Richard Mark Kirkner

PHILADELPHIA – A draft update of criteria for classifying antiphospholipid syndrome (APS) incorporates a much broader spectrum of disease signs and symptoms, such as kidney disease and more variables for pregnancy, and meets a higher level of specificity than the existing Sapporo criteria, although at the expense of lower sensitivity.

Richard Mark Kirkner/MDedge News

Three members of the core planning group that wrote the update, jointly commissioned by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR), reviewed the proposed criteria at the annual meeting of the ACR.

If ACR and EULAR adopt the new criteria, it would be an update to the Sapporo classification criteria for APS, which was last updated in 2006. The pending criteria consist of the following eight domains encompassing clinical findings and laboratory test results:

• Macrovascular – venous thromboembolism (VTE) with and without high VTE risk profile.
• Macrovascular – arterial thrombosis with and without a high cardiovascular disease risk profile.
• Microvascular – additional categories for kidney disease, pulmonary embolism, and other conditions for both suspected and established APS.
• Obstetric – expanded definitions to account for the absence or presence of preeclampsia or premature birth with or without fetal death.
• Cardiac valve – accounts for thickening and vegetation.
• Hematologic – includes thrombocytopenia (defined as the lowest platelet count, 20-130 x 10⁹/L).
• Antiphospholipid (aPL) test – coagulation-based functional assay, assigning greater weight to persistent over one-time positive test results.
• aPL test by solid-phase assay – includes anticardiolipin enzyme-linked immunosorbent assay (aCL ELISA), and aCL/anti-beta 2 glycoprotein-I (aCL/anti-beta 2 GPI) tests, with greater weight assigned for moderate-to-high positive results depending on isotype, whether immunoglobulin G or M.

Changes from Sapporo criteria

The existing Sapporo criteria include two clinical categories, vascular thrombosis and pregnancy morbidity; and three laboratory categories, positive lupus anticoagulant, medium or high antibody titers, and high aCL/anti-beta 2 GPI measured by ELISA. All of these are included in the draft criteria under two domains.

“These novel clinical features will help us better stratify patients according to the risk factor profile,” Stéphane Zuily, MD, PhD, a vascular specialist and European co-principal investigator of the planning group, said in explaining the proposed updated domains.

“We well-defined the microvascular domain items further than the aPL nephropathy; we redefined pregnancy morbidities; we added cardiac valve disease and thrombocytopenia; and, through gathering novel laboratory features, we were able to quantify single, double, and triple aPL positivity based on different domains and weights,” said Dr. Zuily, professor of medicine at Lorraine University in Nancy, France.

Also noteworthy is the separation of aCL/anti-beta 2 GPI testing by IgG and IgM isotypes. “And we were also able to identify different thresholds in terms of aPL positivity,” Dr. Zuily said.
 

Rationale and methodology

Planning group member Medha Barbhaiya, MD, MPH, an attending physician at the Hospital for Special Surgery and assistant professor at Weill Cornell Medicine in New York, explained the rationale for the update. “The existing criteria were drafted in 1999 and updated in 2006 and require one clinical criterion, either vascular thrombosis event or pregnancy morbidity along with antiphospholipid antibodies,” she said.

Those 16-year-old criteria also ignored heterogeneous manifestations such as heart valve disease or thrombocytopenia, failed to stratify thrombotic events as risk factors, and used an outdated definition of pregnancy morbidity related to APS, she said.

“These findings helped to support our rationale for new criteria development, along with the fact that over the last 1 to 2 decades there have been important advancements in the methodology of classification criteria development,” she said. ACR and EULAR both endorsed the new methodology for developing the classification criteria, Dr. Barbhaiya added.

That methodology involved multidisciplinary international panels of experts and data-driven efforts, with the goal of identifying patients with a high likelihood of APS for research purposes. The planning group collected 568 cases from 29 international centers, dividing them into two validation cohorts of 284 cases each.
 

How classification criteria work

Doruk Erkan, MD, MPH, coprincipal investigator representing the United States on the planning group, an attending physician at the Hospital for Special Surgery in New York, and a professor at Weill Cornell Medicine in New York, explained how the classification system works. “If you have a patient that you are considering for APS classification, the story starts with entry criteria, which are one documented clinical criterion plus a positive aPL [antiphospholipid] test within 3 years of observation of the clinical criteria,” he said.

Once the entry criteria for APS are met, there are the clinical and laboratory domains. Dr. Erkan explained that weighted point values are assigned to individual categories under each domain. For example, in the macrovascular VTE domain, VTE with a high VTE risk profile is worth 1 point, but VTE without a high VTE risk profile is worth 3 points.

“APS classification will be achieved with at least three points from clinical domains and at least three points from the laboratory domains,” he said.

The planning group conducted a sensitivity and specificity analysis of the draft classification system using the two validation cohorts. “Our goal was very high specificity to improve the homogeneity in APS research, and we achieved this in both cohorts with 99% specificity,” Dr. Erkan said. That compares to sensitivity of 91% and 86% of the Sapporo criteria in the validation cohorts.

“Our sensitivity was 83% and 84% capturing a broad spectrum of patients assessed with APS suspicion,” he added, vs. 100% and 99% with the Sapporo criteria.

These criteria are not absolute and are structured to permit future modifications, Dr. Erkan said. “When this work is completed, another chapter will start,” he said. “If a case doesn’t meet APS classification criteria, the case may still be uncertain or equivocal rather than not APS. Uncertain or controversial cases should be studied separately to guide future updates of the new criteria.”
 

Comment: Why these updates are needed

April Jorge, MD, a rheumatologist at Massachusetts General Hospital in Boston and moderator of the session on the draft APS criteria, explained why these updated criteria are needed. “It’s very important to get the updated criteria because, as the speakers mentioned, the prior Sapporo criteria were limited to just large-vessel venous thrombosis or pregnancy complications, and so that makes it difficult to study the disease in other manifestations, such as kidney manifestations, if they’re not part of the criteria.”

She added, “I think there was a need for clear classification criteria that was thought to be highly specific for the disease so that future studies can be done in this population.”

Dr. Jorge called the 99% specificity described in the analysis “impressive” and “promising.”

Dr. Barbhaiya and Dr. Zuily have no relevant disclosures. Dr. Erkan disclosed relationships with Aurinia, Eli Lilly, Exagen, and GlaxoSmithKline. Dr. Jorge has no relevant disclosures.
 

PHILADELPHIA – A draft update of criteria for classifying antiphospholipid syndrome (APS) incorporates a much broader spectrum of disease signs and symptoms, such as kidney disease and more variables for pregnancy, and meets a higher level of specificity than the existing Sapporo criteria, although at the expense of lower sensitivity.

Richard Mark Kirkner/MDedge News

Three members of the core planning group that wrote the update, jointly commissioned by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR), reviewed the proposed criteria at the annual meeting of the ACR.

If ACR and EULAR adopt the new criteria, it would be an update to the Sapporo classification criteria for APS, which was last updated in 2006. The pending criteria consist of the following eight domains encompassing clinical findings and laboratory test results:

• Macrovascular – venous thromboembolism (VTE) with and without high VTE risk profile.
• Macrovascular – arterial thrombosis with and without a high cardiovascular disease risk profile.
• Microvascular – additional categories for kidney disease, pulmonary embolism, and other conditions for both suspected and established APS.
• Obstetric – expanded definitions to account for the absence or presence of preeclampsia or premature birth with or without fetal death.
• Cardiac valve – accounts for thickening and vegetation.
• Hematologic – includes thrombocytopenia (defined as the lowest platelet count, 20-130 x 10⁹/L).
• Antiphospholipid (aPL) test – coagulation-based functional assay, assigning greater weight to persistent over one-time positive test results.
• aPL test by solid-phase assay – includes anticardiolipin enzyme-linked immunosorbent assay (aCL ELISA), and aCL/anti-beta 2 glycoprotein-I (aCL/anti-beta 2 GPI) tests, with greater weight assigned for moderate-to-high positive results depending on isotype, whether immunoglobulin G or M.

Changes from Sapporo criteria

The existing Sapporo criteria include two clinical categories, vascular thrombosis and pregnancy morbidity; and three laboratory categories, positive lupus anticoagulant, medium or high antibody titers, and high aCL/anti-beta 2 GPI measured by ELISA. All of these are included in the draft criteria under two domains.

“These novel clinical features will help us better stratify patients according to the risk factor profile,” Stéphane Zuily, MD, PhD, a vascular specialist and European co-principal investigator of the planning group, said in explaining the proposed updated domains.

“We well-defined the microvascular domain items further than the aPL nephropathy; we redefined pregnancy morbidities; we added cardiac valve disease and thrombocytopenia; and, through gathering novel laboratory features, we were able to quantify single, double, and triple aPL positivity based on different domains and weights,” said Dr. Zuily, professor of medicine at Lorraine University in Nancy, France.

Also noteworthy is the separation of aCL/anti-beta 2 GPI testing by IgG and IgM isotypes. “And we were also able to identify different thresholds in terms of aPL positivity,” Dr. Zuily said.
 

Rationale and methodology

Planning group member Medha Barbhaiya, MD, MPH, an attending physician at the Hospital for Special Surgery and assistant professor at Weill Cornell Medicine in New York, explained the rationale for the update. “The existing criteria were drafted in 1999 and updated in 2006 and require one clinical criterion, either vascular thrombosis event or pregnancy morbidity along with antiphospholipid antibodies,” she said.

Those 16-year-old criteria also ignored heterogeneous manifestations such as heart valve disease or thrombocytopenia, failed to stratify thrombotic events as risk factors, and used an outdated definition of pregnancy morbidity related to APS, she said.

“These findings helped to support our rationale for new criteria development, along with the fact that over the last 1 to 2 decades there have been important advancements in the methodology of classification criteria development,” she said. ACR and EULAR both endorsed the new methodology for developing the classification criteria, Dr. Barbhaiya added.

That methodology involved multidisciplinary international panels of experts and data-driven efforts, with the goal of identifying patients with a high likelihood of APS for research purposes. The planning group collected 568 cases from 29 international centers, dividing them into two validation cohorts of 284 cases each.
 

How classification criteria work

Doruk Erkan, MD, MPH, coprincipal investigator representing the United States on the planning group, an attending physician at the Hospital for Special Surgery in New York, and a professor at Weill Cornell Medicine in New York, explained how the classification system works. “If you have a patient that you are considering for APS classification, the story starts with entry criteria, which are one documented clinical criterion plus a positive aPL [antiphospholipid] test within 3 years of observation of the clinical criteria,” he said.

Once the entry criteria for APS are met, there are the clinical and laboratory domains. Dr. Erkan explained that weighted point values are assigned to individual categories under each domain. For example, in the macrovascular VTE domain, VTE with a high VTE risk profile is worth 1 point, but VTE without a high VTE risk profile is worth 3 points.

“APS classification will be achieved with at least three points from clinical domains and at least three points from the laboratory domains,” he said.

The planning group conducted a sensitivity and specificity analysis of the draft classification system using the two validation cohorts. “Our goal was very high specificity to improve the homogeneity in APS research, and we achieved this in both cohorts with 99% specificity,” Dr. Erkan said. That compares to sensitivity of 91% and 86% of the Sapporo criteria in the validation cohorts.

“Our sensitivity was 83% and 84% capturing a broad spectrum of patients assessed with APS suspicion,” he added, vs. 100% and 99% with the Sapporo criteria.

These criteria are not absolute and are structured to permit future modifications, Dr. Erkan said. “When this work is completed, another chapter will start,” he said. “If a case doesn’t meet APS classification criteria, the case may still be uncertain or equivocal rather than not APS. Uncertain or controversial cases should be studied separately to guide future updates of the new criteria.”
 

Comment: Why these updates are needed

April Jorge, MD, a rheumatologist at Massachusetts General Hospital in Boston and moderator of the session on the draft APS criteria, explained why these updated criteria are needed. “It’s very important to get the updated criteria because, as the speakers mentioned, the prior Sapporo criteria were limited to just large-vessel venous thrombosis or pregnancy complications, and so that makes it difficult to study the disease in other manifestations, such as kidney manifestations, if they’re not part of the criteria.”

She added, “I think there was a need for clear classification criteria that was thought to be highly specific for the disease so that future studies can be done in this population.”

Dr. Jorge called the 99% specificity described in the analysis “impressive” and “promising.”

Dr. Barbhaiya and Dr. Zuily have no relevant disclosures. Dr. Erkan disclosed relationships with Aurinia, Eli Lilly, Exagen, and GlaxoSmithKline. Dr. Jorge has no relevant disclosures.
 

PHILADELPHIA – A draft update of criteria for classifying antiphospholipid syndrome (APS) incorporates a much broader spectrum of disease signs and symptoms, such as kidney disease and more variables for pregnancy, and meets a higher level of specificity than the existing Sapporo criteria, although at the expense of lower sensitivity.

Richard Mark Kirkner/MDedge News

Three members of the core planning group that wrote the update, jointly commissioned by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR), reviewed the proposed criteria at the annual meeting of the ACR.

If ACR and EULAR adopt the new criteria, it would be an update to the Sapporo classification criteria for APS, which was last updated in 2006. The pending criteria consist of the following eight domains encompassing clinical findings and laboratory test results:

• Macrovascular – venous thromboembolism (VTE) with and without high VTE risk profile.
• Macrovascular – arterial thrombosis with and without a high cardiovascular disease risk profile.
• Microvascular – additional categories for kidney disease, pulmonary embolism, and other conditions for both suspected and established APS.
• Obstetric – expanded definitions to account for the absence or presence of preeclampsia or premature birth with or without fetal death.
• Cardiac valve – accounts for thickening and vegetation.
• Hematologic – includes thrombocytopenia (defined as the lowest platelet count, 20-130 x 10⁹/L).
• Antiphospholipid (aPL) test – coagulation-based functional assay, assigning greater weight to persistent over one-time positive test results.
• aPL test by solid-phase assay – includes anticardiolipin enzyme-linked immunosorbent assay (aCL ELISA), and aCL/anti-beta 2 glycoprotein-I (aCL/anti-beta 2 GPI) tests, with greater weight assigned for moderate-to-high positive results depending on isotype, whether immunoglobulin G or M.

