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Upadacitinib recommended for nonradiographic axSpA in Europe
Upadacitinib may soon be used for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA) after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) gave it its stamp of approval.
AbbVie, the drug’s manufacturer, announced on June 27 that the committee approved the use on June 23. The recommendation to approve market authorization for upadacitinib for nr-axSpA now goes to the European Commission, which is expected to make a decision by the third quarter of 2022.
“The CHMP’s recommendation to approve upadacitinib for patients with nr-axSpA is an important milestone in providing a new treatment option to patients in need,” said Neil Gallagher, MD, vice president of development and chief medical officer of AbbVie. He noted that currently, there are few options to treat symptoms such as inflammation, back pain, and stiffness for these patients.
Officially, the new indication for upadacitinib (Rinvoq) 15 mg once daily is for the treatment of active nr-axSpA in adult patients with objective signs of inflammation, as indicated by elevated C-reactive protein and/or MRI, whose condition has responded inadequately to NSAIDs.
Upadacitinib is a selective Janus kinase (JAK) inhibitor that in human cellular assays preferentially inhibits signaling by JAK1 or JAK1/3.
In the European Union, upadacitinib is currently approved for use in patients with moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, and moderate to severe atopic dermatitis. In addition to these indications, it is approved in the United States for ulcerative colitis but not for nr-axSpA.
The committee based its decision on the results of the nr-axSpA study within the SELECT-AXIS-2 trial, recently reported at the European Alliance of Associations for Rheumatology (EULAR) 2022 annual meeting.
The nr-axSpA study met the primary endpoint of a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) and the first 12 of 14 ranked secondary endpoints, according to AbbVie.
The most commonly reported adverse reactions with upadacitinib 15 mg were upper respiratory tract infections, elevated blood creatine phosphokinase levels, elevated alanine transaminase levels, bronchitis, nausea, cough, elevated aspartate transaminase levels, and hypercholesterolemia. These occurred in 2% or more of patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in clinical trials.
The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications, AbbVie said.
A version of this article first appeared on Medscape.com.
Upadacitinib may soon be used for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA) after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) gave it its stamp of approval.
AbbVie, the drug’s manufacturer, announced on June 27 that the committee approved the use on June 23. The recommendation to approve market authorization for upadacitinib for nr-axSpA now goes to the European Commission, which is expected to make a decision by the third quarter of 2022.
“The CHMP’s recommendation to approve upadacitinib for patients with nr-axSpA is an important milestone in providing a new treatment option to patients in need,” said Neil Gallagher, MD, vice president of development and chief medical officer of AbbVie. He noted that currently, there are few options to treat symptoms such as inflammation, back pain, and stiffness for these patients.
Officially, the new indication for upadacitinib (Rinvoq) 15 mg once daily is for the treatment of active nr-axSpA in adult patients with objective signs of inflammation, as indicated by elevated C-reactive protein and/or MRI, whose condition has responded inadequately to NSAIDs.
Upadacitinib is a selective Janus kinase (JAK) inhibitor that in human cellular assays preferentially inhibits signaling by JAK1 or JAK1/3.
In the European Union, upadacitinib is currently approved for use in patients with moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, and moderate to severe atopic dermatitis. In addition to these indications, it is approved in the United States for ulcerative colitis but not for nr-axSpA.
The committee based its decision on the results of the nr-axSpA study within the SELECT-AXIS-2 trial, recently reported at the European Alliance of Associations for Rheumatology (EULAR) 2022 annual meeting.
The nr-axSpA study met the primary endpoint of a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) and the first 12 of 14 ranked secondary endpoints, according to AbbVie.
The most commonly reported adverse reactions with upadacitinib 15 mg were upper respiratory tract infections, elevated blood creatine phosphokinase levels, elevated alanine transaminase levels, bronchitis, nausea, cough, elevated aspartate transaminase levels, and hypercholesterolemia. These occurred in 2% or more of patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in clinical trials.
The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications, AbbVie said.
A version of this article first appeared on Medscape.com.
Upadacitinib may soon be used for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA) after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) gave it its stamp of approval.
AbbVie, the drug’s manufacturer, announced on June 27 that the committee approved the use on June 23. The recommendation to approve market authorization for upadacitinib for nr-axSpA now goes to the European Commission, which is expected to make a decision by the third quarter of 2022.
“The CHMP’s recommendation to approve upadacitinib for patients with nr-axSpA is an important milestone in providing a new treatment option to patients in need,” said Neil Gallagher, MD, vice president of development and chief medical officer of AbbVie. He noted that currently, there are few options to treat symptoms such as inflammation, back pain, and stiffness for these patients.
Officially, the new indication for upadacitinib (Rinvoq) 15 mg once daily is for the treatment of active nr-axSpA in adult patients with objective signs of inflammation, as indicated by elevated C-reactive protein and/or MRI, whose condition has responded inadequately to NSAIDs.
Upadacitinib is a selective Janus kinase (JAK) inhibitor that in human cellular assays preferentially inhibits signaling by JAK1 or JAK1/3.
In the European Union, upadacitinib is currently approved for use in patients with moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, and moderate to severe atopic dermatitis. In addition to these indications, it is approved in the United States for ulcerative colitis but not for nr-axSpA.
The committee based its decision on the results of the nr-axSpA study within the SELECT-AXIS-2 trial, recently reported at the European Alliance of Associations for Rheumatology (EULAR) 2022 annual meeting.
The nr-axSpA study met the primary endpoint of a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) and the first 12 of 14 ranked secondary endpoints, according to AbbVie.
The most commonly reported adverse reactions with upadacitinib 15 mg were upper respiratory tract infections, elevated blood creatine phosphokinase levels, elevated alanine transaminase levels, bronchitis, nausea, cough, elevated aspartate transaminase levels, and hypercholesterolemia. These occurred in 2% or more of patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in clinical trials.
The safety profile of upadacitinib with long-term treatment was generally similar to the safety profile during the placebo-controlled period across indications, AbbVie said.
A version of this article first appeared on Medscape.com.
Treat-to-target strategy with tapering proves effective in PsA and axSpA
Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.
The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.
“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”
The study is now published in Annals of the Rheumatic Diseases.
In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).
Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”
Results show strategy is ‘feasible in daily clinical care’
A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.
At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.
The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).
The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).
Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.
Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.
“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”
The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.
“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.
The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.
“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”
This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.
Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.
The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.
“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”
The study is now published in Annals of the Rheumatic Diseases.
In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).
Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”
Results show strategy is ‘feasible in daily clinical care’
A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.
At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.
The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).
The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).
Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.
Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.
“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”
The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.
“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.
The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.
“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”
This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.
Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.
The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.
“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”
The study is now published in Annals of the Rheumatic Diseases.
In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).
Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”
Results show strategy is ‘feasible in daily clinical care’
A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.
At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.
The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).
The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).
Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.
Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.
“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”
The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.
“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.
The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.
“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”
This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.
FROM THE EULAR 2022 CONGRESS
Diagnostic axSpA MRI features differ in men and women
MRI criteria used to diagnose axial spondyloarthritis (axSpA) may require gender-specific revision, according to research conducted at Charité Universitätsmedizin Berlin.
Although established MRI markers were detected in both sexes, their prevalence was substantially different in some cases – ankylosis and fat metaplasia were more prevalent in male than female patients, for example, while sclerosis was far more common in females.
“There’s increasing evidence in the literature and awareness in clinical practice that there are some sex differences in the clinical presentation of axSpA,” said radiologist Sevtap Tugce Ulas, MD, at the annual European Congress of Rheumatology.
She presented the first results of a study examining the diagnostic performance of MRI findings for men and women. “Men have a high risk of structural damage, while women are more likely to be affected by peripheral manifestations with a higher risk for pain, stiffness, and fatigue.”
Joint biomechanics are different in men and women, she pointed out, which might explain some of the disparities. She observed that diagnostic delay – a known problem in axSpA – was “significantly longer” in female patients.
Dr. Ulas and colleagues conducted a post hoc analysis of participants in six prospective axSpA cohorts. From a total of more than 1,100 participants, the researchers identified 684 who had both a clinical diagnosis and complete imaging data available for evaluation. The study population included 379 men and women with and 305 men and women without axSpA.
The mean age overall in all groups was 37 years, with axSpA patients more likely than controls to have elevated C-reactive protein levels; levels were also higher in men with axSpA, compared with in women with axSpA.
Men with axSpA also were more likely than women to be HLA-B27 positive (91% vs. 79%), but there were similar mean Bath Ankylosing Spondylitis Disease Activity Index scores recorded (4.4 vs. 4.6) among the subjects with axSpA.
Two experienced radiologists, blinded to the clinical diagnosis, scored the MRI images independently of each other, looking for the presence of ankylosis; erosions; sclerosis; fat metaplasia; and bone marrow edema in the ventral, mid, and dorsal regions of the sacroiliac joints. Any disagreement between the two reviewers was assessed by a third, more experienced radiologist.
Clear differences in MRI markers
“If you look in detail, we found no major sex-specific differences for erosion and bone marrow edema,” Dr. Ulas reported.
The situation was quite different for other MRI parameters examined. Indeed, more men than women had evidence of ankylosis (24.3% vs. 7.4%) and fat metaplasia (58.8% vs. 42.6%). Conversely, women were more likely than men to have evidence of sclerosis (75.0% vs. 57.6%).
“To make the performance more easily comparable, we calculated a diagnostic odds ratio, which is simply positive likelihood ratio divided by negative likelihood ratio,” Dr. Ulas said.
Doing this showed that the presence of ankylosis had “an almost 10 times stronger performance in men,” with a DOR of 40.1 versus 4.7 for women.
“Interestingly, this was not only caused by low prevalence in females, but also by high rates of false positives,” she said.
DOR for the other parameters in men and women were 18.6 and 6.3 for fat metaplasia, 2.5 and 3.0 for sclerosis, 17.6 and 11.1 for joint erosion, and 2.5 and 3.7 for bone edema.
Overall, diagnostic accuracy was improved only when middle and dorsal lesions were considered.
‘Remarkably different’ results
“By definition, these patients have the same disease,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich (Germany).
Yet these are “remarkably different” findings, Dr. Schulze-Koops said during a closing highlights session of the congress.
Current imaging practices don’t differentiate between the sexes but perhaps they might need to, he said, because these data suggest “female patients have a different MRI pattern from what we learn from the textbooks.
“[The investigators] say diagnostic performance of established imaging markers on MRI is significantly lower in female axSpA patients, and we should consider this when we are in the situation where we question the disease.”
Marta Mosca, MD, PhD, of the University of Pisa (Italy) and who cochaired the session in which Dr. Ulas had presented the findings commented: “I think is very interesting. We always talk about gender differences in treatment and in the assessment.”
However, Dr. Mosca asked if there were plans to study other patient cohorts, notably those not just referred by a rheumatologist, as that was “a big limitation.”
Dr. Ulas replied: “I think we need follow-up studies to investigate this problem, because we know that there are differences in the clinical presentation and also in the imaging, and this is an important point.”
Of course, there are other limitations, Dr. Ulas said, such as the sole use of conventional T1-weighted spin echo sequences. Although often routinely used in clinical practice, this imaging technique can lead to overestimation of structural damage. Moreover, “subtle differences might have been missed” in bone marrow edema because it wasn’t included in the semiquantitative scoring system used.
“Most importantly, the MRI images under investigation were also used in the diagnostic process, which carries the risk of circular reasoning,” Dr. Ulas said.
However, there are clearly some differences in imaging appearance between men and women, and “we show a significantly lower performance of many typical MRI findings in women,” Dr. Ulas said. “We hope that these findings might spark a critical discussion on the appropriateness of sex-blind classification criteria for axSpA, and hopefully, eventually lead to refined criteria for both sexes.”
Dr. Ulas had no conflicts of interest to disclose. Dr. Schulze-Koops and Dr. Mosca were not involved in the study and had no relevant disclosures.
MRI criteria used to diagnose axial spondyloarthritis (axSpA) may require gender-specific revision, according to research conducted at Charité Universitätsmedizin Berlin.
Although established MRI markers were detected in both sexes, their prevalence was substantially different in some cases – ankylosis and fat metaplasia were more prevalent in male than female patients, for example, while sclerosis was far more common in females.
“There’s increasing evidence in the literature and awareness in clinical practice that there are some sex differences in the clinical presentation of axSpA,” said radiologist Sevtap Tugce Ulas, MD, at the annual European Congress of Rheumatology.
She presented the first results of a study examining the diagnostic performance of MRI findings for men and women. “Men have a high risk of structural damage, while women are more likely to be affected by peripheral manifestations with a higher risk for pain, stiffness, and fatigue.”
Joint biomechanics are different in men and women, she pointed out, which might explain some of the disparities. She observed that diagnostic delay – a known problem in axSpA – was “significantly longer” in female patients.
Dr. Ulas and colleagues conducted a post hoc analysis of participants in six prospective axSpA cohorts. From a total of more than 1,100 participants, the researchers identified 684 who had both a clinical diagnosis and complete imaging data available for evaluation. The study population included 379 men and women with and 305 men and women without axSpA.
The mean age overall in all groups was 37 years, with axSpA patients more likely than controls to have elevated C-reactive protein levels; levels were also higher in men with axSpA, compared with in women with axSpA.
Men with axSpA also were more likely than women to be HLA-B27 positive (91% vs. 79%), but there were similar mean Bath Ankylosing Spondylitis Disease Activity Index scores recorded (4.4 vs. 4.6) among the subjects with axSpA.
Two experienced radiologists, blinded to the clinical diagnosis, scored the MRI images independently of each other, looking for the presence of ankylosis; erosions; sclerosis; fat metaplasia; and bone marrow edema in the ventral, mid, and dorsal regions of the sacroiliac joints. Any disagreement between the two reviewers was assessed by a third, more experienced radiologist.
Clear differences in MRI markers
“If you look in detail, we found no major sex-specific differences for erosion and bone marrow edema,” Dr. Ulas reported.
The situation was quite different for other MRI parameters examined. Indeed, more men than women had evidence of ankylosis (24.3% vs. 7.4%) and fat metaplasia (58.8% vs. 42.6%). Conversely, women were more likely than men to have evidence of sclerosis (75.0% vs. 57.6%).
“To make the performance more easily comparable, we calculated a diagnostic odds ratio, which is simply positive likelihood ratio divided by negative likelihood ratio,” Dr. Ulas said.
Doing this showed that the presence of ankylosis had “an almost 10 times stronger performance in men,” with a DOR of 40.1 versus 4.7 for women.
“Interestingly, this was not only caused by low prevalence in females, but also by high rates of false positives,” she said.
DOR for the other parameters in men and women were 18.6 and 6.3 for fat metaplasia, 2.5 and 3.0 for sclerosis, 17.6 and 11.1 for joint erosion, and 2.5 and 3.7 for bone edema.
Overall, diagnostic accuracy was improved only when middle and dorsal lesions were considered.
‘Remarkably different’ results
“By definition, these patients have the same disease,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich (Germany).
Yet these are “remarkably different” findings, Dr. Schulze-Koops said during a closing highlights session of the congress.
Current imaging practices don’t differentiate between the sexes but perhaps they might need to, he said, because these data suggest “female patients have a different MRI pattern from what we learn from the textbooks.
“[The investigators] say diagnostic performance of established imaging markers on MRI is significantly lower in female axSpA patients, and we should consider this when we are in the situation where we question the disease.”
