Ophthalmology. 2017 Jan 30. doi: 10.1016/j.ophtha.2016.12.021).
The AAO revised the guidelines in 2016 to define excess doses of hydroxychloroquine as greater than 5.0 mg/kg of actual body weight (Ophthalmology. 2016;123:1386-94). Based on these new guidelines, the investigators found that 56% of 527 patients who were currently receiving hydroxychloroquine were taking excess doses, and 43% of the 527 patients were still receiving doses that are more than 50 mg in excess of the calculated target dose that is recommended by the guidelines.
“The published ophthalmology screening guidelines have had no appreciable impact on clinical practice, highlighting a persistent deficiency in patient care and a significant medico-legal risk,” they concluded.
“Our findings are particularly concerning given that choosing a proper starting dose is the single safest, simplest, and most cost-effective measure available,” they wrote.
According to the authors, there were several reasons for the widespread inaccurate dosing. Firstly, the guidelines were published in ophthalmology literature and were therefore unlikely to be seen by rheumatologists. Secondly, the formulation of the drug, currently available only in 200-mg tablet form, made it difficult to adjust doses according to a patient’s weight.
This particular issue could be addressed if the drug manufacturers expanded formulation options, or by alternating daily dosing regimens or involving compound pharmacies, they suggested.
System-wide education and prompts via electronic medical records would also go some way toward ensuring that patients are prescribed the correct dose, they added.
The study was supported by intramural research funds within the division of ophthalmology in NorthShore University Health System.
FROM OPHTHALMOLOGY
Key clinical point:
Major finding: Nearly half of the patients seen by rheumatologist in a health system were prescribed excess initial doses of hydroxychloroquine and just over half of the patients (56%) were taking excess maintenance doses, according to 2016 dosing guidelines.
Data source: A retrospective review of the electronic medical records of 554 rheumatology patients.
Disclosures: The study was supported by intramural research funds within the division of ophthalmology in NorthShore University HealthSystem.
Chikungunya arthritis symptoms reduced with immunomodulatory drugs
Several different currently approved immunomodulatory therapies ameliorated arthritis symptoms in chikungunya-infected mice in two studies that separate teams of researchers published online Feb. 1 in Science Translational Medicine.
The first team, led by Jonathan J. Miner, MD, PhD, of Washington University in St. Louis tested six different approved oral and biologic antirheumatic agents (along with control agents) in chikungunya virus-infected mice with acute arthritis and foot swelling (Sci Transl Med. 2017;9:eaah3438).
When the researchers paired abatacept with an antiviral therapy (monoclonal anti-CHIKV human antibody) the combination “was highly effective at reducing joint inflammation, periarticular swelling, migration of inflammatory leukocytes, and infection, even when administered several days after virus inoculation,” Dr. Miner and his colleagues wrote.
The researchers concluded that a combination of anti-inflammatory and antibody-based antiviral therapy “may serve as a model for treating humans with arthritis caused by CHIKV or other related viruses.”
In the second study, researchers led by Teck-Hui Teo, PhD, of the Agency for Science, Technology and Research (A*STAR) in Singapore, further elucidated the mechanisms by which CHIKV proteins act on T cells (Sci Transl Med. 2017;9:eaal1333). They also found that CHIKV-infected mice treated with fingolimod (Gilenya), a drug that blocks T-cell migration from the lymph nodes to the joints and is approved for the treatment of multiple sclerosis, saw reduced arthritis symptoms even without reduction of viral replication.
Infection with the chikungunya virus can produce arthritis that mimics symptoms of rheumatoid arthritis and may in some cases lead to joint damage. Though the mechanisms driving chikungunya-related arthritis are not well understood, preliminary studies have suggested a T-cell–mediated adverse response.
The Singapore team received funding from its own agency, A*STAR, while the Washington University researchers received grants from the National Institutes of Health and the Rheumatology Research Foundation. Two coauthors on the U.S. study reported extensive commercial conflicts, including consulting and advisory relationships with pharmaceutical and vaccine manufacturers, and one patent.
The studies by Dr. Miner and his colleagues and Dr. Teo and his associates demonstrate the potential value of combination therapies for ameliorating heightened T-cell responses and their pathogenic role in joint inflammation. They explored how T-cell responses could be blunted during ongoing viral replication to control overt inflammation, an approach that also may be valuable for treating immune-mediated tissue damage associated with other infectious agents.
Selective T-cell immunomodulatory therapies that offset damaging immune responses offer an attractive option for future pharmacologic interventions for treating chikungunya virus–induced inflammatory disease. The small market size and the rapid sporadic nature of outbreaks could be major obstacles to the development and deployment of virus-specific interventions such as therapeutic antiviral neutralizing monoclonal antibodies or even vaccines. Targeted drug and immunotherapy treatments are likely to offer practical and beneficial options for most patients with chikungunya.
Preliminary reports in humans have suggested that methotrexate may be effective for treating chikungunya virus–induced arthritis. In Dr. Miner and colleagues’ study, a low dose of methotrexate (0.3 mg/kg) was ineffective at treating acute joint swelling in mice. It remains to be addressed whether a higher dose of methotrexate for a longer time period could be of benefit in the setting of chronic chikungunya virus–induced arthritis.
Philippe Gasque, MD, PhD, is with the Université de La Réunion, Saint-Denis, Réunion, and Marie Christine Jaffar-Bandjee, MD, PhD, is with the Centre Hospitalier Universitaire Félix Guyon, Saint-Denis, Réunion. They made these remarks in an editorial (Sci Transl Med. 2017;9:eaam6567).
The studies by Dr. Miner and his colleagues and Dr. Teo and his associates demonstrate the potential value of combination therapies for ameliorating heightened T-cell responses and their pathogenic role in joint inflammation. They explored how T-cell responses could be blunted during ongoing viral replication to control overt inflammation, an approach that also may be valuable for treating immune-mediated tissue damage associated with other infectious agents.
Selective T-cell immunomodulatory therapies that offset damaging immune responses offer an attractive option for future pharmacologic interventions for treating chikungunya virus–induced inflammatory disease. The small market size and the rapid sporadic nature of outbreaks could be major obstacles to the development and deployment of virus-specific interventions such as therapeutic antiviral neutralizing monoclonal antibodies or even vaccines. Targeted drug and immunotherapy treatments are likely to offer practical and beneficial options for most patients with chikungunya.
Preliminary reports in humans have suggested that methotrexate may be effective for treating chikungunya virus–induced arthritis. In Dr. Miner and colleagues’ study, a low dose of methotrexate (0.3 mg/kg) was ineffective at treating acute joint swelling in mice. It remains to be addressed whether a higher dose of methotrexate for a longer time period could be of benefit in the setting of chronic chikungunya virus–induced arthritis.
Philippe Gasque, MD, PhD, is with the Université de La Réunion, Saint-Denis, Réunion, and Marie Christine Jaffar-Bandjee, MD, PhD, is with the Centre Hospitalier Universitaire Félix Guyon, Saint-Denis, Réunion. They made these remarks in an editorial (Sci Transl Med. 2017;9:eaam6567).
The studies by Dr. Miner and his colleagues and Dr. Teo and his associates demonstrate the potential value of combination therapies for ameliorating heightened T-cell responses and their pathogenic role in joint inflammation. They explored how T-cell responses could be blunted during ongoing viral replication to control overt inflammation, an approach that also may be valuable for treating immune-mediated tissue damage associated with other infectious agents.
Selective T-cell immunomodulatory therapies that offset damaging immune responses offer an attractive option for future pharmacologic interventions for treating chikungunya virus–induced inflammatory disease. The small market size and the rapid sporadic nature of outbreaks could be major obstacles to the development and deployment of virus-specific interventions such as therapeutic antiviral neutralizing monoclonal antibodies or even vaccines. Targeted drug and immunotherapy treatments are likely to offer practical and beneficial options for most patients with chikungunya.
Preliminary reports in humans have suggested that methotrexate may be effective for treating chikungunya virus–induced arthritis. In Dr. Miner and colleagues’ study, a low dose of methotrexate (0.3 mg/kg) was ineffective at treating acute joint swelling in mice. It remains to be addressed whether a higher dose of methotrexate for a longer time period could be of benefit in the setting of chronic chikungunya virus–induced arthritis.
Philippe Gasque, MD, PhD, is with the Université de La Réunion, Saint-Denis, Réunion, and Marie Christine Jaffar-Bandjee, MD, PhD, is with the Centre Hospitalier Universitaire Félix Guyon, Saint-Denis, Réunion. They made these remarks in an editorial (Sci Transl Med. 2017;9:eaam6567).
Several different currently approved immunomodulatory therapies ameliorated arthritis symptoms in chikungunya-infected mice in two studies that separate teams of researchers published online Feb. 1 in Science Translational Medicine.
The first team, led by Jonathan J. Miner, MD, PhD, of Washington University in St. Louis tested six different approved oral and biologic antirheumatic agents (along with control agents) in chikungunya virus-infected mice with acute arthritis and foot swelling (Sci Transl Med. 2017;9:eaah3438).
When the researchers paired abatacept with an antiviral therapy (monoclonal anti-CHIKV human antibody) the combination “was highly effective at reducing joint inflammation, periarticular swelling, migration of inflammatory leukocytes, and infection, even when administered several days after virus inoculation,” Dr. Miner and his colleagues wrote.
