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‘We’re in great distress here,’ infusion center CMO says
Count Vikram Sengupta, MD, among the slew of health care workers feeling overwhelmed by the impact that COVID-19 is having on the delivery of health care in Manhattan and its surrounding boroughs.
“Nobody in the country is suffering like New York City,” said Dr. Sengupta, chief medical officer of Thrivewell Infusion, which operates three stand-alone infusion centers in the region: a four-chair center in Crown Heights, a 10-chair center in Borough Park, Brooklyn, and an eight-chair center in Manhasset. “We have 30%-50% of all cases in the country. I’ve been reading the news, and some people think this thing is going away. We’re in great distress here. There need to be new strategies moving forward. The whole world has changed. Our whole approach to ambulatory care has changed.”
In early March 2020, when it became clear that New York hospitals would face a tidal wave of citizens infected with COVID-19, Thrivewell began to receive an influx of referrals originating from concerned patients, providers, payers, and even large integrated health care systems, all in an effort to help prevent infectious exposure through infusion in hospital-based settings. “We are trying to accommodate them as swiftly as possible,” said Dr. Sengupta, who was interviewed for this story on April 9. “There’s been a huge uptick from that standpoint. We’ve made sure that we’ve kept our facilities clean by employing standards that have been released by the CDC, as well as by the major academic centers who are dealing with this firsthand, and also with guidance from the National Infusion Center Association.”
He and his colleagues launched a pop-up infusion center in the Bronx to help offload Montefiore Medical Center, “because they’re so overwhelmed with COVID-19 patients that they need help taking care of the autoimmune patients,” Dr. Sengupta said. “That’s the role we’re playing. We’ve made our resources available to these centers in a very flexible way in order to ensure that we do the best thing we can for everybody.”
Thrivewell is also deploying a mobile infusion unit to recovered COVID-19 patients who require an infusion for their autoimmune disease, in order to minimize the risk of contamination and transmission in their stand-alone centers. The RV-sized unit, about the size of a Bloodmobile, is equipped with infusion chairs and staffed by a physician and nurse practitioner. “The objective is continuant care and reduction of cross-contamination, and also, on a broader health care systems level, to ensure that we as ambulatory infusion center providers can offload an overburdened system,” he said.
Dr. Sengupta, who has assisted on COVID-19 inpatient wards at New York University as a volunteer, is also leading a trial of a stem cell-derived therapy developed by Israel-based Pluristem Therapeutics, to treat New York–area patients severely ill from COVID-19 infection. “There are reports from Wuhan, China, in which clinicians are delivering IV mesenchymal stem cells to patients who are on mechanical ventilators, and the patients are getting better,” he said. “I have initiated a study in which we have three cohorts: One is the outpatient setting in which we are trying to treat COVID-19 patients who have hypoxia but have been turned away from overwhelmed EDs and need some therapy. We will be converting one of our infusion centers to conduct this trial. We are also going to be administering this [stem cell-derived therapy] to COVID-19 patients in ICUs, in EDs, and on med-surg floors throughout the city.”
Count Vikram Sengupta, MD, among the slew of health care workers feeling overwhelmed by the impact that COVID-19 is having on the delivery of health care in Manhattan and its surrounding boroughs.
“Nobody in the country is suffering like New York City,” said Dr. Sengupta, chief medical officer of Thrivewell Infusion, which operates three stand-alone infusion centers in the region: a four-chair center in Crown Heights, a 10-chair center in Borough Park, Brooklyn, and an eight-chair center in Manhasset. “We have 30%-50% of all cases in the country. I’ve been reading the news, and some people think this thing is going away. We’re in great distress here. There need to be new strategies moving forward. The whole world has changed. Our whole approach to ambulatory care has changed.”
In early March 2020, when it became clear that New York hospitals would face a tidal wave of citizens infected with COVID-19, Thrivewell began to receive an influx of referrals originating from concerned patients, providers, payers, and even large integrated health care systems, all in an effort to help prevent infectious exposure through infusion in hospital-based settings. “We are trying to accommodate them as swiftly as possible,” said Dr. Sengupta, who was interviewed for this story on April 9. “There’s been a huge uptick from that standpoint. We’ve made sure that we’ve kept our facilities clean by employing standards that have been released by the CDC, as well as by the major academic centers who are dealing with this firsthand, and also with guidance from the National Infusion Center Association.”
He and his colleagues launched a pop-up infusion center in the Bronx to help offload Montefiore Medical Center, “because they’re so overwhelmed with COVID-19 patients that they need help taking care of the autoimmune patients,” Dr. Sengupta said. “That’s the role we’re playing. We’ve made our resources available to these centers in a very flexible way in order to ensure that we do the best thing we can for everybody.”
Thrivewell is also deploying a mobile infusion unit to recovered COVID-19 patients who require an infusion for their autoimmune disease, in order to minimize the risk of contamination and transmission in their stand-alone centers. The RV-sized unit, about the size of a Bloodmobile, is equipped with infusion chairs and staffed by a physician and nurse practitioner. “The objective is continuant care and reduction of cross-contamination, and also, on a broader health care systems level, to ensure that we as ambulatory infusion center providers can offload an overburdened system,” he said.
Dr. Sengupta, who has assisted on COVID-19 inpatient wards at New York University as a volunteer, is also leading a trial of a stem cell-derived therapy developed by Israel-based Pluristem Therapeutics, to treat New York–area patients severely ill from COVID-19 infection. “There are reports from Wuhan, China, in which clinicians are delivering IV mesenchymal stem cells to patients who are on mechanical ventilators, and the patients are getting better,” he said. “I have initiated a study in which we have three cohorts: One is the outpatient setting in which we are trying to treat COVID-19 patients who have hypoxia but have been turned away from overwhelmed EDs and need some therapy. We will be converting one of our infusion centers to conduct this trial. We are also going to be administering this [stem cell-derived therapy] to COVID-19 patients in ICUs, in EDs, and on med-surg floors throughout the city.”
Count Vikram Sengupta, MD, among the slew of health care workers feeling overwhelmed by the impact that COVID-19 is having on the delivery of health care in Manhattan and its surrounding boroughs.
“Nobody in the country is suffering like New York City,” said Dr. Sengupta, chief medical officer of Thrivewell Infusion, which operates three stand-alone infusion centers in the region: a four-chair center in Crown Heights, a 10-chair center in Borough Park, Brooklyn, and an eight-chair center in Manhasset. “We have 30%-50% of all cases in the country. I’ve been reading the news, and some people think this thing is going away. We’re in great distress here. There need to be new strategies moving forward. The whole world has changed. Our whole approach to ambulatory care has changed.”
In early March 2020, when it became clear that New York hospitals would face a tidal wave of citizens infected with COVID-19, Thrivewell began to receive an influx of referrals originating from concerned patients, providers, payers, and even large integrated health care systems, all in an effort to help prevent infectious exposure through infusion in hospital-based settings. “We are trying to accommodate them as swiftly as possible,” said Dr. Sengupta, who was interviewed for this story on April 9. “There’s been a huge uptick from that standpoint. We’ve made sure that we’ve kept our facilities clean by employing standards that have been released by the CDC, as well as by the major academic centers who are dealing with this firsthand, and also with guidance from the National Infusion Center Association.”
He and his colleagues launched a pop-up infusion center in the Bronx to help offload Montefiore Medical Center, “because they’re so overwhelmed with COVID-19 patients that they need help taking care of the autoimmune patients,” Dr. Sengupta said. “That’s the role we’re playing. We’ve made our resources available to these centers in a very flexible way in order to ensure that we do the best thing we can for everybody.”
Thrivewell is also deploying a mobile infusion unit to recovered COVID-19 patients who require an infusion for their autoimmune disease, in order to minimize the risk of contamination and transmission in their stand-alone centers. The RV-sized unit, about the size of a Bloodmobile, is equipped with infusion chairs and staffed by a physician and nurse practitioner. “The objective is continuant care and reduction of cross-contamination, and also, on a broader health care systems level, to ensure that we as ambulatory infusion center providers can offload an overburdened system,” he said.
Dr. Sengupta, who has assisted on COVID-19 inpatient wards at New York University as a volunteer, is also leading a trial of a stem cell-derived therapy developed by Israel-based Pluristem Therapeutics, to treat New York–area patients severely ill from COVID-19 infection. “There are reports from Wuhan, China, in which clinicians are delivering IV mesenchymal stem cells to patients who are on mechanical ventilators, and the patients are getting better,” he said. “I have initiated a study in which we have three cohorts: One is the outpatient setting in which we are trying to treat COVID-19 patients who have hypoxia but have been turned away from overwhelmed EDs and need some therapy. We will be converting one of our infusion centers to conduct this trial. We are also going to be administering this [stem cell-derived therapy] to COVID-19 patients in ICUs, in EDs, and on med-surg floors throughout the city.”
When the going gets tough, ophthalmologists call the rheumatologist
MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.
Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.
“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.
Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.
However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.
“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.
He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.
Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.
Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.
“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.
Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.
Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.
“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.
The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.
“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.
Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).
It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
Get to know teprotumumab
Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.
“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”
In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.
“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.
Obtaining payer approval
“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.
“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.
Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.
MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.
Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.
“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.
Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.
However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.
“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.
He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.
Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.
Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.
“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.
Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.
Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.
“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.
The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.
“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.
Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).
It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
Get to know teprotumumab
Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.
“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”
In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.
“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.
Obtaining payer approval
“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.
“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.
Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.
MAUI, HAWAII – When a rheumatologist gets a call from an ophthalmologist regarding a patient with an inflamed eye and elevated intraocular pressure unresponsive to the eye specialist’s customary array of topical, systemic, and intraocular implanted corticosteroids, that’s a patient who needs to be seen immediately, Alvin F. Wells, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.
Elevated intraocular pressure due to uveitis or scleritis can result in blindness. Eye specialists call upon rheumatologists here because of their expertise in step-up therapy with methotrexate and other traditional oral disease-modifying antirheumatic drugs as well as biologic agents.
“Here’s my treatment approach to inflammatory eye disease: We’re pulling out all the guns,” declared Dr. Wells, a rheumatologist with a special interest in eye disease. He is director of the Rheumatology and Immunotherapy Center in Franklin, Wisc., with academic appointments to the Karolinska Institute in Stockholm, Duke University, and Marquette University.
Uveitis involves inflammation of the iris, choroid, and ciliary body. A straightforward case of noninfectious anterior uveitis will typically respond to 2 weeks of topical steroid drops, or sometimes even topical NSAID drops.
