Rheumatology News

WASHINGTON — An investigational 12-protein panel of urinary biomarkers predicted histologically active lupus nephritis (LN) with 86% accuracy, according to research presented at the American College of Rheumatology (ACR) 2024 Annual Meeting.

The noninvasive biomarker panel “robustly predicts meaningful and actionable histological findings” in patients with active proliferative LN, Andrea Fava, MD, assistant professor of medicine in the Division of Rheumatology at Johns Hopkins Medicine in Baltimore, told attendees.

“In contrast to proteinuria, which can’t differentiate inflammation from damage, this panel for histological activity includes a set of 12 proteins linked to intrarenal inflammation,” said Fava, director of Lupus Translational Research at Johns Hopkins. A decline in the biomarker score at 3 months predicted a clinical response at 1 year, and persistent elevation of the score at 1 year predicted permanent loss of kidney function, “which makes it tempting as a treatment endpoint,” Fava said. “Upon further validation, this biomarker panel could aid in the diagnosis of lupus nephritis and guide treatment decisions.” 

Alfred Kim, MD, PhD, an associate professor of medicine at Washington University in St. Louis, was not involved in the research but noted the potential value of a reliable biomarker panel.

“If we have urinary biomarkers that strongly associate with histologic activity, this would be a game changer in the management of LN,” Kim told Medscape Medical News. “Right now, the gold standard is to perform another kidney biopsy to determine if therapy is working. But this is invasive, and many patients do not want to do another kidney biopsy. Conversely, the easiest way to assess lupus nephritis activity is through a urinalysis, focusing on urinary protein levels,” but relying on proteinuria has limitations as well.

“The most important [limitation] is that proteinuria cannot distinguish treatable inflammation from chronic damage,” Fava said. Persistent histologic activity in patients without proteinuria predicts flares, but tracking histologic activity, as Kim noted, requires repeat biopsies.

“So we need better biomarkers because biomarkers that can reflect tissue biology in real time can guide personalized treatment, and that’s one of the main goals of the Accelerating Medicines Partnership [AMP],” he said. The AMP is a public-private partnership between the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), multiple biopharmaceutical and life science companies, and nonprofit and other organizations. Lupus is one of the AMP’s funded projects.

Kim agreed that “effective biomarkers are a huge unmet need in LN.” Further, he said, “imagine a world where the diagnosis of LN can be made just through urinary biomarkers and obviate the need for biopsy. Both patients and providers will be ecstatic at this possibility.” 

Fava described the background for how his research team determined what biomarkers to test. They had previously enrolled 225 patients with LN undergoing a clinically indicated kidney biopsy and collected urine samples from them at baseline and at 12, 24, and 52 weeks after their biopsy.

Of the 225 patients included, 9% with only mesangial LN (class I-II), 25% with pure membranous LN (class V), 24% with mixed LN (class III or IV with or without V), 38% with proliferative LN (class III or IV), and 4% with advanced sclerosis LN (class VI). From these samples, they quantified 1200 proteins and looked at how they correlated with histologic activity.

“What was interesting was that in patients who were classified as responders after 1 year, there were many of these proteins that declined as early as 3 months, suggesting that effective immunosuppression is reducing intrarenal inflammation, and we can capture it in real time,” Fava said.

 

Biomarker Panel Predicts Histologically Active LN

So they set to determining whether they could develop a urinary biomarker for histologically active LN that could be useful in clinical decision-making. They focused on one that could detect active proliferative LN with an NIH activity index score > 2. Their 179 participants included 47.5% Black, 27.9% White, and 14.5% Asian participants, with 10.1% of other races. The predominantly female (86.6%) cohort had an average age of 37 years. Among the LN classes, about one third (34.6%) had pure proliferative disease, 17.9% had mixed proliferative, 27.9% had pure membranous, 11.7% had class I or II, and 5% had class VI. Just over half the participants (55.7%) had not responded to treatment at 12 months, whereas 25% had a complete response, and 19.3% had a partial response.

However, both the 78 participants with an NIH activity index score > 2 and the 101 with a score ≤ 2 had a median score of 3 on the NIH chronicity index. And the urine protein-to-creatinine ratio — 2.8 in the group with an NIH activity index score > 2 and 2.4 in the other group — was nearly indistinguishable between the two groups, Fava said.

They then trained multiple algorithms on 80% of the data to find the best performing set of proteins (with an area under the curve [AUC] of 90%) for predicting an NIH activity index score > 2. They reduced the number of proteins to maximize practicality and performance of the panel, Fava said, and ultimately identified a 12-protein panel that was highly predictive of an NIH activity index score > 2. Then, they validated that panel using the other 20% of the data. The training set had an AUC of 90%, and the test set was validated with an AUC of 93%.

The 12-protein panel score outperformed anti-dsDNA, C3 complement, and proteinuria, with a sensitivity of 81%, a specificity of 90%, a positive predictive value of 87%, a negative predictive value of 86%, and an accuracy of 86%. The proteins with the greatest relative importance were CD163, cathepsin S, FOLR2, and CEACAM-1.

“In contrast to proteinuria, these proteins were related to inflammatory processes found in the kidneys in patients with lupus nephritis, such as activation of macrophages, neutrophils and monocytes, lymphocytes, and complement,” Fava said.

When they looked at the trajectories of the probabilities from the biomarker panel at 3, 6, and 12 months, the probability of the NIH activity index score remaining > 2 stayed high in the nonresponders over 1 year, but the trajectory declined at 3 months in the responders, indicating a decrease in kidney inflammation (P < .001).

 

Can the Biomarker Panel Serve as a Treatment Endpoint?

Then, to determine whether the panel could act as a reliable treatment endpoint, the researchers followed the patients for up to 7 years. One third of the patients lost more than 40% of their kidney function during the follow-up. They found that a high urinary biomarker score at 12 months predicted future glomerular filtration rate loss, independent of proteinuria.

This panel was tested specifically for proliferative LN, so “we may need distinct panels for each [LN type] to capture most of these patients,” Kim said. “I think that’s where the gold mine is: A personalized medicine approach where a large biomarker panel identifies which smaller panel that patient best fits, then use that for monitoring.”

Kim did note an important potential limitation in the study regarding how samples are used in biomarker discovery and validation vs in clinical practice. “Most samples in research studies are frozen, then thawed, while urine is assayed within a couple hours after collection in the clinical setting,” he said. “Do sample processing differences create a situation where a biomarker works in a research project but not in the clinical setting?” But more likely, he said, the opposite may be the case, where frozen samples allow for more degradation of proteins and potentially useful LN biomarker candidates are never detected.

Another challenge, Kim added, albeit unrelated to the study findings, is that diagnostic companies are finding it difficult to get payers to cover new tests, so that could become a challenge if the panel undergoes further validation and then FDA qualification.

The research was funded by Exagen. Fava reported disclosures with Arctiva, AstraZeneca, Exagen, Novartis, UCB, Bristol Myers Squibb, Annexon Bio, and Bain Capital. His coauthors reported financial relationships with numerous pharmaceutical and life science companies, including Exagen, and some are employees of Exagen.

Kim reported research agreements with AstraZeneca, Bristol Myers Squibb, Novartis, and CRISPR Therapeutics; receiving royalties from Kypha; and receiving consulting/speaking fees from AbbVie, Amgen, Atara Bio, Aurinia, Cargo Tx, Exagen, GlaxoSmithKline, Hinge Bio, Kypha, and UpToDate.

 

A version of this article appeared on Medscape.com.

WASHINGTON — An investigational 12-protein panel of urinary biomarkers predicted histologically active lupus nephritis (LN) with 86% accuracy, according to research presented at the American College of Rheumatology (ACR) 2024 Annual Meeting.

The noninvasive biomarker panel “robustly predicts meaningful and actionable histological findings” in patients with active proliferative LN, Andrea Fava, MD, assistant professor of medicine in the Division of Rheumatology at Johns Hopkins Medicine in Baltimore, told attendees.

“In contrast to proteinuria, which can’t differentiate inflammation from damage, this panel for histological activity includes a set of 12 proteins linked to intrarenal inflammation,” said Fava, director of Lupus Translational Research at Johns Hopkins. A decline in the biomarker score at 3 months predicted a clinical response at 1 year, and persistent elevation of the score at 1 year predicted permanent loss of kidney function, “which makes it tempting as a treatment endpoint,” Fava said. “Upon further validation, this biomarker panel could aid in the diagnosis of lupus nephritis and guide treatment decisions.” 

Alfred Kim, MD, PhD, an associate professor of medicine at Washington University in St. Louis, was not involved in the research but noted the potential value of a reliable biomarker panel.

“If we have urinary biomarkers that strongly associate with histologic activity, this would be a game changer in the management of LN,” Kim told Medscape Medical News. “Right now, the gold standard is to perform another kidney biopsy to determine if therapy is working. But this is invasive, and many patients do not want to do another kidney biopsy. Conversely, the easiest way to assess lupus nephritis activity is through a urinalysis, focusing on urinary protein levels,” but relying on proteinuria has limitations as well.

“The most important [limitation] is that proteinuria cannot distinguish treatable inflammation from chronic damage,” Fava said. Persistent histologic activity in patients without proteinuria predicts flares, but tracking histologic activity, as Kim noted, requires repeat biopsies.

“So we need better biomarkers because biomarkers that can reflect tissue biology in real time can guide personalized treatment, and that’s one of the main goals of the Accelerating Medicines Partnership [AMP],” he said. The AMP is a public-private partnership between the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), multiple biopharmaceutical and life science companies, and nonprofit and other organizations. Lupus is one of the AMP’s funded projects.

Kim agreed that “effective biomarkers are a huge unmet need in LN.” Further, he said, “imagine a world where the diagnosis of LN can be made just through urinary biomarkers and obviate the need for biopsy. Both patients and providers will be ecstatic at this possibility.” 

Fava described the background for how his research team determined what biomarkers to test. They had previously enrolled 225 patients with LN undergoing a clinically indicated kidney biopsy and collected urine samples from them at baseline and at 12, 24, and 52 weeks after their biopsy.

Of the 225 patients included, 9% with only mesangial LN (class I-II), 25% with pure membranous LN (class V), 24% with mixed LN (class III or IV with or without V), 38% with proliferative LN (class III or IV), and 4% with advanced sclerosis LN (class VI). From these samples, they quantified 1200 proteins and looked at how they correlated with histologic activity.

“What was interesting was that in patients who were classified as responders after 1 year, there were many of these proteins that declined as early as 3 months, suggesting that effective immunosuppression is reducing intrarenal inflammation, and we can capture it in real time,” Fava said.

 

Biomarker Panel Predicts Histologically Active LN

So they set to determining whether they could develop a urinary biomarker for histologically active LN that could be useful in clinical decision-making. They focused on one that could detect active proliferative LN with an NIH activity index score > 2. Their 179 participants included 47.5% Black, 27.9% White, and 14.5% Asian participants, with 10.1% of other races. The predominantly female (86.6%) cohort had an average age of 37 years. Among the LN classes, about one third (34.6%) had pure proliferative disease, 17.9% had mixed proliferative, 27.9% had pure membranous, 11.7% had class I or II, and 5% had class VI. Just over half the participants (55.7%) had not responded to treatment at 12 months, whereas 25% had a complete response, and 19.3% had a partial response.

However, both the 78 participants with an NIH activity index score > 2 and the 101 with a score ≤ 2 had a median score of 3 on the NIH chronicity index. And the urine protein-to-creatinine ratio — 2.8 in the group with an NIH activity index score > 2 and 2.4 in the other group — was nearly indistinguishable between the two groups, Fava said.

They then trained multiple algorithms on 80% of the data to find the best performing set of proteins (with an area under the curve [AUC] of 90%) for predicting an NIH activity index score > 2. They reduced the number of proteins to maximize practicality and performance of the panel, Fava said, and ultimately identified a 12-protein panel that was highly predictive of an NIH activity index score > 2. Then, they validated that panel using the other 20% of the data. The training set had an AUC of 90%, and the test set was validated with an AUC of 93%.

The 12-protein panel score outperformed anti-dsDNA, C3 complement, and proteinuria, with a sensitivity of 81%, a specificity of 90%, a positive predictive value of 87%, a negative predictive value of 86%, and an accuracy of 86%. The proteins with the greatest relative importance were CD163, cathepsin S, FOLR2, and CEACAM-1.

“In contrast to proteinuria, these proteins were related to inflammatory processes found in the kidneys in patients with lupus nephritis, such as activation of macrophages, neutrophils and monocytes, lymphocytes, and complement,” Fava said.

When they looked at the trajectories of the probabilities from the biomarker panel at 3, 6, and 12 months, the probability of the NIH activity index score remaining > 2 stayed high in the nonresponders over 1 year, but the trajectory declined at 3 months in the responders, indicating a decrease in kidney inflammation (P < .001).

 

Can the Biomarker Panel Serve as a Treatment Endpoint?

Then, to determine whether the panel could act as a reliable treatment endpoint, the researchers followed the patients for up to 7 years. One third of the patients lost more than 40% of their kidney function during the follow-up. They found that a high urinary biomarker score at 12 months predicted future glomerular filtration rate loss, independent of proteinuria.

This panel was tested specifically for proliferative LN, so “we may need distinct panels for each [LN type] to capture most of these patients,” Kim said. “I think that’s where the gold mine is: A personalized medicine approach where a large biomarker panel identifies which smaller panel that patient best fits, then use that for monitoring.”

Kim did note an important potential limitation in the study regarding how samples are used in biomarker discovery and validation vs in clinical practice. “Most samples in research studies are frozen, then thawed, while urine is assayed within a couple hours after collection in the clinical setting,” he said. “Do sample processing differences create a situation where a biomarker works in a research project but not in the clinical setting?” But more likely, he said, the opposite may be the case, where frozen samples allow for more degradation of proteins and potentially useful LN biomarker candidates are never detected.

Another challenge, Kim added, albeit unrelated to the study findings, is that diagnostic companies are finding it difficult to get payers to cover new tests, so that could become a challenge if the panel undergoes further validation and then FDA qualification.

The research was funded by Exagen. Fava reported disclosures with Arctiva, AstraZeneca, Exagen, Novartis, UCB, Bristol Myers Squibb, Annexon Bio, and Bain Capital. His coauthors reported financial relationships with numerous pharmaceutical and life science companies, including Exagen, and some are employees of Exagen.

Kim reported research agreements with AstraZeneca, Bristol Myers Squibb, Novartis, and CRISPR Therapeutics; receiving royalties from Kypha; and receiving consulting/speaking fees from AbbVie, Amgen, Atara Bio, Aurinia, Cargo Tx, Exagen, GlaxoSmithKline, Hinge Bio, Kypha, and UpToDate.

 

A version of this article appeared on Medscape.com.

WASHINGTON — An investigational 12-protein panel of urinary biomarkers predicted histologically active lupus nephritis (LN) with 86% accuracy, according to research presented at the American College of Rheumatology (ACR) 2024 Annual Meeting.

The noninvasive biomarker panel “robustly predicts meaningful and actionable histological findings” in patients with active proliferative LN, Andrea Fava, MD, assistant professor of medicine in the Division of Rheumatology at Johns Hopkins Medicine in Baltimore, told attendees.

“In contrast to proteinuria, which can’t differentiate inflammation from damage, this panel for histological activity includes a set of 12 proteins linked to intrarenal inflammation,” said Fava, director of Lupus Translational Research at Johns Hopkins. A decline in the biomarker score at 3 months predicted a clinical response at 1 year, and persistent elevation of the score at 1 year predicted permanent loss of kidney function, “which makes it tempting as a treatment endpoint,” Fava said. “Upon further validation, this biomarker panel could aid in the diagnosis of lupus nephritis and guide treatment decisions.” 

Alfred Kim, MD, PhD, an associate professor of medicine at Washington University in St. Louis, was not involved in the research but noted the potential value of a reliable biomarker panel.

“If we have urinary biomarkers that strongly associate with histologic activity, this would be a game changer in the management of LN,” Kim told Medscape Medical News. “Right now, the gold standard is to perform another kidney biopsy to determine if therapy is working. But this is invasive, and many patients do not want to do another kidney biopsy. Conversely, the easiest way to assess lupus nephritis activity is through a urinalysis, focusing on urinary protein levels,” but relying on proteinuria has limitations as well.

“The most important [limitation] is that proteinuria cannot distinguish treatable inflammation from chronic damage,” Fava said. Persistent histologic activity in patients without proteinuria predicts flares, but tracking histologic activity, as Kim noted, requires repeat biopsies.

“So we need better biomarkers because biomarkers that can reflect tissue biology in real time can guide personalized treatment, and that’s one of the main goals of the Accelerating Medicines Partnership [AMP],” he said. The AMP is a public-private partnership between the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), multiple biopharmaceutical and life science companies, and nonprofit and other organizations. Lupus is one of the AMP’s funded projects.

Kim agreed that “effective biomarkers are a huge unmet need in LN.” Further, he said, “imagine a world where the diagnosis of LN can be made just through urinary biomarkers and obviate the need for biopsy. Both patients and providers will be ecstatic at this possibility.” 

Fava described the background for how his research team determined what biomarkers to test. They had previously enrolled 225 patients with LN undergoing a clinically indicated kidney biopsy and collected urine samples from them at baseline and at 12, 24, and 52 weeks after their biopsy.

Of the 225 patients included, 9% with only mesangial LN (class I-II), 25% with pure membranous LN (class V), 24% with mixed LN (class III or IV with or without V), 38% with proliferative LN (class III or IV), and 4% with advanced sclerosis LN (class VI). From these samples, they quantified 1200 proteins and looked at how they correlated with histologic activity.

“What was interesting was that in patients who were classified as responders after 1 year, there were many of these proteins that declined as early as 3 months, suggesting that effective immunosuppression is reducing intrarenal inflammation, and we can capture it in real time,” Fava said.

 

Biomarker Panel Predicts Histologically Active LN

So they set to determining whether they could develop a urinary biomarker for histologically active LN that could be useful in clinical decision-making. They focused on one that could detect active proliferative LN with an NIH activity index score > 2. Their 179 participants included 47.5% Black, 27.9% White, and 14.5% Asian participants, with 10.1% of other races. The predominantly female (86.6%) cohort had an average age of 37 years. Among the LN classes, about one third (34.6%) had pure proliferative disease, 17.9% had mixed proliferative, 27.9% had pure membranous, 11.7% had class I or II, and 5% had class VI. Just over half the participants (55.7%) had not responded to treatment at 12 months, whereas 25% had a complete response, and 19.3% had a partial response.

However, both the 78 participants with an NIH activity index score > 2 and the 101 with a score ≤ 2 had a median score of 3 on the NIH chronicity index. And the urine protein-to-creatinine ratio — 2.8 in the group with an NIH activity index score > 2 and 2.4 in the other group — was nearly indistinguishable between the two groups, Fava said.

They then trained multiple algorithms on 80% of the data to find the best performing set of proteins (with an area under the curve [AUC] of 90%) for predicting an NIH activity index score > 2. They reduced the number of proteins to maximize practicality and performance of the panel, Fava said, and ultimately identified a 12-protein panel that was highly predictive of an NIH activity index score > 2. Then, they validated that panel using the other 20% of the data. The training set had an AUC of 90%, and the test set was validated with an AUC of 93%.

The 12-protein panel score outperformed anti-dsDNA, C3 complement, and proteinuria, with a sensitivity of 81%, a specificity of 90%, a positive predictive value of 87%, a negative predictive value of 86%, and an accuracy of 86%. The proteins with the greatest relative importance were CD163, cathepsin S, FOLR2, and CEACAM-1.

“In contrast to proteinuria, these proteins were related to inflammatory processes found in the kidneys in patients with lupus nephritis, such as activation of macrophages, neutrophils and monocytes, lymphocytes, and complement,” Fava said.

When they looked at the trajectories of the probabilities from the biomarker panel at 3, 6, and 12 months, the probability of the NIH activity index score remaining > 2 stayed high in the nonresponders over 1 year, but the trajectory declined at 3 months in the responders, indicating a decrease in kidney inflammation (P < .001).