The researchers concluded that a combination of anti-inflammatory and antibody-based antiviral therapy “may serve as a model for treating humans with arthritis caused by CHIKV or other related viruses.”
In the second study, researchers led by Teck-Hui Teo, PhD, of the Agency for Science, Technology and Research (A*STAR) in Singapore, further elucidated the mechanisms by which CHIKV proteins act on T cells (Sci Transl Med. 2017;9:eaal1333). They also found that CHIKV-infected mice treated with fingolimod (Gilenya), a drug that blocks T-cell migration from the lymph nodes to the joints and is approved for the treatment of multiple sclerosis, saw reduced arthritis symptoms even without reduction of viral replication.
Infection with the chikungunya virus can produce arthritis that mimics symptoms of rheumatoid arthritis and may in some cases lead to joint damage. Though the mechanisms driving chikungunya-related arthritis are not well understood, preliminary studies have suggested a T-cell–mediated adverse response.
The Singapore team received funding from its own agency, A*STAR, while the Washington University researchers received grants from the National Institutes of Health and the Rheumatology Research Foundation. Two coauthors on the U.S. study reported extensive commercial conflicts, including consulting and advisory relationships with pharmaceutical and vaccine manufacturers, and one patent.
Several different currently approved immunomodulatory therapies ameliorated arthritis symptoms in chikungunya-infected mice in two studies that separate teams of researchers published online Feb. 1 in Science Translational Medicine.
The first team, led by Jonathan J. Miner, MD, PhD, of Washington University in St. Louis tested six different approved oral and biologic antirheumatic agents (along with control agents) in chikungunya virus-infected mice with acute arthritis and foot swelling (Sci Transl Med. 2017;9:eaah3438).
When the researchers paired abatacept with an antiviral therapy (monoclonal anti-CHIKV human antibody) the combination “was highly effective at reducing joint inflammation, periarticular swelling, migration of inflammatory leukocytes, and infection, even when administered several days after virus inoculation,” Dr. Miner and his colleagues wrote.
The researchers concluded that a combination of anti-inflammatory and antibody-based antiviral therapy “may serve as a model for treating humans with arthritis caused by CHIKV or other related viruses.”
In the second study, researchers led by Teck-Hui Teo, PhD, of the Agency for Science, Technology and Research (A*STAR) in Singapore, further elucidated the mechanisms by which CHIKV proteins act on T cells (Sci Transl Med. 2017;9:eaal1333). They also found that CHIKV-infected mice treated with fingolimod (Gilenya), a drug that blocks T-cell migration from the lymph nodes to the joints and is approved for the treatment of multiple sclerosis, saw reduced arthritis symptoms even without reduction of viral replication.
Infection with the chikungunya virus can produce arthritis that mimics symptoms of rheumatoid arthritis and may in some cases lead to joint damage. Though the mechanisms driving chikungunya-related arthritis are not well understood, preliminary studies have suggested a T-cell–mediated adverse response.
The Singapore team received funding from its own agency, A*STAR, while the Washington University researchers received grants from the National Institutes of Health and the Rheumatology Research Foundation. Two coauthors on the U.S. study reported extensive commercial conflicts, including consulting and advisory relationships with pharmaceutical and vaccine manufacturers, and one patent.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point:
Major finding: Abatacept, tofacitinib, and fingolimod all reduced arthritis symptoms, compared with controls.
Data source: Two studies testing multiple immunomodulatory or antirheumatic agents in chikungunya virus–infected mice.
Disclosures: The Agency for Science, Technology and Research (A*STAR) funded the Singapore researchers, while grants from the NIH and the Rheumatology Research Foundation funded the U.S. team. Two coauthors on the U.S. study disclosed extensive financial relationships with multiple pharmaceutical and vaccine manufacturers.
Refractory RA patients respond well to peficitinib in phase II study
A 12-week course of daily oral peficitinib improved the severity of refractory rheumatoid arthritis in a manufacturer-sponsored phase II trial of the investigational drug, which inhibits all of the intracellular signaling molecules in the Janus kinase family.
The randomized, double-blind dose-finding study was performed at 41 sites in six countries and involved 289 adults with long-standing moderate to severe rheumatoid arthritis (RA) who had not responded to or who were intolerant of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The participants were permitted to take nonsteroidal anti-inflammatory drugs, hydroxychloroquine, chloroquine, sulfasalazine, and/or oral corticosteroids (10 mg or less of prednisone or equivalent) as needed throughout the trial, but not methotrexate, gold, penicillamine, leflunomide, azathioprine, minocycline, and cyclophosphamide. The patients also were allowed to have previously taken a biologic and were not required to have had an inadequate response or intolerance to a previous biologic, said Mark C. Genovese, MD, of the division of immunology and rheumatology at Stanford University, Palo Alto, Calif., and his associates.
Patients receiving the two highest doses of peficitinib also showed a significant improvement in 28-joint Disease Activity Score, compared with those receiving placebo.
On safety outcomes, the investigators reported that peficitinib “demonstrated satisfactory tolerability” with an overall incidence of adverse events similar to that of the placebo group, and there were no new safety signals that differed from the other two previous phase II trials of peficitinib for RA. There were dose-dependent decreases in absolute neutrophil count, platelet count, and white blood cell count, as well as dose-dependent increases in creatine phosphokinase, high-density lipoprotein, and creatinine levels. Three cases of grade 3 or higher hypertriglyceridemia were considered to be drug related, and 10 patients discontinued peficitinib because of dyspepsia, nausea, vomiting, abdominal hernia, hidradenitis, skin lesions, MI, or limb abscess.
Peficitinib inhibits JAK1, JAK2, JAK3, and Tyk2 enzyme activities, with a moderate selectivity for JAK3. Two other phase II efficacy and safety studies of peficitinib have been conducted previously. One of these involved Japanese patients who were not required to fail one or more csDMARDs and received the same doses as in the current study. The 12-week study resulted in statistically significant improvements in ACR20 responses in patients who took 50-mg, 100-mg, and 150-mg doses of peficitinib monotherapy. The second 12-week phase II trial of peficitinib plus methotrexate in patients who had an inadequate response to methotrexate found that the combination was statistically significantly better than placebo plus methotrexate in ACR20 response rate only among those who took 50 mg.
Larger and longer-term phase III trials of the 100-mg and 150-mg doses of peficitinib are now underway, Dr. Genovese and his associates added. One trial is comparing peficitinib alone or in combination with DMARDs against placebo or an open-label active comparator, etanercept, for 52 weeks in patients who had an inadequate response to DMARDs. The other is a 52-week trial comparing peficitinib in combination with methotrexate versus placebo and methotrexate in patients who had an inadequate response to methotrexate.
The phase II trial was sponsored by Astellas Pharma. Dr. Genovese reported ties to Astellas, AbbVie, Johnson & Johnson, Pfizer, Eli Lilly, Vertex, Galapagos NV, and Gilead Sciences; his associates reported ties to numerous industry sources.
A 12-week course of daily oral peficitinib improved the severity of refractory rheumatoid arthritis in a manufacturer-sponsored phase II trial of the investigational drug, which inhibits all of the intracellular signaling molecules in the Janus kinase family.
The randomized, double-blind dose-finding study was performed at 41 sites in six countries and involved 289 adults with long-standing moderate to severe rheumatoid arthritis (RA) who had not responded to or who were intolerant of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The participants were permitted to take nonsteroidal anti-inflammatory drugs, hydroxychloroquine, chloroquine, sulfasalazine, and/or oral corticosteroids (10 mg or less of prednisone or equivalent) as needed throughout the trial, but not methotrexate, gold, penicillamine, leflunomide, azathioprine, minocycline, and cyclophosphamide. The patients also were allowed to have previously taken a biologic and were not required to have had an inadequate response or intolerance to a previous biologic, said Mark C. Genovese, MD, of the division of immunology and rheumatology at Stanford University, Palo Alto, Calif., and his associates.
Patients receiving the two highest doses of peficitinib also showed a significant improvement in 28-joint Disease Activity Score, compared with those receiving placebo.
On safety outcomes, the investigators reported that peficitinib “demonstrated satisfactory tolerability” with an overall incidence of adverse events similar to that of the placebo group, and there were no new safety signals that differed from the other two previous phase II trials of peficitinib for RA. There were dose-dependent decreases in absolute neutrophil count, platelet count, and white blood cell count, as well as dose-dependent increases in creatine phosphokinase, high-density lipoprotein, and creatinine levels. Three cases of grade 3 or higher hypertriglyceridemia were considered to be drug related, and 10 patients discontinued peficitinib because of dyspepsia, nausea, vomiting, abdominal hernia, hidradenitis, skin lesions, MI, or limb abscess.
Peficitinib inhibits JAK1, JAK2, JAK3, and Tyk2 enzyme activities, with a moderate selectivity for JAK3. Two other phase II efficacy and safety studies of peficitinib have been conducted previously. One of these involved Japanese patients who were not required to fail one or more csDMARDs and received the same doses as in the current study. The 12-week study resulted in statistically significant improvements in ACR20 responses in patients who took 50-mg, 100-mg, and 150-mg doses of peficitinib monotherapy. The second 12-week phase II trial of peficitinib plus methotrexate in patients who had an inadequate response to methotrexate found that the combination was statistically significantly better than placebo plus methotrexate in ACR20 response rate only among those who took 50 mg.