However, noninfectious posterior, intermediate, or panuveitis is another matter. In those circumstances, he gives the patient 125 mg of methylprednisolone by intramuscular injection and a 20-mg dose of oral methotrexate at that first clinic visit. The patient is sent home with a prescription for oral prednisone, tapering over 2-3 weeks, and another for methotrexate at 15-25 mg/week plus 1-2 mg/day of folic acid. Dr. Wells also gives consideration to add-on azathioprine or mycophenolate mofetil. He views multidrug therapy as having a sound rationale because multiple inflammatory pathways are involved in noninfectious uveitis.
“Ophthalmologists like to push for cyclophosphamide, but there’s no controlled data out there showing it’s effective in inflammatory eye disorders. It’s a pretty toxic regimen, and when you think about all the complications we see in using this drug to treat patients with lupus, I’d rather hold it in reserve for severe cases where we can go to it if we need to,” the rheumatologist explained.
He conducted a literature review to rank rheumatologic medications in terms of their evidence base for treatment of inflammatory ocular disorders. Among oral agents, at the top of the heap is methotrexate, whose efficacy for both noninfectious uveitis and scleritis is supported by multiple randomized, controlled studies. But mycophenolate mofetil is a reasonable alternative first-line corticosteroid-sparing agent, as demonstrated in the 265-patient multicenter FAST (First-line Antimetabolites as Steroid-sparing Treatment) trial sponsored by the National Eye Institute. That trial demonstrated no significant difference in treatment success at 6 months between methotrexate and mycophenolate mofetil.
Oral apremilast (Otezla) is approved for treatment of the oral ulcers of Behçet’s disease, but not for Behçet’s eye disease, where the experience is anecdotal.
Dr. Wells is quick to turn to adalimumab (Humira) when he deems a biologic to be warranted; indeed, it’s the only biologic approved for noninfectious uveitis. Of course, not everyone is a responder.
“Can we extrapolate that high-quality evidence of benefit for adalimumab to other drugs? Probably yes, and if you did that it would be for the IgG monoclonal antibodies that can cross the blood/aqueous barrier,” he said.
Infliximab (Remicade) is the biologic with the second-strongest supporting evidence in noninfectious uveitis. For the uveitis of Behçet’s disease, one of the most common rheumatic causes of inflammatory eye disease, Spanish investigators who conducted a nationwide nonrandomized study reported that both adalimumab and infliximab were effective, although adalimumab had superior outcomes at 1 year.
Uveitis is the most common extra-articular expression of axial spondyloarthritis (axSpA). In the open-label extension of the randomized RAPID-axSpA trial, patients randomized to certolizumab pegol (Cimzia) had a significantly lower incidence of uveitis flares than with placebo through 204 weeks of follow-up.
“The take-home message is we have some post hoc data here to say, ‘Hey, this could work in those patients who have inflammatory eye diseases in the setting of axSpA,’ ” Dr. Wells said.
The interleukin-6 receptor inhibitor tocilizumab (Actemra) “definitely works” for noninfectious uveitis, according to Dr. Wells, pointing to the positive results of the multicenter U.S. STOP-Uveitis study.
“The caveat here is tocilizumab has only been studied in the IV formulation. It’s too bad they didn’t use the [subcutaneous formulation]; you can’t get IV tocilizumab approved by payers in the U.S.,” according to the rheumatologist.
Based upon positive anecdotal case reports, Dr. Wells has a few patients on rituximab (Rituxan) for uveitis, with favorable results. The same for abatacept (Orencia).
It’s imperative that a patient on a biologic for uveitis undergo weekly ophthalmologic examinations. Only after the intraocular pressure is normal and inflammatory cells in the anterior chamber have waned is it appropriate to discontinue the biologic and slowly taper the methotrexate and any other oral disease-modifying antirheumatic drugs. Some experts argue for lifelong therapy in patients who’ve experienced uveitis. Dr. Wells disagrees, preferring to treat acute uveitis flares as they arise, although if underlying disease such as psoriatic arthritis or axSpA is present, some form of background therapy will probably be necessary.
Get to know teprotumumab
Rheumatologists who operate an infusion center are likely to increasingly be called upon by endocrinologists and ophthalmologists to administer intravenous teprotumumab-trbw (Tepezza), a human monoclonal antibody directed against the insulin-like growth factor 1 receptor that was approved earlier this year by the Food and Drug Administration as the first-ever drug for thyroid eye disease, a disfiguring and potentially blinding condition.
“This is really exciting,” Dr. Wells said. “The disease has an acute inflammatory stage, and that’s when you’ll be called on to give this drug. It makes a dramatic difference. Once a patient gets to the scarring phase there’s not a whole lot they can do other than surgery.”
In the pivotal phase 3 randomized trial, 83% of the teprotumumab group achieved the primary endpoint, a reduction in proptosis, or eye bulging, of at least 2 mm at week 24, compared with 10% of placebo-treated controls. The number needed to treat was 1.4. The chief side effects were muscle spasms, hair loss, fatigue, and nausea.
“You might say, ‘two millimeters, that’s nothing.’ But the primary drug used before teprotumumab was IV steroids, and there a 0.6-mm reduction in proptosis was considered improvement,” Dr. Wells observed.
Obtaining payer approval
“I’ve found over the last 10 years that when it comes to eye disease, insurance companies have a little more wiggle room,” he said. “They’re not going to let somebody go blind. You can get the references I’ve mentioned and show them the data. After all, we only have one biologic drug that’s been approved, and not everybody responds to it.
“Titrate your therapy based upon the intraocular pressure, the number of inflammatory cells in the anterior chamber, and any visual changes. You’ve got to be very aggressive with therapy, and don’t take no for an answer from the insurance companies,” he advised.
Dr. Wells reported serving as a member of an advisory board and/or speakers bureau for more than a dozen pharmaceutical companies.
REPORTING FROM RWCS 2020
Treatment for RA, SpA may not affect COVID-19 severity
Patients being treated for RA or spondyloarthritis who develop symptoms of COVID-19 do not appear to be at higher risk of respiratory or life-threatening complications, results from a new study in Italy suggest.
Such patients, the study authors wrote, do not need to be taken off their immunosuppressive medications if they develop COVID-19 symptoms.
In a letter published in Annals of the Rheumatic Diseases, Sara Monti, MD, and colleagues in the rheumatology department of the Fondazione IRCCS Policlinico in San Matteo, Italy, described results from an observational cohort of 320 patients (68% women; mean age, 55 years) with RA or spondyloarthritis from a single outpatient clinic. The vast majority of subjects (92%) were taking biologic disease-modifying antirheumatic drugs (bDMARD), including tumor necrosis factor inhibitors, while the rest were taking targeted synthetic DMARDs (tsDMARD).
Four patients in the cohort developed laboratory-confirmed COVID-19; another four developed symptoms highly suggestive of the disease but did not receive confirmatory testing, and five had contact with a confirmed COVID-19 case but did not develop symptoms of COVID-19.
Among the eight confirmed and suspected COVID-19 patients, only one was hospitalized. All temporarily withdrew bDMARD or tsDMARD treatment at symptom onset.
“To date, there have been no significant relapses of the rheumatic disease,” Dr. Monti and colleagues reported. “None of the patients with a confirmed diagnosis of COVID-19 or with a highly suggestive clinical picture developed severe respiratory complications or died. Only one patient, aged 65, required admission to hospital and low-flow oxygen supplementation for a few days.”
The findings “do not allow any conclusions on the incidence rate of SARS-CoV-2 infection in patients with rheumatic diseases, nor on the overall outcome of immunocompromised patients affected by COVID-19,” the investigators cautioned, adding that such patients should receive careful attention and follow-up. “However, our preliminary experience shows that patients with chronic arthritis treated with bDMARDs or tsDMARDs do not seem to be at increased risk of respiratory or life-threatening complications from SARS-CoV-2, compared with the general population.”
Dr. Monti and colleagues noted that, during previous outbreaks of other coronaviruses, no increased mortality was reported for people taking immunosuppressive drugs for a range of conditions, including autoimmune diseases.
“These data can support rheumatologists [in] avoiding the unjustifiable preventive withdrawal of DMARDs, which could lead to an increased risk of relapses and morbidity from the chronic rheumatological condition,” the researchers concluded.
Dr. Monti and colleagues reported no outside funding or financial conflicts of interest.
SOURCE: Monti S et al. Ann Rheum Dis. 2020 April 2. doi: 10.1136/annrheumdis-2020-217424.
Patients being treated for RA or spondyloarthritis who develop symptoms of COVID-19 do not appear to be at higher risk of respiratory or life-threatening complications, results from a new study in Italy suggest.
Such patients, the study authors wrote, do not need to be taken off their immunosuppressive medications if they develop COVID-19 symptoms.
In a letter published in Annals of the Rheumatic Diseases, Sara Monti, MD, and colleagues in the rheumatology department of the Fondazione IRCCS Policlinico in San Matteo, Italy, described results from an observational cohort of 320 patients (68% women; mean age, 55 years) with RA or spondyloarthritis from a single outpatient clinic. The vast majority of subjects (92%) were taking biologic disease-modifying antirheumatic drugs (bDMARD), including tumor necrosis factor inhibitors, while the rest were taking targeted synthetic DMARDs (tsDMARD).
Four patients in the cohort developed laboratory-confirmed COVID-19; another four developed symptoms highly suggestive of the disease but did not receive confirmatory testing, and five had contact with a confirmed COVID-19 case but did not develop symptoms of COVID-19.
Among the eight confirmed and suspected COVID-19 patients, only one was hospitalized. All temporarily withdrew bDMARD or tsDMARD treatment at symptom onset.
“To date, there have been no significant relapses of the rheumatic disease,” Dr. Monti and colleagues reported. “None of the patients with a confirmed diagnosis of COVID-19 or with a highly suggestive clinical picture developed severe respiratory complications or died. Only one patient, aged 65, required admission to hospital and low-flow oxygen supplementation for a few days.”
The findings “do not allow any conclusions on the incidence rate of SARS-CoV-2 infection in patients with rheumatic diseases, nor on the overall outcome of immunocompromised patients affected by COVID-19,” the investigators cautioned, adding that such patients should receive careful attention and follow-up. “However, our preliminary experience shows that patients with chronic arthritis treated with bDMARDs or tsDMARDs do not seem to be at increased risk of respiratory or life-threatening complications from SARS-CoV-2, compared with the general population.”
Dr. Monti and colleagues noted that, during previous outbreaks of other coronaviruses, no increased mortality was reported for people taking immunosuppressive drugs for a range of conditions, including autoimmune diseases.
“These data can support rheumatologists [in] avoiding the unjustifiable preventive withdrawal of DMARDs, which could lead to an increased risk of relapses and morbidity from the chronic rheumatological condition,” the researchers concluded.
Dr. Monti and colleagues reported no outside funding or financial conflicts of interest.
SOURCE: Monti S et al. Ann Rheum Dis. 2020 April 2. doi: 10.1136/annrheumdis-2020-217424.