Marta Mosca, MD, PhD, of the University of Pisa (Italy) and who cochaired the session in which Dr. Ulas had presented the findings commented: “I think is very interesting. We always talk about gender differences in treatment and in the assessment.”
However, Dr. Mosca asked if there were plans to study other patient cohorts, notably those not just referred by a rheumatologist, as that was “a big limitation.”
Dr. Ulas replied: “I think we need follow-up studies to investigate this problem, because we know that there are differences in the clinical presentation and also in the imaging, and this is an important point.”
Of course, there are other limitations, Dr. Ulas said, such as the sole use of conventional T1-weighted spin echo sequences. Although often routinely used in clinical practice, this imaging technique can lead to overestimation of structural damage. Moreover, “subtle differences might have been missed” in bone marrow edema because it wasn’t included in the semiquantitative scoring system used.
“Most importantly, the MRI images under investigation were also used in the diagnostic process, which carries the risk of circular reasoning,” Dr. Ulas said.
However, there are clearly some differences in imaging appearance between men and women, and “we show a significantly lower performance of many typical MRI findings in women,” Dr. Ulas said. “We hope that these findings might spark a critical discussion on the appropriateness of sex-blind classification criteria for axSpA, and hopefully, eventually lead to refined criteria for both sexes.”
Dr. Ulas had no conflicts of interest to disclose. Dr. Schulze-Koops and Dr. Mosca were not involved in the study and had no relevant disclosures.
MRI criteria used to diagnose axial spondyloarthritis (axSpA) may require gender-specific revision, according to research conducted at Charité Universitätsmedizin Berlin.
Although established MRI markers were detected in both sexes, their prevalence was substantially different in some cases – ankylosis and fat metaplasia were more prevalent in male than female patients, for example, while sclerosis was far more common in females.
“There’s increasing evidence in the literature and awareness in clinical practice that there are some sex differences in the clinical presentation of axSpA,” said radiologist Sevtap Tugce Ulas, MD, at the annual European Congress of Rheumatology.
She presented the first results of a study examining the diagnostic performance of MRI findings for men and women. “Men have a high risk of structural damage, while women are more likely to be affected by peripheral manifestations with a higher risk for pain, stiffness, and fatigue.”
Joint biomechanics are different in men and women, she pointed out, which might explain some of the disparities. She observed that diagnostic delay – a known problem in axSpA – was “significantly longer” in female patients.
Dr. Ulas and colleagues conducted a post hoc analysis of participants in six prospective axSpA cohorts. From a total of more than 1,100 participants, the researchers identified 684 who had both a clinical diagnosis and complete imaging data available for evaluation. The study population included 379 men and women with and 305 men and women without axSpA.
The mean age overall in all groups was 37 years, with axSpA patients more likely than controls to have elevated C-reactive protein levels; levels were also higher in men with axSpA, compared with in women with axSpA.
Men with axSpA also were more likely than women to be HLA-B27 positive (91% vs. 79%), but there were similar mean Bath Ankylosing Spondylitis Disease Activity Index scores recorded (4.4 vs. 4.6) among the subjects with axSpA.
Two experienced radiologists, blinded to the clinical diagnosis, scored the MRI images independently of each other, looking for the presence of ankylosis; erosions; sclerosis; fat metaplasia; and bone marrow edema in the ventral, mid, and dorsal regions of the sacroiliac joints. Any disagreement between the two reviewers was assessed by a third, more experienced radiologist.
Clear differences in MRI markers
“If you look in detail, we found no major sex-specific differences for erosion and bone marrow edema,” Dr. Ulas reported.
The situation was quite different for other MRI parameters examined. Indeed, more men than women had evidence of ankylosis (24.3% vs. 7.4%) and fat metaplasia (58.8% vs. 42.6%). Conversely, women were more likely than men to have evidence of sclerosis (75.0% vs. 57.6%).
“To make the performance more easily comparable, we calculated a diagnostic odds ratio, which is simply positive likelihood ratio divided by negative likelihood ratio,” Dr. Ulas said.
Doing this showed that the presence of ankylosis had “an almost 10 times stronger performance in men,” with a DOR of 40.1 versus 4.7 for women.
“Interestingly, this was not only caused by low prevalence in females, but also by high rates of false positives,” she said.
DOR for the other parameters in men and women were 18.6 and 6.3 for fat metaplasia, 2.5 and 3.0 for sclerosis, 17.6 and 11.1 for joint erosion, and 2.5 and 3.7 for bone edema.
Overall, diagnostic accuracy was improved only when middle and dorsal lesions were considered.
‘Remarkably different’ results
“By definition, these patients have the same disease,” said Hendrik Schulze-Koops, MD, of Ludwig Maximilian University of Munich (Germany).
Yet these are “remarkably different” findings, Dr. Schulze-Koops said during a closing highlights session of the congress.
Current imaging practices don’t differentiate between the sexes but perhaps they might need to, he said, because these data suggest “female patients have a different MRI pattern from what we learn from the textbooks.
“[The investigators] say diagnostic performance of established imaging markers on MRI is significantly lower in female axSpA patients, and we should consider this when we are in the situation where we question the disease.”
Marta Mosca, MD, PhD, of the University of Pisa (Italy) and who cochaired the session in which Dr. Ulas had presented the findings commented: “I think is very interesting. We always talk about gender differences in treatment and in the assessment.”
However, Dr. Mosca asked if there were plans to study other patient cohorts, notably those not just referred by a rheumatologist, as that was “a big limitation.”
Dr. Ulas replied: “I think we need follow-up studies to investigate this problem, because we know that there are differences in the clinical presentation and also in the imaging, and this is an important point.”
Of course, there are other limitations, Dr. Ulas said, such as the sole use of conventional T1-weighted spin echo sequences. Although often routinely used in clinical practice, this imaging technique can lead to overestimation of structural damage. Moreover, “subtle differences might have been missed” in bone marrow edema because it wasn’t included in the semiquantitative scoring system used.
“Most importantly, the MRI images under investigation were also used in the diagnostic process, which carries the risk of circular reasoning,” Dr. Ulas said.
However, there are clearly some differences in imaging appearance between men and women, and “we show a significantly lower performance of many typical MRI findings in women,” Dr. Ulas said. “We hope that these findings might spark a critical discussion on the appropriateness of sex-blind classification criteria for axSpA, and hopefully, eventually lead to refined criteria for both sexes.”
Dr. Ulas had no conflicts of interest to disclose. Dr. Schulze-Koops and Dr. Mosca were not involved in the study and had no relevant disclosures.
FROM THE EULAR 2022 CONGRESS
Bimekizumab tames active ankylosing spondylitis in BE MOBILE 2
COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.
At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.
“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
IL-17 inhibitor times 2
Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.
In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.
The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.
Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
All endpoints met
The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).
All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.
Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.
In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).
The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.
Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.
‘Promising results’
Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.
“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”
The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.
A version of this article first appeared on Medscape.com.
COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.
At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.
“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
IL-17 inhibitor times 2
Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.
In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.
The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.
Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
All endpoints met
The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).
All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.
Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.
In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).
The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.
Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.
‘Promising results’
Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.
“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”
The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.
A version of this article first appeared on Medscape.com.
COPENHAGEN – Use of the dual interleukin (IL)–17 inhibitor bimekizumab (Bimzelx) was associated with rapid reductions in signs and symptoms of radiographic axial spondyloarthritis, reported investigators in the BE MOBILE 2 phase 3 trial.
At least half of all patients achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 2.1 by week 24 of treatment with bimekizumab, and there were marked reductions in objective signs of inflammation, reported Désiréé van der Heijde, MD, PhD, of Leiden (Netherlands) University Medical Center.
“The safety we have seen in this trial was consistent with what we have seen [with bimekizumab] in other trials and other diseases,” she said at the annual European Congress of Rheumatology.
IL-17 inhibitor times 2
Bimekizumab is a monoclonal immunoglobulin 1 antibody that selectively inhibits IL-17A and IL-17F. It is approved in the European Union for treating adults with moderate to severe plaque psoriasis.
In the BE MOBILE 2 trial, investigators enrolled patients aged 18 years and older who had ankylosing spondylitis, who met modified New York criteria, who had active disease at screening and at baseline, as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 4 or more and spinal pain of 4 or more on a scale of 0-10, and whose disease failed to respond to two different NSAIDs or who were either intolerant of or had contraindications to NSAIDs.
The patients were randomly assigned on a 2:1 basis to receive either bimekizumab 160 mg every 4 weeks (221 patients) or placebo (111 patients) for 16 weeks. All patients were switched over at 16 weeks to bimekizumab maintenance for up to 1 year of total treatment.
Dr. Van der Heijde reported 24-week data from the trial, including data from 8 weeks of additional follow-up.
All endpoints met
The trial met its primary endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 16. There was a 44.8% improvement with bimekizumab, compared with 22.6% with placebo (P < .001).
All secondary endpoints also favored the bimekizumab arm, including ASAS 40 among patients who had not previously received a tumor necrosis factor (TNF)–alpha inhibitor, ASAS 20, BASDAI functional index, ankylosing spondylitis quality-of-life index, and others.
Responses to bimekizumab were consistent across subpopulations of patients with or without prior TNF-alpha inhibitor exposure, Dr. van der Heidje said.
In addition, use of bimekizumab was associated with a significant improvement from baseline, compared with placebo, in objective measures of inflammation, including MRI spine Berlin score at week 16 (mean, –2.3 vs. 0; P < .001), Spondylitis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score at week 16 (mean, –5.6 vs. 1.1), and high-sensitivity C-reactive protein at week 16 (mean, 2.4 vs. 6.3 mg/L; P < .001).
The most frequent treatment-related adverse events were nasopharyngitis, diarrhea, and oral candidiasis, all of which were more common in the bimekizumab arm, as well as headache, the incidence of which was similar between the arms.
Overall, 6.4% of patients taking bimekizumab had fungal infections, compared with none in the placebo group. The infections were mild or moderate, localized, and mucocutaneous in nature. Only two patients discontinued the drug because of fungal infections: one for oral candidiasis, and one for esophageal candidiasis.
‘Promising results’
Fabian Proft, MD, head of the clinical trials unit at Charité University Hospital in Berlin, who was not involved in the study, told this news organization that the data looked very good.
“These are the first phase 3 data on dual inhibition of IL-17A and F with bimekizumab in axial spondyloarthritis, and the data are really promising,” he said. “For nonradiographic disease, the data also look very promising, and when we’re looking into the future, it might be a therapeutic option for us as treating rheumatologists.”
The study was funded by UCB Pharma. Dr. van der Heijde has received consulting fees from the company and others. Dr. Proft has consulted for and has been on the speaker’s bureau for UCB and other pharmaceutical companies.
A version of this article first appeared on Medscape.com.
AT THE EULAR 2022 CONGRESS
Upadacitinib effective against nonradiographic AxSpA
COPENHAGEN – The Janus kinase (JAK) inhibitor upadacitinib (Rinvoq, AbbVie) was associated with significant improvements in disease activity, pain, function, and quality of life, compared with placebo, in patients with nonradiographic axial spondyloarthritis (nr-axSpA), results of the first efficacy analysis of the phase 3, randomized SELECT-AXIS-2 trial showed.
The trial met its primary endpoint of an improvement of Assessment of SpondyloArthritis International Society 40% (ASAS 40) response criteria in the prespecified efficacy analysis at week 14, reported Filip Van den Bosch, MD, PhD, Ghent (Belgium) University.
In all, 45% of patients randomized to receive upadacitinib achieved an ASAS 40, compared with 23% of those assigned to placebo (P < .001).
“This is the first study showing efficacy and showing that the JAK inhibitor upadacitinib might be a therapeutic option in patients with active, nonradiographic spondyloarthritis,” Van den Bosch said at the annual European Congress of Rheumatology.
Although JAK inhibitors have previously been shown to be efficacious and safe for the treatment of ankylosing spondylitis, the SELECT-AXIS-2 trial is the first to evaluate a JAK inhibitor in nonradiographic axSpA, he added.
Study details
Patients 18 years and older with rheumatologist-diagnosed nr-axSpA were eligible for the study if they also met 2009 ASAS classification criteria for axSpA but not the radiologic criterion of modified New York criteria; had objective signs of active inflammation consistent with axSpA on MRI of the sacroiliac joints and/or high-sensitivity C-reactive protein above the upper limit of normal (2.87 mg/L) at screening; and had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and patient-assessment of total back pain scores of 4 or greater based on a 0-10 numeric rating scale at study entry.
Patients were screened with MRI imaging of the spine and x-rays of the sacroiliac joints and spine, and then randomized to receive either placebo (157 patients) or upadacitinib 15 mg daily (158 patients) for 52 weeks. At the end of 52 weeks, all patients on upadacitinib will continue on the drug at the same dose level, and those assigned to placebo will be switched over to 15 mg upadacitinib daily maintenance.
As well as meeting the primary endpoint at week 14, response rates with the JAK inhibitor were higher at all time points over this initial time period, Dr. Van den Bosch noted.
Most targets hit
Of 14 multiplicity-controlled secondary endpoints, 12 were statistically better with upadacitinib, including change from baseline in patient’s assessment of total back pain, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Disease Activity Score, Low Disease Activity, Ankylosing Spondylitis Quality of Life, and MRI Spondyloarthritis Research Consortium of Canada score for sacroiliac joints.
Only the BASDAI and Maastricht Ankylosing Spondylitis Enthesitis Score were not significantly better with the JAK inhibitor.
The safety of upadacitinib in this setting was consistent with its known safety profile, Dr. Van den Bosch said.
Approximately half of all patients in each trial arm had an adverse event. Serious adverse events were reported in four patients assigned to upadacitinib versus two on placebo, and serious adverse events requiring drug discontinuation occurred in two and four patients, respectively.
‘Important’ data
Fabian Proft, MD, head of the clinical trials unit at Charite University Hospital, Berlin, who was not involved in the study, said in an interview that the findings were not surprising.
“We know the efficacy of upadacitinib already in radiographic axial spondyloarthritis, and from all the other drugs that we also know that are effective in radiographic axial spondyloarthritis that are similarly effective in nonradiographic disease,” he said.
“I think it is really important because it is the first data on JAK inhibition also in non-radiographic axial spondyloarthritis – an important step,” said Dr. Proft, who was comoderator of the oral abstract session where Van den Bosch reported the data.
The trial was supported by AbbVie. Dr. Van den Bosch disclosed speaker and consulting fees from AbbVie and others. Dr. Proft disclosed speaker and consulting fees from AbbVie as well.
A version of this article first appeared on Medscape.com.
COPENHAGEN – The Janus kinase (JAK) inhibitor upadacitinib (Rinvoq, AbbVie) was associated with significant improvements in disease activity, pain, function, and quality of life, compared with placebo, in patients with nonradiographic axial spondyloarthritis (nr-axSpA), results of the first efficacy analysis of the phase 3, randomized SELECT-AXIS-2 trial showed.
The trial met its primary endpoint of an improvement of Assessment of SpondyloArthritis International Society 40% (ASAS 40) response criteria in the prespecified efficacy analysis at week 14, reported Filip Van den Bosch, MD, PhD, Ghent (Belgium) University.
In all, 45% of patients randomized to receive upadacitinib achieved an ASAS 40, compared with 23% of those assigned to placebo (P < .001).
“This is the first study showing efficacy and showing that the JAK inhibitor upadacitinib might be a therapeutic option in patients with active, nonradiographic spondyloarthritis,” Van den Bosch said at the annual European Congress of Rheumatology.