 

Can the Biomarker Panel Serve as a Treatment Endpoint?

Then, to determine whether the panel could act as a reliable treatment endpoint, the researchers followed the patients for up to 7 years. One third of the patients lost more than 40% of their kidney function during the follow-up. They found that a high urinary biomarker score at 12 months predicted future glomerular filtration rate loss, independent of proteinuria.

This panel was tested specifically for proliferative LN, so “we may need distinct panels for each [LN type] to capture most of these patients,” Kim said. “I think that’s where the gold mine is: A personalized medicine approach where a large biomarker panel identifies which smaller panel that patient best fits, then use that for monitoring.”

Kim did note an important potential limitation in the study regarding how samples are used in biomarker discovery and validation vs in clinical practice. “Most samples in research studies are frozen, then thawed, while urine is assayed within a couple hours after collection in the clinical setting,” he said. “Do sample processing differences create a situation where a biomarker works in a research project but not in the clinical setting?” But more likely, he said, the opposite may be the case, where frozen samples allow for more degradation of proteins and potentially useful LN biomarker candidates are never detected.

Another challenge, Kim added, albeit unrelated to the study findings, is that diagnostic companies are finding it difficult to get payers to cover new tests, so that could become a challenge if the panel undergoes further validation and then FDA qualification.

The research was funded by Exagen. Fava reported disclosures with Arctiva, AstraZeneca, Exagen, Novartis, UCB, Bristol Myers Squibb, Annexon Bio, and Bain Capital. His coauthors reported financial relationships with numerous pharmaceutical and life science companies, including Exagen, and some are employees of Exagen.

Kim reported research agreements with AstraZeneca, Bristol Myers Squibb, Novartis, and CRISPR Therapeutics; receiving royalties from Kypha; and receiving consulting/speaking fees from AbbVie, Amgen, Atara Bio, Aurinia, Cargo Tx, Exagen, GlaxoSmithKline, Hinge Bio, Kypha, and UpToDate.

 

A version of this article appeared on Medscape.com.

TOPLINE:

Compared with a standard dosing regimen, a reduced-dose glucocorticoid regimen is associated with an increased risk for disease progression, relapse, death, or kidney failure in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, particularly affecting patients receiving rituximab or those with elevated creatinine levels.

METHODOLOGY:

• The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard dosing in terms of death or end-stage kidney disease in ANCA-associated vasculitis. However, the trial did not include disease progression or relapse as a primary endpoint, and cyclophosphamide was the primary induction therapy.
• Researchers conducted this retrospective study across 19 hospitals (18 in France and one in Luxembourg) between January 2018 and November 2022 to compare the effectiveness of a reduced-dose glucocorticoid regimen, as used in the PEXIVAS trial, with a standard-dose regimen in patients with ANCA-associated vasculitis in the real-world setting.
• They included 234 patients aged > 15 years (51% men) with severe granulomatosis with polyangiitis (n = 141) or microscopic polyangiitis (n = 93) who received induction therapy with rituximab or cyclophosphamide; 126 and 108 patients received reduced-dose and standard-dose glucocorticoid regimens, respectively.
• Most patients (70%) had severe renal involvement.
• The primary composite outcome encompassed minor relapse, major relapse, disease progression before remission, end-stage kidney disease requiring dialysis for > 12 weeks or transplantation, and death within 12 months post-induction.

TAKEAWAY:

• The primary composite outcome occurred in a higher proportion of patients receiving reduced-dose glucocorticoid therapy than in those receiving standard-dose therapy (33.3% vs 18.5%; hazard ratio [HR], 2.20; 95% CI, 1.23-3.94).
• However, no significant association was found between reduced-dose glucocorticoids and the risk for death or end-stage kidney disease or the occurrence of serious infections.
• Among patients receiving reduced-dose glucocorticoids, serum creatinine levels > 300 μmol/L were associated with an increased risk for the primary composite outcome (adjusted HR, 3.02; 95% CI, 1.28-7.11).
• In the rituximab induction subgroup, reduced-dose glucocorticoid was associated with an increased risk for the primary composite outcome (adjusted HR, 2.36; 95% CI, 1.18-4.71), compared with standard-dose glucocorticoids.

IN PRACTICE:

“Our data suggest increased vigilance when using the [reduced-dose glucocorticoid] regimen, especially in the two subgroups of patients at higher risk of failure, that is, those receiving [rituximab] as induction therapy and those with a baseline serum creatinine greater than 300 μmol/L,” the authors wrote.

SOURCE:

The study was led by Sophie Nagle, MD, National Referral Centre for Rare Autoimmune and Systemic Diseases, Department of Internal Medicine, Hôpital Cochin, Paris, France. It was published online on November 20, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The retrospective nature of this study may have introduced inherent limitations and potential selection bias. The study lacked data on patient comorbidities, which could have influenced treatment choice and outcomes. Additionally, about a quarter of patients did not receive methylprednisolone pulses prior to oral glucocorticoids, unlike the PEXIVAS trial protocol. The group receiving standard-dose glucocorticoids showed heterogeneity in glucocorticoid regimens, and the minimum follow-up was only 6 months.

DISCLOSURES:

This study did not report any source of funding. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Compared with a standard dosing regimen, a reduced-dose glucocorticoid regimen is associated with an increased risk for disease progression, relapse, death, or kidney failure in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, particularly affecting patients receiving rituximab or those with elevated creatinine levels.

METHODOLOGY:

• The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard dosing in terms of death or end-stage kidney disease in ANCA-associated vasculitis. However, the trial did not include disease progression or relapse as a primary endpoint, and cyclophosphamide was the primary induction therapy.
• Researchers conducted this retrospective study across 19 hospitals (18 in France and one in Luxembourg) between January 2018 and November 2022 to compare the effectiveness of a reduced-dose glucocorticoid regimen, as used in the PEXIVAS trial, with a standard-dose regimen in patients with ANCA-associated vasculitis in the real-world setting.
• They included 234 patients aged > 15 years (51% men) with severe granulomatosis with polyangiitis (n = 141) or microscopic polyangiitis (n = 93) who received induction therapy with rituximab or cyclophosphamide; 126 and 108 patients received reduced-dose and standard-dose glucocorticoid regimens, respectively.
• Most patients (70%) had severe renal involvement.
• The primary composite outcome encompassed minor relapse, major relapse, disease progression before remission, end-stage kidney disease requiring dialysis for > 12 weeks or transplantation, and death within 12 months post-induction.

TAKEAWAY:

• The primary composite outcome occurred in a higher proportion of patients receiving reduced-dose glucocorticoid therapy than in those receiving standard-dose therapy (33.3% vs 18.5%; hazard ratio [HR], 2.20; 95% CI, 1.23-3.94).
• However, no significant association was found between reduced-dose glucocorticoids and the risk for death or end-stage kidney disease or the occurrence of serious infections.
• Among patients receiving reduced-dose glucocorticoids, serum creatinine levels > 300 μmol/L were associated with an increased risk for the primary composite outcome (adjusted HR, 3.02; 95% CI, 1.28-7.11).
• In the rituximab induction subgroup, reduced-dose glucocorticoid was associated with an increased risk for the primary composite outcome (adjusted HR, 2.36; 95% CI, 1.18-4.71), compared with standard-dose glucocorticoids.

IN PRACTICE:

“Our data suggest increased vigilance when using the [reduced-dose glucocorticoid] regimen, especially in the two subgroups of patients at higher risk of failure, that is, those receiving [rituximab] as induction therapy and those with a baseline serum creatinine greater than 300 μmol/L,” the authors wrote.

SOURCE:

The study was led by Sophie Nagle, MD, National Referral Centre for Rare Autoimmune and Systemic Diseases, Department of Internal Medicine, Hôpital Cochin, Paris, France. It was published online on November 20, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The retrospective nature of this study may have introduced inherent limitations and potential selection bias. The study lacked data on patient comorbidities, which could have influenced treatment choice and outcomes. Additionally, about a quarter of patients did not receive methylprednisolone pulses prior to oral glucocorticoids, unlike the PEXIVAS trial protocol. The group receiving standard-dose glucocorticoids showed heterogeneity in glucocorticoid regimens, and the minimum follow-up was only 6 months.

DISCLOSURES:

This study did not report any source of funding. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Compared with a standard dosing regimen, a reduced-dose glucocorticoid regimen is associated with an increased risk for disease progression, relapse, death, or kidney failure in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, particularly affecting patients receiving rituximab or those with elevated creatinine levels.

METHODOLOGY:

• The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard dosing in terms of death or end-stage kidney disease in ANCA-associated vasculitis. However, the trial did not include disease progression or relapse as a primary endpoint, and cyclophosphamide was the primary induction therapy.
• Researchers conducted this retrospective study across 19 hospitals (18 in France and one in Luxembourg) between January 2018 and November 2022 to compare the effectiveness of a reduced-dose glucocorticoid regimen, as used in the PEXIVAS trial, with a standard-dose regimen in patients with ANCA-associated vasculitis in the real-world setting.
• They included 234 patients aged > 15 years (51% men) with severe granulomatosis with polyangiitis (n = 141) or microscopic polyangiitis (n = 93) who received induction therapy with rituximab or cyclophosphamide; 126 and 108 patients received reduced-dose and standard-dose glucocorticoid regimens, respectively.
• Most patients (70%) had severe renal involvement.
• The primary composite outcome encompassed minor relapse, major relapse, disease progression before remission, end-stage kidney disease requiring dialysis for > 12 weeks or transplantation, and death within 12 months post-induction.

TAKEAWAY:

• The primary composite outcome occurred in a higher proportion of patients receiving reduced-dose glucocorticoid therapy than in those receiving standard-dose therapy (33.3% vs 18.5%; hazard ratio [HR], 2.20; 95% CI, 1.23-3.94).
• However, no significant association was found between reduced-dose glucocorticoids and the risk for death or end-stage kidney disease or the occurrence of serious infections.
• Among patients receiving reduced-dose glucocorticoids, serum creatinine levels > 300 μmol/L were associated with an increased risk for the primary composite outcome (adjusted HR, 3.02; 95% CI, 1.28-7.11).
• In the rituximab induction subgroup, reduced-dose glucocorticoid was associated with an increased risk for the primary composite outcome (adjusted HR, 2.36; 95% CI, 1.18-4.71), compared with standard-dose glucocorticoids.

IN PRACTICE:

“Our data suggest increased vigilance when using the [reduced-dose glucocorticoid] regimen, especially in the two subgroups of patients at higher risk of failure, that is, those receiving [rituximab] as induction therapy and those with a baseline serum creatinine greater than 300 μmol/L,” the authors wrote.

SOURCE:

The study was led by Sophie Nagle, MD, National Referral Centre for Rare Autoimmune and Systemic Diseases, Department of Internal Medicine, Hôpital Cochin, Paris, France. It was published online on November 20, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

The retrospective nature of this study may have introduced inherent limitations and potential selection bias. The study lacked data on patient comorbidities, which could have influenced treatment choice and outcomes. Additionally, about a quarter of patients did not receive methylprednisolone pulses prior to oral glucocorticoids, unlike the PEXIVAS trial protocol. The group receiving standard-dose glucocorticoids showed heterogeneity in glucocorticoid regimens, and the minimum follow-up was only 6 months.

DISCLOSURES:

This study did not report any source of funding. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Even before the presidential election, the Federal Trade Commission’s (FTC) national ban on noncompete clauses faced a tough battle for survival in the courts. 

Now, legal specialists forecast a grim prognosis for the ban under Donald Trump’s return to the White House.

In April 2024, a divided FTC board approved a rule that would ban most noncompete agreements, which are the bane of many physicians in the states where they’re allowed. 

But a federal district’s court ruling put the ban on hold, and the Trump administration isn’t expected to support lifting the ban. 

“It is likely that the Trump administration will decline to defend the rule and may not even appeal the district court’s ruling, which means that the ban on noncompetes will not go into effect,” Steven Lubet, JD, a professor emeritus at Northwestern University Pritzker School of Law, Chicago, Illinois, said in an interview.

 

What’s in a Noncompete Clause?

Noncompete clauses in employee contracts typically restrict when and where workers can take future jobs. In medicine, supporters argue that the clauses are fair. Hospitals and practices provide a base of patients to physicians, they say, in return for their agreement not to go work for a competitor. 

But those opposed to these clauses argue that the restrictions harm careers and hurt patients by unfairly preventing physicians from moving to new jobs where they’re needed. 

At an April meeting, the FTC board voted 3 to 2 to ban noncompete clauses; some nonprofit organizations and senior executives were expected to be exempt. The FTC estimated that the move would save the healthcare system alone as much as $194 billion over 10 years. 

“A pandemic killed a million people in this country, and there are doctors who cannot work because of a noncompete,” declared FTC Commissioner Alvaro Bedoya. 

Hospitals protested the move. In a statement, the general counsel for the American Hospital Association called it “bad law, bad policy, and a clear sign of an agency run amok” and said the FTC ignored “mountains of contrary legal precedent and evidence about its adverse impacts on the health care markets.”

Although the American Medical Association does not support a total ban, its House of Delegates adopted policies in 2023 to support the prohibition of noncompete contracts for physicians employed by for-profit and nonprofit hospitals, hospital systems, or staffing companies. 

 

Texas Federal Judge Intervenes to Halt Ban

The ban was supposed to take effect on Sept. 4, 2024. But Texas federal judge Ada E. Brown struck down the ban in an Aug. 20 decision. She ruled that the FTC went beyond its authority.

“The district court based its ruling on a very dubious distinction between ‘unfair practices,’ which the FTC may prohibit, and ‘unfair competition,’ which, according to the court, it may not,” said Lubet. 

In fact, the ban should stand, he said. “This is a classic case of the government intervening on behalf of consumers/patients by prohibiting an unfair and harmful employment practice,” Lubet said. 

Amanda Hill, an attorney in Austin, Texas, who trains physicians about how to negotiate contracts, has a different take. “The Federal Trade Commission came down hard, and honestly, it really overstepped,” she said in an interview. “Congress needs to write laws, not regulatory bodies. I think all the lawyers went: ‘Good try, but you’re not going to get anywhere with that.’ ”

She noted that physicians themselves are divided over the value of noncompete clauses. “I would say 80% of my clients can’t stand noncompetes.” But another 20% own their own practices and hate the idea of losing their physicians to competitors, she said. 

 

Trump Isn’t Seen as Likely to Support Ban

While the Biden administration firmly supported a ban on noncompete clauses, there isn’t a strict Democratic-Republican divide over whether the agreements are a good idea. Some red states have embraced bans, and Hill said this can make sense from a Republican point of view: “We don’t want to run doctors out of town and out of the state because they think they’re going to be bound by big hospitals and corporate interests.”

In fact, former Florida congressman Matt Gaetz, a Republican briefly tapped as President-elect Trump’s nominee for attorney general, supports noncompete clauses. He filed a friend-of-the-court brief with the Texas judge that supported the FTC’s ruling, saying it is a “vindication of economic freedom and free enterprise.” 

But Republicans generally “believe that federal agencies are going too far and beyond the power granted to them by Congress,” Atlanta, Georgia, attorney Benjamin Fink, Esq., said in an interview.

And Trump is no fan of the FTC and its chair, Lina Khan, who may step down. Observers don’t expect that the Trump administration or a newly constituted FTC board will support an appeal of the Texas judge’s ruling.

“I don’t think anybody else — another agency or a private party — could step in place of the FTC if the FTC declines to defend the ban,” Atlanta attorney Neal F. Weinrich, Esq., said in an interview. In that case, “I think it ends.”

Attorneys Weinrich and Fink work at the same firm, which handles noncompete agreements for physicians. 

 

Noncompete Ban Advocates Turn to States 

Even if Kamala Harris had won the presidency, a national ban on noncompete clauses would have faced an uphill battle at the Supreme Court. 

“The Supreme Court majority has been unsympathetic to administrative agencies, interpreting their authority very narrowly,” said Lubet.

So what happens to noncompete clauses now? While bipartisan bills in Congress have tried to ban them, legislation is unlikely to pass now that Republicans will control both the House and Senate, Fink said. 

According to a recent article, 12 states prohibit noncompete clauses for physicians: Alabama, California, Colorado, Delaware, Massachusetts, Montana, New Hampshire, New Mexico, North Dakota, Oklahoma, Rhode Island, and South Dakota. 

The remaining states allow noncompetes in some form, often excluding them for employees earning below a certain threshold. For example, in Oregon, noncompete agreements may apply to employees earning more than $113,241. Most states have provisions to adjust the threshold annually. The District of Columbia permits 2-year noncompetes for “medical specialists” earning over $250,000 annually. 

Indiana employers can no longer enter into noncompete agreements with primary care providers. Other specialties may be subject to the clauses, except when the physician terminates the contract for cause or when an employer terminates the contract without cause. 

“I definitely think states are going to continue to restrict the use of noncompetes,” Fink said. 

Lubet has no disclosures. Hill, Fink, and Weinrich represent physicians in contract negotiations.

A version of this article appeared on Medscape.com.

Even before the presidential election, the Federal Trade Commission’s (FTC) national ban on noncompete clauses faced a tough battle for survival in the courts. 

Now, legal specialists forecast a grim prognosis for the ban under Donald Trump’s return to the White House.

In April 2024, a divided FTC board approved a rule that would ban most noncompete agreements, which are the bane of many physicians in the states where they’re allowed. 

But a federal district’s court ruling put the ban on hold, and the Trump administration isn’t expected to support lifting the ban. 

“It is likely that the Trump administration will decline to defend the rule and may not even appeal the district court’s ruling, which means that the ban on noncompetes will not go into effect,” Steven Lubet, JD, a professor emeritus at Northwestern University Pritzker School of Law, Chicago, Illinois, said in an interview.

 

What’s in a Noncompete Clause?

Noncompete clauses in employee contracts typically restrict when and where workers can take future jobs. In medicine, supporters argue that the clauses are fair. Hospitals and practices provide a base of patients to physicians, they say, in return for their agreement not to go work for a competitor. 

But those opposed to these clauses argue that the restrictions harm careers and hurt patients by unfairly preventing physicians from moving to new jobs where they’re needed. 

At an April meeting, the FTC board voted 3 to 2 to ban noncompete clauses; some nonprofit organizations and senior executives were expected to be exempt. The FTC estimated that the move would save the healthcare system alone as much as $194 billion over 10 years. 

“A pandemic killed a million people in this country, and there are doctors who cannot work because of a noncompete,” declared FTC Commissioner Alvaro Bedoya. 

Hospitals protested the move. In a statement, the general counsel for the American Hospital Association called it “bad law, bad policy, and a clear sign of an agency run amok” and said the FTC ignored “mountains of contrary legal precedent and evidence about its adverse impacts on the health care markets.”

Although the American Medical Association does not support a total ban, its House of Delegates adopted policies in 2023 to support the prohibition of noncompete contracts for physicians employed by for-profit and nonprofit hospitals, hospital systems, or staffing companies. 

 

Texas Federal Judge Intervenes to Halt Ban

The ban was supposed to take effect on Sept. 4, 2024. But Texas federal judge Ada E. Brown struck down the ban in an Aug. 20 decision. She ruled that the FTC went beyond its authority.

“The district court based its ruling on a very dubious distinction between ‘unfair practices,’ which the FTC may prohibit, and ‘unfair competition,’ which, according to the court, it may not,” said Lubet. 

In fact, the ban should stand, he said. “This is a classic case of the government intervening on behalf of consumers/patients by prohibiting an unfair and harmful employment practice,” Lubet said. 

Amanda Hill, an attorney in Austin, Texas, who trains physicians about how to negotiate contracts, has a different take. “The Federal Trade Commission came down hard, and honestly, it really overstepped,” she said in an interview. “Congress needs to write laws, not regulatory bodies. I think all the lawyers went: ‘Good try, but you’re not going to get anywhere with that.’ ”

She noted that physicians themselves are divided over the value of noncompete clauses. “I would say 80% of my clients can’t stand noncompetes.” But another 20% own their own practices and hate the idea of losing their physicians to competitors, she said. 

