TBD Meeting (4970-23)

SEOUL, SOUTH KOREA – A major challenge for clinical trials in systemic lupus erythematosus (SLE) is how to get the placebo response rate down low enough that the effectiveness of a drug can actually be seen. Better patient selection may be the key.

Speaking at an international congress on SLE, Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, presented on how the heterogeneity of lupus is contributing to the ongoing failure of so many potential therapies in clinical trials.

“It’s a miracle that any drug has been successful in clinical trials,” she told the conference, comparing the few drugs approved for the treatment of lupus with the much larger numbers of approved, targeted biologics that are available for rheumatoid arthritis.

Bianca Nogrady/MDedge News

The problem is that placebo response rates in clinical trials for lupus are high – well over 40% – Dr. Merrill said, and trials aren’t showing a big difference in response rates between the treatment and placebo arms. “If the placebo response is 40%, wouldn’t an effective drug help 80%?” she said. “If it also affects only 40%, does that mean it’s a failed drug?”

Dr. Merrill suggested that better patient selection could be key to achieving lower placebo response rates, which could in turn reveal if and in whom a drug might be effective. “If we could get the placebo response rate down, at least we’d be able to see a little bit better whether the drug is effective, even if it only could work in 50% of the patients,” she said.

Data from research done by the Oklahoma Medical Research Foundation suggested that patients with SLE could be loosely categorized into seven different clusters based on patterns of gene expression in areas such as interferon expression and inflammation pathways.

For example, two of those clusters represented patients with high levels of expression for both interferons and inflammation. “Maybe those are the patients who’d want to be put in a trial for interferon inhibition,” Dr. Merrill said.

This was demonstrated in a trial of type 1 interferon inhibitor anifrolumab (Saphnelo), where patients were sorted into groups according to their level of interferon expression – either high or low – based on expression of certain interferon genes. This revealed that patients in the interferon-high group had a much higher treatment effect than patients in the interferon-low group. But the difference lay in the placebo response.

“The efficacy rate was not that different between the interferon-high and the interferon-low patients,” Dr. Merrill said. “The difference was in the placebo response rate – what they had managed to find was a great marker for sicker patients.”

This phenomenon is not limited to interferon-targeted therapies. Dr. Merrill cited another literature review which looked at subset studies within clinical trials that had delivered disappointing results. This showed consistently that patients who were considered more unwell, by virtue of higher SLE Disease Activity Index (SLEDAI) scores, for example, were more likely to show an effect of treatment.

“You begin to see bigger differences between treatment and placebo because the treatment rate might go up, but mostly because the placebo rate goes down,” she said.

Another issue that could be affecting both placebo and treatment response rates is background medication. “Subset analysis of people on less background drugs was showing lower placebo response rates and better differences between treatments and placebo,” Dr. Merrill said. For example, a recent phase 2 study of anifrolumab took the strategy of actively pursuing tapering of glucocorticoids in patients where that could be done safely. That achieved a lowering of the placebo response rate to the point where a greater difference could be seen between the placebo response and the treatment response rates.

The challenge for clinical trials is therefore to identify which patients to include. “If we could figure out which patients would be the most appropriate [to enroll to fit a particular drug’s mechanism of action], then we could really get ahead of the game,” she said.

The unique problem for lupus clinic trials is the heterogeneity of lupus as a disease, Dr. Merrill said in an interview. “We’re going to have to find combinations of treatments that fit right for each patient, and they won’t necessarily be one size fits all,” she said.

Dr. Merrill said that subset analyses at the phase 2 stage could help identify the patients who responded better to the treatment and could therefore be targeted in phase 3 trials. “Once you take that hypothesis, and if you can establish and validate it in phase 3, now you’ve got yourself a biomarker,” she said.

Richard A. Furie, MD, chief of the division of rheumatology at Northwell Health in New York, agreed that the high placebo response rate was a particular nemesis for researchers involved in lupus clinical trials.

Sara Freeman/MDedge News

Dr. Furie said it could be that selecting sicker patients is a solution to this, as had been suggested in the subset analysis of the anifrolumab studies – which he was involved in – that identified differences in the response rates between interferon-high and interferon-low patients.

But if that was the case, the challenge would be recruiting enough of any particular subset of patients. For example, relatively few patients in the anifrolumab trial were classified as interferon low.

If the interferon expression levels are a marker for patients who are sicker, that could serve as a way to better select patients for clinical trials, he said. But it would also make it harder to achieve recruitment targets.

“I think the major problem in SLE trials is that patients have inflated activity scores, so you can gain SLEDAI scores with a little alopecia and an oral ulcer,” he said. “You can start eliminating those parameters from counting towards entry, but then as soon as you do that, you’re going to have trouble recruiting.”

Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and anifrolumab manufacturer AstraZeneca. Dr. Furie reported financial relationships with Genentech/Roche, GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda.

SEOUL, SOUTH KOREA – A major challenge for clinical trials in systemic lupus erythematosus (SLE) is how to get the placebo response rate down low enough that the effectiveness of a drug can actually be seen. Better patient selection may be the key.

Speaking at an international congress on SLE, Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, presented on how the heterogeneity of lupus is contributing to the ongoing failure of so many potential therapies in clinical trials.

“It’s a miracle that any drug has been successful in clinical trials,” she told the conference, comparing the few drugs approved for the treatment of lupus with the much larger numbers of approved, targeted biologics that are available for rheumatoid arthritis.

Bianca Nogrady/MDedge News

The problem is that placebo response rates in clinical trials for lupus are high – well over 40% – Dr. Merrill said, and trials aren’t showing a big difference in response rates between the treatment and placebo arms. “If the placebo response is 40%, wouldn’t an effective drug help 80%?” she said. “If it also affects only 40%, does that mean it’s a failed drug?”

Dr. Merrill suggested that better patient selection could be key to achieving lower placebo response rates, which could in turn reveal if and in whom a drug might be effective. “If we could get the placebo response rate down, at least we’d be able to see a little bit better whether the drug is effective, even if it only could work in 50% of the patients,” she said.

Data from research done by the Oklahoma Medical Research Foundation suggested that patients with SLE could be loosely categorized into seven different clusters based on patterns of gene expression in areas such as interferon expression and inflammation pathways.

For example, two of those clusters represented patients with high levels of expression for both interferons and inflammation. “Maybe those are the patients who’d want to be put in a trial for interferon inhibition,” Dr. Merrill said.

This was demonstrated in a trial of type 1 interferon inhibitor anifrolumab (Saphnelo), where patients were sorted into groups according to their level of interferon expression – either high or low – based on expression of certain interferon genes. This revealed that patients in the interferon-high group had a much higher treatment effect than patients in the interferon-low group. But the difference lay in the placebo response.

“The efficacy rate was not that different between the interferon-high and the interferon-low patients,” Dr. Merrill said. “The difference was in the placebo response rate – what they had managed to find was a great marker for sicker patients.”

