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Autoantibodies could help predict cancer risk in scleroderma
TOPLINE:
METHODOLOGY:
- Included patients from the Johns Hopkins Scleroderma Center Research Registry and the University of Pittsburgh Scleroderma Center, Pittsburgh.
- A total of 676 patients with scleroderma and a history of cancer were compared with 687 control patients with scleroderma but without a history of cancer.
- Serum tested via line blot and enzyme-linked immunosorbent assay for an array of scleroderma autoantibodies.
- Examined association between autoantibodies and overall cancer risk.
TAKEAWAYS:
- Anti-POLR3 and monospecific anti-Ro52 were associated with significantly increased overall cancer risk.
- Anti-centromere and anti-U1RNP were associated with a decreased cancer risk.
- These associations remained when looking specifically at cancer-associated scleroderma.
- Patients positive for anti-Ro52 in combination with either anti-U1RNP or anti-Th/To had a decreased risk of cancer, compared with those who had anti-Ro52 alone.
IN PRACTICE:
This study is too preliminary to have practice application.
SOURCE:
Ji Soo Kim, PhD, of John Hopkins University, Baltimore, was the first author of the study, published in Arthritis & Rheumatology on July 24, 2023. Fellow Johns Hopkins researchers Livia Casciola-Rosen, PhD, and Ami A. Shah, MD, were joint senior authors.
DISCLOSURES:
The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Martha McCrory Professorship, and the Johns Hopkins inHealth initiative. The authors disclosed the following patents or patent applications: Autoimmune Antigens and Cancer, Materials and Methods for Assessing Cancer Risk and Treating Cancer.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Included patients from the Johns Hopkins Scleroderma Center Research Registry and the University of Pittsburgh Scleroderma Center, Pittsburgh.
- A total of 676 patients with scleroderma and a history of cancer were compared with 687 control patients with scleroderma but without a history of cancer.
- Serum tested via line blot and enzyme-linked immunosorbent assay for an array of scleroderma autoantibodies.
- Examined association between autoantibodies and overall cancer risk.
TAKEAWAYS:
- Anti-POLR3 and monospecific anti-Ro52 were associated with significantly increased overall cancer risk.
- Anti-centromere and anti-U1RNP were associated with a decreased cancer risk.
- These associations remained when looking specifically at cancer-associated scleroderma.
- Patients positive for anti-Ro52 in combination with either anti-U1RNP or anti-Th/To had a decreased risk of cancer, compared with those who had anti-Ro52 alone.
IN PRACTICE:
This study is too preliminary to have practice application.
SOURCE:
Ji Soo Kim, PhD, of John Hopkins University, Baltimore, was the first author of the study, published in Arthritis & Rheumatology on July 24, 2023. Fellow Johns Hopkins researchers Livia Casciola-Rosen, PhD, and Ami A. Shah, MD, were joint senior authors.
DISCLOSURES:
The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Martha McCrory Professorship, and the Johns Hopkins inHealth initiative. The authors disclosed the following patents or patent applications: Autoimmune Antigens and Cancer, Materials and Methods for Assessing Cancer Risk and Treating Cancer.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Included patients from the Johns Hopkins Scleroderma Center Research Registry and the University of Pittsburgh Scleroderma Center, Pittsburgh.
- A total of 676 patients with scleroderma and a history of cancer were compared with 687 control patients with scleroderma but without a history of cancer.
- Serum tested via line blot and enzyme-linked immunosorbent assay for an array of scleroderma autoantibodies.
- Examined association between autoantibodies and overall cancer risk.
TAKEAWAYS:
- Anti-POLR3 and monospecific anti-Ro52 were associated with significantly increased overall cancer risk.
- Anti-centromere and anti-U1RNP were associated with a decreased cancer risk.
- These associations remained when looking specifically at cancer-associated scleroderma.
- Patients positive for anti-Ro52 in combination with either anti-U1RNP or anti-Th/To had a decreased risk of cancer, compared with those who had anti-Ro52 alone.
IN PRACTICE:
This study is too preliminary to have practice application.