Although JAK inhibitors have previously been shown to be efficacious and safe for the treatment of ankylosing spondylitis, the SELECT-AXIS-2 trial is the first to evaluate a JAK inhibitor in nonradiographic axSpA, he added.
Study details
Patients 18 years and older with rheumatologist-diagnosed nr-axSpA were eligible for the study if they also met 2009 ASAS classification criteria for axSpA but not the radiologic criterion of modified New York criteria; had objective signs of active inflammation consistent with axSpA on MRI of the sacroiliac joints and/or high-sensitivity C-reactive protein above the upper limit of normal (2.87 mg/L) at screening; and had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and patient-assessment of total back pain scores of 4 or greater based on a 0-10 numeric rating scale at study entry.
Patients were screened with MRI imaging of the spine and x-rays of the sacroiliac joints and spine, and then randomized to receive either placebo (157 patients) or upadacitinib 15 mg daily (158 patients) for 52 weeks. At the end of 52 weeks, all patients on upadacitinib will continue on the drug at the same dose level, and those assigned to placebo will be switched over to 15 mg upadacitinib daily maintenance.
As well as meeting the primary endpoint at week 14, response rates with the JAK inhibitor were higher at all time points over this initial time period, Dr. Van den Bosch noted.
Most targets hit
Of 14 multiplicity-controlled secondary endpoints, 12 were statistically better with upadacitinib, including change from baseline in patient’s assessment of total back pain, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Disease Activity Score, Low Disease Activity, Ankylosing Spondylitis Quality of Life, and MRI Spondyloarthritis Research Consortium of Canada score for sacroiliac joints.
Only the BASDAI and Maastricht Ankylosing Spondylitis Enthesitis Score were not significantly better with the JAK inhibitor.
The safety of upadacitinib in this setting was consistent with its known safety profile, Dr. Van den Bosch said.
Approximately half of all patients in each trial arm had an adverse event. Serious adverse events were reported in four patients assigned to upadacitinib versus two on placebo, and serious adverse events requiring drug discontinuation occurred in two and four patients, respectively.
‘Important’ data
Fabian Proft, MD, head of the clinical trials unit at Charite University Hospital, Berlin, who was not involved in the study, said in an interview that the findings were not surprising.
“We know the efficacy of upadacitinib already in radiographic axial spondyloarthritis, and from all the other drugs that we also know that are effective in radiographic axial spondyloarthritis that are similarly effective in nonradiographic disease,” he said.
“I think it is really important because it is the first data on JAK inhibition also in non-radiographic axial spondyloarthritis – an important step,” said Dr. Proft, who was comoderator of the oral abstract session where Van den Bosch reported the data.
The trial was supported by AbbVie. Dr. Van den Bosch disclosed speaker and consulting fees from AbbVie and others. Dr. Proft disclosed speaker and consulting fees from AbbVie as well.
A version of this article first appeared on Medscape.com.
COPENHAGEN – The Janus kinase (JAK) inhibitor upadacitinib (Rinvoq, AbbVie) was associated with significant improvements in disease activity, pain, function, and quality of life, compared with placebo, in patients with nonradiographic axial spondyloarthritis (nr-axSpA), results of the first efficacy analysis of the phase 3, randomized SELECT-AXIS-2 trial showed.
The trial met its primary endpoint of an improvement of Assessment of SpondyloArthritis International Society 40% (ASAS 40) response criteria in the prespecified efficacy analysis at week 14, reported Filip Van den Bosch, MD, PhD, Ghent (Belgium) University.
In all, 45% of patients randomized to receive upadacitinib achieved an ASAS 40, compared with 23% of those assigned to placebo (P < .001).
“This is the first study showing efficacy and showing that the JAK inhibitor upadacitinib might be a therapeutic option in patients with active, nonradiographic spondyloarthritis,” Van den Bosch said at the annual European Congress of Rheumatology.
Although JAK inhibitors have previously been shown to be efficacious and safe for the treatment of ankylosing spondylitis, the SELECT-AXIS-2 trial is the first to evaluate a JAK inhibitor in nonradiographic axSpA, he added.
Study details
Patients 18 years and older with rheumatologist-diagnosed nr-axSpA were eligible for the study if they also met 2009 ASAS classification criteria for axSpA but not the radiologic criterion of modified New York criteria; had objective signs of active inflammation consistent with axSpA on MRI of the sacroiliac joints and/or high-sensitivity C-reactive protein above the upper limit of normal (2.87 mg/L) at screening; and had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and patient-assessment of total back pain scores of 4 or greater based on a 0-10 numeric rating scale at study entry.
Patients were screened with MRI imaging of the spine and x-rays of the sacroiliac joints and spine, and then randomized to receive either placebo (157 patients) or upadacitinib 15 mg daily (158 patients) for 52 weeks. At the end of 52 weeks, all patients on upadacitinib will continue on the drug at the same dose level, and those assigned to placebo will be switched over to 15 mg upadacitinib daily maintenance.
As well as meeting the primary endpoint at week 14, response rates with the JAK inhibitor were higher at all time points over this initial time period, Dr. Van den Bosch noted.
Most targets hit
Of 14 multiplicity-controlled secondary endpoints, 12 were statistically better with upadacitinib, including change from baseline in patient’s assessment of total back pain, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Disease Activity Score, Low Disease Activity, Ankylosing Spondylitis Quality of Life, and MRI Spondyloarthritis Research Consortium of Canada score for sacroiliac joints.
Only the BASDAI and Maastricht Ankylosing Spondylitis Enthesitis Score were not significantly better with the JAK inhibitor.
The safety of upadacitinib in this setting was consistent with its known safety profile, Dr. Van den Bosch said.
Approximately half of all patients in each trial arm had an adverse event. Serious adverse events were reported in four patients assigned to upadacitinib versus two on placebo, and serious adverse events requiring drug discontinuation occurred in two and four patients, respectively.
‘Important’ data
Fabian Proft, MD, head of the clinical trials unit at Charite University Hospital, Berlin, who was not involved in the study, said in an interview that the findings were not surprising.
“We know the efficacy of upadacitinib already in radiographic axial spondyloarthritis, and from all the other drugs that we also know that are effective in radiographic axial spondyloarthritis that are similarly effective in nonradiographic disease,” he said.
“I think it is really important because it is the first data on JAK inhibition also in non-radiographic axial spondyloarthritis – an important step,” said Dr. Proft, who was comoderator of the oral abstract session where Van den Bosch reported the data.
The trial was supported by AbbVie. Dr. Van den Bosch disclosed speaker and consulting fees from AbbVie and others. Dr. Proft disclosed speaker and consulting fees from AbbVie as well.
A version of this article first appeared on Medscape.com.
AT THE EULAR 2022 CONGRESS
Abortion debate may affect Rx decisions for pregnant women
Obstetrician Beverly Gray, MD, is already seeing the effects of the Roe v. Wade abortion debate in her North Carolina practice.
The state allows abortion but requires that women get counseling with a qualified health professional 72 hours before the procedure. “Aside from that, we still have patients asking for more efficacious contraceptive methods just in case,” said Dr. Gray, residency director and division director for women’s community and population health and associate professor for obstetrics and gynecology at Duke University, Durham, N.C.
Patients and staff in her clinic have also been approaching her about tubal ligation. “They’re asking about additional birth control methods because they’re concerned about what’s going to happen” with the challenge to the historic Roe v. Wade decision in the Supreme Court and subsequent actions in the states to restrict or ban abortion, she said.
This has implications not just for abortion but for medications known to affect pregnancy. “What I’m really worried about is physicians will be withholding medicine because they’re concerned about teratogenic effects,” said Dr. Gray.
With more states issuing restrictions on abortion, doctors are worried that patients needing certain drugs to maintain their lupus flares, cancer, or other diseases may decide not to take them in the event they accidentally become pregnant. If the drug is known to affect the fetus, the fear is a patient who lives in a state with abortion restrictions will no longer have the option to terminate a pregnancy.
Instead, a scenario may arise in which the patient – and their physician – may opt not to treat at all with an otherwise lifesaving medication, experts told this news organization.
The U.S. landscape on abortion restrictions
A leaked draft of a U.S. Supreme Court opinion on Mississippi’s 15-week abortion ban has sent the medical community into a tailspin. The case, Dobbs v. Jackson Women’s Health Organization, challenges the 1973 Roe v. Wade decision that affirms the constitutional right to abortion. It’s anticipated the high court will decide on the case in June.
Although the upcoming decision is subject to change, the draft indicated the high court would uphold the Mississippi ban. This would essentially overturn the 1973 ruling. An earlier Supreme Court decision allowing a Texas law banning abortion at 6 weeks suggests the court may already be heading in this direction. At the state level, legislatures have been moving on divergent paths – some taking steps to preserve abortion rights, others initiating restrictions.
More than 100 abortion restrictions in 19 states took effect in 2021, according to the Guttmacher Institute, which tracks such metrics. In 2022, “two key themes are anti-abortion policymakers’ continued pursuit of various types of abortion bans and restrictions on medication abortion,” the institute reported.
Forty-six states and the District of Columbia have introduced 2,025 restrictions or proactive measures on sexual and reproductive health and rights so far this year. The latest tally from Guttmacher, updated in late May, revealed that 11 states so far have enacted 42 abortion restrictions. A total of 6 states (Arizona, Florida, Idaho, Kentucky, Oklahoma, and Wyoming) have issued nine bans on abortion.
Comparatively, 11 states have enacted 19 protective abortion measures.
Twenty-two states have introduced 117 restrictions on medication abortions, which account for 54% of U.S. abortions. This includes seven measures that would ban medication abortion outright, according to Guttmacher. Kentucky and South Dakota collectively have enacted 14 restrictions on medication abortion, as well as provisions that ban mailing of abortion pills.
Chilling effect on prescribing
Some physicians anticipate that drugs such as the “morning-after” pill (levonorgestrel) will become less available as restrictions go into effect, since these are medications designed to prevent pregnancy.*
However, the ongoing effort to put a lid on abortion measures has prompted concerns about a trickle-down effect on other medications that are otherwise life-changing or lifesaving to patients but pose a risk to the fetus.
Several drugs are well documented to affect fetal growth and development of the fetus, ranging from mild, transitory effects to severe, permanent birth defects, said Ronald G. Grifka, MD, chief medical officer of University of Michigan Health-West and clinical professor of pediatrics at the University of Michigan Medical School, Ann Arbor. “As new medications are developed, we will need heightened attention to make sure they are safe for the fetus,” he added.
Certain teratogenic medications are associated with a high risk of abortion even though this isn’t their primary use, noted Christina Chambers, PhD, MPH, co-director of the Center for Better Beginnings and associate director with the Altman Clinical & Translational Research Institute at the University of California, San Diego.
“I don’t think anyone would intentionally take these drugs to induce spontaneous abortion. But if the drugs pose a risk for it, I can see how the laws might be stretched” to include them, said Dr. Chambers.
Methotrexate, a medication for autoimmune disorders, has a high risk of spontaneous abortion. So do acne medications such as isotretinoin.
Patients are usually told they’re not supposed to get pregnant on these drugs because there’s a high risk of pregnancy loss and risk of malformations and potential learning problems in the fetus. But many pregnancies aren’t planned, said Dr. Chambers. “Patients may forget about the side effects or think their birth control will protect them. And the next time they refill the medication, they may not hear about the warnings again.”
With a restrictive abortion law or ban in effect, a woman might think: “I won’t take this drug because if there’s any potential that I might get pregnant, I won’t have the option to abort an at-risk pregnancy.” Women and their doctors, for that matter, don’t want to put themselves in this position, said Dr. Chambers.
Rheumatologist Megan Clowse, MD, who prescribes several medications that potentially cause major birth defects and pregnancy loss, worries about the ramifications of these accumulating bans.
“Methotrexate has been a leading drug for us for decades for rheumatoid arthritis. Mycophenolate is a vital drug for lupus,” said Dr. Clowse, associate professor of medicine at Duke University’s division of rheumatology and immunology.
Both methotrexate and mycophenolate pose about a 40% risk of pregnancy loss and significantly increase the risk for birth defects. “I’m definitely concerned that there might be doctors or women who elect not to use those medications in women of reproductive age because of the potential risk for pregnancy and absence of abortion rights,” said Dr. Clowse.
These situations might force women to use contraceptives they don’t want to use, such as hormonal implants or intrauterine devices, she added. Another side effect is that women and their partners may decide to abstain from sex.
The iPLEDGE factor
Some rheumatology drugs like lenalidomide (Revlimid) require a valid negative pregnancy test in a lab every month. Similarly, the iPLEDGE Risk Evaluation and Mitigation Strategy seeks to reduce the teratogenicity of isotretinoin by requiring two types of birth control and regular pregnancy tests by users.
For isotretinoin specifically, abortion restrictions “could lead to increased adherence to pregnancy prevention measures which are already stringent in iPLEDGE. But on the other hand, it could lead to reduced willingness of physicians to prescribe or patients to take the medication,” said Dr. Chambers.
With programs like iPLEDGE in effect, the rate of pregnancies and abortions that occur in dermatology are relatively low, said Jenny Murase, MD, associate clinical professor of dermatology at the University of California, San Francisco.
Nevertheless, as a physician who regularly prescribes medications like isotretinoin in women of childbearing age, “it’s terrifying to me that a woman wouldn’t have the option to terminate the pregnancy if a teratogenic effect from the medication caused a severe birth defect,” said Dr. Murase.
Dermatologists use other teratogenic medications such as thalidomide, mycophenolate mofetil, and methotrexate for chronic dermatologic disease like psoriasis and atopic dermatitis.
The situation is especially tricky for dermatologists since most patients – about 80% – never discuss their pregnancy with their specialist prior to pregnancy initiation. Dr. Murase recalls when a patient with chronic plaque psoriasis on methotrexate in her late 40s became pregnant and had an abortion even before Dr. Murase became aware of the pregnancy.
Because dermatologists routinely prescribe long-term medications for chronic diseases like acne, psoriasis, and atopic dermatitis, it is important to have a conversation regarding the risks and benefits of long-term medication should a pregnancy occur in any woman of childbearing age, she said.
Fewer women in clinical trials?
Abortion restrictions could possibly discourage women of reproductive age to participate in a clinical trial for a new medication, said Dr. Chambers.
A female patient with a chronic disease who’s randomized to receive a new medication may be required to use certain types of birth control because of unknown potential adverse effects the drug may have on the fetus. But in some cases, accidental pregnancies happen.
The participant in the trial may say, “I don’t know enough about the safety of this drug in pregnancy, and I’ve already taken it. I want to terminate the pregnancy,” said Dr. Chambers. Thinking ahead, a woman may decide not to do the trial to avoid the risk of getting pregnant and not having the option to terminate the pregnancy.
This could apply to new drugs such as antiviral treatments, or medications for severe chronic disease that typically have no clinical trial data in pregnancy prior to initial release into the market.
Women may start taking the drug without thinking about getting pregnant, then realize there are no safety data and become concerned about its effects on a future pregnancy.
The question is: Will abortion restrictions have a chilling effect on these new drugs as well? Patients and their doctors may decide not to try it until more data are available. “I can see where abortion restrictions would change the risk or benefit calculation in thinking about what you do or don’t prescribe or take during reproductive age,” said Dr. Chambers.
The upside of restrictions?
If there’s a positive side to these developments with abortion bans, it may encourage women taking new medications or joining clinical trials to think even more carefully about adherence to effective contraception, said Dr. Chambers.