This phenomenon is not limited to interferon-targeted therapies. Dr. Merrill cited another literature review which looked at subset studies within clinical trials that had delivered disappointing results. This showed consistently that patients who were considered more unwell, by virtue of higher SLE Disease Activity Index (SLEDAI) scores, for example, were more likely to show an effect of treatment.

“You begin to see bigger differences between treatment and placebo because the treatment rate might go up, but mostly because the placebo rate goes down,” she said.

Another issue that could be affecting both placebo and treatment response rates is background medication. “Subset analysis of people on less background drugs was showing lower placebo response rates and better differences between treatments and placebo,” Dr. Merrill said. For example, a recent phase 2 study of anifrolumab took the strategy of actively pursuing tapering of glucocorticoids in patients where that could be done safely. That achieved a lowering of the placebo response rate to the point where a greater difference could be seen between the placebo response and the treatment response rates.

The challenge for clinical trials is therefore to identify which patients to include. “If we could figure out which patients would be the most appropriate [to enroll to fit a particular drug’s mechanism of action], then we could really get ahead of the game,” she said.

The unique problem for lupus clinic trials is the heterogeneity of lupus as a disease, Dr. Merrill said in an interview. “We’re going to have to find combinations of treatments that fit right for each patient, and they won’t necessarily be one size fits all,” she said.

Dr. Merrill said that subset analyses at the phase 2 stage could help identify the patients who responded better to the treatment and could therefore be targeted in phase 3 trials. “Once you take that hypothesis, and if you can establish and validate it in phase 3, now you’ve got yourself a biomarker,” she said.

Richard A. Furie, MD, chief of the division of rheumatology at Northwell Health in New York, agreed that the high placebo response rate was a particular nemesis for researchers involved in lupus clinical trials.

Sara Freeman/MDedge News

Dr. Furie said it could be that selecting sicker patients is a solution to this, as had been suggested in the subset analysis of the anifrolumab studies – which he was involved in – that identified differences in the response rates between interferon-high and interferon-low patients.

But if that was the case, the challenge would be recruiting enough of any particular subset of patients. For example, relatively few patients in the anifrolumab trial were classified as interferon low.

If the interferon expression levels are a marker for patients who are sicker, that could serve as a way to better select patients for clinical trials, he said. But it would also make it harder to achieve recruitment targets.

“I think the major problem in SLE trials is that patients have inflated activity scores, so you can gain SLEDAI scores with a little alopecia and an oral ulcer,” he said. “You can start eliminating those parameters from counting towards entry, but then as soon as you do that, you’re going to have trouble recruiting.”

Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and anifrolumab manufacturer AstraZeneca. Dr. Furie reported financial relationships with Genentech/Roche, GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda.

SEOUL, SOUTH KOREA – A major challenge for clinical trials in systemic lupus erythematosus (SLE) is how to get the placebo response rate down low enough that the effectiveness of a drug can actually be seen. Better patient selection may be the key.

Speaking at an international congress on SLE, Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, presented on how the heterogeneity of lupus is contributing to the ongoing failure of so many potential therapies in clinical trials.

“It’s a miracle that any drug has been successful in clinical trials,” she told the conference, comparing the few drugs approved for the treatment of lupus with the much larger numbers of approved, targeted biologics that are available for rheumatoid arthritis.

Bianca Nogrady/MDedge News

The problem is that placebo response rates in clinical trials for lupus are high – well over 40% – Dr. Merrill said, and trials aren’t showing a big difference in response rates between the treatment and placebo arms. “If the placebo response is 40%, wouldn’t an effective drug help 80%?” she said. “If it also affects only 40%, does that mean it’s a failed drug?”

Dr. Merrill suggested that better patient selection could be key to achieving lower placebo response rates, which could in turn reveal if and in whom a drug might be effective. “If we could get the placebo response rate down, at least we’d be able to see a little bit better whether the drug is effective, even if it only could work in 50% of the patients,” she said.

Data from research done by the Oklahoma Medical Research Foundation suggested that patients with SLE could be loosely categorized into seven different clusters based on patterns of gene expression in areas such as interferon expression and inflammation pathways.

For example, two of those clusters represented patients with high levels of expression for both interferons and inflammation. “Maybe those are the patients who’d want to be put in a trial for interferon inhibition,” Dr. Merrill said.

This was demonstrated in a trial of type 1 interferon inhibitor anifrolumab (Saphnelo), where patients were sorted into groups according to their level of interferon expression – either high or low – based on expression of certain interferon genes. This revealed that patients in the interferon-high group had a much higher treatment effect than patients in the interferon-low group. But the difference lay in the placebo response.

“The efficacy rate was not that different between the interferon-high and the interferon-low patients,” Dr. Merrill said. “The difference was in the placebo response rate – what they had managed to find was a great marker for sicker patients.”

This phenomenon is not limited to interferon-targeted therapies. Dr. Merrill cited another literature review which looked at subset studies within clinical trials that had delivered disappointing results. This showed consistently that patients who were considered more unwell, by virtue of higher SLE Disease Activity Index (SLEDAI) scores, for example, were more likely to show an effect of treatment.

“You begin to see bigger differences between treatment and placebo because the treatment rate might go up, but mostly because the placebo rate goes down,” she said.

Another issue that could be affecting both placebo and treatment response rates is background medication. “Subset analysis of people on less background drugs was showing lower placebo response rates and better differences between treatments and placebo,” Dr. Merrill said. For example, a recent phase 2 study of anifrolumab took the strategy of actively pursuing tapering of glucocorticoids in patients where that could be done safely. That achieved a lowering of the placebo response rate to the point where a greater difference could be seen between the placebo response and the treatment response rates.

The challenge for clinical trials is therefore to identify which patients to include. “If we could figure out which patients would be the most appropriate [to enroll to fit a particular drug’s mechanism of action], then we could really get ahead of the game,” she said.

The unique problem for lupus clinic trials is the heterogeneity of lupus as a disease, Dr. Merrill said in an interview. “We’re going to have to find combinations of treatments that fit right for each patient, and they won’t necessarily be one size fits all,” she said.

Dr. Merrill said that subset analyses at the phase 2 stage could help identify the patients who responded better to the treatment and could therefore be targeted in phase 3 trials. “Once you take that hypothesis, and if you can establish and validate it in phase 3, now you’ve got yourself a biomarker,” she said.

Richard A. Furie, MD, chief of the division of rheumatology at Northwell Health in New York, agreed that the high placebo response rate was a particular nemesis for researchers involved in lupus clinical trials.

Sara Freeman/MDedge News

Dr. Furie said it could be that selecting sicker patients is a solution to this, as had been suggested in the subset analysis of the anifrolumab studies – which he was involved in – that identified differences in the response rates between interferon-high and interferon-low patients.