SOURCE:
Ji Soo Kim, PhD, of John Hopkins University, Baltimore, was the first author of the study, published in Arthritis & Rheumatology on July 24, 2023. Fellow Johns Hopkins researchers Livia Casciola-Rosen, PhD, and Ami A. Shah, MD, were joint senior authors.
DISCLOSURES:
The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Martha McCrory Professorship, and the Johns Hopkins inHealth initiative. The authors disclosed the following patents or patent applications: Autoimmune Antigens and Cancer, Materials and Methods for Assessing Cancer Risk and Treating Cancer.
A version of this article appeared on Medscape.com.
FROM ARTHRITIS & RHEUMATOLOGY
Rheumatology summit tackles racial disparities in lupus trials
Clinical research in lupus has a mammoth diversity problem: Black individuals are most likely to develop the disease, but they’re the least likely to take part in studies. By the numbers, a 2018 analysis of randomized controlled trials in systemic lupus erythematosus from the years 1997 to 2017 found that 51% of trial participants were White and 14% were Black, even though an estimated 33% of patients with lupus were White and 43% were Black.
Are there ways to fix this disparity? The topic is getting plenty of attention, and speakers at a July 21 online conference touted research projects that aim to boost the numbers of non-White participants in lupus trials.
So far there doesn’t seem to be anything like a magic bullet. Still, the stakes are high. “While race is a social construct, genetic polymorphisms as well as environmental and social differences may influence drugs, safety, and efficacy,” Joy Buie, PhD, MSCR, research director for the Lupus Foundation of America, said at the “Engaging Diverse Participants in Lupus Clinical Trials: The Path Forward” summit held by the American College of Rheumatology (ACR).
As African American patients explained, minority populations often don’t trust the medical system and feel burned by their lengthy struggles to get diagnosed. In some cases, they don’t have full faith in their clinicians and feel unheard.
In a video presentation developed as part of a federal education campaign, Shanelle Gabriel, a poet and musician diagnosed with lupus, described her first reaction when her physician suggested she join a clinical trial. “My first reaction was no. I know my history,” she said, apparently referring to the infamous Tuskegee study that withheld proper treatment from Black men with syphilis for decades. “As an African American woman, I was scared. I didn’t want to be a guinea pig.”
Stacey Kennedy-Conner, a Chicago-area patient and advocate, told the summit audience about how patients can feel that clinical trial information can add “an extra layer of confusion” to their experience. “There’s also the mentality of, ‘If it’s not broke, don’t fix it’: If this medication regimen is working, I don’t want anybody to touch me.”
Monique Gore-Massy, a New York City patient and advocate, added that there can be a perception that patients with lupus “are stuck at home in bed.” In reality, she said, “we have jobs, we have families. Think about that, and consider everything that you’re asking from us: Is this taking me away from my family? Am I going to have to take off work? There may be incentives, but is that worth me taking time off work that I may not get paid for? These are some of the realities that we have to look at in terms of the whole entire clinical trial process.”
It’s also important to keep patients informed of progress being made in trials, she said. “You don’t want to say you just felt like a number and then not get any kind of follow-up.”
In the big picture, “there has to be something that builds up the confidence of individuals so that they are more mindful to participate in these clinical trials,” said Aleta McLean, an Atlanta patient who was diagnosed with lupus 14 years ago.
Several researchers highlighted ongoing projects at the summit. The ACR, for example, has launched a $500,000 initiative called Training to Increase Minority Enrollment in Lupus Clinical Trials with Community Engagement (TIMELY). The federally funded project aims to evaluate whether training of health care professionals can boost clinical trial participation among Black and Hispanic patients.
“We hope to disseminate the results of our project to the scientific community through abstracts, manuscripts, presentations at national meetings,” said rheumatologist Saira Z. Sheikh, MD, of the University of North Carolina at Chapel Hill. “Overall, our goal is to establish new partnerships to support the TIMELY model and advance the education and engagement of providers and community health workers.”