Changes from Sapporo criteria

The existing Sapporo criteria include two clinical categories, vascular thrombosis and pregnancy morbidity; and three laboratory categories, positive lupus anticoagulant, medium or high antibody titers, and high aCL/anti-beta 2 GPI measured by ELISA. All of these are included in the draft criteria under two domains.

“These novel clinical features will help us better stratify patients according to the risk factor profile,” Stéphane Zuily, MD, PhD, a vascular specialist and European co-principal investigator of the planning group, said in explaining the proposed updated domains.

“We well-defined the microvascular domain items further than the aPL nephropathy; we redefined pregnancy morbidities; we added cardiac valve disease and thrombocytopenia; and, through gathering novel laboratory features, we were able to quantify single, double, and triple aPL positivity based on different domains and weights,” said Dr. Zuily, professor of medicine at Lorraine University in Nancy, France.

Also noteworthy is the separation of aCL/anti-beta 2 GPI testing by IgG and IgM isotypes. “And we were also able to identify different thresholds in terms of aPL positivity,” Dr. Zuily said.
 

Rationale and methodology

Planning group member Medha Barbhaiya, MD, MPH, an attending physician at the Hospital for Special Surgery and assistant professor at Weill Cornell Medicine in New York, explained the rationale for the update. “The existing criteria were drafted in 1999 and updated in 2006 and require one clinical criterion, either vascular thrombosis event or pregnancy morbidity along with antiphospholipid antibodies,” she said.

Those 16-year-old criteria also ignored heterogeneous manifestations such as heart valve disease or thrombocytopenia, failed to stratify thrombotic events as risk factors, and used an outdated definition of pregnancy morbidity related to APS, she said.

“These findings helped to support our rationale for new criteria development, along with the fact that over the last 1 to 2 decades there have been important advancements in the methodology of classification criteria development,” she said. ACR and EULAR both endorsed the new methodology for developing the classification criteria, Dr. Barbhaiya added.

That methodology involved multidisciplinary international panels of experts and data-driven efforts, with the goal of identifying patients with a high likelihood of APS for research purposes. The planning group collected 568 cases from 29 international centers, dividing them into two validation cohorts of 284 cases each.
 

How classification criteria work

Doruk Erkan, MD, MPH, coprincipal investigator representing the United States on the planning group, an attending physician at the Hospital for Special Surgery in New York, and a professor at Weill Cornell Medicine in New York, explained how the classification system works. “If you have a patient that you are considering for APS classification, the story starts with entry criteria, which are one documented clinical criterion plus a positive aPL [antiphospholipid] test within 3 years of observation of the clinical criteria,” he said.

Once the entry criteria for APS are met, there are the clinical and laboratory domains. Dr. Erkan explained that weighted point values are assigned to individual categories under each domain. For example, in the macrovascular VTE domain, VTE with a high VTE risk profile is worth 1 point, but VTE without a high VTE risk profile is worth 3 points.

“APS classification will be achieved with at least three points from clinical domains and at least three points from the laboratory domains,” he said.

The planning group conducted a sensitivity and specificity analysis of the draft classification system using the two validation cohorts. “Our goal was very high specificity to improve the homogeneity in APS research, and we achieved this in both cohorts with 99% specificity,” Dr. Erkan said. That compares to sensitivity of 91% and 86% of the Sapporo criteria in the validation cohorts.

“Our sensitivity was 83% and 84% capturing a broad spectrum of patients assessed with APS suspicion,” he added, vs. 100% and 99% with the Sapporo criteria.

These criteria are not absolute and are structured to permit future modifications, Dr. Erkan said. “When this work is completed, another chapter will start,” he said. “If a case doesn’t meet APS classification criteria, the case may still be uncertain or equivocal rather than not APS. Uncertain or controversial cases should be studied separately to guide future updates of the new criteria.”
 

Comment: Why these updates are needed

April Jorge, MD, a rheumatologist at Massachusetts General Hospital in Boston and moderator of the session on the draft APS criteria, explained why these updated criteria are needed. “It’s very important to get the updated criteria because, as the speakers mentioned, the prior Sapporo criteria were limited to just large-vessel venous thrombosis or pregnancy complications, and so that makes it difficult to study the disease in other manifestations, such as kidney manifestations, if they’re not part of the criteria.”

She added, “I think there was a need for clear classification criteria that was thought to be highly specific for the disease so that future studies can be done in this population.”

Dr. Jorge called the 99% specificity described in the analysis “impressive” and “promising.”

Dr. Barbhaiya and Dr. Zuily have no relevant disclosures. Dr. Erkan disclosed relationships with Aurinia, Eli Lilly, Exagen, and GlaxoSmithKline. Dr. Jorge has no relevant disclosures.
 

PHILADELPHIA – A double dose of the antiosteoporosis biologic denosumab (Prolia) slowed progression and repaired joints in erosive hand osteoarthritis (OA) but showed no impact on pain levels until 2 years after patients received the first dose, the lead investigator of a Belgium-based randomized clinical trial reported at the annual meeting of the American College of Rheumatology.

“This is the first placebo-controlled, randomized clinical trial showing the efficacy of denosumab double-dosing regimen in structural modification of erosive hand osteoarthritis,” Ruth Wittoek, MD, PhD, a rheumatologist at Ghent (Belgium) University, said in presenting the results.

“Our primary endpoint was confirmed by a more robust secondary endpoint, both showing that denosumab stopped erosive progression and induced remodeling in patients with erosive hand OA,” she added. “Moreover, the double-dosing regimen was well-tolerated.”

However, during the question-and-answer period after her presentation, Dr. Wittoek acknowledged the study didn’t evaluate the impact denosumab had on cartilage and didn’t detect a signal for pain resolution until 96 weeks during the open-label extension phase. “I’m not quite sure if denosumab is sufficient to treat symptoms in osteoarthritis,” she said. “There were positive signals but, of course, having to wait 2 years for an effect is kind of hard for our patients.”

The trial randomized 100 adult patients 1:1 to denosumab 60 mg every 12 weeks – double the normal dose for osteoporosis – or placebo. The primary endpoint was changes in erosive progression and signs of repair based on x-ray at 48 weeks, after which all patients were switched to denosumab for the open-label study. To quantify changes, the investigators used the Ghent University Scoring System (GUSS), which uses a scale of 0-300 to quantify radiographic changes in erosive hand OA.

Dr. Wittoek said that the average change in GUSS at week 24 was +6 vs. –2.8 (P = .024) in the treatment and placebo groups, respectively, widening at week 48 to +10.1 and –7.9 (P = .003). By week 96, the variation was +18.8 for denosumab and +17 for placebo with switch to denosumab (P = .03).

“During the open-label extension the denosumab treatment group continued to increase to show remodeling while the former placebo treatment group, now also receiving denosumab, also  showed signs of remodeling,” she said. “So, there was no more erosive progression.”

The secondary endpoint was the percentage of new erosive joint development at week 48: 1.8% in the denosumab group and 7% in placebo group (odds ratio, 0.23; 95% confidence interval, 0.10-0.50; P < .001). “Meaning the odds of erosive progression is 77% lower in the denosumab treatment group,” Dr. Wittoek said.

By week 96, those percentages were 0% and 0.7% in the respective treatment groups. “During the open-label extension, it was clear that denosumab blocked all new development of erosive joints,” she said.

Pain was one of the study’s exploratory endpoints, and the mean numeric rating scale showed no difference between treatment arms until the 96-week results, with a reduction by almost half in the denosumab group (from 4.2 at week 48 to 2.4) and a lesser reduction in the placebo-switched-to-denosumab arm (from 4.2 to 3.5; P = .028) between arms.

The placebo group was more susceptible to adverse events, namely musculoskeletal complaints and nervous system disorders, Dr. Wittoek noted. Infection rates, the most common adverse event, were similar between the two groups: 41 and 39 in the respective arms. Despite the double dose of denosumab, safety and tolerability in this trial was comparable to other trials, she said.

In comments submitted by e-mail, Dr. Wittoek noted that the extension study results will go out to 144 weeks. She also addressed the issues surrounding pain as an outcome.

“Besides disability, pain is also important from the patient’s perspective,” Dr. Wittoek said in the e-mailed comments. “However, pain and radiographic progression are undeniably coupled, but it’s unclear how.”

In erosive hand OA, structural progression and pain may not be related on a molecular level, she said. “Therefore, we don’t deny that pain levels should also be covered by treatment, but they should not be confused with structural modification; it is just another domain, not more nor less important.

The second year of the open-label extension study should clarify the pain outcomes, she said.

Richard Mark Kirkner/MDedge News

In an interview, David T. Felson, MD, MPH, professor and director of clinical epidemiology research at Boston University, questioned the delayed pain effect the study suggested. “It didn’t make any sense to me that there would be because both groups at that point got denosumab, so if there was going to be a pain effect that would’ve happened,” he said.

The pain effect is “really important,” he said. “We don’t use denosumab in rheumatoid arthritis to treat erosions because it doesn’t necessarily affect the pain and dysfunction of rheumatoid arthritis, and I’m not sure that isn’t going to be true in erosive hand osteoarthritis, but it’s possible.”

To clarify the pain outcomes, he said, “They’re going to have to work on the data.”

Amgen sponsored the trial but had no role in the design. Dr. Wittoek and Dr. Felson reported no relevant disclosures.
 

PHILADELPHIA – A double dose of the antiosteoporosis biologic denosumab (Prolia) slowed progression and repaired joints in erosive hand osteoarthritis (OA) but showed no impact on pain levels until 2 years after patients received the first dose, the lead investigator of a Belgium-based randomized clinical trial reported at the annual meeting of the American College of Rheumatology.

“This is the first placebo-controlled, randomized clinical trial showing the efficacy of denosumab double-dosing regimen in structural modification of erosive hand osteoarthritis,” Ruth Wittoek, MD, PhD, a rheumatologist at Ghent (Belgium) University, said in presenting the results.

“Our primary endpoint was confirmed by a more robust secondary endpoint, both showing that denosumab stopped erosive progression and induced remodeling in patients with erosive hand OA,” she added. “Moreover, the double-dosing regimen was well-tolerated.”

However, during the question-and-answer period after her presentation, Dr. Wittoek acknowledged the study didn’t evaluate the impact denosumab had on cartilage and didn’t detect a signal for pain resolution until 96 weeks during the open-label extension phase. “I’m not quite sure if denosumab is sufficient to treat symptoms in osteoarthritis,” she said. “There were positive signals but, of course, having to wait 2 years for an effect is kind of hard for our patients.”

The trial randomized 100 adult patients 1:1 to denosumab 60 mg every 12 weeks – double the normal dose for osteoporosis – or placebo. The primary endpoint was changes in erosive progression and signs of repair based on x-ray at 48 weeks, after which all patients were switched to denosumab for the open-label study. To quantify changes, the investigators used the Ghent University Scoring System (GUSS), which uses a scale of 0-300 to quantify radiographic changes in erosive hand OA.

Dr. Wittoek said that the average change in GUSS at week 24 was +6 vs. –2.8 (P = .024) in the treatment and placebo groups, respectively, widening at week 48 to +10.1 and –7.9 (P = .003). By week 96, the variation was +18.8 for denosumab and +17 for placebo with switch to denosumab (P = .03).

“During the open-label extension the denosumab treatment group continued to increase to show remodeling while the former placebo treatment group, now also receiving denosumab, also  showed signs of remodeling,” she said. “So, there was no more erosive progression.”

The secondary endpoint was the percentage of new erosive joint development at week 48: 1.8% in the denosumab group and 7% in placebo group (odds ratio, 0.23; 95% confidence interval, 0.10-0.50; P < .001). “Meaning the odds of erosive progression is 77% lower in the denosumab treatment group,” Dr. Wittoek said.

By week 96, those percentages were 0% and 0.7% in the respective treatment groups. “During the open-label extension, it was clear that denosumab blocked all new development of erosive joints,” she said.

Pain was one of the study’s exploratory endpoints, and the mean numeric rating scale showed no difference between treatment arms until the 96-week results, with a reduction by almost half in the denosumab group (from 4.2 at week 48 to 2.4) and a lesser reduction in the placebo-switched-to-denosumab arm (from 4.2 to 3.5; P = .028) between arms.

The placebo group was more susceptible to adverse events, namely musculoskeletal complaints and nervous system disorders, Dr. Wittoek noted. Infection rates, the most common adverse event, were similar between the two groups: 41 and 39 in the respective arms. Despite the double dose of denosumab, safety and tolerability in this trial was comparable to other trials, she said.

In comments submitted by e-mail, Dr. Wittoek noted that the extension study results will go out to 144 weeks. She also addressed the issues surrounding pain as an outcome.

“Besides disability, pain is also important from the patient’s perspective,” Dr. Wittoek said in the e-mailed comments. “However, pain and radiographic progression are undeniably coupled, but it’s unclear how.”

In erosive hand OA, structural progression and pain may not be related on a molecular level, she said. “Therefore, we don’t deny that pain levels should also be covered by treatment, but they should not be confused with structural modification; it is just another domain, not more nor less important.

The second year of the open-label extension study should clarify the pain outcomes, she said.

Richard Mark Kirkner/MDedge News

In an interview, David T. Felson, MD, MPH, professor and director of clinical epidemiology research at Boston University, questioned the delayed pain effect the study suggested. “It didn’t make any sense to me that there would be because both groups at that point got denosumab, so if there was going to be a pain effect that would’ve happened,” he said.

The pain effect is “really important,” he said. “We don’t use denosumab in rheumatoid arthritis to treat erosions because it doesn’t necessarily affect the pain and dysfunction of rheumatoid arthritis, and I’m not sure that isn’t going to be true in erosive hand osteoarthritis, but it’s possible.”

To clarify the pain outcomes, he said, “They’re going to have to work on the data.”

Amgen sponsored the trial but had no role in the design. Dr. Wittoek and Dr. Felson reported no relevant disclosures.
 

PHILADELPHIA – A double dose of the antiosteoporosis biologic denosumab (Prolia) slowed progression and repaired joints in erosive hand osteoarthritis (OA) but showed no impact on pain levels until 2 years after patients received the first dose, the lead investigator of a Belgium-based randomized clinical trial reported at the annual meeting of the American College of Rheumatology.