But if that was the case, the challenge would be recruiting enough of any particular subset of patients. For example, relatively few patients in the anifrolumab trial were classified as interferon low.

If the interferon expression levels are a marker for patients who are sicker, that could serve as a way to better select patients for clinical trials, he said. But it would also make it harder to achieve recruitment targets.

“I think the major problem in SLE trials is that patients have inflated activity scores, so you can gain SLEDAI scores with a little alopecia and an oral ulcer,” he said. “You can start eliminating those parameters from counting towards entry, but then as soon as you do that, you’re going to have trouble recruiting.”

Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and anifrolumab manufacturer AstraZeneca. Dr. Furie reported financial relationships with Genentech/Roche, GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda.

SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).

“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.

Sara Freeman/MDedge News

The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.

It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
 

More potent B-cell depletion with obinutuzumab

Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.

The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.

That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.

“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.

Bianca Nogrady/MDedge News

Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.

Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”

However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.
 

Newer strategies for greater B-cell depletion

A third strategy for achieving greater B-cell depletion is bispecific T-cell engagers, or BiTEs. “I called it a ‘frenemy,’ where it’s taking the activated T cell and introducing it to the B cell, and it can kill it via direct T-cell killing,” Dr. Furie said in an interview. Mosunetuzumab (Lunsumio) is one example, and is currently in a phase 1 clinical trial of patients with SLE.

And the fourth strategy, which has proved so successful in lymphoma, is chimeric antigen receptor T-cell therapy (CAR T). Dr. Furie cited the recent publication of data from a CAR T clinical trial in five patients with refractory SLE. He said the data were impressive but the question for this treatment approach will be which patients are most likely to benefit and whether CAR T will experience the same ceiling effect because of pre-existing kidney damage.

“We won’t be seeing 100% response rates,” he said. “What we’ll be seeing, as a maximum, might be about 70%.” The big question for B-cell depletion in lupus was therefore how best to achieve it. “Is the future a potent monoclonal antibody, or is it in fact CAR T?”

Dr. Merrill said the analyses from B-cell depletion trials, showing greater response rates among more complete depleters, highlighted the importance of a personalized approach to treating lupus.

“One size fits all is never optimal in any disease, but it will prove a nonstarter in lupus, where we ought to be trying to find the optimal treatment regimen for each patient guided by biomarkers,” she said in an interview.

Dr. Furie reported having financial relationships with Genentech/Roche, which manufactures obinutuzumab and rituximab, as well as GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda. Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and AstraZeneca.

SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).

“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.

Sara Freeman/MDedge News

The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.

It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
 

More potent B-cell depletion with obinutuzumab

Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.

The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.

That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.

“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.

Bianca Nogrady/MDedge News

Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.

Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”

However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.
 

Newer strategies for greater B-cell depletion

A third strategy for achieving greater B-cell depletion is bispecific T-cell engagers, or BiTEs. “I called it a ‘frenemy,’ where it’s taking the activated T cell and introducing it to the B cell, and it can kill it via direct T-cell killing,” Dr. Furie said in an interview. Mosunetuzumab (Lunsumio) is one example, and is currently in a phase 1 clinical trial of patients with SLE.

And the fourth strategy, which has proved so successful in lymphoma, is chimeric antigen receptor T-cell therapy (CAR T). Dr. Furie cited the recent publication of data from a CAR T clinical trial in five patients with refractory SLE. He said the data were impressive but the question for this treatment approach will be which patients are most likely to benefit and whether CAR T will experience the same ceiling effect because of pre-existing kidney damage.

“We won’t be seeing 100% response rates,” he said. “What we’ll be seeing, as a maximum, might be about 70%.” The big question for B-cell depletion in lupus was therefore how best to achieve it. “Is the future a potent monoclonal antibody, or is it in fact CAR T?”

Dr. Merrill said the analyses from B-cell depletion trials, showing greater response rates among more complete depleters, highlighted the importance of a personalized approach to treating lupus.

“One size fits all is never optimal in any disease, but it will prove a nonstarter in lupus, where we ought to be trying to find the optimal treatment regimen for each patient guided by biomarkers,” she said in an interview.

Dr. Furie reported having financial relationships with Genentech/Roche, which manufactures obinutuzumab and rituximab, as well as GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda. Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and AstraZeneca.

SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).

“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.

Sara Freeman/MDedge News

The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.

It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
 

More potent B-cell depletion with obinutuzumab

Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.

The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.

That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.

“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.

Bianca Nogrady/MDedge News

Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.

Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”

However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.
 

Newer strategies for greater B-cell depletion

A third strategy for achieving greater B-cell depletion is bispecific T-cell engagers, or BiTEs. “I called it a ‘frenemy,’ where it’s taking the activated T cell and introducing it to the B cell, and it can kill it via direct T-cell killing,” Dr. Furie said in an interview. Mosunetuzumab (Lunsumio) is one example, and is currently in a phase 1 clinical trial of patients with SLE.

And the fourth strategy, which has proved so successful in lymphoma, is chimeric antigen receptor T-cell therapy (CAR T). Dr. Furie cited the recent publication of data from a CAR T clinical trial in five patients with refractory SLE. He said the data were impressive but the question for this treatment approach will be which patients are most likely to benefit and whether CAR T will experience the same ceiling effect because of pre-existing kidney damage.

“We won’t be seeing 100% response rates,” he said. “What we’ll be seeing, as a maximum, might be about 70%.” The big question for B-cell depletion in lupus was therefore how best to achieve it. “Is the future a potent monoclonal antibody, or is it in fact CAR T?”

Dr. Merrill said the analyses from B-cell depletion trials, showing greater response rates among more complete depleters, highlighted the importance of a personalized approach to treating lupus.

“One size fits all is never optimal in any disease, but it will prove a nonstarter in lupus, where we ought to be trying to find the optimal treatment regimen for each patient guided by biomarkers,” she said in an interview.

Dr. Furie reported having financial relationships with Genentech/Roche, which manufactures obinutuzumab and rituximab, as well as GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda. Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and AstraZeneca.

SEOUL, SOUTH KOREA – A once-daily, oral dose of the investigational drug cenerimod, developed for the treatment of systemic lupus erythematosus, has shown a greater response rate among individuals with more severe disease, according to data presented at an international congress on SLE.

Cenerimod is a potent, highly-selective sphingosine 1–phosphate receptor 1 (S1P1) modulator with attenuated calcium signaling, which targets an important signaling molecule in immunity and cell migration, said rheumatologist Sandra Navarra, MD, of the University of Santo Tomas Hospital and St. Luke’s Medical Center in Manila, Philippines.

SEOUL, SOUTH KOREA – A once-daily, oral dose of the investigational drug cenerimod, developed for the treatment of systemic lupus erythematosus, has shown a greater response rate among individuals with more severe disease, according to data presented at an international congress on SLE.