Pamela Payne-Foster, MD, MPH, preventive medicine/public health physician at the University of Alabama College of Community Health Sciences, Tuscaloosa, spoke about the federally funded Deep South Health Equity Project, which is paying patients to take part in an online education program and attend an online regional conference.
Other efforts are underway. The Lupus Research Alliance and its clinical affiliate Lupus Therapeutics have launched two initiatives. One is a program called Project Change (Community-based Health Action Network to Generate Trial Participation and Eliminate Disparities), and the Diversity in Lupus Research Program aims to fund scientists’ work.
Will any of this work boost diversity in clinical trials? As one audience member noted in a Q&A session, health care disparities – and knowledge about them – are nothing new: “Why are we not able to narrow the gap?”
Rear Admiral Richardae Araojo, PharmD, MS, director of the FDA’s Office of Minority Health and Health Equity and associate commissioner for minority health, replied that waves of interest in disparities come and go. “That contributes to why we may not see solutions. But ultimately, there are a lot of people doing a lot of work trying to solve the issues.”
The summit was sponsored by Bristol-Myers Squibb, Genentech, and RemeGen.
A version of this article appeared on Medscape.com.
Clinical research in lupus has a mammoth diversity problem: Black individuals are most likely to develop the disease, but they’re the least likely to take part in studies. By the numbers, a 2018 analysis of randomized controlled trials in systemic lupus erythematosus from the years 1997 to 2017 found that 51% of trial participants were White and 14% were Black, even though an estimated 33% of patients with lupus were White and 43% were Black.
Are there ways to fix this disparity? The topic is getting plenty of attention, and speakers at a July 21 online conference touted research projects that aim to boost the numbers of non-White participants in lupus trials.
So far there doesn’t seem to be anything like a magic bullet. Still, the stakes are high. “While race is a social construct, genetic polymorphisms as well as environmental and social differences may influence drugs, safety, and efficacy,” Joy Buie, PhD, MSCR, research director for the Lupus Foundation of America, said at the “Engaging Diverse Participants in Lupus Clinical Trials: The Path Forward” summit held by the American College of Rheumatology (ACR).
As African American patients explained, minority populations often don’t trust the medical system and feel burned by their lengthy struggles to get diagnosed. In some cases, they don’t have full faith in their clinicians and feel unheard.
In a video presentation developed as part of a federal education campaign, Shanelle Gabriel, a poet and musician diagnosed with lupus, described her first reaction when her physician suggested she join a clinical trial. “My first reaction was no. I know my history,” she said, apparently referring to the infamous Tuskegee study that withheld proper treatment from Black men with syphilis for decades. “As an African American woman, I was scared. I didn’t want to be a guinea pig.”
Stacey Kennedy-Conner, a Chicago-area patient and advocate, told the summit audience about how patients can feel that clinical trial information can add “an extra layer of confusion” to their experience. “There’s also the mentality of, ‘If it’s not broke, don’t fix it’: If this medication regimen is working, I don’t want anybody to touch me.”
Monique Gore-Massy, a New York City patient and advocate, added that there can be a perception that patients with lupus “are stuck at home in bed.” In reality, she said, “we have jobs, we have families. Think about that, and consider everything that you’re asking from us: Is this taking me away from my family? Am I going to have to take off work? There may be incentives, but is that worth me taking time off work that I may not get paid for? These are some of the realities that we have to look at in terms of the whole entire clinical trial process.”
It’s also important to keep patients informed of progress being made in trials, she said. “You don’t want to say you just felt like a number and then not get any kind of follow-up.”
In the big picture, “there has to be something that builds up the confidence of individuals so that they are more mindful to participate in these clinical trials,” said Aleta McLean, an Atlanta patient who was diagnosed with lupus 14 years ago.
Several researchers highlighted ongoing projects at the summit. The ACR, for example, has launched a $500,000 initiative called Training to Increase Minority Enrollment in Lupus Clinical Trials with Community Engagement (TIMELY). The federally funded project aims to evaluate whether training of health care professionals can boost clinical trial participation among Black and Hispanic patients.
