Rheumatology

Interleukin-6 receptor (IL-6r) inhibition is a promising approach for the treatment of calcium pyrophosphate deposition disease (CPPD), although no prospective studies have been conducted to date. Nevertheless, a retrospective analysis of patients treated with the IL-6r inhibitor tocilizumab, presented at American College of Rheumatology (ACR) 2024 Annual Meeting, showed improved CPPD control in more than two thirds of patients who had failed or could not tolerate usual therapies.

Both the monosodium urate (MSU) crystals associated with gout and CPP crystals induce inflammation dependent on IL-1 beta, but IL-1 beta inhibitors have been investigated more as treatments for gout than for CPPD, and they are recommended by both ACR and European Alliance of Associations for Rheumatology (EULAR) guidelines for patients with gout who have flares despite efforts to treat with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. However, IL-1 beta inhibitors are sometimes used off label in CPPD.

There are similarities among the various crystal types that induce arthritis, typically producing similar clinical features of acute arthritis and severe pain and local inflammation and tending to self-resolve within days to weeks. Those shared clinical features suggest common inflammatory mechanisms, likely stemming from the innate immune system, said Augustin Latourte, MD, PhD, of Lariboisière Hospital, Paris, France, during a talk on the topic at the annual research symposium of the Gout Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

CPPD management is generally derived from strategies developed for gout, but there is little evidence supporting IL-1 beta inhibitors outside of case reports, he said. One clinical trial published in 2020 showed efficacy of the IL-1 inhibitor anakinra, but the study was halted due to low patient recruitment, resulting in a small study population. In that study, “anakinra seems to have a faster onset of action than prednisone and could be useful in specific situations regarding acute CPPD arthritis. But it’s not relevant for chronic CPPD arthritis when you have persistent polyarthritis requiring chronic treatment. Anakinra requires daily injections and may not be appropriate in this situation,” he said.

IL-6r inhibition has been studied since IL-6 was first discovered in 1989 as a mediator of inflammatory responses in gout and CPPD, when it was shown that both CPP and MSU crystals can stimulate its production. In monocytes, IL-6 is expressed at higher levels than IL-1 beta in response to both CPP and MSU crystals. IL-6 production in monocytes in response to crystals is dependent on IL-1, and IL-1 inhibition reduces IL-6 production. “So the hypothesis is that IL-1 beta is the first event, and the production of IL-6 and the amplification of crystal inflammation occurs downstream before the self-limitation of the crystal-induced arthritis. IL-6 may be a very important event in the onset of crystal-induced inflammation,” Latourte said.

 

Building on Mechanistic Insights to Test Off-Label Use of Tocilizumab

Inspired by this insight, Latourte’s group tested tocilizumab in a 28-year-old man with a familial ANKH mutation who had not responded to anakinra and other conventional treatments. The patient experienced a reduction in flare intensity in the first month after the initial treatment and no flares after the second tocilizumab infusion. The group went on to test tocilizumab in 10 additional patients with CPPD (median age, 62.5 years), including 6 with idiopathic CPPD, 3 with Gitelman syndrome, and 1 with ANKH mutation. The clinical presentation included four with recurrent acute arthritis and six with chronic polyarthritis, and all had x-ray–proven disease, with a median visual analog scale (VAS) of 60 mm out of 100 mm. Tocilizumab was administered intravenously or subcutaneously. At 3 months, there was a median improvement of 30 mm in the VAS. Treatment efficacy continued for a median follow-up of 5.5 months at the time of publication, and the researchers have noted ongoing efficacy out to 50 months for some patients.

Tocilizumab has gone on to more frequent use in Europe as a second- or third-line therapy for CPPD, which led Latourte and his colleagues to perform the retrospective analysis that they presented at the ACR meeting. It included 55 patients who received tocilizumab for chronic inflammatory CPPD at two university hospitals. Participants had a median age of 72 years, and 67.3% were women. The patient group included 39 with chronic CPPD, 14 with recurrent acute CPPD (who experienced 0-4 attacks per month), and two patients with mixed CPPD. All participants had been treated with colchicine, and 20 had been treated also with prednisone and 24 with anakinra. Patients had stopped anakinra because it was either ineffective (n = 13) or poorly tolerated (n = 11).

Tocilizumab was administered intravenously in 46 patients and subcutaneously in nine patients for a median duration of 16.5 months (range, 0.8-76.4 months). The median VAS for pain (0- to 100-mm scale) dropped from 60 mm at baseline to 40 mm at 3 months and 30 mm at 6 months. There were 21 adverse events, including 8 cytopenias, 6 transaminase elevations, 4 infections (two severe), and 3 injection-site reactions. After a median of 7.8 months, 26 patients discontinued tocilizumab because of lack of efficacy in 15 patients and intolerance in 11. Among those who continued on tocilizumab, the median length of treatment was 26.0 months (range, 3-76.5 months).

 

Comments on the Study

The study population had some unusual characteristics, according to G-CAN President Robert Terkeltaub, MD, who was asked to comment on the study. “Almost half the patients had received anakinra and then, basically, they failed. In about half of the people who got anakinra, it didn’t work, and in the other half, it wasn’t well tolerated. It’s just rather odd. I find anakinra reasonably well tolerated by people, but we’re dealing with an older population of patients, and the subcutaneous administration of anakinra sometimes can give you injection site reactions, but people started off with a pain level that was close to what we register as severe pain, and the pain level decreased,” he said.

Treatment decisions can be difficult in patients with chronic or acute recurrent CPPD, said Terkeltaub, professor of medicine at the University of California, San Diego. “What’s the lesser evil? Putting people on chronic prednisone is really hard on patients or using a biologic that’s more of an immunologic scalpel here, and more selective, and trying to get people through a long course of therapy. If you have chronic arthritis, it took a while for it to get chronic, and it generally doesn’t go away overnight.”

Terkeltaub also pointed out the gastrointestinal side effects of IL-6r inhibitors, which can include diverticulitis, but there are also concerns over infections and lipid and liver abnormalities. Subcutaneously injected tocilizumab also has a longer half-life than something like anakinra.

Beyond the retrospective nature of the study and the limits it imposes on conclusions that can be drawn, Terkeltaub noted a lack of data on the number of “inflamed joints [in each patient] and what the functioning of the patients was.”

Still, the findings are encouraging. “What I can glean from this study is that the first biologic drug might be an IL-6 inhibitor, but you really need prospective, controlled, blinded clinical trials to know, and it’s hard. It’s just hard to do those trials” because patients tend to be of advanced age, Terkeltaub said.

Latourte said a randomized controlled trial of tocilizumab vs placebo, called TociCCAre, is planned to begin in France in 2025.

Latourte has financial relationships with Fresenius Kabi, Roche Chugai, AbbVie, Arsylab, Celltrion, Janssen, Nordic, Pfizer, UCB, Amgen, Biogen, Galapagos, and Eli Lilly. Terkeltaub had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Interleukin-6 receptor (IL-6r) inhibition is a promising approach for the treatment of calcium pyrophosphate deposition disease (CPPD), although no prospective studies have been conducted to date. Nevertheless, a retrospective analysis of patients treated with the IL-6r inhibitor tocilizumab, presented at American College of Rheumatology (ACR) 2024 Annual Meeting, showed improved CPPD control in more than two thirds of patients who had failed or could not tolerate usual therapies.

Both the monosodium urate (MSU) crystals associated with gout and CPP crystals induce inflammation dependent on IL-1 beta, but IL-1 beta inhibitors have been investigated more as treatments for gout than for CPPD, and they are recommended by both ACR and European Alliance of Associations for Rheumatology (EULAR) guidelines for patients with gout who have flares despite efforts to treat with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. However, IL-1 beta inhibitors are sometimes used off label in CPPD.

There are similarities among the various crystal types that induce arthritis, typically producing similar clinical features of acute arthritis and severe pain and local inflammation and tending to self-resolve within days to weeks. Those shared clinical features suggest common inflammatory mechanisms, likely stemming from the innate immune system, said Augustin Latourte, MD, PhD, of Lariboisière Hospital, Paris, France, during a talk on the topic at the annual research symposium of the Gout Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

CPPD management is generally derived from strategies developed for gout, but there is little evidence supporting IL-1 beta inhibitors outside of case reports, he said. One clinical trial published in 2020 showed efficacy of the IL-1 inhibitor anakinra, but the study was halted due to low patient recruitment, resulting in a small study population. In that study, “anakinra seems to have a faster onset of action than prednisone and could be useful in specific situations regarding acute CPPD arthritis. But it’s not relevant for chronic CPPD arthritis when you have persistent polyarthritis requiring chronic treatment. Anakinra requires daily injections and may not be appropriate in this situation,” he said.

IL-6r inhibition has been studied since IL-6 was first discovered in 1989 as a mediator of inflammatory responses in gout and CPPD, when it was shown that both CPP and MSU crystals can stimulate its production. In monocytes, IL-6 is expressed at higher levels than IL-1 beta in response to both CPP and MSU crystals. IL-6 production in monocytes in response to crystals is dependent on IL-1, and IL-1 inhibition reduces IL-6 production. “So the hypothesis is that IL-1 beta is the first event, and the production of IL-6 and the amplification of crystal inflammation occurs downstream before the self-limitation of the crystal-induced arthritis. IL-6 may be a very important event in the onset of crystal-induced inflammation,” Latourte said.

 

Building on Mechanistic Insights to Test Off-Label Use of Tocilizumab

Inspired by this insight, Latourte’s group tested tocilizumab in a 28-year-old man with a familial ANKH mutation who had not responded to anakinra and other conventional treatments. The patient experienced a reduction in flare intensity in the first month after the initial treatment and no flares after the second tocilizumab infusion. The group went on to test tocilizumab in 10 additional patients with CPPD (median age, 62.5 years), including 6 with idiopathic CPPD, 3 with Gitelman syndrome, and 1 with ANKH mutation. The clinical presentation included four with recurrent acute arthritis and six with chronic polyarthritis, and all had x-ray–proven disease, with a median visual analog scale (VAS) of 60 mm out of 100 mm. Tocilizumab was administered intravenously or subcutaneously. At 3 months, there was a median improvement of 30 mm in the VAS. Treatment efficacy continued for a median follow-up of 5.5 months at the time of publication, and the researchers have noted ongoing efficacy out to 50 months for some patients.

Tocilizumab has gone on to more frequent use in Europe as a second- or third-line therapy for CPPD, which led Latourte and his colleagues to perform the retrospective analysis that they presented at the ACR meeting. It included 55 patients who received tocilizumab for chronic inflammatory CPPD at two university hospitals. Participants had a median age of 72 years, and 67.3% were women. The patient group included 39 with chronic CPPD, 14 with recurrent acute CPPD (who experienced 0-4 attacks per month), and two patients with mixed CPPD. All participants had been treated with colchicine, and 20 had been treated also with prednisone and 24 with anakinra. Patients had stopped anakinra because it was either ineffective (n = 13) or poorly tolerated (n = 11).