Some methods are more effective than others, she emphasized. “When you have an unplanned pregnancy, it could mean that the method you used wasn’t optimal or you weren’t using it as recommended.” A goal moving forward is to encourage more thoughtful use of highly effective contraceptives, thus reducing the number of unplanned pregnancies, she added.
If patients are taking methotrexate, “the time to think about pregnancy is before getting pregnant so you can switch to a drug that’s compatible with pregnancy,” she said.
This whole thought process regarding pregnancy planning could work toward useful health goals, said Dr. Chambers. “Nobody thinks termination is the preferred method, but planning ahead should involve a discussion of what works best for the patient.”
Patients do have other choices, said Dr. Grifka. “Fortunately, there are many commonly prescribed medications which cross the placenta and have no ill effects on the fetus.”
Talking to patients about choices
Dr. Clowse, who spends a lot of time training rheumatologists, encourages them to have conversations with patients about pregnancy planning. It’s a lot to manage, getting the right drug to a female patient with chronic illness, especially in this current climate of abortion upheaval, she noted.
Her approach is to have an open and honest conversation with patients about their concerns and fears, what the realities are, and what the potential future options are for certain rheumatology drugs in the United States.
Some women who see what’s happening across the country may become so risk averse that they may choose to die rather than take a lifesaving drug that poses certain risks under new restrictions.
“I think that’s tragic,” said Dr. Clowse.
To help their patients, Dr. Gray believes physicians across specialties should better educate themselves about physiology in pregnancy and how to counsel patients on the impact of not taking medications in pregnancy.
In her view, it’s almost coercive to say to a patient, “You really need to have effective contraception if I’m going to give you this lifesaving or quality-of-life-improving medication.”
When confronting such scenarios, Dr. Gray doesn’t think physicians need to change how they counsel patients about contraception. “I don’t think we should be putting pressure on patients to consider other permanent methods just because there’s a lack of abortion options.”
Patients will eventually make those decisions for themselves, she said. “They’re going to want a more efficacious method because they’re worried about not having access to abortion if they get pregnant.”
Dr. Gray reports being a site principal investigator for a phase 3 trial for VeraCept IUD, funded by Sebela Pharmaceuticals. Dr. Clowse reports receiving research funding and doing consulting for GlaxoSmithKline.
*Correction, 6/2/2022: A previous version of this article misstated the intended use of drugs such as the “morning-after” pill (levonorgestrel). They are taken to prevent unintended pregnancy.
A version of this article first appeared on Medscape.com .
Obstetrician Beverly Gray, MD, is already seeing the effects of the Roe v. Wade abortion debate in her North Carolina practice.
The state allows abortion but requires that women get counseling with a qualified health professional 72 hours before the procedure. “Aside from that, we still have patients asking for more efficacious contraceptive methods just in case,” said Dr. Gray, residency director and division director for women’s community and population health and associate professor for obstetrics and gynecology at Duke University, Durham, N.C.
Patients and staff in her clinic have also been approaching her about tubal ligation. “They’re asking about additional birth control methods because they’re concerned about what’s going to happen” with the challenge to the historic Roe v. Wade decision in the Supreme Court and subsequent actions in the states to restrict or ban abortion, she said.
This has implications not just for abortion but for medications known to affect pregnancy. “What I’m really worried about is physicians will be withholding medicine because they’re concerned about teratogenic effects,” said Dr. Gray.
With more states issuing restrictions on abortion, doctors are worried that patients needing certain drugs to maintain their lupus flares, cancer, or other diseases may decide not to take them in the event they accidentally become pregnant. If the drug is known to affect the fetus, the fear is a patient who lives in a state with abortion restrictions will no longer have the option to terminate a pregnancy.
Instead, a scenario may arise in which the patient – and their physician – may opt not to treat at all with an otherwise lifesaving medication, experts told this news organization.
The U.S. landscape on abortion restrictions
A leaked draft of a U.S. Supreme Court opinion on Mississippi’s 15-week abortion ban has sent the medical community into a tailspin. The case, Dobbs v. Jackson Women’s Health Organization, challenges the 1973 Roe v. Wade decision that affirms the constitutional right to abortion. It’s anticipated the high court will decide on the case in June.
Although the upcoming decision is subject to change, the draft indicated the high court would uphold the Mississippi ban. This would essentially overturn the 1973 ruling. An earlier Supreme Court decision allowing a Texas law banning abortion at 6 weeks suggests the court may already be heading in this direction. At the state level, legislatures have been moving on divergent paths – some taking steps to preserve abortion rights, others initiating restrictions.
More than 100 abortion restrictions in 19 states took effect in 2021, according to the Guttmacher Institute, which tracks such metrics. In 2022, “two key themes are anti-abortion policymakers’ continued pursuit of various types of abortion bans and restrictions on medication abortion,” the institute reported.
Forty-six states and the District of Columbia have introduced 2,025 restrictions or proactive measures on sexual and reproductive health and rights so far this year. The latest tally from Guttmacher, updated in late May, revealed that 11 states so far have enacted 42 abortion restrictions. A total of 6 states (Arizona, Florida, Idaho, Kentucky, Oklahoma, and Wyoming) have issued nine bans on abortion.
Comparatively, 11 states have enacted 19 protective abortion measures.
Twenty-two states have introduced 117 restrictions on medication abortions, which account for 54% of U.S. abortions. This includes seven measures that would ban medication abortion outright, according to Guttmacher. Kentucky and South Dakota collectively have enacted 14 restrictions on medication abortion, as well as provisions that ban mailing of abortion pills.
Chilling effect on prescribing
Some physicians anticipate that drugs such as the “morning-after” pill (levonorgestrel) will become less available as restrictions go into effect, since these are medications designed to prevent pregnancy.*
However, the ongoing effort to put a lid on abortion measures has prompted concerns about a trickle-down effect on other medications that are otherwise life-changing or lifesaving to patients but pose a risk to the fetus.
Several drugs are well documented to affect fetal growth and development of the fetus, ranging from mild, transitory effects to severe, permanent birth defects, said Ronald G. Grifka, MD, chief medical officer of University of Michigan Health-West and clinical professor of pediatrics at the University of Michigan Medical School, Ann Arbor. “As new medications are developed, we will need heightened attention to make sure they are safe for the fetus,” he added.
Certain teratogenic medications are associated with a high risk of abortion even though this isn’t their primary use, noted Christina Chambers, PhD, MPH, co-director of the Center for Better Beginnings and associate director with the Altman Clinical & Translational Research Institute at the University of California, San Diego.
“I don’t think anyone would intentionally take these drugs to induce spontaneous abortion. But if the drugs pose a risk for it, I can see how the laws might be stretched” to include them, said Dr. Chambers.
Methotrexate, a medication for autoimmune disorders, has a high risk of spontaneous abortion. So do acne medications such as isotretinoin.
Patients are usually told they’re not supposed to get pregnant on these drugs because there’s a high risk of pregnancy loss and risk of malformations and potential learning problems in the fetus. But many pregnancies aren’t planned, said Dr. Chambers. “Patients may forget about the side effects or think their birth control will protect them. And the next time they refill the medication, they may not hear about the warnings again.”
With a restrictive abortion law or ban in effect, a woman might think: “I won’t take this drug because if there’s any potential that I might get pregnant, I won’t have the option to abort an at-risk pregnancy.” Women and their doctors, for that matter, don’t want to put themselves in this position, said Dr. Chambers.
Rheumatologist Megan Clowse, MD, who prescribes several medications that potentially cause major birth defects and pregnancy loss, worries about the ramifications of these accumulating bans.
“Methotrexate has been a leading drug for us for decades for rheumatoid arthritis. Mycophenolate is a vital drug for lupus,” said Dr. Clowse, associate professor of medicine at Duke University’s division of rheumatology and immunology.
Both methotrexate and mycophenolate pose about a 40% risk of pregnancy loss and significantly increase the risk for birth defects. “I’m definitely concerned that there might be doctors or women who elect not to use those medications in women of reproductive age because of the potential risk for pregnancy and absence of abortion rights,” said Dr. Clowse.
These situations might force women to use contraceptives they don’t want to use, such as hormonal implants or intrauterine devices, she added. Another side effect is that women and their partners may decide to abstain from sex.
The iPLEDGE factor
Some rheumatology drugs like lenalidomide (Revlimid) require a valid negative pregnancy test in a lab every month. Similarly, the iPLEDGE Risk Evaluation and Mitigation Strategy seeks to reduce the teratogenicity of isotretinoin by requiring two types of birth control and regular pregnancy tests by users.
For isotretinoin specifically, abortion restrictions “could lead to increased adherence to pregnancy prevention measures which are already stringent in iPLEDGE. But on the other hand, it could lead to reduced willingness of physicians to prescribe or patients to take the medication,” said Dr. Chambers.
With programs like iPLEDGE in effect, the rate of pregnancies and abortions that occur in dermatology are relatively low, said Jenny Murase, MD, associate clinical professor of dermatology at the University of California, San Francisco.
Nevertheless, as a physician who regularly prescribes medications like isotretinoin in women of childbearing age, “it’s terrifying to me that a woman wouldn’t have the option to terminate the pregnancy if a teratogenic effect from the medication caused a severe birth defect,” said Dr. Murase.
Dermatologists use other teratogenic medications such as thalidomide, mycophenolate mofetil, and methotrexate for chronic dermatologic disease like psoriasis and atopic dermatitis.
The situation is especially tricky for dermatologists since most patients – about 80% – never discuss their pregnancy with their specialist prior to pregnancy initiation. Dr. Murase recalls when a patient with chronic plaque psoriasis on methotrexate in her late 40s became pregnant and had an abortion even before Dr. Murase became aware of the pregnancy.
Because dermatologists routinely prescribe long-term medications for chronic diseases like acne, psoriasis, and atopic dermatitis, it is important to have a conversation regarding the risks and benefits of long-term medication should a pregnancy occur in any woman of childbearing age, she said.
Fewer women in clinical trials?
Abortion restrictions could possibly discourage women of reproductive age to participate in a clinical trial for a new medication, said Dr. Chambers.
A female patient with a chronic disease who’s randomized to receive a new medication may be required to use certain types of birth control because of unknown potential adverse effects the drug may have on the fetus. But in some cases, accidental pregnancies happen.
The participant in the trial may say, “I don’t know enough about the safety of this drug in pregnancy, and I’ve already taken it. I want to terminate the pregnancy,” said Dr. Chambers. Thinking ahead, a woman may decide not to do the trial to avoid the risk of getting pregnant and not having the option to terminate the pregnancy.
This could apply to new drugs such as antiviral treatments, or medications for severe chronic disease that typically have no clinical trial data in pregnancy prior to initial release into the market.
Women may start taking the drug without thinking about getting pregnant, then realize there are no safety data and become concerned about its effects on a future pregnancy.
The question is: Will abortion restrictions have a chilling effect on these new drugs as well? Patients and their doctors may decide not to try it until more data are available. “I can see where abortion restrictions would change the risk or benefit calculation in thinking about what you do or don’t prescribe or take during reproductive age,” said Dr. Chambers.
The upside of restrictions?
If there’s a positive side to these developments with abortion bans, it may encourage women taking new medications or joining clinical trials to think even more carefully about adherence to effective contraception, said Dr. Chambers.
Some methods are more effective than others, she emphasized. “When you have an unplanned pregnancy, it could mean that the method you used wasn’t optimal or you weren’t using it as recommended.” A goal moving forward is to encourage more thoughtful use of highly effective contraceptives, thus reducing the number of unplanned pregnancies, she added.
If patients are taking methotrexate, “the time to think about pregnancy is before getting pregnant so you can switch to a drug that’s compatible with pregnancy,” she said.
This whole thought process regarding pregnancy planning could work toward useful health goals, said Dr. Chambers. “Nobody thinks termination is the preferred method, but planning ahead should involve a discussion of what works best for the patient.”
Patients do have other choices, said Dr. Grifka. “Fortunately, there are many commonly prescribed medications which cross the placenta and have no ill effects on the fetus.”
Talking to patients about choices
Dr. Clowse, who spends a lot of time training rheumatologists, encourages them to have conversations with patients about pregnancy planning. It’s a lot to manage, getting the right drug to a female patient with chronic illness, especially in this current climate of abortion upheaval, she noted.
Her approach is to have an open and honest conversation with patients about their concerns and fears, what the realities are, and what the potential future options are for certain rheumatology drugs in the United States.
Some women who see what’s happening across the country may become so risk averse that they may choose to die rather than take a lifesaving drug that poses certain risks under new restrictions.
“I think that’s tragic,” said Dr. Clowse.
To help their patients, Dr. Gray believes physicians across specialties should better educate themselves about physiology in pregnancy and how to counsel patients on the impact of not taking medications in pregnancy.
In her view, it’s almost coercive to say to a patient, “You really need to have effective contraception if I’m going to give you this lifesaving or quality-of-life-improving medication.”
When confronting such scenarios, Dr. Gray doesn’t think physicians need to change how they counsel patients about contraception. “I don’t think we should be putting pressure on patients to consider other permanent methods just because there’s a lack of abortion options.”
Patients will eventually make those decisions for themselves, she said. “They’re going to want a more efficacious method because they’re worried about not having access to abortion if they get pregnant.”
Dr. Gray reports being a site principal investigator for a phase 3 trial for VeraCept IUD, funded by Sebela Pharmaceuticals. Dr. Clowse reports receiving research funding and doing consulting for GlaxoSmithKline.
*Correction, 6/2/2022: A previous version of this article misstated the intended use of drugs such as the “morning-after” pill (levonorgestrel). They are taken to prevent unintended pregnancy.
A version of this article first appeared on Medscape.com .
Obstetrician Beverly Gray, MD, is already seeing the effects of the Roe v. Wade abortion debate in her North Carolina practice.
The state allows abortion but requires that women get counseling with a qualified health professional 72 hours before the procedure. “Aside from that, we still have patients asking for more efficacious contraceptive methods just in case,” said Dr. Gray, residency director and division director for women’s community and population health and associate professor for obstetrics and gynecology at Duke University, Durham, N.C.
Patients and staff in her clinic have also been approaching her about tubal ligation. “They’re asking about additional birth control methods because they’re concerned about what’s going to happen” with the challenge to the historic Roe v. Wade decision in the Supreme Court and subsequent actions in the states to restrict or ban abortion, she said.
This has implications not just for abortion but for medications known to affect pregnancy. “What I’m really worried about is physicians will be withholding medicine because they’re concerned about teratogenic effects,” said Dr. Gray.
With more states issuing restrictions on abortion, doctors are worried that patients needing certain drugs to maintain their lupus flares, cancer, or other diseases may decide not to take them in the event they accidentally become pregnant. If the drug is known to affect the fetus, the fear is a patient who lives in a state with abortion restrictions will no longer have the option to terminate a pregnancy.
Instead, a scenario may arise in which the patient – and their physician – may opt not to treat at all with an otherwise lifesaving medication, experts told this news organization.
The U.S. landscape on abortion restrictions
A leaked draft of a U.S. Supreme Court opinion on Mississippi’s 15-week abortion ban has sent the medical community into a tailspin. The case, Dobbs v. Jackson Women’s Health Organization, challenges the 1973 Roe v. Wade decision that affirms the constitutional right to abortion. It’s anticipated the high court will decide on the case in June.