“We hope to disseminate the results of our project to the scientific community through abstracts, manuscripts, presentations at national meetings,” said rheumatologist Saira Z. Sheikh, MD, of the University of North Carolina at Chapel Hill. “Overall, our goal is to establish new partnerships to support the TIMELY model and advance the education and engagement of providers and community health workers.”
Pamela Payne-Foster, MD, MPH, preventive medicine/public health physician at the University of Alabama College of Community Health Sciences, Tuscaloosa, spoke about the federally funded Deep South Health Equity Project, which is paying patients to take part in an online education program and attend an online regional conference.
Other efforts are underway. The Lupus Research Alliance and its clinical affiliate Lupus Therapeutics have launched two initiatives. One is a program called Project Change (Community-based Health Action Network to Generate Trial Participation and Eliminate Disparities), and the Diversity in Lupus Research Program aims to fund scientists’ work.
Will any of this work boost diversity in clinical trials? As one audience member noted in a Q&A session, health care disparities – and knowledge about them – are nothing new: “Why are we not able to narrow the gap?”
Rear Admiral Richardae Araojo, PharmD, MS, director of the FDA’s Office of Minority Health and Health Equity and associate commissioner for minority health, replied that waves of interest in disparities come and go. “That contributes to why we may not see solutions. But ultimately, there are a lot of people doing a lot of work trying to solve the issues.”
The summit was sponsored by Bristol-Myers Squibb, Genentech, and RemeGen.
A version of this article appeared on Medscape.com.
Clinical research in lupus has a mammoth diversity problem: Black individuals are most likely to develop the disease, but they’re the least likely to take part in studies. By the numbers, a 2018 analysis of randomized controlled trials in systemic lupus erythematosus from the years 1997 to 2017 found that 51% of trial participants were White and 14% were Black, even though an estimated 33% of patients with lupus were White and 43% were Black.
Are there ways to fix this disparity? The topic is getting plenty of attention, and speakers at a July 21 online conference touted research projects that aim to boost the numbers of non-White participants in lupus trials.
So far there doesn’t seem to be anything like a magic bullet. Still, the stakes are high. “While race is a social construct, genetic polymorphisms as well as environmental and social differences may influence drugs, safety, and efficacy,” Joy Buie, PhD, MSCR, research director for the Lupus Foundation of America, said at the “Engaging Diverse Participants in Lupus Clinical Trials: The Path Forward” summit held by the American College of Rheumatology (ACR).
As African American patients explained, minority populations often don’t trust the medical system and feel burned by their lengthy struggles to get diagnosed. In some cases, they don’t have full faith in their clinicians and feel unheard.
In a video presentation developed as part of a federal education campaign, Shanelle Gabriel, a poet and musician diagnosed with lupus, described her first reaction when her physician suggested she join a clinical trial. “My first reaction was no. I know my history,” she said, apparently referring to the infamous Tuskegee study that withheld proper treatment from Black men with syphilis for decades. “As an African American woman, I was scared. I didn’t want to be a guinea pig.”
Stacey Kennedy-Conner, a Chicago-area patient and advocate, told the summit audience about how patients can feel that clinical trial information can add “an extra layer of confusion” to their experience. “There’s also the mentality of, ‘If it’s not broke, don’t fix it’: If this medication regimen is working, I don’t want anybody to touch me.”
Monique Gore-Massy, a New York City patient and advocate, added that there can be a perception that patients with lupus “are stuck at home in bed.” In reality, she said, “we have jobs, we have families. Think about that, and consider everything that you’re asking from us: Is this taking me away from my family? Am I going to have to take off work? There may be incentives, but is that worth me taking time off work that I may not get paid for? These are some of the realities that we have to look at in terms of the whole entire clinical trial process.”
It’s also important to keep patients informed of progress being made in trials, she said. “You don’t want to say you just felt like a number and then not get any kind of follow-up.”
In the big picture, “there has to be something that builds up the confidence of individuals so that they are more mindful to participate in these clinical trials,” said Aleta McLean, an Atlanta patient who was diagnosed with lupus 14 years ago.