Patients being treated for RA or spondyloarthritis who develop symptoms of COVID-19 do not appear to be at higher risk of respiratory or life-threatening complications, results from a new study in Italy suggest.
Such patients, the study authors wrote, do not need to be taken off their immunosuppressive medications if they develop COVID-19 symptoms.
In a letter published in Annals of the Rheumatic Diseases, Sara Monti, MD, and colleagues in the rheumatology department of the Fondazione IRCCS Policlinico in San Matteo, Italy, described results from an observational cohort of 320 patients (68% women; mean age, 55 years) with RA or spondyloarthritis from a single outpatient clinic. The vast majority of subjects (92%) were taking biologic disease-modifying antirheumatic drugs (bDMARD), including tumor necrosis factor inhibitors, while the rest were taking targeted synthetic DMARDs (tsDMARD).
Four patients in the cohort developed laboratory-confirmed COVID-19; another four developed symptoms highly suggestive of the disease but did not receive confirmatory testing, and five had contact with a confirmed COVID-19 case but did not develop symptoms of COVID-19.
Among the eight confirmed and suspected COVID-19 patients, only one was hospitalized. All temporarily withdrew bDMARD or tsDMARD treatment at symptom onset.
“To date, there have been no significant relapses of the rheumatic disease,” Dr. Monti and colleagues reported. “None of the patients with a confirmed diagnosis of COVID-19 or with a highly suggestive clinical picture developed severe respiratory complications or died. Only one patient, aged 65, required admission to hospital and low-flow oxygen supplementation for a few days.”
The findings “do not allow any conclusions on the incidence rate of SARS-CoV-2 infection in patients with rheumatic diseases, nor on the overall outcome of immunocompromised patients affected by COVID-19,” the investigators cautioned, adding that such patients should receive careful attention and follow-up. “However, our preliminary experience shows that patients with chronic arthritis treated with bDMARDs or tsDMARDs do not seem to be at increased risk of respiratory or life-threatening complications from SARS-CoV-2, compared with the general population.”
Dr. Monti and colleagues noted that, during previous outbreaks of other coronaviruses, no increased mortality was reported for people taking immunosuppressive drugs for a range of conditions, including autoimmune diseases.
“These data can support rheumatologists [in] avoiding the unjustifiable preventive withdrawal of DMARDs, which could lead to an increased risk of relapses and morbidity from the chronic rheumatological condition,” the researchers concluded.
Dr. Monti and colleagues reported no outside funding or financial conflicts of interest.
SOURCE: Monti S et al. Ann Rheum Dis. 2020 April 2. doi: 10.1136/annrheumdis-2020-217424.
FROM ANNALS OF THE RHEUMATIC DISEASES
JAK inhibitors may increase risk of herpes zoster
For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.
Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.
“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.
The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).
Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.
Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.
“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.
Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).
“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.
Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.
“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”
The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.
“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.
The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.
SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.
The multiple different cytokines contributing to intestinal inflammation in IBD patients have been a major challenge in the design of therapies. Because the JAK signaling pathway (comprised of JAK1, JAK2, JAK3, and TYK2) is required for responses to a broad range of cytokines, therapies that inhibit JAK signaling have been an active area of interest. A simultaneous and important concern, however, has been the potential for adverse consequences when inhibiting the breadth of immune and hematopoietic molecules that depend on JAK family members for their functions. This meta-analysis by Olivera et al. examined adverse outcomes of four different JAK inhibitors in clinical trials across four immune-mediated diseases (rheumatoid arthritis, IBD, psoriasis, and ankylosing spondylitis), finding that herpes zoster infection was significantly increased (relative risk, 1.57). In contrast, patients treated with JAK inhibitors were not at a significantly increased risk for various other adverse events.
Reduced dosing of JAK inhibitors has been implemented as a means of improving safety profiles in select immune-mediated diseases. Another approach is more selective JAK inhibition, although it is unclear whether this will eliminate the risk of herpes zoster infection. In the current meta-analysis, about 87% of the studies had evaluated tofacitinib treatment, which inhibits both JAK1 and JAK3; more selective JAK inhibitors could not be evaluated in an equivalent manner. Of note, JAK1 is required for signaling by various cytokines that participate in the response to viruses, including type I IFNs and gamma c family members (such as IL-2 and IL-15); therefore, even the more selective JAK1 inhibitors do not leave this immune function fully intact. However, simply reducing the number of JAK family members inhibited simultaneously may be sufficient to reduce risk.
JAK inhibitors warrant further evaluation as additional infectious challenges arise, particularly with respect to viruses. In addition, more selective targeting of JAK inhibition of intestinal tissues may ultimately reduce systemic effects, including the risk of herpes zoster.
Clara Abraham, MD, professor of medicine, section of digestive diseases, Yale University, New Haven, Conn.
The multiple different cytokines contributing to intestinal inflammation in IBD patients have been a major challenge in the design of therapies. Because the JAK signaling pathway (comprised of JAK1, JAK2, JAK3, and TYK2) is required for responses to a broad range of cytokines, therapies that inhibit JAK signaling have been an active area of interest. A simultaneous and important concern, however, has been the potential for adverse consequences when inhibiting the breadth of immune and hematopoietic molecules that depend on JAK family members for their functions. This meta-analysis by Olivera et al. examined adverse outcomes of four different JAK inhibitors in clinical trials across four immune-mediated diseases (rheumatoid arthritis, IBD, psoriasis, and ankylosing spondylitis), finding that herpes zoster infection was significantly increased (relative risk, 1.57). In contrast, patients treated with JAK inhibitors were not at a significantly increased risk for various other adverse events.
Reduced dosing of JAK inhibitors has been implemented as a means of improving safety profiles in select immune-mediated diseases. Another approach is more selective JAK inhibition, although it is unclear whether this will eliminate the risk of herpes zoster infection. In the current meta-analysis, about 87% of the studies had evaluated tofacitinib treatment, which inhibits both JAK1 and JAK3; more selective JAK inhibitors could not be evaluated in an equivalent manner. Of note, JAK1 is required for signaling by various cytokines that participate in the response to viruses, including type I IFNs and gamma c family members (such as IL-2 and IL-15); therefore, even the more selective JAK1 inhibitors do not leave this immune function fully intact. However, simply reducing the number of JAK family members inhibited simultaneously may be sufficient to reduce risk.
JAK inhibitors warrant further evaluation as additional infectious challenges arise, particularly with respect to viruses. In addition, more selective targeting of JAK inhibition of intestinal tissues may ultimately reduce systemic effects, including the risk of herpes zoster.
Clara Abraham, MD, professor of medicine, section of digestive diseases, Yale University, New Haven, Conn.
The multiple different cytokines contributing to intestinal inflammation in IBD patients have been a major challenge in the design of therapies. Because the JAK signaling pathway (comprised of JAK1, JAK2, JAK3, and TYK2) is required for responses to a broad range of cytokines, therapies that inhibit JAK signaling have been an active area of interest. A simultaneous and important concern, however, has been the potential for adverse consequences when inhibiting the breadth of immune and hematopoietic molecules that depend on JAK family members for their functions. This meta-analysis by Olivera et al. examined adverse outcomes of four different JAK inhibitors in clinical trials across four immune-mediated diseases (rheumatoid arthritis, IBD, psoriasis, and ankylosing spondylitis), finding that herpes zoster infection was significantly increased (relative risk, 1.57). In contrast, patients treated with JAK inhibitors were not at a significantly increased risk for various other adverse events.
Reduced dosing of JAK inhibitors has been implemented as a means of improving safety profiles in select immune-mediated diseases. Another approach is more selective JAK inhibition, although it is unclear whether this will eliminate the risk of herpes zoster infection. In the current meta-analysis, about 87% of the studies had evaluated tofacitinib treatment, which inhibits both JAK1 and JAK3; more selective JAK inhibitors could not be evaluated in an equivalent manner. Of note, JAK1 is required for signaling by various cytokines that participate in the response to viruses, including type I IFNs and gamma c family members (such as IL-2 and IL-15); therefore, even the more selective JAK1 inhibitors do not leave this immune function fully intact. However, simply reducing the number of JAK family members inhibited simultaneously may be sufficient to reduce risk.
JAK inhibitors warrant further evaluation as additional infectious challenges arise, particularly with respect to viruses. In addition, more selective targeting of JAK inhibition of intestinal tissues may ultimately reduce systemic effects, including the risk of herpes zoster.
Clara Abraham, MD, professor of medicine, section of digestive diseases, Yale University, New Haven, Conn.
For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.
Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.
“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.
The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).
Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.
Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.
“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.
Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).
“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.
Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.
“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”
The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.
“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.
The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.
SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.
For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.
Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.
“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.
The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).
Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.
Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.
“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.
Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).
“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.
Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.
“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”
The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.
“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.
The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.
SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.
FROM GASTROENTEROLOGY
Rapid shift to adalimumab biosimilars in Denmark contrasts with U.S. experience
Adalimumab biosimilars are years away from entering the marketplace in the United States because of patent disputes, but they already have led to substantial discounts in Denmark, researchers wrote in JAMA Internal Medicine.
The Danish health care system switched almost entirely to adalimumab biosimilars after the patent on the original adalimumab product, Humira, expired there in October 2018. The switch to biosimilars led to an 82% decrease in costs for the medication, wrote Thomas Bo Jensen, MD, and colleagues in a research letter.
Denmark did not automatically substitute biosimilars, but the Danish Medicines Council recommended adalimumab biosimilars for all indications following Humira’s patent expiration. The recommendations “included switching patients to a biosimilar who were already well treated with the originator,” the researchers wrote.
To study the shift to adalimumab biosimilars across all indications in Denmark and calculate cost reductions, Dr. Jensen, of the department of clinical pharmacology at Copenhagen University Hospital Bispebjerg, and coinvestigators examined monthly data on drug sales from Amgros, which purchases all hospital drugs in the country.
“The proportion of adalimumab biosimilars increased from 71.6% (7,040 of 9,829 pens) in November 2018 to 95.1% (8,974 of 9,438 pens) in December 2018,” the researchers wrote. “Costs of adalimumab decreased by 82.8% from September 2018 to December 2018 (September: 8,197 pens at $5.13 million; December: 9,438 pens at $1.01 million).” The results were similar in rheumatology, dermatology, and gastroenterology.
The Food and Drug Administration has approved five adalimumab biosimilars in the United States, but “they will not enter the market until 2023 owing to patent disputes with AbbVie, the manufacturer of Humira,” wrote Jennifer D. Claytor, MD, of the department of internal medicine at University of California, San Francisco, and Walid Gellad, MD, of the division of general internal medicine at University of Pittsburgh, in an accompanying editorial.