 

Trump Isn’t Seen as Likely to Support Ban

While the Biden administration firmly supported a ban on noncompete clauses, there isn’t a strict Democratic-Republican divide over whether the agreements are a good idea. Some red states have embraced bans, and Hill said this can make sense from a Republican point of view: “We don’t want to run doctors out of town and out of the state because they think they’re going to be bound by big hospitals and corporate interests.”

In fact, former Florida congressman Matt Gaetz, a Republican briefly tapped as President-elect Trump’s nominee for attorney general, supports noncompete clauses. He filed a friend-of-the-court brief with the Texas judge that supported the FTC’s ruling, saying it is a “vindication of economic freedom and free enterprise.” 

But Republicans generally “believe that federal agencies are going too far and beyond the power granted to them by Congress,” Atlanta, Georgia, attorney Benjamin Fink, Esq., said in an interview.

And Trump is no fan of the FTC and its chair, Lina Khan, who may step down. Observers don’t expect that the Trump administration or a newly constituted FTC board will support an appeal of the Texas judge’s ruling.

“I don’t think anybody else — another agency or a private party — could step in place of the FTC if the FTC declines to defend the ban,” Atlanta attorney Neal F. Weinrich, Esq., said in an interview. In that case, “I think it ends.”

Attorneys Weinrich and Fink work at the same firm, which handles noncompete agreements for physicians. 

 

Noncompete Ban Advocates Turn to States 

Even if Kamala Harris had won the presidency, a national ban on noncompete clauses would have faced an uphill battle at the Supreme Court. 

“The Supreme Court majority has been unsympathetic to administrative agencies, interpreting their authority very narrowly,” said Lubet.

So what happens to noncompete clauses now? While bipartisan bills in Congress have tried to ban them, legislation is unlikely to pass now that Republicans will control both the House and Senate, Fink said. 

According to a recent article, 12 states prohibit noncompete clauses for physicians: Alabama, California, Colorado, Delaware, Massachusetts, Montana, New Hampshire, New Mexico, North Dakota, Oklahoma, Rhode Island, and South Dakota. 

The remaining states allow noncompetes in some form, often excluding them for employees earning below a certain threshold. For example, in Oregon, noncompete agreements may apply to employees earning more than $113,241. Most states have provisions to adjust the threshold annually. The District of Columbia permits 2-year noncompetes for “medical specialists” earning over $250,000 annually. 

Indiana employers can no longer enter into noncompete agreements with primary care providers. Other specialties may be subject to the clauses, except when the physician terminates the contract for cause or when an employer terminates the contract without cause. 

“I definitely think states are going to continue to restrict the use of noncompetes,” Fink said. 

Lubet has no disclosures. Hill, Fink, and Weinrich represent physicians in contract negotiations.

A version of this article appeared on Medscape.com.

Even before the presidential election, the Federal Trade Commission’s (FTC) national ban on noncompete clauses faced a tough battle for survival in the courts. 

Now, legal specialists forecast a grim prognosis for the ban under Donald Trump’s return to the White House.

In April 2024, a divided FTC board approved a rule that would ban most noncompete agreements, which are the bane of many physicians in the states where they’re allowed. 

But a federal district’s court ruling put the ban on hold, and the Trump administration isn’t expected to support lifting the ban. 

“It is likely that the Trump administration will decline to defend the rule and may not even appeal the district court’s ruling, which means that the ban on noncompetes will not go into effect,” Steven Lubet, JD, a professor emeritus at Northwestern University Pritzker School of Law, Chicago, Illinois, said in an interview.

 

What’s in a Noncompete Clause?

Noncompete clauses in employee contracts typically restrict when and where workers can take future jobs. In medicine, supporters argue that the clauses are fair. Hospitals and practices provide a base of patients to physicians, they say, in return for their agreement not to go work for a competitor. 

But those opposed to these clauses argue that the restrictions harm careers and hurt patients by unfairly preventing physicians from moving to new jobs where they’re needed. 

At an April meeting, the FTC board voted 3 to 2 to ban noncompete clauses; some nonprofit organizations and senior executives were expected to be exempt. The FTC estimated that the move would save the healthcare system alone as much as $194 billion over 10 years. 

“A pandemic killed a million people in this country, and there are doctors who cannot work because of a noncompete,” declared FTC Commissioner Alvaro Bedoya. 

Hospitals protested the move. In a statement, the general counsel for the American Hospital Association called it “bad law, bad policy, and a clear sign of an agency run amok” and said the FTC ignored “mountains of contrary legal precedent and evidence about its adverse impacts on the health care markets.”

Although the American Medical Association does not support a total ban, its House of Delegates adopted policies in 2023 to support the prohibition of noncompete contracts for physicians employed by for-profit and nonprofit hospitals, hospital systems, or staffing companies. 

 

Texas Federal Judge Intervenes to Halt Ban

The ban was supposed to take effect on Sept. 4, 2024. But Texas federal judge Ada E. Brown struck down the ban in an Aug. 20 decision. She ruled that the FTC went beyond its authority.

“The district court based its ruling on a very dubious distinction between ‘unfair practices,’ which the FTC may prohibit, and ‘unfair competition,’ which, according to the court, it may not,” said Lubet. 

In fact, the ban should stand, he said. “This is a classic case of the government intervening on behalf of consumers/patients by prohibiting an unfair and harmful employment practice,” Lubet said. 

Amanda Hill, an attorney in Austin, Texas, who trains physicians about how to negotiate contracts, has a different take. “The Federal Trade Commission came down hard, and honestly, it really overstepped,” she said in an interview. “Congress needs to write laws, not regulatory bodies. I think all the lawyers went: ‘Good try, but you’re not going to get anywhere with that.’ ”

She noted that physicians themselves are divided over the value of noncompete clauses. “I would say 80% of my clients can’t stand noncompetes.” But another 20% own their own practices and hate the idea of losing their physicians to competitors, she said. 

 

Trump Isn’t Seen as Likely to Support Ban

While the Biden administration firmly supported a ban on noncompete clauses, there isn’t a strict Democratic-Republican divide over whether the agreements are a good idea. Some red states have embraced bans, and Hill said this can make sense from a Republican point of view: “We don’t want to run doctors out of town and out of the state because they think they’re going to be bound by big hospitals and corporate interests.”

In fact, former Florida congressman Matt Gaetz, a Republican briefly tapped as President-elect Trump’s nominee for attorney general, supports noncompete clauses. He filed a friend-of-the-court brief with the Texas judge that supported the FTC’s ruling, saying it is a “vindication of economic freedom and free enterprise.” 

But Republicans generally “believe that federal agencies are going too far and beyond the power granted to them by Congress,” Atlanta, Georgia, attorney Benjamin Fink, Esq., said in an interview.

And Trump is no fan of the FTC and its chair, Lina Khan, who may step down. Observers don’t expect that the Trump administration or a newly constituted FTC board will support an appeal of the Texas judge’s ruling.

“I don’t think anybody else — another agency or a private party — could step in place of the FTC if the FTC declines to defend the ban,” Atlanta attorney Neal F. Weinrich, Esq., said in an interview. In that case, “I think it ends.”

Attorneys Weinrich and Fink work at the same firm, which handles noncompete agreements for physicians. 

 

Noncompete Ban Advocates Turn to States 

Even if Kamala Harris had won the presidency, a national ban on noncompete clauses would have faced an uphill battle at the Supreme Court. 

“The Supreme Court majority has been unsympathetic to administrative agencies, interpreting their authority very narrowly,” said Lubet.

So what happens to noncompete clauses now? While bipartisan bills in Congress have tried to ban them, legislation is unlikely to pass now that Republicans will control both the House and Senate, Fink said. 

According to a recent article, 12 states prohibit noncompete clauses for physicians: Alabama, California, Colorado, Delaware, Massachusetts, Montana, New Hampshire, New Mexico, North Dakota, Oklahoma, Rhode Island, and South Dakota. 

The remaining states allow noncompetes in some form, often excluding them for employees earning below a certain threshold. For example, in Oregon, noncompete agreements may apply to employees earning more than $113,241. Most states have provisions to adjust the threshold annually. The District of Columbia permits 2-year noncompetes for “medical specialists” earning over $250,000 annually. 

Indiana employers can no longer enter into noncompete agreements with primary care providers. Other specialties may be subject to the clauses, except when the physician terminates the contract for cause or when an employer terminates the contract without cause. 

“I definitely think states are going to continue to restrict the use of noncompetes,” Fink said. 

Lubet has no disclosures. Hill, Fink, and Weinrich represent physicians in contract negotiations.

A version of this article appeared on Medscape.com.

WASHINGTON — Investigational treatments aimed specifically at reducing pain in knee osteoarthritis (OA) are moving forward in parallel with disease-modifying approaches.

“We still have very few treatments for the pain of osteoarthritis…It worries me that people think the only way forward is structure modification. I think while we’re waiting for some drugs to be structure modifying, we still need more pain relief. About 70% of people can’t tolerate or shouldn’t be on a [nonsteroidal anti-inflammatory drug], and that leaves a large number of people with pain,” Philip Conaghan, MBBS, PhD, Chair of Musculoskeletal Medicine at the University of Leeds in England, said in an interview.

At the annual meeting of the American College of Rheumatology, Conaghan, who is also honorary consultant rheumatologist for the Leeds Teaching Hospitals NHS Trust, presented new data for two novel approaches, both targeting peripheral nociceptive pain signaling.

In a late-breaking poster, he presented phase 2 trial data on RTX-GRT7039 (resiniferatoxin [RTX]), an agonist of the transient receptor potential vanilloid 1 that is a driver of OA pain. The trial investigated the efficacy and safety of a single intra-articular injection of RTX-GRT7039 in people with knee OA.

And separately, in a late-breaking oral abstract session, Conaghan presented phase 2 trial safety and efficacy data for another investigational agent called LEVI-04, a first-in-class neurotrophin receptor fusion protein (p75NTR-Fc) that supplements the endogenous protein and provides analgesia via inhibition of NT-3 activity.

“I think both have potential to provide good pain relief, through slightly different mechanisms,” Conaghan said in an interview.

Asked to comment, session moderator Gregory C. Gardner, MD, emeritus professor in the Division of Rheumatology at the University of Washington, Seattle, said in an interview: “I think the results are really exciting terms of the ability to control pain to a significant degree in patients with osteoarthritis.”

However, Gardner also said, “The molecules can be very expensive ... so who do we give them to? Will insurance companies pay for this simply for OA pain? They improve function ... so clearly, [they] will be a boon to treating osteoarthritis, but do we give them to people with only more advanced forms of osteoarthritis or earlier on?”

Moreover, Gardner said, “One of my concerns about treating osteoarthritis is I don’t want to do too good of a job treating pain in somebody who has a biomechanically abnormal joint. ... You’ve got a knee that’s worn out some of the cartilage, and now you feel like you can go out and play soccer again. That’s not a good thing. That joint will wear out very quickly, even though it doesn’t feel pain.”

Another OA expert, Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, said in an interview, “I think we don’t focus nearly enough on pain, and that’s [partly] because the [Food and Drug Administration] has defined endpoints for knee OA trials that are radiographic. ... Patients do not care what their joint space narrowing is. They care what their pain is. And joint space changes and pain do not correlate in knee OA. ... About 20% or 30% of patients who have completely normal x-rays have a lot of pain…I hope that we’ll have some new OA pain therapeutics in the future because that’s what patients actually care about.”

But Jeffries noted that it will be very important to ensure that these agents don’t produce significant side effects, as had been seen previously in several large industry-sponsored trials of drugs targeting nerve growth factors.

“The big concern that we have in the field ... is that the nerve growth factor antibody trials were all stopped because there was a low but persistent risk of rapidly progressive OA in a small percent of patients. I think one of the questions in the field is whether targeting other things having to do with OA pain is going to result in similar bad outcomes. I think the answer is probably not, but that’s one thing that people do worry about, and they never really figured out why the [rapidly progressive OA] was happening.”

 

‘Potential to Provide Meaningful and Sustained Analgesia’

The phase 2 trial of RTX-GRT7039, funded by manufacturer Grünenthal, enrolled 40 patients with a baseline visual analog pain score (VAS) of > 40 mm on motion for average joint pain in the target knee over the past 2 days with or without analgesic medication and Kellgren-Lawrence grades 2-4.

They were randomized to receive a single intra-articular injection of 2 mg or 4 mg RTX-GRT7039 within 1 minute after receiving 5 mL ropivacaine (0.5%) or 4 mg or 8 mg RTX-GRT7039 administered 15 minutes after 5 mL ropivacaine pretreatment, or equivalent placebo treatments plus ropivacaine.

Plasma samples were collected for up to 2 hours, and VAS pain scores were collected for up to 3 hours post injection.

Reductions in VAS scores from baseline in the treated knee were seen in all RTX treatment groups as early as day 8 post injection and were maintained up to 6 months, while no reductions in VAS pain on motion scores were seen in the placebo group.

At 3 months, the absolute baseline-adjusted reductions in VAS scores were similar for RTX 2 mg (–39.75), RTX 4 mg (–40.20), and RTX 8 mg (–30.25), while the reduction in the placebo group was just –8.50. At 6 months, the mean absolute reduction in VAS score was numerically greater in the RTX 2-mg (–46.49), RTX 4-mg (–43.40), and RTX 8-mg (–38.60) groups vs the group that received RTX 4 mg within 1 minute after receiving ropivacaine (–22.00).

At both 3 and 6 months, a higher proportion of patients receiving any dose of RTX-GRT7039 achieved ≥ 50% and ≥ 70% reduction in pain on motion, compared with those who received placebo. All RTX-GRT7039 treatment groups reported a greater improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score than the placebo group at both 3 and 6 months.

Rates of treatment-emergent adverse events were similar between the RTX groups (85.7%-90.9%) and placebo (85.7%) and slightly lower in the group that received RTX 4 mg within 1 minute of receiving ropivacaine (60.0%).

There was a trend toward greater procedural/injection site pain in the RTX treatment groups, compared with placebo, most commonly arthralgia (37.5%), headache (17.5%), and back pain (10%). This tended to peak around 0.5 hours post injection and resolve by 1.5-3.0 hours.

No treatment-related serious adverse events occurred, and no treatment-emergent adverse events led to discontinuation or death.

“This early-phase trial indicates that RTX-GRT7039 has the potential to provide meaningful and sustained analgesia for patients with knee OA pain,” Conaghan and colleagues wrote in their poster.

The drug is now being evaluated in three phase 3 trials (NCT05248386, NCT05449132, and NCT05377489).

 

LEVI-04: Modulation of NT-3 Appears to Work Safely

LEVI-04 was evaluated in a phase 2, 20-week, 13-center (Europe and Hong Kong) randomized, double-blind, placebo-controlled trial in 518 people with knee OA who had WOMAC pain subscale scores ≥ 20, mean average daily pain numeric rating scale score of 4-9, and radiographic Kellgren-Lawrence grade ≥ 2.

They were randomized to a total of five infusions of placebo or 0.3 mg/kg, 0.1 mg/kg, or 2 mg/kg LEVI-04 from baseline through week 16, with safety follow-up to week 30.

The primary endpoint, change in WOMAC pain from baseline to weeks 5 and 17, was met for all three doses. At 17 weeks, those were –2.79, –2.89, and –3.08 for 0.3 mg, 1.0 mg, and 2 mg, respectively, vs –2.28 for placebo (all P < .05).

Secondary endpoints, including WOMAC physical function, WOMAC stiffness, and Patient Global Assessment, and > 50% pain responders, were also all met at weeks 5 and 17. More than 50% of the LEVI-04–treated patients reported ≥ 50% reduction in pain, and > 25% reported ≥ 75% reduction at weeks 5 and 17.

“So, this modulation of NT-3 is working,” Conaghan commented.

There were no increased incidences of severe adverse events, treatment-emergent adverse events, or joint pathologies, including rapidly progressive OA, compared with placebo.

There were more paresthesias reported with the active drug, 2-4 vs 1 with placebo. “That says to me that the drug is working and that it’s having an effect on peripheral nerves, but luckily these were all mild or moderate and didn’t lead to any study withdrawal or discontinuation,” Conaghan said.

Phase 3 trials are in the planning stages, he noted.

 

Other Approaches to Treating OA Pain

Other approaches to treating OA pain have included methotrexate, for which Conaghan was also a coauthor on one paper that came out earlier in 2024. “This presumably works by treating inflammation, but it’s not clear if that is within-joint inflammation or systemic inflammation,” he said in an interview.

Another approach, using the weight loss drug semaglutide, was presented in April 2024 at the 2024 World Congress on Osteoarthritis annual meeting and published in October 2024 in The New England Journal of Medicine

The trial involving RTX-GRT7039 was funded by Grünenthal, and some study coauthors are employees of the company. The trial involving LEVI-04 was funded by Levicept, and some study coauthors are employees of the company. Conaghan is a consultant and/or speaker for Eli Lilly, Eupraxia Pharmaceuticals, Formation Bio, Galapagos, Genascence, GlaxoSmithKline, Grünenthal, Janssen Pharmaceuticals, Kolon TissueGene, Levicept, Medipost, Moebius, Novartis, Pacira, Sandoz, Stryker Corporation, and Takeda. Gardner and Jeffries had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — Investigational treatments aimed specifically at reducing pain in knee osteoarthritis (OA) are moving forward in parallel with disease-modifying approaches.

“We still have very few treatments for the pain of osteoarthritis…It worries me that people think the only way forward is structure modification. I think while we’re waiting for some drugs to be structure modifying, we still need more pain relief. About 70% of people can’t tolerate or shouldn’t be on a [nonsteroidal anti-inflammatory drug], and that leaves a large number of people with pain,” Philip Conaghan, MBBS, PhD, Chair of Musculoskeletal Medicine at the University of Leeds in England, said in an interview.

At the annual meeting of the American College of Rheumatology, Conaghan, who is also honorary consultant rheumatologist for the Leeds Teaching Hospitals NHS Trust, presented new data for two novel approaches, both targeting peripheral nociceptive pain signaling.

In a late-breaking poster, he presented phase 2 trial data on RTX-GRT7039 (resiniferatoxin [RTX]), an agonist of the transient receptor potential vanilloid 1 that is a driver of OA pain. The trial investigated the efficacy and safety of a single intra-articular injection of RTX-GRT7039 in people with knee OA.

And separately, in a late-breaking oral abstract session, Conaghan presented phase 2 trial safety and efficacy data for another investigational agent called LEVI-04, a first-in-class neurotrophin receptor fusion protein (p75NTR-Fc) that supplements the endogenous protein and provides analgesia via inhibition of NT-3 activity.

“I think both have potential to provide good pain relief, through slightly different mechanisms,” Conaghan said in an interview.

Asked to comment, session moderator Gregory C. Gardner, MD, emeritus professor in the Division of Rheumatology at the University of Washington, Seattle, said in an interview: “I think the results are really exciting terms of the ability to control pain to a significant degree in patients with osteoarthritis.”

However, Gardner also said, “The molecules can be very expensive ... so who do we give them to? Will insurance companies pay for this simply for OA pain? They improve function ... so clearly, [they] will be a boon to treating osteoarthritis, but do we give them to people with only more advanced forms of osteoarthritis or earlier on?”

Moreover, Gardner said, “One of my concerns about treating osteoarthritis is I don’t want to do too good of a job treating pain in somebody who has a biomechanically abnormal joint. ... You’ve got a knee that’s worn out some of the cartilage, and now you feel like you can go out and play soccer again. That’s not a good thing. That joint will wear out very quickly, even though it doesn’t feel pain.”

Another OA expert, Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, said in an interview, “I think we don’t focus nearly enough on pain, and that’s [partly] because the [Food and Drug Administration] has defined endpoints for knee OA trials that are radiographic. ... Patients do not care what their joint space narrowing is. They care what their pain is. And joint space changes and pain do not correlate in knee OA. ... About 20% or 30% of patients who have completely normal x-rays have a lot of pain…I hope that we’ll have some new OA pain therapeutics in the future because that’s what patients actually care about.”

But Jeffries noted that it will be very important to ensure that these agents don’t produce significant side effects, as had been seen previously in several large industry-sponsored trials of drugs targeting nerve growth factors.