Several researchers highlighted ongoing projects at the summit. The ACR, for example, has launched a $500,000 initiative called Training to Increase Minority Enrollment in Lupus Clinical Trials with Community Engagement (TIMELY). The federally funded project aims to evaluate whether training of health care professionals can boost clinical trial participation among Black and Hispanic patients.
“We hope to disseminate the results of our project to the scientific community through abstracts, manuscripts, presentations at national meetings,” said rheumatologist Saira Z. Sheikh, MD, of the University of North Carolina at Chapel Hill. “Overall, our goal is to establish new partnerships to support the TIMELY model and advance the education and engagement of providers and community health workers.”
Pamela Payne-Foster, MD, MPH, preventive medicine/public health physician at the University of Alabama College of Community Health Sciences, Tuscaloosa, spoke about the federally funded Deep South Health Equity Project, which is paying patients to take part in an online education program and attend an online regional conference.
Other efforts are underway. The Lupus Research Alliance and its clinical affiliate Lupus Therapeutics have launched two initiatives. One is a program called Project Change (Community-based Health Action Network to Generate Trial Participation and Eliminate Disparities), and the Diversity in Lupus Research Program aims to fund scientists’ work.
Will any of this work boost diversity in clinical trials? As one audience member noted in a Q&A session, health care disparities – and knowledge about them – are nothing new: “Why are we not able to narrow the gap?”
Rear Admiral Richardae Araojo, PharmD, MS, director of the FDA’s Office of Minority Health and Health Equity and associate commissioner for minority health, replied that waves of interest in disparities come and go. “That contributes to why we may not see solutions. But ultimately, there are a lot of people doing a lot of work trying to solve the issues.”
The summit was sponsored by Bristol-Myers Squibb, Genentech, and RemeGen.
A version of this article appeared on Medscape.com.
FROM AN ACR CLINICAL TRIAL SUMMIT
Lupus flares linked to gut bacteria overgrowth
Flares of systemic lupus erythematosus (SLE), particularly those involving severe kidney disease, were associated with growth spikes of the gut bacteria Ruminococcus blautia gnavus in a small, 4-year observational study that also demonstrated an underlying, inherent instability in the gut microbiome of patients with SLE.
Of 16 patients with SLE studied during the provision of routine care and monitoring, 5 had R. gnavus blooms that were “strikingly concordant with periods of raised disease activity,” Gregg J. Silverman, MD, of NYU Grossman School of Medicine, New York, and coinvestigators reported in Annals of the Rheumatic Diseases.
Four of the five patients with flare-associated R. gnavus blooms had lupus nephritis (LN); the other had a flare involving inflammation in multiple joints. The four patients with concurrent LN and spikes in R. gnavus also represented almost half of patients who had LN disease flares (four of nine) during the study period. The nine patients in the study with renal involvement, and the four with concurrent R. gnavus spikes and flares, represented different races and ethnicities.
The findings build upon research published by the NYU group several years ago showing that patients with SLE had more R. gnavus in the gut than similar patients without the disease, and that flares closely tracked major increases in R. gnavus growth. Evidence of R. gnavus expansions in patients with SLE now comes from several cohorts in the United States as well as cohorts in Europe and China, the researchers noted in their new paper.
An underlying, unstable microbiome
The new study at NYU took a “deeper dive” than previous research, looking at individuals over a longer period of time, Dr. Silverman, the study’s senior investigator and associate director of rheumatology at NYU Langone Health, said in an interview. Blood and a total of 44 stool samples from the 16 patients were analyzed, as were a total of 72 stool samples from 22 healthy control volunteers.
Importantly, he said, the gut microbiome in patients with SLE was found to be inherently unstable over time, compared with the microbiota communities of the controls. “There was an instability, a shifting dynamic composition of the microbiome [in patients with lupus]. ... Healthy individuals had more of a balance, with small changes over time” and a stable, low abundance of R. gnavus, Dr. Silverman said.