The annual postrebate price of Humira doubled between 2013 and 2018, from $19,000 to $38,000, and these price increases may influence the price of biosimilars, “which will be priced using Humira’s price as an anchor,” Dr. Claytor and Dr. Gellad wrote.
A rapid shift to adalimumab biosimilars across the United States when they become available is “unlikely,” they wrote. Nonetheless, “some health care systems of comparable size to Denmark (e.g., the Veterans Affairs system) and others that are larger (e.g., Kaiser Permanente) ... have the ability to switch products quickly through use of formularies and a prescriber workforce. For example, Kaiser Permanente has successfully replaced Remicade (infliximab) with biosimilars in 80% of patients.”
Given the many biologics in development and increasing health care spending, “we need to take seriously the substantial savings offered by biosimilars and the feasibility, as evidenced by Denmark, of switching to biosimilars quickly once they are available on the market,” Dr. Claytor and Dr. Gellad concluded.
The research was supported by an unrestricted grant from Helsefonden. One author disclosed receiving grants from Pfizer, AbbVie, Roche, and Bristol-Myers Squibb outside the current study. The editorial authors had no disclosures.
SOURCE: Jensen TB et al. JAMA Intern Med. 2020 Mar 30. doi: 10.1001/jamainternmed.2020.0338.
Adalimumab biosimilars are years away from entering the marketplace in the United States because of patent disputes, but they already have led to substantial discounts in Denmark, researchers wrote in JAMA Internal Medicine.
The Danish health care system switched almost entirely to adalimumab biosimilars after the patent on the original adalimumab product, Humira, expired there in October 2018. The switch to biosimilars led to an 82% decrease in costs for the medication, wrote Thomas Bo Jensen, MD, and colleagues in a research letter.
Denmark did not automatically substitute biosimilars, but the Danish Medicines Council recommended adalimumab biosimilars for all indications following Humira’s patent expiration. The recommendations “included switching patients to a biosimilar who were already well treated with the originator,” the researchers wrote.
To study the shift to adalimumab biosimilars across all indications in Denmark and calculate cost reductions, Dr. Jensen, of the department of clinical pharmacology at Copenhagen University Hospital Bispebjerg, and coinvestigators examined monthly data on drug sales from Amgros, which purchases all hospital drugs in the country.
“The proportion of adalimumab biosimilars increased from 71.6% (7,040 of 9,829 pens) in November 2018 to 95.1% (8,974 of 9,438 pens) in December 2018,” the researchers wrote. “Costs of adalimumab decreased by 82.8% from September 2018 to December 2018 (September: 8,197 pens at $5.13 million; December: 9,438 pens at $1.01 million).” The results were similar in rheumatology, dermatology, and gastroenterology.
The Food and Drug Administration has approved five adalimumab biosimilars in the United States, but “they will not enter the market until 2023 owing to patent disputes with AbbVie, the manufacturer of Humira,” wrote Jennifer D. Claytor, MD, of the department of internal medicine at University of California, San Francisco, and Walid Gellad, MD, of the division of general internal medicine at University of Pittsburgh, in an accompanying editorial.
The annual postrebate price of Humira doubled between 2013 and 2018, from $19,000 to $38,000, and these price increases may influence the price of biosimilars, “which will be priced using Humira’s price as an anchor,” Dr. Claytor and Dr. Gellad wrote.
A rapid shift to adalimumab biosimilars across the United States when they become available is “unlikely,” they wrote. Nonetheless, “some health care systems of comparable size to Denmark (e.g., the Veterans Affairs system) and others that are larger (e.g., Kaiser Permanente) ... have the ability to switch products quickly through use of formularies and a prescriber workforce. For example, Kaiser Permanente has successfully replaced Remicade (infliximab) with biosimilars in 80% of patients.”
Given the many biologics in development and increasing health care spending, “we need to take seriously the substantial savings offered by biosimilars and the feasibility, as evidenced by Denmark, of switching to biosimilars quickly once they are available on the market,” Dr. Claytor and Dr. Gellad concluded.
The research was supported by an unrestricted grant from Helsefonden. One author disclosed receiving grants from Pfizer, AbbVie, Roche, and Bristol-Myers Squibb outside the current study. The editorial authors had no disclosures.
SOURCE: Jensen TB et al. JAMA Intern Med. 2020 Mar 30. doi: 10.1001/jamainternmed.2020.0338.
Adalimumab biosimilars are years away from entering the marketplace in the United States because of patent disputes, but they already have led to substantial discounts in Denmark, researchers wrote in JAMA Internal Medicine.
The Danish health care system switched almost entirely to adalimumab biosimilars after the patent on the original adalimumab product, Humira, expired there in October 2018. The switch to biosimilars led to an 82% decrease in costs for the medication, wrote Thomas Bo Jensen, MD, and colleagues in a research letter.
Denmark did not automatically substitute biosimilars, but the Danish Medicines Council recommended adalimumab biosimilars for all indications following Humira’s patent expiration. The recommendations “included switching patients to a biosimilar who were already well treated with the originator,” the researchers wrote.
To study the shift to adalimumab biosimilars across all indications in Denmark and calculate cost reductions, Dr. Jensen, of the department of clinical pharmacology at Copenhagen University Hospital Bispebjerg, and coinvestigators examined monthly data on drug sales from Amgros, which purchases all hospital drugs in the country.
“The proportion of adalimumab biosimilars increased from 71.6% (7,040 of 9,829 pens) in November 2018 to 95.1% (8,974 of 9,438 pens) in December 2018,” the researchers wrote. “Costs of adalimumab decreased by 82.8% from September 2018 to December 2018 (September: 8,197 pens at $5.13 million; December: 9,438 pens at $1.01 million).” The results were similar in rheumatology, dermatology, and gastroenterology.
The Food and Drug Administration has approved five adalimumab biosimilars in the United States, but “they will not enter the market until 2023 owing to patent disputes with AbbVie, the manufacturer of Humira,” wrote Jennifer D. Claytor, MD, of the department of internal medicine at University of California, San Francisco, and Walid Gellad, MD, of the division of general internal medicine at University of Pittsburgh, in an accompanying editorial.
The annual postrebate price of Humira doubled between 2013 and 2018, from $19,000 to $38,000, and these price increases may influence the price of biosimilars, “which will be priced using Humira’s price as an anchor,” Dr. Claytor and Dr. Gellad wrote.
A rapid shift to adalimumab biosimilars across the United States when they become available is “unlikely,” they wrote. Nonetheless, “some health care systems of comparable size to Denmark (e.g., the Veterans Affairs system) and others that are larger (e.g., Kaiser Permanente) ... have the ability to switch products quickly through use of formularies and a prescriber workforce. For example, Kaiser Permanente has successfully replaced Remicade (infliximab) with biosimilars in 80% of patients.”
Given the many biologics in development and increasing health care spending, “we need to take seriously the substantial savings offered by biosimilars and the feasibility, as evidenced by Denmark, of switching to biosimilars quickly once they are available on the market,” Dr. Claytor and Dr. Gellad concluded.
The research was supported by an unrestricted grant from Helsefonden. One author disclosed receiving grants from Pfizer, AbbVie, Roche, and Bristol-Myers Squibb outside the current study. The editorial authors had no disclosures.
SOURCE: Jensen TB et al. JAMA Intern Med. 2020 Mar 30. doi: 10.1001/jamainternmed.2020.0338.
FROM JAMA INTERNAL MEDICINE
Reduced TNFi dose does not maintain axial spondyloarthritis improvement
Patients with axial spondyloarthritis have a significantly lower likelihood of achieving improvement in disease activity or remission when their dose of tumor necrosis factor inhibitor therapy is reduced, based on a systematic review and meta-analysis of six trials that included 747 adults.
Tumor necrosis factor inhibitors (TNFi) “have shown significant sustained clinical improvement in axSpA and are introduced in patients with axial disease or as the next line of treatment after inadequate response to nonsteroidal anti-inflammatory drugs,” but this improvement comes with a degree of immunosuppression that can increase infection risk, wrote Daeria O. Lawson of Toronto Western Hospital and colleagues. However, the impact of reducing or discontinuing TNFi therapy, compared with standard dosing, has not been well examined, they said.
In a study published in Arthritis Care & Research, the investigators identified six randomized, controlled trials with a total of 747 adults. Overall, patients on a reduced dose had a lower likelihood of achieving 40% improvement in Assessment of SpondyloArthritis international Society response criteria (ASAS40) or ASAS partial remission, compared with those on a standard TNFi dose (risk ratios, 0.62 and 0.17, respectively).
In addition, the mean increase in the Bath Ankylosing Spondylitis Disease Activity Index score was 0.35 for patients on reduced TNFi therapy, and no differences were seen in C-reactive protein levels, infection rates, or injection/infusion reactions in patients on a reduced dose, compared with those on the standard dose.
Patients on the reduced TNFi dose also had more disease flares and/or relapses, compared with the standard group (risk ratio, 1.73).
The study findings were limited by several factors including the inability to compare subgroups based on dosing regimens, potential blinding and selection bias, and inadequate data to assess certain patient outcomes, including maintenance of disease remission and quality of life, the researchers noted. The results confirm findings from previous studies and support the benefit of standard dosing for maintaining stable disease, they said.
However, more research is needed to identify patients who may be more responsive to TNFi reduction, they wrote. “Although treatment recommendations for the best dose reduction strategies cannot be made at this time given the heterogeneity in tapering strategies reported in the literature, this decision should be an individualized one between the patient and their physician,” the researchers emphasized.
The study received no outside funding. Dr. Lawson is supported in part by the Ontario Drug Policy Research Network Student Training Program.
SOURCE: Lawson DO et al. Arthritis Care Res. 2020 Mar 12. doi: 10.1002/ACR.24184.
Patients with axial spondyloarthritis have a significantly lower likelihood of achieving improvement in disease activity or remission when their dose of tumor necrosis factor inhibitor therapy is reduced, based on a systematic review and meta-analysis of six trials that included 747 adults.
Tumor necrosis factor inhibitors (TNFi) “have shown significant sustained clinical improvement in axSpA and are introduced in patients with axial disease or as the next line of treatment after inadequate response to nonsteroidal anti-inflammatory drugs,” but this improvement comes with a degree of immunosuppression that can increase infection risk, wrote Daeria O. Lawson of Toronto Western Hospital and colleagues. However, the impact of reducing or discontinuing TNFi therapy, compared with standard dosing, has not been well examined, they said.
In a study published in Arthritis Care & Research, the investigators identified six randomized, controlled trials with a total of 747 adults. Overall, patients on a reduced dose had a lower likelihood of achieving 40% improvement in Assessment of SpondyloArthritis international Society response criteria (ASAS40) or ASAS partial remission, compared with those on a standard TNFi dose (risk ratios, 0.62 and 0.17, respectively).