“This is the first placebo-controlled, randomized clinical trial showing the efficacy of denosumab double-dosing regimen in structural modification of erosive hand osteoarthritis,” Ruth Wittoek, MD, PhD, a rheumatologist at Ghent (Belgium) University, said in presenting the results.

“Our primary endpoint was confirmed by a more robust secondary endpoint, both showing that denosumab stopped erosive progression and induced remodeling in patients with erosive hand OA,” she added. “Moreover, the double-dosing regimen was well-tolerated.”

However, during the question-and-answer period after her presentation, Dr. Wittoek acknowledged the study didn’t evaluate the impact denosumab had on cartilage and didn’t detect a signal for pain resolution until 96 weeks during the open-label extension phase. “I’m not quite sure if denosumab is sufficient to treat symptoms in osteoarthritis,” she said. “There were positive signals but, of course, having to wait 2 years for an effect is kind of hard for our patients.”

The trial randomized 100 adult patients 1:1 to denosumab 60 mg every 12 weeks – double the normal dose for osteoporosis – or placebo. The primary endpoint was changes in erosive progression and signs of repair based on x-ray at 48 weeks, after which all patients were switched to denosumab for the open-label study. To quantify changes, the investigators used the Ghent University Scoring System (GUSS), which uses a scale of 0-300 to quantify radiographic changes in erosive hand OA.

Dr. Wittoek said that the average change in GUSS at week 24 was +6 vs. –2.8 (P = .024) in the treatment and placebo groups, respectively, widening at week 48 to +10.1 and –7.9 (P = .003). By week 96, the variation was +18.8 for denosumab and +17 for placebo with switch to denosumab (P = .03).

“During the open-label extension the denosumab treatment group continued to increase to show remodeling while the former placebo treatment group, now also receiving denosumab, also  showed signs of remodeling,” she said. “So, there was no more erosive progression.”

The secondary endpoint was the percentage of new erosive joint development at week 48: 1.8% in the denosumab group and 7% in placebo group (odds ratio, 0.23; 95% confidence interval, 0.10-0.50; P < .001). “Meaning the odds of erosive progression is 77% lower in the denosumab treatment group,” Dr. Wittoek said.

By week 96, those percentages were 0% and 0.7% in the respective treatment groups. “During the open-label extension, it was clear that denosumab blocked all new development of erosive joints,” she said.

Pain was one of the study’s exploratory endpoints, and the mean numeric rating scale showed no difference between treatment arms until the 96-week results, with a reduction by almost half in the denosumab group (from 4.2 at week 48 to 2.4) and a lesser reduction in the placebo-switched-to-denosumab arm (from 4.2 to 3.5; P = .028) between arms.

The placebo group was more susceptible to adverse events, namely musculoskeletal complaints and nervous system disorders, Dr. Wittoek noted. Infection rates, the most common adverse event, were similar between the two groups: 41 and 39 in the respective arms. Despite the double dose of denosumab, safety and tolerability in this trial was comparable to other trials, she said.

In comments submitted by e-mail, Dr. Wittoek noted that the extension study results will go out to 144 weeks. She also addressed the issues surrounding pain as an outcome.

“Besides disability, pain is also important from the patient’s perspective,” Dr. Wittoek said in the e-mailed comments. “However, pain and radiographic progression are undeniably coupled, but it’s unclear how.”

In erosive hand OA, structural progression and pain may not be related on a molecular level, she said. “Therefore, we don’t deny that pain levels should also be covered by treatment, but they should not be confused with structural modification; it is just another domain, not more nor less important.

The second year of the open-label extension study should clarify the pain outcomes, she said.

Richard Mark Kirkner/MDedge News

In an interview, David T. Felson, MD, MPH, professor and director of clinical epidemiology research at Boston University, questioned the delayed pain effect the study suggested. “It didn’t make any sense to me that there would be because both groups at that point got denosumab, so if there was going to be a pain effect that would’ve happened,” he said.

The pain effect is “really important,” he said. “We don’t use denosumab in rheumatoid arthritis to treat erosions because it doesn’t necessarily affect the pain and dysfunction of rheumatoid arthritis, and I’m not sure that isn’t going to be true in erosive hand osteoarthritis, but it’s possible.”

To clarify the pain outcomes, he said, “They’re going to have to work on the data.”

Amgen sponsored the trial but had no role in the design. Dr. Wittoek and Dr. Felson reported no relevant disclosures.
 

PHILADELPHIA – Hydroxychloroquine (HCQ) isn’t any more effective at preventing or delaying the onset of rheumatoid arthritis than placebo, based on interim results of a randomized clinical trial reported at the annual meeting of the American College of Rheumatology. Despite that futility, the percentage of patients who actually went on to develop clinical RA was lower than investigators expected, and the trial supports the use of a key biomarker for identifying RA.

While the StopRA trial was halted early because of futility of the treatment, investigators are continuing to mine the gathered data to deepen their understanding of disease progression and the potential of HCQ to improve symptoms in RA patients, said lead study author Kevin D. Deane, MD, PhD, of the University of Colorado at Denver, Aurora.

Richard Mark Kirkner/MDedge News

Overall, around 35% of the study participants on average developed RA, Dr. Deane said. “We were expecting somewhat more,” he said. “Teasing out who’s really going to progress to RA during a study and who’s not is going to be incredibly important.”

StopRA enrolled 144 adults who had elevated anti–cyclic citrullinated peptide antibodies (CCP3) levels of at least 40 units (about twice the normal level) but no history if inflammatory arthritis, randomizing them on a 1:1 basis to either HCQ (200-400 mg a day based on weight) or placebo for a 1-year treatment regimen.

The study identified participants through rheumatology clinics, testing of first-degree relatives with established RA, health fairs, blood donors, and biobanks. The interim findings are based on 2 years of follow-up after the last dose.

The study focused on HCQ because it has a relatively low risk profile with good safety and tolerability, is easy to administer, and is relatively low cost, Dr. Deane said.

StopRA study failed to meet its primary endpoint: to determine if 1 year of treatment with HCQ reduced the risk of developing inflammatory arthritis and classifiable RA at the end of 3 years in the study population. At the time of the interim analysis, 34% of patients in the HCQ arm and 36% in the placebo arm had developed RA (P = .844), Dr. Deane said. Baseline characteristics were balanced in both treatment arms.

The findings also support the use of CCP3 as a biomarker for RA, Dr. Deane said.

Now that the trial has been terminated, Dr. Deane said investigators are going to review the final data and perform secondary analyses for further clarity on the impact HCQ may have on RA.

“The future analysis should hopefully say if this treatment actually changes symptoms,” he said in an interview. “Because, if somebody felt better on the drug or had a milder form of rheumatoid arthritis once they developed it, that could potentially be a benefit.”

Dr. Deane noted the TREAT EARLIER trial similarly found that a 1-year course of methotrexate didn’t prevent the onset of clinical arthritis, but it did alter the disease course as measured in MRI-detected inflammation, related symptoms, and impairment.

“We’re hoping to look at those things and hopefully look at biologic changes over time,” Dr. Deane said of the extended analysis. “We’re not sure if the drug was associated with changes in biomarkers yet still didn’t halt progression to RA. That might be interesting, because those biomarkers might not be fundamentally related to the disease, but other mechanisms may be. That could give us some insights.”

Richard Mark Kirkner/MDedge News

Session moderator Ted Mikuls, MD, a professor of rheumatology at the University of Nebraska Medical Center, Omaha, said further mining of the study data is warranted.

“It’s common in a study like that, which took a lot of time and investment, to really take a deep dive into the data to make sure there aren’t signals that we’re missing,” he said in an interview.

One of the challenges with the study may have been patient enrollment, Dr. Mikuls noted. “I wonder about the study population in terms of where they recruit patients from. Who’s more likely to get RA? Is it patients who already have symptoms? Is it asymptomatic patients from biobanks? If it’s arthralgia joint pain patients, maybe by the time you have joint and autoantibody positivity it’s too late to have an intervention.”

The National Institute of Allergy and Infectious Diseases sponsored the study. Dr. Deane disclosed a relationship with Werfen. Dr. Mikuls has no relevant disclosures.
 

PHILADELPHIA – Hydroxychloroquine (HCQ) isn’t any more effective at preventing or delaying the onset of rheumatoid arthritis than placebo, based on interim results of a randomized clinical trial reported at the annual meeting of the American College of Rheumatology. Despite that futility, the percentage of patients who actually went on to develop clinical RA was lower than investigators expected, and the trial supports the use of a key biomarker for identifying RA.

While the StopRA trial was halted early because of futility of the treatment, investigators are continuing to mine the gathered data to deepen their understanding of disease progression and the potential of HCQ to improve symptoms in RA patients, said lead study author Kevin D. Deane, MD, PhD, of the University of Colorado at Denver, Aurora.

Richard Mark Kirkner/MDedge News

Overall, around 35% of the study participants on average developed RA, Dr. Deane said. “We were expecting somewhat more,” he said. “Teasing out who’s really going to progress to RA during a study and who’s not is going to be incredibly important.”

StopRA enrolled 144 adults who had elevated anti–cyclic citrullinated peptide antibodies (CCP3) levels of at least 40 units (about twice the normal level) but no history if inflammatory arthritis, randomizing them on a 1:1 basis to either HCQ (200-400 mg a day based on weight) or placebo for a 1-year treatment regimen.

The study identified participants through rheumatology clinics, testing of first-degree relatives with established RA, health fairs, blood donors, and biobanks. The interim findings are based on 2 years of follow-up after the last dose.

The study focused on HCQ because it has a relatively low risk profile with good safety and tolerability, is easy to administer, and is relatively low cost, Dr. Deane said.

StopRA study failed to meet its primary endpoint: to determine if 1 year of treatment with HCQ reduced the risk of developing inflammatory arthritis and classifiable RA at the end of 3 years in the study population. At the time of the interim analysis, 34% of patients in the HCQ arm and 36% in the placebo arm had developed RA (P = .844), Dr. Deane said. Baseline characteristics were balanced in both treatment arms.

The findings also support the use of CCP3 as a biomarker for RA, Dr. Deane said.

Now that the trial has been terminated, Dr. Deane said investigators are going to review the final data and perform secondary analyses for further clarity on the impact HCQ may have on RA.

“The future analysis should hopefully say if this treatment actually changes symptoms,” he said in an interview. “Because, if somebody felt better on the drug or had a milder form of rheumatoid arthritis once they developed it, that could potentially be a benefit.”

Dr. Deane noted the TREAT EARLIER trial similarly found that a 1-year course of methotrexate didn’t prevent the onset of clinical arthritis, but it did alter the disease course as measured in MRI-detected inflammation, related symptoms, and impairment.

“We’re hoping to look at those things and hopefully look at biologic changes over time,” Dr. Deane said of the extended analysis. “We’re not sure if the drug was associated with changes in biomarkers yet still didn’t halt progression to RA. That might be interesting, because those biomarkers might not be fundamentally related to the disease, but other mechanisms may be. That could give us some insights.”

Richard Mark Kirkner/MDedge News

Session moderator Ted Mikuls, MD, a professor of rheumatology at the University of Nebraska Medical Center, Omaha, said further mining of the study data is warranted.

“It’s common in a study like that, which took a lot of time and investment, to really take a deep dive into the data to make sure there aren’t signals that we’re missing,” he said in an interview.

One of the challenges with the study may have been patient enrollment, Dr. Mikuls noted. “I wonder about the study population in terms of where they recruit patients from. Who’s more likely to get RA? Is it patients who already have symptoms? Is it asymptomatic patients from biobanks? If it’s arthralgia joint pain patients, maybe by the time you have joint and autoantibody positivity it’s too late to have an intervention.”

The National Institute of Allergy and Infectious Diseases sponsored the study. Dr. Deane disclosed a relationship with Werfen. Dr. Mikuls has no relevant disclosures.
 

PHILADELPHIA – Hydroxychloroquine (HCQ) isn’t any more effective at preventing or delaying the onset of rheumatoid arthritis than placebo, based on interim results of a randomized clinical trial reported at the annual meeting of the American College of Rheumatology. Despite that futility, the percentage of patients who actually went on to develop clinical RA was lower than investigators expected, and the trial supports the use of a key biomarker for identifying RA.

While the StopRA trial was halted early because of futility of the treatment, investigators are continuing to mine the gathered data to deepen their understanding of disease progression and the potential of HCQ to improve symptoms in RA patients, said lead study author Kevin D. Deane, MD, PhD, of the University of Colorado at Denver, Aurora.

Richard Mark Kirkner/MDedge News

Overall, around 35% of the study participants on average developed RA, Dr. Deane said. “We were expecting somewhat more,” he said. “Teasing out who’s really going to progress to RA during a study and who’s not is going to be incredibly important.”

StopRA enrolled 144 adults who had elevated anti–cyclic citrullinated peptide antibodies (CCP3) levels of at least 40 units (about twice the normal level) but no history if inflammatory arthritis, randomizing them on a 1:1 basis to either HCQ (200-400 mg a day based on weight) or placebo for a 1-year treatment regimen.

The study identified participants through rheumatology clinics, testing of first-degree relatives with established RA, health fairs, blood donors, and biobanks. The interim findings are based on 2 years of follow-up after the last dose.

The study focused on HCQ because it has a relatively low risk profile with good safety and tolerability, is easy to administer, and is relatively low cost, Dr. Deane said.

StopRA study failed to meet its primary endpoint: to determine if 1 year of treatment with HCQ reduced the risk of developing inflammatory arthritis and classifiable RA at the end of 3 years in the study population. At the time of the interim analysis, 34% of patients in the HCQ arm and 36% in the placebo arm had developed RA (P = .844), Dr. Deane said. Baseline characteristics were balanced in both treatment arms.

The findings also support the use of CCP3 as a biomarker for RA, Dr. Deane said.

Now that the trial has been terminated, Dr. Deane said investigators are going to review the final data and perform secondary analyses for further clarity on the impact HCQ may have on RA.

“The future analysis should hopefully say if this treatment actually changes symptoms,” he said in an interview. “Because, if somebody felt better on the drug or had a milder form of rheumatoid arthritis once they developed it, that could potentially be a benefit.”