Transient expansions of several pathogenic species occurred in some of the patients with lupus (and not in controls), but blooms of R. gnavus were the most common. The researchers said in their paper that they “speculate that susceptibility for specific clinical features during R. gnavus blooms reflect in part differences in genetic susceptibility of the patient.”
Patients on cytotoxic agents or antibiotics were excluded from the study, but the study was not designed to disentangle the potential influence of diet or prior antibiotic exposure, they noted. Larger studies are needed that are better controlled and that include more frequent assessments, Dr. Silverman added.
A sure association and probable cause
“There seems to be a special connection [of R. gnavus] to lupus nephritis, which is an important, major subset of disease,” said Martin Kriegel, MD, PhD, chief or rheumatology and clinical immunology at the University of Munster (Germany). Dr. Kriegel also researches the gut microbiome in lupus and was asked to comment on the new findings from NYU.
The “difficult question is, is the bug driving the flare [as the NYU paper proposes], or is it the lupus nephritis that leads to overgrowth?” he said, noting that it “is well known that kidney disease, whether from lupus or other causes, creates disturbances in the microbiome.”
It’s “likely the case” that the pathobiome – with R. gnavus being an important pathobiont – helps to drive flares, he said. The new research shows only an association, but studies done in mice – including prior research by Dr. Silverman – support a mechanistic link, said Dr. Kriegel, also adjunct associate professor of immunobiology and of medicine at Yale University, New Haven, Conn.
Investigators in the microbiome space are moving toward more strain-level analysis – “not only measuring what organisms are there, but culturing them and sequencing them,” Dr. Kriegel noted, and the new study does just this.
The R. gnavus strains isolated during lupus flares were distinguishable from strains found in healthy people – and from strains found by other researchers in patients with inflammatory bowel disease – by their common expression of a novel type of cell membrane–associated lipoglycan. The lipoglycans were recognized by specific serum IgG2 antibodies that were detected concurrently with R. gnavus blooms and lupus flares, Dr. Silverman and his colleagues reported.
Dr. Silverman and Dr. Kriegel both study the paradigm of a gut-barrier breach, whereby pathogenic bacteria cause intestinal permeability, allowing bacterial leakages that trigger inflammation and immune responses. “We think that in lupus and other rheumatic diseases like rheumatoid arthritis, a leaky gut barrier is an important mechanism, even though these patients don’t have gastrointestinal symptoms,” said Dr. Kriegel, who has studied the role of another potentially pathogenic bacteria, Enterococcus gallinarum, in SLE.
Strengthening the gut barrier may be a plausible, general approach to reducing the severity of diseases like SLE and RA until more personalized approaches targeting individuals’ microbiome are developed, he noted.
Future treatments involving antibacterial agents, probiotics or dietary regimens that prevent imbalances in the gut microbiome would be “benign,” compared with currently utilized immunosuppressive medications, Dr. Silverman said.
The NYU study was funded in part by grants from the National Institutes of Health and the Lupus Research Alliance. Dr. Silverman disclosed that NYU has filed a patent application for an antibody test to detect serum antibodies to the lipoglycan made by some strains of R. gnavus. Dr. Kriegel disclosed that he holds a patent at Yale related to the Enterococcus bacteria he studies, and that he consults for Roche, Enterome, and Eligo Biosciences.
Flares of systemic lupus erythematosus (SLE), particularly those involving severe kidney disease, were associated with growth spikes of the gut bacteria Ruminococcus blautia gnavus in a small, 4-year observational study that also demonstrated an underlying, inherent instability in the gut microbiome of patients with SLE.
Of 16 patients with SLE studied during the provision of routine care and monitoring, 5 had R. gnavus blooms that were “strikingly concordant with periods of raised disease activity,” Gregg J. Silverman, MD, of NYU Grossman School of Medicine, New York, and coinvestigators reported in Annals of the Rheumatic Diseases.
Four of the five patients with flare-associated R. gnavus blooms had lupus nephritis (LN); the other had a flare involving inflammation in multiple joints. The four patients with concurrent LN and spikes in R. gnavus also represented almost half of patients who had LN disease flares (four of nine) during the study period. The nine patients in the study with renal involvement, and the four with concurrent R. gnavus spikes and flares, represented different races and ethnicities.