Cenerimod is a potent, highly-selective sphingosine 1–phosphate receptor 1 (S1P1) modulator with attenuated calcium signaling, which targets an important signaling molecule in immunity and cell migration, said rheumatologist Sandra Navarra, MD, of the University of Santo Tomas Hospital and St. Luke’s Medical Center in Manila, Philippines.

SEOUL, SOUTH KOREA – A once-daily, oral dose of the investigational drug cenerimod, developed for the treatment of systemic lupus erythematosus, has shown a greater response rate among individuals with more severe disease, according to data presented at an international congress on SLE.

Cenerimod is a potent, highly-selective sphingosine 1–phosphate receptor 1 (S1P1) modulator with attenuated calcium signaling, which targets an important signaling molecule in immunity and cell migration, said rheumatologist Sandra Navarra, MD, of the University of Santo Tomas Hospital and St. Luke’s Medical Center in Manila, Philippines.

SEOUL, SOUTH KOREA – Regular testing of hydroxychloroquine levels in patients with systemic lupus erythematosus – especially those who are experiencing a disease flare – could help to identify patients who are not taking their treatment and are at risk of worse outcomes.

Data presented at an international congress on systemic lupus erythematosus showed that 7.3% of patients with SLE are severely nonadherent to their medication and have a higher risk of flare, early damage, and mortality.

Rheumatologist Nathalie Costedoat-Chalumeau, MD, PhD, professor of internal medicine at Cochin Hospital, Paris, presented data from 660 patients enrolled in the international longitudinal SLICC Inception Cohort, who had all been on hydroxychloroquine therapy for at least 3 months at baseline.

Bianca Nogrady/MDedge News

Patients’ serum hydroxychloroquine levels were measured at baseline and follow-up, and severe nonadherence was defined as below 106 ng/mL for those on 400 mg/day or 53 ng/mL for those on 200 mg/day.

Dr. Costedoat-Chalumeau said that those thresholds were chosen based on earlier work that analyzed the blood concentration of hydroxychloroquine in a group of patients and identified a group with very low concentrations corresponding to severe nonadherence.

“Since then, it has been reproduced by others with the same threshold,” she said. “When you have very low levels of hydroxychloroquine in their blood, you know that your patients don’t take their treatment.”

In the present study, the 7.3% of patients who met the criteria for severe nonadherence had a significant 3.3-fold higher risk of disease flare within a year of enrollment than did those who were adherent. They also had significantly higher mortality at 5 years after enrollment.

While the study didn’t show a significant difference in the level of damage at 5 years – defined as a worsening of their SLICC damage index – Dr. Costedoat-Chalumeau said they saw significantly greater damage occurring at 1, 2, and 3 years after enrollment among those who were severely nonadherent.

The challenge with recognizing these nonadherent patients is that they have no obvious differences at baseline from those who are adherent, Dr. Costedoat-Chalumeau said. The rates of nonadherence were similar regardless of what dose the patient was on, their ethnicity, gender, education level, or other demographic variables.

“I believe strongly that there is a benefit of testing hydroxychloroquine levels in the blood or serum to detect severe nonadherence,” she said.

At Dr. Costedoat-Chalumeau’s clinic, patients’ hydroxychloroquine levels are tested at every clinic visit, she said in an interview, and especially if they are experiencing a disease flare. “We want to know if the flare is because the patient is not taking the treatment or if it’s because the treatment is not effective, which is very different in terms of management,” she said. She recommended waiting at least 1 month after patients start treatment before measuring their hydroxychloroquine levels.

As to why some patients choose to stop taking their medication, Dr. Costedoat-Chalumeau said sometimes it was because patients were worried about side effects, but others were also unclear about why they needed to keep taking hydroxychloroquine.

“They think steroids are effective because when they take it they are better, but they don’t see the effect of hydroxychloroquine,” she said. “You have to explain that it doesn’t work the same.”

Commenting on the findings, session chair Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data show that severe nonadherence does have prognostic significance. “Many patients with SLE have low-grade disease or inflammation in the blood vessels that may not be clinically apparent and which hydroxychloroquine can help, so it might be wise to routinely get blood levels,” she said.

Dr. Costedoat-Chalumeau reported no relevant financial relationships apart from unrestricted institutional research grants from UCB and Roche.

SEOUL, SOUTH KOREA – Regular testing of hydroxychloroquine levels in patients with systemic lupus erythematosus – especially those who are experiencing a disease flare – could help to identify patients who are not taking their treatment and are at risk of worse outcomes.

Data presented at an international congress on systemic lupus erythematosus showed that 7.3% of patients with SLE are severely nonadherent to their medication and have a higher risk of flare, early damage, and mortality.

Rheumatologist Nathalie Costedoat-Chalumeau, MD, PhD, professor of internal medicine at Cochin Hospital, Paris, presented data from 660 patients enrolled in the international longitudinal SLICC Inception Cohort, who had all been on hydroxychloroquine therapy for at least 3 months at baseline.

Bianca Nogrady/MDedge News

Patients’ serum hydroxychloroquine levels were measured at baseline and follow-up, and severe nonadherence was defined as below 106 ng/mL for those on 400 mg/day or 53 ng/mL for those on 200 mg/day.

Dr. Costedoat-Chalumeau said that those thresholds were chosen based on earlier work that analyzed the blood concentration of hydroxychloroquine in a group of patients and identified a group with very low concentrations corresponding to severe nonadherence.

“Since then, it has been reproduced by others with the same threshold,” she said. “When you have very low levels of hydroxychloroquine in their blood, you know that your patients don’t take their treatment.”

In the present study, the 7.3% of patients who met the criteria for severe nonadherence had a significant 3.3-fold higher risk of disease flare within a year of enrollment than did those who were adherent. They also had significantly higher mortality at 5 years after enrollment.

While the study didn’t show a significant difference in the level of damage at 5 years – defined as a worsening of their SLICC damage index – Dr. Costedoat-Chalumeau said they saw significantly greater damage occurring at 1, 2, and 3 years after enrollment among those who were severely nonadherent.

The challenge with recognizing these nonadherent patients is that they have no obvious differences at baseline from those who are adherent, Dr. Costedoat-Chalumeau said. The rates of nonadherence were similar regardless of what dose the patient was on, their ethnicity, gender, education level, or other demographic variables.

“I believe strongly that there is a benefit of testing hydroxychloroquine levels in the blood or serum to detect severe nonadherence,” she said.

At Dr. Costedoat-Chalumeau’s clinic, patients’ hydroxychloroquine levels are tested at every clinic visit, she said in an interview, and especially if they are experiencing a disease flare. “We want to know if the flare is because the patient is not taking the treatment or if it’s because the treatment is not effective, which is very different in terms of management,” she said. She recommended waiting at least 1 month after patients start treatment before measuring their hydroxychloroquine levels.