Larger and longer-term phase III trials of the 100-mg and 150-mg doses of peficitinib are now underway, Dr. Genovese and his associates added. One trial is comparing peficitinib alone or in combination with DMARDs against placebo or an open-label active comparator, etanercept, for 52 weeks in patients who had an inadequate response to DMARDs. The other is a 52-week trial comparing peficitinib in combination with methotrexate versus placebo and methotrexate in patients who had an inadequate response to methotrexate.
The phase II trial was sponsored by Astellas Pharma. Dr. Genovese reported ties to Astellas, AbbVie, Johnson & Johnson, Pfizer, Eli Lilly, Vertex, Galapagos NV, and Gilead Sciences; his associates reported ties to numerous industry sources.
A 12-week course of daily oral peficitinib improved the severity of refractory rheumatoid arthritis in a manufacturer-sponsored phase II trial of the investigational drug, which inhibits all of the intracellular signaling molecules in the Janus kinase family.
The randomized, double-blind dose-finding study was performed at 41 sites in six countries and involved 289 adults with long-standing moderate to severe rheumatoid arthritis (RA) who had not responded to or who were intolerant of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The participants were permitted to take nonsteroidal anti-inflammatory drugs, hydroxychloroquine, chloroquine, sulfasalazine, and/or oral corticosteroids (10 mg or less of prednisone or equivalent) as needed throughout the trial, but not methotrexate, gold, penicillamine, leflunomide, azathioprine, minocycline, and cyclophosphamide. The patients also were allowed to have previously taken a biologic and were not required to have had an inadequate response or intolerance to a previous biologic, said Mark C. Genovese, MD, of the division of immunology and rheumatology at Stanford University, Palo Alto, Calif., and his associates.
Patients receiving the two highest doses of peficitinib also showed a significant improvement in 28-joint Disease Activity Score, compared with those receiving placebo.
On safety outcomes, the investigators reported that peficitinib “demonstrated satisfactory tolerability” with an overall incidence of adverse events similar to that of the placebo group, and there were no new safety signals that differed from the other two previous phase II trials of peficitinib for RA. There were dose-dependent decreases in absolute neutrophil count, platelet count, and white blood cell count, as well as dose-dependent increases in creatine phosphokinase, high-density lipoprotein, and creatinine levels. Three cases of grade 3 or higher hypertriglyceridemia were considered to be drug related, and 10 patients discontinued peficitinib because of dyspepsia, nausea, vomiting, abdominal hernia, hidradenitis, skin lesions, MI, or limb abscess.
Peficitinib inhibits JAK1, JAK2, JAK3, and Tyk2 enzyme activities, with a moderate selectivity for JAK3. Two other phase II efficacy and safety studies of peficitinib have been conducted previously. One of these involved Japanese patients who were not required to fail one or more csDMARDs and received the same doses as in the current study. The 12-week study resulted in statistically significant improvements in ACR20 responses in patients who took 50-mg, 100-mg, and 150-mg doses of peficitinib monotherapy. The second 12-week phase II trial of peficitinib plus methotrexate in patients who had an inadequate response to methotrexate found that the combination was statistically significantly better than placebo plus methotrexate in ACR20 response rate only among those who took 50 mg.
Larger and longer-term phase III trials of the 100-mg and 150-mg doses of peficitinib are now underway, Dr. Genovese and his associates added. One trial is comparing peficitinib alone or in combination with DMARDs against placebo or an open-label active comparator, etanercept, for 52 weeks in patients who had an inadequate response to DMARDs. The other is a 52-week trial comparing peficitinib in combination with methotrexate versus placebo and methotrexate in patients who had an inadequate response to methotrexate.
The phase II trial was sponsored by Astellas Pharma. Dr. Genovese reported ties to Astellas, AbbVie, Johnson & Johnson, Pfizer, Eli Lilly, Vertex, Galapagos NV, and Gilead Sciences; his associates reported ties to numerous industry sources.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point:
Major finding: The primary efficacy endpoint – the percentage of patients achieving an ACR20 level of improvement at week 12 – was significantly higher in patients taking the 100-mg dose (48.3%) and the 150-mg dose (56.3%) than in those taking placebo (29.4%).
Data source: An international, manufacturer-sponsored, randomized, double-blind, placebo-controlled phase II trial involving 289 adults with RA.
Disclosures: The phase II trial was sponsored by Astellas Pharma. Dr. Genovese reported ties to Astellas, AbbVie, Johnson & Johnson, Pfizer, Eli Lilly, Vertex, Galapagos NV, and Gilead Sciences; his associates reported ties to numerous industry sources.
FDA opens abbreviated approval pathway for interchangeable biosimilars
The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique drugs.
But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.
The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.
The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.
Interchangeables jump a higher regulatory bar
An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.
Like biosimilars, interchangeable products need not be tested in every disease for which the reference drug is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.
The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:
• Sandoz’ filgrastim-sndz (Zarxio).
• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).
• Sandoz’ etanercept-szzs (Erelzi).
• Amgen’s adalimumab-atto (Amjevita).
Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.
But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.
Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.
The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.
Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.
“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.
The E.U. vs. U.S. experience
The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such drugs have come on the market, at an average price of about 30% less than the reference drug. Prices for some drugs have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.
“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.
It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive drugs. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount on the drug to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.
There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.
In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer drugs (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those drugs to make up for the money they were losing on the Russian market.
“I think most of the cost benefits will accrue to insurance plans and pharmacy managers, but maybe not to the patients themselves,” he said in an interview. “The most important beneficiaries may not see a single penny of benefit.”
It may be difficult to extrapolate the European economic experience into the U.S. health care market, but the safety record of its biosimilar armamentarium is solid. None of the biosimilars approved in the E.U. have ever been recalled or removed from the European market because of regulatory or safety concerns.
Nonmedical switching raises concerns
Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive drugs, they uniformly insist that patient safety – not economic pressure – should be the driving force here.
“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”
He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.
“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).
“In general, the GI field is OK with the idea of starting someone on a new prescription [of an interchangeable biosimilar], but not so much with the idea of switching around,” said Dr. Hanauer, who is the Clifford Joseph Barborka Professor of Gastroenterology at Northwestern University, Chicago. “In these biologic compounds, very small differences can be amplified” and alter therapeutic response.
The possibility of switching from the reference to the biosimilar and maybe back again worries him. He hearkened back to the approval of Remicade, when patients who had taken it during clinical trials only were finally able to obtain it on the market. Dr. Hanauer explained that, “20% of them developed serum sickness reactions after the reexposure.”
He also expressed some concern about quality control in international manufacturing plants, citing a 2005 epidemic of immune-mediated pure red cell anemia in patients who received an epoetin alfa biosimilar manufactured in Thailand. The prefilled syringes had an uncoated rubber stopper that apparently reacted with polysorbate 60 in the solution – an interaction that increased immunogenicity when the drug was administered subcutaneously.
Dr. Smith concurred. “We know that some patients produce antibodies to biologics if they come on and off, and so we discourage that. The concern is that switching may lead to an increased rate of medication failure, if you have to switch back. This is especially troubling in the case of a hard-to-control patient with severe flares. If they’re being well controlled on a medication, the last thing you want to do is change it for no good clinical reason. And we may well be forced to do that.”
Neither the AAD nor the American College of Gastroenterology has a published stand on the FDA’s proposed guidance for interchangeable biosimilars. The preliminary view of the American College of Rheumatology is a positive one, Dr. Worthing said. However, ACR feels pharmacy-level switching should be a joint, not unilateral, decision.
“Our position statement on biosimilars has been that if it’s legal for a pharmacy to make that switch then we want the doctor and the patient to know, so we can track for safety signals.”
Bringing any biosimilar to market, though, takes a lot of money and a lot of time. And while companies are growing cell lines and producing new molecules that mimic existing drugs, science marches on, said Dr. Smith.
“If we keep dragging our feet on this issue, it might end up being a moot point,” he said. Newer drugs are achieving better results, raising the bar for therapeutic success. An example is the monoclonal antibody secukinumab (Cosentyx), an inhibitor of interleukin 17A. In October 2016, late-breaking data released at the annual meeting of the European Academy of Dermatology and Venereology impressed the dermatology community. In psoriasis patients, the drug maintained 90% skin clearance for 4 years in 66% of patients, and 100% clearance for 4 years in 43%.
Not only does this kind of efficacy provide symptomatic relief, it also prevents the expensive long-term morbidity associated with psoriasis, Dr. Smith said.
“Even if these new medications are considerably more expensive upfront than a biosimilar for an older drug, they may end up being less expensive in the long run.”
Dr. Krant and Dr. Worthing had no financial disclosures. Dr. Smith has received grants from Allergan and Cipher Pharmaceuticals. Dr. Hanauer has received grants from numerous pharmaceutical companies that manufacture biologics.
*This article was updated 1/31/2017.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique drugs.
But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.
The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.
The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.
Interchangeables jump a higher regulatory bar
An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.
Like biosimilars, interchangeable products need not be tested in every disease for which the reference drug is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.
The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:
• Sandoz’ filgrastim-sndz (Zarxio).
• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).
• Sandoz’ etanercept-szzs (Erelzi).
• Amgen’s adalimumab-atto (Amjevita).
Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.
But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.
Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.
The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.
Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.
“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.
The E.U. vs. U.S. experience
The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such drugs have come on the market, at an average price of about 30% less than the reference drug. Prices for some drugs have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.