“The big concern that we have in the field ... is that the nerve growth factor antibody trials were all stopped because there was a low but persistent risk of rapidly progressive OA in a small percent of patients. I think one of the questions in the field is whether targeting other things having to do with OA pain is going to result in similar bad outcomes. I think the answer is probably not, but that’s one thing that people do worry about, and they never really figured out why the [rapidly progressive OA] was happening.”

 

‘Potential to Provide Meaningful and Sustained Analgesia’

The phase 2 trial of RTX-GRT7039, funded by manufacturer Grünenthal, enrolled 40 patients with a baseline visual analog pain score (VAS) of > 40 mm on motion for average joint pain in the target knee over the past 2 days with or without analgesic medication and Kellgren-Lawrence grades 2-4.

They were randomized to receive a single intra-articular injection of 2 mg or 4 mg RTX-GRT7039 within 1 minute after receiving 5 mL ropivacaine (0.5%) or 4 mg or 8 mg RTX-GRT7039 administered 15 minutes after 5 mL ropivacaine pretreatment, or equivalent placebo treatments plus ropivacaine.

Plasma samples were collected for up to 2 hours, and VAS pain scores were collected for up to 3 hours post injection.

Reductions in VAS scores from baseline in the treated knee were seen in all RTX treatment groups as early as day 8 post injection and were maintained up to 6 months, while no reductions in VAS pain on motion scores were seen in the placebo group.

At 3 months, the absolute baseline-adjusted reductions in VAS scores were similar for RTX 2 mg (–39.75), RTX 4 mg (–40.20), and RTX 8 mg (–30.25), while the reduction in the placebo group was just –8.50. At 6 months, the mean absolute reduction in VAS score was numerically greater in the RTX 2-mg (–46.49), RTX 4-mg (–43.40), and RTX 8-mg (–38.60) groups vs the group that received RTX 4 mg within 1 minute after receiving ropivacaine (–22.00).

At both 3 and 6 months, a higher proportion of patients receiving any dose of RTX-GRT7039 achieved ≥ 50% and ≥ 70% reduction in pain on motion, compared with those who received placebo. All RTX-GRT7039 treatment groups reported a greater improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score than the placebo group at both 3 and 6 months.

Rates of treatment-emergent adverse events were similar between the RTX groups (85.7%-90.9%) and placebo (85.7%) and slightly lower in the group that received RTX 4 mg within 1 minute of receiving ropivacaine (60.0%).

There was a trend toward greater procedural/injection site pain in the RTX treatment groups, compared with placebo, most commonly arthralgia (37.5%), headache (17.5%), and back pain (10%). This tended to peak around 0.5 hours post injection and resolve by 1.5-3.0 hours.

No treatment-related serious adverse events occurred, and no treatment-emergent adverse events led to discontinuation or death.

“This early-phase trial indicates that RTX-GRT7039 has the potential to provide meaningful and sustained analgesia for patients with knee OA pain,” Conaghan and colleagues wrote in their poster.

The drug is now being evaluated in three phase 3 trials (NCT05248386, NCT05449132, and NCT05377489).

 

LEVI-04: Modulation of NT-3 Appears to Work Safely

LEVI-04 was evaluated in a phase 2, 20-week, 13-center (Europe and Hong Kong) randomized, double-blind, placebo-controlled trial in 518 people with knee OA who had WOMAC pain subscale scores ≥ 20, mean average daily pain numeric rating scale score of 4-9, and radiographic Kellgren-Lawrence grade ≥ 2.

They were randomized to a total of five infusions of placebo or 0.3 mg/kg, 0.1 mg/kg, or 2 mg/kg LEVI-04 from baseline through week 16, with safety follow-up to week 30.

The primary endpoint, change in WOMAC pain from baseline to weeks 5 and 17, was met for all three doses. At 17 weeks, those were –2.79, –2.89, and –3.08 for 0.3 mg, 1.0 mg, and 2 mg, respectively, vs –2.28 for placebo (all P < .05).

Secondary endpoints, including WOMAC physical function, WOMAC stiffness, and Patient Global Assessment, and > 50% pain responders, were also all met at weeks 5 and 17. More than 50% of the LEVI-04–treated patients reported ≥ 50% reduction in pain, and > 25% reported ≥ 75% reduction at weeks 5 and 17.

“So, this modulation of NT-3 is working,” Conaghan commented.

There were no increased incidences of severe adverse events, treatment-emergent adverse events, or joint pathologies, including rapidly progressive OA, compared with placebo.

There were more paresthesias reported with the active drug, 2-4 vs 1 with placebo. “That says to me that the drug is working and that it’s having an effect on peripheral nerves, but luckily these were all mild or moderate and didn’t lead to any study withdrawal or discontinuation,” Conaghan said.

Phase 3 trials are in the planning stages, he noted.

 

Other Approaches to Treating OA Pain

Other approaches to treating OA pain have included methotrexate, for which Conaghan was also a coauthor on one paper that came out earlier in 2024. “This presumably works by treating inflammation, but it’s not clear if that is within-joint inflammation or systemic inflammation,” he said in an interview.

Another approach, using the weight loss drug semaglutide, was presented in April 2024 at the 2024 World Congress on Osteoarthritis annual meeting and published in October 2024 in The New England Journal of Medicine

The trial involving RTX-GRT7039 was funded by Grünenthal, and some study coauthors are employees of the company. The trial involving LEVI-04 was funded by Levicept, and some study coauthors are employees of the company. Conaghan is a consultant and/or speaker for Eli Lilly, Eupraxia Pharmaceuticals, Formation Bio, Galapagos, Genascence, GlaxoSmithKline, Grünenthal, Janssen Pharmaceuticals, Kolon TissueGene, Levicept, Medipost, Moebius, Novartis, Pacira, Sandoz, Stryker Corporation, and Takeda. Gardner and Jeffries had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — Investigational treatments aimed specifically at reducing pain in knee osteoarthritis (OA) are moving forward in parallel with disease-modifying approaches.

“We still have very few treatments for the pain of osteoarthritis…It worries me that people think the only way forward is structure modification. I think while we’re waiting for some drugs to be structure modifying, we still need more pain relief. About 70% of people can’t tolerate or shouldn’t be on a [nonsteroidal anti-inflammatory drug], and that leaves a large number of people with pain,” Philip Conaghan, MBBS, PhD, Chair of Musculoskeletal Medicine at the University of Leeds in England, said in an interview.

At the annual meeting of the American College of Rheumatology, Conaghan, who is also honorary consultant rheumatologist for the Leeds Teaching Hospitals NHS Trust, presented new data for two novel approaches, both targeting peripheral nociceptive pain signaling.

In a late-breaking poster, he presented phase 2 trial data on RTX-GRT7039 (resiniferatoxin [RTX]), an agonist of the transient receptor potential vanilloid 1 that is a driver of OA pain. The trial investigated the efficacy and safety of a single intra-articular injection of RTX-GRT7039 in people with knee OA.

And separately, in a late-breaking oral abstract session, Conaghan presented phase 2 trial safety and efficacy data for another investigational agent called LEVI-04, a first-in-class neurotrophin receptor fusion protein (p75NTR-Fc) that supplements the endogenous protein and provides analgesia via inhibition of NT-3 activity.

“I think both have potential to provide good pain relief, through slightly different mechanisms,” Conaghan said in an interview.

Asked to comment, session moderator Gregory C. Gardner, MD, emeritus professor in the Division of Rheumatology at the University of Washington, Seattle, said in an interview: “I think the results are really exciting terms of the ability to control pain to a significant degree in patients with osteoarthritis.”

However, Gardner also said, “The molecules can be very expensive ... so who do we give them to? Will insurance companies pay for this simply for OA pain? They improve function ... so clearly, [they] will be a boon to treating osteoarthritis, but do we give them to people with only more advanced forms of osteoarthritis or earlier on?”

Moreover, Gardner said, “One of my concerns about treating osteoarthritis is I don’t want to do too good of a job treating pain in somebody who has a biomechanically abnormal joint. ... You’ve got a knee that’s worn out some of the cartilage, and now you feel like you can go out and play soccer again. That’s not a good thing. That joint will wear out very quickly, even though it doesn’t feel pain.”

Another OA expert, Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, said in an interview, “I think we don’t focus nearly enough on pain, and that’s [partly] because the [Food and Drug Administration] has defined endpoints for knee OA trials that are radiographic. ... Patients do not care what their joint space narrowing is. They care what their pain is. And joint space changes and pain do not correlate in knee OA. ... About 20% or 30% of patients who have completely normal x-rays have a lot of pain…I hope that we’ll have some new OA pain therapeutics in the future because that’s what patients actually care about.”

But Jeffries noted that it will be very important to ensure that these agents don’t produce significant side effects, as had been seen previously in several large industry-sponsored trials of drugs targeting nerve growth factors.

“The big concern that we have in the field ... is that the nerve growth factor antibody trials were all stopped because there was a low but persistent risk of rapidly progressive OA in a small percent of patients. I think one of the questions in the field is whether targeting other things having to do with OA pain is going to result in similar bad outcomes. I think the answer is probably not, but that’s one thing that people do worry about, and they never really figured out why the [rapidly progressive OA] was happening.”

 

‘Potential to Provide Meaningful and Sustained Analgesia’

The phase 2 trial of RTX-GRT7039, funded by manufacturer Grünenthal, enrolled 40 patients with a baseline visual analog pain score (VAS) of > 40 mm on motion for average joint pain in the target knee over the past 2 days with or without analgesic medication and Kellgren-Lawrence grades 2-4.

They were randomized to receive a single intra-articular injection of 2 mg or 4 mg RTX-GRT7039 within 1 minute after receiving 5 mL ropivacaine (0.5%) or 4 mg or 8 mg RTX-GRT7039 administered 15 minutes after 5 mL ropivacaine pretreatment, or equivalent placebo treatments plus ropivacaine.

Plasma samples were collected for up to 2 hours, and VAS pain scores were collected for up to 3 hours post injection.

Reductions in VAS scores from baseline in the treated knee were seen in all RTX treatment groups as early as day 8 post injection and were maintained up to 6 months, while no reductions in VAS pain on motion scores were seen in the placebo group.

At 3 months, the absolute baseline-adjusted reductions in VAS scores were similar for RTX 2 mg (–39.75), RTX 4 mg (–40.20), and RTX 8 mg (–30.25), while the reduction in the placebo group was just –8.50. At 6 months, the mean absolute reduction in VAS score was numerically greater in the RTX 2-mg (–46.49), RTX 4-mg (–43.40), and RTX 8-mg (–38.60) groups vs the group that received RTX 4 mg within 1 minute after receiving ropivacaine (–22.00).

At both 3 and 6 months, a higher proportion of patients receiving any dose of RTX-GRT7039 achieved ≥ 50% and ≥ 70% reduction in pain on motion, compared with those who received placebo. All RTX-GRT7039 treatment groups reported a greater improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score than the placebo group at both 3 and 6 months.

Rates of treatment-emergent adverse events were similar between the RTX groups (85.7%-90.9%) and placebo (85.7%) and slightly lower in the group that received RTX 4 mg within 1 minute of receiving ropivacaine (60.0%).

There was a trend toward greater procedural/injection site pain in the RTX treatment groups, compared with placebo, most commonly arthralgia (37.5%), headache (17.5%), and back pain (10%). This tended to peak around 0.5 hours post injection and resolve by 1.5-3.0 hours.

No treatment-related serious adverse events occurred, and no treatment-emergent adverse events led to discontinuation or death.

“This early-phase trial indicates that RTX-GRT7039 has the potential to provide meaningful and sustained analgesia for patients with knee OA pain,” Conaghan and colleagues wrote in their poster.

The drug is now being evaluated in three phase 3 trials (NCT05248386, NCT05449132, and NCT05377489).

 

LEVI-04: Modulation of NT-3 Appears to Work Safely

LEVI-04 was evaluated in a phase 2, 20-week, 13-center (Europe and Hong Kong) randomized, double-blind, placebo-controlled trial in 518 people with knee OA who had WOMAC pain subscale scores ≥ 20, mean average daily pain numeric rating scale score of 4-9, and radiographic Kellgren-Lawrence grade ≥ 2.

They were randomized to a total of five infusions of placebo or 0.3 mg/kg, 0.1 mg/kg, or 2 mg/kg LEVI-04 from baseline through week 16, with safety follow-up to week 30.

The primary endpoint, change in WOMAC pain from baseline to weeks 5 and 17, was met for all three doses. At 17 weeks, those were –2.79, –2.89, and –3.08 for 0.3 mg, 1.0 mg, and 2 mg, respectively, vs –2.28 for placebo (all P < .05).

Secondary endpoints, including WOMAC physical function, WOMAC stiffness, and Patient Global Assessment, and > 50% pain responders, were also all met at weeks 5 and 17. More than 50% of the LEVI-04–treated patients reported ≥ 50% reduction in pain, and > 25% reported ≥ 75% reduction at weeks 5 and 17.

“So, this modulation of NT-3 is working,” Conaghan commented.

There were no increased incidences of severe adverse events, treatment-emergent adverse events, or joint pathologies, including rapidly progressive OA, compared with placebo.

There were more paresthesias reported with the active drug, 2-4 vs 1 with placebo. “That says to me that the drug is working and that it’s having an effect on peripheral nerves, but luckily these were all mild or moderate and didn’t lead to any study withdrawal or discontinuation,” Conaghan said.

Phase 3 trials are in the planning stages, he noted.

 

Other Approaches to Treating OA Pain

Other approaches to treating OA pain have included methotrexate, for which Conaghan was also a coauthor on one paper that came out earlier in 2024. “This presumably works by treating inflammation, but it’s not clear if that is within-joint inflammation or systemic inflammation,” he said in an interview.

Another approach, using the weight loss drug semaglutide, was presented in April 2024 at the 2024 World Congress on Osteoarthritis annual meeting and published in October 2024 in The New England Journal of Medicine

The trial involving RTX-GRT7039 was funded by Grünenthal, and some study coauthors are employees of the company. The trial involving LEVI-04 was funded by Levicept, and some study coauthors are employees of the company. Conaghan is a consultant and/or speaker for Eli Lilly, Eupraxia Pharmaceuticals, Formation Bio, Galapagos, Genascence, GlaxoSmithKline, Grünenthal, Janssen Pharmaceuticals, Kolon TissueGene, Levicept, Medipost, Moebius, Novartis, Pacira, Sandoz, Stryker Corporation, and Takeda. Gardner and Jeffries had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with serum ferritin levels higher than 1000 μg/L show a 91% increased risk for any fracture, with a doubled risk for vertebral and humerus fractures compared with those without iron overload.

 

METHODOLOGY:

• Iron overload’s association with decreased bone mineral density is established, but its relationship to osteoporotic fracture risk has remained understudied and inconsistent across fracture sites.
• Researchers conducted a population-based cohort study using a UK general practice database to evaluate the fracture risk in 20,264 patients with iron overload and 192,956 matched controls without elevated ferritin (mean age, 57 years; about 40% women).
• Patients with iron overload were identified as those with laboratory-confirmed iron overload (serum ferritin levels > 1000 μg/L; n = 13,510) or a diagnosis of an iron overloading disorder, such as thalassemia major, sickle cell disease, or hemochromatosis (n = 6754).
• The primary outcome of interest was the first occurrence of an osteoporotic fracture after the diagnosis of iron overload or first record of high ferritin.
• A sensitivity analysis was conducted to check the impact of laboratory-confirmed iron overload on the risk for osteoporotic fracture compared with a diagnosis code without elevated ferritin.

TAKEAWAY:

• In the overall cohort, patients with iron overload had a 55% higher risk for any osteoporotic fracture than control individuals (adjusted hazard ratio [aHR], 1.55; 95% CI, 1.42-1.68), with the highest risk observed for vertebral fractures (aHR, 1.97; 95% CI, 1.63-2.37) and humerus fractures (aHR, 1.91; 95% CI, 1.61-2.26).
• Patients with laboratory-confirmed iron overload showed a 91% increased risk for any fracture (aHR, 1.91; 95% CI, 1.73-2.10), with a 2.5-fold higher risk observed for vertebral fractures (aHR, 2.51; 95% CI, 2.01-3.12), followed by humerus fractures (aHR, 2.41; 95% CI, 1.96-2.95).
• There was no increased risk for fracture at any site in patients with a diagnosis of an iron overloading disorder but no laboratory-confirmed iron overload.
• No sex-specific differences were identified in the association between iron overload and fracture risk.

IN PRACTICE:

“The main clinical message from our findings is that clinicians should consider iron overloading as a risk factor for fracture. Importantly, among high-risk patients presenting with serum ferritin values exceeding 1000 μg/L, osteoporosis screening and treatment strategies should be initiated in accordance with the guidelines for patients with hepatic disease,” the authors wrote.

 

SOURCE:

The study was led by Andrea Michelle Burden, PhD, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich in Switzerland, and was published online in The Journal of Clinical Endocrinology & Metabolism.

 

LIMITATIONS:

The study could not assess the duration of iron overload on fracture risk, and thus, patients could enter the cohort with a single elevated serum ferritin value that may not have reflected systemic iron overload. The authors also acknowledged potential exposure misclassification among matched control individuals because only 2.9% had a serum ferritin value available at baseline. Also, researchers were unable to adjust for inflammation status due to the limited availability of C-reactive protein measurements and the lack of leukocyte count data in primary care settings.

 

DISCLOSURES:

This study received support through grants from the German Research Foundation. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Patients with serum ferritin levels higher than 1000 μg/L show a 91% increased risk for any fracture, with a doubled risk for vertebral and humerus fractures compared with those without iron overload.

 

METHODOLOGY:

• Iron overload’s association with decreased bone mineral density is established, but its relationship to osteoporotic fracture risk has remained understudied and inconsistent across fracture sites.
• Researchers conducted a population-based cohort study using a UK general practice database to evaluate the fracture risk in 20,264 patients with iron overload and 192,956 matched controls without elevated ferritin (mean age, 57 years; about 40% women).
• Patients with iron overload were identified as those with laboratory-confirmed iron overload (serum ferritin levels > 1000 μg/L; n = 13,510) or a diagnosis of an iron overloading disorder, such as thalassemia major, sickle cell disease, or hemochromatosis (n = 6754).
• The primary outcome of interest was the first occurrence of an osteoporotic fracture after the diagnosis of iron overload or first record of high ferritin.
• A sensitivity analysis was conducted to check the impact of laboratory-confirmed iron overload on the risk for osteoporotic fracture compared with a diagnosis code without elevated ferritin.

TAKEAWAY:

• In the overall cohort, patients with iron overload had a 55% higher risk for any osteoporotic fracture than control individuals (adjusted hazard ratio [aHR], 1.55; 95% CI, 1.42-1.68), with the highest risk observed for vertebral fractures (aHR, 1.97; 95% CI, 1.63-2.37) and humerus fractures (aHR, 1.91; 95% CI, 1.61-2.26).
• Patients with laboratory-confirmed iron overload showed a 91% increased risk for any fracture (aHR, 1.91; 95% CI, 1.73-2.10), with a 2.5-fold higher risk observed for vertebral fractures (aHR, 2.51; 95% CI, 2.01-3.12), followed by humerus fractures (aHR, 2.41; 95% CI, 1.96-2.95).
• There was no increased risk for fracture at any site in patients with a diagnosis of an iron overloading disorder but no laboratory-confirmed iron overload.
• No sex-specific differences were identified in the association between iron overload and fracture risk.

IN PRACTICE:

“The main clinical message from our findings is that clinicians should consider iron overloading as a risk factor for fracture. Importantly, among high-risk patients presenting with serum ferritin values exceeding 1000 μg/L, osteoporosis screening and treatment strategies should be initiated in accordance with the guidelines for patients with hepatic disease,” the authors wrote.

 

SOURCE:

The study was led by Andrea Michelle Burden, PhD, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich in Switzerland, and was published online in The Journal of Clinical Endocrinology & Metabolism.