Tocilizumab was administered intravenously in 46 patients and subcutaneously in nine patients for a median duration of 16.5 months (range, 0.8-76.4 months). The median VAS for pain (0- to 100-mm scale) dropped from 60 mm at baseline to 40 mm at 3 months and 30 mm at 6 months. There were 21 adverse events, including 8 cytopenias, 6 transaminase elevations, 4 infections (two severe), and 3 injection-site reactions. After a median of 7.8 months, 26 patients discontinued tocilizumab because of lack of efficacy in 15 patients and intolerance in 11. Among those who continued on tocilizumab, the median length of treatment was 26.0 months (range, 3-76.5 months).

 

Comments on the Study

The study population had some unusual characteristics, according to G-CAN President Robert Terkeltaub, MD, who was asked to comment on the study. “Almost half the patients had received anakinra and then, basically, they failed. In about half of the people who got anakinra, it didn’t work, and in the other half, it wasn’t well tolerated. It’s just rather odd. I find anakinra reasonably well tolerated by people, but we’re dealing with an older population of patients, and the subcutaneous administration of anakinra sometimes can give you injection site reactions, but people started off with a pain level that was close to what we register as severe pain, and the pain level decreased,” he said.

Treatment decisions can be difficult in patients with chronic or acute recurrent CPPD, said Terkeltaub, professor of medicine at the University of California, San Diego. “What’s the lesser evil? Putting people on chronic prednisone is really hard on patients or using a biologic that’s more of an immunologic scalpel here, and more selective, and trying to get people through a long course of therapy. If you have chronic arthritis, it took a while for it to get chronic, and it generally doesn’t go away overnight.”

Terkeltaub also pointed out the gastrointestinal side effects of IL-6r inhibitors, which can include diverticulitis, but there are also concerns over infections and lipid and liver abnormalities. Subcutaneously injected tocilizumab also has a longer half-life than something like anakinra.

Beyond the retrospective nature of the study and the limits it imposes on conclusions that can be drawn, Terkeltaub noted a lack of data on the number of “inflamed joints [in each patient] and what the functioning of the patients was.”

Still, the findings are encouraging. “What I can glean from this study is that the first biologic drug might be an IL-6 inhibitor, but you really need prospective, controlled, blinded clinical trials to know, and it’s hard. It’s just hard to do those trials” because patients tend to be of advanced age, Terkeltaub said.

Latourte said a randomized controlled trial of tocilizumab vs placebo, called TociCCAre, is planned to begin in France in 2025.

Latourte has financial relationships with Fresenius Kabi, Roche Chugai, AbbVie, Arsylab, Celltrion, Janssen, Nordic, Pfizer, UCB, Amgen, Biogen, Galapagos, and Eli Lilly. Terkeltaub had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Interleukin-6 receptor (IL-6r) inhibition is a promising approach for the treatment of calcium pyrophosphate deposition disease (CPPD), although no prospective studies have been conducted to date. Nevertheless, a retrospective analysis of patients treated with the IL-6r inhibitor tocilizumab, presented at American College of Rheumatology (ACR) 2024 Annual Meeting, showed improved CPPD control in more than two thirds of patients who had failed or could not tolerate usual therapies.

Both the monosodium urate (MSU) crystals associated with gout and CPP crystals induce inflammation dependent on IL-1 beta, but IL-1 beta inhibitors have been investigated more as treatments for gout than for CPPD, and they are recommended by both ACR and European Alliance of Associations for Rheumatology (EULAR) guidelines for patients with gout who have flares despite efforts to treat with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. However, IL-1 beta inhibitors are sometimes used off label in CPPD.

There are similarities among the various crystal types that induce arthritis, typically producing similar clinical features of acute arthritis and severe pain and local inflammation and tending to self-resolve within days to weeks. Those shared clinical features suggest common inflammatory mechanisms, likely stemming from the innate immune system, said Augustin Latourte, MD, PhD, of Lariboisière Hospital, Paris, France, during a talk on the topic at the annual research symposium of the Gout Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

CPPD management is generally derived from strategies developed for gout, but there is little evidence supporting IL-1 beta inhibitors outside of case reports, he said. One clinical trial published in 2020 showed efficacy of the IL-1 inhibitor anakinra, but the study was halted due to low patient recruitment, resulting in a small study population. In that study, “anakinra seems to have a faster onset of action than prednisone and could be useful in specific situations regarding acute CPPD arthritis. But it’s not relevant for chronic CPPD arthritis when you have persistent polyarthritis requiring chronic treatment. Anakinra requires daily injections and may not be appropriate in this situation,” he said.

IL-6r inhibition has been studied since IL-6 was first discovered in 1989 as a mediator of inflammatory responses in gout and CPPD, when it was shown that both CPP and MSU crystals can stimulate its production. In monocytes, IL-6 is expressed at higher levels than IL-1 beta in response to both CPP and MSU crystals. IL-6 production in monocytes in response to crystals is dependent on IL-1, and IL-1 inhibition reduces IL-6 production. “So the hypothesis is that IL-1 beta is the first event, and the production of IL-6 and the amplification of crystal inflammation occurs downstream before the self-limitation of the crystal-induced arthritis. IL-6 may be a very important event in the onset of crystal-induced inflammation,” Latourte said.

 

Building on Mechanistic Insights to Test Off-Label Use of Tocilizumab

Inspired by this insight, Latourte’s group tested tocilizumab in a 28-year-old man with a familial ANKH mutation who had not responded to anakinra and other conventional treatments. The patient experienced a reduction in flare intensity in the first month after the initial treatment and no flares after the second tocilizumab infusion. The group went on to test tocilizumab in 10 additional patients with CPPD (median age, 62.5 years), including 6 with idiopathic CPPD, 3 with Gitelman syndrome, and 1 with ANKH mutation. The clinical presentation included four with recurrent acute arthritis and six with chronic polyarthritis, and all had x-ray–proven disease, with a median visual analog scale (VAS) of 60 mm out of 100 mm. Tocilizumab was administered intravenously or subcutaneously. At 3 months, there was a median improvement of 30 mm in the VAS. Treatment efficacy continued for a median follow-up of 5.5 months at the time of publication, and the researchers have noted ongoing efficacy out to 50 months for some patients.

Tocilizumab has gone on to more frequent use in Europe as a second- or third-line therapy for CPPD, which led Latourte and his colleagues to perform the retrospective analysis that they presented at the ACR meeting. It included 55 patients who received tocilizumab for chronic inflammatory CPPD at two university hospitals. Participants had a median age of 72 years, and 67.3% were women. The patient group included 39 with chronic CPPD, 14 with recurrent acute CPPD (who experienced 0-4 attacks per month), and two patients with mixed CPPD. All participants had been treated with colchicine, and 20 had been treated also with prednisone and 24 with anakinra. Patients had stopped anakinra because it was either ineffective (n = 13) or poorly tolerated (n = 11).

Tocilizumab was administered intravenously in 46 patients and subcutaneously in nine patients for a median duration of 16.5 months (range, 0.8-76.4 months). The median VAS for pain (0- to 100-mm scale) dropped from 60 mm at baseline to 40 mm at 3 months and 30 mm at 6 months. There were 21 adverse events, including 8 cytopenias, 6 transaminase elevations, 4 infections (two severe), and 3 injection-site reactions. After a median of 7.8 months, 26 patients discontinued tocilizumab because of lack of efficacy in 15 patients and intolerance in 11. Among those who continued on tocilizumab, the median length of treatment was 26.0 months (range, 3-76.5 months).

 

Comments on the Study

The study population had some unusual characteristics, according to G-CAN President Robert Terkeltaub, MD, who was asked to comment on the study. “Almost half the patients had received anakinra and then, basically, they failed. In about half of the people who got anakinra, it didn’t work, and in the other half, it wasn’t well tolerated. It’s just rather odd. I find anakinra reasonably well tolerated by people, but we’re dealing with an older population of patients, and the subcutaneous administration of anakinra sometimes can give you injection site reactions, but people started off with a pain level that was close to what we register as severe pain, and the pain level decreased,” he said.

Treatment decisions can be difficult in patients with chronic or acute recurrent CPPD, said Terkeltaub, professor of medicine at the University of California, San Diego. “What’s the lesser evil? Putting people on chronic prednisone is really hard on patients or using a biologic that’s more of an immunologic scalpel here, and more selective, and trying to get people through a long course of therapy. If you have chronic arthritis, it took a while for it to get chronic, and it generally doesn’t go away overnight.”

Terkeltaub also pointed out the gastrointestinal side effects of IL-6r inhibitors, which can include diverticulitis, but there are also concerns over infections and lipid and liver abnormalities. Subcutaneously injected tocilizumab also has a longer half-life than something like anakinra.

Beyond the retrospective nature of the study and the limits it imposes on conclusions that can be drawn, Terkeltaub noted a lack of data on the number of “inflamed joints [in each patient] and what the functioning of the patients was.”

Still, the findings are encouraging. “What I can glean from this study is that the first biologic drug might be an IL-6 inhibitor, but you really need prospective, controlled, blinded clinical trials to know, and it’s hard. It’s just hard to do those trials” because patients tend to be of advanced age, Terkeltaub said.

Latourte said a randomized controlled trial of tocilizumab vs placebo, called TociCCAre, is planned to begin in France in 2025.

Latourte has financial relationships with Fresenius Kabi, Roche Chugai, AbbVie, Arsylab, Celltrion, Janssen, Nordic, Pfizer, UCB, Amgen, Biogen, Galapagos, and Eli Lilly. Terkeltaub had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Achieving serum urate to below 6 mg/dL with urate-lowering therapy (ULT) in patients with gout and chronic kidney disease (CKD) stage III is not linked to an increased risk for severe or end-stage kidney disease.

METHODOLOGY:

• Researchers emulated analyses of a hypothetical target trial using a cloning, censoring, and weighting approach to evaluate the association between achieving target serum urate level with ULT and the progression of CKD in patients with gout and CKD stage III.
• They included 14,972 patients (mean age, 73.1 years; 37.7% women) from a general practice database who had a mean baseline serum urate level of 8.9 mg/dL and initiated ULTs such as allopurinol or febuxostat.
• Participants were divided into two groups: Those who achieved a target serum urate level < 6 mg/dL and those who did not within 1 year after the initiation of ULT; the mean follow-up duration was a little more than 3 years in both groups.
• The primary outcome was the occurrence of severe or end-stage kidney disease over 5 years of initiating ULT, defined by an estimated glomerular filtration rate below 30 mL/min per 1.73 m² on two occasions more than 90 days apart within 1 year, or at least one Read code for CKD stages IV or V, dialysis, or kidney transplant.
• A prespecified noninferiority margin for the hazard ratio was set at 1.2 to compare the outcomes between those who achieved the target serum urate level < 6 mg/dL and those who did not.

TAKEAWAY:

• Among the patients who initiated ULT, 31.8% achieved a target serum urate level < 6 mg/dL within 1 year.
• The 5-year risk for severe or end-stage kidney disease was lower (10.32%) in participants with gout and stage III CKD who achieved the target serum urate level than in those who did not (12.73%).
• The adjusted 5-year risk difference for severe to end-stage kidney disease was not inferior in patients who achieved the target serum urate level vs those who did not (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.80-0.98; P for noninferiority < .001); results were consistent for end-stage kidney disease alone (aHR, 0.67; P for noninferiority = .001).
• Similarly, in participants with gout and CKD stages II-III, the 5-year risks for severe or end-stage kidney disease (aHR, 0.91) and end-stage kidney disease alone (aHR, 0.73) were noninferior in the group that did vs that did not achieve target serum urate levels, with P for noninferiority being < .001 and .003, respectively.