“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.
It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive drugs. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount on the drug to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.
There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.
In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer drugs (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those drugs to make up for the money they were losing on the Russian market.
“I think most of the cost benefits will accrue to insurance plans and pharmacy managers, but maybe not to the patients themselves,” he said in an interview. “The most important beneficiaries may not see a single penny of benefit.”
It may be difficult to extrapolate the European economic experience into the U.S. health care market, but the safety record of its biosimilar armamentarium is solid. None of the biosimilars approved in the E.U. have ever been recalled or removed from the European market because of regulatory or safety concerns.
Nonmedical switching raises concerns
Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive drugs, they uniformly insist that patient safety – not economic pressure – should be the driving force here.
“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”
He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.
“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).
“In general, the GI field is OK with the idea of starting someone on a new prescription [of an interchangeable biosimilar], but not so much with the idea of switching around,” said Dr. Hanauer, who is the Clifford Joseph Barborka Professor of Gastroenterology at Northwestern University, Chicago. “In these biologic compounds, very small differences can be amplified” and alter therapeutic response.
The possibility of switching from the reference to the biosimilar and maybe back again worries him. He hearkened back to the approval of Remicade, when patients who had taken it during clinical trials only were finally able to obtain it on the market. Dr. Hanauer explained that, “20% of them developed serum sickness reactions after the reexposure.”
He also expressed some concern about quality control in international manufacturing plants, citing a 2005 epidemic of immune-mediated pure red cell anemia in patients who received an epoetin alfa biosimilar manufactured in Thailand. The prefilled syringes had an uncoated rubber stopper that apparently reacted with polysorbate 60 in the solution – an interaction that increased immunogenicity when the drug was administered subcutaneously.
Dr. Smith concurred. “We know that some patients produce antibodies to biologics if they come on and off, and so we discourage that. The concern is that switching may lead to an increased rate of medication failure, if you have to switch back. This is especially troubling in the case of a hard-to-control patient with severe flares. If they’re being well controlled on a medication, the last thing you want to do is change it for no good clinical reason. And we may well be forced to do that.”
Neither the AAD nor the American College of Gastroenterology has a published stand on the FDA’s proposed guidance for interchangeable biosimilars. The preliminary view of the American College of Rheumatology is a positive one, Dr. Worthing said. However, ACR feels pharmacy-level switching should be a joint, not unilateral, decision.
“Our position statement on biosimilars has been that if it’s legal for a pharmacy to make that switch then we want the doctor and the patient to know, so we can track for safety signals.”
Bringing any biosimilar to market, though, takes a lot of money and a lot of time. And while companies are growing cell lines and producing new molecules that mimic existing drugs, science marches on, said Dr. Smith.
“If we keep dragging our feet on this issue, it might end up being a moot point,” he said. Newer drugs are achieving better results, raising the bar for therapeutic success. An example is the monoclonal antibody secukinumab (Cosentyx), an inhibitor of interleukin 17A. In October 2016, late-breaking data released at the annual meeting of the European Academy of Dermatology and Venereology impressed the dermatology community. In psoriasis patients, the drug maintained 90% skin clearance for 4 years in 66% of patients, and 100% clearance for 4 years in 43%.
Not only does this kind of efficacy provide symptomatic relief, it also prevents the expensive long-term morbidity associated with psoriasis, Dr. Smith said.
“Even if these new medications are considerably more expensive upfront than a biosimilar for an older drug, they may end up being less expensive in the long run.”
Dr. Krant and Dr. Worthing had no financial disclosures. Dr. Smith has received grants from Allergan and Cipher Pharmaceuticals. Dr. Hanauer has received grants from numerous pharmaceutical companies that manufacture biologics.
*This article was updated 1/31/2017.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
The Food and Drug Administration has proposed a regulatory path for biosimilar biologics that are interchangeable with the reference product, paving the way for a new generation of less-expensive versions of these unique drugs.
But bringing an interchangeable biosimilar to market won’t be easy. The bar for interchangeability will be high, requiring that manufacturers prove switching between the new and older products is safe. And clinicians, while cautiously optimistic, aren’t thrilled with the industry payoff that could come with the designation: freedom for insurance companies and pharmacies to switch products at the dispensing level without requiring a new prescription.
The draft FDA guidance for industry, “Considerations in Demonstrating Interchangeability With a Reference Product,” arises from the Biologics Price Competition and Innovation Act of 2009. That section of the Affordable Care Act provides for abbreviated approval pathways for biological products that are demonstrated to be “highly similar” (biosimilar) to or “interchangeable” with an FDA-approved biological product.
The difference between these appellations is subtle but critical to the regulatory process – and perhaps to patient safety. Regulators recognize that the structure of these large, highly complex molecules can never precisely replicate the reference product. But to be labeled a “biosimilar,” developers must prove that the new product functions essentially the same; there can be no clinically meaningful differences in terms of safety, purity, and potency. Unlike a generic medication, a biosimilar can’t be substituted for its reference product at the pharmacy level. If a physician wants the patient on that biosimilar, the script must specify it.
Interchangeables jump a higher regulatory bar
An “interchangeable biosimilar,” though, would have to jump a higher regulatory bar. Not only must it produce the same clinical result as the reference product, it also must be benignly interchangeable with it, conferring no additional risk if a patient switches from the reference to the biosimilar and back again. A pharmacist could, if permitted by state law, substitute an interchangeable product for the reference product without going through the prescriber.
Like biosimilars, interchangeable products need not be tested in every disease for which the reference drug is approved, according to the document. Once they are proved safe for one indication, those data can be extrapolated to allow approval for the other indications as well. Nor do biosimilars need to prove efficacy per se, as their molecular similarity to the reference product ensures that they bind to the same receptor and exert the same therapeutic effect.
The biosimilar/interchangeable market has been slow to take off in the United States. There are no approved interchangeable biosimilars, and only four biosimilars – three of which were approved in 2016:
• Sandoz’ filgrastim-sndz (Zarxio).
• Pfizer’s and Celltrion’s infliximab-dyyb (Inflectra).
• Sandoz’ etanercept-szzs (Erelzi).
• Amgen’s adalimumab-atto (Amjevita).
Switching studies is the key to achieving the interchangeable designation, according to the FDA document. They must include at least two full switches between the candidate product and the reference product, which must be licensed in the United States.
But because these products are so structurally diverse, the FDA isn’t imposing a one-size-fits-all process on them. Instead, the molecular complexity and immunogenicity of each product will dictate its approval requirements.
Those with relatively low structural complexity, high molecular similarity to the reference product, and a low incidence of immunogenic adverse events may only need a single switching study to achieve the “interchangeability” designation.
The bar will be higher for a product with high structural complexity that is not as similar to the reference product, or which has been associated with immunogenic adverse events. For this product, FDA might also require extensive safety postmarketing data for the product as a licensed biosimilar, as well as a switching study.
Pharmacokinetics, pharmacodynamics, immunogenicity, and safety will be the primary endpoints of a switching study. Efficacy data are not necessary but can be used as supportive endpoints. Any safety signals in a switching study would raise regulatory eyebrows whether they came from the candidate product or the reference product. Since the study replicates what could happen if the two were used sequentially, it makes little difference from which product the event might arise.
“If an apparent difference in immune response or adverse events is noticed between the switching and nonswitching arms of the study ... it would raise concerns as to whether the proposed interchangeable product is interchangeable, regardless of whether the proposed interchangeable product or the reference product or the switching of the two products actually caused the event,” the document notes.
The E.U. vs. U.S. experience
The United States is only now getting a taste of what has become common fare in the European Union, said Angus Worthing, MD, chair of the American College of Rheumatology’s Government Affairs Committee. The European Medicines Agency approved its first biosimilar in 2006. Since then, 23 such drugs have come on the market, at an average price of about 30% less than the reference drug. Prices for some drugs have dropped as much as 70% in countries in which national health care systems abandoned the reference product in favor of the competing biosimilar, Dr. Worthing said in an interview.
“But the U.S. doesn’t have a national health care system, so it won’t work like that here.” In fact, he noted, brand-new data show that Medicare actually paid 22% more for the infliximab biosimilar Inflectra than it did for Remicade in the last quarter of 2016.
It’s not immediately apparent why this is the case, but it’s probably related to company discounts and rebates on these very expensive drugs. According to the report in Inside Health Policy, Janssen Biotech may have increased its discount on the drug to compete with Inflectra’s launch price of 15% below Remicade’s wholesale cost. Prices won’t moderate as much in the United States as in the European Union until several biosimilars of the same class appear, Dr. Worthing said.
There have already been allegations that big pharma manipulates international and national pricing to reduce biosimilar competition.
In June, Russian biotech company Biocad filed a lawsuit in New York charging Roche/Genentech with price fixing. The suit alleges that the companies cut the cost of three cancer drugs (Avastin, Herceptin, and Rituxan/MabThera) in Russia, where Biocad markets biosimilars for each. At the same time, Biocad alleges, the companies raised U.S. prices on those drugs to make up for the money they were losing on the Russian market.
“I think most of the cost benefits will accrue to insurance plans and pharmacy managers, but maybe not to the patients themselves,” he said in an interview. “The most important beneficiaries may not see a single penny of benefit.”
It may be difficult to extrapolate the European economic experience into the U.S. health care market, but the safety record of its biosimilar armamentarium is solid. None of the biosimilars approved in the E.U. have ever been recalled or removed from the European market because of regulatory or safety concerns.