As to why some patients choose to stop taking their medication, Dr. Costedoat-Chalumeau said sometimes it was because patients were worried about side effects, but others were also unclear about why they needed to keep taking hydroxychloroquine.

“They think steroids are effective because when they take it they are better, but they don’t see the effect of hydroxychloroquine,” she said. “You have to explain that it doesn’t work the same.”

Commenting on the findings, session chair Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data show that severe nonadherence does have prognostic significance. “Many patients with SLE have low-grade disease or inflammation in the blood vessels that may not be clinically apparent and which hydroxychloroquine can help, so it might be wise to routinely get blood levels,” she said.

Dr. Costedoat-Chalumeau reported no relevant financial relationships apart from unrestricted institutional research grants from UCB and Roche.

SEOUL, SOUTH KOREA – Regular testing of hydroxychloroquine levels in patients with systemic lupus erythematosus – especially those who are experiencing a disease flare – could help to identify patients who are not taking their treatment and are at risk of worse outcomes.

Data presented at an international congress on systemic lupus erythematosus showed that 7.3% of patients with SLE are severely nonadherent to their medication and have a higher risk of flare, early damage, and mortality.

Rheumatologist Nathalie Costedoat-Chalumeau, MD, PhD, professor of internal medicine at Cochin Hospital, Paris, presented data from 660 patients enrolled in the international longitudinal SLICC Inception Cohort, who had all been on hydroxychloroquine therapy for at least 3 months at baseline.

Bianca Nogrady/MDedge News

Patients’ serum hydroxychloroquine levels were measured at baseline and follow-up, and severe nonadherence was defined as below 106 ng/mL for those on 400 mg/day or 53 ng/mL for those on 200 mg/day.

Dr. Costedoat-Chalumeau said that those thresholds were chosen based on earlier work that analyzed the blood concentration of hydroxychloroquine in a group of patients and identified a group with very low concentrations corresponding to severe nonadherence.

“Since then, it has been reproduced by others with the same threshold,” she said. “When you have very low levels of hydroxychloroquine in their blood, you know that your patients don’t take their treatment.”

In the present study, the 7.3% of patients who met the criteria for severe nonadherence had a significant 3.3-fold higher risk of disease flare within a year of enrollment than did those who were adherent. They also had significantly higher mortality at 5 years after enrollment.

While the study didn’t show a significant difference in the level of damage at 5 years – defined as a worsening of their SLICC damage index – Dr. Costedoat-Chalumeau said they saw significantly greater damage occurring at 1, 2, and 3 years after enrollment among those who were severely nonadherent.

The challenge with recognizing these nonadherent patients is that they have no obvious differences at baseline from those who are adherent, Dr. Costedoat-Chalumeau said. The rates of nonadherence were similar regardless of what dose the patient was on, their ethnicity, gender, education level, or other demographic variables.

“I believe strongly that there is a benefit of testing hydroxychloroquine levels in the blood or serum to detect severe nonadherence,” she said.

At Dr. Costedoat-Chalumeau’s clinic, patients’ hydroxychloroquine levels are tested at every clinic visit, she said in an interview, and especially if they are experiencing a disease flare. “We want to know if the flare is because the patient is not taking the treatment or if it’s because the treatment is not effective, which is very different in terms of management,” she said. She recommended waiting at least 1 month after patients start treatment before measuring their hydroxychloroquine levels.

As to why some patients choose to stop taking their medication, Dr. Costedoat-Chalumeau said sometimes it was because patients were worried about side effects, but others were also unclear about why they needed to keep taking hydroxychloroquine.

“They think steroids are effective because when they take it they are better, but they don’t see the effect of hydroxychloroquine,” she said. “You have to explain that it doesn’t work the same.”

Commenting on the findings, session chair Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data show that severe nonadherence does have prognostic significance. “Many patients with SLE have low-grade disease or inflammation in the blood vessels that may not be clinically apparent and which hydroxychloroquine can help, so it might be wise to routinely get blood levels,” she said.

Dr. Costedoat-Chalumeau reported no relevant financial relationships apart from unrestricted institutional research grants from UCB and Roche.

SEOUL, SOUTH KOREA – Nearly 8% of people with lupus nephritis who achieve complete remission of disease within 1 year of starting treatment will still go on to develop advanced chronic kidney disease (CKD), according to a presentation at an international congress on systemic lupus erythematosus.

Rheumatologist Dafna Gladman, MD, professor of medicine at the University of Toronto and codirector of the Lupus Clinic at Toronto Western Hospital, showed data from the Lupus Clinic’s prospective longitudinal cohort study in 273 patients with confirmed lupus nephritis who achieved complete remission within 12 months of baseline.

Bianca Nogrady/MDedge News

Remission was defined as less than 0.5 g proteinuria over 24 hours, inactive urinary sediment, and serum creatinine less than 120% of baseline.

Of this group, 21 (7.7%) progressed to advanced CKD during follow-up, which ranged from 0.7 to 31.7 years with a median of 5.8 years, after enrollment.

Patients who had experienced at least one flare during their first 5 years were around 4.5 times more likely to progress to advanced CKD than were those who did not experience a flare.

While the study excluded patients who already had advanced CKD, the analysis found those with evidence of impaired kidney function at baseline also had more than a fourfold higher risk of developing advanced CKD.

Other significant risk factors for progression were having low complement C3 levels at baseline and having had a longer duration of disease before enrollment.

“Those patients already have abnormal renal function, so the message is that patients who are already in trouble, you’ve got to watch them very carefully,” Dr. Gladman said in an interview.

The study also looked at whether there was a difference between patients who developed advanced CKD earlier – before the median of 5.8 years – or later. While the numbers were small, Dr. Gladman said patients who progressed earlier tended to be older and were more likely to be on antihypertensive treatment and have lower estimated glomerular filtration rate and a lower Systemic Lupus Erythematosus Disease Activity Index–2K, compared with those who progressed later. Some patients also were noncompliant and/or experienced concomitant infections; four had moderate to severe interstitial fibrosis and tubular atrophy.

“We conclude that such patients should be monitored closely despite early remission, and we also highlight the importance of maintenance therapy, which should be communicated to the patients to prevent noncompliance and subsequent flare,” Dr. Gladman told the conference.

Dr. Gladman said her clinic told patients from the very beginning of their treatment that they would need to be seen at 2- to 6-month intervals, regardless of how well their disease was doing.

Commenting on the presentation, rheumatologist Mandana Nikpour MD, PhD, of St. Vincent’s Hospital in Melbourne, said the findings showed the importance of keeping a close eye on patients with lupus nephritis, even if their disease appears to be in remission.

“If you’ve had nephritis, and you go into remission, you may already have a degree of damage in your kidneys,” said Dr. Nikpour, also from the University of Melbourne. “If there’s a degree of uncontrolled hypertension, or if a patient is noncompliant with their treatment, and there’s a degree of grumbling disease activity, that can all conspire and add up to result in long-term kidney damage and loss of renal function.”