In addition, the mean increase in the Bath Ankylosing Spondylitis Disease Activity Index score was 0.35 for patients on reduced TNFi therapy, and no differences were seen in C-reactive protein levels, infection rates, or injection/infusion reactions in patients on a reduced dose, compared with those on the standard dose.
Patients on the reduced TNFi dose also had more disease flares and/or relapses, compared with the standard group (risk ratio, 1.73).
The study findings were limited by several factors including the inability to compare subgroups based on dosing regimens, potential blinding and selection bias, and inadequate data to assess certain patient outcomes, including maintenance of disease remission and quality of life, the researchers noted. The results confirm findings from previous studies and support the benefit of standard dosing for maintaining stable disease, they said.
However, more research is needed to identify patients who may be more responsive to TNFi reduction, they wrote. “Although treatment recommendations for the best dose reduction strategies cannot be made at this time given the heterogeneity in tapering strategies reported in the literature, this decision should be an individualized one between the patient and their physician,” the researchers emphasized.
The study received no outside funding. Dr. Lawson is supported in part by the Ontario Drug Policy Research Network Student Training Program.
SOURCE: Lawson DO et al. Arthritis Care Res. 2020 Mar 12. doi: 10.1002/ACR.24184.
Patients with axial spondyloarthritis have a significantly lower likelihood of achieving improvement in disease activity or remission when their dose of tumor necrosis factor inhibitor therapy is reduced, based on a systematic review and meta-analysis of six trials that included 747 adults.
Tumor necrosis factor inhibitors (TNFi) “have shown significant sustained clinical improvement in axSpA and are introduced in patients with axial disease or as the next line of treatment after inadequate response to nonsteroidal anti-inflammatory drugs,” but this improvement comes with a degree of immunosuppression that can increase infection risk, wrote Daeria O. Lawson of Toronto Western Hospital and colleagues. However, the impact of reducing or discontinuing TNFi therapy, compared with standard dosing, has not been well examined, they said.
In a study published in Arthritis Care & Research, the investigators identified six randomized, controlled trials with a total of 747 adults. Overall, patients on a reduced dose had a lower likelihood of achieving 40% improvement in Assessment of SpondyloArthritis international Society response criteria (ASAS40) or ASAS partial remission, compared with those on a standard TNFi dose (risk ratios, 0.62 and 0.17, respectively).
In addition, the mean increase in the Bath Ankylosing Spondylitis Disease Activity Index score was 0.35 for patients on reduced TNFi therapy, and no differences were seen in C-reactive protein levels, infection rates, or injection/infusion reactions in patients on a reduced dose, compared with those on the standard dose.
Patients on the reduced TNFi dose also had more disease flares and/or relapses, compared with the standard group (risk ratio, 1.73).
The study findings were limited by several factors including the inability to compare subgroups based on dosing regimens, potential blinding and selection bias, and inadequate data to assess certain patient outcomes, including maintenance of disease remission and quality of life, the researchers noted. The results confirm findings from previous studies and support the benefit of standard dosing for maintaining stable disease, they said.
However, more research is needed to identify patients who may be more responsive to TNFi reduction, they wrote. “Although treatment recommendations for the best dose reduction strategies cannot be made at this time given the heterogeneity in tapering strategies reported in the literature, this decision should be an individualized one between the patient and their physician,” the researchers emphasized.
The study received no outside funding. Dr. Lawson is supported in part by the Ontario Drug Policy Research Network Student Training Program.
SOURCE: Lawson DO et al. Arthritis Care Res. 2020 Mar 12. doi: 10.1002/ACR.24184.
FROM ARTHRITIS CARE & RESEARCH
Advances in ankylosing spondylitis hailed as rheumatology’s story of the year
MAUI, HAWAII – Arguably the most important development in the field of rheumatology during the past year was the emergence of persuasive clinical trials data predictive of a bright future for the oral Janus kinase inhibitors as major new drugs for treating ankylosing spondylitis, two experts agreed at the 2020 Rheumatology Winter Clinical Symposium.
“These drugs are the first oral DMARDs [disease-modifying antirheumatic drugs], if you will, in AS [ankylosing spondylitis] ... I think obviously they are going to move forward to regulatory approval,” commented Arthur F. Kavanaugh, MD, professor of medicine at the University of California, San Diego, and the RWCS program director.
“I think they’re going to hit the ground running,” predicted Eric M. Ruderman, MD, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.
Upon approval, the Janus kinase (JAK) inhibitors will quickly change the treatment paradigm in AS, the rheumatologists forecast.
“I think this is a way forward to go with strictly oral therapy without necessarily going first with parenteral therapy in these patients. It gives you an alternative, and my guess is, by the time these drugs are approved in this space, there’ll be more and more of their preferential use over biologics in rheumatoid arthritis and potentially in psoriatic arthritis, so people will be more familiar with them. A lot of patients are much happier taking a pill once a day with none of the tolerability issues that we have with shots,” Dr. Ruderman said.
“And they act fast,” noted Dr. Kavanaugh. “You can make a case for trying a JAK inhibitor for a month or 2, and then if you’re not better, then we go to the other option.”
Dr. Ruderman cautioned that the increased need for laboratory monitoring with the oral JAK inhibitors as compared with the annual monitoring with tumor necrosis factor inhibitors could be an issue, especially since AS patients tend to be on the younger side and often dislike coming in regularly for office visits and laboratory tests.
“There may be more of a headache in having to tell patients, ‘You’re not getting your JAK inhibitor refilled until you get your labs done,’ ” he said.
In December 2019, rheumatologists received a holiday present in the form of publication of the results of SELECT-AXIS 1, a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial in which 187 patients with active AS were randomized to placebo or to the JAK inhibitor upadacitinib (Rinvoq) at the same 15-mg dose approved by the FDA earlier in the year for rheumatoid arthritis. In SELECT-AXIS 1, upadacitinib not only demonstrated clinical efficacy, with a week-14 Assessment of SpondyloArthritis International Society-40 (ASAS 40) response rate of 52% – twice that for placebo – but the active treatment arm also experienced significantly reduced inflammatory disease activity as measured by Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores of the spine and sacroiliac joint. In contrast, MRI scores remained unchanged from baseline in the placebo arm.
“This suggests a biologic effect, a hook beyond clinical disease. And the time of onset was pretty impressive, much like with our experience with JAK inhibitors in RA. Within 2 weeks, there was significant separation from placebo on the ASDAS [Ankylosing Spondylitis Disease Activity Score],” Dr. Ruderman noted.
Positive clinical trials in AS have also been reported for the oral JAK inhibitors filgotinib and tofacitinib (Xeljanz).
Dr. Ruderman and Dr. Kavanaugh also touched on other major developments in AS within the past year, including the landmark FDA approval of certolizumab pegol (Cimzia) as the first-ever drug for treatment of nonradiographic axial spondyloarthritis (nr-axSpA). Also, Dr. Kavanaugh and Dr. Ruderman gave two thumbs down to the 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.
More biologics coming for nr-AxSpA
In order to gain an indication for treatment of nr-axSpA, the FDA requires completion of a 52-week, randomized, placebo-controlled clinical trial. That’s what UCB did with the company’s TNF inhibitor, certolizumab. Similarly, Eli Lilly sprang for the mandated 52-week trial in 303 nr-axSpA patients for its interleukin-17 inhibitor ixekizumab (Taltz), with positive findings (Lancet. 2020 Jan 4;395[10217]:53-64). And Novartis has done so with its IL-17 inhibitor secukinumab (Cosentyx) in the 555-patient PREVENT trial, again with positive outcomes. So the two IL-17 inhibitors, which are already approved for AS, are seemingly a lock for approval in nr-axSpA as well.
Will the makers of other TNF inhibitors already approved for AS fork over the considerable money entailed in a 52-week randomized trial, or will they ride on certolizumab’s coattails? Dr. Ruderman said he doesn’t know the answer, but it’s certain that, if they don’t complete the trial, they can’t market their biologic for nr-axSpA in the United States, even though there might well be a drug class effect at work.
ACR/SAA/SPARTAN guidelines critiqued
The two panelists had plenty to say about the 2019 update of the guidelines, none of it favorable. Among their criticisms: The guidelines are already out of date several months after their release, they are based heavily on opinion rather than on evidence, they appear to take medication cost into consideration when they’re not supposed to, they are complicated, and they are just not practical or useful.
“I don’t know when these guidelines would potentially be used,” Dr. Kavanaugh commented in response to an audience question.
Specifically, the guidelines strongly recommend a TNF inhibitor over the IL-17 inhibitors secukinumab or ixekizumab as the first-line biologic in AS patients with active disease while on NSAIDs, guidance that is already out of date.
“You’d almost think it would have been better just to wait a few months to see the published literature, which I think is going to have a tremendous impact on practice,” Dr. Kavanaugh said.
He also said he was troubled by the strong recommendation against switching to a TNF inhibitor–biosimilar after receiving treatment with an originator TNF inhibitor. That’s something rheumatologists all across Europe are routinely doing now for economic reasons without known harm, with the caveat that patients must be switched to a biosimilar of a different TNF inhibitor than the originator.
“There’s absolutely no data to support a recommendation against switching. I think they’re going out on a limb a little bit,” he added.
Dr. Ruderman said he struggles with the guideline development methodology, which involves posing a series of key questions at the outset, with a strict charge to provide answers.
“They always have to have an answer to the question. And in the event that there’s no data to support an answer, then it becomes a matter of the expert opinion of the people on the committee. I think many rheumatologists would say, ‘Why are they any more expert than a clinical rheumatologist who’s been seeing AS patients for 20 years?’ And the answer is they’re probably not. The fact that most of these are conditional recommendations, meaning they’re not supported by strong evidence, makes them less useful,” according to Dr. Ruderman.
Both he and Dr. Kavanaugh reported receiving research funding from and/or serving as a consultant to numerous pharmaceutical companies.
MAUI, HAWAII – Arguably the most important development in the field of rheumatology during the past year was the emergence of persuasive clinical trials data predictive of a bright future for the oral Janus kinase inhibitors as major new drugs for treating ankylosing spondylitis, two experts agreed at the 2020 Rheumatology Winter Clinical Symposium.
“These drugs are the first oral DMARDs [disease-modifying antirheumatic drugs], if you will, in AS [ankylosing spondylitis] ... I think obviously they are going to move forward to regulatory approval,” commented Arthur F. Kavanaugh, MD, professor of medicine at the University of California, San Diego, and the RWCS program director.
“I think they’re going to hit the ground running,” predicted Eric M. Ruderman, MD, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.
Upon approval, the Janus kinase (JAK) inhibitors will quickly change the treatment paradigm in AS, the rheumatologists forecast.