IN PRACTICE:

“Our findings suggest that lowering serum urate levels to < 6 mg/dL is generally well tolerated and may even slow CKD progression in these individuals. Initiatives to optimize the use and adherence to ULT could benefit clinicians and patients,” the authors wrote.

SOURCE:

This study was led by Yilun Wang, MD, PhD, Xiangya Hospital, Central South University, Changsha, China. It was published online in JAMA Internal Medicine.

LIMITATIONS:

Residual confounding may still have been present despite rigorous methods to control it, as is common in observational studies. Participants who achieved target serum urate levels may have received better healthcare, adhered to other treatments more consistently, and used ULT for a longer duration. The findings may have limited generalizability, as participants who did not achieve target serum urate levels prior to initiation were excluded.

DISCLOSURES:

This study was supported by the China National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of the National Clinical Research Center for Geriatric Disorders, and other sources. Two authors reported receiving personal fees and/or grants from multiple pharmaceutical companies.

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

TOPLINE:

Achieving serum urate to below 6 mg/dL with urate-lowering therapy (ULT) in patients with gout and chronic kidney disease (CKD) stage III is not linked to an increased risk for severe or end-stage kidney disease.

METHODOLOGY:

• Researchers emulated analyses of a hypothetical target trial using a cloning, censoring, and weighting approach to evaluate the association between achieving target serum urate level with ULT and the progression of CKD in patients with gout and CKD stage III.
• They included 14,972 patients (mean age, 73.1 years; 37.7% women) from a general practice database who had a mean baseline serum urate level of 8.9 mg/dL and initiated ULTs such as allopurinol or febuxostat.
• Participants were divided into two groups: Those who achieved a target serum urate level < 6 mg/dL and those who did not within 1 year after the initiation of ULT; the mean follow-up duration was a little more than 3 years in both groups.
• The primary outcome was the occurrence of severe or end-stage kidney disease over 5 years of initiating ULT, defined by an estimated glomerular filtration rate below 30 mL/min per 1.73 m² on two occasions more than 90 days apart within 1 year, or at least one Read code for CKD stages IV or V, dialysis, or kidney transplant.
• A prespecified noninferiority margin for the hazard ratio was set at 1.2 to compare the outcomes between those who achieved the target serum urate level < 6 mg/dL and those who did not.

TAKEAWAY:

• Among the patients who initiated ULT, 31.8% achieved a target serum urate level < 6 mg/dL within 1 year.
• The 5-year risk for severe or end-stage kidney disease was lower (10.32%) in participants with gout and stage III CKD who achieved the target serum urate level than in those who did not (12.73%).
• The adjusted 5-year risk difference for severe to end-stage kidney disease was not inferior in patients who achieved the target serum urate level vs those who did not (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.80-0.98; P for noninferiority < .001); results were consistent for end-stage kidney disease alone (aHR, 0.67; P for noninferiority = .001).
• Similarly, in participants with gout and CKD stages II-III, the 5-year risks for severe or end-stage kidney disease (aHR, 0.91) and end-stage kidney disease alone (aHR, 0.73) were noninferior in the group that did vs that did not achieve target serum urate levels, with P for noninferiority being < .001 and .003, respectively.

IN PRACTICE:

“Our findings suggest that lowering serum urate levels to < 6 mg/dL is generally well tolerated and may even slow CKD progression in these individuals. Initiatives to optimize the use and adherence to ULT could benefit clinicians and patients,” the authors wrote.

SOURCE:

This study was led by Yilun Wang, MD, PhD, Xiangya Hospital, Central South University, Changsha, China. It was published online in JAMA Internal Medicine.

LIMITATIONS:

Residual confounding may still have been present despite rigorous methods to control it, as is common in observational studies. Participants who achieved target serum urate levels may have received better healthcare, adhered to other treatments more consistently, and used ULT for a longer duration. The findings may have limited generalizability, as participants who did not achieve target serum urate levels prior to initiation were excluded.

DISCLOSURES:

This study was supported by the China National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of the National Clinical Research Center for Geriatric Disorders, and other sources. Two authors reported receiving personal fees and/or grants from multiple pharmaceutical companies.

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

TOPLINE:

Achieving serum urate to below 6 mg/dL with urate-lowering therapy (ULT) in patients with gout and chronic kidney disease (CKD) stage III is not linked to an increased risk for severe or end-stage kidney disease.

METHODOLOGY:

• Researchers emulated analyses of a hypothetical target trial using a cloning, censoring, and weighting approach to evaluate the association between achieving target serum urate level with ULT and the progression of CKD in patients with gout and CKD stage III.
• They included 14,972 patients (mean age, 73.1 years; 37.7% women) from a general practice database who had a mean baseline serum urate level of 8.9 mg/dL and initiated ULTs such as allopurinol or febuxostat.
• Participants were divided into two groups: Those who achieved a target serum urate level < 6 mg/dL and those who did not within 1 year after the initiation of ULT; the mean follow-up duration was a little more than 3 years in both groups.
• The primary outcome was the occurrence of severe or end-stage kidney disease over 5 years of initiating ULT, defined by an estimated glomerular filtration rate below 30 mL/min per 1.73 m² on two occasions more than 90 days apart within 1 year, or at least one Read code for CKD stages IV or V, dialysis, or kidney transplant.
• A prespecified noninferiority margin for the hazard ratio was set at 1.2 to compare the outcomes between those who achieved the target serum urate level < 6 mg/dL and those who did not.

TAKEAWAY:

• Among the patients who initiated ULT, 31.8% achieved a target serum urate level < 6 mg/dL within 1 year.
• The 5-year risk for severe or end-stage kidney disease was lower (10.32%) in participants with gout and stage III CKD who achieved the target serum urate level than in those who did not (12.73%).
• The adjusted 5-year risk difference for severe to end-stage kidney disease was not inferior in patients who achieved the target serum urate level vs those who did not (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.80-0.98; P for noninferiority < .001); results were consistent for end-stage kidney disease alone (aHR, 0.67; P for noninferiority = .001).
• Similarly, in participants with gout and CKD stages II-III, the 5-year risks for severe or end-stage kidney disease (aHR, 0.91) and end-stage kidney disease alone (aHR, 0.73) were noninferior in the group that did vs that did not achieve target serum urate levels, with P for noninferiority being < .001 and .003, respectively.

IN PRACTICE:

“Our findings suggest that lowering serum urate levels to < 6 mg/dL is generally well tolerated and may even slow CKD progression in these individuals. Initiatives to optimize the use and adherence to ULT could benefit clinicians and patients,” the authors wrote.

SOURCE:

This study was led by Yilun Wang, MD, PhD, Xiangya Hospital, Central South University, Changsha, China. It was published online in JAMA Internal Medicine.

LIMITATIONS:

Residual confounding may still have been present despite rigorous methods to control it, as is common in observational studies. Participants who achieved target serum urate levels may have received better healthcare, adhered to other treatments more consistently, and used ULT for a longer duration. The findings may have limited generalizability, as participants who did not achieve target serum urate levels prior to initiation were excluded.

DISCLOSURES:

This study was supported by the China National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of the National Clinical Research Center for Geriatric Disorders, and other sources. Two authors reported receiving personal fees and/or grants from multiple pharmaceutical companies.

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

The Food and Drug Administration (FDA) has approved ustekinumab-stba (Steqeyma) as a biosimilar to the interleukin-12 and -23 inhibitor ustekinumab (Stelara) for the treatment of adults with active Crohn’s disease or ulcerative colitis and for both children aged ≥ 6 years and adults with moderate to severe plaque psoriasis or active psoriatic arthritis.

This is the seventh ustekinumab biosimilar approved by the FDA. The biosimilar, developed by Celltrion, has a license entry date in February 2025 as part of the settlement and license agreement with the manufacturer of the reference biologic, Johnson & Johnson.

Ustekinumab-stba will be available in two formulations: A subcutaneous injection in two strengths — a 45 mg/0.5 mL or 90 mg/1 mL solution in a single-dose, prefilled syringe — and an intravenous infusion of a 130 mg/26 mL (5 mg/mL) solution in a single-dose vial.

“The approval of Steqeyma reflects Celltrion’s continued investment in providing treatment options to patients diagnosed with ulcerative colitis, Crohn’s disease, psoriasis, and psoriatic arthritis,” said Thomas Nusbickel, Chief Commercial Officer at Celltrion USA, Jersey City, New Jersey, in a press release.

The FDA has previously approved the company’s adalimumab biosimilar Yuflyma and its infliximab biosimilar Zymfentra.

The full prescribing information for ustekinumab-stba is available here.

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

The Food and Drug Administration (FDA) has approved ustekinumab-stba (Steqeyma) as a biosimilar to the interleukin-12 and -23 inhibitor ustekinumab (Stelara) for the treatment of adults with active Crohn’s disease or ulcerative colitis and for both children aged ≥ 6 years and adults with moderate to severe plaque psoriasis or active psoriatic arthritis.

This is the seventh ustekinumab biosimilar approved by the FDA. The biosimilar, developed by Celltrion, has a license entry date in February 2025 as part of the settlement and license agreement with the manufacturer of the reference biologic, Johnson & Johnson.

Ustekinumab-stba will be available in two formulations: A subcutaneous injection in two strengths — a 45 mg/0.5 mL or 90 mg/1 mL solution in a single-dose, prefilled syringe — and an intravenous infusion of a 130 mg/26 mL (5 mg/mL) solution in a single-dose vial.

“The approval of Steqeyma reflects Celltrion’s continued investment in providing treatment options to patients diagnosed with ulcerative colitis, Crohn’s disease, psoriasis, and psoriatic arthritis,” said Thomas Nusbickel, Chief Commercial Officer at Celltrion USA, Jersey City, New Jersey, in a press release.

The FDA has previously approved the company’s adalimumab biosimilar Yuflyma and its infliximab biosimilar Zymfentra.

The full prescribing information for ustekinumab-stba is available here.

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

The Food and Drug Administration (FDA) has approved ustekinumab-stba (Steqeyma) as a biosimilar to the interleukin-12 and -23 inhibitor ustekinumab (Stelara) for the treatment of adults with active Crohn’s disease or ulcerative colitis and for both children aged ≥ 6 years and adults with moderate to severe plaque psoriasis or active psoriatic arthritis.

This is the seventh ustekinumab biosimilar approved by the FDA. The biosimilar, developed by Celltrion, has a license entry date in February 2025 as part of the settlement and license agreement with the manufacturer of the reference biologic, Johnson & Johnson.

Ustekinumab-stba will be available in two formulations: A subcutaneous injection in two strengths — a 45 mg/0.5 mL or 90 mg/1 mL solution in a single-dose, prefilled syringe — and an intravenous infusion of a 130 mg/26 mL (5 mg/mL) solution in a single-dose vial.