Dr. Deane noted the TREAT EARLIER trial similarly found that a 1-year course of methotrexate didn’t prevent the onset of clinical arthritis, but it did alter the disease course as measured in MRI-detected inflammation, related symptoms, and impairment.

“We’re hoping to look at those things and hopefully look at biologic changes over time,” Dr. Deane said of the extended analysis. “We’re not sure if the drug was associated with changes in biomarkers yet still didn’t halt progression to RA. That might be interesting, because those biomarkers might not be fundamentally related to the disease, but other mechanisms may be. That could give us some insights.”

Richard Mark Kirkner/MDedge News

Session moderator Ted Mikuls, MD, a professor of rheumatology at the University of Nebraska Medical Center, Omaha, said further mining of the study data is warranted.

“It’s common in a study like that, which took a lot of time and investment, to really take a deep dive into the data to make sure there aren’t signals that we’re missing,” he said in an interview.

One of the challenges with the study may have been patient enrollment, Dr. Mikuls noted. “I wonder about the study population in terms of where they recruit patients from. Who’s more likely to get RA? Is it patients who already have symptoms? Is it asymptomatic patients from biobanks? If it’s arthralgia joint pain patients, maybe by the time you have joint and autoantibody positivity it’s too late to have an intervention.”

The National Institute of Allergy and Infectious Diseases sponsored the study. Dr. Deane disclosed a relationship with Werfen. Dr. Mikuls has no relevant disclosures.
 

PHILADELPHIA – Combining the immunomodulatory agent mycophenolate with the antifibrotic pirfenidone led to more rapid improvement and showed a trend to be more effective than mycophenolate mofetil alone for treating the signs and symptoms of scleroderma-related interstitial lung disease, but the combination therapy came with an increase in side effects, according to results from the Scleroderma Lung Study III.

Dinesh Khanna, MBBS, MSc, of the University of Michigan, Ann Arbor, presented the results at the annual meeting of the American College of Rheumatology. He noted some problems with the study – namely its small size, enrolling only 51 patients, about one-third of its original goal. But he also said it showed a potential signal for efficacy and that the study itself could serve as a “template” for future studies of combination mycophenolate mofetil (MMF) plus pirfenidone therapy for scleroderma-related interstitial lung disease (SSc-ILD).

“The pirfenidone patients had quite a bit more GI side effects and photosensitivity, and those are known side effects,” Dr. Khanna said in an interview. “So the combination therapy had more side effects but trends to higher efficacy.”

The design of SLS-III, a phase 2 clinical trial, was a challenge, Dr. Khanna explained. The goal was to enroll 150 SSc-ILD patients who hadn’t had any previous treatment for their disease. Finding those patients proved difficult. “In fact, if you look at the recent history, 70% of the patients with early diffuse scleroderma are on MMF,” he said in his presentation. Compounding low study enrollment was the intervening COVID-19 pandemic, he added.
 

Testing a faster-acting combination

Nonetheless, the trial managed to enroll 27 patients in the combination therapy group and 24 in the MMF-plus-placebo group and compared their outcomes over 18 months. Study dosing was 1,500 mg MMF twice daily and pirfenidone 801 mg three times daily, titrated to the tolerable dose.

Despite the study’s being underpowered, Dr. Khanna said, it still reported some notable outcomes that merit further investigation. “I think what was intriguing in the study was the long-term benefit in the patient-reported outcomes and the structural changes,” he said in the interview.

Among those notable outcomes was a clinically significant change in forced vital capacity (FVC) percentage for the combination vs. the placebo groups: 2.24% vs. 2.09%. He also noted that the combination group saw a somewhat more robust improvement in FVC at six months: 2.59% (± 0.98%) vs. 0.92% (± 1.1%) in the placebo group.

The combination group showed greater improvements in high-resolution computed tomography-evaluated lung involvement and lung fibrosis and patient-reported outcomes, including a statistically significant 3.67-point greater improvement in PROMIS-29 physical function score (4.42 vs. 0.75).

The patients on combination therapy had higher rates of serious adverse events (SAEs), and seven discontinued one or both study drugs early, all in the combined arm. Four combination therapy patients had six SAEs, compared to two placebo patients with three SAEs. In the combination group, SAEs included chest pain, herpes zoster ophthalmicus, nodular basal cell cancer, marginal zone B cell lymphoma, renal crisis, and dyspnea. SAEs in the placebo group were colitis, COVID-19 and hypoxic respiratory failure.

Study design challenges

Nonetheless, Dr. Khanna said the SLS-III data are consistent with the SLS-II findings, with mean improvements in FVC of 2.24% and 2.1%, respectively.

“The next study may be able to replicate what we tried to do, keeping in mind that there are really no MMF-naive patients who are walking around,” Dr. Khanna said. “So the challenge is about the feasibility of recruiting within a trial vs. trying to show a statistical difference between the drug and placebo.”

This study could serve as a foundation for future studies of MMF in patients with SSc-ILD, Robert Spiera, MD, of the Hospital for Special Surgery in New York, said in an interview. “There are lessons to be learned both from the study but also from prior studies looking at MMF use in the background in patients treated with other drugs in clinical trials,” he said.

Dr. Spiera noted that the study had other challenges besides the difficulty in recruiting patients who hadn’t been on MMF therapy. “A great challenge is that the benefit with regard to the impact on the lungs from MMF seems most prominent in the first 6 months to a year to even 2 years that somebody is on the drug,” he said.

The other challenge with this study is that a large proportion of patients had limited systemic disease and relatively lower levels of skin disease compared with other studies of patients on MMF, Dr. Spiera said.

“The optimal treatment of scleroderma-associated lung disease remains a very important and not-adequately met need,” he said. “Particularly, we’re looking for drugs that are tolerable in a patient population that are very prone to GI side effects in general. This study and others have taught us a lot about trial design, and I think more globally this will allow us to move this field forward.”

Dr. Khanna disclosed relationships with Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Horizon Therapeutics USA, Janssen Global Services, Prometheus Biosciences, Mitsubishi Tanabe Pharma Corp., Genentech/Roche, Theraly, and Pfizer. Genentech provided funding for the study and pirfenidone and placebo drugs at no cost.

Dr. Spiera disclosed relationships with GlaxoSmithKline, Boehringer-Ingelheim, Corbus Pharmaceutical, InflaRx, AbbVie/Abbott, Sanofi, Novartis, Chemocentryx, Roche and Vera.

PHILADELPHIA – Combining the immunomodulatory agent mycophenolate with the antifibrotic pirfenidone led to more rapid improvement and showed a trend to be more effective than mycophenolate mofetil alone for treating the signs and symptoms of scleroderma-related interstitial lung disease, but the combination therapy came with an increase in side effects, according to results from the Scleroderma Lung Study III.

Dinesh Khanna, MBBS, MSc, of the University of Michigan, Ann Arbor, presented the results at the annual meeting of the American College of Rheumatology. He noted some problems with the study – namely its small size, enrolling only 51 patients, about one-third of its original goal. But he also said it showed a potential signal for efficacy and that the study itself could serve as a “template” for future studies of combination mycophenolate mofetil (MMF) plus pirfenidone therapy for scleroderma-related interstitial lung disease (SSc-ILD).

“The pirfenidone patients had quite a bit more GI side effects and photosensitivity, and those are known side effects,” Dr. Khanna said in an interview. “So the combination therapy had more side effects but trends to higher efficacy.”

The design of SLS-III, a phase 2 clinical trial, was a challenge, Dr. Khanna explained. The goal was to enroll 150 SSc-ILD patients who hadn’t had any previous treatment for their disease. Finding those patients proved difficult. “In fact, if you look at the recent history, 70% of the patients with early diffuse scleroderma are on MMF,” he said in his presentation. Compounding low study enrollment was the intervening COVID-19 pandemic, he added.
 

Testing a faster-acting combination

Nonetheless, the trial managed to enroll 27 patients in the combination therapy group and 24 in the MMF-plus-placebo group and compared their outcomes over 18 months. Study dosing was 1,500 mg MMF twice daily and pirfenidone 801 mg three times daily, titrated to the tolerable dose.

Despite the study’s being underpowered, Dr. Khanna said, it still reported some notable outcomes that merit further investigation. “I think what was intriguing in the study was the long-term benefit in the patient-reported outcomes and the structural changes,” he said in the interview.

Among those notable outcomes was a clinically significant change in forced vital capacity (FVC) percentage for the combination vs. the placebo groups: 2.24% vs. 2.09%. He also noted that the combination group saw a somewhat more robust improvement in FVC at six months: 2.59% (± 0.98%) vs. 0.92% (± 1.1%) in the placebo group.

The combination group showed greater improvements in high-resolution computed tomography-evaluated lung involvement and lung fibrosis and patient-reported outcomes, including a statistically significant 3.67-point greater improvement in PROMIS-29 physical function score (4.42 vs. 0.75).

The patients on combination therapy had higher rates of serious adverse events (SAEs), and seven discontinued one or both study drugs early, all in the combined arm. Four combination therapy patients had six SAEs, compared to two placebo patients with three SAEs. In the combination group, SAEs included chest pain, herpes zoster ophthalmicus, nodular basal cell cancer, marginal zone B cell lymphoma, renal crisis, and dyspnea. SAEs in the placebo group were colitis, COVID-19 and hypoxic respiratory failure.

Study design challenges

Nonetheless, Dr. Khanna said the SLS-III data are consistent with the SLS-II findings, with mean improvements in FVC of 2.24% and 2.1%, respectively.

“The next study may be able to replicate what we tried to do, keeping in mind that there are really no MMF-naive patients who are walking around,” Dr. Khanna said. “So the challenge is about the feasibility of recruiting within a trial vs. trying to show a statistical difference between the drug and placebo.”

This study could serve as a foundation for future studies of MMF in patients with SSc-ILD, Robert Spiera, MD, of the Hospital for Special Surgery in New York, said in an interview. “There are lessons to be learned both from the study but also from prior studies looking at MMF use in the background in patients treated with other drugs in clinical trials,” he said.

Dr. Spiera noted that the study had other challenges besides the difficulty in recruiting patients who hadn’t been on MMF therapy. “A great challenge is that the benefit with regard to the impact on the lungs from MMF seems most prominent in the first 6 months to a year to even 2 years that somebody is on the drug,” he said.

The other challenge with this study is that a large proportion of patients had limited systemic disease and relatively lower levels of skin disease compared with other studies of patients on MMF, Dr. Spiera said.

“The optimal treatment of scleroderma-associated lung disease remains a very important and not-adequately met need,” he said. “Particularly, we’re looking for drugs that are tolerable in a patient population that are very prone to GI side effects in general. This study and others have taught us a lot about trial design, and I think more globally this will allow us to move this field forward.”

Dr. Khanna disclosed relationships with Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Horizon Therapeutics USA, Janssen Global Services, Prometheus Biosciences, Mitsubishi Tanabe Pharma Corp., Genentech/Roche, Theraly, and Pfizer. Genentech provided funding for the study and pirfenidone and placebo drugs at no cost.

Dr. Spiera disclosed relationships with GlaxoSmithKline, Boehringer-Ingelheim, Corbus Pharmaceutical, InflaRx, AbbVie/Abbott, Sanofi, Novartis, Chemocentryx, Roche and Vera.

PHILADELPHIA – Combining the immunomodulatory agent mycophenolate with the antifibrotic pirfenidone led to more rapid improvement and showed a trend to be more effective than mycophenolate mofetil alone for treating the signs and symptoms of scleroderma-related interstitial lung disease, but the combination therapy came with an increase in side effects, according to results from the Scleroderma Lung Study III.

Dinesh Khanna, MBBS, MSc, of the University of Michigan, Ann Arbor, presented the results at the annual meeting of the American College of Rheumatology. He noted some problems with the study – namely its small size, enrolling only 51 patients, about one-third of its original goal. But he also said it showed a potential signal for efficacy and that the study itself could serve as a “template” for future studies of combination mycophenolate mofetil (MMF) plus pirfenidone therapy for scleroderma-related interstitial lung disease (SSc-ILD).

“The pirfenidone patients had quite a bit more GI side effects and photosensitivity, and those are known side effects,” Dr. Khanna said in an interview. “So the combination therapy had more side effects but trends to higher efficacy.”

The design of SLS-III, a phase 2 clinical trial, was a challenge, Dr. Khanna explained. The goal was to enroll 150 SSc-ILD patients who hadn’t had any previous treatment for their disease. Finding those patients proved difficult. “In fact, if you look at the recent history, 70% of the patients with early diffuse scleroderma are on MMF,” he said in his presentation. Compounding low study enrollment was the intervening COVID-19 pandemic, he added.
 

Testing a faster-acting combination

Nonetheless, the trial managed to enroll 27 patients in the combination therapy group and 24 in the MMF-plus-placebo group and compared their outcomes over 18 months. Study dosing was 1,500 mg MMF twice daily and pirfenidone 801 mg three times daily, titrated to the tolerable dose.

Despite the study’s being underpowered, Dr. Khanna said, it still reported some notable outcomes that merit further investigation. “I think what was intriguing in the study was the long-term benefit in the patient-reported outcomes and the structural changes,” he said in the interview.

Among those notable outcomes was a clinically significant change in forced vital capacity (FVC) percentage for the combination vs. the placebo groups: 2.24% vs. 2.09%. He also noted that the combination group saw a somewhat more robust improvement in FVC at six months: 2.59% (± 0.98%) vs. 0.92% (± 1.1%) in the placebo group.

The combination group showed greater improvements in high-resolution computed tomography-evaluated lung involvement and lung fibrosis and patient-reported outcomes, including a statistically significant 3.67-point greater improvement in PROMIS-29 physical function score (4.42 vs. 0.75).

The patients on combination therapy had higher rates of serious adverse events (SAEs), and seven discontinued one or both study drugs early, all in the combined arm. Four combination therapy patients had six SAEs, compared to two placebo patients with three SAEs. In the combination group, SAEs included chest pain, herpes zoster ophthalmicus, nodular basal cell cancer, marginal zone B cell lymphoma, renal crisis, and dyspnea. SAEs in the placebo group were colitis, COVID-19 and hypoxic respiratory failure.