 

LIMITATIONS:

The study could not assess the duration of iron overload on fracture risk, and thus, patients could enter the cohort with a single elevated serum ferritin value that may not have reflected systemic iron overload. The authors also acknowledged potential exposure misclassification among matched control individuals because only 2.9% had a serum ferritin value available at baseline. Also, researchers were unable to adjust for inflammation status due to the limited availability of C-reactive protein measurements and the lack of leukocyte count data in primary care settings.

 

DISCLOSURES:

This study received support through grants from the German Research Foundation. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Patients with serum ferritin levels higher than 1000 μg/L show a 91% increased risk for any fracture, with a doubled risk for vertebral and humerus fractures compared with those without iron overload.

 

METHODOLOGY:

• Iron overload’s association with decreased bone mineral density is established, but its relationship to osteoporotic fracture risk has remained understudied and inconsistent across fracture sites.
• Researchers conducted a population-based cohort study using a UK general practice database to evaluate the fracture risk in 20,264 patients with iron overload and 192,956 matched controls without elevated ferritin (mean age, 57 years; about 40% women).
• Patients with iron overload were identified as those with laboratory-confirmed iron overload (serum ferritin levels > 1000 μg/L; n = 13,510) or a diagnosis of an iron overloading disorder, such as thalassemia major, sickle cell disease, or hemochromatosis (n = 6754).
• The primary outcome of interest was the first occurrence of an osteoporotic fracture after the diagnosis of iron overload or first record of high ferritin.
• A sensitivity analysis was conducted to check the impact of laboratory-confirmed iron overload on the risk for osteoporotic fracture compared with a diagnosis code without elevated ferritin.

TAKEAWAY:

• In the overall cohort, patients with iron overload had a 55% higher risk for any osteoporotic fracture than control individuals (adjusted hazard ratio [aHR], 1.55; 95% CI, 1.42-1.68), with the highest risk observed for vertebral fractures (aHR, 1.97; 95% CI, 1.63-2.37) and humerus fractures (aHR, 1.91; 95% CI, 1.61-2.26).
• Patients with laboratory-confirmed iron overload showed a 91% increased risk for any fracture (aHR, 1.91; 95% CI, 1.73-2.10), with a 2.5-fold higher risk observed for vertebral fractures (aHR, 2.51; 95% CI, 2.01-3.12), followed by humerus fractures (aHR, 2.41; 95% CI, 1.96-2.95).
• There was no increased risk for fracture at any site in patients with a diagnosis of an iron overloading disorder but no laboratory-confirmed iron overload.
• No sex-specific differences were identified in the association between iron overload and fracture risk.

IN PRACTICE:

“The main clinical message from our findings is that clinicians should consider iron overloading as a risk factor for fracture. Importantly, among high-risk patients presenting with serum ferritin values exceeding 1000 μg/L, osteoporosis screening and treatment strategies should be initiated in accordance with the guidelines for patients with hepatic disease,” the authors wrote.

 

SOURCE:

The study was led by Andrea Michelle Burden, PhD, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich in Switzerland, and was published online in The Journal of Clinical Endocrinology & Metabolism.

 

LIMITATIONS:

The study could not assess the duration of iron overload on fracture risk, and thus, patients could enter the cohort with a single elevated serum ferritin value that may not have reflected systemic iron overload. The authors also acknowledged potential exposure misclassification among matched control individuals because only 2.9% had a serum ferritin value available at baseline. Also, researchers were unable to adjust for inflammation status due to the limited availability of C-reactive protein measurements and the lack of leukocyte count data in primary care settings.

 

DISCLOSURES:

This study received support through grants from the German Research Foundation. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

WASHINGTON — A new guideline for management of lupus nephritis (LN) was unveiled at the annual meeting of the American College of Rheumatology (ACR), updating the 2012 LN guideline to recommend a more aggressive first-line approach to treating the disease.

“The biggest differences are that we are recommending what we’re calling triple therapy, where we incorporate the glucocorticoid therapy with baseline conventional immunosuppressants, usually mycophenolate with cyclophosphamide, and the addition of one of the newer agents more recently approved by the FDA [Food and Drug Administration] — belimumab, voclosporin, or another CNI [calcineurin inhibitor],” said Lisa Sammaritano, MD, director of the Rheumatology Reproductive Health Program of the Barbara Volcker Center for Women and Rheumatic Diseases at the Hospital for Special Surgery and professor of clinical medicine at Weill Cornell Medical College, both in New York City.

“This is a bit of a change from not only our previous guideline but some of the other guidelines out there, and it is based on the fact that we have very convincing evidence that starting with triple therapy yields to better long-term outcomes for our patients than starting with only two agents and waiting to see if they respond before escalating therapy,” she said. Other key updates include recommending use of pulse glucocorticoid therapy with a lower dose and more rapid steroid taper and treating patients with the recommended therapy for 3-5 years.

The guiding principles of the guideline are not only to preserve kidney function and minimize morbidity and mortality but also to ensure collaborative care with nephrology, to utilize shared decision-making that includes patients’ values and preferences, to reduce healthcare disparities, and to consider pediatric and geriatric populations. The guidelines are based on a quantitative synthesis of 105 studies that yielded 7 strong recommendations, 21 conditional recommendations, and 13 good practice statements — those commonly accepted as beneficial or practical advice even if there is little direct evidence to support them. The voting panel of 19 members included not only 3 nephrologists and 2 pediatric rheumatologists but also 2 patient representatives with LN.

The recommendations are just that, “a recommendation, not an order,” Sammaritano said, and strong recommendations are those “where we think, unequivocally, almost everybody should follow that recommendation. When we feel that we cannot make a strong recommendation, then we call our recommendation conditional, and it is conditional on looking at different things,” she said.

“Patients are different, especially lupus patients, and so one lupus nephritis patient may have different clinical characteristics, different thoughts about what therapy will work for them in their lives, or what therapy they really do not want to pursue,” Sammaritano said. “Maybe they can’t conceive of coming to the hospital once a month for intravenous therapy. Maybe they’re concerned about pill burden, which is something that our patient panel really emphasized to us. So, conditional recommendation means this voting panel thought that this was the best overall for most patients and most circumstances, recognizing there will still be a significant number of people, clinicians and patients, who may feel differently for that particular situation. So, that’s where you know the patient-clinician discussion can help with decision-making.”

 

What Are the Recommendations?

All patients with systemic lupus erythematosus (SLE) are strongly recommended to undergo proteinuria screening every 6-12 months or at the time of a flare. Those suspected of having LN should receive a prompt kidney biopsy and treatment with glucocorticoids while awaiting the biopsy and results. Two conditional recommendations for kidney biopsy include patients with SLE with unexplained impaired kidney function or a protein to creatinine ratio > 0.5 g/g, and patients with LN with a suspected flare after initial response or a lack of response or worsening after 6 months of therapy.

The guidelines include a strong recommendation for all patients with SLE to receive hydroxychloroquine and a conditional recommendation for all patients with elevated proteinuria (> 0.5 g/g) to receive renin-angiotensin-aldosterone system inhibitors (RAAS-I). Dosages in patients with LN with decreased glomerular filtration rate (GFR) should be adjusted as needed.

Sammaritano then reviewed the specifics on medication treatment. The glucocorticoid therapy in all patients with LN should begin with Pulse IV Therapy at 250-1000 mg/d for 1-3 days, followed by oral prednisone ≤ 0.5 mg/kg per day up to 40 mg/d, then tapered to a target dose > 5 mg/d within 6 months. The justification for this course comes from a 2024 systematic review finding pulse followed by oral glucocorticoids maximized complete renal response while minimizing toxicities, Sammaritano said.

“We have all become acutely aware of the very high risk of prolonged high dose of glucocorticoids for our patients,” she said, “and importantly, our patient panel participants strongly emphasized their preference for minimizing glucocorticoids dose.”

In addition to the recommendation of all patients receiving hydroxychloroquine and RAAS-I, first-line treatment of active, new-onset, or flaring LN should begin with triple therapy — glucocorticoids with two additional immunosuppressive agents. For patients with class III/IV LN, triple therapy includes the glucocorticoids course with a mycophenolic acid analog (MPAA) and either belimumab or a CNI. Conditional recommendations support MPAA with belimumab for significant extrarenal manifestations and MPAA with CNI for proteinuria ≥ 3 g/g.

An alternative triple therapy for class III/IV is glucocorticoids with low-dose cyclophosphamide and belimumab, but MPAA at 2-3 g/d is preferred over cyclophosphamide. The preferred regimen for cyclophosphamide is derived from the Euro-Lupus Nephritis Trial: Intravenous 500 mg every 2 weeks for six doses and then MPAA. Sammaritano noted that there are some limited data on using cyclophosphamide with belimumab, but “we do not specifically recommend cyclophosphamide with a CNI as one of our options because this combination has not been studied in randomized controlled trials.”

There are less data supporting class V recommendations, Sammaritano said, but for those with proteinuria of at least 1 g/g, the panel still recommends triple therapy with glucocorticoids, a MPAA, and a CNI. A CNI is preferred over belimumab because of its stabilizing effects on the podocyte cytoskeleton. Two alternative triple therapies for class V–only patients are glucocorticoids with belimumab and either low-dose cyclophosphamide or MPAA.

Dual therapy is only recommended if triple therapy is not available or not tolerated. The voting panel chose to recommend triple therapy over dual therapy with escalation for two reasons. First, the BLISS-LN and AURORA 1 trials showed improved outcomes with initial triple therapy over initial dual therapies.

Second, “nephron loss proceeds throughout a person’s lifetime even for those who do not have lupus nephritis, and every case of lupus nephritis or every period of time with uncontrolled lupus nephritis changes the course of that decline for the worse,” Sammaritano said. “So, we feel we can’t wait for nephron loss to implement what has been shown to be the most efficacious therapy. We want to gain rapid control of inflammation using the most effective regimen to prevent further damage and flare and maintain survival.”

Therapy is conditionally recommended for at least 3-5 years because “not only do we want to gain rapid control of disease activity [but we also] want to maintain control of disease activity until there’s sustained inactive disease,” Sammaritano said. “Repeat kidney biopsies show that immunologic activity persists in the kidneys for several years, and the withdrawal of immunosuppression when there is histologic activity predisposes patients to flare.” But immunosuppressive therapy can be tapered over time as determined by renal disease activity and medication tolerability.

For patients with refractory disease, consider additional factors that could be affecting the disease, such as adherence, the presence of other diagnoses, or advanced chronicity.

“If true refractory nephritis is present,” she said, “we recommend escalation to a more intensive regimen,” including the addition of anti-CD20 agents, combination therapy with three immunosuppressives, or referral for investigational therapy.

“We also emphasize the importance of other adjunctive therapies preventing comorbidities, such as cardiovascular disease, changes in bone health, or infection risk,” she said. In older patients, avoid polypharmacy as much as possible and be mindful of age-related GFR, she added.

A strong recommendation supported monitoring patients with LN and proteinuria at least every 3 months if they have not achieved complete renal response and every 3-6 months after sustained complete renal response.

Last, in patients with LN and end-stage kidney disease (ESKD), the voting panel strongly recommends transplant over dialysis and conditionally recommends proceeding to the transplant without requiring a complete clinical or serologic remission as long as no other organs are involved. In patients with LN at risk for ESKD, the guideline conditionally recommends consideration of a preemptive transplant, and patients on dialysis or post transplant are strongly recommended to regularly follow up with rheumatology.

Gabriel Kirsch, MD, a resident rheumatologist at the University of Florida College of Medicine, Jacksonville, said he found the guidelines helpful, “especially the guidance on the dichotomy between using belimumab and voclosporin and the clinical and patient preference that help you make that decision.”

Kirsch had hoped, however, to hear more about the impact of therapeutic drug monitoring of hydroxychloroquine on LN outcomes. He also noted a clinical scenario he’s come across that wasn’t addressed.

“When you’re checking GFR on these folks, a lot of our eGFR calculators are creatinine based, and creatinine at the extremes of muscle mass can be inaccurate,” such as getting artificially low creatinine readings from pediatric patients because of their low muscle mass or from patients with muscle atrophy caused by a lot of glucocorticoid exposure. “I was hoping for some more guidance on that,” he said.

Ellen Ginzler, MD, MPH, chief of rheumatology at SUNY Health Science Center in Brooklyn, New York, said the guidelines were pretty much what she expected them to be. She agreed with the panel’s advice that, when deciding between belimumab or voclosporin, “if it’s pure proteinuria, then you add voclosporin. If the patient has extra renal manifestations, you go with belimumab first.” 

“They really made it quite clear that, despite the fact that people really want to reduce the amount of immunosuppression — and I agree you should taper steroids quickly — you really need to keep the immunosuppression for a prolonged period of time because all of the studies that have been done for years show that the longer you’re on immunosuppression after you achieve remission or a low disease activity state, the better your chance of not flaring,” Ginzler said. “Rapid tapering or discontinuation really increases the risk of flare.”

Sammaritano, Kirsch, and Ginzler had no disclosures. No external funding was used.

A version of this article appeared on Medscape.com.

WASHINGTON — A new guideline for management of lupus nephritis (LN) was unveiled at the annual meeting of the American College of Rheumatology (ACR), updating the 2012 LN guideline to recommend a more aggressive first-line approach to treating the disease.

“The biggest differences are that we are recommending what we’re calling triple therapy, where we incorporate the glucocorticoid therapy with baseline conventional immunosuppressants, usually mycophenolate with cyclophosphamide, and the addition of one of the newer agents more recently approved by the FDA [Food and Drug Administration] — belimumab, voclosporin, or another CNI [calcineurin inhibitor],” said Lisa Sammaritano, MD, director of the Rheumatology Reproductive Health Program of the Barbara Volcker Center for Women and Rheumatic Diseases at the Hospital for Special Surgery and professor of clinical medicine at Weill Cornell Medical College, both in New York City.

“This is a bit of a change from not only our previous guideline but some of the other guidelines out there, and it is based on the fact that we have very convincing evidence that starting with triple therapy yields to better long-term outcomes for our patients than starting with only two agents and waiting to see if they respond before escalating therapy,” she said. Other key updates include recommending use of pulse glucocorticoid therapy with a lower dose and more rapid steroid taper and treating patients with the recommended therapy for 3-5 years.

The guiding principles of the guideline are not only to preserve kidney function and minimize morbidity and mortality but also to ensure collaborative care with nephrology, to utilize shared decision-making that includes patients’ values and preferences, to reduce healthcare disparities, and to consider pediatric and geriatric populations. The guidelines are based on a quantitative synthesis of 105 studies that yielded 7 strong recommendations, 21 conditional recommendations, and 13 good practice statements — those commonly accepted as beneficial or practical advice even if there is little direct evidence to support them. The voting panel of 19 members included not only 3 nephrologists and 2 pediatric rheumatologists but also 2 patient representatives with LN.

The recommendations are just that, “a recommendation, not an order,” Sammaritano said, and strong recommendations are those “where we think, unequivocally, almost everybody should follow that recommendation. When we feel that we cannot make a strong recommendation, then we call our recommendation conditional, and it is conditional on looking at different things,” she said.

“Patients are different, especially lupus patients, and so one lupus nephritis patient may have different clinical characteristics, different thoughts about what therapy will work for them in their lives, or what therapy they really do not want to pursue,” Sammaritano said. “Maybe they can’t conceive of coming to the hospital once a month for intravenous therapy. Maybe they’re concerned about pill burden, which is something that our patient panel really emphasized to us. So, conditional recommendation means this voting panel thought that this was the best overall for most patients and most circumstances, recognizing there will still be a significant number of people, clinicians and patients, who may feel differently for that particular situation. So, that’s where you know the patient-clinician discussion can help with decision-making.”

 

What Are the Recommendations?

All patients with systemic lupus erythematosus (SLE) are strongly recommended to undergo proteinuria screening every 6-12 months or at the time of a flare. Those suspected of having LN should receive a prompt kidney biopsy and treatment with glucocorticoids while awaiting the biopsy and results. Two conditional recommendations for kidney biopsy include patients with SLE with unexplained impaired kidney function or a protein to creatinine ratio > 0.5 g/g, and patients with LN with a suspected flare after initial response or a lack of response or worsening after 6 months of therapy.

The guidelines include a strong recommendation for all patients with SLE to receive hydroxychloroquine and a conditional recommendation for all patients with elevated proteinuria (> 0.5 g/g) to receive renin-angiotensin-aldosterone system inhibitors (RAAS-I). Dosages in patients with LN with decreased glomerular filtration rate (GFR) should be adjusted as needed.

Sammaritano then reviewed the specifics on medication treatment. The glucocorticoid therapy in all patients with LN should begin with Pulse IV Therapy at 250-1000 mg/d for 1-3 days, followed by oral prednisone ≤ 0.5 mg/kg per day up to 40 mg/d, then tapered to a target dose > 5 mg/d within 6 months. The justification for this course comes from a 2024 systematic review finding pulse followed by oral glucocorticoids maximized complete renal response while minimizing toxicities, Sammaritano said.

“We have all become acutely aware of the very high risk of prolonged high dose of glucocorticoids for our patients,” she said, “and importantly, our patient panel participants strongly emphasized their preference for minimizing glucocorticoids dose.”

In addition to the recommendation of all patients receiving hydroxychloroquine and RAAS-I, first-line treatment of active, new-onset, or flaring LN should begin with triple therapy — glucocorticoids with two additional immunosuppressive agents. For patients with class III/IV LN, triple therapy includes the glucocorticoids course with a mycophenolic acid analog (MPAA) and either belimumab or a CNI. Conditional recommendations support MPAA with belimumab for significant extrarenal manifestations and MPAA with CNI for proteinuria ≥ 3 g/g.

An alternative triple therapy for class III/IV is glucocorticoids with low-dose cyclophosphamide and belimumab, but MPAA at 2-3 g/d is preferred over cyclophosphamide. The preferred regimen for cyclophosphamide is derived from the Euro-Lupus Nephritis Trial: Intravenous 500 mg every 2 weeks for six doses and then MPAA. Sammaritano noted that there are some limited data on using cyclophosphamide with belimumab, but “we do not specifically recommend cyclophosphamide with a CNI as one of our options because this combination has not been studied in randomized controlled trials.”

There are less data supporting class V recommendations, Sammaritano said, but for those with proteinuria of at least 1 g/g, the panel still recommends triple therapy with glucocorticoids, a MPAA, and a CNI. A CNI is preferred over belimumab because of its stabilizing effects on the podocyte cytoskeleton. Two alternative triple therapies for class V–only patients are glucocorticoids with belimumab and either low-dose cyclophosphamide or MPAA.

Dual therapy is only recommended if triple therapy is not available or not tolerated. The voting panel chose to recommend triple therapy over dual therapy with escalation for two reasons. First, the BLISS-LN and AURORA 1 trials showed improved outcomes with initial triple therapy over initial dual therapies.

Second, “nephron loss proceeds throughout a person’s lifetime even for those who do not have lupus nephritis, and every case of lupus nephritis or every period of time with uncontrolled lupus nephritis changes the course of that decline for the worse,” Sammaritano said. “So, we feel we can’t wait for nephron loss to implement what has been shown to be the most efficacious therapy. We want to gain rapid control of inflammation using the most effective regimen to prevent further damage and flare and maintain survival.”

Therapy is conditionally recommended for at least 3-5 years because “not only do we want to gain rapid control of disease activity [but we also] want to maintain control of disease activity until there’s sustained inactive disease,” Sammaritano said. “Repeat kidney biopsies show that immunologic activity persists in the kidneys for several years, and the withdrawal of immunosuppression when there is histologic activity predisposes patients to flare.” But immunosuppressive therapy can be tapered over time as determined by renal disease activity and medication tolerability.

For patients with refractory disease, consider additional factors that could be affecting the disease, such as adherence, the presence of other diagnoses, or advanced chronicity.

“If true refractory nephritis is present,” she said, “we recommend escalation to a more intensive regimen,” including the addition of anti-CD20 agents, combination therapy with three immunosuppressives, or referral for investigational therapy.

“We also emphasize the importance of other adjunctive therapies preventing comorbidities, such as cardiovascular disease, changes in bone health, or infection risk,” she said. In older patients, avoid polypharmacy as much as possible and be mindful of age-related GFR, she added.