“The approval of Steqeyma reflects Celltrion’s continued investment in providing treatment options to patients diagnosed with ulcerative colitis, Crohn’s disease, psoriasis, and psoriatic arthritis,” said Thomas Nusbickel, Chief Commercial Officer at Celltrion USA, Jersey City, New Jersey, in a press release.

The FDA has previously approved the company’s adalimumab biosimilar Yuflyma and its infliximab biosimilar Zymfentra.

The full prescribing information for ustekinumab-stba is available here.

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

A new diagnostic test can accurately distinguish osteoarthritis (OA) from inflammatory arthritis using two synovial fluid biomarkers, according to research published in the Journal of Orthopaedic Research on December 18, 2024.

However, experts question whether such a test would be useful.

“The need would seem to be fairly limited, mostly those with single joint involvement and a lack of other systemic features to specify a diagnosis, which is not that common, at least in rheumatology, where there are usually features in the history and physical that can clarify the diagnosis,” said Amanda E. Nelson, MD, MSCR, professor of medicine in the Division of Rheumatology, Allergy, and Immunology at the University of North Carolina at Chapel Hill. She was not involved with the research.

The test uses an algorithm that incorporates concentrations of cartilage oligomeric matrix protein (COMP) and interleukin 8 (IL-8) in synovial fluid. The researchers hypothesized that a ratio of the two biomarkers could distinguish between primary OA and other inflammatory arthritic diagnoses.

“Primary OA is unlikely when either COMP concentration or COMP/IL‐8 ratio in the synovial fluid is low since these conditions indicate either lack of cartilage degradation or presence of high inflammation,” wrote Daniel Keter and coauthors at CD Diagnostics, Claymont, Delaware, and CD Laboratories, Towson, Maryland. “In contrast, a high COMP concentration result in combination with high COMP/IL‐8 ratio would be suggestive of low inflammation in the setting of cartilage deterioration, which is indicative of primary OA.”

In patients with OA, synovial fluid can be difficult to aspirate in sufficient amounts for testing, Nelson said.

“If synovial fluid is present and able to be aspirated, it is unclear if this test has any benefit over a simple, standard cell count and crystal assessment, which can also distinguish between osteoarthritis and more inflammatory arthritides,” she said.

 

Differentiating OA

To test this potential diagnostic algorithm, researchers obtained 171 knee synovial fluid samples from approved clinical remnant sample sources and a biovendor. All samples were annotated with an existing arthritic diagnosis, including 54 with primary OA, 57 with rheumatoid arthritis (RA), 30 with crystal arthritis (CA), and 30 with native septic arthritis (NSA).

Researchers assigned a CA diagnosis based on the presence of monosodium urate or calcium pyrophosphate dehydrate crystals in the synovial fluid, and NSA was determined via the Synovasure Alpha Defensin test. OA was confirmed via radiograph as Kellgren‐Lawrence grades 2‐4 with no other arthritic diagnoses. RA samples were purchased via a biovendor, and researchers were not provided with diagnosis‐confirming data.

All samples were randomized and blinded before testing, and researchers used enzyme-linked immunosorbent assay tests for both COMP and IL-8 biomarkers.

Of the 54 OA samples, 47 tested positive for OA using the COMP + COMP/IL-8 ratio algorithm. Of the 117 samples with inflammatory arthritis, 13 tested positive for OA. Overall, the diagnostic algorithm demonstrated a clinical sensitivity of 87.0% and specificity of 88.9%. The positive predictive value was 78.3%, while the negative predictive value was 93.7%.

 

Unclear Clinical Need

Nelson noted that while this test aims to differentiate between arthritic diagnoses, patients can also have multiple conditions.

“Many individuals with rheumatoid arthritis will develop osteoarthritis, but they can have both, so a yes/no test is of unclear utility,” she said. OA and calcium pyrophosphate deposition (CPPD) disease can often occur together, “but the driver is really the OA, and the CPPD is present but not actively inflammatory,” she continued. “Septic arthritis should be readily distinguishable by cell count alone [and again, can coexist with any of the other conditions], and a thorough history and physical should be able to differentiate in most cases.”

While these results from this study are “reasonably impressive,” more clinical information is needed to interpret these results, added C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center and professor of medicine and medical imaging at the University of Arizona College of Medicine, Tucson, Arizona.

Because the study is retrospective in nature and researchers obtained specimens from different sources, it was not clear if these patients were being treated when these samples were taken and if their various conditions were controlled or flaring.

“I would say this is a reasonable first step,” Kwoh said. “We would need prospective studies, more clinical characterization, and potentially longitudinal studies to understand when this test may be useful.”

This research was internally funded by Zimmer Biomet. All authors were employees of CD Diagnostics or CD Laboratories, both of which are subsidiaries of Zimmer Biomet. Kwoh reported receiving grants or contracts with AbbVie, Artiva, Eli Lilly and Company, Bristol Myers Squibb, Cumberland, Pfizer, GSK, and Galapagos, and consulting fees from TrialSpark/Formation Bio, Express Scripts, GSK, TLC BioSciences, and AposHealth. He participates on Data Safety Monitoring or Advisory Boards of Moebius Medical, Sun Pharma, Novartis, Xalud, and Kolon TissueGene. Nelson reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

A new diagnostic test can accurately distinguish osteoarthritis (OA) from inflammatory arthritis using two synovial fluid biomarkers, according to research published in the Journal of Orthopaedic Research on December 18, 2024.

However, experts question whether such a test would be useful.

“The need would seem to be fairly limited, mostly those with single joint involvement and a lack of other systemic features to specify a diagnosis, which is not that common, at least in rheumatology, where there are usually features in the history and physical that can clarify the diagnosis,” said Amanda E. Nelson, MD, MSCR, professor of medicine in the Division of Rheumatology, Allergy, and Immunology at the University of North Carolina at Chapel Hill. She was not involved with the research.

The test uses an algorithm that incorporates concentrations of cartilage oligomeric matrix protein (COMP) and interleukin 8 (IL-8) in synovial fluid. The researchers hypothesized that a ratio of the two biomarkers could distinguish between primary OA and other inflammatory arthritic diagnoses.

“Primary OA is unlikely when either COMP concentration or COMP/IL‐8 ratio in the synovial fluid is low since these conditions indicate either lack of cartilage degradation or presence of high inflammation,” wrote Daniel Keter and coauthors at CD Diagnostics, Claymont, Delaware, and CD Laboratories, Towson, Maryland. “In contrast, a high COMP concentration result in combination with high COMP/IL‐8 ratio would be suggestive of low inflammation in the setting of cartilage deterioration, which is indicative of primary OA.”

In patients with OA, synovial fluid can be difficult to aspirate in sufficient amounts for testing, Nelson said.

“If synovial fluid is present and able to be aspirated, it is unclear if this test has any benefit over a simple, standard cell count and crystal assessment, which can also distinguish between osteoarthritis and more inflammatory arthritides,” she said.

 

Differentiating OA

To test this potential diagnostic algorithm, researchers obtained 171 knee synovial fluid samples from approved clinical remnant sample sources and a biovendor. All samples were annotated with an existing arthritic diagnosis, including 54 with primary OA, 57 with rheumatoid arthritis (RA), 30 with crystal arthritis (CA), and 30 with native septic arthritis (NSA).

Researchers assigned a CA diagnosis based on the presence of monosodium urate or calcium pyrophosphate dehydrate crystals in the synovial fluid, and NSA was determined via the Synovasure Alpha Defensin test. OA was confirmed via radiograph as Kellgren‐Lawrence grades 2‐4 with no other arthritic diagnoses. RA samples were purchased via a biovendor, and researchers were not provided with diagnosis‐confirming data.

All samples were randomized and blinded before testing, and researchers used enzyme-linked immunosorbent assay tests for both COMP and IL-8 biomarkers.

Of the 54 OA samples, 47 tested positive for OA using the COMP + COMP/IL-8 ratio algorithm. Of the 117 samples with inflammatory arthritis, 13 tested positive for OA. Overall, the diagnostic algorithm demonstrated a clinical sensitivity of 87.0% and specificity of 88.9%. The positive predictive value was 78.3%, while the negative predictive value was 93.7%.

 

Unclear Clinical Need

Nelson noted that while this test aims to differentiate between arthritic diagnoses, patients can also have multiple conditions.

“Many individuals with rheumatoid arthritis will develop osteoarthritis, but they can have both, so a yes/no test is of unclear utility,” she said. OA and calcium pyrophosphate deposition (CPPD) disease can often occur together, “but the driver is really the OA, and the CPPD is present but not actively inflammatory,” she continued. “Septic arthritis should be readily distinguishable by cell count alone [and again, can coexist with any of the other conditions], and a thorough history and physical should be able to differentiate in most cases.”

While these results from this study are “reasonably impressive,” more clinical information is needed to interpret these results, added C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center and professor of medicine and medical imaging at the University of Arizona College of Medicine, Tucson, Arizona.

Because the study is retrospective in nature and researchers obtained specimens from different sources, it was not clear if these patients were being treated when these samples were taken and if their various conditions were controlled or flaring.

“I would say this is a reasonable first step,” Kwoh said. “We would need prospective studies, more clinical characterization, and potentially longitudinal studies to understand when this test may be useful.”

This research was internally funded by Zimmer Biomet. All authors were employees of CD Diagnostics or CD Laboratories, both of which are subsidiaries of Zimmer Biomet. Kwoh reported receiving grants or contracts with AbbVie, Artiva, Eli Lilly and Company, Bristol Myers Squibb, Cumberland, Pfizer, GSK, and Galapagos, and consulting fees from TrialSpark/Formation Bio, Express Scripts, GSK, TLC BioSciences, and AposHealth. He participates on Data Safety Monitoring or Advisory Boards of Moebius Medical, Sun Pharma, Novartis, Xalud, and Kolon TissueGene. Nelson reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

A new diagnostic test can accurately distinguish osteoarthritis (OA) from inflammatory arthritis using two synovial fluid biomarkers, according to research published in the Journal of Orthopaedic Research on December 18, 2024.

However, experts question whether such a test would be useful.

“The need would seem to be fairly limited, mostly those with single joint involvement and a lack of other systemic features to specify a diagnosis, which is not that common, at least in rheumatology, where there are usually features in the history and physical that can clarify the diagnosis,” said Amanda E. Nelson, MD, MSCR, professor of medicine in the Division of Rheumatology, Allergy, and Immunology at the University of North Carolina at Chapel Hill. She was not involved with the research.

The test uses an algorithm that incorporates concentrations of cartilage oligomeric matrix protein (COMP) and interleukin 8 (IL-8) in synovial fluid. The researchers hypothesized that a ratio of the two biomarkers could distinguish between primary OA and other inflammatory arthritic diagnoses.

“Primary OA is unlikely when either COMP concentration or COMP/IL‐8 ratio in the synovial fluid is low since these conditions indicate either lack of cartilage degradation or presence of high inflammation,” wrote Daniel Keter and coauthors at CD Diagnostics, Claymont, Delaware, and CD Laboratories, Towson, Maryland. “In contrast, a high COMP concentration result in combination with high COMP/IL‐8 ratio would be suggestive of low inflammation in the setting of cartilage deterioration, which is indicative of primary OA.”