Dr. Gladman has received grants or research support from, or has consulted for, Amgen, AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Bristol-Myers Squibb, Galapagos, and Gilead.

SEOUL, SOUTH KOREA – Nearly 8% of people with lupus nephritis who achieve complete remission of disease within 1 year of starting treatment will still go on to develop advanced chronic kidney disease (CKD), according to a presentation at an international congress on systemic lupus erythematosus.

Rheumatologist Dafna Gladman, MD, professor of medicine at the University of Toronto and codirector of the Lupus Clinic at Toronto Western Hospital, showed data from the Lupus Clinic’s prospective longitudinal cohort study in 273 patients with confirmed lupus nephritis who achieved complete remission within 12 months of baseline.

Bianca Nogrady/MDedge News

Remission was defined as less than 0.5 g proteinuria over 24 hours, inactive urinary sediment, and serum creatinine less than 120% of baseline.

Of this group, 21 (7.7%) progressed to advanced CKD during follow-up, which ranged from 0.7 to 31.7 years with a median of 5.8 years, after enrollment.

Patients who had experienced at least one flare during their first 5 years were around 4.5 times more likely to progress to advanced CKD than were those who did not experience a flare.

While the study excluded patients who already had advanced CKD, the analysis found those with evidence of impaired kidney function at baseline also had more than a fourfold higher risk of developing advanced CKD.

Other significant risk factors for progression were having low complement C3 levels at baseline and having had a longer duration of disease before enrollment.

“Those patients already have abnormal renal function, so the message is that patients who are already in trouble, you’ve got to watch them very carefully,” Dr. Gladman said in an interview.

The study also looked at whether there was a difference between patients who developed advanced CKD earlier – before the median of 5.8 years – or later. While the numbers were small, Dr. Gladman said patients who progressed earlier tended to be older and were more likely to be on antihypertensive treatment and have lower estimated glomerular filtration rate and a lower Systemic Lupus Erythematosus Disease Activity Index–2K, compared with those who progressed later. Some patients also were noncompliant and/or experienced concomitant infections; four had moderate to severe interstitial fibrosis and tubular atrophy.

“We conclude that such patients should be monitored closely despite early remission, and we also highlight the importance of maintenance therapy, which should be communicated to the patients to prevent noncompliance and subsequent flare,” Dr. Gladman told the conference.

Dr. Gladman said her clinic told patients from the very beginning of their treatment that they would need to be seen at 2- to 6-month intervals, regardless of how well their disease was doing.

Commenting on the presentation, rheumatologist Mandana Nikpour MD, PhD, of St. Vincent’s Hospital in Melbourne, said the findings showed the importance of keeping a close eye on patients with lupus nephritis, even if their disease appears to be in remission.

“If you’ve had nephritis, and you go into remission, you may already have a degree of damage in your kidneys,” said Dr. Nikpour, also from the University of Melbourne. “If there’s a degree of uncontrolled hypertension, or if a patient is noncompliant with their treatment, and there’s a degree of grumbling disease activity, that can all conspire and add up to result in long-term kidney damage and loss of renal function.”

Dr. Gladman has received grants or research support from, or has consulted for, Amgen, AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Bristol-Myers Squibb, Galapagos, and Gilead.

SEOUL, SOUTH KOREA – Nearly 8% of people with lupus nephritis who achieve complete remission of disease within 1 year of starting treatment will still go on to develop advanced chronic kidney disease (CKD), according to a presentation at an international congress on systemic lupus erythematosus.

Rheumatologist Dafna Gladman, MD, professor of medicine at the University of Toronto and codirector of the Lupus Clinic at Toronto Western Hospital, showed data from the Lupus Clinic’s prospective longitudinal cohort study in 273 patients with confirmed lupus nephritis who achieved complete remission within 12 months of baseline.

Bianca Nogrady/MDedge News

Remission was defined as less than 0.5 g proteinuria over 24 hours, inactive urinary sediment, and serum creatinine less than 120% of baseline.

Of this group, 21 (7.7%) progressed to advanced CKD during follow-up, which ranged from 0.7 to 31.7 years with a median of 5.8 years, after enrollment.

Patients who had experienced at least one flare during their first 5 years were around 4.5 times more likely to progress to advanced CKD than were those who did not experience a flare.

While the study excluded patients who already had advanced CKD, the analysis found those with evidence of impaired kidney function at baseline also had more than a fourfold higher risk of developing advanced CKD.

Other significant risk factors for progression were having low complement C3 levels at baseline and having had a longer duration of disease before enrollment.

“Those patients already have abnormal renal function, so the message is that patients who are already in trouble, you’ve got to watch them very carefully,” Dr. Gladman said in an interview.

The study also looked at whether there was a difference between patients who developed advanced CKD earlier – before the median of 5.8 years – or later. While the numbers were small, Dr. Gladman said patients who progressed earlier tended to be older and were more likely to be on antihypertensive treatment and have lower estimated glomerular filtration rate and a lower Systemic Lupus Erythematosus Disease Activity Index–2K, compared with those who progressed later. Some patients also were noncompliant and/or experienced concomitant infections; four had moderate to severe interstitial fibrosis and tubular atrophy.

“We conclude that such patients should be monitored closely despite early remission, and we also highlight the importance of maintenance therapy, which should be communicated to the patients to prevent noncompliance and subsequent flare,” Dr. Gladman told the conference.

Dr. Gladman said her clinic told patients from the very beginning of their treatment that they would need to be seen at 2- to 6-month intervals, regardless of how well their disease was doing.

Commenting on the presentation, rheumatologist Mandana Nikpour MD, PhD, of St. Vincent’s Hospital in Melbourne, said the findings showed the importance of keeping a close eye on patients with lupus nephritis, even if their disease appears to be in remission.

“If you’ve had nephritis, and you go into remission, you may already have a degree of damage in your kidneys,” said Dr. Nikpour, also from the University of Melbourne. “If there’s a degree of uncontrolled hypertension, or if a patient is noncompliant with their treatment, and there’s a degree of grumbling disease activity, that can all conspire and add up to result in long-term kidney damage and loss of renal function.”

Dr. Gladman has received grants or research support from, or has consulted for, Amgen, AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Bristol-Myers Squibb, Galapagos, and Gilead.

SEOUL, SOUTH KOREA – A panel of urinary biomarkers may do better than measuring proteinuria in predicting which patients with lupus nephritis are going to respond to treatment, according to a presentation at an international congress on systemic lupus erythematosus.

Physician-scientist Andrea Fava, MD, of the division of rheumatology at Johns Hopkins University, Baltimore, presented data from a study using urine proteomics to identify biomarkers present in the urine of patients with lupus nephritis at 3 months after starting treatment that were linked to better outcomes from that treatment at 1 year.