Although the upcoming decision is subject to change, the draft indicated the high court would uphold the Mississippi ban. This would essentially overturn the 1973 ruling. An earlier Supreme Court decision allowing a Texas law banning abortion at 6 weeks suggests the court may already be heading in this direction. At the state level, legislatures have been moving on divergent paths – some taking steps to preserve abortion rights, others initiating restrictions.
More than 100 abortion restrictions in 19 states took effect in 2021, according to the Guttmacher Institute, which tracks such metrics. In 2022, “two key themes are anti-abortion policymakers’ continued pursuit of various types of abortion bans and restrictions on medication abortion,” the institute reported.
Forty-six states and the District of Columbia have introduced 2,025 restrictions or proactive measures on sexual and reproductive health and rights so far this year. The latest tally from Guttmacher, updated in late May, revealed that 11 states so far have enacted 42 abortion restrictions. A total of 6 states (Arizona, Florida, Idaho, Kentucky, Oklahoma, and Wyoming) have issued nine bans on abortion.
Comparatively, 11 states have enacted 19 protective abortion measures.
Twenty-two states have introduced 117 restrictions on medication abortions, which account for 54% of U.S. abortions. This includes seven measures that would ban medication abortion outright, according to Guttmacher. Kentucky and South Dakota collectively have enacted 14 restrictions on medication abortion, as well as provisions that ban mailing of abortion pills.
Chilling effect on prescribing
Some physicians anticipate that drugs such as the “morning-after” pill (levonorgestrel) will become less available as restrictions go into effect, since these are medications designed to prevent pregnancy.*
However, the ongoing effort to put a lid on abortion measures has prompted concerns about a trickle-down effect on other medications that are otherwise life-changing or lifesaving to patients but pose a risk to the fetus.
Several drugs are well documented to affect fetal growth and development of the fetus, ranging from mild, transitory effects to severe, permanent birth defects, said Ronald G. Grifka, MD, chief medical officer of University of Michigan Health-West and clinical professor of pediatrics at the University of Michigan Medical School, Ann Arbor. “As new medications are developed, we will need heightened attention to make sure they are safe for the fetus,” he added.
Certain teratogenic medications are associated with a high risk of abortion even though this isn’t their primary use, noted Christina Chambers, PhD, MPH, co-director of the Center for Better Beginnings and associate director with the Altman Clinical & Translational Research Institute at the University of California, San Diego.
“I don’t think anyone would intentionally take these drugs to induce spontaneous abortion. But if the drugs pose a risk for it, I can see how the laws might be stretched” to include them, said Dr. Chambers.
Methotrexate, a medication for autoimmune disorders, has a high risk of spontaneous abortion. So do acne medications such as isotretinoin.
Patients are usually told they’re not supposed to get pregnant on these drugs because there’s a high risk of pregnancy loss and risk of malformations and potential learning problems in the fetus. But many pregnancies aren’t planned, said Dr. Chambers. “Patients may forget about the side effects or think their birth control will protect them. And the next time they refill the medication, they may not hear about the warnings again.”
With a restrictive abortion law or ban in effect, a woman might think: “I won’t take this drug because if there’s any potential that I might get pregnant, I won’t have the option to abort an at-risk pregnancy.” Women and their doctors, for that matter, don’t want to put themselves in this position, said Dr. Chambers.
Rheumatologist Megan Clowse, MD, who prescribes several medications that potentially cause major birth defects and pregnancy loss, worries about the ramifications of these accumulating bans.
“Methotrexate has been a leading drug for us for decades for rheumatoid arthritis. Mycophenolate is a vital drug for lupus,” said Dr. Clowse, associate professor of medicine at Duke University’s division of rheumatology and immunology.
Both methotrexate and mycophenolate pose about a 40% risk of pregnancy loss and significantly increase the risk for birth defects. “I’m definitely concerned that there might be doctors or women who elect not to use those medications in women of reproductive age because of the potential risk for pregnancy and absence of abortion rights,” said Dr. Clowse.
These situations might force women to use contraceptives they don’t want to use, such as hormonal implants or intrauterine devices, she added. Another side effect is that women and their partners may decide to abstain from sex.
The iPLEDGE factor
Some rheumatology drugs like lenalidomide (Revlimid) require a valid negative pregnancy test in a lab every month. Similarly, the iPLEDGE Risk Evaluation and Mitigation Strategy seeks to reduce the teratogenicity of isotretinoin by requiring two types of birth control and regular pregnancy tests by users.
For isotretinoin specifically, abortion restrictions “could lead to increased adherence to pregnancy prevention measures which are already stringent in iPLEDGE. But on the other hand, it could lead to reduced willingness of physicians to prescribe or patients to take the medication,” said Dr. Chambers.
With programs like iPLEDGE in effect, the rate of pregnancies and abortions that occur in dermatology are relatively low, said Jenny Murase, MD, associate clinical professor of dermatology at the University of California, San Francisco.
Nevertheless, as a physician who regularly prescribes medications like isotretinoin in women of childbearing age, “it’s terrifying to me that a woman wouldn’t have the option to terminate the pregnancy if a teratogenic effect from the medication caused a severe birth defect,” said Dr. Murase.
Dermatologists use other teratogenic medications such as thalidomide, mycophenolate mofetil, and methotrexate for chronic dermatologic disease like psoriasis and atopic dermatitis.
The situation is especially tricky for dermatologists since most patients – about 80% – never discuss their pregnancy with their specialist prior to pregnancy initiation. Dr. Murase recalls when a patient with chronic plaque psoriasis on methotrexate in her late 40s became pregnant and had an abortion even before Dr. Murase became aware of the pregnancy.
Because dermatologists routinely prescribe long-term medications for chronic diseases like acne, psoriasis, and atopic dermatitis, it is important to have a conversation regarding the risks and benefits of long-term medication should a pregnancy occur in any woman of childbearing age, she said.
Fewer women in clinical trials?
Abortion restrictions could possibly discourage women of reproductive age to participate in a clinical trial for a new medication, said Dr. Chambers.
A female patient with a chronic disease who’s randomized to receive a new medication may be required to use certain types of birth control because of unknown potential adverse effects the drug may have on the fetus. But in some cases, accidental pregnancies happen.
The participant in the trial may say, “I don’t know enough about the safety of this drug in pregnancy, and I’ve already taken it. I want to terminate the pregnancy,” said Dr. Chambers. Thinking ahead, a woman may decide not to do the trial to avoid the risk of getting pregnant and not having the option to terminate the pregnancy.
This could apply to new drugs such as antiviral treatments, or medications for severe chronic disease that typically have no clinical trial data in pregnancy prior to initial release into the market.
Women may start taking the drug without thinking about getting pregnant, then realize there are no safety data and become concerned about its effects on a future pregnancy.
The question is: Will abortion restrictions have a chilling effect on these new drugs as well? Patients and their doctors may decide not to try it until more data are available. “I can see where abortion restrictions would change the risk or benefit calculation in thinking about what you do or don’t prescribe or take during reproductive age,” said Dr. Chambers.
The upside of restrictions?
If there’s a positive side to these developments with abortion bans, it may encourage women taking new medications or joining clinical trials to think even more carefully about adherence to effective contraception, said Dr. Chambers.
Some methods are more effective than others, she emphasized. “When you have an unplanned pregnancy, it could mean that the method you used wasn’t optimal or you weren’t using it as recommended.” A goal moving forward is to encourage more thoughtful use of highly effective contraceptives, thus reducing the number of unplanned pregnancies, she added.
If patients are taking methotrexate, “the time to think about pregnancy is before getting pregnant so you can switch to a drug that’s compatible with pregnancy,” she said.
This whole thought process regarding pregnancy planning could work toward useful health goals, said Dr. Chambers. “Nobody thinks termination is the preferred method, but planning ahead should involve a discussion of what works best for the patient.”
Patients do have other choices, said Dr. Grifka. “Fortunately, there are many commonly prescribed medications which cross the placenta and have no ill effects on the fetus.”
Talking to patients about choices
Dr. Clowse, who spends a lot of time training rheumatologists, encourages them to have conversations with patients about pregnancy planning. It’s a lot to manage, getting the right drug to a female patient with chronic illness, especially in this current climate of abortion upheaval, she noted.
Her approach is to have an open and honest conversation with patients about their concerns and fears, what the realities are, and what the potential future options are for certain rheumatology drugs in the United States.
Some women who see what’s happening across the country may become so risk averse that they may choose to die rather than take a lifesaving drug that poses certain risks under new restrictions.
“I think that’s tragic,” said Dr. Clowse.
To help their patients, Dr. Gray believes physicians across specialties should better educate themselves about physiology in pregnancy and how to counsel patients on the impact of not taking medications in pregnancy.
In her view, it’s almost coercive to say to a patient, “You really need to have effective contraception if I’m going to give you this lifesaving or quality-of-life-improving medication.”
When confronting such scenarios, Dr. Gray doesn’t think physicians need to change how they counsel patients about contraception. “I don’t think we should be putting pressure on patients to consider other permanent methods just because there’s a lack of abortion options.”
Patients will eventually make those decisions for themselves, she said. “They’re going to want a more efficacious method because they’re worried about not having access to abortion if they get pregnant.”
Dr. Gray reports being a site principal investigator for a phase 3 trial for VeraCept IUD, funded by Sebela Pharmaceuticals. Dr. Clowse reports receiving research funding and doing consulting for GlaxoSmithKline.
*Correction, 6/2/2022: A previous version of this article misstated the intended use of drugs such as the “morning-after” pill (levonorgestrel). They are taken to prevent unintended pregnancy.
A version of this article first appeared on Medscape.com .
‘Shielding’ status provides best indicator of COVID-19 mortality in U.K. arthritis population
Being identified as someone that was advised to stay at home and shield, or keep away from face-to-face interactions with others, during the COVID-19 pandemic was indicative of an increased risk for dying from COVID-19 within 28 days of infection, a U.K. study of inflammatory arthritis patients versus the general population suggests.
In fact, shielding status was the highest ranked of all the risk factors identified for early mortality from COVID-19, with a hazard ratio of 1.52 (95% confidence interval, 1.40-1.64) comparing people with and without inflammatory arthritis (IA) who had tested positive.
The list of risk factors associated with higher mortality in the IA patients versus the general population also included diabetes (HR, 1.38), smoking (HR, 1.27), hypertension (HR, 1.19), glucocorticoid use (HR, 1.17), and cancer (HR, 1.10), as well as increasing age (HR, 1.08) and body mass index (HR, 1.01).
Also important was the person’s prior hospitalization history, with those needing in-hospital care in the year running up to their admission for COVID-19 associated with a 34% higher risk for death, and being hospitalized previously with a serious infection was associated with a 20% higher risk.
This has more to do people’s overall vulnerability than their IA, suggested the team behind the findings, who also found that the risk of catching COVID-19 was significantly lower among patients with IA than the general population (3.5% vs. 6%), presumably because of shielding.
Examining the risks for COVID-19 in real-life practice
“COVID-19 has caused over 10 million deaths,” Roxanne Cooksey, PhD, said at the annual meeting of the British Society for Rheumatology. “It’s greatly affected vulnerable individuals, which includes individuals with IA, this is due to their compromised immune system and increased risk of infection and the medications that they take to manage their conditions.
“Previous studies have had mixed results about whether people with IA have an increased risk of poor outcome,” added Dr. Cooksey, who is a postdoctoral researcher in the division of infection and immunity at Cardiff (Wales) University.
“So, our research question looks to investigate inflammatory arthritis – that’s rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis – to see whether the conditions themselves or indeed their medications predispose individuals to an increased risk of contracting COVID or even more adverse outcomes.”
Dr. Cooksey and colleagues looked specifically at COVID-19 infection rates and outcomes in adults living in Wales during the first year of the pandemic (March 2020 to May 2021). As such they used routinely collected, anonymized health data from the SAIL Databank and performed a retrospective, population-based cohort study. In total, there were 1,966 people with inflammatory arthritis identified as having COVID-19 and 166,602 people without IA but who had COVID-19 in the study population.
As might be expected, people with inflammatory arthritis who tested positive for COVID-19 were older than those testing positive in the general population, at a mean of 62 years versus 46 years. They were also more likely to have been advised to shield (49.4% versus 4.6%), which in the United Kingdom constituted of receiving a letter telling them about the importance of social distancing, wearing a mask when out in public, and quarantining themselves at home whenever possible.
The main outcomes were hospitalizations and mortality within 28 days of COVID-19 infection. Considering the overall inflammatory arthritis population, rates of both outcomes were higher versus the general population. And when the researchers analyzed the risks according to the type of inflammatory arthritis, the associations were not statistically significant in a multivariable analysis for people with any of the inflammatory arthritis diagnoses: rheumatoid arthritis (n = 1,283), psoriatic arthritis (n = 514), or ankylosing spondylitis (n = 246). Some patients had more than one inflammatory arthritis diagnosis.
What does this all mean?
Dr. Cooksey conceded that there were lots of limitations to the data collected – from misclassification bias to data possibly not have been recorded completely or missing because of the disruption to health care services during the early stages of the pandemic. Patients may have been told to shield but not actually shielded, she observed, and maybe because a lack of testing COVID-19 cases were missed or people could have been asymptomatic or unable to be tested.
“The study supports the role of shielding in inflammatory arthritis,” Dr. Cooksey said, particularly in those with RA and the risk factors associated with an increased risk in death. However, that may not mean the entire population, she suggested, saying that “refining the criteria for shielding will help mitigate the negative effects of the entire IA population.”
Senior team member Ernest Choy, MD, added his thoughts, saying that, rather than giving generic shielding recommendations to all IA patients, not everyone has the same risk, so maybe not everyone needs to shield to the same level.
“Psoriatic arthritis patients and ankylosing spondylitis patients are younger, so they really don’t have as high a risk like patients with rheumatoid arthritis,” he said.
Dr. Choy, who is professor of rheumatology at the Cardiff Institute of Infection & Immunity, commented that it was not surprising to find that a prior serious infection was a risk for COVID-19 mortality. This risk factor was examined because of the known association between biologic use and the risk for serious infection.
Moreover, he said that, “if you have a serious comorbidity that requires you to get admitted to hospital, that is a reflection of your vulnerability.”
Dr. Cooksey and Dr. Choy had no relevant conflicts of interest to disclose.
Being identified as someone that was advised to stay at home and shield, or keep away from face-to-face interactions with others, during the COVID-19 pandemic was indicative of an increased risk for dying from COVID-19 within 28 days of infection, a U.K. study of inflammatory arthritis patients versus the general population suggests.
In fact, shielding status was the highest ranked of all the risk factors identified for early mortality from COVID-19, with a hazard ratio of 1.52 (95% confidence interval, 1.40-1.64) comparing people with and without inflammatory arthritis (IA) who had tested positive.
The list of risk factors associated with higher mortality in the IA patients versus the general population also included diabetes (HR, 1.38), smoking (HR, 1.27), hypertension (HR, 1.19), glucocorticoid use (HR, 1.17), and cancer (HR, 1.10), as well as increasing age (HR, 1.08) and body mass index (HR, 1.01).
Also important was the person’s prior hospitalization history, with those needing in-hospital care in the year running up to their admission for COVID-19 associated with a 34% higher risk for death, and being hospitalized previously with a serious infection was associated with a 20% higher risk.
This has more to do people’s overall vulnerability than their IA, suggested the team behind the findings, who also found that the risk of catching COVID-19 was significantly lower among patients with IA than the general population (3.5% vs. 6%), presumably because of shielding.