In patients with OA, synovial fluid can be difficult to aspirate in sufficient amounts for testing, Nelson said.

“If synovial fluid is present and able to be aspirated, it is unclear if this test has any benefit over a simple, standard cell count and crystal assessment, which can also distinguish between osteoarthritis and more inflammatory arthritides,” she said.

 

Differentiating OA

To test this potential diagnostic algorithm, researchers obtained 171 knee synovial fluid samples from approved clinical remnant sample sources and a biovendor. All samples were annotated with an existing arthritic diagnosis, including 54 with primary OA, 57 with rheumatoid arthritis (RA), 30 with crystal arthritis (CA), and 30 with native septic arthritis (NSA).

Researchers assigned a CA diagnosis based on the presence of monosodium urate or calcium pyrophosphate dehydrate crystals in the synovial fluid, and NSA was determined via the Synovasure Alpha Defensin test. OA was confirmed via radiograph as Kellgren‐Lawrence grades 2‐4 with no other arthritic diagnoses. RA samples were purchased via a biovendor, and researchers were not provided with diagnosis‐confirming data.

All samples were randomized and blinded before testing, and researchers used enzyme-linked immunosorbent assay tests for both COMP and IL-8 biomarkers.

Of the 54 OA samples, 47 tested positive for OA using the COMP + COMP/IL-8 ratio algorithm. Of the 117 samples with inflammatory arthritis, 13 tested positive for OA. Overall, the diagnostic algorithm demonstrated a clinical sensitivity of 87.0% and specificity of 88.9%. The positive predictive value was 78.3%, while the negative predictive value was 93.7%.

 

Unclear Clinical Need

Nelson noted that while this test aims to differentiate between arthritic diagnoses, patients can also have multiple conditions.

“Many individuals with rheumatoid arthritis will develop osteoarthritis, but they can have both, so a yes/no test is of unclear utility,” she said. OA and calcium pyrophosphate deposition (CPPD) disease can often occur together, “but the driver is really the OA, and the CPPD is present but not actively inflammatory,” she continued. “Septic arthritis should be readily distinguishable by cell count alone [and again, can coexist with any of the other conditions], and a thorough history and physical should be able to differentiate in most cases.”

While these results from this study are “reasonably impressive,” more clinical information is needed to interpret these results, added C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center and professor of medicine and medical imaging at the University of Arizona College of Medicine, Tucson, Arizona.

Because the study is retrospective in nature and researchers obtained specimens from different sources, it was not clear if these patients were being treated when these samples were taken and if their various conditions were controlled or flaring.

“I would say this is a reasonable first step,” Kwoh said. “We would need prospective studies, more clinical characterization, and potentially longitudinal studies to understand when this test may be useful.”

This research was internally funded by Zimmer Biomet. All authors were employees of CD Diagnostics or CD Laboratories, both of which are subsidiaries of Zimmer Biomet. Kwoh reported receiving grants or contracts with AbbVie, Artiva, Eli Lilly and Company, Bristol Myers Squibb, Cumberland, Pfizer, GSK, and Galapagos, and consulting fees from TrialSpark/Formation Bio, Express Scripts, GSK, TLC BioSciences, and AposHealth. He participates on Data Safety Monitoring or Advisory Boards of Moebius Medical, Sun Pharma, Novartis, Xalud, and Kolon TissueGene. Nelson reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

TOPLINE:

The initiation of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), particularly rituximab and abatacept, is associated with an increased risk for incident cancer in patients with rheumatoid arthritis (RA) within 2 years of starting treatment.

METHODOLOGY:

• The researchers conducted a retrospective cohort study to assess the safety of tumor necrosis factor (TNF) inhibitors, non-TNF inhibitors, and Janus kinase (JAK) inhibitors in patients with RA using US administrative claims data from the Merative Marketscan Research Databases from November 2012 to December 2021.
• A total of 25,305 patients with RA (median age, 50 years; 79% women; 49% from the southern United States) were identified using diagnostic codes on or before treatment initiation.
• Treatment exposures, including the initiation of TNF inhibitors (adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab), non-TNF inhibitors (abatacept, interleukin 6 [IL-6] inhibitors, and rituximab), and JAK inhibitors (tofacitinib, baricitinib, and upadacitinib), were compared.
• The primary outcome was any incident cancer (excluding nonmelanoma skin cancer) occurring after a minimum of 90 days and within 2 years of treatment initiation.
• Sensitivity analyses used 1:1 propensity matching to compare cancer rates between populations treated with rituximab, IL-6 inhibitors, abatacept, or JAK inhibitors and matched reference populations treated with TNF inhibitors.

TAKEAWAY:

• Rituximab (adjusted hazard ratio [aHR], 1.91; 95% CI, 1.17-3.14) and abatacept (aHR, 1.47; 95% CI, 1.03-2.11) were significantly associated with an increased risk for incident cancer, compared with TNF inhibitors.
• In the propensity-matched analysis, a statistically significant increase in risk was observed in patients treated with rituximab (aHR, 4.37; 95% CI, 1.48-12.93) and abatacept (aHR, 3.12; 95%CI, 1.52-6.44).
• IL-6 inhibitors showed no significant association with cancer in the primary analysis, but a significantly increased risk was observed in the propensity-matched analysis (HR, 5.65; 95% CI, 1.11-28.79).
• JAK inhibitors were not associated with a significant increase in the risk for cancer, compared with TNF inhibitors.

IN PRACTICE:

“Given the limitations of using private insurance claims data and confounding by indication, it is likely that these patients may have a higher disease burden, resulting in channeling bias,” the authors wrote. “To understand these associations, larger studies with longer follow-up and more granular collection of data, including medication indications and RA disease activity measures, would be needed for better comparison of incident cancer risk among these drugs,” they added.

SOURCE:

The study was led by Xavier Sendaydiego, MD, University of Washington, Seattle. It was published online in JAMA Network Open.

LIMITATIONS:

A relatively small number of cancer outcomes may have affected the ability to adjust for confounders. The follow-up period was limited to 2 years, potentially missing long-term cancer risks. The use of US-specific administrative claims data, including only patients aged 18-64 years, may limit the generalizability of the findings. Additionally, the claims data lacked direct measures of disease activity or severity of RA, and information on treatment adherence was unavailable, leading to potential misclassification.

DISCLOSURES:

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging. Some authors reported receiving personal fees, nonfinancial support, and grants from various pharmaceutical companies or government sources. One author reported having a pending patent and another author reported receiving a fellowship, travel reimbursement, and royalties outside the submitted work.

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

TOPLINE:

The initiation of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), particularly rituximab and abatacept, is associated with an increased risk for incident cancer in patients with rheumatoid arthritis (RA) within 2 years of starting treatment.

METHODOLOGY:

• The researchers conducted a retrospective cohort study to assess the safety of tumor necrosis factor (TNF) inhibitors, non-TNF inhibitors, and Janus kinase (JAK) inhibitors in patients with RA using US administrative claims data from the Merative Marketscan Research Databases from November 2012 to December 2021.
• A total of 25,305 patients with RA (median age, 50 years; 79% women; 49% from the southern United States) were identified using diagnostic codes on or before treatment initiation.
• Treatment exposures, including the initiation of TNF inhibitors (adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab), non-TNF inhibitors (abatacept, interleukin 6 [IL-6] inhibitors, and rituximab), and JAK inhibitors (tofacitinib, baricitinib, and upadacitinib), were compared.
• The primary outcome was any incident cancer (excluding nonmelanoma skin cancer) occurring after a minimum of 90 days and within 2 years of treatment initiation.
• Sensitivity analyses used 1:1 propensity matching to compare cancer rates between populations treated with rituximab, IL-6 inhibitors, abatacept, or JAK inhibitors and matched reference populations treated with TNF inhibitors.

TAKEAWAY:

• Rituximab (adjusted hazard ratio [aHR], 1.91; 95% CI, 1.17-3.14) and abatacept (aHR, 1.47; 95% CI, 1.03-2.11) were significantly associated with an increased risk for incident cancer, compared with TNF inhibitors.
• In the propensity-matched analysis, a statistically significant increase in risk was observed in patients treated with rituximab (aHR, 4.37; 95% CI, 1.48-12.93) and abatacept (aHR, 3.12; 95%CI, 1.52-6.44).
• IL-6 inhibitors showed no significant association with cancer in the primary analysis, but a significantly increased risk was observed in the propensity-matched analysis (HR, 5.65; 95% CI, 1.11-28.79).
• JAK inhibitors were not associated with a significant increase in the risk for cancer, compared with TNF inhibitors.

IN PRACTICE:

“Given the limitations of using private insurance claims data and confounding by indication, it is likely that these patients may have a higher disease burden, resulting in channeling bias,” the authors wrote. “To understand these associations, larger studies with longer follow-up and more granular collection of data, including medication indications and RA disease activity measures, would be needed for better comparison of incident cancer risk among these drugs,” they added.

SOURCE:

The study was led by Xavier Sendaydiego, MD, University of Washington, Seattle. It was published online in JAMA Network Open.

LIMITATIONS:

A relatively small number of cancer outcomes may have affected the ability to adjust for confounders. The follow-up period was limited to 2 years, potentially missing long-term cancer risks. The use of US-specific administrative claims data, including only patients aged 18-64 years, may limit the generalizability of the findings. Additionally, the claims data lacked direct measures of disease activity or severity of RA, and information on treatment adherence was unavailable, leading to potential misclassification.

DISCLOSURES:

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging. Some authors reported receiving personal fees, nonfinancial support, and grants from various pharmaceutical companies or government sources. One author reported having a pending patent and another author reported receiving a fellowship, travel reimbursement, and royalties outside the submitted work.

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

TOPLINE:

The initiation of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), particularly rituximab and abatacept, is associated with an increased risk for incident cancer in patients with rheumatoid arthritis (RA) within 2 years of starting treatment.

METHODOLOGY:

• The researchers conducted a retrospective cohort study to assess the safety of tumor necrosis factor (TNF) inhibitors, non-TNF inhibitors, and Janus kinase (JAK) inhibitors in patients with RA using US administrative claims data from the Merative Marketscan Research Databases from November 2012 to December 2021.
• A total of 25,305 patients with RA (median age, 50 years; 79% women; 49% from the southern United States) were identified using diagnostic codes on or before treatment initiation.
• Treatment exposures, including the initiation of TNF inhibitors (adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab), non-TNF inhibitors (abatacept, interleukin 6 [IL-6] inhibitors, and rituximab), and JAK inhibitors (tofacitinib, baricitinib, and upadacitinib), were compared.
• The primary outcome was any incident cancer (excluding nonmelanoma skin cancer) occurring after a minimum of 90 days and within 2 years of treatment initiation.
• Sensitivity analyses used 1:1 propensity matching to compare cancer rates between populations treated with rituximab, IL-6 inhibitors, abatacept, or JAK inhibitors and matched reference populations treated with TNF inhibitors.