Nonmedical switching raises concerns
Academic medical societies and clinicians interviewed for this article view the proposed approval pathway with cautious optimism. While acknowledging the potential benefit of reducing the costs of prohibitively expensive drugs, they uniformly insist that patient safety – not economic pressure – should be the driving force here.
“I was initially skeptical, and I do believe that we need very close pharmacovigilance in monitoring these for safety,” said Gideon Smith, MD, PhD, a dermatologist at Massachusetts General Hospital, Boston. “But there has been huge uptake of these products in the E.U., and the data are so extensive that we can be reasonably confident these drugs are effective, and no good reason to believe the safety will be any different.”
He is not as comfortable with the prospect of pharmacy-level substitution of an interchangeable biosimilar with the reference product – a feeling that other clinicians echoed.
“I think this is a fundamental issue that should have been dealt with on a federal level. Physicians should always be involved in the decision,” said Dr. Smith, who spoke at an FDA advisory committee meeting last summer on behalf of the American Academy of Dermatology (AAD).
“In general, the GI field is OK with the idea of starting someone on a new prescription [of an interchangeable biosimilar], but not so much with the idea of switching around,” said Dr. Hanauer, who is the Clifford Joseph Barborka Professor of Gastroenterology at Northwestern University, Chicago. “In these biologic compounds, very small differences can be amplified” and alter therapeutic response.
The possibility of switching from the reference to the biosimilar and maybe back again worries him. He hearkened back to the approval of Remicade, when patients who had taken it during clinical trials only were finally able to obtain it on the market. Dr. Hanauer explained that, “20% of them developed serum sickness reactions after the reexposure.”
He also expressed some concern about quality control in international manufacturing plants, citing a 2005 epidemic of immune-mediated pure red cell anemia in patients who received an epoetin alfa biosimilar manufactured in Thailand. The prefilled syringes had an uncoated rubber stopper that apparently reacted with polysorbate 60 in the solution – an interaction that increased immunogenicity when the drug was administered subcutaneously.
Dr. Smith concurred. “We know that some patients produce antibodies to biologics if they come on and off, and so we discourage that. The concern is that switching may lead to an increased rate of medication failure, if you have to switch back. This is especially troubling in the case of a hard-to-control patient with severe flares. If they’re being well controlled on a medication, the last thing you want to do is change it for no good clinical reason. And we may well be forced to do that.”
Neither the AAD nor the American College of Gastroenterology has a published stand on the FDA’s proposed guidance for interchangeable biosimilars. The preliminary view of the American College of Rheumatology is a positive one, Dr. Worthing said. However, ACR feels pharmacy-level switching should be a joint, not unilateral, decision.
“Our position statement on biosimilars has been that if it’s legal for a pharmacy to make that switch then we want the doctor and the patient to know, so we can track for safety signals.”
Bringing any biosimilar to market, though, takes a lot of money and a lot of time. And while companies are growing cell lines and producing new molecules that mimic existing drugs, science marches on, said Dr. Smith.
“If we keep dragging our feet on this issue, it might end up being a moot point,” he said. Newer drugs are achieving better results, raising the bar for therapeutic success. An example is the monoclonal antibody secukinumab (Cosentyx), an inhibitor of interleukin 17A. In October 2016, late-breaking data released at the annual meeting of the European Academy of Dermatology and Venereology impressed the dermatology community. In psoriasis patients, the drug maintained 90% skin clearance for 4 years in 66% of patients, and 100% clearance for 4 years in 43%.
Not only does this kind of efficacy provide symptomatic relief, it also prevents the expensive long-term morbidity associated with psoriasis, Dr. Smith said.
“Even if these new medications are considerably more expensive upfront than a biosimilar for an older drug, they may end up being less expensive in the long run.”
Dr. Krant and Dr. Worthing had no financial disclosures. Dr. Smith has received grants from Allergan and Cipher Pharmaceuticals. Dr. Hanauer has received grants from numerous pharmaceutical companies that manufacture biologics.
*This article was updated 1/31/2017.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Lyme arthritis changes its immune response profile if it persists after antibiotics
The persistence of Lyme arthritis after treatment with antibiotics comes with a shift from an immune response expected for bacterial infection to one characterized by chronic inflammation, synovial proliferation, and breakdown of wound repair processes, according to an analysis of microRNA expression in patients before, during, and after infection.
Based on the findings, investigators led by Robert B. Lochhead, PhD, of Massachusetts General Hospital, Boston, said that they “suspect that, in humans, genetic variables determine whether the response to B. burgdorferi infection elicits an appropriate wound repair response … or a maladaptive inflammatory cellular response and arrest of wound repair processes.”
The investigators studied synovial fluid or tissue from 32 patients with LA who were representative of the spectrum of disease severity and treatment responses seen in this disease. In 18 patients for whom synovial fluid samples were available, 5 illustrated the differences in miRNA expression that occur from the time before any antibiotic treatment to the time after antibiotic treatment that successfully resolves arthritis symptoms, and 13 showed how an incomplete response to antibiotic treatment can affect miRNA expression. The expression profile of miRNA in synovial tissue samples from another 14 patients who underwent arthroscopic synovectomies 4-48 months after oral and intravenous antibiotics demonstrated the change in immune response seen in postinfectious LA.
The group of five patients with synovial fluid samples who were referred prior to antibiotic therapy when they had active B. burgdorferi infection (group 1) had a history of mild to severe knee swelling and pain for a median duration of 1 month prior to evaluation and the start of antibiotic treatment. A 1-month course of oral doxycycline resolved arthritis in three of the patients, and the other two continued to have marked knee swelling that later resolved after 1 month of IV ceftriaxone. Of six different miRNAs that the investigators measured, five were at low levels in these patients. The lone exception was a hematopoietic-specific miRNA, miR-223, which is abundantly expressed in polymorphonuclear lymphocytes (PMNs) and is associated with downregulation of acute inflammation and tissue remodeling.
In the group of 13 who still had joint swelling despite oral or IV antibiotics (group 2), only 2 had resolution of their swelling after IV antibiotics. Most of the remaining 11 had successful treatment with methotrexate. The synovial fluid samples for seven patients were collected after oral antibiotics but before IV antibiotics, and in the other six the samples were collected after both therapies. These 13 patients had significantly lower white blood cell counts in synovial fluid, fewer PMNs, and greater percentages of lymphocytes and monocytes than did group 1 patients. The five miRNAs that were found at low levels among the patients in group 1 were higher in these patients, which “suggested that the nature of the arthritis had changed after spirochetal killing.” The higher miR-223 levels seen in group 1 also occurred in group 2.
A separate analysis of synovial fluid samples from four patients with osteoarthritis and six patients with RA showed that levels of the six miRNAs from RA patients were similar to those of patients from group 2, and the low levels that were observed for most of the miRNAs in group 1 were similar to those seen in OA patients.
The investigators found that the five miRNAs with elevated levels in group 2 patients, but not miR-223, were positively correlated with arthritis duration after start of oral antibiotic therapy. B. burgdorferi IgG antibody titers negatively correlated with some of the elevated miRNAs in group 2.
The investigators analyzed a larger set of miRNAs in the synovial tissue samples obtained from 14 patients who underwent synovectomies for treatment of persistent synovitis a median of 15.5 months after they had undergone 2-3 months of antibiotic therapy (group 3). Some of the miRNAs overexpressed in these postinfectious LA samples, relative to samples from five OA patients, were associated with proliferative, tumor-associated responses and regulation of inflammatory processes. However, miRNAs overexpressed in tissues from OA patients relative to postinfectious LA patients were thought to affect genes that control tissue remodeling and cell proliferation, but not inflammation. The “distinct oncogenic miRNA profile” exhibited by postinfectious synovial tissue, according to the investigators, showed that “in these patients, the transition to the postinfectious phase was blocked by chronic inflammation, which stalled the wound repair process.”
The investigators concluded that “miRNAs hold promise as potential biomarkers to identify LA patients who are developing maladaptive immune responses during the period of infection. In such patients, it will be important to learn whether simultaneous treatment with antibiotics and DMARDs, rather than sequential treatment with these medications, will reduce the period of therapy and improve outcome, creating a new paradigm in treatment of this form of chronic inflammatory arthritis.”
The study was supported by grants from the National Institutes of Health, the Lucius N. Littauer Foundation, the Roland Foundation, the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital, the Rheumatology Research Foundation, and the English, Bonter, Mitchell Foundation.
The persistence of Lyme arthritis after treatment with antibiotics comes with a shift from an immune response expected for bacterial infection to one characterized by chronic inflammation, synovial proliferation, and breakdown of wound repair processes, according to an analysis of microRNA expression in patients before, during, and after infection.
Based on the findings, investigators led by Robert B. Lochhead, PhD, of Massachusetts General Hospital, Boston, said that they “suspect that, in humans, genetic variables determine whether the response to B. burgdorferi infection elicits an appropriate wound repair response … or a maladaptive inflammatory cellular response and arrest of wound repair processes.”