Examining the risks for COVID-19 in real-life practice
“COVID-19 has caused over 10 million deaths,” Roxanne Cooksey, PhD, said at the annual meeting of the British Society for Rheumatology. “It’s greatly affected vulnerable individuals, which includes individuals with IA, this is due to their compromised immune system and increased risk of infection and the medications that they take to manage their conditions.
“Previous studies have had mixed results about whether people with IA have an increased risk of poor outcome,” added Dr. Cooksey, who is a postdoctoral researcher in the division of infection and immunity at Cardiff (Wales) University.
“So, our research question looks to investigate inflammatory arthritis – that’s rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis – to see whether the conditions themselves or indeed their medications predispose individuals to an increased risk of contracting COVID or even more adverse outcomes.”
Dr. Cooksey and colleagues looked specifically at COVID-19 infection rates and outcomes in adults living in Wales during the first year of the pandemic (March 2020 to May 2021). As such they used routinely collected, anonymized health data from the SAIL Databank and performed a retrospective, population-based cohort study. In total, there were 1,966 people with inflammatory arthritis identified as having COVID-19 and 166,602 people without IA but who had COVID-19 in the study population.
As might be expected, people with inflammatory arthritis who tested positive for COVID-19 were older than those testing positive in the general population, at a mean of 62 years versus 46 years. They were also more likely to have been advised to shield (49.4% versus 4.6%), which in the United Kingdom constituted of receiving a letter telling them about the importance of social distancing, wearing a mask when out in public, and quarantining themselves at home whenever possible.
The main outcomes were hospitalizations and mortality within 28 days of COVID-19 infection. Considering the overall inflammatory arthritis population, rates of both outcomes were higher versus the general population. And when the researchers analyzed the risks according to the type of inflammatory arthritis, the associations were not statistically significant in a multivariable analysis for people with any of the inflammatory arthritis diagnoses: rheumatoid arthritis (n = 1,283), psoriatic arthritis (n = 514), or ankylosing spondylitis (n = 246). Some patients had more than one inflammatory arthritis diagnosis.
What does this all mean?
Dr. Cooksey conceded that there were lots of limitations to the data collected – from misclassification bias to data possibly not have been recorded completely or missing because of the disruption to health care services during the early stages of the pandemic. Patients may have been told to shield but not actually shielded, she observed, and maybe because a lack of testing COVID-19 cases were missed or people could have been asymptomatic or unable to be tested.
“The study supports the role of shielding in inflammatory arthritis,” Dr. Cooksey said, particularly in those with RA and the risk factors associated with an increased risk in death. However, that may not mean the entire population, she suggested, saying that “refining the criteria for shielding will help mitigate the negative effects of the entire IA population.”
Senior team member Ernest Choy, MD, added his thoughts, saying that, rather than giving generic shielding recommendations to all IA patients, not everyone has the same risk, so maybe not everyone needs to shield to the same level.
“Psoriatic arthritis patients and ankylosing spondylitis patients are younger, so they really don’t have as high a risk like patients with rheumatoid arthritis,” he said.
Dr. Choy, who is professor of rheumatology at the Cardiff Institute of Infection & Immunity, commented that it was not surprising to find that a prior serious infection was a risk for COVID-19 mortality. This risk factor was examined because of the known association between biologic use and the risk for serious infection.
Moreover, he said that, “if you have a serious comorbidity that requires you to get admitted to hospital, that is a reflection of your vulnerability.”
Dr. Cooksey and Dr. Choy had no relevant conflicts of interest to disclose.
Being identified as someone that was advised to stay at home and shield, or keep away from face-to-face interactions with others, during the COVID-19 pandemic was indicative of an increased risk for dying from COVID-19 within 28 days of infection, a U.K. study of inflammatory arthritis patients versus the general population suggests.
In fact, shielding status was the highest ranked of all the risk factors identified for early mortality from COVID-19, with a hazard ratio of 1.52 (95% confidence interval, 1.40-1.64) comparing people with and without inflammatory arthritis (IA) who had tested positive.
The list of risk factors associated with higher mortality in the IA patients versus the general population also included diabetes (HR, 1.38), smoking (HR, 1.27), hypertension (HR, 1.19), glucocorticoid use (HR, 1.17), and cancer (HR, 1.10), as well as increasing age (HR, 1.08) and body mass index (HR, 1.01).
Also important was the person’s prior hospitalization history, with those needing in-hospital care in the year running up to their admission for COVID-19 associated with a 34% higher risk for death, and being hospitalized previously with a serious infection was associated with a 20% higher risk.
This has more to do people’s overall vulnerability than their IA, suggested the team behind the findings, who also found that the risk of catching COVID-19 was significantly lower among patients with IA than the general population (3.5% vs. 6%), presumably because of shielding.
Examining the risks for COVID-19 in real-life practice
“COVID-19 has caused over 10 million deaths,” Roxanne Cooksey, PhD, said at the annual meeting of the British Society for Rheumatology. “It’s greatly affected vulnerable individuals, which includes individuals with IA, this is due to their compromised immune system and increased risk of infection and the medications that they take to manage their conditions.
“Previous studies have had mixed results about whether people with IA have an increased risk of poor outcome,” added Dr. Cooksey, who is a postdoctoral researcher in the division of infection and immunity at Cardiff (Wales) University.
“So, our research question looks to investigate inflammatory arthritis – that’s rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis – to see whether the conditions themselves or indeed their medications predispose individuals to an increased risk of contracting COVID or even more adverse outcomes.”
Dr. Cooksey and colleagues looked specifically at COVID-19 infection rates and outcomes in adults living in Wales during the first year of the pandemic (March 2020 to May 2021). As such they used routinely collected, anonymized health data from the SAIL Databank and performed a retrospective, population-based cohort study. In total, there were 1,966 people with inflammatory arthritis identified as having COVID-19 and 166,602 people without IA but who had COVID-19 in the study population.
As might be expected, people with inflammatory arthritis who tested positive for COVID-19 were older than those testing positive in the general population, at a mean of 62 years versus 46 years. They were also more likely to have been advised to shield (49.4% versus 4.6%), which in the United Kingdom constituted of receiving a letter telling them about the importance of social distancing, wearing a mask when out in public, and quarantining themselves at home whenever possible.
The main outcomes were hospitalizations and mortality within 28 days of COVID-19 infection. Considering the overall inflammatory arthritis population, rates of both outcomes were higher versus the general population. And when the researchers analyzed the risks according to the type of inflammatory arthritis, the associations were not statistically significant in a multivariable analysis for people with any of the inflammatory arthritis diagnoses: rheumatoid arthritis (n = 1,283), psoriatic arthritis (n = 514), or ankylosing spondylitis (n = 246). Some patients had more than one inflammatory arthritis diagnosis.
What does this all mean?
Dr. Cooksey conceded that there were lots of limitations to the data collected – from misclassification bias to data possibly not have been recorded completely or missing because of the disruption to health care services during the early stages of the pandemic. Patients may have been told to shield but not actually shielded, she observed, and maybe because a lack of testing COVID-19 cases were missed or people could have been asymptomatic or unable to be tested.
“The study supports the role of shielding in inflammatory arthritis,” Dr. Cooksey said, particularly in those with RA and the risk factors associated with an increased risk in death. However, that may not mean the entire population, she suggested, saying that “refining the criteria for shielding will help mitigate the negative effects of the entire IA population.”
Senior team member Ernest Choy, MD, added his thoughts, saying that, rather than giving generic shielding recommendations to all IA patients, not everyone has the same risk, so maybe not everyone needs to shield to the same level.
“Psoriatic arthritis patients and ankylosing spondylitis patients are younger, so they really don’t have as high a risk like patients with rheumatoid arthritis,” he said.
Dr. Choy, who is professor of rheumatology at the Cardiff Institute of Infection & Immunity, commented that it was not surprising to find that a prior serious infection was a risk for COVID-19 mortality. This risk factor was examined because of the known association between biologic use and the risk for serious infection.
Moreover, he said that, “if you have a serious comorbidity that requires you to get admitted to hospital, that is a reflection of your vulnerability.”
Dr. Cooksey and Dr. Choy had no relevant conflicts of interest to disclose.
FROM BSR 2022
Upadacitinib earns FDA approval for ankylosing spondylitis
The Food and Drug Administration has approved upadacitinib (Rinvoq) as an oral treatment for active ankylosing spondylitis in adults, its manufacturer AbbVie announced April 29.
Upadacitinib, a selective and reversible Janus kinase inhibitor, is the second drug in its class to be FDA approved for ankylosing spondylitis, after tofacitinib (Xeljanz) in December.
Upadacitinib is now indicated for patients with active ankylosing spondylitis (AS) who have had an insufficient response or intolerance with one or more tumor necrosis factor (TNF) blockers. Upadacitinib is already approved by the FDA for adults with active psoriatic arthritis, moderately to severely active rheumatoid arthritis, and moderately to severely active ulcerative colitis who have had an insufficient response or intolerance with one or more TNF inhibitors. It also has been approved for adults and pediatric patients 12 years of age and older with refractory, moderate to severe atopic dermatitis.
The European Medicines Agency gave marketing approval for upadacitinib in adults with active AS in January 2021.
Two main clinical studies form the basis for the FDA’s approval decision. The phase 3 SELECT-AXIS 2 clinical trial involved patients with an inadequate response or intolerance to one or two biologic disease-modifying antirheumatic drugs (bDMARDs). A total of 44.5% patients with AS who were randomly assigned to upadacitinib 15 mg once daily met the primary endpoint of at least 40% improvement in Assessment in Spondyloarthritis International Society response criteria (ASAS 40) at 14 weeks, compared against 18.2% with placebo.
The second study, the phase 2/3 SELECT-AXIS 1 clinical trial, tested upadacitinib in patients who had never taken bDMARDs and had an inadequate response or intolerance to at least two NSAIDs. In this study, significantly more patients randomly assigned to 15 mg upadacitinib achieved ASAS 40 at 14 weeks, compared with placebo (51% vs. 26%).
Patients randomly assigned to upadacitinib also showed significant improvements in signs and symptoms of AS, as well as improvements in physical function and disease activity, compared with placebo, after 14 weeks. The safety profile for patients with AS treated with upadacitinib was similar to that seen in studies of patients with rheumatoid arthritis or psoriatic arthritis. Potential severe side effects include increased risk for death in patients aged 50 years and older with at least one cardiovascular risk factor; increased risk of serious infections, such as tuberculosis; and increased risk of certain cancers, according to the company statement.
Read the complete prescribing information here.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved upadacitinib (Rinvoq) as an oral treatment for active ankylosing spondylitis in adults, its manufacturer AbbVie announced April 29.
Upadacitinib, a selective and reversible Janus kinase inhibitor, is the second drug in its class to be FDA approved for ankylosing spondylitis, after tofacitinib (Xeljanz) in December.
Upadacitinib is now indicated for patients with active ankylosing spondylitis (AS) who have had an insufficient response or intolerance with one or more tumor necrosis factor (TNF) blockers. Upadacitinib is already approved by the FDA for adults with active psoriatic arthritis, moderately to severely active rheumatoid arthritis, and moderately to severely active ulcerative colitis who have had an insufficient response or intolerance with one or more TNF inhibitors. It also has been approved for adults and pediatric patients 12 years of age and older with refractory, moderate to severe atopic dermatitis.
The European Medicines Agency gave marketing approval for upadacitinib in adults with active AS in January 2021.
Two main clinical studies form the basis for the FDA’s approval decision. The phase 3 SELECT-AXIS 2 clinical trial involved patients with an inadequate response or intolerance to one or two biologic disease-modifying antirheumatic drugs (bDMARDs). A total of 44.5% patients with AS who were randomly assigned to upadacitinib 15 mg once daily met the primary endpoint of at least 40% improvement in Assessment in Spondyloarthritis International Society response criteria (ASAS 40) at 14 weeks, compared against 18.2% with placebo.
The second study, the phase 2/3 SELECT-AXIS 1 clinical trial, tested upadacitinib in patients who had never taken bDMARDs and had an inadequate response or intolerance to at least two NSAIDs. In this study, significantly more patients randomly assigned to 15 mg upadacitinib achieved ASAS 40 at 14 weeks, compared with placebo (51% vs. 26%).
Patients randomly assigned to upadacitinib also showed significant improvements in signs and symptoms of AS, as well as improvements in physical function and disease activity, compared with placebo, after 14 weeks. The safety profile for patients with AS treated with upadacitinib was similar to that seen in studies of patients with rheumatoid arthritis or psoriatic arthritis. Potential severe side effects include increased risk for death in patients aged 50 years and older with at least one cardiovascular risk factor; increased risk of serious infections, such as tuberculosis; and increased risk of certain cancers, according to the company statement.
Read the complete prescribing information here.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved upadacitinib (Rinvoq) as an oral treatment for active ankylosing spondylitis in adults, its manufacturer AbbVie announced April 29.
Upadacitinib, a selective and reversible Janus kinase inhibitor, is the second drug in its class to be FDA approved for ankylosing spondylitis, after tofacitinib (Xeljanz) in December.
Upadacitinib is now indicated for patients with active ankylosing spondylitis (AS) who have had an insufficient response or intolerance with one or more tumor necrosis factor (TNF) blockers. Upadacitinib is already approved by the FDA for adults with active psoriatic arthritis, moderately to severely active rheumatoid arthritis, and moderately to severely active ulcerative colitis who have had an insufficient response or intolerance with one or more TNF inhibitors. It also has been approved for adults and pediatric patients 12 years of age and older with refractory, moderate to severe atopic dermatitis.
The European Medicines Agency gave marketing approval for upadacitinib in adults with active AS in January 2021.
Two main clinical studies form the basis for the FDA’s approval decision. The phase 3 SELECT-AXIS 2 clinical trial involved patients with an inadequate response or intolerance to one or two biologic disease-modifying antirheumatic drugs (bDMARDs). A total of 44.5% patients with AS who were randomly assigned to upadacitinib 15 mg once daily met the primary endpoint of at least 40% improvement in Assessment in Spondyloarthritis International Society response criteria (ASAS 40) at 14 weeks, compared against 18.2% with placebo.
The second study, the phase 2/3 SELECT-AXIS 1 clinical trial, tested upadacitinib in patients who had never taken bDMARDs and had an inadequate response or intolerance to at least two NSAIDs. In this study, significantly more patients randomly assigned to 15 mg upadacitinib achieved ASAS 40 at 14 weeks, compared with placebo (51% vs. 26%).
Patients randomly assigned to upadacitinib also showed significant improvements in signs and symptoms of AS, as well as improvements in physical function and disease activity, compared with placebo, after 14 weeks. The safety profile for patients with AS treated with upadacitinib was similar to that seen in studies of patients with rheumatoid arthritis or psoriatic arthritis. Potential severe side effects include increased risk for death in patients aged 50 years and older with at least one cardiovascular risk factor; increased risk of serious infections, such as tuberculosis; and increased risk of certain cancers, according to the company statement.
Read the complete prescribing information here.
A version of this article first appeared on Medscape.com.
IBD risk ‘uncertain’ in biologic-treated AxSpA patients
Considerable uncertainty surrounds whether people with axial spondyloarthritis (axSpA) who are treated with biologic drugs have an increased risk for developing inflammatory bowel disease (IBD) that is higher than if they receive other treatments, according to data reported at the annual meeting of the British Society for Rheumatology.
“We noticed two patterns,” Gary Macfarlane, MD, PhD, Dsc, of the University of Aberdeen (Scotland) said in presenting findings from an analysis of the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS) and a meta-analysis of available studies.