TAKEAWAY:

• Rituximab (adjusted hazard ratio [aHR], 1.91; 95% CI, 1.17-3.14) and abatacept (aHR, 1.47; 95% CI, 1.03-2.11) were significantly associated with an increased risk for incident cancer, compared with TNF inhibitors.
• In the propensity-matched analysis, a statistically significant increase in risk was observed in patients treated with rituximab (aHR, 4.37; 95% CI, 1.48-12.93) and abatacept (aHR, 3.12; 95%CI, 1.52-6.44).
• IL-6 inhibitors showed no significant association with cancer in the primary analysis, but a significantly increased risk was observed in the propensity-matched analysis (HR, 5.65; 95% CI, 1.11-28.79).
• JAK inhibitors were not associated with a significant increase in the risk for cancer, compared with TNF inhibitors.

IN PRACTICE:

“Given the limitations of using private insurance claims data and confounding by indication, it is likely that these patients may have a higher disease burden, resulting in channeling bias,” the authors wrote. “To understand these associations, larger studies with longer follow-up and more granular collection of data, including medication indications and RA disease activity measures, would be needed for better comparison of incident cancer risk among these drugs,” they added.

SOURCE:

The study was led by Xavier Sendaydiego, MD, University of Washington, Seattle. It was published online in JAMA Network Open.

LIMITATIONS:

A relatively small number of cancer outcomes may have affected the ability to adjust for confounders. The follow-up period was limited to 2 years, potentially missing long-term cancer risks. The use of US-specific administrative claims data, including only patients aged 18-64 years, may limit the generalizability of the findings. Additionally, the claims data lacked direct measures of disease activity or severity of RA, and information on treatment adherence was unavailable, leading to potential misclassification.

DISCLOSURES:

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging. Some authors reported receiving personal fees, nonfinancial support, and grants from various pharmaceutical companies or government sources. One author reported having a pending patent and another author reported receiving a fellowship, travel reimbursement, and royalties outside the submitted work.

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

For gout, xanthine oxidase (XO) inhibitors are the choice for first-line urate-lowering therapy (ULT) according to the 2020 American College of Rheumatology Guideline for the Management of Gout, which endorsed allopurinol, but should that be the approach for all patients, or should first-line therapy be tailored to the mechanism of each patient’s hyperuricemia? Two gout experts, Lisa Stamp, MBChB, PhD, a rheumatologist and professor of medicine at the University of Otago in Christchurch, New Zealand, and Fernando Pérez-Ruiz, MD, PhD, consultant in the Rheumatology Division of Cruces University Hospital, Barakaldo, head of the Investigation Group for Arthritis at Biocruces Health Research Institute, Barakaldo, and associate professor in the Department of Medicine at the Faculty of Medicine and Nursing at the University of the Basque Country in Leioa, Spain, debated this question recently at the annual research symposium of the Gout, Hyperuricemia and Crystal-Associated Disease Network.

Before the debate began, audience members voted on the question and 56% favored using XO inhibitors as a first-line therapy for all rather than tailoring first-line therapy to disease mechanism.

Up first, Stamp argued that XO inhibitors should be first-line therapy for all patients with gout. She said that XO inhibitors have been demonstrated to work regardless of the cause of hyperuricemia and degree of kidney function, and they are cheap, readily available, and easy to administer. She showed results from a study published by her debate opponent, Pérez-Ruiz, which demonstrated efficacy of XO inhibitors in both under-excreters and over-excreters of uric acid. That study compared the efficacy of the XO inhibitor allopurinol to the uricosuric agent benzbromarone and found the latter to be more effective, but Stamp argued that the allopurinol dose used in the study — 300 mg/d — “may not be enough for many patients who have gout. Dose-restricting allopurinol is one way to demonstrate that an alternative agent is superior,” she said.

A more recent study showed low-dose benzbromarone was better than low-dose febuxostat, another XO inhibitor. “I think we do need to have clinical trials that reflect real-world practice. I accept that this may have reflected [accepted practice where the studies] were undertaken, but these [XO inhibitor] doses don’t represent what many of us would do in other parts of the world,” Stamp said.

One concern is the utility of a ULT in patients with impaired renal function. Stamp cited her own post hoc analysis of a randomized, controlled trial showing that allopurinol is effective irrespective of renal function, as long as the dose is escalated to achieve target urate level, and a meta-analysis of observational studies suggesting that febuxostat is effective irrespective of renal function.

On the other hand, she showed data from a 1994 study of benzbromarone in renal transplant recipients, which showed that the drug’s effect on decreasing plasma uric acid dropped off significantly with lower creatinine clearance. “It does work, but the efficacy really drops off as renal function decreases. Benzbromarone is probably the most effective uricosuric in patients with renal impairment, but this agent is not readily available,” Stamp said.

The uricosuric agent probenecid, which is generally available across the world, led to only about 30% success in achieving target levels of uric acid among patients with an estimated glomerular filtration rate < 50 mL/min/1.73 m². “I think we can all agree that getting 30% of our patients to target uric acid is not an acceptable outcome,” she said.

Stamp emphasized the importance of drug availability and noted that allopurinol is also the only medication for gout that is on the World Health Organization list of essential medications. “I think we should be recommending medications that are readily available, irrespective of where you live,” she said, noting that this is true of allopurinol, febuxostat, and probenecid.

Stamp also addressed the mechanism of action of ULTs. “Does the cause of hyperuricemia affect treatment response? I don’t think it does. Most people respond to allopurinol whether they’re a normal excreter or an under-excreter. Everyone who is lacking uricase will respond to allopurinol. Not everyone will respond to a uricosuric [agent], particularly in the setting of comorbidities such as renal impairment, which many of our patients with gout have,” she said.

 

Counterargument: Combine Therapies With Different Mechanisms of Action

In his counterargument, Pérez-Ruiz contended that gout is not in fact a metabolic disease and suggested that combining therapies with different mechanisms of action could be the best approach for difficult-to-treat gout. “The problem we face in clinical practice is how to treat difficult-to-treat patients,” he said. He referenced his own PhD thesis, which showed both high urinary uric acid output and underexcretion among patients with gout.

Pérez-Ruiz agreed that XO inhibitors should be used as first-line therapy but noted that the effect of allopurinol tapers off at higher doses. “If you use very high doses of allopurinol, you cannot expect to get much more effect,” he said. This is also true of febuxostat, he said.

He showed another study that illustrated difficulties in achieving target serum urate level with intensive therapy. “Even using a high dose of allopurinol, if you would like to get lower than 3 mg/dL for intensive therapy, close to 50% of patients will fail,” he said.

Pérez-Ruiz described a strategy of combining XO inhibitors with a uricosuric therapy, creating what he called a “uricase-like effect” on serum uric acid levels. Ruiz-Perez uses high-dose febuxostat in patients with chronic kidney disease who cannot be given uricosuric agents. “You can go to very low [serum urate levels] by raising up the doses,” he said.

He does not believe that allopurinol is the best agent for combination therapy in the treatment of tophaceous deposits. Instead, he favors combinations with febuxostat. He presented his own experience with 12 patients with very severe tophaceous gout who he treated with a combination of febuxostat and benzbromarone, which reduced serum urate to just over 2 mg/dL. “So this is a pegloticase-like effect [that is] very useful for tophaceous gout,” he said.

In her response, Stamp noted that most of the studies presented by Pérez-Ruiz showed XO inhibitors as first-line therapies, with other medications added on. “I think I heard Fernando agree with me. In just about all of those slides, he showed that a xanthine oxidase inhibitor was the first-line therapy, and subsequently a uricosuric was added,” she said.

Still, Stamp took issue with the idea that serum urate needs to get as low as Pérez-Ruiz advocated for. “What’s the risk associated with getting a serum urate to that level? I’m not sure that a sustained serum urate of around 1 [mg/dL] is necessarily good in the long term,” she said.

Stamp also pointed out the potential risks of polypharmacy, along with adherence issues. “If we can give our patients one therapy, one drug that’s going to get them to a target that we know is going to have beneficial long-term effects, that’s going to help improve our adherence. Maybe we are coming to a new era of [treatment, with] remission induction driving the serum urate very low, and then a maintenance therapy where we can back off. But irrespective, if you use that strategy, Fernando nicely showed that every time you’re going to start with a xanthine oxidase inhibitor,” she said.

After the debate, audience members voted again, and this time the result was 66% in favor of XO inhibitors as a first-line treatment.

Pérez-Ruiz is an adviser for Arthrosi, LG, Novartis, Protalix, and SOBI. He is a speaker for Menarini Central America and the Spanish Foundation for Rheumatology and has received funding from Cruces Rheumatology Association. Stamp did not disclose any financial relationships.

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

For gout, xanthine oxidase (XO) inhibitors are the choice for first-line urate-lowering therapy (ULT) according to the 2020 American College of Rheumatology Guideline for the Management of Gout, which endorsed allopurinol, but should that be the approach for all patients, or should first-line therapy be tailored to the mechanism of each patient’s hyperuricemia? Two gout experts, Lisa Stamp, MBChB, PhD, a rheumatologist and professor of medicine at the University of Otago in Christchurch, New Zealand, and Fernando Pérez-Ruiz, MD, PhD, consultant in the Rheumatology Division of Cruces University Hospital, Barakaldo, head of the Investigation Group for Arthritis at Biocruces Health Research Institute, Barakaldo, and associate professor in the Department of Medicine at the Faculty of Medicine and Nursing at the University of the Basque Country in Leioa, Spain, debated this question recently at the annual research symposium of the Gout, Hyperuricemia and Crystal-Associated Disease Network.

Before the debate began, audience members voted on the question and 56% favored using XO inhibitors as a first-line therapy for all rather than tailoring first-line therapy to disease mechanism.

Up first, Stamp argued that XO inhibitors should be first-line therapy for all patients with gout. She said that XO inhibitors have been demonstrated to work regardless of the cause of hyperuricemia and degree of kidney function, and they are cheap, readily available, and easy to administer. She showed results from a study published by her debate opponent, Pérez-Ruiz, which demonstrated efficacy of XO inhibitors in both under-excreters and over-excreters of uric acid. That study compared the efficacy of the XO inhibitor allopurinol to the uricosuric agent benzbromarone and found the latter to be more effective, but Stamp argued that the allopurinol dose used in the study — 300 mg/d — “may not be enough for many patients who have gout. Dose-restricting allopurinol is one way to demonstrate that an alternative agent is superior,” she said.

A more recent study showed low-dose benzbromarone was better than low-dose febuxostat, another XO inhibitor. “I think we do need to have clinical trials that reflect real-world practice. I accept that this may have reflected [accepted practice where the studies] were undertaken, but these [XO inhibitor] doses don’t represent what many of us would do in other parts of the world,” Stamp said.

One concern is the utility of a ULT in patients with impaired renal function. Stamp cited her own post hoc analysis of a randomized, controlled trial showing that allopurinol is effective irrespective of renal function, as long as the dose is escalated to achieve target urate level, and a meta-analysis of observational studies suggesting that febuxostat is effective irrespective of renal function.