The investigators studied synovial fluid or tissue from 32 patients with LA who were representative of the spectrum of disease severity and treatment responses seen in this disease. In 18 patients for whom synovial fluid samples were available, 5 illustrated the differences in miRNA expression that occur from the time before any antibiotic treatment to the time after antibiotic treatment that successfully resolves arthritis symptoms, and 13 showed how an incomplete response to antibiotic treatment can affect miRNA expression. The expression profile of miRNA in synovial tissue samples from another 14 patients who underwent arthroscopic synovectomies 4-48 months after oral and intravenous antibiotics demonstrated the change in immune response seen in postinfectious LA.
The group of five patients with synovial fluid samples who were referred prior to antibiotic therapy when they had active B. burgdorferi infection (group 1) had a history of mild to severe knee swelling and pain for a median duration of 1 month prior to evaluation and the start of antibiotic treatment. A 1-month course of oral doxycycline resolved arthritis in three of the patients, and the other two continued to have marked knee swelling that later resolved after 1 month of IV ceftriaxone. Of six different miRNAs that the investigators measured, five were at low levels in these patients. The lone exception was a hematopoietic-specific miRNA, miR-223, which is abundantly expressed in polymorphonuclear lymphocytes (PMNs) and is associated with downregulation of acute inflammation and tissue remodeling.
In the group of 13 who still had joint swelling despite oral or IV antibiotics (group 2), only 2 had resolution of their swelling after IV antibiotics. Most of the remaining 11 had successful treatment with methotrexate. The synovial fluid samples for seven patients were collected after oral antibiotics but before IV antibiotics, and in the other six the samples were collected after both therapies. These 13 patients had significantly lower white blood cell counts in synovial fluid, fewer PMNs, and greater percentages of lymphocytes and monocytes than did group 1 patients. The five miRNAs that were found at low levels among the patients in group 1 were higher in these patients, which “suggested that the nature of the arthritis had changed after spirochetal killing.” The higher miR-223 levels seen in group 1 also occurred in group 2.
A separate analysis of synovial fluid samples from four patients with osteoarthritis and six patients with RA showed that levels of the six miRNAs from RA patients were similar to those of patients from group 2, and the low levels that were observed for most of the miRNAs in group 1 were similar to those seen in OA patients.
The investigators found that the five miRNAs with elevated levels in group 2 patients, but not miR-223, were positively correlated with arthritis duration after start of oral antibiotic therapy. B. burgdorferi IgG antibody titers negatively correlated with some of the elevated miRNAs in group 2.
The investigators analyzed a larger set of miRNAs in the synovial tissue samples obtained from 14 patients who underwent synovectomies for treatment of persistent synovitis a median of 15.5 months after they had undergone 2-3 months of antibiotic therapy (group 3). Some of the miRNAs overexpressed in these postinfectious LA samples, relative to samples from five OA patients, were associated with proliferative, tumor-associated responses and regulation of inflammatory processes. However, miRNAs overexpressed in tissues from OA patients relative to postinfectious LA patients were thought to affect genes that control tissue remodeling and cell proliferation, but not inflammation. The “distinct oncogenic miRNA profile” exhibited by postinfectious synovial tissue, according to the investigators, showed that “in these patients, the transition to the postinfectious phase was blocked by chronic inflammation, which stalled the wound repair process.”
The investigators concluded that “miRNAs hold promise as potential biomarkers to identify LA patients who are developing maladaptive immune responses during the period of infection. In such patients, it will be important to learn whether simultaneous treatment with antibiotics and DMARDs, rather than sequential treatment with these medications, will reduce the period of therapy and improve outcome, creating a new paradigm in treatment of this form of chronic inflammatory arthritis.”
The study was supported by grants from the National Institutes of Health, the Lucius N. Littauer Foundation, the Roland Foundation, the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital, the Rheumatology Research Foundation, and the English, Bonter, Mitchell Foundation.
The persistence of Lyme arthritis after treatment with antibiotics comes with a shift from an immune response expected for bacterial infection to one characterized by chronic inflammation, synovial proliferation, and breakdown of wound repair processes, according to an analysis of microRNA expression in patients before, during, and after infection.
Based on the findings, investigators led by Robert B. Lochhead, PhD, of Massachusetts General Hospital, Boston, said that they “suspect that, in humans, genetic variables determine whether the response to B. burgdorferi infection elicits an appropriate wound repair response … or a maladaptive inflammatory cellular response and arrest of wound repair processes.”
The investigators studied synovial fluid or tissue from 32 patients with LA who were representative of the spectrum of disease severity and treatment responses seen in this disease. In 18 patients for whom synovial fluid samples were available, 5 illustrated the differences in miRNA expression that occur from the time before any antibiotic treatment to the time after antibiotic treatment that successfully resolves arthritis symptoms, and 13 showed how an incomplete response to antibiotic treatment can affect miRNA expression. The expression profile of miRNA in synovial tissue samples from another 14 patients who underwent arthroscopic synovectomies 4-48 months after oral and intravenous antibiotics demonstrated the change in immune response seen in postinfectious LA.
The group of five patients with synovial fluid samples who were referred prior to antibiotic therapy when they had active B. burgdorferi infection (group 1) had a history of mild to severe knee swelling and pain for a median duration of 1 month prior to evaluation and the start of antibiotic treatment. A 1-month course of oral doxycycline resolved arthritis in three of the patients, and the other two continued to have marked knee swelling that later resolved after 1 month of IV ceftriaxone. Of six different miRNAs that the investigators measured, five were at low levels in these patients. The lone exception was a hematopoietic-specific miRNA, miR-223, which is abundantly expressed in polymorphonuclear lymphocytes (PMNs) and is associated with downregulation of acute inflammation and tissue remodeling.
In the group of 13 who still had joint swelling despite oral or IV antibiotics (group 2), only 2 had resolution of their swelling after IV antibiotics. Most of the remaining 11 had successful treatment with methotrexate. The synovial fluid samples for seven patients were collected after oral antibiotics but before IV antibiotics, and in the other six the samples were collected after both therapies. These 13 patients had significantly lower white blood cell counts in synovial fluid, fewer PMNs, and greater percentages of lymphocytes and monocytes than did group 1 patients. The five miRNAs that were found at low levels among the patients in group 1 were higher in these patients, which “suggested that the nature of the arthritis had changed after spirochetal killing.” The higher miR-223 levels seen in group 1 also occurred in group 2.
A separate analysis of synovial fluid samples from four patients with osteoarthritis and six patients with RA showed that levels of the six miRNAs from RA patients were similar to those of patients from group 2, and the low levels that were observed for most of the miRNAs in group 1 were similar to those seen in OA patients.
The investigators found that the five miRNAs with elevated levels in group 2 patients, but not miR-223, were positively correlated with arthritis duration after start of oral antibiotic therapy. B. burgdorferi IgG antibody titers negatively correlated with some of the elevated miRNAs in group 2.
The investigators analyzed a larger set of miRNAs in the synovial tissue samples obtained from 14 patients who underwent synovectomies for treatment of persistent synovitis a median of 15.5 months after they had undergone 2-3 months of antibiotic therapy (group 3). Some of the miRNAs overexpressed in these postinfectious LA samples, relative to samples from five OA patients, were associated with proliferative, tumor-associated responses and regulation of inflammatory processes. However, miRNAs overexpressed in tissues from OA patients relative to postinfectious LA patients were thought to affect genes that control tissue remodeling and cell proliferation, but not inflammation. The “distinct oncogenic miRNA profile” exhibited by postinfectious synovial tissue, according to the investigators, showed that “in these patients, the transition to the postinfectious phase was blocked by chronic inflammation, which stalled the wound repair process.”
The investigators concluded that “miRNAs hold promise as potential biomarkers to identify LA patients who are developing maladaptive immune responses during the period of infection. In such patients, it will be important to learn whether simultaneous treatment with antibiotics and DMARDs, rather than sequential treatment with these medications, will reduce the period of therapy and improve outcome, creating a new paradigm in treatment of this form of chronic inflammatory arthritis.”
The study was supported by grants from the National Institutes of Health, the Lucius N. Littauer Foundation, the Roland Foundation, the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital, the Rheumatology Research Foundation, and the English, Bonter, Mitchell Foundation.
Key clinical point:
Major finding: miRNAs overexpressed in synovial tissue samples from 14 patients with postinfectious Lyme arthritis, relative to samples from five OA patients, were associated with proliferative, tumor-associated responses and regulation of inflammatory processes.
Data source: A retrospective study of synovial fluid or tissue samples from 32 patients with Lyme arthritis.
Disclosures: The study was supported by grants from the National Institutes of Health, the Lucius N. Littauer Foundation, the Roland Foundation, the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital, the Rheumatology Research Foundation, and the English, Bonter, Mitchell Foundation.
All systemic steroid guidelines for RA offer little guidance
Every current guideline and consensus statement regarding systemic glucocorticoid therapy in rheumatoid arthritis falls short of offering clinicians practical, evidence-based guidance, according to a systematic review of all 15 such documents published in 2011-2015 in English, French, German, and Spanish.
Despite the abundant and convincing evidence that systemic glucocorticoids are very beneficial and despite their widespread use for rheumatoid arthritis (RA), fewer than half of the existing guidelines explicitly recommend these agents. Even fewer specify the optimal treatment duration, and about one-third don’t even provide dosage recommendations.
Their report, published in Arthritis Care & Research, does not address intra-articular administration of glucocorticoids. The 15 sets of guidelines were developed by 13 different rheumatology associations and networks across five continents (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23185).