There was a “large excess risk in observational studies associated with biologic therapies, which was not replicated in RCTs [randomized, controlled trials],” he said, “and trials under extensions suggested a small absolute increased risk associated with etanercept and with [interleukin]-17 [inhibitors], although again with considerable uncertainty.”
While these data make it difficult to draw any firm conclusions, “we should be reassured that the patient groups receiving these specific biologics in routine clinical care have not demonstrated an excess risk of IBD,” Dr. Macfarlane told delegates at the meeting.
Addressing clinical questions
IBD is a known extra-articular manifestation of axSpA, with an estimated prevalence of about 7%, according to a 2015 meta-analysis of 69 studies involving more than 30,000 patients.
The idea that people being treated with biologics may be at higher risk for developing IBD than those taking other treatments was suggested by the results of a large (n = 80,326) Danish study in which patients who were treated with an anti–tumor necrosis factor (TNF)–alpha medication were found to be more likely to develop de novo ulcerative colitis or Crohn’s disease than were patients who did not receive biologics.
Notably, the risk for IBD seemed higher with etanercept than with other anti–TNF-alpha agents, such as infliximab and adalimumab.
The aim of the analyses that Dr. Macfarlane presented was therefore to see if there was a difference in IBD risk among patients treated with biologic agents versus other agents, and if etanercept really did pose a greater cause for concern.
“The reason that we are asking this question is that a clinician called us up and asked us if we had any data on it,” Dr. Macfarlane said. “I think that’s really important to say that one of the things the registers are designed for are to answer questions that clinicians may have.”
Looking for new-onset IBD
Although no longer recruiting patients, the BSRBR-AS provides a wealth of data on the real-life management of patients with axSpA who were or were not taking a biologic. Patients were recruited into the register between 2012 and 2017, with follow-up until 2018. Data analyses are still ongoing and expected to continue for another couple of years.
The current analysis of data from the BSRBR-AS included patients who did not already have IBD at enrollment into the register, and patients who had been treated with a biologic could have been treated only with a single agent. Of just over 1,800 eligible patients, 793 had been treated with a biologic and 1,058 had been given nonbiologic treatment.
As expected, there were some differences between the two groups of patients studied, with biologic-treated patients having a younger age than non–biologic-treated patients. Those who took a biologic also had higher disease activity, inflammatory scores, and rates of psoriasis, enthesitis, and peripheral joint involvement.
Incidence rates for new-onset IBD per 1,000 person-years of treatment were calculated as 17 (95% confidence interval, 10.7-25.8) for patients taking a biologic and 5.1 (95% CI, 2.7-8.7) for those not taking a biologic, giving an incidence rate difference of 11.9 (95% CI, 4.3-19.6).
There was some observed differences in the incidence of new-onset IBD associated with specific agents. Etanercept did not have a higher rate (13.9/1,000 patient-years; 95% CI, 5.1-30.3) than did other agents. But in comparison, the incidence of new-onset IBD for adalimumab was 20.4 (95% CI, 11.7-33.1) and zero for other anti-TNF agents such as certolizumab pegol and infliximab, although the duration of exposure to these drugs was much lower.
The IRDs for etanercept versus nonbiologic treatment and versus other anti-TNFs were 8.8 (95% CI, –2.7 to 20.3) and -6.4 (95% CI, –21.3 to 8.5), but with “considerable uncertainty” because the confidence intervals were very wide.
Uncertainty not helped by meta-analysis
“Given the uncertainty associated with the results from BSRBR-AS, we decided to undertake a meta-analysis to try to accumulate other data that could help us answer this question,” Dr. Macfarlane explained.
However, this didn’t really help clarify things because combining BSRBR-AS data with the results of a couple of observational studies suggested that the odds of of IBD doubled with any biologic treatment versus no biologic treatment (odds ratio, 2.19), and a 2.5-fold higher likelihood considering etanercept versus no biologic treatment, but no difference was seen comparing etanercept to other anti-TNF agents (OR, 0.93).
When the meta-analysis was restricted to RCTs, the rate of IBD per 1,000 person-years was 3.43 for placebo, 5.64 for all biologics, 8.14 for etanercept, 2.35 for other anti-TNFs, and 7.02 for IL-17 inhibitors.
For extensions of RCTs, IBD rates per 1,000 person-years of follow-up were 2.91 for etanercept, 0.83 for other anti-TNFs, 3.61 for IL-17 inhibitors, and 2.79 for all biologics.
“There was only a small difference in IBD incidence between the biologic therapy and the placebo groups” in the RCTs and associated studies, Dr. Macfarlane said, adding that “there was a small excess incidence associated with etanercept, compared to other anti-TNF agents, and [for] IL-17 therapy, compared to nonetanercept, anti–TNF-alpha therapies.”
Of course, the different study designs and durations of exposure to the various treatments raises significant methodological issues.
“Randomized, controlled trials should provide the highest quality evidence as a result of their design and randomizing patients to treatment,” Dr. Macfarlane said. “However, their relatively short follow-up, as well as their restrictive eligibility criteria, may work against finding a difference in IBD incidence if it were to exist.”
Observational studies are very valuable in the data they can provide but are also beset with problems, such as surveillance bias and confounding by indication.
The higher risk of IBD that was observed in observational studies could be an issue with study design, or perhaps, “in routine clinical practice, rheumatologists are taking on board factors that we have not measured, that are negating any slight increased risk,” Dr. Macfarlane said.
Session chair Nicola Goodson, MBChB, PhD, of Liverpool (England) University NHS Foundation Trust, commented: “I think that could well be a very reasonable explanation, because I think as a clinician, you do tend to channel drugs away from some people and channel drugs towards others.
However, Dr. Goodson noted that there was “a glimmer” of signal coming from the RCTs.
“Methodologically, that is what you would have to take as the most robust evidence,” Dr. Macfarlane said, “but even with all the evidence available, it’s still very hard for us to quantify; that has enormous uncertainty.”
Dr. Macfarlane and Dr. Goodson had no relevant conflicts of interest to disclose. The BSRBR-AS is supported by the BSR, which receives funds to support the registry from Pfizer, AbbVie, and UCB.
Considerable uncertainty surrounds whether people with axial spondyloarthritis (axSpA) who are treated with biologic drugs have an increased risk for developing inflammatory bowel disease (IBD) that is higher than if they receive other treatments, according to data reported at the annual meeting of the British Society for Rheumatology.
“We noticed two patterns,” Gary Macfarlane, MD, PhD, Dsc, of the University of Aberdeen (Scotland) said in presenting findings from an analysis of the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS) and a meta-analysis of available studies.
There was a “large excess risk in observational studies associated with biologic therapies, which was not replicated in RCTs [randomized, controlled trials],” he said, “and trials under extensions suggested a small absolute increased risk associated with etanercept and with [interleukin]-17 [inhibitors], although again with considerable uncertainty.”
While these data make it difficult to draw any firm conclusions, “we should be reassured that the patient groups receiving these specific biologics in routine clinical care have not demonstrated an excess risk of IBD,” Dr. Macfarlane told delegates at the meeting.
Addressing clinical questions
IBD is a known extra-articular manifestation of axSpA, with an estimated prevalence of about 7%, according to a 2015 meta-analysis of 69 studies involving more than 30,000 patients.
The idea that people being treated with biologics may be at higher risk for developing IBD than those taking other treatments was suggested by the results of a large (n = 80,326) Danish study in which patients who were treated with an anti–tumor necrosis factor (TNF)–alpha medication were found to be more likely to develop de novo ulcerative colitis or Crohn’s disease than were patients who did not receive biologics.
Notably, the risk for IBD seemed higher with etanercept than with other anti–TNF-alpha agents, such as infliximab and adalimumab.
The aim of the analyses that Dr. Macfarlane presented was therefore to see if there was a difference in IBD risk among patients treated with biologic agents versus other agents, and if etanercept really did pose a greater cause for concern.
“The reason that we are asking this question is that a clinician called us up and asked us if we had any data on it,” Dr. Macfarlane said. “I think that’s really important to say that one of the things the registers are designed for are to answer questions that clinicians may have.”
Looking for new-onset IBD
Although no longer recruiting patients, the BSRBR-AS provides a wealth of data on the real-life management of patients with axSpA who were or were not taking a biologic. Patients were recruited into the register between 2012 and 2017, with follow-up until 2018. Data analyses are still ongoing and expected to continue for another couple of years.
The current analysis of data from the BSRBR-AS included patients who did not already have IBD at enrollment into the register, and patients who had been treated with a biologic could have been treated only with a single agent. Of just over 1,800 eligible patients, 793 had been treated with a biologic and 1,058 had been given nonbiologic treatment.
As expected, there were some differences between the two groups of patients studied, with biologic-treated patients having a younger age than non–biologic-treated patients. Those who took a biologic also had higher disease activity, inflammatory scores, and rates of psoriasis, enthesitis, and peripheral joint involvement.
Incidence rates for new-onset IBD per 1,000 person-years of treatment were calculated as 17 (95% confidence interval, 10.7-25.8) for patients taking a biologic and 5.1 (95% CI, 2.7-8.7) for those not taking a biologic, giving an incidence rate difference of 11.9 (95% CI, 4.3-19.6).
There was some observed differences in the incidence of new-onset IBD associated with specific agents. Etanercept did not have a higher rate (13.9/1,000 patient-years; 95% CI, 5.1-30.3) than did other agents. But in comparison, the incidence of new-onset IBD for adalimumab was 20.4 (95% CI, 11.7-33.1) and zero for other anti-TNF agents such as certolizumab pegol and infliximab, although the duration of exposure to these drugs was much lower.
The IRDs for etanercept versus nonbiologic treatment and versus other anti-TNFs were 8.8 (95% CI, –2.7 to 20.3) and -6.4 (95% CI, –21.3 to 8.5), but with “considerable uncertainty” because the confidence intervals were very wide.
Uncertainty not helped by meta-analysis
“Given the uncertainty associated with the results from BSRBR-AS, we decided to undertake a meta-analysis to try to accumulate other data that could help us answer this question,” Dr. Macfarlane explained.
However, this didn’t really help clarify things because combining BSRBR-AS data with the results of a couple of observational studies suggested that the odds of of IBD doubled with any biologic treatment versus no biologic treatment (odds ratio, 2.19), and a 2.5-fold higher likelihood considering etanercept versus no biologic treatment, but no difference was seen comparing etanercept to other anti-TNF agents (OR, 0.93).
When the meta-analysis was restricted to RCTs, the rate of IBD per 1,000 person-years was 3.43 for placebo, 5.64 for all biologics, 8.14 for etanercept, 2.35 for other anti-TNFs, and 7.02 for IL-17 inhibitors.
For extensions of RCTs, IBD rates per 1,000 person-years of follow-up were 2.91 for etanercept, 0.83 for other anti-TNFs, 3.61 for IL-17 inhibitors, and 2.79 for all biologics.
“There was only a small difference in IBD incidence between the biologic therapy and the placebo groups” in the RCTs and associated studies, Dr. Macfarlane said, adding that “there was a small excess incidence associated with etanercept, compared to other anti-TNF agents, and [for] IL-17 therapy, compared to nonetanercept, anti–TNF-alpha therapies.”
Of course, the different study designs and durations of exposure to the various treatments raises significant methodological issues.
“Randomized, controlled trials should provide the highest quality evidence as a result of their design and randomizing patients to treatment,” Dr. Macfarlane said. “However, their relatively short follow-up, as well as their restrictive eligibility criteria, may work against finding a difference in IBD incidence if it were to exist.”
Observational studies are very valuable in the data they can provide but are also beset with problems, such as surveillance bias and confounding by indication.
The higher risk of IBD that was observed in observational studies could be an issue with study design, or perhaps, “in routine clinical practice, rheumatologists are taking on board factors that we have not measured, that are negating any slight increased risk,” Dr. Macfarlane said.
Session chair Nicola Goodson, MBChB, PhD, of Liverpool (England) University NHS Foundation Trust, commented: “I think that could well be a very reasonable explanation, because I think as a clinician, you do tend to channel drugs away from some people and channel drugs towards others.
However, Dr. Goodson noted that there was “a glimmer” of signal coming from the RCTs.
“Methodologically, that is what you would have to take as the most robust evidence,” Dr. Macfarlane said, “but even with all the evidence available, it’s still very hard for us to quantify; that has enormous uncertainty.”
Dr. Macfarlane and Dr. Goodson had no relevant conflicts of interest to disclose. The BSRBR-AS is supported by the BSR, which receives funds to support the registry from Pfizer, AbbVie, and UCB.
Considerable uncertainty surrounds whether people with axial spondyloarthritis (axSpA) who are treated with biologic drugs have an increased risk for developing inflammatory bowel disease (IBD) that is higher than if they receive other treatments, according to data reported at the annual meeting of the British Society for Rheumatology.
“We noticed two patterns,” Gary Macfarlane, MD, PhD, Dsc, of the University of Aberdeen (Scotland) said in presenting findings from an analysis of the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS) and a meta-analysis of available studies.
There was a “large excess risk in observational studies associated with biologic therapies, which was not replicated in RCTs [randomized, controlled trials],” he said, “and trials under extensions suggested a small absolute increased risk associated with etanercept and with [interleukin]-17 [inhibitors], although again with considerable uncertainty.”
While these data make it difficult to draw any firm conclusions, “we should be reassured that the patient groups receiving these specific biologics in routine clinical care have not demonstrated an excess risk of IBD,” Dr. Macfarlane told delegates at the meeting.
Addressing clinical questions
IBD is a known extra-articular manifestation of axSpA, with an estimated prevalence of about 7%, according to a 2015 meta-analysis of 69 studies involving more than 30,000 patients.
The idea that people being treated with biologics may be at higher risk for developing IBD than those taking other treatments was suggested by the results of a large (n = 80,326) Danish study in which patients who were treated with an anti–tumor necrosis factor (TNF)–alpha medication were found to be more likely to develop de novo ulcerative colitis or Crohn’s disease than were patients who did not receive biologics.
Notably, the risk for IBD seemed higher with etanercept than with other anti–TNF-alpha agents, such as infliximab and adalimumab.
The aim of the analyses that Dr. Macfarlane presented was therefore to see if there was a difference in IBD risk among patients treated with biologic agents versus other agents, and if etanercept really did pose a greater cause for concern.
“The reason that we are asking this question is that a clinician called us up and asked us if we had any data on it,” Dr. Macfarlane said. “I think that’s really important to say that one of the things the registers are designed for are to answer questions that clinicians may have.”
Looking for new-onset IBD
Although no longer recruiting patients, the BSRBR-AS provides a wealth of data on the real-life management of patients with axSpA who were or were not taking a biologic. Patients were recruited into the register between 2012 and 2017, with follow-up until 2018. Data analyses are still ongoing and expected to continue for another couple of years.
The current analysis of data from the BSRBR-AS included patients who did not already have IBD at enrollment into the register, and patients who had been treated with a biologic could have been treated only with a single agent. Of just over 1,800 eligible patients, 793 had been treated with a biologic and 1,058 had been given nonbiologic treatment.
As expected, there were some differences between the two groups of patients studied, with biologic-treated patients having a younger age than non–biologic-treated patients. Those who took a biologic also had higher disease activity, inflammatory scores, and rates of psoriasis, enthesitis, and peripheral joint involvement.
Incidence rates for new-onset IBD per 1,000 person-years of treatment were calculated as 17 (95% confidence interval, 10.7-25.8) for patients taking a biologic and 5.1 (95% CI, 2.7-8.7) for those not taking a biologic, giving an incidence rate difference of 11.9 (95% CI, 4.3-19.6).