While proteinuria is the standard measure used to guide decisions about whether to do a kidney biopsy and how to treat lupus nephritis, it doesn’t always correlate with what’s actually going on inside the kidney in terms of histology and inflammation, Dr. Fava said.

Bianca Nogrady/MDedge News

He pointed to an earlier study in which researchers did kidney biopsies 6 months after patients with lupus nephritis started treatment with mycophenolate. This suggested that around half of patients who showed a clinical response to treatment – defined as proteinuria below 500 mg/day – still had significant histologic disease activity. Another study suggested that this elevated histologic disease activity is associated with a risk of flare, which can result in significant nephron loss. On the flip side, nearly two-thirds of patients in complete histologic remission still had elevated proteinuria.

Unfortunately, it’s not possible or practical to biopsy patients on a regular basis, Dr. Fava said. “So we need better biomarkers, and to do so, we need better knowledge of the pathophysiology because if we have biomarkers that reflect tissue biology in real-time, that may surely guide personalized treatments,” he said at the congress.

Dr. Fava and colleagues enrolled 225 patients with SLE who were undergoing kidney biopsy and 10 healthy controls and used proteomics to quantify the urinary levels of around 1,200 proteins at baseline, 3, 6, and 12 months after initiating treatment.

The team then analyzed these data to look for protein signatures that correlated with histologic phenotypes – particularly the amount of inflammation in the kidney – and clinical features such as response to treatment.

They found several protein biomarkers that appeared to be linked to histologic activity in the kidney, including interleukin (IL)-16, CD163, and neutrophil granule proteins.

Initially, the team looked at baseline levels of these proteins to see if they predicted who responded to treatment, but found no difference between responders and nonresponders.

However, when they looked at levels at 3 months after treatment, a pattern emerged. “We found that in patients who were not responding, there were no changes after 3 months of treatment in the urine proteome,” Dr. Fava said. Among those who did respond to treatment, the levels of these proteins – IL-16, CD163, galectin-1, and CD206 – decreased significantly.

“So the proteins that are linked to renal activity decrease only in responders, suggesting that effective immunosuppression is effective in reducing intrarenal inflammation, which eventually results in low proteinuria at 1 year.”

The decline in these biomarkers persisted at 1 year, and the study suggested it was a better predictor of which patients would respond to treatment at 1 year than proteinuria.

Dr. Fava said in an interview that better biomarkers could revolutionize the treatment and management of lupus nephritis.

“First of all, it can shift the management strategy from treatment to prevention, because at the very beginning we can nip it in the bud maybe with very gentle treatment,” he said. Different panels of urine biomarkers could identify patients at risk of treatment failure, and also help patients to taper off their immunosuppressive therapy without an increased risk of flare. “If we have a way to tell us there’s still inflammation that needs treatment, that could change the way we do it,” he said.

He acknowledged there are significant challenges to developing these biomarkers for clinical use; one is the decision of how to define disease activity without relying on proteinuria as a measure. “Why do I want a biomarker that can predict another biomarker?” he said.

Another presentation during the same session, by Huihua Ding, MD, of Shanghai Jiao Tong University in Shanghai, China, reported on the use of urinary L-selectin to assess renal disease activity and response to treatment in a multiethnic cohort.

This study, involving 474 patients with SLE with or without renal involvement in the United States and China, found levels of urinary L-selectin were elevated only in patients with active lupus nephritis and showed patterns that correlated with renal histologic characteristics.

Clinical rheumatologist Eric F. Morand, MD, PhD, and head of the School of Clinical Sciences at Monash University in Melbourne said one challenge with using urinary biomarkers was that it was not yet clear what these biomarkers reveal about the kidney. “It will be important to see whether this proteomic data actually link to renal outcomes,” Dr. Morand said in an interview. “I think predicting the response to treatment should be based around GFR [glomerular filtration rate] preservation, and I don’t think I’ve seen data yet that the urine biomarkers are going to tell us how to do that better.”

Dr. Morand is optimistic that urine biomarkers will one day be able to achieve that, but he stressed the importance of having urine biomarker tests available in the field at low cost. “You’re going to be doing the tests repeatedly, so therefore, you’re probably going to need to come down to a smaller list of proteins that you measure.”

Dr. Fava reported receiving support from Sanofi and Annexion Bio.

SEOUL, SOUTH KOREA – A panel of urinary biomarkers may do better than measuring proteinuria in predicting which patients with lupus nephritis are going to respond to treatment, according to a presentation at an international congress on systemic lupus erythematosus.

Physician-scientist Andrea Fava, MD, of the division of rheumatology at Johns Hopkins University, Baltimore, presented data from a study using urine proteomics to identify biomarkers present in the urine of patients with lupus nephritis at 3 months after starting treatment that were linked to better outcomes from that treatment at 1 year.

While proteinuria is the standard measure used to guide decisions about whether to do a kidney biopsy and how to treat lupus nephritis, it doesn’t always correlate with what’s actually going on inside the kidney in terms of histology and inflammation, Dr. Fava said.

Bianca Nogrady/MDedge News

He pointed to an earlier study in which researchers did kidney biopsies 6 months after patients with lupus nephritis started treatment with mycophenolate. This suggested that around half of patients who showed a clinical response to treatment – defined as proteinuria below 500 mg/day – still had significant histologic disease activity. Another study suggested that this elevated histologic disease activity is associated with a risk of flare, which can result in significant nephron loss. On the flip side, nearly two-thirds of patients in complete histologic remission still had elevated proteinuria.

Unfortunately, it’s not possible or practical to biopsy patients on a regular basis, Dr. Fava said. “So we need better biomarkers, and to do so, we need better knowledge of the pathophysiology because if we have biomarkers that reflect tissue biology in real-time, that may surely guide personalized treatments,” he said at the congress.

Dr. Fava and colleagues enrolled 225 patients with SLE who were undergoing kidney biopsy and 10 healthy controls and used proteomics to quantify the urinary levels of around 1,200 proteins at baseline, 3, 6, and 12 months after initiating treatment.

The team then analyzed these data to look for protein signatures that correlated with histologic phenotypes – particularly the amount of inflammation in the kidney – and clinical features such as response to treatment.

They found several protein biomarkers that appeared to be linked to histologic activity in the kidney, including interleukin (IL)-16, CD163, and neutrophil granule proteins.

Initially, the team looked at baseline levels of these proteins to see if they predicted who responded to treatment, but found no difference between responders and nonresponders.

However, when they looked at levels at 3 months after treatment, a pattern emerged. “We found that in patients who were not responding, there were no changes after 3 months of treatment in the urine proteome,” Dr. Fava said. Among those who did respond to treatment, the levels of these proteins – IL-16, CD163, galectin-1, and CD206 – decreased significantly.

“So the proteins that are linked to renal activity decrease only in responders, suggesting that effective immunosuppression is effective in reducing intrarenal inflammation, which eventually results in low proteinuria at 1 year.”