In this comprehensive review of 3,742 relevant publications, there was general agreement that initial treatment should center on disease-modifying antirheumatic drugs (DMARDs) plus systemic glucocorticoids. If remission, or at least reduced disease activity with preserved function, doesn’t occur within 3-6 months, another synthetic or a biologic DMARD should be tried, with or without concomitant glucocorticoids. But none of the guidelines adequately address the timing or frequency of use, either in early RA or in established disease.
All the guidelines refer to using “low-dose” or the “lowest possible dose” to avoid adverse effects, but what they mean by that is unclear. Some define “low-dose” as less than or equal to 7.5 mg per day, but others define it at higher levels, up to 15 mg per day. “Moderate” and “high” doses are not defined at all, and some guidelines refer to unspecified “low to moderate doses” or “moderately high” doses. This causes “considerable confusion for the practicing clinician and investigators,” Mr. Palmowski and his associates noted.
Similarly, the guidelines are unclear as to which routes of administration are preferred, or are even acceptable. Most specifically mention oral systemic glucocorticoids; four mention the intramuscular route, with one guideline calling this preferable “in certain situations” because it facilitates better dosing control. One guideline recommends intravenous glucocorticoids, but only for severe extra-articular manifestations. And another advocates parenteral methylprednisolone in patients who have “weaning difficulties,” but gives no further details about using this route.
The guidelines all are similarly vague regarding the duration of glucocorticoid therapy. Two do not address treatment duration at all; the other 13 recommend “short-term” or “the shortest possible duration,” but do not adequately define these terms. Six guidelines discuss maximum treatment duration, but they define that as anywhere from 3 to 24 months. Only 4 of the 15 guidelines discuss treatment periods of longer than 6 months, and all of them are vague and sometimes contradict each other regarding such prolonged use.
The daily timing of glucocorticoid therapy is virtually ignored in all the guidelines, even though researchers have known for more than 50 years that the time of day when these agents are taken has a considerable impact on their efficacy and safety. Similarly, the use of delayed-release prednisone and the question of single versus multiple doses per day “remain to be tackled,” Mr. Palmowski and his associates said.
Tapering of glucocorticoid therapy to avoid triggering a recurrence is another topic given short shrift. Five of the guidelines don’t address it at all, and another five merely state that glucocorticoids should be tapered “as rapidly as possible.” The three guidelines that do stress the importance of gradual dose reductions offer conflicting advice about accomplishing that.
Existing guidelines also neglect to address patient-specific factors that may require special attention. Two explicitly allow the use of these agents during pregnancy, but the other 13 do not even consider the question. Three guidelines address possible interactions with other medications, but the other 12 do not. Only one guideline discusses the use of glucocorticoids in relation to common RA-associated cormorbidities such as cardiovascular disease and diabetes. And none of the guidelines make any age- or sex-specific recommendations.
Finally, many of the current guidelines fail to fully identify their funding sources. Five that never mentioned funding at all “were published (and probably funded) by rheumatology associations.” And at least two of the guidelines that ignored funding sources did receive support from pharmaceutical companies, Mr. Palmowski and his associates said.
This study was sponsored by the GLORIA (Glucocorticoid Low-dose Outcome in RA) Project of the European Commission’s Horizon 2020 Initiative. Mr. Palmowski reported having no relevant financial disclosures; his associates reported ties to Merck, Roche, Mundipharma, Pfizer, SUN, Novartis, Bristol-Myers Squibb, Takeda, UCB, Serono, and Horizon Pharma.
Some may read the report by Mr. Palmowski and his colleagues and fault the people who wrote the guidelines for these inadequacies. But the true culprit is the lack of good data on which to base guidelines.
And the data are lacking mainly because there is no funding for studies of dosing, treatment duration, timing of therapy, and patient-specific factors. Glucocorticoids are old drugs, so no industry sources would consider laying out the multiple millions of dollars necessary to conduct adequate research. Moreover, as many as 60% of all patients who could participate in such studies are already taking these agents, and this makes it difficult to determine their unique risk profiles.
Tina D. Mahajan, MD, is in the division of rheumatology and immunology at the University of Nebraska, Omaha. James R. O’Dell, MD, is chief of that division. The authors’ financial disclosures were not provided. Dr. Mahajan and Dr. O’Dell made these remarks in an editorial accompanying the report by Mr. Palmowski and his associates (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23184).
Some may read the report by Mr. Palmowski and his colleagues and fault the people who wrote the guidelines for these inadequacies. But the true culprit is the lack of good data on which to base guidelines.
And the data are lacking mainly because there is no funding for studies of dosing, treatment duration, timing of therapy, and patient-specific factors. Glucocorticoids are old drugs, so no industry sources would consider laying out the multiple millions of dollars necessary to conduct adequate research. Moreover, as many as 60% of all patients who could participate in such studies are already taking these agents, and this makes it difficult to determine their unique risk profiles.
Tina D. Mahajan, MD, is in the division of rheumatology and immunology at the University of Nebraska, Omaha. James R. O’Dell, MD, is chief of that division. The authors’ financial disclosures were not provided. Dr. Mahajan and Dr. O’Dell made these remarks in an editorial accompanying the report by Mr. Palmowski and his associates (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23184).
Some may read the report by Mr. Palmowski and his colleagues and fault the people who wrote the guidelines for these inadequacies. But the true culprit is the lack of good data on which to base guidelines.
And the data are lacking mainly because there is no funding for studies of dosing, treatment duration, timing of therapy, and patient-specific factors. Glucocorticoids are old drugs, so no industry sources would consider laying out the multiple millions of dollars necessary to conduct adequate research. Moreover, as many as 60% of all patients who could participate in such studies are already taking these agents, and this makes it difficult to determine their unique risk profiles.
Tina D. Mahajan, MD, is in the division of rheumatology and immunology at the University of Nebraska, Omaha. James R. O’Dell, MD, is chief of that division. The authors’ financial disclosures were not provided. Dr. Mahajan and Dr. O’Dell made these remarks in an editorial accompanying the report by Mr. Palmowski and his associates (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23184).
Every current guideline and consensus statement regarding systemic glucocorticoid therapy in rheumatoid arthritis falls short of offering clinicians practical, evidence-based guidance, according to a systematic review of all 15 such documents published in 2011-2015 in English, French, German, and Spanish.
Despite the abundant and convincing evidence that systemic glucocorticoids are very beneficial and despite their widespread use for rheumatoid arthritis (RA), fewer than half of the existing guidelines explicitly recommend these agents. Even fewer specify the optimal treatment duration, and about one-third don’t even provide dosage recommendations.
Their report, published in Arthritis Care & Research, does not address intra-articular administration of glucocorticoids. The 15 sets of guidelines were developed by 13 different rheumatology associations and networks across five continents (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23185).
In this comprehensive review of 3,742 relevant publications, there was general agreement that initial treatment should center on disease-modifying antirheumatic drugs (DMARDs) plus systemic glucocorticoids. If remission, or at least reduced disease activity with preserved function, doesn’t occur within 3-6 months, another synthetic or a biologic DMARD should be tried, with or without concomitant glucocorticoids. But none of the guidelines adequately address the timing or frequency of use, either in early RA or in established disease.
All the guidelines refer to using “low-dose” or the “lowest possible dose” to avoid adverse effects, but what they mean by that is unclear. Some define “low-dose” as less than or equal to 7.5 mg per day, but others define it at higher levels, up to 15 mg per day. “Moderate” and “high” doses are not defined at all, and some guidelines refer to unspecified “low to moderate doses” or “moderately high” doses. This causes “considerable confusion for the practicing clinician and investigators,” Mr. Palmowski and his associates noted.
Similarly, the guidelines are unclear as to which routes of administration are preferred, or are even acceptable. Most specifically mention oral systemic glucocorticoids; four mention the intramuscular route, with one guideline calling this preferable “in certain situations” because it facilitates better dosing control. One guideline recommends intravenous glucocorticoids, but only for severe extra-articular manifestations. And another advocates parenteral methylprednisolone in patients who have “weaning difficulties,” but gives no further details about using this route.
The guidelines all are similarly vague regarding the duration of glucocorticoid therapy. Two do not address treatment duration at all; the other 13 recommend “short-term” or “the shortest possible duration,” but do not adequately define these terms. Six guidelines discuss maximum treatment duration, but they define that as anywhere from 3 to 24 months. Only 4 of the 15 guidelines discuss treatment periods of longer than 6 months, and all of them are vague and sometimes contradict each other regarding such prolonged use.
The daily timing of glucocorticoid therapy is virtually ignored in all the guidelines, even though researchers have known for more than 50 years that the time of day when these agents are taken has a considerable impact on their efficacy and safety. Similarly, the use of delayed-release prednisone and the question of single versus multiple doses per day “remain to be tackled,” Mr. Palmowski and his associates said.
Tapering of glucocorticoid therapy to avoid triggering a recurrence is another topic given short shrift. Five of the guidelines don’t address it at all, and another five merely state that glucocorticoids should be tapered “as rapidly as possible.” The three guidelines that do stress the importance of gradual dose reductions offer conflicting advice about accomplishing that.
Existing guidelines also neglect to address patient-specific factors that may require special attention. Two explicitly allow the use of these agents during pregnancy, but the other 13 do not even consider the question. Three guidelines address possible interactions with other medications, but the other 12 do not. Only one guideline discusses the use of glucocorticoids in relation to common RA-associated cormorbidities such as cardiovascular disease and diabetes. And none of the guidelines make any age- or sex-specific recommendations.