Study design challenges

Nonetheless, Dr. Khanna said the SLS-III data are consistent with the SLS-II findings, with mean improvements in FVC of 2.24% and 2.1%, respectively.

“The next study may be able to replicate what we tried to do, keeping in mind that there are really no MMF-naive patients who are walking around,” Dr. Khanna said. “So the challenge is about the feasibility of recruiting within a trial vs. trying to show a statistical difference between the drug and placebo.”

This study could serve as a foundation for future studies of MMF in patients with SSc-ILD, Robert Spiera, MD, of the Hospital for Special Surgery in New York, said in an interview. “There are lessons to be learned both from the study but also from prior studies looking at MMF use in the background in patients treated with other drugs in clinical trials,” he said.

Dr. Spiera noted that the study had other challenges besides the difficulty in recruiting patients who hadn’t been on MMF therapy. “A great challenge is that the benefit with regard to the impact on the lungs from MMF seems most prominent in the first 6 months to a year to even 2 years that somebody is on the drug,” he said.

The other challenge with this study is that a large proportion of patients had limited systemic disease and relatively lower levels of skin disease compared with other studies of patients on MMF, Dr. Spiera said.

“The optimal treatment of scleroderma-associated lung disease remains a very important and not-adequately met need,” he said. “Particularly, we’re looking for drugs that are tolerable in a patient population that are very prone to GI side effects in general. This study and others have taught us a lot about trial design, and I think more globally this will allow us to move this field forward.”

Dr. Khanna disclosed relationships with Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Horizon Therapeutics USA, Janssen Global Services, Prometheus Biosciences, Mitsubishi Tanabe Pharma Corp., Genentech/Roche, Theraly, and Pfizer. Genentech provided funding for the study and pirfenidone and placebo drugs at no cost.

Dr. Spiera disclosed relationships with GlaxoSmithKline, Boehringer-Ingelheim, Corbus Pharmaceutical, InflaRx, AbbVie/Abbott, Sanofi, Novartis, Chemocentryx, Roche and Vera.

PHILADELPHIA – Aggressive therapy using conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in combination with biologic agents early, soon after a child is diagnosed with polyarticular juvenile idiopathic arthritis (pJIA), enabled more patients to achieve clinical remission and longer times in inactive disease than more conventional therapeutic approaches, 3-year results of prospective, observational study demonstrated.

The results of The Childhood Arthritis and Rheumatology Research Alliance STOP-JIA study, which Yukiko Kimura, MD, presented at the annual meeting of the American College of Rheumatology, showed early combination therapy had benefits, compared with other treatment strategies that were more evident at 3 years than at 1 year of study.

“The STOP-JIA study showed that, after 3 years, patients who started a biologic early on in combination with methotrexate spent more time in inactive disease and achieved clinical remission more often when compared to those started on traditional step-up therapy,” Dr. Kimura, chief of pediatric rheumatology at Hackensack (N.J.) Meridian Health and professor of pediatrics at the Hackensack Meridian School of Medicine, said at a press conference. “This study shows that the treatment of poly-JIA patients receive initially very early on in their disease matters even 3 years after that treatment was started.”

The study compared three CARRA consensus treatment plans (CTP) for untreated pediatric pJIA patients: step-up (SU) – starting conventional synthetic DMARD therapy and adding a biologic if needed after 3 or more months; early-combination (EC) therapy – starting synthetic and biologic DMARDs together; and biologic first (BF) therapy – starting biologic DMARD monotherapy.

Dr. Kimura explained the rationale for the study. “Since biologic treatments were introduced more than 20 years ago, the prognosis for JIA significantly improved. These very effective medicines often work wonders, quickly reducing pain and inflammation in joint disease activity,” she said in the press conference. “What is not known, however, is when is the best time to start these very effective treatments.”

The most common approach is to start with a synthetic DMARD, typically methotrexate, and wait before starting a biologic, Dr. Kimura said.

“But even though methotrexate can work very well by itself, it does not work for every patient, and we don’t know whether waiting months for it to work and then starting a biologic might potentially lessen their effectiveness,” Dr. Kimura added. “We don’t know if there’s a window of opportunity that’s lost while waiting to see whether methotrexate will work.”

The study originally enrolled 400 patients, 297 of whom completed the 3-year visit – 190 in SU, 76 in EC and 31 in BF. At 12 months, the study found no statistically significant difference in clinically inactive disease (CID) between the groups, Dr. Kimura said.

Even at the 3-year visit, the percentage of patients in CID off glucocorticoids and clinical Juvenile Arthritis Disease Activity Score based on 10 joints inactive disease (cJADAS 10 ID) did not differ among the three groups, Dr. Kimura said in presenting the results. “But,” she added, “greater proportions of early-combination CTP group were able to achieve clinical remissions and spend more time with inactive disease in both CID and cJADAS 10.”

A closer look at the outcomes showed some separation between early-combination therapy and the other two treatment plans. The incidence of clinical remission (at any time point over 36 months) was 67.1% in the EC group vs. 49.1% and 47.3%, respectively, in the BF and SU groups, Dr. Kimura said. “The difference between the early-combination and step-up groups was highly significant [P = .007],” she added.

EC also had an edge in the percentage of time patients spent in CID (over 36 months): 39.2% versus 32% and 27.4%, respectively, in the BF and SU groups (P = .006 for EV vs. SU), as well as cJADAS 10 ID (50.6% in EC group vs. 42.8% and 37.5%, respectively in the BF and SU groups; P = .005 for EC vs. SU).

Dr. Kimura said that the STOP JIA trial will continue with longer-term analysis and ongoing monitoring of study patients through the CARRA registry. “These longer-term analyses and readouts will be important because even though the results at 12 months didn’t seem as definitive, it seems the longer we go, the more impact we see of the treatments that were started early on in this disease.”

The findings from this study are “significantly important,” Nina T. Washington, MD, MPH, a pediatric rheumatologist at the University of New Mexico Hospital, Albuquerque, and the Mary Bridge Children’s Hospital in Tacoma, Wash., said in an interview. “At least for the past decade we’ve really been advocating towards earlier and aggressive therapy, and that’s what this study shows: the sooner you can treat this disease, the sooner you can attack those joints that are inflamed, the better outcome you give the patient.”

The study also confirms that pediatric rheumatologists are not overtreating patients with pJIA, she added.

“In a sense we’re actually treating and preventing and if you have a child that has arthritis, it’s okay to treat that child,” Dr. Washington said. “For me that’s the most reassuring thing: that I’m not necessarily going overboard. If I have a child with polyarticular JIA and they have multiple inflamed joints and I have the evidence as they’re sitting in front of me, and I treat them. I’m going to give them the best outcome.”

The Patient Centered Outcomes Research Institute provided study funding. Dr. Kimura is chair of the CARRA JIA disease research committee and cochair of the CARRA Registry and Research Oversight Committee. She disclosed a financial relationship with Genentech. Dr. Washington has no relevant relationships to disclose.
 

PHILADELPHIA – Aggressive therapy using conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in combination with biologic agents early, soon after a child is diagnosed with polyarticular juvenile idiopathic arthritis (pJIA), enabled more patients to achieve clinical remission and longer times in inactive disease than more conventional therapeutic approaches, 3-year results of prospective, observational study demonstrated.

The results of The Childhood Arthritis and Rheumatology Research Alliance STOP-JIA study, which Yukiko Kimura, MD, presented at the annual meeting of the American College of Rheumatology, showed early combination therapy had benefits, compared with other treatment strategies that were more evident at 3 years than at 1 year of study.

“The STOP-JIA study showed that, after 3 years, patients who started a biologic early on in combination with methotrexate spent more time in inactive disease and achieved clinical remission more often when compared to those started on traditional step-up therapy,” Dr. Kimura, chief of pediatric rheumatology at Hackensack (N.J.) Meridian Health and professor of pediatrics at the Hackensack Meridian School of Medicine, said at a press conference. “This study shows that the treatment of poly-JIA patients receive initially very early on in their disease matters even 3 years after that treatment was started.”

The study compared three CARRA consensus treatment plans (CTP) for untreated pediatric pJIA patients: step-up (SU) – starting conventional synthetic DMARD therapy and adding a biologic if needed after 3 or more months; early-combination (EC) therapy – starting synthetic and biologic DMARDs together; and biologic first (BF) therapy – starting biologic DMARD monotherapy.

Dr. Kimura explained the rationale for the study. “Since biologic treatments were introduced more than 20 years ago, the prognosis for JIA significantly improved. These very effective medicines often work wonders, quickly reducing pain and inflammation in joint disease activity,” she said in the press conference. “What is not known, however, is when is the best time to start these very effective treatments.”

The most common approach is to start with a synthetic DMARD, typically methotrexate, and wait before starting a biologic, Dr. Kimura said.

“But even though methotrexate can work very well by itself, it does not work for every patient, and we don’t know whether waiting months for it to work and then starting a biologic might potentially lessen their effectiveness,” Dr. Kimura added. “We don’t know if there’s a window of opportunity that’s lost while waiting to see whether methotrexate will work.”

The study originally enrolled 400 patients, 297 of whom completed the 3-year visit – 190 in SU, 76 in EC and 31 in BF. At 12 months, the study found no statistically significant difference in clinically inactive disease (CID) between the groups, Dr. Kimura said.

Even at the 3-year visit, the percentage of patients in CID off glucocorticoids and clinical Juvenile Arthritis Disease Activity Score based on 10 joints inactive disease (cJADAS 10 ID) did not differ among the three groups, Dr. Kimura said in presenting the results. “But,” she added, “greater proportions of early-combination CTP group were able to achieve clinical remissions and spend more time with inactive disease in both CID and cJADAS 10.”

A closer look at the outcomes showed some separation between early-combination therapy and the other two treatment plans. The incidence of clinical remission (at any time point over 36 months) was 67.1% in the EC group vs. 49.1% and 47.3%, respectively, in the BF and SU groups, Dr. Kimura said. “The difference between the early-combination and step-up groups was highly significant [P = .007],” she added.

EC also had an edge in the percentage of time patients spent in CID (over 36 months): 39.2% versus 32% and 27.4%, respectively, in the BF and SU groups (P = .006 for EV vs. SU), as well as cJADAS 10 ID (50.6% in EC group vs. 42.8% and 37.5%, respectively in the BF and SU groups; P = .005 for EC vs. SU).

Dr. Kimura said that the STOP JIA trial will continue with longer-term analysis and ongoing monitoring of study patients through the CARRA registry. “These longer-term analyses and readouts will be important because even though the results at 12 months didn’t seem as definitive, it seems the longer we go, the more impact we see of the treatments that were started early on in this disease.”

The findings from this study are “significantly important,” Nina T. Washington, MD, MPH, a pediatric rheumatologist at the University of New Mexico Hospital, Albuquerque, and the Mary Bridge Children’s Hospital in Tacoma, Wash., said in an interview. “At least for the past decade we’ve really been advocating towards earlier and aggressive therapy, and that’s what this study shows: the sooner you can treat this disease, the sooner you can attack those joints that are inflamed, the better outcome you give the patient.”

The study also confirms that pediatric rheumatologists are not overtreating patients with pJIA, she added.

“In a sense we’re actually treating and preventing and if you have a child that has arthritis, it’s okay to treat that child,” Dr. Washington said. “For me that’s the most reassuring thing: that I’m not necessarily going overboard. If I have a child with polyarticular JIA and they have multiple inflamed joints and I have the evidence as they’re sitting in front of me, and I treat them. I’m going to give them the best outcome.”

The Patient Centered Outcomes Research Institute provided study funding. Dr. Kimura is chair of the CARRA JIA disease research committee and cochair of the CARRA Registry and Research Oversight Committee. She disclosed a financial relationship with Genentech. Dr. Washington has no relevant relationships to disclose.
 

PHILADELPHIA – Aggressive therapy using conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in combination with biologic agents early, soon after a child is diagnosed with polyarticular juvenile idiopathic arthritis (pJIA), enabled more patients to achieve clinical remission and longer times in inactive disease than more conventional therapeutic approaches, 3-year results of prospective, observational study demonstrated.

The results of The Childhood Arthritis and Rheumatology Research Alliance STOP-JIA study, which Yukiko Kimura, MD, presented at the annual meeting of the American College of Rheumatology, showed early combination therapy had benefits, compared with other treatment strategies that were more evident at 3 years than at 1 year of study.

“The STOP-JIA study showed that, after 3 years, patients who started a biologic early on in combination with methotrexate spent more time in inactive disease and achieved clinical remission more often when compared to those started on traditional step-up therapy,” Dr. Kimura, chief of pediatric rheumatology at Hackensack (N.J.) Meridian Health and professor of pediatrics at the Hackensack Meridian School of Medicine, said at a press conference. “This study shows that the treatment of poly-JIA patients receive initially very early on in their disease matters even 3 years after that treatment was started.”

The study compared three CARRA consensus treatment plans (CTP) for untreated pediatric pJIA patients: step-up (SU) – starting conventional synthetic DMARD therapy and adding a biologic if needed after 3 or more months; early-combination (EC) therapy – starting synthetic and biologic DMARDs together; and biologic first (BF) therapy – starting biologic DMARD monotherapy.

Dr. Kimura explained the rationale for the study. “Since biologic treatments were introduced more than 20 years ago, the prognosis for JIA significantly improved. These very effective medicines often work wonders, quickly reducing pain and inflammation in joint disease activity,” she said in the press conference. “What is not known, however, is when is the best time to start these very effective treatments.”

The most common approach is to start with a synthetic DMARD, typically methotrexate, and wait before starting a biologic, Dr. Kimura said.

“But even though methotrexate can work very well by itself, it does not work for every patient, and we don’t know whether waiting months for it to work and then starting a biologic might potentially lessen their effectiveness,” Dr. Kimura added. “We don’t know if there’s a window of opportunity that’s lost while waiting to see whether methotrexate will work.”

The study originally enrolled 400 patients, 297 of whom completed the 3-year visit – 190 in SU, 76 in EC and 31 in BF. At 12 months, the study found no statistically significant difference in clinically inactive disease (CID) between the groups, Dr. Kimura said.