A strong recommendation supported monitoring patients with LN and proteinuria at least every 3 months if they have not achieved complete renal response and every 3-6 months after sustained complete renal response.

Last, in patients with LN and end-stage kidney disease (ESKD), the voting panel strongly recommends transplant over dialysis and conditionally recommends proceeding to the transplant without requiring a complete clinical or serologic remission as long as no other organs are involved. In patients with LN at risk for ESKD, the guideline conditionally recommends consideration of a preemptive transplant, and patients on dialysis or post transplant are strongly recommended to regularly follow up with rheumatology.

Gabriel Kirsch, MD, a resident rheumatologist at the University of Florida College of Medicine, Jacksonville, said he found the guidelines helpful, “especially the guidance on the dichotomy between using belimumab and voclosporin and the clinical and patient preference that help you make that decision.”

Kirsch had hoped, however, to hear more about the impact of therapeutic drug monitoring of hydroxychloroquine on LN outcomes. He also noted a clinical scenario he’s come across that wasn’t addressed.

“When you’re checking GFR on these folks, a lot of our eGFR calculators are creatinine based, and creatinine at the extremes of muscle mass can be inaccurate,” such as getting artificially low creatinine readings from pediatric patients because of their low muscle mass or from patients with muscle atrophy caused by a lot of glucocorticoid exposure. “I was hoping for some more guidance on that,” he said.

Ellen Ginzler, MD, MPH, chief of rheumatology at SUNY Health Science Center in Brooklyn, New York, said the guidelines were pretty much what she expected them to be. She agreed with the panel’s advice that, when deciding between belimumab or voclosporin, “if it’s pure proteinuria, then you add voclosporin. If the patient has extra renal manifestations, you go with belimumab first.” 

“They really made it quite clear that, despite the fact that people really want to reduce the amount of immunosuppression — and I agree you should taper steroids quickly — you really need to keep the immunosuppression for a prolonged period of time because all of the studies that have been done for years show that the longer you’re on immunosuppression after you achieve remission or a low disease activity state, the better your chance of not flaring,” Ginzler said. “Rapid tapering or discontinuation really increases the risk of flare.”

Sammaritano, Kirsch, and Ginzler had no disclosures. No external funding was used.

A version of this article appeared on Medscape.com.

WASHINGTON — A new guideline for management of lupus nephritis (LN) was unveiled at the annual meeting of the American College of Rheumatology (ACR), updating the 2012 LN guideline to recommend a more aggressive first-line approach to treating the disease.

“The biggest differences are that we are recommending what we’re calling triple therapy, where we incorporate the glucocorticoid therapy with baseline conventional immunosuppressants, usually mycophenolate with cyclophosphamide, and the addition of one of the newer agents more recently approved by the FDA [Food and Drug Administration] — belimumab, voclosporin, or another CNI [calcineurin inhibitor],” said Lisa Sammaritano, MD, director of the Rheumatology Reproductive Health Program of the Barbara Volcker Center for Women and Rheumatic Diseases at the Hospital for Special Surgery and professor of clinical medicine at Weill Cornell Medical College, both in New York City.

“This is a bit of a change from not only our previous guideline but some of the other guidelines out there, and it is based on the fact that we have very convincing evidence that starting with triple therapy yields to better long-term outcomes for our patients than starting with only two agents and waiting to see if they respond before escalating therapy,” she said. Other key updates include recommending use of pulse glucocorticoid therapy with a lower dose and more rapid steroid taper and treating patients with the recommended therapy for 3-5 years.

The guiding principles of the guideline are not only to preserve kidney function and minimize morbidity and mortality but also to ensure collaborative care with nephrology, to utilize shared decision-making that includes patients’ values and preferences, to reduce healthcare disparities, and to consider pediatric and geriatric populations. The guidelines are based on a quantitative synthesis of 105 studies that yielded 7 strong recommendations, 21 conditional recommendations, and 13 good practice statements — those commonly accepted as beneficial or practical advice even if there is little direct evidence to support them. The voting panel of 19 members included not only 3 nephrologists and 2 pediatric rheumatologists but also 2 patient representatives with LN.

The recommendations are just that, “a recommendation, not an order,” Sammaritano said, and strong recommendations are those “where we think, unequivocally, almost everybody should follow that recommendation. When we feel that we cannot make a strong recommendation, then we call our recommendation conditional, and it is conditional on looking at different things,” she said.

“Patients are different, especially lupus patients, and so one lupus nephritis patient may have different clinical characteristics, different thoughts about what therapy will work for them in their lives, or what therapy they really do not want to pursue,” Sammaritano said. “Maybe they can’t conceive of coming to the hospital once a month for intravenous therapy. Maybe they’re concerned about pill burden, which is something that our patient panel really emphasized to us. So, conditional recommendation means this voting panel thought that this was the best overall for most patients and most circumstances, recognizing there will still be a significant number of people, clinicians and patients, who may feel differently for that particular situation. So, that’s where you know the patient-clinician discussion can help with decision-making.”

 

What Are the Recommendations?

All patients with systemic lupus erythematosus (SLE) are strongly recommended to undergo proteinuria screening every 6-12 months or at the time of a flare. Those suspected of having LN should receive a prompt kidney biopsy and treatment with glucocorticoids while awaiting the biopsy and results. Two conditional recommendations for kidney biopsy include patients with SLE with unexplained impaired kidney function or a protein to creatinine ratio > 0.5 g/g, and patients with LN with a suspected flare after initial response or a lack of response or worsening after 6 months of therapy.

The guidelines include a strong recommendation for all patients with SLE to receive hydroxychloroquine and a conditional recommendation for all patients with elevated proteinuria (> 0.5 g/g) to receive renin-angiotensin-aldosterone system inhibitors (RAAS-I). Dosages in patients with LN with decreased glomerular filtration rate (GFR) should be adjusted as needed.

Sammaritano then reviewed the specifics on medication treatment. The glucocorticoid therapy in all patients with LN should begin with Pulse IV Therapy at 250-1000 mg/d for 1-3 days, followed by oral prednisone ≤ 0.5 mg/kg per day up to 40 mg/d, then tapered to a target dose > 5 mg/d within 6 months. The justification for this course comes from a 2024 systematic review finding pulse followed by oral glucocorticoids maximized complete renal response while minimizing toxicities, Sammaritano said.

“We have all become acutely aware of the very high risk of prolonged high dose of glucocorticoids for our patients,” she said, “and importantly, our patient panel participants strongly emphasized their preference for minimizing glucocorticoids dose.”

In addition to the recommendation of all patients receiving hydroxychloroquine and RAAS-I, first-line treatment of active, new-onset, or flaring LN should begin with triple therapy — glucocorticoids with two additional immunosuppressive agents. For patients with class III/IV LN, triple therapy includes the glucocorticoids course with a mycophenolic acid analog (MPAA) and either belimumab or a CNI. Conditional recommendations support MPAA with belimumab for significant extrarenal manifestations and MPAA with CNI for proteinuria ≥ 3 g/g.

An alternative triple therapy for class III/IV is glucocorticoids with low-dose cyclophosphamide and belimumab, but MPAA at 2-3 g/d is preferred over cyclophosphamide. The preferred regimen for cyclophosphamide is derived from the Euro-Lupus Nephritis Trial: Intravenous 500 mg every 2 weeks for six doses and then MPAA. Sammaritano noted that there are some limited data on using cyclophosphamide with belimumab, but “we do not specifically recommend cyclophosphamide with a CNI as one of our options because this combination has not been studied in randomized controlled trials.”

There are less data supporting class V recommendations, Sammaritano said, but for those with proteinuria of at least 1 g/g, the panel still recommends triple therapy with glucocorticoids, a MPAA, and a CNI. A CNI is preferred over belimumab because of its stabilizing effects on the podocyte cytoskeleton. Two alternative triple therapies for class V–only patients are glucocorticoids with belimumab and either low-dose cyclophosphamide or MPAA.

Dual therapy is only recommended if triple therapy is not available or not tolerated. The voting panel chose to recommend triple therapy over dual therapy with escalation for two reasons. First, the BLISS-LN and AURORA 1 trials showed improved outcomes with initial triple therapy over initial dual therapies.

Second, “nephron loss proceeds throughout a person’s lifetime even for those who do not have lupus nephritis, and every case of lupus nephritis or every period of time with uncontrolled lupus nephritis changes the course of that decline for the worse,” Sammaritano said. “So, we feel we can’t wait for nephron loss to implement what has been shown to be the most efficacious therapy. We want to gain rapid control of inflammation using the most effective regimen to prevent further damage and flare and maintain survival.”

Therapy is conditionally recommended for at least 3-5 years because “not only do we want to gain rapid control of disease activity [but we also] want to maintain control of disease activity until there’s sustained inactive disease,” Sammaritano said. “Repeat kidney biopsies show that immunologic activity persists in the kidneys for several years, and the withdrawal of immunosuppression when there is histologic activity predisposes patients to flare.” But immunosuppressive therapy can be tapered over time as determined by renal disease activity and medication tolerability.

For patients with refractory disease, consider additional factors that could be affecting the disease, such as adherence, the presence of other diagnoses, or advanced chronicity.

“If true refractory nephritis is present,” she said, “we recommend escalation to a more intensive regimen,” including the addition of anti-CD20 agents, combination therapy with three immunosuppressives, or referral for investigational therapy.

“We also emphasize the importance of other adjunctive therapies preventing comorbidities, such as cardiovascular disease, changes in bone health, or infection risk,” she said. In older patients, avoid polypharmacy as much as possible and be mindful of age-related GFR, she added.

A strong recommendation supported monitoring patients with LN and proteinuria at least every 3 months if they have not achieved complete renal response and every 3-6 months after sustained complete renal response.

Last, in patients with LN and end-stage kidney disease (ESKD), the voting panel strongly recommends transplant over dialysis and conditionally recommends proceeding to the transplant without requiring a complete clinical or serologic remission as long as no other organs are involved. In patients with LN at risk for ESKD, the guideline conditionally recommends consideration of a preemptive transplant, and patients on dialysis or post transplant are strongly recommended to regularly follow up with rheumatology.

Gabriel Kirsch, MD, a resident rheumatologist at the University of Florida College of Medicine, Jacksonville, said he found the guidelines helpful, “especially the guidance on the dichotomy between using belimumab and voclosporin and the clinical and patient preference that help you make that decision.”

Kirsch had hoped, however, to hear more about the impact of therapeutic drug monitoring of hydroxychloroquine on LN outcomes. He also noted a clinical scenario he’s come across that wasn’t addressed.

“When you’re checking GFR on these folks, a lot of our eGFR calculators are creatinine based, and creatinine at the extremes of muscle mass can be inaccurate,” such as getting artificially low creatinine readings from pediatric patients because of their low muscle mass or from patients with muscle atrophy caused by a lot of glucocorticoid exposure. “I was hoping for some more guidance on that,” he said.

Ellen Ginzler, MD, MPH, chief of rheumatology at SUNY Health Science Center in Brooklyn, New York, said the guidelines were pretty much what she expected them to be. She agreed with the panel’s advice that, when deciding between belimumab or voclosporin, “if it’s pure proteinuria, then you add voclosporin. If the patient has extra renal manifestations, you go with belimumab first.” 

“They really made it quite clear that, despite the fact that people really want to reduce the amount of immunosuppression — and I agree you should taper steroids quickly — you really need to keep the immunosuppression for a prolonged period of time because all of the studies that have been done for years show that the longer you’re on immunosuppression after you achieve remission or a low disease activity state, the better your chance of not flaring,” Ginzler said. “Rapid tapering or discontinuation really increases the risk of flare.”

Sammaritano, Kirsch, and Ginzler had no disclosures. No external funding was used.

A version of this article appeared on Medscape.com.

TOPLINE:

Biosimilars demonstrate comparable drug survival and safety with adalimumab among new users, but patients switching from Humira (the originator product) to biosimilars had a 35% higher discontinuation rate than those who remained on Humira.

 

METHODOLOGY:

• Researchers conducted a cohort study using data on patients with psoriasis who were treated with adalimumab, a tumor necrosis factor alpha inhibitor used to treat moderate to severe psoriasis, from the French National Health Data System, British Association of Dermatologists Biologics and Immunomodulators Register, and Spanish Registry of Systemic Therapy in Psoriasis.
• The analysis included 7387 adalimumab-naive patients who were new users of an adalimumab biosimilar and 3654 patients (switchers) who switched from Humira to a biosimilar. Patients were matched and compared with patients receiving Humira.
• Co-primary outcomes of the study were drug discontinuation and serious adverse events.
• Researchers assessed the following adalimumab biosimilar brands: Amgevita, Imraldi, Hyrimoz, Idacio, and Hulio.

TAKEAWAY:

• All-cause drug discontinuation rates were similar between new users of biosimilars and Humira new users (hazard ratio [HR], 0.99; 95% CI, 0.94-1.04).
• Discontinuation rates were higher among those who switched from Humira to a biosimilar (HR, 1.35; 95% CI, 1.19-1.52) than among those who stayed on Humira. Switching to Amgevita (HR, 1.25; 95% CI, 1.13-1.27), Imraldi (HR, 1.53; 95% CI, 1.33-1.76), and Hyrimoz (HR, 1.80; 95% CI, 1.29-2.52) was associated with higher discontinuation rates.
• Serious adverse events were not significantly different between new users of Humira and biosimilar new users (incidence rate ratio [IRR], 0.91; 95% CI, 0.80-1.05), and between patients who switched from a biosimilar to Humira and those who stayed on Humira (IRR, 0.92; 95% CI, 0.83-1.01).
• No significant differences in discontinuation because of ineffectiveness were found between biosimilar and Humira new users (HR, 0.97; 95% CI, 0.88-1.08). Discontinuation because of adverse events was also comparable for all biosimilars among new users, except for Hyrimoz (HR, 0.54; 95% CI, 0.35-0.85), which showed fewer discontinuations than Humira.

IN PRACTICE:

“This study found comparable drug survival and safety between adalimumab biosimilars and Humira in adalimumab-naive patients, supporting the use of biosimilars as viable alternatives for new patients,” the authors wrote. However, noting that discontinuation was more likely among those who switched from Humira to a biosimilar, they added: “Changes in treatment response, skin or injection site reactions, and nocebo effects may contribute to treatment discontinuation post-switch. Thus, patients who switch from Humira to biosimilars may require closer monitoring and support to alleviate these challenges.”

SOURCE:

The study was led by Duc Binh Phan, Dermatology Centre, Northern Care Alliance NHS Foundation Trust in Manchester, England. It was published online in The British Journal of Dermatology.

LIMITATIONS:

Unmeasured factors including psychological perceptions, regional policies, and drug availability could influence drug survival, making the results not fully reflective of treatment effectiveness or safety. Most Humira users in registries were enrolled before biosimilars became available, making it impractical to match new users on the basis of treatment initiation years. Additionally, reasons for discontinuation were not available in the French National Health Data System.

DISCLOSURES:

In the United Kingdom, the research was funded by the Psoriasis Association PhD studentship and supported by the NIHR Manchester Biomedical Research Centre. In France, the authors are employees of the French National Health Insurance, the French National Agency for the Safety of Medicines and Health Products, and the Assistance Publique — Hôpitaux de Paris and received no funding. The authors reported receiving consulting and speaker fees and clinical trial sponsorship from various pharmaceutical companies. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Biosimilars demonstrate comparable drug survival and safety with adalimumab among new users, but patients switching from Humira (the originator product) to biosimilars had a 35% higher discontinuation rate than those who remained on Humira.

 

METHODOLOGY:

• Researchers conducted a cohort study using data on patients with psoriasis who were treated with adalimumab, a tumor necrosis factor alpha inhibitor used to treat moderate to severe psoriasis, from the French National Health Data System, British Association of Dermatologists Biologics and Immunomodulators Register, and Spanish Registry of Systemic Therapy in Psoriasis.
• The analysis included 7387 adalimumab-naive patients who were new users of an adalimumab biosimilar and 3654 patients (switchers) who switched from Humira to a biosimilar. Patients were matched and compared with patients receiving Humira.
• Co-primary outcomes of the study were drug discontinuation and serious adverse events.
• Researchers assessed the following adalimumab biosimilar brands: Amgevita, Imraldi, Hyrimoz, Idacio, and Hulio.

TAKEAWAY:

• All-cause drug discontinuation rates were similar between new users of biosimilars and Humira new users (hazard ratio [HR], 0.99; 95% CI, 0.94-1.04).
• Discontinuation rates were higher among those who switched from Humira to a biosimilar (HR, 1.35; 95% CI, 1.19-1.52) than among those who stayed on Humira. Switching to Amgevita (HR, 1.25; 95% CI, 1.13-1.27), Imraldi (HR, 1.53; 95% CI, 1.33-1.76), and Hyrimoz (HR, 1.80; 95% CI, 1.29-2.52) was associated with higher discontinuation rates.
• Serious adverse events were not significantly different between new users of Humira and biosimilar new users (incidence rate ratio [IRR], 0.91; 95% CI, 0.80-1.05), and between patients who switched from a biosimilar to Humira and those who stayed on Humira (IRR, 0.92; 95% CI, 0.83-1.01).
• No significant differences in discontinuation because of ineffectiveness were found between biosimilar and Humira new users (HR, 0.97; 95% CI, 0.88-1.08). Discontinuation because of adverse events was also comparable for all biosimilars among new users, except for Hyrimoz (HR, 0.54; 95% CI, 0.35-0.85), which showed fewer discontinuations than Humira.

IN PRACTICE:

“This study found comparable drug survival and safety between adalimumab biosimilars and Humira in adalimumab-naive patients, supporting the use of biosimilars as viable alternatives for new patients,” the authors wrote. However, noting that discontinuation was more likely among those who switched from Humira to a biosimilar, they added: “Changes in treatment response, skin or injection site reactions, and nocebo effects may contribute to treatment discontinuation post-switch. Thus, patients who switch from Humira to biosimilars may require closer monitoring and support to alleviate these challenges.”

SOURCE:

The study was led by Duc Binh Phan, Dermatology Centre, Northern Care Alliance NHS Foundation Trust in Manchester, England. It was published online in The British Journal of Dermatology.

LIMITATIONS:

Unmeasured factors including psychological perceptions, regional policies, and drug availability could influence drug survival, making the results not fully reflective of treatment effectiveness or safety. Most Humira users in registries were enrolled before biosimilars became available, making it impractical to match new users on the basis of treatment initiation years. Additionally, reasons for discontinuation were not available in the French National Health Data System.

DISCLOSURES:

In the United Kingdom, the research was funded by the Psoriasis Association PhD studentship and supported by the NIHR Manchester Biomedical Research Centre. In France, the authors are employees of the French National Health Insurance, the French National Agency for the Safety of Medicines and Health Products, and the Assistance Publique — Hôpitaux de Paris and received no funding. The authors reported receiving consulting and speaker fees and clinical trial sponsorship from various pharmaceutical companies. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Biosimilars demonstrate comparable drug survival and safety with adalimumab among new users, but patients switching from Humira (the originator product) to biosimilars had a 35% higher discontinuation rate than those who remained on Humira.

 

METHODOLOGY:

• Researchers conducted a cohort study using data on patients with psoriasis who were treated with adalimumab, a tumor necrosis factor alpha inhibitor used to treat moderate to severe psoriasis, from the French National Health Data System, British Association of Dermatologists Biologics and Immunomodulators Register, and Spanish Registry of Systemic Therapy in Psoriasis.
• The analysis included 7387 adalimumab-naive patients who were new users of an adalimumab biosimilar and 3654 patients (switchers) who switched from Humira to a biosimilar. Patients were matched and compared with patients receiving Humira.
• Co-primary outcomes of the study were drug discontinuation and serious adverse events.
• Researchers assessed the following adalimumab biosimilar brands: Amgevita, Imraldi, Hyrimoz, Idacio, and Hulio.