Finally, many of the current guidelines fail to fully identify their funding sources. Five that never mentioned funding at all “were published (and probably funded) by rheumatology associations.” And at least two of the guidelines that ignored funding sources did receive support from pharmaceutical companies, Mr. Palmowski and his associates said.
This study was sponsored by the GLORIA (Glucocorticoid Low-dose Outcome in RA) Project of the European Commission’s Horizon 2020 Initiative. Mr. Palmowski reported having no relevant financial disclosures; his associates reported ties to Merck, Roche, Mundipharma, Pfizer, SUN, Novartis, Bristol-Myers Squibb, Takeda, UCB, Serono, and Horizon Pharma.
Every current guideline and consensus statement regarding systemic glucocorticoid therapy in rheumatoid arthritis falls short of offering clinicians practical, evidence-based guidance, according to a systematic review of all 15 such documents published in 2011-2015 in English, French, German, and Spanish.
Despite the abundant and convincing evidence that systemic glucocorticoids are very beneficial and despite their widespread use for rheumatoid arthritis (RA), fewer than half of the existing guidelines explicitly recommend these agents. Even fewer specify the optimal treatment duration, and about one-third don’t even provide dosage recommendations.
Their report, published in Arthritis Care & Research, does not address intra-articular administration of glucocorticoids. The 15 sets of guidelines were developed by 13 different rheumatology associations and networks across five continents (Arthritis Care Res. 2016 Dec 28. doi: 10.1002/acr.23185).
In this comprehensive review of 3,742 relevant publications, there was general agreement that initial treatment should center on disease-modifying antirheumatic drugs (DMARDs) plus systemic glucocorticoids. If remission, or at least reduced disease activity with preserved function, doesn’t occur within 3-6 months, another synthetic or a biologic DMARD should be tried, with or without concomitant glucocorticoids. But none of the guidelines adequately address the timing or frequency of use, either in early RA or in established disease.
All the guidelines refer to using “low-dose” or the “lowest possible dose” to avoid adverse effects, but what they mean by that is unclear. Some define “low-dose” as less than or equal to 7.5 mg per day, but others define it at higher levels, up to 15 mg per day. “Moderate” and “high” doses are not defined at all, and some guidelines refer to unspecified “low to moderate doses” or “moderately high” doses. This causes “considerable confusion for the practicing clinician and investigators,” Mr. Palmowski and his associates noted.
Similarly, the guidelines are unclear as to which routes of administration are preferred, or are even acceptable. Most specifically mention oral systemic glucocorticoids; four mention the intramuscular route, with one guideline calling this preferable “in certain situations” because it facilitates better dosing control. One guideline recommends intravenous glucocorticoids, but only for severe extra-articular manifestations. And another advocates parenteral methylprednisolone in patients who have “weaning difficulties,” but gives no further details about using this route.
The guidelines all are similarly vague regarding the duration of glucocorticoid therapy. Two do not address treatment duration at all; the other 13 recommend “short-term” or “the shortest possible duration,” but do not adequately define these terms. Six guidelines discuss maximum treatment duration, but they define that as anywhere from 3 to 24 months. Only 4 of the 15 guidelines discuss treatment periods of longer than 6 months, and all of them are vague and sometimes contradict each other regarding such prolonged use.
The daily timing of glucocorticoid therapy is virtually ignored in all the guidelines, even though researchers have known for more than 50 years that the time of day when these agents are taken has a considerable impact on their efficacy and safety. Similarly, the use of delayed-release prednisone and the question of single versus multiple doses per day “remain to be tackled,” Mr. Palmowski and his associates said.
Tapering of glucocorticoid therapy to avoid triggering a recurrence is another topic given short shrift. Five of the guidelines don’t address it at all, and another five merely state that glucocorticoids should be tapered “as rapidly as possible.” The three guidelines that do stress the importance of gradual dose reductions offer conflicting advice about accomplishing that.
Existing guidelines also neglect to address patient-specific factors that may require special attention. Two explicitly allow the use of these agents during pregnancy, but the other 13 do not even consider the question. Three guidelines address possible interactions with other medications, but the other 12 do not. Only one guideline discusses the use of glucocorticoids in relation to common RA-associated cormorbidities such as cardiovascular disease and diabetes. And none of the guidelines make any age- or sex-specific recommendations.
Finally, many of the current guidelines fail to fully identify their funding sources. Five that never mentioned funding at all “were published (and probably funded) by rheumatology associations.” And at least two of the guidelines that ignored funding sources did receive support from pharmaceutical companies, Mr. Palmowski and his associates said.
This study was sponsored by the GLORIA (Glucocorticoid Low-dose Outcome in RA) Project of the European Commission’s Horizon 2020 Initiative. Mr. Palmowski reported having no relevant financial disclosures; his associates reported ties to Merck, Roche, Mundipharma, Pfizer, SUN, Novartis, Bristol-Myers Squibb, Takeda, UCB, Serono, and Horizon Pharma.
Key clinical point:
Major finding: All 15 guidelines refer to using “low-dose” or the “lowest possible dose” of glucocorticoids to avoid adverse effects, but some define that as 7.5 mg per day while others define it at higher levels, all the way up to 15 mg per day.
Data source: A comprehensive, systematic review of all 15 guidelines and consensus statements regarding glucocorticoid therapy in RA that were published in 2011-2015 in English, French, German, and Spanish.
Disclosures: This study was sponsored by the GLORIA (Glucocorticoid Low-dose Outcome in RA) Project of the European Commission’s Horizon 2020 Initiative. Mr. Palmowski reported having no relevant financial disclosures; his associates reported ties to Merck, Roche, Mundipharma, Pfizer, SUN, Novartis, Bristol-Myers Squibb, Takeda, UCB, Serono, and Horizon Pharma.
Medicare payments set for infliximab biosimilar Inflectra
Payment for the infliximab biosimilar drug Inflectra will now be covered by Medicare, the drug’s manufacturer, Pfizer, said in an announcement.
The Centers for Medicare & Medicaid Services (CMS) included Inflectra (infliximab-dyyb) in its January 2017 Average Sales Price pricing file, which went into effect Jan. 1, 2017. Pfizer said that Inflectra is priced at a 15% discount to the current wholesale acquisition cost for the infliximab originator Remicade, but this price does not include discounts to payers, providers, distributors, and other purchasing organizations.
For the first quarter of 2017, the payment limit set by the CMS for Inflectra is $100.306 per 10-mg unit and $82.218 for Remicade.
Various national and regional wholesalers across the country began receiving shipments of Inflectra in November 2016, according to Pfizer.
In conjunction with the availability of Inflectra, Pfizer announced its enCompass program, “a comprehensive reimbursement service and patient support program offering coding and reimbursement support for providers, copay assistance to eligible patients who have commercial insurance that covers Inflectra, and financial assistance for eligible uninsured and underinsured patients.”
The FDA approved Inflectra in April 2016 for all of the same indications as Remicade: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, plaque psoriasis, and ulcerative colitis.
Payment for the infliximab biosimilar drug Inflectra will now be covered by Medicare, the drug’s manufacturer, Pfizer, said in an announcement.
The Centers for Medicare & Medicaid Services (CMS) included Inflectra (infliximab-dyyb) in its January 2017 Average Sales Price pricing file, which went into effect Jan. 1, 2017. Pfizer said that Inflectra is priced at a 15% discount to the current wholesale acquisition cost for the infliximab originator Remicade, but this price does not include discounts to payers, providers, distributors, and other purchasing organizations.
For the first quarter of 2017, the payment limit set by the CMS for Inflectra is $100.306 per 10-mg unit and $82.218 for Remicade.
Various national and regional wholesalers across the country began receiving shipments of Inflectra in November 2016, according to Pfizer.
In conjunction with the availability of Inflectra, Pfizer announced its enCompass program, “a comprehensive reimbursement service and patient support program offering coding and reimbursement support for providers, copay assistance to eligible patients who have commercial insurance that covers Inflectra, and financial assistance for eligible uninsured and underinsured patients.”
The FDA approved Inflectra in April 2016 for all of the same indications as Remicade: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, plaque psoriasis, and ulcerative colitis.
Payment for the infliximab biosimilar drug Inflectra will now be covered by Medicare, the drug’s manufacturer, Pfizer, said in an announcement.
The Centers for Medicare & Medicaid Services (CMS) included Inflectra (infliximab-dyyb) in its January 2017 Average Sales Price pricing file, which went into effect Jan. 1, 2017. Pfizer said that Inflectra is priced at a 15% discount to the current wholesale acquisition cost for the infliximab originator Remicade, but this price does not include discounts to payers, providers, distributors, and other purchasing organizations.
For the first quarter of 2017, the payment limit set by the CMS for Inflectra is $100.306 per 10-mg unit and $82.218 for Remicade.
Various national and regional wholesalers across the country began receiving shipments of Inflectra in November 2016, according to Pfizer.
In conjunction with the availability of Inflectra, Pfizer announced its enCompass program, “a comprehensive reimbursement service and patient support program offering coding and reimbursement support for providers, copay assistance to eligible patients who have commercial insurance that covers Inflectra, and financial assistance for eligible uninsured and underinsured patients.”
The FDA approved Inflectra in April 2016 for all of the same indications as Remicade: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, plaque psoriasis, and ulcerative colitis.