Even at the 3-year visit, the percentage of patients in CID off glucocorticoids and clinical Juvenile Arthritis Disease Activity Score based on 10 joints inactive disease (cJADAS 10 ID) did not differ among the three groups, Dr. Kimura said in presenting the results. “But,” she added, “greater proportions of early-combination CTP group were able to achieve clinical remissions and spend more time with inactive disease in both CID and cJADAS 10.”

A closer look at the outcomes showed some separation between early-combination therapy and the other two treatment plans. The incidence of clinical remission (at any time point over 36 months) was 67.1% in the EC group vs. 49.1% and 47.3%, respectively, in the BF and SU groups, Dr. Kimura said. “The difference between the early-combination and step-up groups was highly significant [P = .007],” she added.

EC also had an edge in the percentage of time patients spent in CID (over 36 months): 39.2% versus 32% and 27.4%, respectively, in the BF and SU groups (P = .006 for EV vs. SU), as well as cJADAS 10 ID (50.6% in EC group vs. 42.8% and 37.5%, respectively in the BF and SU groups; P = .005 for EC vs. SU).

Dr. Kimura said that the STOP JIA trial will continue with longer-term analysis and ongoing monitoring of study patients through the CARRA registry. “These longer-term analyses and readouts will be important because even though the results at 12 months didn’t seem as definitive, it seems the longer we go, the more impact we see of the treatments that were started early on in this disease.”

The findings from this study are “significantly important,” Nina T. Washington, MD, MPH, a pediatric rheumatologist at the University of New Mexico Hospital, Albuquerque, and the Mary Bridge Children’s Hospital in Tacoma, Wash., said in an interview. “At least for the past decade we’ve really been advocating towards earlier and aggressive therapy, and that’s what this study shows: the sooner you can treat this disease, the sooner you can attack those joints that are inflamed, the better outcome you give the patient.”

The study also confirms that pediatric rheumatologists are not overtreating patients with pJIA, she added.

“In a sense we’re actually treating and preventing and if you have a child that has arthritis, it’s okay to treat that child,” Dr. Washington said. “For me that’s the most reassuring thing: that I’m not necessarily going overboard. If I have a child with polyarticular JIA and they have multiple inflamed joints and I have the evidence as they’re sitting in front of me, and I treat them. I’m going to give them the best outcome.”

The Patient Centered Outcomes Research Institute provided study funding. Dr. Kimura is chair of the CARRA JIA disease research committee and cochair of the CARRA Registry and Research Oversight Committee. She disclosed a financial relationship with Genentech. Dr. Washington has no relevant relationships to disclose.
 

PHILADELPHIA – In the first controlled clinical trial to compare the two drugs, rituximab and cyclophosphamide were similarly effective in improving lung function in patients with interstitial lung disease (ILD) associated with idiopathic inflammatory myositis and mixed connective tissue disease (CTD). The findings also revealed some nuanced findings that could help clarify which drug to use in specific patients.

“We feel that rituximab is a reasonable alternative to cyclophosphamide as a treatment in patients with these diseases,” said Toby Maher, MD, of the University of Southern California, Los Angeles, who presented results of an analysis of three disease subgroups from the RECITAL (Rituximab versus Cyclophosphamide for the Treatment of Connective Tissue Disease Associated Interstitial Lung Disease) study at the annual meeting of the American College of Rheumatology.

“We didn’t show it to be better, so I think you can reasonably choose between the two, but rituximab almost certainly has the advantage of being safer and better tolerated than cyclophosphamide,” Dr. Maher said in an interview. The findings were published simultaneously in The Lancet Respiratory Medicine.
 

Double-blind, double-dummy

RECITAL is a phase 2b, randomized, controlled trial to test the hypothesis that intravenous rituximab would be superior to cyclophosphamide for ILD-associated CTD.

The study included adults with three separate diagnoses: myositis (n = 44), mixed CTD (n = 16), and systemic sclerosis (SSc, n = 37). The study was done in the United Kingdom when Dr. Maher was with Imperial College London.

Patients in the rituximab group received 1,000 mg of IV treatment at baseline and 2 weeks, then placebo treatment every 4 weeks to week 20. Cyclophosphamide patients received 600 mg/m² of body surface area intravenously every 4 weeks for six doses.

“When we designed this study there was limited evidence for any treatment for any disease associated with ILD,” Dr. Maher said. “But cyclophosphamide brings with it many challenges. It can be poorly tolerated and carries issues like infertility and risk of bladder cancer.”
 

Improved lung function

While the study failed to meet its primary endpoint – superiority of rituximab versus cyclophosphamide – it did show that both drugs led to improvement in lung function, measured by the rate of change in forced vital capacity (FVC), as well as quality of life measures, Dr. Maher said.

“Overall by week 48, we saw about a 5% improvement in FVC in the cyclophosphamide group and approximately a 4% improvement in FVC from baseline in the rituximab group, suggesting that both drugs almost certainly had a positive benefit in this patient group,” he said.

But secondary outcomes varied somewhat across the different disease groups. Patients with SSc saw a slight deterioration with cyclophosphamide in the modified Rodnan skin score at 24 weeks (1.6 ± 5.7 units) but an improvement with rituximab (–3.4 ± 8.1 units).

“One area where we did see a difference was in the number of adverse events,” Dr. Maher said. “They were fewer in the rituximab arm – namely gastrointestinal disorders [and] nausea, which we saw quite frequently following cyclophosphamide. Also, they had fewer headaches, which we saw quite frequently following cyclophosphamide.”

Rituximab patients also had fewer infusion reactions, but the number of infections was similar between the two treatment groups, he said.

“The patient group that responded best to treatment was the myositis group,” Dr. Maher said in his presentation. “Cyclophosphamide actually appears to be more effective than rituximab in improving their disease. By the end of 48 weeks, the cyclophosphamide group actually gained about 400 mL in FVC, so a close to 20% improvement.”

The rituximab group had “a little bit of a drop-off” in efficacy from weeks 24 to 48, although the trial didn’t repeat dosing at 6 months, “which is what perhaps one might do in clinical practice,” he said.

Oliver Distler, MD, chair of rheumatology at the University Hospital Zürich, raised questions about concurrent corticosteroid use in study patients that may have caused a “spillover” in the study’s efficacy analysis. But Dr. Maher noted that steroid use was balanced in all treatment arms. Patients in the cyclophosphamide arm averaged 42.9 mg of hydrocortisone daily versus 37.6 mg daily in the rituximab arm. That represents a 12.3% reduction in steroid exposure for the latter.

Dr. Distler noted that the myositis population represented the bulk of those study patients on steroids. “So in the myositis subanalysis we do see a combination of high-dose steroid plus cyclophosphamide and rituximab.”

Dr. Maher disclosed relationships with Boehringer Ingelheim, Genentech, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Trevi, CSL Behring, Pliant and Veracyte. Dr. Distler disclosed relationships with numerous pharmaceutical companies.






 

PHILADELPHIA – In the first controlled clinical trial to compare the two drugs, rituximab and cyclophosphamide were similarly effective in improving lung function in patients with interstitial lung disease (ILD) associated with idiopathic inflammatory myositis and mixed connective tissue disease (CTD). The findings also revealed some nuanced findings that could help clarify which drug to use in specific patients.

“We feel that rituximab is a reasonable alternative to cyclophosphamide as a treatment in patients with these diseases,” said Toby Maher, MD, of the University of Southern California, Los Angeles, who presented results of an analysis of three disease subgroups from the RECITAL (Rituximab versus Cyclophosphamide for the Treatment of Connective Tissue Disease Associated Interstitial Lung Disease) study at the annual meeting of the American College of Rheumatology.

“We didn’t show it to be better, so I think you can reasonably choose between the two, but rituximab almost certainly has the advantage of being safer and better tolerated than cyclophosphamide,” Dr. Maher said in an interview. The findings were published simultaneously in The Lancet Respiratory Medicine.
 

Double-blind, double-dummy

RECITAL is a phase 2b, randomized, controlled trial to test the hypothesis that intravenous rituximab would be superior to cyclophosphamide for ILD-associated CTD.

The study included adults with three separate diagnoses: myositis (n = 44), mixed CTD (n = 16), and systemic sclerosis (SSc, n = 37). The study was done in the United Kingdom when Dr. Maher was with Imperial College London.

Patients in the rituximab group received 1,000 mg of IV treatment at baseline and 2 weeks, then placebo treatment every 4 weeks to week 20. Cyclophosphamide patients received 600 mg/m² of body surface area intravenously every 4 weeks for six doses.

“When we designed this study there was limited evidence for any treatment for any disease associated with ILD,” Dr. Maher said. “But cyclophosphamide brings with it many challenges. It can be poorly tolerated and carries issues like infertility and risk of bladder cancer.”
 

Improved lung function

While the study failed to meet its primary endpoint – superiority of rituximab versus cyclophosphamide – it did show that both drugs led to improvement in lung function, measured by the rate of change in forced vital capacity (FVC), as well as quality of life measures, Dr. Maher said.

“Overall by week 48, we saw about a 5% improvement in FVC in the cyclophosphamide group and approximately a 4% improvement in FVC from baseline in the rituximab group, suggesting that both drugs almost certainly had a positive benefit in this patient group,” he said.

But secondary outcomes varied somewhat across the different disease groups. Patients with SSc saw a slight deterioration with cyclophosphamide in the modified Rodnan skin score at 24 weeks (1.6 ± 5.7 units) but an improvement with rituximab (–3.4 ± 8.1 units).

“One area where we did see a difference was in the number of adverse events,” Dr. Maher said. “They were fewer in the rituximab arm – namely gastrointestinal disorders [and] nausea, which we saw quite frequently following cyclophosphamide. Also, they had fewer headaches, which we saw quite frequently following cyclophosphamide.”

Rituximab patients also had fewer infusion reactions, but the number of infections was similar between the two treatment groups, he said.

“The patient group that responded best to treatment was the myositis group,” Dr. Maher said in his presentation. “Cyclophosphamide actually appears to be more effective than rituximab in improving their disease. By the end of 48 weeks, the cyclophosphamide group actually gained about 400 mL in FVC, so a close to 20% improvement.”

The rituximab group had “a little bit of a drop-off” in efficacy from weeks 24 to 48, although the trial didn’t repeat dosing at 6 months, “which is what perhaps one might do in clinical practice,” he said.

Oliver Distler, MD, chair of rheumatology at the University Hospital Zürich, raised questions about concurrent corticosteroid use in study patients that may have caused a “spillover” in the study’s efficacy analysis. But Dr. Maher noted that steroid use was balanced in all treatment arms. Patients in the cyclophosphamide arm averaged 42.9 mg of hydrocortisone daily versus 37.6 mg daily in the rituximab arm. That represents a 12.3% reduction in steroid exposure for the latter.

Dr. Distler noted that the myositis population represented the bulk of those study patients on steroids. “So in the myositis subanalysis we do see a combination of high-dose steroid plus cyclophosphamide and rituximab.”

Dr. Maher disclosed relationships with Boehringer Ingelheim, Genentech, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Trevi, CSL Behring, Pliant and Veracyte. Dr. Distler disclosed relationships with numerous pharmaceutical companies.






 

PHILADELPHIA – In the first controlled clinical trial to compare the two drugs, rituximab and cyclophosphamide were similarly effective in improving lung function in patients with interstitial lung disease (ILD) associated with idiopathic inflammatory myositis and mixed connective tissue disease (CTD). The findings also revealed some nuanced findings that could help clarify which drug to use in specific patients.

“We feel that rituximab is a reasonable alternative to cyclophosphamide as a treatment in patients with these diseases,” said Toby Maher, MD, of the University of Southern California, Los Angeles, who presented results of an analysis of three disease subgroups from the RECITAL (Rituximab versus Cyclophosphamide for the Treatment of Connective Tissue Disease Associated Interstitial Lung Disease) study at the annual meeting of the American College of Rheumatology.

“We didn’t show it to be better, so I think you can reasonably choose between the two, but rituximab almost certainly has the advantage of being safer and better tolerated than cyclophosphamide,” Dr. Maher said in an interview. The findings were published simultaneously in The Lancet Respiratory Medicine.
 

Double-blind, double-dummy

RECITAL is a phase 2b, randomized, controlled trial to test the hypothesis that intravenous rituximab would be superior to cyclophosphamide for ILD-associated CTD.

The study included adults with three separate diagnoses: myositis (n = 44), mixed CTD (n = 16), and systemic sclerosis (SSc, n = 37). The study was done in the United Kingdom when Dr. Maher was with Imperial College London.

Patients in the rituximab group received 1,000 mg of IV treatment at baseline and 2 weeks, then placebo treatment every 4 weeks to week 20. Cyclophosphamide patients received 600 mg/m² of body surface area intravenously every 4 weeks for six doses.

“When we designed this study there was limited evidence for any treatment for any disease associated with ILD,” Dr. Maher said. “But cyclophosphamide brings with it many challenges. It can be poorly tolerated and carries issues like infertility and risk of bladder cancer.”
 

Improved lung function

While the study failed to meet its primary endpoint – superiority of rituximab versus cyclophosphamide – it did show that both drugs led to improvement in lung function, measured by the rate of change in forced vital capacity (FVC), as well as quality of life measures, Dr. Maher said.

“Overall by week 48, we saw about a 5% improvement in FVC in the cyclophosphamide group and approximately a 4% improvement in FVC from baseline in the rituximab group, suggesting that both drugs almost certainly had a positive benefit in this patient group,” he said.

But secondary outcomes varied somewhat across the different disease groups. Patients with SSc saw a slight deterioration with cyclophosphamide in the modified Rodnan skin score at 24 weeks (1.6 ± 5.7 units) but an improvement with rituximab (–3.4 ± 8.1 units).

“One area where we did see a difference was in the number of adverse events,” Dr. Maher said. “They were fewer in the rituximab arm – namely gastrointestinal disorders [and] nausea, which we saw quite frequently following cyclophosphamide. Also, they had fewer headaches, which we saw quite frequently following cyclophosphamide.”

Rituximab patients also had fewer infusion reactions, but the number of infections was similar between the two treatment groups, he said.

“The patient group that responded best to treatment was the myositis group,” Dr. Maher said in his presentation. “Cyclophosphamide actually appears to be more effective than rituximab in improving their disease. By the end of 48 weeks, the cyclophosphamide group actually gained about 400 mL in FVC, so a close to 20% improvement.”