On the other hand, she showed data from a 1994 study of benzbromarone in renal transplant recipients, which showed that the drug’s effect on decreasing plasma uric acid dropped off significantly with lower creatinine clearance. “It does work, but the efficacy really drops off as renal function decreases. Benzbromarone is probably the most effective uricosuric in patients with renal impairment, but this agent is not readily available,” Stamp said.

The uricosuric agent probenecid, which is generally available across the world, led to only about 30% success in achieving target levels of uric acid among patients with an estimated glomerular filtration rate < 50 mL/min/1.73 m². “I think we can all agree that getting 30% of our patients to target uric acid is not an acceptable outcome,” she said.

Stamp emphasized the importance of drug availability and noted that allopurinol is also the only medication for gout that is on the World Health Organization list of essential medications. “I think we should be recommending medications that are readily available, irrespective of where you live,” she said, noting that this is true of allopurinol, febuxostat, and probenecid.

Stamp also addressed the mechanism of action of ULTs. “Does the cause of hyperuricemia affect treatment response? I don’t think it does. Most people respond to allopurinol whether they’re a normal excreter or an under-excreter. Everyone who is lacking uricase will respond to allopurinol. Not everyone will respond to a uricosuric [agent], particularly in the setting of comorbidities such as renal impairment, which many of our patients with gout have,” she said.

 

Counterargument: Combine Therapies With Different Mechanisms of Action

In his counterargument, Pérez-Ruiz contended that gout is not in fact a metabolic disease and suggested that combining therapies with different mechanisms of action could be the best approach for difficult-to-treat gout. “The problem we face in clinical practice is how to treat difficult-to-treat patients,” he said. He referenced his own PhD thesis, which showed both high urinary uric acid output and underexcretion among patients with gout.

Pérez-Ruiz agreed that XO inhibitors should be used as first-line therapy but noted that the effect of allopurinol tapers off at higher doses. “If you use very high doses of allopurinol, you cannot expect to get much more effect,” he said. This is also true of febuxostat, he said.

He showed another study that illustrated difficulties in achieving target serum urate level with intensive therapy. “Even using a high dose of allopurinol, if you would like to get lower than 3 mg/dL for intensive therapy, close to 50% of patients will fail,” he said.

Pérez-Ruiz described a strategy of combining XO inhibitors with a uricosuric therapy, creating what he called a “uricase-like effect” on serum uric acid levels. Ruiz-Perez uses high-dose febuxostat in patients with chronic kidney disease who cannot be given uricosuric agents. “You can go to very low [serum urate levels] by raising up the doses,” he said.

He does not believe that allopurinol is the best agent for combination therapy in the treatment of tophaceous deposits. Instead, he favors combinations with febuxostat. He presented his own experience with 12 patients with very severe tophaceous gout who he treated with a combination of febuxostat and benzbromarone, which reduced serum urate to just over 2 mg/dL. “So this is a pegloticase-like effect [that is] very useful for tophaceous gout,” he said.

In her response, Stamp noted that most of the studies presented by Pérez-Ruiz showed XO inhibitors as first-line therapies, with other medications added on. “I think I heard Fernando agree with me. In just about all of those slides, he showed that a xanthine oxidase inhibitor was the first-line therapy, and subsequently a uricosuric was added,” she said.

Still, Stamp took issue with the idea that serum urate needs to get as low as Pérez-Ruiz advocated for. “What’s the risk associated with getting a serum urate to that level? I’m not sure that a sustained serum urate of around 1 [mg/dL] is necessarily good in the long term,” she said.

Stamp also pointed out the potential risks of polypharmacy, along with adherence issues. “If we can give our patients one therapy, one drug that’s going to get them to a target that we know is going to have beneficial long-term effects, that’s going to help improve our adherence. Maybe we are coming to a new era of [treatment, with] remission induction driving the serum urate very low, and then a maintenance therapy where we can back off. But irrespective, if you use that strategy, Fernando nicely showed that every time you’re going to start with a xanthine oxidase inhibitor,” she said.

After the debate, audience members voted again, and this time the result was 66% in favor of XO inhibitors as a first-line treatment.

Pérez-Ruiz is an adviser for Arthrosi, LG, Novartis, Protalix, and SOBI. He is a speaker for Menarini Central America and the Spanish Foundation for Rheumatology and has received funding from Cruces Rheumatology Association. Stamp did not disclose any financial relationships.

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

For gout, xanthine oxidase (XO) inhibitors are the choice for first-line urate-lowering therapy (ULT) according to the 2020 American College of Rheumatology Guideline for the Management of Gout, which endorsed allopurinol, but should that be the approach for all patients, or should first-line therapy be tailored to the mechanism of each patient’s hyperuricemia? Two gout experts, Lisa Stamp, MBChB, PhD, a rheumatologist and professor of medicine at the University of Otago in Christchurch, New Zealand, and Fernando Pérez-Ruiz, MD, PhD, consultant in the Rheumatology Division of Cruces University Hospital, Barakaldo, head of the Investigation Group for Arthritis at Biocruces Health Research Institute, Barakaldo, and associate professor in the Department of Medicine at the Faculty of Medicine and Nursing at the University of the Basque Country in Leioa, Spain, debated this question recently at the annual research symposium of the Gout, Hyperuricemia and Crystal-Associated Disease Network.

Before the debate began, audience members voted on the question and 56% favored using XO inhibitors as a first-line therapy for all rather than tailoring first-line therapy to disease mechanism.

Up first, Stamp argued that XO inhibitors should be first-line therapy for all patients with gout. She said that XO inhibitors have been demonstrated to work regardless of the cause of hyperuricemia and degree of kidney function, and they are cheap, readily available, and easy to administer. She showed results from a study published by her debate opponent, Pérez-Ruiz, which demonstrated efficacy of XO inhibitors in both under-excreters and over-excreters of uric acid. That study compared the efficacy of the XO inhibitor allopurinol to the uricosuric agent benzbromarone and found the latter to be more effective, but Stamp argued that the allopurinol dose used in the study — 300 mg/d — “may not be enough for many patients who have gout. Dose-restricting allopurinol is one way to demonstrate that an alternative agent is superior,” she said.

A more recent study showed low-dose benzbromarone was better than low-dose febuxostat, another XO inhibitor. “I think we do need to have clinical trials that reflect real-world practice. I accept that this may have reflected [accepted practice where the studies] were undertaken, but these [XO inhibitor] doses don’t represent what many of us would do in other parts of the world,” Stamp said.

One concern is the utility of a ULT in patients with impaired renal function. Stamp cited her own post hoc analysis of a randomized, controlled trial showing that allopurinol is effective irrespective of renal function, as long as the dose is escalated to achieve target urate level, and a meta-analysis of observational studies suggesting that febuxostat is effective irrespective of renal function.

On the other hand, she showed data from a 1994 study of benzbromarone in renal transplant recipients, which showed that the drug’s effect on decreasing plasma uric acid dropped off significantly with lower creatinine clearance. “It does work, but the efficacy really drops off as renal function decreases. Benzbromarone is probably the most effective uricosuric in patients with renal impairment, but this agent is not readily available,” Stamp said.

The uricosuric agent probenecid, which is generally available across the world, led to only about 30% success in achieving target levels of uric acid among patients with an estimated glomerular filtration rate < 50 mL/min/1.73 m². “I think we can all agree that getting 30% of our patients to target uric acid is not an acceptable outcome,” she said.

Stamp emphasized the importance of drug availability and noted that allopurinol is also the only medication for gout that is on the World Health Organization list of essential medications. “I think we should be recommending medications that are readily available, irrespective of where you live,” she said, noting that this is true of allopurinol, febuxostat, and probenecid.

Stamp also addressed the mechanism of action of ULTs. “Does the cause of hyperuricemia affect treatment response? I don’t think it does. Most people respond to allopurinol whether they’re a normal excreter or an under-excreter. Everyone who is lacking uricase will respond to allopurinol. Not everyone will respond to a uricosuric [agent], particularly in the setting of comorbidities such as renal impairment, which many of our patients with gout have,” she said.

 

Counterargument: Combine Therapies With Different Mechanisms of Action

In his counterargument, Pérez-Ruiz contended that gout is not in fact a metabolic disease and suggested that combining therapies with different mechanisms of action could be the best approach for difficult-to-treat gout. “The problem we face in clinical practice is how to treat difficult-to-treat patients,” he said. He referenced his own PhD thesis, which showed both high urinary uric acid output and underexcretion among patients with gout.

Pérez-Ruiz agreed that XO inhibitors should be used as first-line therapy but noted that the effect of allopurinol tapers off at higher doses. “If you use very high doses of allopurinol, you cannot expect to get much more effect,” he said. This is also true of febuxostat, he said.

He showed another study that illustrated difficulties in achieving target serum urate level with intensive therapy. “Even using a high dose of allopurinol, if you would like to get lower than 3 mg/dL for intensive therapy, close to 50% of patients will fail,” he said.

Pérez-Ruiz described a strategy of combining XO inhibitors with a uricosuric therapy, creating what he called a “uricase-like effect” on serum uric acid levels. Ruiz-Perez uses high-dose febuxostat in patients with chronic kidney disease who cannot be given uricosuric agents. “You can go to very low [serum urate levels] by raising up the doses,” he said.

He does not believe that allopurinol is the best agent for combination therapy in the treatment of tophaceous deposits. Instead, he favors combinations with febuxostat. He presented his own experience with 12 patients with very severe tophaceous gout who he treated with a combination of febuxostat and benzbromarone, which reduced serum urate to just over 2 mg/dL. “So this is a pegloticase-like effect [that is] very useful for tophaceous gout,” he said.

In her response, Stamp noted that most of the studies presented by Pérez-Ruiz showed XO inhibitors as first-line therapies, with other medications added on. “I think I heard Fernando agree with me. In just about all of those slides, he showed that a xanthine oxidase inhibitor was the first-line therapy, and subsequently a uricosuric was added,” she said.

Still, Stamp took issue with the idea that serum urate needs to get as low as Pérez-Ruiz advocated for. “What’s the risk associated with getting a serum urate to that level? I’m not sure that a sustained serum urate of around 1 [mg/dL] is necessarily good in the long term,” she said.

Stamp also pointed out the potential risks of polypharmacy, along with adherence issues. “If we can give our patients one therapy, one drug that’s going to get them to a target that we know is going to have beneficial long-term effects, that’s going to help improve our adherence. Maybe we are coming to a new era of [treatment, with] remission induction driving the serum urate very low, and then a maintenance therapy where we can back off. But irrespective, if you use that strategy, Fernando nicely showed that every time you’re going to start with a xanthine oxidase inhibitor,” she said.

After the debate, audience members voted again, and this time the result was 66% in favor of XO inhibitors as a first-line treatment.

Pérez-Ruiz is an adviser for Arthrosi, LG, Novartis, Protalix, and SOBI. He is a speaker for Menarini Central America and the Spanish Foundation for Rheumatology and has received funding from Cruces Rheumatology Association. Stamp did not disclose any financial relationships.