TAKEAWAY:

• All-cause drug discontinuation rates were similar between new users of biosimilars and Humira new users (hazard ratio [HR], 0.99; 95% CI, 0.94-1.04).
• Discontinuation rates were higher among those who switched from Humira to a biosimilar (HR, 1.35; 95% CI, 1.19-1.52) than among those who stayed on Humira. Switching to Amgevita (HR, 1.25; 95% CI, 1.13-1.27), Imraldi (HR, 1.53; 95% CI, 1.33-1.76), and Hyrimoz (HR, 1.80; 95% CI, 1.29-2.52) was associated with higher discontinuation rates.
• Serious adverse events were not significantly different between new users of Humira and biosimilar new users (incidence rate ratio [IRR], 0.91; 95% CI, 0.80-1.05), and between patients who switched from a biosimilar to Humira and those who stayed on Humira (IRR, 0.92; 95% CI, 0.83-1.01).
• No significant differences in discontinuation because of ineffectiveness were found between biosimilar and Humira new users (HR, 0.97; 95% CI, 0.88-1.08). Discontinuation because of adverse events was also comparable for all biosimilars among new users, except for Hyrimoz (HR, 0.54; 95% CI, 0.35-0.85), which showed fewer discontinuations than Humira.

IN PRACTICE:

“This study found comparable drug survival and safety between adalimumab biosimilars and Humira in adalimumab-naive patients, supporting the use of biosimilars as viable alternatives for new patients,” the authors wrote. However, noting that discontinuation was more likely among those who switched from Humira to a biosimilar, they added: “Changes in treatment response, skin or injection site reactions, and nocebo effects may contribute to treatment discontinuation post-switch. Thus, patients who switch from Humira to biosimilars may require closer monitoring and support to alleviate these challenges.”

SOURCE:

The study was led by Duc Binh Phan, Dermatology Centre, Northern Care Alliance NHS Foundation Trust in Manchester, England. It was published online in The British Journal of Dermatology.

LIMITATIONS:

Unmeasured factors including psychological perceptions, regional policies, and drug availability could influence drug survival, making the results not fully reflective of treatment effectiveness or safety. Most Humira users in registries were enrolled before biosimilars became available, making it impractical to match new users on the basis of treatment initiation years. Additionally, reasons for discontinuation were not available in the French National Health Data System.

DISCLOSURES:

In the United Kingdom, the research was funded by the Psoriasis Association PhD studentship and supported by the NIHR Manchester Biomedical Research Centre. In France, the authors are employees of the French National Health Insurance, the French National Agency for the Safety of Medicines and Health Products, and the Assistance Publique — Hôpitaux de Paris and received no funding. The authors reported receiving consulting and speaker fees and clinical trial sponsorship from various pharmaceutical companies. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Heather K. Schopper, MD, a head and neck surgeon at Penn State Health, Hershey, Pennsylvania, wasn’t long into her career when she began feeling its physical demands. Standing for 12 hours at a time, holding awkward positions for long periods, and working with surgical tables and instruments made for doctors much taller and larger meant severe back, shoulder, and neck pain at the end of every shift.

“You just want to lie down on the floor at the end of the day,” Schopper explained. “The wear and tear of our profession is really challenging.”

Here’s the thing: At the time Schopper wasn’t particularly out of shape. She only knew she needed to build up her body for long days and a long career. What, physically, would that look like?

This was the catalyst for what she calls a “health and fitness journey” that transformed the way she practices.

“Medicine is unique in its physical demands,” said Meghan Wieser, PT, DPT, a doctor of physical therapy at Recharge Health and Fitness in Ellicott City, Maryland. Wieser frequently works with physicians and others in high-stress career environments, and she’s observed the serious toll that physically demanding medical practice can take on the body.

It’s not just about preventing acute or chronic injury, she said. It’s about performing better for longer periods. And every doctor knows the only way to build a more functional body is training.

 

The Fantasy of Physical Perfection vs the Reality of, Well, Reality

Jordan D. Metzl, MD, is a sports medicine physician at Hospital for Special Surgery (HSS) in New York City. He’s also a lifelong triathlete and marathon runner and has parlayed that passion into an online fitness community of more than 10,000 people called Ironstrength. Through that, Metzl has led free exercise classes in Central Park for years. He doesn’t dabble. Three times a year he leads a boot camp class of more than 1000 people on the flight deck of the USS Intrepid on the Hudson River.

“I get it, being a doctor is all about the hours,” he said. “The time sacrifices get brutal and you have to cut something out, sometimes every day. For a lot of us, that’s exercise.”

Metzl understands it so well that he recently began leading twice-monthly boot camp classes just for his HSS physician colleagues on Wednesday mornings. He says those doctors both want and need that extra boost and will be aggressive about making time for it.

“The better shape you’re in, the better job you’ll do as a physician,” he said. “You’ll feel better when the hours get long. In my own career, I have always been a better doctor when I’m active and in shape.”

Knowledge isn’t really the issue for physicians. Reality is. And reality dictates that doctors have just as much issue with achieving consistency as any patient they prescribe exercise to.

Metzl suggests total body functional training to mimic real-world movement, particularly core and lower body to keep you upright for hours at a time. How do you schedule that? He uses early mornings and weekends to train for his races and run his fitness classes, which is why his primary advice is to focus not on the activity, but on time.

“Schedule full workouts when you can and steal the rest,” he said.

Schopper agrees. “You may not be able to fit in 60 minutes of exercise every day, but 20-30 minutes of intentional movement is key,” she explained. “When you have a day off, prioritize a longer session of something you can’t fit in on workdays.”

Those shorter bouts of exercise might include “bookending” the day with 10 minutes of burpees in the morning and then 10 minutes of bodyweight strength moves like planks, push-ups, and air squats in the evening.

“Bodyweight exercises are low-hanging fruit,” said Wieser. “If you’ve got a short window, aim for something that can shoot your heart rate up quickly.”

You can also throw in “movement snacks” throughout the day — skip the elevator and run up a flight of stairs, walk around during a quick lunch break, or throw in a set of jumping jacks between patients. (Don’t worry — you won’t be dripping sweat when they walk in.)

Remember, the rehab room in the orthopedic wing may have a few dumbbells and exercise bands you can utilize when you have 5 extra minutes in your day. “Any way you can squeeze in extra movement counts,” said Wieser.

 

Feats of Strength? Neighborhood Sprints? It All Matters

Kissinger Goldman, DO, a Florida-based ER physician, began his dedication to exercise 17 years ago, after a high-cholesterol diagnosis. “Did I have time to exercise in medical school and residency? Yes,” Goldman admitted. “But I didn’t have the same commitment to my health until I received that number. I set about to change everything.”

Goldman follows the approach of dividing up his exercise routine into short or long sessions, depending on his schedule. “If I’m off, I’ll aim for 30 minutes of cardio and 30 minutes of strength and core work,” he explained. “When I have to work, I’ll do a compressed version of that routine as soon as I wake up, and make sure the cardio is very intense — I’ll sprint in my neighborhood, for instance.”

Matt Klein, a doctor of physical therapy and professor at George Fox University in Newberg, Oregon, who has treated many doctors, says that, when pushed for time, just 20 minutes of “heavy” strength training can deliver good results. “The definition of heavy will vary, but aim for a weight that is challenging, whether a beginner or a more experienced exerciser,” he said. “Most doctors won’t have time to go to the gym, so a simple set of dumbbells or kettlebells will work just fine. The easier it is to access, the more likely you are to do it consistently.”

Klein is a fan of strength training with good reason: “Strength is a predictor of chronic disease, so doing some high-level strength training or power training can go a long way,” he said.

The endorphin high and overall sense of improved well-being are an extra bonus. Goldman credits it with ensuring he rarely misses a workout.

 

Get Hardcore About Sleep

Consider the following passage: “There are clear negative effects of sleep deprivation on performance, including reaction time, accuracy, vigor, submaximal strength, and endurance. Cognitive functions such as judgment and decision-making also suffer.”

Does that sound like how you feel on suboptimal sleep? That’s from an International Journal of Sports Medicine study on the effects of sleep deprivation on athletes.

Athletes aren’t doctors — but when you consider “reaction time, accuracy, endurance, judgment, and decision-making” — doctors could certainly benefit by thinking like athletes.

Schopper is serious about sleep and sets firm boundaries.

“It’s hard,” she admitted. “We want to work, see our families, have fun. But I work hard to say, ‘I’m done,’ and go to bed.”

“Rest is crucial for this job,” agreed Goldman. “If you don’t have adequate sleep, your cortisone levels are going to go up. When you’re exhausted and you’re working, you’re likely to miss something.” Goldman is consistent with early bedtimes around 9:00 or 9:30 PM, and he allows for a bit of “wind-down” time by reading for about 20 minutes before nodding off.

Goldman also sees a link between rest and improved interactions with patients. “There’s a direct correlation between number of hours worked in a row with respect to ‘customer service’ with patients,” he said.

But don’t aim for perfection. Allow some wiggle room for the time you spend asleep, Klein recommends. “We’ve always aimed for 8 hours, but there’s evidence that even 6 or 7 hours can be enough to allow you to recover as needed,” he said. “Optimally, you want that to be uninterrupted, but if not, a 10-minute power nap can help with mental clarity.”

 

Keep Searching, Keep Trying, Keep Training

Schopper was never, nor has she become, a gym rat. Still, “I knew I needed to build upper body strength,” she said. That meant expanding her fitness possibilities beyond the obvious. She discovered aerial arts — intense workouts using straps and other suspension tools to work every muscle in her body while hanging from the ceiling. Increased strength was a given, but she also seriously increased her range of motion.

For Schopper, the improvements to her lifestyle have been game changers. “I still have long days, but I’m no longer sore and tired after them,” she said. “I sleep better and have more energy. I’m proud of myself for putting the effort into this.”

A journey toward health and fitness may look different for everyone, but (as doctors frequently tell their patients) it’s a path anyone can follow.

“Being a doctor is not necessarily good for your health,” said Klein. “The body can handle the job, however, if you train for it.”

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

Heather K. Schopper, MD, a head and neck surgeon at Penn State Health, Hershey, Pennsylvania, wasn’t long into her career when she began feeling its physical demands. Standing for 12 hours at a time, holding awkward positions for long periods, and working with surgical tables and instruments made for doctors much taller and larger meant severe back, shoulder, and neck pain at the end of every shift.

“You just want to lie down on the floor at the end of the day,” Schopper explained. “The wear and tear of our profession is really challenging.”

Here’s the thing: At the time Schopper wasn’t particularly out of shape. She only knew she needed to build up her body for long days and a long career. What, physically, would that look like?

This was the catalyst for what she calls a “health and fitness journey” that transformed the way she practices.

“Medicine is unique in its physical demands,” said Meghan Wieser, PT, DPT, a doctor of physical therapy at Recharge Health and Fitness in Ellicott City, Maryland. Wieser frequently works with physicians and others in high-stress career environments, and she’s observed the serious toll that physically demanding medical practice can take on the body.

It’s not just about preventing acute or chronic injury, she said. It’s about performing better for longer periods. And every doctor knows the only way to build a more functional body is training.

 

The Fantasy of Physical Perfection vs the Reality of, Well, Reality

Jordan D. Metzl, MD, is a sports medicine physician at Hospital for Special Surgery (HSS) in New York City. He’s also a lifelong triathlete and marathon runner and has parlayed that passion into an online fitness community of more than 10,000 people called Ironstrength. Through that, Metzl has led free exercise classes in Central Park for years. He doesn’t dabble. Three times a year he leads a boot camp class of more than 1000 people on the flight deck of the USS Intrepid on the Hudson River.

“I get it, being a doctor is all about the hours,” he said. “The time sacrifices get brutal and you have to cut something out, sometimes every day. For a lot of us, that’s exercise.”

Metzl understands it so well that he recently began leading twice-monthly boot camp classes just for his HSS physician colleagues on Wednesday mornings. He says those doctors both want and need that extra boost and will be aggressive about making time for it.

“The better shape you’re in, the better job you’ll do as a physician,” he said. “You’ll feel better when the hours get long. In my own career, I have always been a better doctor when I’m active and in shape.”

Knowledge isn’t really the issue for physicians. Reality is. And reality dictates that doctors have just as much issue with achieving consistency as any patient they prescribe exercise to.

Metzl suggests total body functional training to mimic real-world movement, particularly core and lower body to keep you upright for hours at a time. How do you schedule that? He uses early mornings and weekends to train for his races and run his fitness classes, which is why his primary advice is to focus not on the activity, but on time.

“Schedule full workouts when you can and steal the rest,” he said.

Schopper agrees. “You may not be able to fit in 60 minutes of exercise every day, but 20-30 minutes of intentional movement is key,” she explained. “When you have a day off, prioritize a longer session of something you can’t fit in on workdays.”

Those shorter bouts of exercise might include “bookending” the day with 10 minutes of burpees in the morning and then 10 minutes of bodyweight strength moves like planks, push-ups, and air squats in the evening.

“Bodyweight exercises are low-hanging fruit,” said Wieser. “If you’ve got a short window, aim for something that can shoot your heart rate up quickly.”

You can also throw in “movement snacks” throughout the day — skip the elevator and run up a flight of stairs, walk around during a quick lunch break, or throw in a set of jumping jacks between patients. (Don’t worry — you won’t be dripping sweat when they walk in.)

Remember, the rehab room in the orthopedic wing may have a few dumbbells and exercise bands you can utilize when you have 5 extra minutes in your day. “Any way you can squeeze in extra movement counts,” said Wieser.

 

Feats of Strength? Neighborhood Sprints? It All Matters

Kissinger Goldman, DO, a Florida-based ER physician, began his dedication to exercise 17 years ago, after a high-cholesterol diagnosis. “Did I have time to exercise in medical school and residency? Yes,” Goldman admitted. “But I didn’t have the same commitment to my health until I received that number. I set about to change everything.”

Goldman follows the approach of dividing up his exercise routine into short or long sessions, depending on his schedule. “If I’m off, I’ll aim for 30 minutes of cardio and 30 minutes of strength and core work,” he explained. “When I have to work, I’ll do a compressed version of that routine as soon as I wake up, and make sure the cardio is very intense — I’ll sprint in my neighborhood, for instance.”

Matt Klein, a doctor of physical therapy and professor at George Fox University in Newberg, Oregon, who has treated many doctors, says that, when pushed for time, just 20 minutes of “heavy” strength training can deliver good results. “The definition of heavy will vary, but aim for a weight that is challenging, whether a beginner or a more experienced exerciser,” he said. “Most doctors won’t have time to go to the gym, so a simple set of dumbbells or kettlebells will work just fine. The easier it is to access, the more likely you are to do it consistently.”

Klein is a fan of strength training with good reason: “Strength is a predictor of chronic disease, so doing some high-level strength training or power training can go a long way,” he said.

The endorphin high and overall sense of improved well-being are an extra bonus. Goldman credits it with ensuring he rarely misses a workout.

 

Get Hardcore About Sleep

Consider the following passage: “There are clear negative effects of sleep deprivation on performance, including reaction time, accuracy, vigor, submaximal strength, and endurance. Cognitive functions such as judgment and decision-making also suffer.”

Does that sound like how you feel on suboptimal sleep? That’s from an International Journal of Sports Medicine study on the effects of sleep deprivation on athletes.

Athletes aren’t doctors — but when you consider “reaction time, accuracy, endurance, judgment, and decision-making” — doctors could certainly benefit by thinking like athletes.

Schopper is serious about sleep and sets firm boundaries.

“It’s hard,” she admitted. “We want to work, see our families, have fun. But I work hard to say, ‘I’m done,’ and go to bed.”

“Rest is crucial for this job,” agreed Goldman. “If you don’t have adequate sleep, your cortisone levels are going to go up. When you’re exhausted and you’re working, you’re likely to miss something.” Goldman is consistent with early bedtimes around 9:00 or 9:30 PM, and he allows for a bit of “wind-down” time by reading for about 20 minutes before nodding off.

Goldman also sees a link between rest and improved interactions with patients. “There’s a direct correlation between number of hours worked in a row with respect to ‘customer service’ with patients,” he said.

But don’t aim for perfection. Allow some wiggle room for the time you spend asleep, Klein recommends. “We’ve always aimed for 8 hours, but there’s evidence that even 6 or 7 hours can be enough to allow you to recover as needed,” he said. “Optimally, you want that to be uninterrupted, but if not, a 10-minute power nap can help with mental clarity.”

 

Keep Searching, Keep Trying, Keep Training

Schopper was never, nor has she become, a gym rat. Still, “I knew I needed to build upper body strength,” she said. That meant expanding her fitness possibilities beyond the obvious. She discovered aerial arts — intense workouts using straps and other suspension tools to work every muscle in her body while hanging from the ceiling. Increased strength was a given, but she also seriously increased her range of motion.

For Schopper, the improvements to her lifestyle have been game changers. “I still have long days, but I’m no longer sore and tired after them,” she said. “I sleep better and have more energy. I’m proud of myself for putting the effort into this.”

A journey toward health and fitness may look different for everyone, but (as doctors frequently tell their patients) it’s a path anyone can follow.

“Being a doctor is not necessarily good for your health,” said Klein. “The body can handle the job, however, if you train for it.”

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

Heather K. Schopper, MD, a head and neck surgeon at Penn State Health, Hershey, Pennsylvania, wasn’t long into her career when she began feeling its physical demands. Standing for 12 hours at a time, holding awkward positions for long periods, and working with surgical tables and instruments made for doctors much taller and larger meant severe back, shoulder, and neck pain at the end of every shift.

“You just want to lie down on the floor at the end of the day,” Schopper explained. “The wear and tear of our profession is really challenging.”

Here’s the thing: At the time Schopper wasn’t particularly out of shape. She only knew she needed to build up her body for long days and a long career. What, physically, would that look like?

This was the catalyst for what she calls a “health and fitness journey” that transformed the way she practices.

“Medicine is unique in its physical demands,” said Meghan Wieser, PT, DPT, a doctor of physical therapy at Recharge Health and Fitness in Ellicott City, Maryland. Wieser frequently works with physicians and others in high-stress career environments, and she’s observed the serious toll that physically demanding medical practice can take on the body.

It’s not just about preventing acute or chronic injury, she said. It’s about performing better for longer periods. And every doctor knows the only way to build a more functional body is training.

 

The Fantasy of Physical Perfection vs the Reality of, Well, Reality

Jordan D. Metzl, MD, is a sports medicine physician at Hospital for Special Surgery (HSS) in New York City. He’s also a lifelong triathlete and marathon runner and has parlayed that passion into an online fitness community of more than 10,000 people called Ironstrength. Through that, Metzl has led free exercise classes in Central Park for years. He doesn’t dabble. Three times a year he leads a boot camp class of more than 1000 people on the flight deck of the USS Intrepid on the Hudson River.

“I get it, being a doctor is all about the hours,” he said. “The time sacrifices get brutal and you have to cut something out, sometimes every day. For a lot of us, that’s exercise.”

Metzl understands it so well that he recently began leading twice-monthly boot camp classes just for his HSS physician colleagues on Wednesday mornings. He says those doctors both want and need that extra boost and will be aggressive about making time for it.

“The better shape you’re in, the better job you’ll do as a physician,” he said. “You’ll feel better when the hours get long. In my own career, I have always been a better doctor when I’m active and in shape.”

Knowledge isn’t really the issue for physicians. Reality is. And reality dictates that doctors have just as much issue with achieving consistency as any patient they prescribe exercise to.

Metzl suggests total body functional training to mimic real-world movement, particularly core and lower body to keep you upright for hours at a time. How do you schedule that? He uses early mornings and weekends to train for his races and run his fitness classes, which is why his primary advice is to focus not on the activity, but on time.

“Schedule full workouts when you can and steal the rest,” he said.

Schopper agrees. “You may not be able to fit in 60 minutes of exercise every day, but 20-30 minutes of intentional movement is key,” she explained. “When you have a day off, prioritize a longer session of something you can’t fit in on workdays.”

Those shorter bouts of exercise might include “bookending” the day with 10 minutes of burpees in the morning and then 10 minutes of bodyweight strength moves like planks, push-ups, and air squats in the evening.

“Bodyweight exercises are low-hanging fruit,” said Wieser. “If you’ve got a short window, aim for something that can shoot your heart rate up quickly.”