The rituximab group had “a little bit of a drop-off” in efficacy from weeks 24 to 48, although the trial didn’t repeat dosing at 6 months, “which is what perhaps one might do in clinical practice,” he said.

Oliver Distler, MD, chair of rheumatology at the University Hospital Zürich, raised questions about concurrent corticosteroid use in study patients that may have caused a “spillover” in the study’s efficacy analysis. But Dr. Maher noted that steroid use was balanced in all treatment arms. Patients in the cyclophosphamide arm averaged 42.9 mg of hydrocortisone daily versus 37.6 mg daily in the rituximab arm. That represents a 12.3% reduction in steroid exposure for the latter.

Dr. Distler noted that the myositis population represented the bulk of those study patients on steroids. “So in the myositis subanalysis we do see a combination of high-dose steroid plus cyclophosphamide and rituximab.”

Dr. Maher disclosed relationships with Boehringer Ingelheim, Genentech, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Trevi, CSL Behring, Pliant and Veracyte. Dr. Distler disclosed relationships with numerous pharmaceutical companies.






 

People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).

The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.

The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
 

Expert commentary

This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”

The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.

“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”

The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.

A version of this article first appeared on Medscape.com.

People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).

The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.

The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
 

Expert commentary

This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”

The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.

“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”

The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.

A version of this article first appeared on Medscape.com.

People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).

The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.

The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
 

Expert commentary

This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”

The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.

“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”

The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.

A version of this article first appeared on Medscape.com.

Diabetes persists as a risk factor for cardiovascular events, but where it once meant the same risk of heart attack or stroke as cardiovascular disease itself, a large Canadian population study reports that’s no longer the case. Thanks to advances in diabetes management over the past quarter century, diabetes is no longer considered equivalent to CVD as a risk factor for cardiovascular events, researchers from the University of Toronto reported.

The retrospective, population-based study used administrative data from Ontario’s provincial universal health care system. The researchers created five population-based cohorts of adults at 5-year intervals from 1994 to 2014, consisting of 1.87 million adults in the first cohort and 1.5 million in the last. In that 20-year span, the prevalence of diabetes in this population tripled, from 3.1% to 9%.

“In the last 25 years we’ve seen wholesale changes in the way people approach diabetes,” lead study author Calvin Ke, MD, PhD, an endocrinologist and assistant professor at the University of Toronto, said in an interview. “Part of the findings show that diabetes and cardiovascular disease were equivalent for risk of cardiovascular events in 1994, but by 2014 that was not the case.”

However, Dr. Ke added, “Diabetes is still a very strong cardiovascular risk factor.”

The investigators for the study, reported as a research letter in JAMA, analyzed the risk of cardiovascular events in four subgroups: those who had both diabetes and CVD, CVD only, diabetes only, and no CVD or diabetes.

Between 1994 and 2014, the cardiovascular event rates declined significantly among people with diabetes alone, compared with people with no disease: from 28.4 to 12.7 per 1,000 person-years, or an absolute risk increase (ARI) of 4.4% and a relative risk (RR) more than double (2.06), in 1994 to 14 vs. 8 per 1,000 person-years, and an ARI of 2% and RR less than double (1.58) 20 years later.

Among people with CVD only, those values shifted from 36.1 per 1,000 person-years, ARI of 5.1% and RR of 2.16 in 1994 to 23.9, ARI of 3.7% and RR still more than double (2.06) in 2014.

People with both CVD and diabetes had the highest CVD event rates across all 5-year cohorts: 74 per 1,000 person-years, ARI of 12% and RR almost four times greater (3.81) in 1994 than people with no disease. By 2014, the ARI in this group was 7.6% and the RR 3.10.

The investigators calculated that event rates from 1994 to 2014 declined across all four subgroups, with rate ratios of 0.49 for diabetes only, 0.66 for CVD only, 0.60 for both diabetes and CVD, and 0.63 for neither disease.

Shift in practice

The study noted that the shift in diabetes as a risk factor for heart attack and stroke is “a change that likely reflects the use of modern, multifactorial approaches to diabetes.”

“A number of changes have occurred in practice that really focus on this idea of a multifactorial approach to diabetes: more aggressive management of blood sugar, blood pressure, and lipids,” Dr. Ke said. “We know from the statin trials that statins can reduce the risk of heart disease significantly, and the use of statins increased from 28.4% in 1999 to 56.3% in 2018 in the United States,” Dr. Ke said. He added that statin use in Canada in adults ages 40 and older went from 1.2% in 1994 to 58.4% in 2010-2015. Use of ACE inhibitors and angiotensin receptor blockers for hypertension followed similar trends, contributing further to reducing risks for heart attack and stroke, Dr. Ke said.

Dr. Ke also noted that the evolution of guidelines and advances in treatments for both CVD and diabetes since 1994 have contributed to improving risks for people with diabetes. SGLT2 inhibitors have been linked to a 2%-6% reduction in hemoglobin A1c, he said. “All of these factors combined have had a major effect on the reduced risk of cardiovascular events.”

Prakash Deedwania, MD, professor at the University of California, San Francisco, Fresno, said that this study confirms a trend that others have reported regarding the risk of CVD in diabetes. The large database covering millions of adults is a study strength, he said.

And the findings, Dr. Deedwania added, underscore what’s been published in clinical guidelines, notably the American Heart Association scientific statement for managing CVD risk in patients with diabetes. “This means that, from observations made 20-plus years ago, when most people were not being treated for diabetes or heart disease, the pendulum has swung,” he said.

However, he added, “The authors state clearly that it does not mean that diabetes is not associated with a higher risk of cardiovascular events; it just means it is no longer equivalent to CVD.”

Managing diabetes continues to be “particularly important,” Dr. Deedwania said, because the prevalence of diabetes continues to rise. “This is a phenomenal risk, and it emphasizes that, to really conquer or control diabetes, we should make every effort to prevent diabetes,” he said.

Dr. Ke and Dr. Deedwania have no relevant financial relationships to disclose.

Diabetes persists as a risk factor for cardiovascular events, but where it once meant the same risk of heart attack or stroke as cardiovascular disease itself, a large Canadian population study reports that’s no longer the case. Thanks to advances in diabetes management over the past quarter century, diabetes is no longer considered equivalent to CVD as a risk factor for cardiovascular events, researchers from the University of Toronto reported.

The retrospective, population-based study used administrative data from Ontario’s provincial universal health care system. The researchers created five population-based cohorts of adults at 5-year intervals from 1994 to 2014, consisting of 1.87 million adults in the first cohort and 1.5 million in the last. In that 20-year span, the prevalence of diabetes in this population tripled, from 3.1% to 9%.

“In the last 25 years we’ve seen wholesale changes in the way people approach diabetes,” lead study author Calvin Ke, MD, PhD, an endocrinologist and assistant professor at the University of Toronto, said in an interview. “Part of the findings show that diabetes and cardiovascular disease were equivalent for risk of cardiovascular events in 1994, but by 2014 that was not the case.”

However, Dr. Ke added, “Diabetes is still a very strong cardiovascular risk factor.”

The investigators for the study, reported as a research letter in JAMA, analyzed the risk of cardiovascular events in four subgroups: those who had both diabetes and CVD, CVD only, diabetes only, and no CVD or diabetes.

Between 1994 and 2014, the cardiovascular event rates declined significantly among people with diabetes alone, compared with people with no disease: from 28.4 to 12.7 per 1,000 person-years, or an absolute risk increase (ARI) of 4.4% and a relative risk (RR) more than double (2.06), in 1994 to 14 vs. 8 per 1,000 person-years, and an ARI of 2% and RR less than double (1.58) 20 years later.

Among people with CVD only, those values shifted from 36.1 per 1,000 person-years, ARI of 5.1% and RR of 2.16 in 1994 to 23.9, ARI of 3.7% and RR still more than double (2.06) in 2014.

People with both CVD and diabetes had the highest CVD event rates across all 5-year cohorts: 74 per 1,000 person-years, ARI of 12% and RR almost four times greater (3.81) in 1994 than people with no disease. By 2014, the ARI in this group was 7.6% and the RR 3.10.

The investigators calculated that event rates from 1994 to 2014 declined across all four subgroups, with rate ratios of 0.49 for diabetes only, 0.66 for CVD only, 0.60 for both diabetes and CVD, and 0.63 for neither disease.

Shift in practice

The study noted that the shift in diabetes as a risk factor for heart attack and stroke is “a change that likely reflects the use of modern, multifactorial approaches to diabetes.”

“A number of changes have occurred in practice that really focus on this idea of a multifactorial approach to diabetes: more aggressive management of blood sugar, blood pressure, and lipids,” Dr. Ke said. “We know from the statin trials that statins can reduce the risk of heart disease significantly, and the use of statins increased from 28.4% in 1999 to 56.3% in 2018 in the United States,” Dr. Ke said. He added that statin use in Canada in adults ages 40 and older went from 1.2% in 1994 to 58.4% in 2010-2015. Use of ACE inhibitors and angiotensin receptor blockers for hypertension followed similar trends, contributing further to reducing risks for heart attack and stroke, Dr. Ke said.

Dr. Ke also noted that the evolution of guidelines and advances in treatments for both CVD and diabetes since 1994 have contributed to improving risks for people with diabetes. SGLT2 inhibitors have been linked to a 2%-6% reduction in hemoglobin A1c, he said. “All of these factors combined have had a major effect on the reduced risk of cardiovascular events.”

Prakash Deedwania, MD, professor at the University of California, San Francisco, Fresno, said that this study confirms a trend that others have reported regarding the risk of CVD in diabetes. The large database covering millions of adults is a study strength, he said.

And the findings, Dr. Deedwania added, underscore what’s been published in clinical guidelines, notably the American Heart Association scientific statement for managing CVD risk in patients with diabetes. “This means that, from observations made 20-plus years ago, when most people were not being treated for diabetes or heart disease, the pendulum has swung,” he said.

However, he added, “The authors state clearly that it does not mean that diabetes is not associated with a higher risk of cardiovascular events; it just means it is no longer equivalent to CVD.”

Managing diabetes continues to be “particularly important,” Dr. Deedwania said, because the prevalence of diabetes continues to rise. “This is a phenomenal risk, and it emphasizes that, to really conquer or control diabetes, we should make every effort to prevent diabetes,” he said.

Dr. Ke and Dr. Deedwania have no relevant financial relationships to disclose.

Diabetes persists as a risk factor for cardiovascular events, but where it once meant the same risk of heart attack or stroke as cardiovascular disease itself, a large Canadian population study reports that’s no longer the case. Thanks to advances in diabetes management over the past quarter century, diabetes is no longer considered equivalent to CVD as a risk factor for cardiovascular events, researchers from the University of Toronto reported.

The retrospective, population-based study used administrative data from Ontario’s provincial universal health care system. The researchers created five population-based cohorts of adults at 5-year intervals from 1994 to 2014, consisting of 1.87 million adults in the first cohort and 1.5 million in the last. In that 20-year span, the prevalence of diabetes in this population tripled, from 3.1% to 9%.

“In the last 25 years we’ve seen wholesale changes in the way people approach diabetes,” lead study author Calvin Ke, MD, PhD, an endocrinologist and assistant professor at the University of Toronto, said in an interview. “Part of the findings show that diabetes and cardiovascular disease were equivalent for risk of cardiovascular events in 1994, but by 2014 that was not the case.”

However, Dr. Ke added, “Diabetes is still a very strong cardiovascular risk factor.”

The investigators for the study, reported as a research letter in JAMA, analyzed the risk of cardiovascular events in four subgroups: those who had both diabetes and CVD, CVD only, diabetes only, and no CVD or diabetes.

Between 1994 and 2014, the cardiovascular event rates declined significantly among people with diabetes alone, compared with people with no disease: from 28.4 to 12.7 per 1,000 person-years, or an absolute risk increase (ARI) of 4.4% and a relative risk (RR) more than double (2.06), in 1994 to 14 vs. 8 per 1,000 person-years, and an ARI of 2% and RR less than double (1.58) 20 years later.

Among people with CVD only, those values shifted from 36.1 per 1,000 person-years, ARI of 5.1% and RR of 2.16 in 1994 to 23.9, ARI of 3.7% and RR still more than double (2.06) in 2014.

People with both CVD and diabetes had the highest CVD event rates across all 5-year cohorts: 74 per 1,000 person-years, ARI of 12% and RR almost four times greater (3.81) in 1994 than people with no disease. By 2014, the ARI in this group was 7.6% and the RR 3.10.

The investigators calculated that event rates from 1994 to 2014 declined across all four subgroups, with rate ratios of 0.49 for diabetes only, 0.66 for CVD only, 0.60 for both diabetes and CVD, and 0.63 for neither disease.

Shift in practice

The study noted that the shift in diabetes as a risk factor for heart attack and stroke is “a change that likely reflects the use of modern, multifactorial approaches to diabetes.”

“A number of changes have occurred in practice that really focus on this idea of a multifactorial approach to diabetes: more aggressive management of blood sugar, blood pressure, and lipids,” Dr. Ke said. “We know from the statin trials that statins can reduce the risk of heart disease significantly, and the use of statins increased from 28.4% in 1999 to 56.3% in 2018 in the United States,” Dr. Ke said. He added that statin use in Canada in adults ages 40 and older went from 1.2% in 1994 to 58.4% in 2010-2015. Use of ACE inhibitors and angiotensin receptor blockers for hypertension followed similar trends, contributing further to reducing risks for heart attack and stroke, Dr. Ke said.

Dr. Ke also noted that the evolution of guidelines and advances in treatments for both CVD and diabetes since 1994 have contributed to improving risks for people with diabetes. SGLT2 inhibitors have been linked to a 2%-6% reduction in hemoglobin A1c, he said. “All of these factors combined have had a major effect on the reduced risk of cardiovascular events.”

Prakash Deedwania, MD, professor at the University of California, San Francisco, Fresno, said that this study confirms a trend that others have reported regarding the risk of CVD in diabetes. The large database covering millions of adults is a study strength, he said.