“I think this is a way forward to go with strictly oral therapy without necessarily going first with parenteral therapy in these patients. It gives you an alternative, and my guess is, by the time these drugs are approved in this space, there’ll be more and more of their preferential use over biologics in rheumatoid arthritis and potentially in psoriatic arthritis, so people will be more familiar with them. A lot of patients are much happier taking a pill once a day with none of the tolerability issues that we have with shots,” Dr. Ruderman said.
“And they act fast,” noted Dr. Kavanaugh. “You can make a case for trying a JAK inhibitor for a month or 2, and then if you’re not better, then we go to the other option.”
Dr. Ruderman cautioned that the increased need for laboratory monitoring with the oral JAK inhibitors as compared with the annual monitoring with tumor necrosis factor inhibitors could be an issue, especially since AS patients tend to be on the younger side and often dislike coming in regularly for office visits and laboratory tests.
“There may be more of a headache in having to tell patients, ‘You’re not getting your JAK inhibitor refilled until you get your labs done,’ ” he said.
In December 2019, rheumatologists received a holiday present in the form of publication of the results of SELECT-AXIS 1, a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial in which 187 patients with active AS were randomized to placebo or to the JAK inhibitor upadacitinib (Rinvoq) at the same 15-mg dose approved by the FDA earlier in the year for rheumatoid arthritis. In SELECT-AXIS 1, upadacitinib not only demonstrated clinical efficacy, with a week-14 Assessment of SpondyloArthritis International Society-40 (ASAS 40) response rate of 52% – twice that for placebo – but the active treatment arm also experienced significantly reduced inflammatory disease activity as measured by Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores of the spine and sacroiliac joint. In contrast, MRI scores remained unchanged from baseline in the placebo arm.
“This suggests a biologic effect, a hook beyond clinical disease. And the time of onset was pretty impressive, much like with our experience with JAK inhibitors in RA. Within 2 weeks, there was significant separation from placebo on the ASDAS [Ankylosing Spondylitis Disease Activity Score],” Dr. Ruderman noted.
Positive clinical trials in AS have also been reported for the oral JAK inhibitors filgotinib and tofacitinib (Xeljanz).
Dr. Ruderman and Dr. Kavanaugh also touched on other major developments in AS within the past year, including the landmark FDA approval of certolizumab pegol (Cimzia) as the first-ever drug for treatment of nonradiographic axial spondyloarthritis (nr-axSpA). Also, Dr. Kavanaugh and Dr. Ruderman gave two thumbs down to the 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.
More biologics coming for nr-AxSpA
In order to gain an indication for treatment of nr-axSpA, the FDA requires completion of a 52-week, randomized, placebo-controlled clinical trial. That’s what UCB did with the company’s TNF inhibitor, certolizumab. Similarly, Eli Lilly sprang for the mandated 52-week trial in 303 nr-axSpA patients for its interleukin-17 inhibitor ixekizumab (Taltz), with positive findings (Lancet. 2020 Jan 4;395[10217]:53-64). And Novartis has done so with its IL-17 inhibitor secukinumab (Cosentyx) in the 555-patient PREVENT trial, again with positive outcomes. So the two IL-17 inhibitors, which are already approved for AS, are seemingly a lock for approval in nr-axSpA as well.
Will the makers of other TNF inhibitors already approved for AS fork over the considerable money entailed in a 52-week randomized trial, or will they ride on certolizumab’s coattails? Dr. Ruderman said he doesn’t know the answer, but it’s certain that, if they don’t complete the trial, they can’t market their biologic for nr-axSpA in the United States, even though there might well be a drug class effect at work.
ACR/SAA/SPARTAN guidelines critiqued
The two panelists had plenty to say about the 2019 update of the guidelines, none of it favorable. Among their criticisms: The guidelines are already out of date several months after their release, they are based heavily on opinion rather than on evidence, they appear to take medication cost into consideration when they’re not supposed to, they are complicated, and they are just not practical or useful.
“I don’t know when these guidelines would potentially be used,” Dr. Kavanaugh commented in response to an audience question.
Specifically, the guidelines strongly recommend a TNF inhibitor over the IL-17 inhibitors secukinumab or ixekizumab as the first-line biologic in AS patients with active disease while on NSAIDs, guidance that is already out of date.
“You’d almost think it would have been better just to wait a few months to see the published literature, which I think is going to have a tremendous impact on practice,” Dr. Kavanaugh said.
He also said he was troubled by the strong recommendation against switching to a TNF inhibitor–biosimilar after receiving treatment with an originator TNF inhibitor. That’s something rheumatologists all across Europe are routinely doing now for economic reasons without known harm, with the caveat that patients must be switched to a biosimilar of a different TNF inhibitor than the originator.
“There’s absolutely no data to support a recommendation against switching. I think they’re going out on a limb a little bit,” he added.
Dr. Ruderman said he struggles with the guideline development methodology, which involves posing a series of key questions at the outset, with a strict charge to provide answers.
“They always have to have an answer to the question. And in the event that there’s no data to support an answer, then it becomes a matter of the expert opinion of the people on the committee. I think many rheumatologists would say, ‘Why are they any more expert than a clinical rheumatologist who’s been seeing AS patients for 20 years?’ And the answer is they’re probably not. The fact that most of these are conditional recommendations, meaning they’re not supported by strong evidence, makes them less useful,” according to Dr. Ruderman.
Both he and Dr. Kavanaugh reported receiving research funding from and/or serving as a consultant to numerous pharmaceutical companies.
MAUI, HAWAII – Arguably the most important development in the field of rheumatology during the past year was the emergence of persuasive clinical trials data predictive of a bright future for the oral Janus kinase inhibitors as major new drugs for treating ankylosing spondylitis, two experts agreed at the 2020 Rheumatology Winter Clinical Symposium.
“These drugs are the first oral DMARDs [disease-modifying antirheumatic drugs], if you will, in AS [ankylosing spondylitis] ... I think obviously they are going to move forward to regulatory approval,” commented Arthur F. Kavanaugh, MD, professor of medicine at the University of California, San Diego, and the RWCS program director.
“I think they’re going to hit the ground running,” predicted Eric M. Ruderman, MD, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.
Upon approval, the Janus kinase (JAK) inhibitors will quickly change the treatment paradigm in AS, the rheumatologists forecast.
“I think this is a way forward to go with strictly oral therapy without necessarily going first with parenteral therapy in these patients. It gives you an alternative, and my guess is, by the time these drugs are approved in this space, there’ll be more and more of their preferential use over biologics in rheumatoid arthritis and potentially in psoriatic arthritis, so people will be more familiar with them. A lot of patients are much happier taking a pill once a day with none of the tolerability issues that we have with shots,” Dr. Ruderman said.
“And they act fast,” noted Dr. Kavanaugh. “You can make a case for trying a JAK inhibitor for a month or 2, and then if you’re not better, then we go to the other option.”
Dr. Ruderman cautioned that the increased need for laboratory monitoring with the oral JAK inhibitors as compared with the annual monitoring with tumor necrosis factor inhibitors could be an issue, especially since AS patients tend to be on the younger side and often dislike coming in regularly for office visits and laboratory tests.
“There may be more of a headache in having to tell patients, ‘You’re not getting your JAK inhibitor refilled until you get your labs done,’ ” he said.
In December 2019, rheumatologists received a holiday present in the form of publication of the results of SELECT-AXIS 1, a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial in which 187 patients with active AS were randomized to placebo or to the JAK inhibitor upadacitinib (Rinvoq) at the same 15-mg dose approved by the FDA earlier in the year for rheumatoid arthritis. In SELECT-AXIS 1, upadacitinib not only demonstrated clinical efficacy, with a week-14 Assessment of SpondyloArthritis International Society-40 (ASAS 40) response rate of 52% – twice that for placebo – but the active treatment arm also experienced significantly reduced inflammatory disease activity as measured by Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores of the spine and sacroiliac joint. In contrast, MRI scores remained unchanged from baseline in the placebo arm.
“This suggests a biologic effect, a hook beyond clinical disease. And the time of onset was pretty impressive, much like with our experience with JAK inhibitors in RA. Within 2 weeks, there was significant separation from placebo on the ASDAS [Ankylosing Spondylitis Disease Activity Score],” Dr. Ruderman noted.
Positive clinical trials in AS have also been reported for the oral JAK inhibitors filgotinib and tofacitinib (Xeljanz).
Dr. Ruderman and Dr. Kavanaugh also touched on other major developments in AS within the past year, including the landmark FDA approval of certolizumab pegol (Cimzia) as the first-ever drug for treatment of nonradiographic axial spondyloarthritis (nr-axSpA). Also, Dr. Kavanaugh and Dr. Ruderman gave two thumbs down to the 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.
More biologics coming for nr-AxSpA
In order to gain an indication for treatment of nr-axSpA, the FDA requires completion of a 52-week, randomized, placebo-controlled clinical trial. That’s what UCB did with the company’s TNF inhibitor, certolizumab. Similarly, Eli Lilly sprang for the mandated 52-week trial in 303 nr-axSpA patients for its interleukin-17 inhibitor ixekizumab (Taltz), with positive findings (Lancet. 2020 Jan 4;395[10217]:53-64). And Novartis has done so with its IL-17 inhibitor secukinumab (Cosentyx) in the 555-patient PREVENT trial, again with positive outcomes. So the two IL-17 inhibitors, which are already approved for AS, are seemingly a lock for approval in nr-axSpA as well.
Will the makers of other TNF inhibitors already approved for AS fork over the considerable money entailed in a 52-week randomized trial, or will they ride on certolizumab’s coattails? Dr. Ruderman said he doesn’t know the answer, but it’s certain that, if they don’t complete the trial, they can’t market their biologic for nr-axSpA in the United States, even though there might well be a drug class effect at work.
ACR/SAA/SPARTAN guidelines critiqued
The two panelists had plenty to say about the 2019 update of the guidelines, none of it favorable. Among their criticisms: The guidelines are already out of date several months after their release, they are based heavily on opinion rather than on evidence, they appear to take medication cost into consideration when they’re not supposed to, they are complicated, and they are just not practical or useful.
“I don’t know when these guidelines would potentially be used,” Dr. Kavanaugh commented in response to an audience question.
Specifically, the guidelines strongly recommend a TNF inhibitor over the IL-17 inhibitors secukinumab or ixekizumab as the first-line biologic in AS patients with active disease while on NSAIDs, guidance that is already out of date.
“You’d almost think it would have been better just to wait a few months to see the published literature, which I think is going to have a tremendous impact on practice,” Dr. Kavanaugh said.
He also said he was troubled by the strong recommendation against switching to a TNF inhibitor–biosimilar after receiving treatment with an originator TNF inhibitor. That’s something rheumatologists all across Europe are routinely doing now for economic reasons without known harm, with the caveat that patients must be switched to a biosimilar of a different TNF inhibitor than the originator.