The decline in these biomarkers persisted at 1 year, and the study suggested it was a better predictor of which patients would respond to treatment at 1 year than proteinuria.

Dr. Fava said in an interview that better biomarkers could revolutionize the treatment and management of lupus nephritis.

“First of all, it can shift the management strategy from treatment to prevention, because at the very beginning we can nip it in the bud maybe with very gentle treatment,” he said. Different panels of urine biomarkers could identify patients at risk of treatment failure, and also help patients to taper off their immunosuppressive therapy without an increased risk of flare. “If we have a way to tell us there’s still inflammation that needs treatment, that could change the way we do it,” he said.

He acknowledged there are significant challenges to developing these biomarkers for clinical use; one is the decision of how to define disease activity without relying on proteinuria as a measure. “Why do I want a biomarker that can predict another biomarker?” he said.

Another presentation during the same session, by Huihua Ding, MD, of Shanghai Jiao Tong University in Shanghai, China, reported on the use of urinary L-selectin to assess renal disease activity and response to treatment in a multiethnic cohort.

This study, involving 474 patients with SLE with or without renal involvement in the United States and China, found levels of urinary L-selectin were elevated only in patients with active lupus nephritis and showed patterns that correlated with renal histologic characteristics.

Clinical rheumatologist Eric F. Morand, MD, PhD, and head of the School of Clinical Sciences at Monash University in Melbourne said one challenge with using urinary biomarkers was that it was not yet clear what these biomarkers reveal about the kidney. “It will be important to see whether this proteomic data actually link to renal outcomes,” Dr. Morand said in an interview. “I think predicting the response to treatment should be based around GFR [glomerular filtration rate] preservation, and I don’t think I’ve seen data yet that the urine biomarkers are going to tell us how to do that better.”

Dr. Morand is optimistic that urine biomarkers will one day be able to achieve that, but he stressed the importance of having urine biomarker tests available in the field at low cost. “You’re going to be doing the tests repeatedly, so therefore, you’re probably going to need to come down to a smaller list of proteins that you measure.”

Dr. Fava reported receiving support from Sanofi and Annexion Bio.

SEOUL, SOUTH KOREA – A panel of urinary biomarkers may do better than measuring proteinuria in predicting which patients with lupus nephritis are going to respond to treatment, according to a presentation at an international congress on systemic lupus erythematosus.

Physician-scientist Andrea Fava, MD, of the division of rheumatology at Johns Hopkins University, Baltimore, presented data from a study using urine proteomics to identify biomarkers present in the urine of patients with lupus nephritis at 3 months after starting treatment that were linked to better outcomes from that treatment at 1 year.

While proteinuria is the standard measure used to guide decisions about whether to do a kidney biopsy and how to treat lupus nephritis, it doesn’t always correlate with what’s actually going on inside the kidney in terms of histology and inflammation, Dr. Fava said.

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He pointed to an earlier study in which researchers did kidney biopsies 6 months after patients with lupus nephritis started treatment with mycophenolate. This suggested that around half of patients who showed a clinical response to treatment – defined as proteinuria below 500 mg/day – still had significant histologic disease activity. Another study suggested that this elevated histologic disease activity is associated with a risk of flare, which can result in significant nephron loss. On the flip side, nearly two-thirds of patients in complete histologic remission still had elevated proteinuria.

Unfortunately, it’s not possible or practical to biopsy patients on a regular basis, Dr. Fava said. “So we need better biomarkers, and to do so, we need better knowledge of the pathophysiology because if we have biomarkers that reflect tissue biology in real-time, that may surely guide personalized treatments,” he said at the congress.

Dr. Fava and colleagues enrolled 225 patients with SLE who were undergoing kidney biopsy and 10 healthy controls and used proteomics to quantify the urinary levels of around 1,200 proteins at baseline, 3, 6, and 12 months after initiating treatment.

The team then analyzed these data to look for protein signatures that correlated with histologic phenotypes – particularly the amount of inflammation in the kidney – and clinical features such as response to treatment.

They found several protein biomarkers that appeared to be linked to histologic activity in the kidney, including interleukin (IL)-16, CD163, and neutrophil granule proteins.

Initially, the team looked at baseline levels of these proteins to see if they predicted who responded to treatment, but found no difference between responders and nonresponders.

However, when they looked at levels at 3 months after treatment, a pattern emerged. “We found that in patients who were not responding, there were no changes after 3 months of treatment in the urine proteome,” Dr. Fava said. Among those who did respond to treatment, the levels of these proteins – IL-16, CD163, galectin-1, and CD206 – decreased significantly.

“So the proteins that are linked to renal activity decrease only in responders, suggesting that effective immunosuppression is effective in reducing intrarenal inflammation, which eventually results in low proteinuria at 1 year.”

The decline in these biomarkers persisted at 1 year, and the study suggested it was a better predictor of which patients would respond to treatment at 1 year than proteinuria.

Dr. Fava said in an interview that better biomarkers could revolutionize the treatment and management of lupus nephritis.

“First of all, it can shift the management strategy from treatment to prevention, because at the very beginning we can nip it in the bud maybe with very gentle treatment,” he said. Different panels of urine biomarkers could identify patients at risk of treatment failure, and also help patients to taper off their immunosuppressive therapy without an increased risk of flare. “If we have a way to tell us there’s still inflammation that needs treatment, that could change the way we do it,” he said.

He acknowledged there are significant challenges to developing these biomarkers for clinical use; one is the decision of how to define disease activity without relying on proteinuria as a measure. “Why do I want a biomarker that can predict another biomarker?” he said.

Another presentation during the same session, by Huihua Ding, MD, of Shanghai Jiao Tong University in Shanghai, China, reported on the use of urinary L-selectin to assess renal disease activity and response to treatment in a multiethnic cohort.

This study, involving 474 patients with SLE with or without renal involvement in the United States and China, found levels of urinary L-selectin were elevated only in patients with active lupus nephritis and showed patterns that correlated with renal histologic characteristics.

Clinical rheumatologist Eric F. Morand, MD, PhD, and head of the School of Clinical Sciences at Monash University in Melbourne said one challenge with using urinary biomarkers was that it was not yet clear what these biomarkers reveal about the kidney. “It will be important to see whether this proteomic data actually link to renal outcomes,” Dr. Morand said in an interview. “I think predicting the response to treatment should be based around GFR [glomerular filtration rate] preservation, and I don’t think I’ve seen data yet that the urine biomarkers are going to tell us how to do that better.”

Dr. Morand is optimistic that urine biomarkers will one day be able to achieve that, but he stressed the importance of having urine biomarker tests available in the field at low cost. “You’re going to be doing the tests repeatedly, so therefore, you’re probably going to need to come down to a smaller list of proteins that you measure.”

Dr. Fava reported receiving support from Sanofi and Annexion Bio.