And the findings, Dr. Deedwania added, underscore what’s been published in clinical guidelines, notably the American Heart Association scientific statement for managing CVD risk in patients with diabetes. “This means that, from observations made 20-plus years ago, when most people were not being treated for diabetes or heart disease, the pendulum has swung,” he said.

However, he added, “The authors state clearly that it does not mean that diabetes is not associated with a higher risk of cardiovascular events; it just means it is no longer equivalent to CVD.”

Managing diabetes continues to be “particularly important,” Dr. Deedwania said, because the prevalence of diabetes continues to rise. “This is a phenomenal risk, and it emphasizes that, to really conquer or control diabetes, we should make every effort to prevent diabetes,” he said.

Dr. Ke and Dr. Deedwania have no relevant financial relationships to disclose.

The COVID-19 pandemic has been associated with the development of anorexia nervosa in Canadian children and adolescents, data suggest.

Preliminary results of the Canadian Paediatric Surveillance Program (CPSP) indicate that the pandemic has been a precipitating factor in the development of anorexia nervosa in almost half of children and adolescents studied. The pandemic also has precipitated hospitalizations for anorexia in more than one-third of cases.

“Data globally, and certainly our data here in Canada, have shown a real increase in health care utilization with the onset of the COVID-19 pandemic,” study author Debra Katzman, MD, professor of pediatrics at the Hospital for Sick Children in Toronto and the University of Toronto, said in an interview. “And when I talk about health care utilization, I’m talking about hospitalizations for eating disorders.”

The data were included in the 2021 results of the CPSP.
 

Focus on appearance

CPSP is a collaboration between the Public Health Agency of Canada and the Canadian Pediatric Society that consists of a network of 2,800 pediatricians and pediatric subspecialists across Canada. The latest results include surveillance studies on 14 diseases and conditions, with data collected during various periods.

From April 2020 to May 2021, researchers identified 1,800 COVID-19 cases in children and collected detailed information on 1,456 of them, including 405 cases hospitalized with pediatric inflammatory multisystem syndrome (PIMS). The median age of hospitalized cases was 3.2 years for SARS-CoV-2 infection and 5.4 years for PIMS.

Dr. Katzman and colleagues observed 118 first-time hospitalizations for anorexia nervosa between Sept. 1 and Dec. 31, 2021. More than 90% of reported cases were female, with 66% of verified cases in teens aged 14-17 years and the remainder in adolescents aged 11-13 years.

In 49% of cases, the reporting physician identified the COVID-19 pandemic as a precipitating factor in the development of anorexia nervosa. In 37% of cases, the reporting physician identified the pandemic as having precipitated the anorexia-related hospitalization.

Last year, a cross-sectional analysis of children in Canada reported that monthly hospitalizations for anorexia nervosa increased from 7.5 to 20 from March through November 2020. The monthly rate in the CPSP study was closer to 30 for first-time hospitalizations.

Dr. Katzman said that the findings about anorexia nervosa didn’t surprise her. “There was so much disruption and [so many] restrictions to young peoples’ daily routines – closures of schools and recreational activities – they lost regular connection with their peers, and they lost extracurricular and social activities,” she said. “That led to heightened anxiety and depression and really a lack of control.”

Adolescents and teens were also spending more time on social media than they were before the pandemic, she noted. “They were looking at themselves all the time, so they were getting preoccupied with their body image. There was a heightened focus on appearance, and I think that things like public-health mitigation strategies – things like hand washing, social distancing, mask wearing – may have impacted the psychological well-being of young people.”

The closure of outpatient facilities, long waiting lists to get into facilities that were opened, and “coronaphobia” about going to physicians’ offices and emergency departments compounded the problem, Dr. Katzman added.

The long-term effects of COVID and eating disorders in children are unknown, Dr. Katzman said. “This is sort of a wake-up call for the health care system that during times of stress or pandemics or crises, these kinds of things can happen, and we need to be prepared to provide the resources for vulnerable populations moving forward,” she said.
 

Heightened anxiety

Commenting on the data, Margaret Thew, APNP, director of the eating disorders program at Children’s Wisconsin in Milwaukee, said that isolation due to school closures and negative social media messages created the “perfect storm” for eating disorders in adolescents and teenagers because of higher rates of anxiety and depression. Ms. Thew was not involved in the research.

The storm is not over yet, she said. “What everyone needs to keep in mind is that we still have this very heightened state of anxiety and depression ... for adolescents, teenagers, and preteens alike,” Ms. Thew said in an interview, “and we know that many of them are not coping with their anxiety very well.”

In her experience, since the start of the pandemic, the average age of pediatric patients with eating disorders declined from 16 to 15 years, and the youngest age declined from 12 to 11 years.

Overall, the CPSP results show that children are affected by mental health issues at an earlier age than before the pandemic, said Ms. Thew. “Years ago, we wouldn’t have thought that an 8-year-old needed to be screened for some of these risk factors, but now we’re definitely getting more younger children who are struggling, and I think it’s taking too long for them to get the care they need because it’s being overlooked,” she said.

The report was funded by the Public Health Agency of Canada, Health Canada, Alberta Children’s Hospital Research Institute, Bethanys Hope Foundation, CHEO Research Institute, and Children’s Hospital Research Institute of Manitoba. Dr. Katzman and Ms. Thew have no relevant disclosures.

A version of this article first appeared on Medscape.com.

The COVID-19 pandemic has been associated with the development of anorexia nervosa in Canadian children and adolescents, data suggest.

Preliminary results of the Canadian Paediatric Surveillance Program (CPSP) indicate that the pandemic has been a precipitating factor in the development of anorexia nervosa in almost half of children and adolescents studied. The pandemic also has precipitated hospitalizations for anorexia in more than one-third of cases.

“Data globally, and certainly our data here in Canada, have shown a real increase in health care utilization with the onset of the COVID-19 pandemic,” study author Debra Katzman, MD, professor of pediatrics at the Hospital for Sick Children in Toronto and the University of Toronto, said in an interview. “And when I talk about health care utilization, I’m talking about hospitalizations for eating disorders.”

The data were included in the 2021 results of the CPSP.
 

Focus on appearance

CPSP is a collaboration between the Public Health Agency of Canada and the Canadian Pediatric Society that consists of a network of 2,800 pediatricians and pediatric subspecialists across Canada. The latest results include surveillance studies on 14 diseases and conditions, with data collected during various periods.

From April 2020 to May 2021, researchers identified 1,800 COVID-19 cases in children and collected detailed information on 1,456 of them, including 405 cases hospitalized with pediatric inflammatory multisystem syndrome (PIMS). The median age of hospitalized cases was 3.2 years for SARS-CoV-2 infection and 5.4 years for PIMS.

Dr. Katzman and colleagues observed 118 first-time hospitalizations for anorexia nervosa between Sept. 1 and Dec. 31, 2021. More than 90% of reported cases were female, with 66% of verified cases in teens aged 14-17 years and the remainder in adolescents aged 11-13 years.

In 49% of cases, the reporting physician identified the COVID-19 pandemic as a precipitating factor in the development of anorexia nervosa. In 37% of cases, the reporting physician identified the pandemic as having precipitated the anorexia-related hospitalization.

Last year, a cross-sectional analysis of children in Canada reported that monthly hospitalizations for anorexia nervosa increased from 7.5 to 20 from March through November 2020. The monthly rate in the CPSP study was closer to 30 for first-time hospitalizations.

Dr. Katzman said that the findings about anorexia nervosa didn’t surprise her. “There was so much disruption and [so many] restrictions to young peoples’ daily routines – closures of schools and recreational activities – they lost regular connection with their peers, and they lost extracurricular and social activities,” she said. “That led to heightened anxiety and depression and really a lack of control.”

Adolescents and teens were also spending more time on social media than they were before the pandemic, she noted. “They were looking at themselves all the time, so they were getting preoccupied with their body image. There was a heightened focus on appearance, and I think that things like public-health mitigation strategies – things like hand washing, social distancing, mask wearing – may have impacted the psychological well-being of young people.”

The closure of outpatient facilities, long waiting lists to get into facilities that were opened, and “coronaphobia” about going to physicians’ offices and emergency departments compounded the problem, Dr. Katzman added.

The long-term effects of COVID and eating disorders in children are unknown, Dr. Katzman said. “This is sort of a wake-up call for the health care system that during times of stress or pandemics or crises, these kinds of things can happen, and we need to be prepared to provide the resources for vulnerable populations moving forward,” she said.
 

Heightened anxiety

Commenting on the data, Margaret Thew, APNP, director of the eating disorders program at Children’s Wisconsin in Milwaukee, said that isolation due to school closures and negative social media messages created the “perfect storm” for eating disorders in adolescents and teenagers because of higher rates of anxiety and depression. Ms. Thew was not involved in the research.

The storm is not over yet, she said. “What everyone needs to keep in mind is that we still have this very heightened state of anxiety and depression ... for adolescents, teenagers, and preteens alike,” Ms. Thew said in an interview, “and we know that many of them are not coping with their anxiety very well.”

In her experience, since the start of the pandemic, the average age of pediatric patients with eating disorders declined from 16 to 15 years, and the youngest age declined from 12 to 11 years.

Overall, the CPSP results show that children are affected by mental health issues at an earlier age than before the pandemic, said Ms. Thew. “Years ago, we wouldn’t have thought that an 8-year-old needed to be screened for some of these risk factors, but now we’re definitely getting more younger children who are struggling, and I think it’s taking too long for them to get the care they need because it’s being overlooked,” she said.

The report was funded by the Public Health Agency of Canada, Health Canada, Alberta Children’s Hospital Research Institute, Bethanys Hope Foundation, CHEO Research Institute, and Children’s Hospital Research Institute of Manitoba. Dr. Katzman and Ms. Thew have no relevant disclosures.

A version of this article first appeared on Medscape.com.

The COVID-19 pandemic has been associated with the development of anorexia nervosa in Canadian children and adolescents, data suggest.

Preliminary results of the Canadian Paediatric Surveillance Program (CPSP) indicate that the pandemic has been a precipitating factor in the development of anorexia nervosa in almost half of children and adolescents studied. The pandemic also has precipitated hospitalizations for anorexia in more than one-third of cases.

“Data globally, and certainly our data here in Canada, have shown a real increase in health care utilization with the onset of the COVID-19 pandemic,” study author Debra Katzman, MD, professor of pediatrics at the Hospital for Sick Children in Toronto and the University of Toronto, said in an interview. “And when I talk about health care utilization, I’m talking about hospitalizations for eating disorders.”

The data were included in the 2021 results of the CPSP.
 

Focus on appearance

CPSP is a collaboration between the Public Health Agency of Canada and the Canadian Pediatric Society that consists of a network of 2,800 pediatricians and pediatric subspecialists across Canada. The latest results include surveillance studies on 14 diseases and conditions, with data collected during various periods.

From April 2020 to May 2021, researchers identified 1,800 COVID-19 cases in children and collected detailed information on 1,456 of them, including 405 cases hospitalized with pediatric inflammatory multisystem syndrome (PIMS). The median age of hospitalized cases was 3.2 years for SARS-CoV-2 infection and 5.4 years for PIMS.

Dr. Katzman and colleagues observed 118 first-time hospitalizations for anorexia nervosa between Sept. 1 and Dec. 31, 2021. More than 90% of reported cases were female, with 66% of verified cases in teens aged 14-17 years and the remainder in adolescents aged 11-13 years.

In 49% of cases, the reporting physician identified the COVID-19 pandemic as a precipitating factor in the development of anorexia nervosa. In 37% of cases, the reporting physician identified the pandemic as having precipitated the anorexia-related hospitalization.

Last year, a cross-sectional analysis of children in Canada reported that monthly hospitalizations for anorexia nervosa increased from 7.5 to 20 from March through November 2020. The monthly rate in the CPSP study was closer to 30 for first-time hospitalizations.

Dr. Katzman said that the findings about anorexia nervosa didn’t surprise her. “There was so much disruption and [so many] restrictions to young peoples’ daily routines – closures of schools and recreational activities – they lost regular connection with their peers, and they lost extracurricular and social activities,” she said. “That led to heightened anxiety and depression and really a lack of control.”

Adolescents and teens were also spending more time on social media than they were before the pandemic, she noted. “They were looking at themselves all the time, so they were getting preoccupied with their body image. There was a heightened focus on appearance, and I think that things like public-health mitigation strategies – things like hand washing, social distancing, mask wearing – may have impacted the psychological well-being of young people.”

The closure of outpatient facilities, long waiting lists to get into facilities that were opened, and “coronaphobia” about going to physicians’ offices and emergency departments compounded the problem, Dr. Katzman added.

The long-term effects of COVID and eating disorders in children are unknown, Dr. Katzman said. “This is sort of a wake-up call for the health care system that during times of stress or pandemics or crises, these kinds of things can happen, and we need to be prepared to provide the resources for vulnerable populations moving forward,” she said.
 

Heightened anxiety

Commenting on the data, Margaret Thew, APNP, director of the eating disorders program at Children’s Wisconsin in Milwaukee, said that isolation due to school closures and negative social media messages created the “perfect storm” for eating disorders in adolescents and teenagers because of higher rates of anxiety and depression. Ms. Thew was not involved in the research.

The storm is not over yet, she said. “What everyone needs to keep in mind is that we still have this very heightened state of anxiety and depression ... for adolescents, teenagers, and preteens alike,” Ms. Thew said in an interview, “and we know that many of them are not coping with their anxiety very well.”

In her experience, since the start of the pandemic, the average age of pediatric patients with eating disorders declined from 16 to 15 years, and the youngest age declined from 12 to 11 years.

Overall, the CPSP results show that children are affected by mental health issues at an earlier age than before the pandemic, said Ms. Thew. “Years ago, we wouldn’t have thought that an 8-year-old needed to be screened for some of these risk factors, but now we’re definitely getting more younger children who are struggling, and I think it’s taking too long for them to get the care they need because it’s being overlooked,” she said.

The report was funded by the Public Health Agency of Canada, Health Canada, Alberta Children’s Hospital Research Institute, Bethanys Hope Foundation, CHEO Research Institute, and Children’s Hospital Research Institute of Manitoba. Dr. Katzman and Ms. Thew have no relevant disclosures.

A version of this article first appeared on Medscape.com.

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.