“There’s absolutely no data to support a recommendation against switching. I think they’re going out on a limb a little bit,” he added.
Dr. Ruderman said he struggles with the guideline development methodology, which involves posing a series of key questions at the outset, with a strict charge to provide answers.
“They always have to have an answer to the question. And in the event that there’s no data to support an answer, then it becomes a matter of the expert opinion of the people on the committee. I think many rheumatologists would say, ‘Why are they any more expert than a clinical rheumatologist who’s been seeing AS patients for 20 years?’ And the answer is they’re probably not. The fact that most of these are conditional recommendations, meaning they’re not supported by strong evidence, makes them less useful,” according to Dr. Ruderman.
Both he and Dr. Kavanaugh reported receiving research funding from and/or serving as a consultant to numerous pharmaceutical companies.
REPORTING FROM RWCS 2020
HLA-B27 status predicts radiographic phenotype of axSpA
The presence of HLA-B27 may predict the radiographic phenotype of patients with axial spondyloarthritis (axSpA), according to recent research.
The findings suggest HLA-B27-positive patients have worse radiographic damage, more typical marginal syndesmophytes, and a greater number of bilateral fused sacroiliac joints in the spine, reported Laura C. Coates, MBChB, PhD, of the University of Oxford (England) and colleagues. Their report was published in Arthritis Care & Research.
“In order to achieve phenotypic diversity, we studied patients with PsA [psoriatic arthritis] and axial involvement (a group of patients recognized to have less frequent carriage of HLA-B27), and AS [ankylosing spondylitis],” they wrote.
The researchers conducted a multicenter, cross-sectional cohort study involving 198 patients with AS and 244 with PsA. Various clinical, radiographic, and laboratory data were collected from databases in Ireland, Spain, Germany, Russia, Canada, and Italy.
HLA-B27-positive patients were older (mean 49.1 years vs. 53.8 years), were more often male (73% vs. 59%), and had longer disease duration (mean 13.6 years vs. 11.0 years).
The team compared HLA-B27 carriers and noncarriers on syndesmophyte morphology, the symmetry of the sacroiliac joints and syndesmophytes, in addition to radiographic damage, as measured by the modified Stoke Ankylosing spondylitis spinal score (mSASSS) and PsA Spondylitis Radiology Index (PASRI).
After analysis, the researchers found that HLA-B27 positivity was associated with higher median mSASSS (6 vs. 2; P = .04) and PASRI scores (12 vs. 6; P less than .0001), marginal syndesmophytes (odds ratio, 1.97; 95% confidence interval, 1.16-3.36), and syndesmophyte symmetry (OR, 3.02; 95% CI, 1.38-6.61).
“[Our] study [showed] no difference in sacroiliac symmetry, and no difference in nonmarginal syndesmophytes, according to HLA-B27 status,” they reported.
In addition, they reported that male sex (OR, 1.66; 95% CI, 1.04-2.66) and age (OR, 1.08; 95% CI, 1.05-1.10) were positive predictors of marginal syndesmophytes.
In contrast, only male sex (OR, 2.55; 95% CI, 1.46-4.64) and age (OR, 1.05; 95% CI, 1.03-1.07) predicted the presence of nonmarginal syndesmophytes.
The researchers acknowledged that two key limitations of the study were the absence of disease-group matching and lack of independent central reading of radiographs.
“This analysis suggests less difference in radiographic phenotype between AS and axial PsA than previously found but emphasizes the importance of HLA-B27 status in severity and the phenotypic expression of disease radiographically,” they concluded.
The study was funded by the Academy of Medical Sciences (U.K.). The authors reported having no conflicts of interest.
SOURCE: Coates LC et al. Arthritis Care Res. 2020 Feb 26. doi: 10.1002/acr.24174.
The presence of HLA-B27 may predict the radiographic phenotype of patients with axial spondyloarthritis (axSpA), according to recent research.
The findings suggest HLA-B27-positive patients have worse radiographic damage, more typical marginal syndesmophytes, and a greater number of bilateral fused sacroiliac joints in the spine, reported Laura C. Coates, MBChB, PhD, of the University of Oxford (England) and colleagues. Their report was published in Arthritis Care & Research.
“In order to achieve phenotypic diversity, we studied patients with PsA [psoriatic arthritis] and axial involvement (a group of patients recognized to have less frequent carriage of HLA-B27), and AS [ankylosing spondylitis],” they wrote.
The researchers conducted a multicenter, cross-sectional cohort study involving 198 patients with AS and 244 with PsA. Various clinical, radiographic, and laboratory data were collected from databases in Ireland, Spain, Germany, Russia, Canada, and Italy.
HLA-B27-positive patients were older (mean 49.1 years vs. 53.8 years), were more often male (73% vs. 59%), and had longer disease duration (mean 13.6 years vs. 11.0 years).
The team compared HLA-B27 carriers and noncarriers on syndesmophyte morphology, the symmetry of the sacroiliac joints and syndesmophytes, in addition to radiographic damage, as measured by the modified Stoke Ankylosing spondylitis spinal score (mSASSS) and PsA Spondylitis Radiology Index (PASRI).
After analysis, the researchers found that HLA-B27 positivity was associated with higher median mSASSS (6 vs. 2; P = .04) and PASRI scores (12 vs. 6; P less than .0001), marginal syndesmophytes (odds ratio, 1.97; 95% confidence interval, 1.16-3.36), and syndesmophyte symmetry (OR, 3.02; 95% CI, 1.38-6.61).
“[Our] study [showed] no difference in sacroiliac symmetry, and no difference in nonmarginal syndesmophytes, according to HLA-B27 status,” they reported.
In addition, they reported that male sex (OR, 1.66; 95% CI, 1.04-2.66) and age (OR, 1.08; 95% CI, 1.05-1.10) were positive predictors of marginal syndesmophytes.
In contrast, only male sex (OR, 2.55; 95% CI, 1.46-4.64) and age (OR, 1.05; 95% CI, 1.03-1.07) predicted the presence of nonmarginal syndesmophytes.
The researchers acknowledged that two key limitations of the study were the absence of disease-group matching and lack of independent central reading of radiographs.
“This analysis suggests less difference in radiographic phenotype between AS and axial PsA than previously found but emphasizes the importance of HLA-B27 status in severity and the phenotypic expression of disease radiographically,” they concluded.
The study was funded by the Academy of Medical Sciences (U.K.). The authors reported having no conflicts of interest.
SOURCE: Coates LC et al. Arthritis Care Res. 2020 Feb 26. doi: 10.1002/acr.24174.
The presence of HLA-B27 may predict the radiographic phenotype of patients with axial spondyloarthritis (axSpA), according to recent research.
The findings suggest HLA-B27-positive patients have worse radiographic damage, more typical marginal syndesmophytes, and a greater number of bilateral fused sacroiliac joints in the spine, reported Laura C. Coates, MBChB, PhD, of the University of Oxford (England) and colleagues. Their report was published in Arthritis Care & Research.
“In order to achieve phenotypic diversity, we studied patients with PsA [psoriatic arthritis] and axial involvement (a group of patients recognized to have less frequent carriage of HLA-B27), and AS [ankylosing spondylitis],” they wrote.
The researchers conducted a multicenter, cross-sectional cohort study involving 198 patients with AS and 244 with PsA. Various clinical, radiographic, and laboratory data were collected from databases in Ireland, Spain, Germany, Russia, Canada, and Italy.
HLA-B27-positive patients were older (mean 49.1 years vs. 53.8 years), were more often male (73% vs. 59%), and had longer disease duration (mean 13.6 years vs. 11.0 years).
The team compared HLA-B27 carriers and noncarriers on syndesmophyte morphology, the symmetry of the sacroiliac joints and syndesmophytes, in addition to radiographic damage, as measured by the modified Stoke Ankylosing spondylitis spinal score (mSASSS) and PsA Spondylitis Radiology Index (PASRI).
After analysis, the researchers found that HLA-B27 positivity was associated with higher median mSASSS (6 vs. 2; P = .04) and PASRI scores (12 vs. 6; P less than .0001), marginal syndesmophytes (odds ratio, 1.97; 95% confidence interval, 1.16-3.36), and syndesmophyte symmetry (OR, 3.02; 95% CI, 1.38-6.61).
“[Our] study [showed] no difference in sacroiliac symmetry, and no difference in nonmarginal syndesmophytes, according to HLA-B27 status,” they reported.
In addition, they reported that male sex (OR, 1.66; 95% CI, 1.04-2.66) and age (OR, 1.08; 95% CI, 1.05-1.10) were positive predictors of marginal syndesmophytes.
In contrast, only male sex (OR, 2.55; 95% CI, 1.46-4.64) and age (OR, 1.05; 95% CI, 1.03-1.07) predicted the presence of nonmarginal syndesmophytes.
The researchers acknowledged that two key limitations of the study were the absence of disease-group matching and lack of independent central reading of radiographs.
“This analysis suggests less difference in radiographic phenotype between AS and axial PsA than previously found but emphasizes the importance of HLA-B27 status in severity and the phenotypic expression of disease radiographically,” they concluded.
The study was funded by the Academy of Medical Sciences (U.K.). The authors reported having no conflicts of interest.
SOURCE: Coates LC et al. Arthritis Care Res. 2020 Feb 26. doi: 10.1002/acr.24174.
FROM ARTHRITIS CARE & RESEARCH
Meta-analysis highlights safety concerns with interleukin inhibition
MAUI, HAWAII – The use of interleukin inhibitors for treatment of rheumatologic diseases doubles a patient’s risk of serious infections, according to a comprehensive systematic review and meta-analysis of 74 randomized, placebo-controlled trials presented by Jawad Bilal, MBBS, at the 2020 Rheumatology Winter Clinical Symposium.
The meta-analysis, which incorporated 29,214 patients with a variety of rheumatic diseases, demonstrated that patients receiving interleukin (IL) inhibitors had a 1.97-fold increased risk of serious infections, a finding accompanied by a high degree of statistical certainty. The number-needed-to-harm was 67 patients treated for a median of 24 weeks in order to generate one additional serious infection.
“That number-needed-to-harm is a significant finding because having a serious infection means by definition you’re getting admitted to the hospital and receiving IV antibiotics,” Dr. Bilal observed in an interview.
The meta-analysis also found that IL inhibition was associated with a 2.35-fold increased risk of opportunistic infections and a 1.52-fold higher risk of developing cancer, both findings with statistical significance (P =.03) but only moderate certainty because fewer of those events were captured in the trials compared to the numbers of serious infections, explained Dr. Bilal of the University of Arizona, Tucson.
For opportunistic infections, the number-needed-to-harm was 250 patients treated with an IL inhibitor for a median of 54 weeks in order to result in one additional opportunistic infection. For cancer, the number-needed-to-harm was 250 for a median of 24 weeks.