There was some observed differences in the incidence of new-onset IBD associated with specific agents. Etanercept did not have a higher rate (13.9/1,000 patient-years; 95% CI, 5.1-30.3) than did other agents. But in comparison, the incidence of new-onset IBD for adalimumab was 20.4 (95% CI, 11.7-33.1) and zero for other anti-TNF agents such as certolizumab pegol and infliximab, although the duration of exposure to these drugs was much lower.
The IRDs for etanercept versus nonbiologic treatment and versus other anti-TNFs were 8.8 (95% CI, –2.7 to 20.3) and -6.4 (95% CI, –21.3 to 8.5), but with “considerable uncertainty” because the confidence intervals were very wide.
Uncertainty not helped by meta-analysis
“Given the uncertainty associated with the results from BSRBR-AS, we decided to undertake a meta-analysis to try to accumulate other data that could help us answer this question,” Dr. Macfarlane explained.
However, this didn’t really help clarify things because combining BSRBR-AS data with the results of a couple of observational studies suggested that the odds of of IBD doubled with any biologic treatment versus no biologic treatment (odds ratio, 2.19), and a 2.5-fold higher likelihood considering etanercept versus no biologic treatment, but no difference was seen comparing etanercept to other anti-TNF agents (OR, 0.93).
When the meta-analysis was restricted to RCTs, the rate of IBD per 1,000 person-years was 3.43 for placebo, 5.64 for all biologics, 8.14 for etanercept, 2.35 for other anti-TNFs, and 7.02 for IL-17 inhibitors.
For extensions of RCTs, IBD rates per 1,000 person-years of follow-up were 2.91 for etanercept, 0.83 for other anti-TNFs, 3.61 for IL-17 inhibitors, and 2.79 for all biologics.
“There was only a small difference in IBD incidence between the biologic therapy and the placebo groups” in the RCTs and associated studies, Dr. Macfarlane said, adding that “there was a small excess incidence associated with etanercept, compared to other anti-TNF agents, and [for] IL-17 therapy, compared to nonetanercept, anti–TNF-alpha therapies.”
Of course, the different study designs and durations of exposure to the various treatments raises significant methodological issues.
“Randomized, controlled trials should provide the highest quality evidence as a result of their design and randomizing patients to treatment,” Dr. Macfarlane said. “However, their relatively short follow-up, as well as their restrictive eligibility criteria, may work against finding a difference in IBD incidence if it were to exist.”
Observational studies are very valuable in the data they can provide but are also beset with problems, such as surveillance bias and confounding by indication.
The higher risk of IBD that was observed in observational studies could be an issue with study design, or perhaps, “in routine clinical practice, rheumatologists are taking on board factors that we have not measured, that are negating any slight increased risk,” Dr. Macfarlane said.
Session chair Nicola Goodson, MBChB, PhD, of Liverpool (England) University NHS Foundation Trust, commented: “I think that could well be a very reasonable explanation, because I think as a clinician, you do tend to channel drugs away from some people and channel drugs towards others.
However, Dr. Goodson noted that there was “a glimmer” of signal coming from the RCTs.
“Methodologically, that is what you would have to take as the most robust evidence,” Dr. Macfarlane said, “but even with all the evidence available, it’s still very hard for us to quantify; that has enormous uncertainty.”
Dr. Macfarlane and Dr. Goodson had no relevant conflicts of interest to disclose. The BSRBR-AS is supported by the BSR, which receives funds to support the registry from Pfizer, AbbVie, and UCB.
FROM BSR 2022
TNF inhibitor treatment models promote personalized care in ankylosing spondylitis
A small number of patient and physician-reported outcomes, as well as laboratory and clinical factors, may help to predict the response of patients with ankylosing spondylitis (AS) to treatment with tumor necrosis factor (TNF) inhibitors when they have never taken them before, according to an analysis of data from nearly 2,000 individuals in 10 clinical trials.
TNF inhibitors are recommended for patients with AS whose symptoms persist despite use of NSAIDs, Runsheng Wang, MD, adjunct assistant professor at Columbia University Medical Center, New York, and a practicing rheumatologist at Garden State Rheumatology Consultants, Union, N.J., and colleagues wrote. Randomized, controlled clinical trials have shown that TNF inhibitors are effective in treating AS, but approximately half of patients fail to achieve notable improvement, which suggests the need for a predictive model.
“In clinical practice, before starting a treatment, physicians and patients want to know how likely a patient would be to respond to the treatment, particularly when more than one treatment option is available,” Dr. Wang said in an interview. “In this study, we developed predictive models that can potentially answer this question.”
The results suggest that the models in the study can be used to personalize clinical decision-making for patients with AS, whether to promote confidence in choosing a TNF inhibitor or to terminate treatment in nonresponders who had a higher probability of nonresponse at baseline, the researchers wrote. Similar models for other biologic treatments can help prioritize treatment options.
The predictive models are practical for clinical use because the variables in the reduced models – can be collected easily during patient visits, Dr. Wang explained. However, data from clinical practice are needed to further validate the study findings.
In a retrospective cohort study published in JAMA Network Open, the researchers analyzed data from 10 randomized, controlled clinical trials of TNF inhibitor treatment in patients with active AS conducted during 2002-2016. The study population included 1,899 adults with active AS who received an originator TNF inhibitor for at least 12 weeks, and the training set included 1,207 individuals. In the training set, the mean age of the participants was 39 years, and 75% were men.
The outcomes included major response and no response based on change in AS Disease Activity Score (ASDAS) from baseline to 12 weeks, and the researchers used machine-learning algorithms to estimate the probability of major response or no response. Major response was defined as a decrease in ASDAS of 2.0 or greater; no response was defined as a decrease in ASDAS of less than 1.1.
In the training set, a total of 407 patients (33.7%) had a major response, and 414 (34.3%) had no response.
The key features in the full, 21-variable model that increased the probability of a major response were higher C-reactive protein (CRP) levels, higher patient global assessment (PGA) of disease activity, and Bath AS Disease Activity Index (BASDAI) question 2 scores. (Question 2 asks for the overall level of back, hip, or neck pain associated with AS.) The probability of a major response decreased with higher body mass index and Bath AS Functional Index (BASFI) scores.
The key features in the model that increased the probability of no response were older age and higher BASFI scores. The probability of no response decreased with higher CRP levels, higher BASDAI question 2 scores, and higher PGA scores.
Overall, the researchers found that models using smaller subsets of variables (three or five variables in total) that would be easier to gather clinically yielded similar predictive performance.
The models were externally validated in a testing set of 692 individuals. Baseline characteristics were similar in the testing and training sets. In the testing set, the full models demonstrated moderate to high accuracy of 0.71 in the random forest model for major response and 0.76 in the random forest model for no response, with similar results in the reduced models.
At a prevalence of 25% for major response, the positive predictive values (PPVs) for random forest and logistic regression models ranged from 0.49 to 0.60, and the negative predictive values (NPVs) ranged from 0.82 to 0.84. At a prevalence of 25% for no response, PPVs ranged from 0.61 to 0.77, and NPVs ranged from 0.81 to 0.83.
The study findings were limited by several factors including the lack of data on smoking, which has been linked both to shorter treatment adherence and worse response to TNF inhibitors; the inclusion of only TNF inhibitor–naive patients; and the exclusion of NSAIDs from the models, the researchers wrote.
Dr. Wang disclosed support from the Rheumatology Research Foundation. The study’s two other authors disclosed receiving support from the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The study was based on an analysis of data from AbbVie and Pfizer that were made available through Vivli.
A small number of patient and physician-reported outcomes, as well as laboratory and clinical factors, may help to predict the response of patients with ankylosing spondylitis (AS) to treatment with tumor necrosis factor (TNF) inhibitors when they have never taken them before, according to an analysis of data from nearly 2,000 individuals in 10 clinical trials.
TNF inhibitors are recommended for patients with AS whose symptoms persist despite use of NSAIDs, Runsheng Wang, MD, adjunct assistant professor at Columbia University Medical Center, New York, and a practicing rheumatologist at Garden State Rheumatology Consultants, Union, N.J., and colleagues wrote. Randomized, controlled clinical trials have shown that TNF inhibitors are effective in treating AS, but approximately half of patients fail to achieve notable improvement, which suggests the need for a predictive model.
“In clinical practice, before starting a treatment, physicians and patients want to know how likely a patient would be to respond to the treatment, particularly when more than one treatment option is available,” Dr. Wang said in an interview. “In this study, we developed predictive models that can potentially answer this question.”
The results suggest that the models in the study can be used to personalize clinical decision-making for patients with AS, whether to promote confidence in choosing a TNF inhibitor or to terminate treatment in nonresponders who had a higher probability of nonresponse at baseline, the researchers wrote. Similar models for other biologic treatments can help prioritize treatment options.
The predictive models are practical for clinical use because the variables in the reduced models – can be collected easily during patient visits, Dr. Wang explained. However, data from clinical practice are needed to further validate the study findings.
In a retrospective cohort study published in JAMA Network Open, the researchers analyzed data from 10 randomized, controlled clinical trials of TNF inhibitor treatment in patients with active AS conducted during 2002-2016. The study population included 1,899 adults with active AS who received an originator TNF inhibitor for at least 12 weeks, and the training set included 1,207 individuals. In the training set, the mean age of the participants was 39 years, and 75% were men.
The outcomes included major response and no response based on change in AS Disease Activity Score (ASDAS) from baseline to 12 weeks, and the researchers used machine-learning algorithms to estimate the probability of major response or no response. Major response was defined as a decrease in ASDAS of 2.0 or greater; no response was defined as a decrease in ASDAS of less than 1.1.
In the training set, a total of 407 patients (33.7%) had a major response, and 414 (34.3%) had no response.
The key features in the full, 21-variable model that increased the probability of a major response were higher C-reactive protein (CRP) levels, higher patient global assessment (PGA) of disease activity, and Bath AS Disease Activity Index (BASDAI) question 2 scores. (Question 2 asks for the overall level of back, hip, or neck pain associated with AS.) The probability of a major response decreased with higher body mass index and Bath AS Functional Index (BASFI) scores.
The key features in the model that increased the probability of no response were older age and higher BASFI scores. The probability of no response decreased with higher CRP levels, higher BASDAI question 2 scores, and higher PGA scores.
Overall, the researchers found that models using smaller subsets of variables (three or five variables in total) that would be easier to gather clinically yielded similar predictive performance.
The models were externally validated in a testing set of 692 individuals. Baseline characteristics were similar in the testing and training sets. In the testing set, the full models demonstrated moderate to high accuracy of 0.71 in the random forest model for major response and 0.76 in the random forest model for no response, with similar results in the reduced models.
At a prevalence of 25% for major response, the positive predictive values (PPVs) for random forest and logistic regression models ranged from 0.49 to 0.60, and the negative predictive values (NPVs) ranged from 0.82 to 0.84. At a prevalence of 25% for no response, PPVs ranged from 0.61 to 0.77, and NPVs ranged from 0.81 to 0.83.
The study findings were limited by several factors including the lack of data on smoking, which has been linked both to shorter treatment adherence and worse response to TNF inhibitors; the inclusion of only TNF inhibitor–naive patients; and the exclusion of NSAIDs from the models, the researchers wrote.
Dr. Wang disclosed support from the Rheumatology Research Foundation. The study’s two other authors disclosed receiving support from the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The study was based on an analysis of data from AbbVie and Pfizer that were made available through Vivli.
A small number of patient and physician-reported outcomes, as well as laboratory and clinical factors, may help to predict the response of patients with ankylosing spondylitis (AS) to treatment with tumor necrosis factor (TNF) inhibitors when they have never taken them before, according to an analysis of data from nearly 2,000 individuals in 10 clinical trials.
TNF inhibitors are recommended for patients with AS whose symptoms persist despite use of NSAIDs, Runsheng Wang, MD, adjunct assistant professor at Columbia University Medical Center, New York, and a practicing rheumatologist at Garden State Rheumatology Consultants, Union, N.J., and colleagues wrote. Randomized, controlled clinical trials have shown that TNF inhibitors are effective in treating AS, but approximately half of patients fail to achieve notable improvement, which suggests the need for a predictive model.
“In clinical practice, before starting a treatment, physicians and patients want to know how likely a patient would be to respond to the treatment, particularly when more than one treatment option is available,” Dr. Wang said in an interview. “In this study, we developed predictive models that can potentially answer this question.”
The results suggest that the models in the study can be used to personalize clinical decision-making for patients with AS, whether to promote confidence in choosing a TNF inhibitor or to terminate treatment in nonresponders who had a higher probability of nonresponse at baseline, the researchers wrote. Similar models for other biologic treatments can help prioritize treatment options.
The predictive models are practical for clinical use because the variables in the reduced models – can be collected easily during patient visits, Dr. Wang explained. However, data from clinical practice are needed to further validate the study findings.
In a retrospective cohort study published in JAMA Network Open, the researchers analyzed data from 10 randomized, controlled clinical trials of TNF inhibitor treatment in patients with active AS conducted during 2002-2016. The study population included 1,899 adults with active AS who received an originator TNF inhibitor for at least 12 weeks, and the training set included 1,207 individuals. In the training set, the mean age of the participants was 39 years, and 75% were men.
The outcomes included major response and no response based on change in AS Disease Activity Score (ASDAS) from baseline to 12 weeks, and the researchers used machine-learning algorithms to estimate the probability of major response or no response. Major response was defined as a decrease in ASDAS of 2.0 or greater; no response was defined as a decrease in ASDAS of less than 1.1.
In the training set, a total of 407 patients (33.7%) had a major response, and 414 (34.3%) had no response.
The key features in the full, 21-variable model that increased the probability of a major response were higher C-reactive protein (CRP) levels, higher patient global assessment (PGA) of disease activity, and Bath AS Disease Activity Index (BASDAI) question 2 scores. (Question 2 asks for the overall level of back, hip, or neck pain associated with AS.) The probability of a major response decreased with higher body mass index and Bath AS Functional Index (BASFI) scores.
The key features in the model that increased the probability of no response were older age and higher BASFI scores. The probability of no response decreased with higher CRP levels, higher BASDAI question 2 scores, and higher PGA scores.
Overall, the researchers found that models using smaller subsets of variables (three or five variables in total) that would be easier to gather clinically yielded similar predictive performance.
The models were externally validated in a testing set of 692 individuals. Baseline characteristics were similar in the testing and training sets. In the testing set, the full models demonstrated moderate to high accuracy of 0.71 in the random forest model for major response and 0.76 in the random forest model for no response, with similar results in the reduced models.
At a prevalence of 25% for major response, the positive predictive values (PPVs) for random forest and logistic regression models ranged from 0.49 to 0.60, and the negative predictive values (NPVs) ranged from 0.82 to 0.84. At a prevalence of 25% for no response, PPVs ranged from 0.61 to 0.77, and NPVs ranged from 0.81 to 0.83.
The study findings were limited by several factors including the lack of data on smoking, which has been linked both to shorter treatment adherence and worse response to TNF inhibitors; the inclusion of only TNF inhibitor–naive patients; and the exclusion of NSAIDs from the models, the researchers wrote.
Dr. Wang disclosed support from the Rheumatology Research Foundation. The study’s two other authors disclosed receiving support from the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The study was based on an analysis of data from AbbVie and Pfizer that were made available through Vivli.
FROM JAMA NETWORK OPEN