You can also throw in “movement snacks” throughout the day — skip the elevator and run up a flight of stairs, walk around during a quick lunch break, or throw in a set of jumping jacks between patients. (Don’t worry — you won’t be dripping sweat when they walk in.)

Remember, the rehab room in the orthopedic wing may have a few dumbbells and exercise bands you can utilize when you have 5 extra minutes in your day. “Any way you can squeeze in extra movement counts,” said Wieser.

 

Feats of Strength? Neighborhood Sprints? It All Matters

Kissinger Goldman, DO, a Florida-based ER physician, began his dedication to exercise 17 years ago, after a high-cholesterol diagnosis. “Did I have time to exercise in medical school and residency? Yes,” Goldman admitted. “But I didn’t have the same commitment to my health until I received that number. I set about to change everything.”

Goldman follows the approach of dividing up his exercise routine into short or long sessions, depending on his schedule. “If I’m off, I’ll aim for 30 minutes of cardio and 30 minutes of strength and core work,” he explained. “When I have to work, I’ll do a compressed version of that routine as soon as I wake up, and make sure the cardio is very intense — I’ll sprint in my neighborhood, for instance.”

Matt Klein, a doctor of physical therapy and professor at George Fox University in Newberg, Oregon, who has treated many doctors, says that, when pushed for time, just 20 minutes of “heavy” strength training can deliver good results. “The definition of heavy will vary, but aim for a weight that is challenging, whether a beginner or a more experienced exerciser,” he said. “Most doctors won’t have time to go to the gym, so a simple set of dumbbells or kettlebells will work just fine. The easier it is to access, the more likely you are to do it consistently.”

Klein is a fan of strength training with good reason: “Strength is a predictor of chronic disease, so doing some high-level strength training or power training can go a long way,” he said.

The endorphin high and overall sense of improved well-being are an extra bonus. Goldman credits it with ensuring he rarely misses a workout.

 

Get Hardcore About Sleep

Consider the following passage: “There are clear negative effects of sleep deprivation on performance, including reaction time, accuracy, vigor, submaximal strength, and endurance. Cognitive functions such as judgment and decision-making also suffer.”

Does that sound like how you feel on suboptimal sleep? That’s from an International Journal of Sports Medicine study on the effects of sleep deprivation on athletes.

Athletes aren’t doctors — but when you consider “reaction time, accuracy, endurance, judgment, and decision-making” — doctors could certainly benefit by thinking like athletes.

Schopper is serious about sleep and sets firm boundaries.

“It’s hard,” she admitted. “We want to work, see our families, have fun. But I work hard to say, ‘I’m done,’ and go to bed.”

“Rest is crucial for this job,” agreed Goldman. “If you don’t have adequate sleep, your cortisone levels are going to go up. When you’re exhausted and you’re working, you’re likely to miss something.” Goldman is consistent with early bedtimes around 9:00 or 9:30 PM, and he allows for a bit of “wind-down” time by reading for about 20 minutes before nodding off.

Goldman also sees a link between rest and improved interactions with patients. “There’s a direct correlation between number of hours worked in a row with respect to ‘customer service’ with patients,” he said.

But don’t aim for perfection. Allow some wiggle room for the time you spend asleep, Klein recommends. “We’ve always aimed for 8 hours, but there’s evidence that even 6 or 7 hours can be enough to allow you to recover as needed,” he said. “Optimally, you want that to be uninterrupted, but if not, a 10-minute power nap can help with mental clarity.”

 

Keep Searching, Keep Trying, Keep Training

Schopper was never, nor has she become, a gym rat. Still, “I knew I needed to build upper body strength,” she said. That meant expanding her fitness possibilities beyond the obvious. She discovered aerial arts — intense workouts using straps and other suspension tools to work every muscle in her body while hanging from the ceiling. Increased strength was a given, but she also seriously increased her range of motion.

For Schopper, the improvements to her lifestyle have been game changers. “I still have long days, but I’m no longer sore and tired after them,” she said. “I sleep better and have more energy. I’m proud of myself for putting the effort into this.”

A journey toward health and fitness may look different for everyone, but (as doctors frequently tell their patients) it’s a path anyone can follow.

“Being a doctor is not necessarily good for your health,” said Klein. “The body can handle the job, however, if you train for it.”

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

Disparate views on managing incidental imaging findings made during clinical research — particularly for unclear results — signal a need for standardized guidance, according to recent survey results.

Respondents were split on whether it was the site primary investigator’s responsibility to decide which incidental findings should be reported back to the patient, and the most commonly cited challenges included adequately explaining these findings and the follow-up required. These issues were most present when dealing with nonspecific incidental findings or findings of unclear importance, said lead author Jane S. Kang, MD, a bioethicist and associate professor of medicine in the Division of Rheumatology at Columbia University Irving Medical Center, New York City.

 

“It can be difficult to have a clear approach” when it comes to these situations that are not black and white, and it is hard to get a clear answer, she said in an interview.

The survey included responses from investigators from the Treatments Against Rheumatoid Arthritis and Effect on 18F-fluorodeoxyglucose (FDG) PET/CT (TARGET) trial, conducted between 2015 and 2021. The 24-week trial included patients from 28 centers in the United States to investigate how different disease-modifying antirheumatic drugs can reduce cardiovascular and joint inflammation, assessed via whole body FDG PET/CT. The survey was a planned substudy of the TARGET trial and is “the first study that examines researchers’ attitudes and beliefs regarding incidental research findings from whole body FDG PET/CT,” Kang and her coauthors wrote.

This news organization reported the main results of the TARGET trial in 2022.

Eighteen of the 28 site primary investigators (PIs) of the TARGET trial participated in the survey, which was published in Arthritis Care & Research in September 2024.

 

TARGET Trial Incidental Findings

The TARGET trial enrolled 159 patients, of whom 82% had at least one incidental finding and 62% had one or more FDG-avid incidental findings. There were 46 “clinically actionable findings” for 40 participants overall; the reading radiologists recommended additional imaging for 28 findings and specialist consultation or procedural evaluation for 15 findings.

Details on these incidental findings were presented in a poster at the annual meeting of the American College of Rheumatology (ACR), held in Washington, DC.

The most common non–FDG-avid findings were pulmonary nodules, diverticulosis, cholelithiasis, sinus disease, and vascular calcifications. The most common FDG-avid findings were hypermetabolic lymphadenopathy, increased gastric/esophageal uptake, increased bowel uptake, and increased pharyngeal uptake.

In the related survey, 11 respondents (61%) said they returned any incidental findings to participants and 5 (28%) did not; the remaining 2 respondents did not know.

Across all study PIs, 22% felt that incidental findings were beneficial, 39% said they were potentially beneficial, and 11% said they were potentially detrimental. PIs that ranked incidental findings as potentially detrimental pointed to how these findings led to invasive additional testing.

“One of my subjects was found to have diverticulosis, which needed an invasive procedure to rule out malignancy,” one respondent wrote. “However, the subject had already had a colonoscopy months prior to the PET findings, which was still not deemed sufficient by the nuclear radiologist and GI consultant, so he had to have another colonoscopy, which was benign, but uncomfortable.” 

 

Obligation to Return Findings

All investigators agreed that incidental findings should be shared with patients if they revealed a high-risk medical condition that can be treated; had important health implications such as premature death or substantial morbidity; and their health could be improved with proven preventive or therapeutic interventions.

There was more disagreement on whether to share that the FDG PET/CT revealed no findings or if the test revealed a finding without clear medical importance of which the research participant may not be aware.

An example of a less-specific finding could be something like increased FDG uptake in a particular area, like the bowel, Kang explained.

“The question is: What does that mean?” she said. “How do you interpret that?”

While some PIs might feel obligated to share all results with patients, sharing ambiguous incidental findings will likely not be helpful to the patient, said Arthur Caplan, PhD, of the Division of Medical Ethics at New York University (NYU) Grossman School of Medicine, New York City.

“Dealing in unknowns and uncertainties when you’re diagnosing doesn’t really do people very much good,” he said in an interview.

While most survey respondents said they were at least moderately obligated to disclose incidental research findings if a patient requests them, Caplan noted that it was ultimately the researchers’ decision.

“Patient preferences are something to take into account, but they’re not final. If the research team says, ‘we don’t know, it’s too uncertain, it’s too new,’ then I don’t think they have any obligation to return that [information],” he said. “You can’t tell somebody what you don’t understand.”

Conversely, the clearer the incidental finding, the stronger the obligation to share that information with research participants, he continued.

 

Need for a Standardized Approach 

The TARGET study, like many research studies, left the management of incidental imaging findings to individual research sites and investigators.

It’s possible that different sites responded to these ambiguous clinical findings in different ways, Kang noted.

“If there’s a situation that’s difficult to interpret as it is, you can imagine that the resulting actions that may result from that can vary, too,” she said, which highlights the need for more specific and standardized guidance.

One way to approach this, Caplan noted, is establishing an agreed-upon approach for dealing with any incidental findings across all research sites before a study begins.

“If there is going to be a common study at many sites, then they should have a common response on what they are going to do,” he noted, and how they will share that information effectively with the research participants to ensure it’s understandable. However, in a lot of research studies, each site has its own approach.

“Right now, it’s all over the place and that shouldn’t be,” he said.

Institutional review boards (IRBs) could be one resource to help build detailed guidance on managing unclear incidental findings in future research, wrote Kang and coauthors.

“For incidental findings from whole body FDG PET/CT that are not clearly actionable or less straightforward, IRBs may consider requiring a certain level of follow-up for different categories or types of incidental findings or require that all incidental findings are reviewed by an independent group that would provide timely recommendations on the most appropriate return and management of those findings,” Kang and colleagues wrote. “With IRB guidance, very specific and detailed policies and procedures for returning and managing incidental findings should be established for every study, with consistency among the research sites of multicenter trials.”

The TARGET trial and survey were funded by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Kang reported receiving research funding from the National Institutes of Health and the Rheumatology Research Foundation. Caplan serves as a contributing author for this news organization and served on an independent bioethics panel for compassionate drug use that was funded by Johnson & Johnson through the NYU Grossman School of Medicine.

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

Disparate views on managing incidental imaging findings made during clinical research — particularly for unclear results — signal a need for standardized guidance, according to recent survey results.

Respondents were split on whether it was the site primary investigator’s responsibility to decide which incidental findings should be reported back to the patient, and the most commonly cited challenges included adequately explaining these findings and the follow-up required. These issues were most present when dealing with nonspecific incidental findings or findings of unclear importance, said lead author Jane S. Kang, MD, a bioethicist and associate professor of medicine in the Division of Rheumatology at Columbia University Irving Medical Center, New York City.

 

“It can be difficult to have a clear approach” when it comes to these situations that are not black and white, and it is hard to get a clear answer, she said in an interview.

The survey included responses from investigators from the Treatments Against Rheumatoid Arthritis and Effect on 18F-fluorodeoxyglucose (FDG) PET/CT (TARGET) trial, conducted between 2015 and 2021. The 24-week trial included patients from 28 centers in the United States to investigate how different disease-modifying antirheumatic drugs can reduce cardiovascular and joint inflammation, assessed via whole body FDG PET/CT. The survey was a planned substudy of the TARGET trial and is “the first study that examines researchers’ attitudes and beliefs regarding incidental research findings from whole body FDG PET/CT,” Kang and her coauthors wrote.

This news organization reported the main results of the TARGET trial in 2022.

Eighteen of the 28 site primary investigators (PIs) of the TARGET trial participated in the survey, which was published in Arthritis Care & Research in September 2024.

 

TARGET Trial Incidental Findings

The TARGET trial enrolled 159 patients, of whom 82% had at least one incidental finding and 62% had one or more FDG-avid incidental findings. There were 46 “clinically actionable findings” for 40 participants overall; the reading radiologists recommended additional imaging for 28 findings and specialist consultation or procedural evaluation for 15 findings.

Details on these incidental findings were presented in a poster at the annual meeting of the American College of Rheumatology (ACR), held in Washington, DC.

The most common non–FDG-avid findings were pulmonary nodules, diverticulosis, cholelithiasis, sinus disease, and vascular calcifications. The most common FDG-avid findings were hypermetabolic lymphadenopathy, increased gastric/esophageal uptake, increased bowel uptake, and increased pharyngeal uptake.

In the related survey, 11 respondents (61%) said they returned any incidental findings to participants and 5 (28%) did not; the remaining 2 respondents did not know.

Across all study PIs, 22% felt that incidental findings were beneficial, 39% said they were potentially beneficial, and 11% said they were potentially detrimental. PIs that ranked incidental findings as potentially detrimental pointed to how these findings led to invasive additional testing.

“One of my subjects was found to have diverticulosis, which needed an invasive procedure to rule out malignancy,” one respondent wrote. “However, the subject had already had a colonoscopy months prior to the PET findings, which was still not deemed sufficient by the nuclear radiologist and GI consultant, so he had to have another colonoscopy, which was benign, but uncomfortable.” 

 

Obligation to Return Findings

All investigators agreed that incidental findings should be shared with patients if they revealed a high-risk medical condition that can be treated; had important health implications such as premature death or substantial morbidity; and their health could be improved with proven preventive or therapeutic interventions.

There was more disagreement on whether to share that the FDG PET/CT revealed no findings or if the test revealed a finding without clear medical importance of which the research participant may not be aware.

An example of a less-specific finding could be something like increased FDG uptake in a particular area, like the bowel, Kang explained.

“The question is: What does that mean?” she said. “How do you interpret that?”

While some PIs might feel obligated to share all results with patients, sharing ambiguous incidental findings will likely not be helpful to the patient, said Arthur Caplan, PhD, of the Division of Medical Ethics at New York University (NYU) Grossman School of Medicine, New York City.

“Dealing in unknowns and uncertainties when you’re diagnosing doesn’t really do people very much good,” he said in an interview.

While most survey respondents said they were at least moderately obligated to disclose incidental research findings if a patient requests them, Caplan noted that it was ultimately the researchers’ decision.

“Patient preferences are something to take into account, but they’re not final. If the research team says, ‘we don’t know, it’s too uncertain, it’s too new,’ then I don’t think they have any obligation to return that [information],” he said. “You can’t tell somebody what you don’t understand.”

Conversely, the clearer the incidental finding, the stronger the obligation to share that information with research participants, he continued.

 

Need for a Standardized Approach 

The TARGET study, like many research studies, left the management of incidental imaging findings to individual research sites and investigators.

It’s possible that different sites responded to these ambiguous clinical findings in different ways, Kang noted.

“If there’s a situation that’s difficult to interpret as it is, you can imagine that the resulting actions that may result from that can vary, too,” she said, which highlights the need for more specific and standardized guidance.

One way to approach this, Caplan noted, is establishing an agreed-upon approach for dealing with any incidental findings across all research sites before a study begins.

“If there is going to be a common study at many sites, then they should have a common response on what they are going to do,” he noted, and how they will share that information effectively with the research participants to ensure it’s understandable. However, in a lot of research studies, each site has its own approach.

“Right now, it’s all over the place and that shouldn’t be,” he said.

Institutional review boards (IRBs) could be one resource to help build detailed guidance on managing unclear incidental findings in future research, wrote Kang and coauthors.

“For incidental findings from whole body FDG PET/CT that are not clearly actionable or less straightforward, IRBs may consider requiring a certain level of follow-up for different categories or types of incidental findings or require that all incidental findings are reviewed by an independent group that would provide timely recommendations on the most appropriate return and management of those findings,” Kang and colleagues wrote. “With IRB guidance, very specific and detailed policies and procedures for returning and managing incidental findings should be established for every study, with consistency among the research sites of multicenter trials.”

The TARGET trial and survey were funded by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Kang reported receiving research funding from the National Institutes of Health and the Rheumatology Research Foundation. Caplan serves as a contributing author for this news organization and served on an independent bioethics panel for compassionate drug use that was funded by Johnson & Johnson through the NYU Grossman School of Medicine.

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

Disparate views on managing incidental imaging findings made during clinical research — particularly for unclear results — signal a need for standardized guidance, according to recent survey results.

Respondents were split on whether it was the site primary investigator’s responsibility to decide which incidental findings should be reported back to the patient, and the most commonly cited challenges included adequately explaining these findings and the follow-up required. These issues were most present when dealing with nonspecific incidental findings or findings of unclear importance, said lead author Jane S. Kang, MD, a bioethicist and associate professor of medicine in the Division of Rheumatology at Columbia University Irving Medical Center, New York City.

 

“It can be difficult to have a clear approach” when it comes to these situations that are not black and white, and it is hard to get a clear answer, she said in an interview.

The survey included responses from investigators from the Treatments Against Rheumatoid Arthritis and Effect on 18F-fluorodeoxyglucose (FDG) PET/CT (TARGET) trial, conducted between 2015 and 2021. The 24-week trial included patients from 28 centers in the United States to investigate how different disease-modifying antirheumatic drugs can reduce cardiovascular and joint inflammation, assessed via whole body FDG PET/CT. The survey was a planned substudy of the TARGET trial and is “the first study that examines researchers’ attitudes and beliefs regarding incidental research findings from whole body FDG PET/CT,” Kang and her coauthors wrote.

This news organization reported the main results of the TARGET trial in 2022.

Eighteen of the 28 site primary investigators (PIs) of the TARGET trial participated in the survey, which was published in Arthritis Care & Research in September 2024.

 

TARGET Trial Incidental Findings

The TARGET trial enrolled 159 patients, of whom 82% had at least one incidental finding and 62% had one or more FDG-avid incidental findings. There were 46 “clinically actionable findings” for 40 participants overall; the reading radiologists recommended additional imaging for 28 findings and specialist consultation or procedural evaluation for 15 findings.

Details on these incidental findings were presented in a poster at the annual meeting of the American College of Rheumatology (ACR), held in Washington, DC.

The most common non–FDG-avid findings were pulmonary nodules, diverticulosis, cholelithiasis, sinus disease, and vascular calcifications. The most common FDG-avid findings were hypermetabolic lymphadenopathy, increased gastric/esophageal uptake, increased bowel uptake, and increased pharyngeal uptake.

In the related survey, 11 respondents (61%) said they returned any incidental findings to participants and 5 (28%) did not; the remaining 2 respondents did not know.

Across all study PIs, 22% felt that incidental findings were beneficial, 39% said they were potentially beneficial, and 11% said they were potentially detrimental. PIs that ranked incidental findings as potentially detrimental pointed to how these findings led to invasive additional testing.

“One of my subjects was found to have diverticulosis, which needed an invasive procedure to rule out malignancy,” one respondent wrote. “However, the subject had already had a colonoscopy months prior to the PET findings, which was still not deemed sufficient by the nuclear radiologist and GI consultant, so he had to have another colonoscopy, which was benign, but uncomfortable.” 

 

Obligation to Return Findings

All investigators agreed that incidental findings should be shared with patients if they revealed a high-risk medical condition that can be treated; had important health implications such as premature death or substantial morbidity; and their health could be improved with proven preventive or therapeutic interventions.

There was more disagreement on whether to share that the FDG PET/CT revealed no findings or if the test revealed a finding without clear medical importance of which the research participant may not be aware.

An example of a less-specific finding could be something like increased FDG uptake in a particular area, like the bowel, Kang explained.

“The question is: What does that mean?” she said. “How do you interpret that?”

While some PIs might feel obligated to share all results with patients, sharing ambiguous incidental findings will likely not be helpful to the patient, said Arthur Caplan, PhD, of the Division of Medical Ethics at New York University (NYU) Grossman School of Medicine, New York City.

“Dealing in unknowns and uncertainties when you’re diagnosing doesn’t really do people very much good,” he said in an interview.

While most survey respondents said they were at least moderately obligated to disclose incidental research findings if a patient requests them, Caplan noted that it was ultimately the researchers’ decision.

“Patient preferences are something to take into account, but they’re not final. If the research team says, ‘we don’t know, it’s too uncertain, it’s too new,’ then I don’t think they have any obligation to return that [information],” he said. “You can’t tell somebody what you don’t understand.”

Conversely, the clearer the incidental finding, the stronger the obligation to share that information with research participants, he continued.