Dr. Bilal noted that while the IL inhibitors are drugs of established efficacy in rheumatologic diseases, their safety has not previously undergone anything approaching the comprehensive scrutiny carried out in this meta-analysis. The meta-analysis, which included all published placebo-controlled randomized trials and their extension studies, employed rigorous methodology in accord with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement and the GRADE approach to data analysis. Studies of IL inhibitors in patients with dermatologic and GI diseases were excluded from the meta-analysis.
He offered a caveat regarding the cancer risk findings: “Our analysis showed that the cancer risk is increased, but the results are not conclusive because we only had a few years of data. With cancer, you really need at least 8-10 years of data. So the real-world experience with the interleukin inhibitors in the large registries is what’s going to tell if the cancer risk is really increased or not. In the meantime, we all have to be cautious.”
The number of serious infections collected in the meta-analysis afforded sufficient statistical power for the investigators to break down differential risks based on individual drugs and indications. Among the drugs associated with significantly increased risk of serious infections were anakinra, with an odds ratio of 2.67, compared with placebo; secukinumab with an OR of 2.43; and tocilizumab with an OR or 1.76. Ustekinumab and ixekizumab were associated with 2.57- and 3.89-fold increased risks, respectively, but the number of rheumatology patients treated with those two biologics wasn’t large enough for those findings to achieve statistical significance.
Rheumatoid arthritis patients who received an IL inhibitor rather than placebo had a 1.98-fold increased risk of serious infection, while those with psoriatic arthritis had a 2.21-fold increased risk. Patients treated for SLE had a 6.44-fold increased risk, and those with juvenile idiopathic arthritis had a 5.37-fold higher risk, but the margins for error were such that those results weren’t statistically significant.
“I think this study is going to help clinicians and patients when they’re trying to weigh the risks and benefits of IL inhibitors, especially if they already have risk factors, like a recent history of serious infection or a history of cancer or of opportunistic infection,” Dr. Bilal commented.
A study limitation was that he and his coinvestigators had to lump together the various IL inhibitors in order to gain statistical power, even though the drugs work differently, he noted.
Dr. Bilal reported having no financial conflicts regarding his study, the full details of which have been published (JAMA Netw Open. 2019 Oct 2. doi: 10.1001/jamanetworkopen.2019.13102).
MAUI, HAWAII – The use of interleukin inhibitors for treatment of rheumatologic diseases doubles a patient’s risk of serious infections, according to a comprehensive systematic review and meta-analysis of 74 randomized, placebo-controlled trials presented by Jawad Bilal, MBBS, at the 2020 Rheumatology Winter Clinical Symposium.
The meta-analysis, which incorporated 29,214 patients with a variety of rheumatic diseases, demonstrated that patients receiving interleukin (IL) inhibitors had a 1.97-fold increased risk of serious infections, a finding accompanied by a high degree of statistical certainty. The number-needed-to-harm was 67 patients treated for a median of 24 weeks in order to generate one additional serious infection.
“That number-needed-to-harm is a significant finding because having a serious infection means by definition you’re getting admitted to the hospital and receiving IV antibiotics,” Dr. Bilal observed in an interview.
The meta-analysis also found that IL inhibition was associated with a 2.35-fold increased risk of opportunistic infections and a 1.52-fold higher risk of developing cancer, both findings with statistical significance (P =.03) but only moderate certainty because fewer of those events were captured in the trials compared to the numbers of serious infections, explained Dr. Bilal of the University of Arizona, Tucson.
For opportunistic infections, the number-needed-to-harm was 250 patients treated with an IL inhibitor for a median of 54 weeks in order to result in one additional opportunistic infection. For cancer, the number-needed-to-harm was 250 for a median of 24 weeks.
Dr. Bilal noted that while the IL inhibitors are drugs of established efficacy in rheumatologic diseases, their safety has not previously undergone anything approaching the comprehensive scrutiny carried out in this meta-analysis. The meta-analysis, which included all published placebo-controlled randomized trials and their extension studies, employed rigorous methodology in accord with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement and the GRADE approach to data analysis. Studies of IL inhibitors in patients with dermatologic and GI diseases were excluded from the meta-analysis.
He offered a caveat regarding the cancer risk findings: “Our analysis showed that the cancer risk is increased, but the results are not conclusive because we only had a few years of data. With cancer, you really need at least 8-10 years of data. So the real-world experience with the interleukin inhibitors in the large registries is what’s going to tell if the cancer risk is really increased or not. In the meantime, we all have to be cautious.”
The number of serious infections collected in the meta-analysis afforded sufficient statistical power for the investigators to break down differential risks based on individual drugs and indications. Among the drugs associated with significantly increased risk of serious infections were anakinra, with an odds ratio of 2.67, compared with placebo; secukinumab with an OR of 2.43; and tocilizumab with an OR or 1.76. Ustekinumab and ixekizumab were associated with 2.57- and 3.89-fold increased risks, respectively, but the number of rheumatology patients treated with those two biologics wasn’t large enough for those findings to achieve statistical significance.
Rheumatoid arthritis patients who received an IL inhibitor rather than placebo had a 1.98-fold increased risk of serious infection, while those with psoriatic arthritis had a 2.21-fold increased risk. Patients treated for SLE had a 6.44-fold increased risk, and those with juvenile idiopathic arthritis had a 5.37-fold higher risk, but the margins for error were such that those results weren’t statistically significant.
“I think this study is going to help clinicians and patients when they’re trying to weigh the risks and benefits of IL inhibitors, especially if they already have risk factors, like a recent history of serious infection or a history of cancer or of opportunistic infection,” Dr. Bilal commented.
A study limitation was that he and his coinvestigators had to lump together the various IL inhibitors in order to gain statistical power, even though the drugs work differently, he noted.
Dr. Bilal reported having no financial conflicts regarding his study, the full details of which have been published (JAMA Netw Open. 2019 Oct 2. doi: 10.1001/jamanetworkopen.2019.13102).
MAUI, HAWAII – The use of interleukin inhibitors for treatment of rheumatologic diseases doubles a patient’s risk of serious infections, according to a comprehensive systematic review and meta-analysis of 74 randomized, placebo-controlled trials presented by Jawad Bilal, MBBS, at the 2020 Rheumatology Winter Clinical Symposium.
The meta-analysis, which incorporated 29,214 patients with a variety of rheumatic diseases, demonstrated that patients receiving interleukin (IL) inhibitors had a 1.97-fold increased risk of serious infections, a finding accompanied by a high degree of statistical certainty. The number-needed-to-harm was 67 patients treated for a median of 24 weeks in order to generate one additional serious infection.
“That number-needed-to-harm is a significant finding because having a serious infection means by definition you’re getting admitted to the hospital and receiving IV antibiotics,” Dr. Bilal observed in an interview.
The meta-analysis also found that IL inhibition was associated with a 2.35-fold increased risk of opportunistic infections and a 1.52-fold higher risk of developing cancer, both findings with statistical significance (P =.03) but only moderate certainty because fewer of those events were captured in the trials compared to the numbers of serious infections, explained Dr. Bilal of the University of Arizona, Tucson.
For opportunistic infections, the number-needed-to-harm was 250 patients treated with an IL inhibitor for a median of 54 weeks in order to result in one additional opportunistic infection. For cancer, the number-needed-to-harm was 250 for a median of 24 weeks.
Dr. Bilal noted that while the IL inhibitors are drugs of established efficacy in rheumatologic diseases, their safety has not previously undergone anything approaching the comprehensive scrutiny carried out in this meta-analysis. The meta-analysis, which included all published placebo-controlled randomized trials and their extension studies, employed rigorous methodology in accord with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement and the GRADE approach to data analysis. Studies of IL inhibitors in patients with dermatologic and GI diseases were excluded from the meta-analysis.
He offered a caveat regarding the cancer risk findings: “Our analysis showed that the cancer risk is increased, but the results are not conclusive because we only had a few years of data. With cancer, you really need at least 8-10 years of data. So the real-world experience with the interleukin inhibitors in the large registries is what’s going to tell if the cancer risk is really increased or not. In the meantime, we all have to be cautious.”
The number of serious infections collected in the meta-analysis afforded sufficient statistical power for the investigators to break down differential risks based on individual drugs and indications. Among the drugs associated with significantly increased risk of serious infections were anakinra, with an odds ratio of 2.67, compared with placebo; secukinumab with an OR of 2.43; and tocilizumab with an OR or 1.76. Ustekinumab and ixekizumab were associated with 2.57- and 3.89-fold increased risks, respectively, but the number of rheumatology patients treated with those two biologics wasn’t large enough for those findings to achieve statistical significance.
Rheumatoid arthritis patients who received an IL inhibitor rather than placebo had a 1.98-fold increased risk of serious infection, while those with psoriatic arthritis had a 2.21-fold increased risk. Patients treated for SLE had a 6.44-fold increased risk, and those with juvenile idiopathic arthritis had a 5.37-fold higher risk, but the margins for error were such that those results weren’t statistically significant.
“I think this study is going to help clinicians and patients when they’re trying to weigh the risks and benefits of IL inhibitors, especially if they already have risk factors, like a recent history of serious infection or a history of cancer or of opportunistic infection,” Dr. Bilal commented.
A study limitation was that he and his coinvestigators had to lump together the various IL inhibitors in order to gain statistical power, even though the drugs work differently, he noted.
Dr. Bilal reported having no financial conflicts regarding his study, the full details of which have been published (JAMA Netw Open. 2019 Oct 2. doi: 10.1001/jamanetworkopen.2019.13102).
REPORTING FROM RWCS 2020
New guideline offers recommendations for reproductive health in patients with rheumatic diseases
A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).
“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.
To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.
In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”
“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.
“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
Contraception
In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.
For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
Assisted reproductive technology
In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.
For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
Fertility preservation
In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.
Hormone therapy
In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.
Pregnancy assessment and management
Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.
For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”
Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily
For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.
For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.
Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.
Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.
The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.
The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.
The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.
SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.
A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).
“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.
To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.
In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”
“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.
“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
Contraception
In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.
For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
Assisted reproductive technology
In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.
For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
Fertility preservation
In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.
Hormone therapy
In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.
Pregnancy assessment and management
Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.
For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”
Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily
For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.
For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.
Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.
Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.
The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.
The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.
The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.
SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.
A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).
“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.
To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.
In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”
“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.
“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
Contraception
In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.
For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
Assisted reproductive technology
In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.
For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
Fertility preservation
In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.
Hormone therapy
In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.
Pregnancy assessment and management
Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.
For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”
Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily
For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.
For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.
Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.
Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.
The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.
The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.
The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.
SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.
FROM ARTHRITIS & RHEUMATOLOGY