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

TOPLINE:

The association persists even after accounting for adverse pregnancy outcomes. Women who have experienced infertility without fertility treatment show a 25% higher risk for systemic autoimmune rheumatic disease (SARD) up to 9 years after delivery, compared with those without infertility.

METHODOLOGY:

• Population-based cohort study analyzed 568,053 singleton births among 465,078 women aged 18-50 years without pre-existing SARD in Ontario, Canada, from 2012 to 2021.
• Participants were categorized into four groups: No infertility with unassisted conception (88.0%), infertility without fertility treatment (9.2%), infertility with noninvasive fertility treatment (1.4%), and infertility with invasive fertility treatment (1.4%).
• Researchers used marginal structural Cox proportional hazards models to generate hazard ratios and 95% CIs, adjusting for sociodemographic characteristics, comorbidities, smoking, and adverse pregnancy outcomes.
• Analysis included a median follow-up duration of 6.5 years (interquartile range: 4-9 years) from delivery date until SARD diagnosis, death, loss of health insurance, or study end.

TAKEAWAY:

• The incidence rate of SARD was 12.5 per 10,000 person-years in women with untreated infertility, compared with 9.3 per 10,000 person-years in women without infertility.
• Women with untreated infertility showed an elevated risk for SARD (controlled direct effect hazard ratio [HR], 1.25; 95% CI, 1.12-1.40) even after accounting for adverse pregnancy outcomes.
• Neither noninvasive fertility treatment (total effect HR, 1.06; 95% CI, 0.79-1.42) nor invasive fertility treatment (total effect HR, 0.97; 95% CI, 0.69-1.36) were associated with increased SARD risk.
• The association between untreated infertility and SARD persisted in analyses restricted to women aged < 38 years and in those without endometriosis or other autoimmune diseases.

IN PRACTICE:

“Future research efforts should seek to corroborate this association by infertility cause, with a focus on possible mechanisms related to ovulatory, ovarian, and sexual dysfunction. Greater health provider awareness of SARD symptoms and related gynecological issues that may present in women with infertility could facilitate earlier detection and treatment of SARD during the reproductive years,” wrote the authors of the study.

SOURCE:

The study was led by Natalie V. Scime of the Department of Health and Society, University of Toronto Scarborough in Ontario, Canada. It was published online in Human Reproduction.

LIMITATIONS:

Exposure and outcome misclassification was possible due to the use of published algorithms in health administrative data with unknown or imperfect sensitivity and specificity. The researchers noted that individual-level social and lifestyle factors and underlying causes of infertility were not available, and thus, were not included in the analysis.

DISCLOSURES:

This research received funding through a Banting Postdoctoral Fellowship to Scime and Canada Research Chair to Hilary K. Brown (2019-00158), with support from ICES, funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. One coauthor disclosed consulting for Celltrion, Werfen, Organon, MitogenDx, AstraZeneca, Mallinckrodt Canada, and GlaxoSmithKline. All other authors reported 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 first appeared on Medscape.com.

TOPLINE:

The association persists even after accounting for adverse pregnancy outcomes. Women who have experienced infertility without fertility treatment show a 25% higher risk for systemic autoimmune rheumatic disease (SARD) up to 9 years after delivery, compared with those without infertility.

METHODOLOGY:

• Population-based cohort study analyzed 568,053 singleton births among 465,078 women aged 18-50 years without pre-existing SARD in Ontario, Canada, from 2012 to 2021.
• Participants were categorized into four groups: No infertility with unassisted conception (88.0%), infertility without fertility treatment (9.2%), infertility with noninvasive fertility treatment (1.4%), and infertility with invasive fertility treatment (1.4%).
• Researchers used marginal structural Cox proportional hazards models to generate hazard ratios and 95% CIs, adjusting for sociodemographic characteristics, comorbidities, smoking, and adverse pregnancy outcomes.
• Analysis included a median follow-up duration of 6.5 years (interquartile range: 4-9 years) from delivery date until SARD diagnosis, death, loss of health insurance, or study end.

TAKEAWAY:

• The incidence rate of SARD was 12.5 per 10,000 person-years in women with untreated infertility, compared with 9.3 per 10,000 person-years in women without infertility.
• Women with untreated infertility showed an elevated risk for SARD (controlled direct effect hazard ratio [HR], 1.25; 95% CI, 1.12-1.40) even after accounting for adverse pregnancy outcomes.
• Neither noninvasive fertility treatment (total effect HR, 1.06; 95% CI, 0.79-1.42) nor invasive fertility treatment (total effect HR, 0.97; 95% CI, 0.69-1.36) were associated with increased SARD risk.
• The association between untreated infertility and SARD persisted in analyses restricted to women aged < 38 years and in those without endometriosis or other autoimmune diseases.

IN PRACTICE:

“Future research efforts should seek to corroborate this association by infertility cause, with a focus on possible mechanisms related to ovulatory, ovarian, and sexual dysfunction. Greater health provider awareness of SARD symptoms and related gynecological issues that may present in women with infertility could facilitate earlier detection and treatment of SARD during the reproductive years,” wrote the authors of the study.

SOURCE:

The study was led by Natalie V. Scime of the Department of Health and Society, University of Toronto Scarborough in Ontario, Canada. It was published online in Human Reproduction.

LIMITATIONS:

Exposure and outcome misclassification was possible due to the use of published algorithms in health administrative data with unknown or imperfect sensitivity and specificity. The researchers noted that individual-level social and lifestyle factors and underlying causes of infertility were not available, and thus, were not included in the analysis.

DISCLOSURES:

This research received funding through a Banting Postdoctoral Fellowship to Scime and Canada Research Chair to Hilary K. Brown (2019-00158), with support from ICES, funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. One coauthor disclosed consulting for Celltrion, Werfen, Organon, MitogenDx, AstraZeneca, Mallinckrodt Canada, and GlaxoSmithKline. All other authors reported 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 first appeared on Medscape.com.

TOPLINE:

The association persists even after accounting for adverse pregnancy outcomes. Women who have experienced infertility without fertility treatment show a 25% higher risk for systemic autoimmune rheumatic disease (SARD) up to 9 years after delivery, compared with those without infertility.

METHODOLOGY:

• Population-based cohort study analyzed 568,053 singleton births among 465,078 women aged 18-50 years without pre-existing SARD in Ontario, Canada, from 2012 to 2021.
• Participants were categorized into four groups: No infertility with unassisted conception (88.0%), infertility without fertility treatment (9.2%), infertility with noninvasive fertility treatment (1.4%), and infertility with invasive fertility treatment (1.4%).
• Researchers used marginal structural Cox proportional hazards models to generate hazard ratios and 95% CIs, adjusting for sociodemographic characteristics, comorbidities, smoking, and adverse pregnancy outcomes.
• Analysis included a median follow-up duration of 6.5 years (interquartile range: 4-9 years) from delivery date until SARD diagnosis, death, loss of health insurance, or study end.

TAKEAWAY:

• The incidence rate of SARD was 12.5 per 10,000 person-years in women with untreated infertility, compared with 9.3 per 10,000 person-years in women without infertility.
• Women with untreated infertility showed an elevated risk for SARD (controlled direct effect hazard ratio [HR], 1.25; 95% CI, 1.12-1.40) even after accounting for adverse pregnancy outcomes.
• Neither noninvasive fertility treatment (total effect HR, 1.06; 95% CI, 0.79-1.42) nor invasive fertility treatment (total effect HR, 0.97; 95% CI, 0.69-1.36) were associated with increased SARD risk.
• The association between untreated infertility and SARD persisted in analyses restricted to women aged < 38 years and in those without endometriosis or other autoimmune diseases.

IN PRACTICE:

“Future research efforts should seek to corroborate this association by infertility cause, with a focus on possible mechanisms related to ovulatory, ovarian, and sexual dysfunction. Greater health provider awareness of SARD symptoms and related gynecological issues that may present in women with infertility could facilitate earlier detection and treatment of SARD during the reproductive years,” wrote the authors of the study.

SOURCE:

The study was led by Natalie V. Scime of the Department of Health and Society, University of Toronto Scarborough in Ontario, Canada. It was published online in Human Reproduction.

LIMITATIONS:

Exposure and outcome misclassification was possible due to the use of published algorithms in health administrative data with unknown or imperfect sensitivity and specificity. The researchers noted that individual-level social and lifestyle factors and underlying causes of infertility were not available, and thus, were not included in the analysis.

DISCLOSURES:

This research received funding through a Banting Postdoctoral Fellowship to Scime and Canada Research Chair to Hilary K. Brown (2019-00158), with support from ICES, funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. One coauthor disclosed consulting for Celltrion, Werfen, Organon, MitogenDx, AstraZeneca, Mallinckrodt Canada, and GlaxoSmithKline. All other authors reported 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 first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. 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 first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. 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 first appeared on Medscape.com.

TOPLINE:

Atherosclerotic cardiovascular disease (ASCVD) risk is higher with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) than with psoriasis.

METHODOLOGY:

• A retrospective matched longitudinal study compared the incidence and prevalence of ASCVD of 8138 individuals with CLE; 24,675 with SLE; 192,577 with psoriasis; and 81,380 control individuals.
• The disease-free control population was matched in a 10:1 ratio to the CLE population on the basis of age, sex, insurance type, and enrollment duration.
• Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident, with ASCVD incidence assessed by number of hospitalizations over 3 years.

TAKEAWAY:

• Persons with CLE had higher ASCVD risk than control individuals (odds ratio [OR], 1.72; P < .001), similar to those with SLE (OR, 2.41; P < .001) but unlike those with psoriasis (OR, 1.03; P = .48).
• ASCVD incidence at 3 years was 24.8 per 1000 person-years for SLE, 15.2 per 1000 person-years for CLE, 14.0 per 1000 person-years for psoriasis, and 10.3 per 1000 person-years for controls.
• Multivariable Cox proportional regression modeling showed ASCVD risk was highest in those with SLE (hazard ratio [HR], 2.23; P < .001) vs CLE (HR, 1.32; P < .001) and psoriasis (HR, 1.06; P = .09).
• ASCVD prevalence was higher in individuals with CLE receiving systemic therapy (2.7%) than in those receiving no therapy (1.6%), suggesting a potential link between disease severity and CVD risk.

IN PRACTICE:

“Persons with CLE are at higher risk for ASCVD, and guidelines for the evaluation and management of ASCVD may improve their quality of care,” the authors wrote.

SOURCE:

The study was led by Henry W. Chen, MD, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas. It was published online on December 4, 2024, in JAMA Dermatology.

LIMITATIONS: 

The study was limited by its relatively young population (median age, 49 years) and the exclusion of adults aged > 65 years on Medicare insurance plans. The database lacked race and ethnicity data, and the analysis was restricted to a shorter 3-year period. The study could not fully evaluate detailed risk factors such as blood pressure levels, cholesterol measurements, or glycemic control, nor could it accurately assess smoking status.

DISCLOSURES:

The research was supported by the Department of Dermatology at the University of Texas Southwestern Medical Center and a grant from the National Institutes of Health. Several authors reported receiving grants or personal fees from various pharmaceutical companies. One author reported being a deputy editor for diversity, equity, and inclusion at JAMA Cardiology. 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 first 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.

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.