The findings build upon research published by the NYU group several years ago showing that patients with SLE had more R. gnavus in the gut than similar patients without the disease, and that flares closely tracked major increases in R. gnavus growth. Evidence of R. gnavus expansions in patients with SLE now comes from several cohorts in the United States as well as cohorts in Europe and China, the researchers noted in their new paper.
An underlying, unstable microbiome
The new study at NYU took a “deeper dive” than previous research, looking at individuals over a longer period of time, Dr. Silverman, the study’s senior investigator and associate director of rheumatology at NYU Langone Health, said in an interview. Blood and a total of 44 stool samples from the 16 patients were analyzed, as were a total of 72 stool samples from 22 healthy control volunteers.
Importantly, he said, the gut microbiome in patients with SLE was found to be inherently unstable over time, compared with the microbiota communities of the controls. “There was an instability, a shifting dynamic composition of the microbiome [in patients with lupus]. ... Healthy individuals had more of a balance, with small changes over time” and a stable, low abundance of R. gnavus, Dr. Silverman said.
Transient expansions of several pathogenic species occurred in some of the patients with lupus (and not in controls), but blooms of R. gnavus were the most common. The researchers said in their paper that they “speculate that susceptibility for specific clinical features during R. gnavus blooms reflect in part differences in genetic susceptibility of the patient.”
Patients on cytotoxic agents or antibiotics were excluded from the study, but the study was not designed to disentangle the potential influence of diet or prior antibiotic exposure, they noted. Larger studies are needed that are better controlled and that include more frequent assessments, Dr. Silverman added.
A sure association and probable cause
“There seems to be a special connection [of R. gnavus] to lupus nephritis, which is an important, major subset of disease,” said Martin Kriegel, MD, PhD, chief or rheumatology and clinical immunology at the University of Munster (Germany). Dr. Kriegel also researches the gut microbiome in lupus and was asked to comment on the new findings from NYU.
The “difficult question is, is the bug driving the flare [as the NYU paper proposes], or is it the lupus nephritis that leads to overgrowth?” he said, noting that it “is well known that kidney disease, whether from lupus or other causes, creates disturbances in the microbiome.”
It’s “likely the case” that the pathobiome – with R. gnavus being an important pathobiont – helps to drive flares, he said. The new research shows only an association, but studies done in mice – including prior research by Dr. Silverman – support a mechanistic link, said Dr. Kriegel, also adjunct associate professor of immunobiology and of medicine at Yale University, New Haven, Conn.
Investigators in the microbiome space are moving toward more strain-level analysis – “not only measuring what organisms are there, but culturing them and sequencing them,” Dr. Kriegel noted, and the new study does just this.
The R. gnavus strains isolated during lupus flares were distinguishable from strains found in healthy people – and from strains found by other researchers in patients with inflammatory bowel disease – by their common expression of a novel type of cell membrane–associated lipoglycan. The lipoglycans were recognized by specific serum IgG2 antibodies that were detected concurrently with R. gnavus blooms and lupus flares, Dr. Silverman and his colleagues reported.
Dr. Silverman and Dr. Kriegel both study the paradigm of a gut-barrier breach, whereby pathogenic bacteria cause intestinal permeability, allowing bacterial leakages that trigger inflammation and immune responses. “We think that in lupus and other rheumatic diseases like rheumatoid arthritis, a leaky gut barrier is an important mechanism, even though these patients don’t have gastrointestinal symptoms,” said Dr. Kriegel, who has studied the role of another potentially pathogenic bacteria, Enterococcus gallinarum, in SLE.
Strengthening the gut barrier may be a plausible, general approach to reducing the severity of diseases like SLE and RA until more personalized approaches targeting individuals’ microbiome are developed, he noted.
Future treatments involving antibacterial agents, probiotics or dietary regimens that prevent imbalances in the gut microbiome would be “benign,” compared with currently utilized immunosuppressive medications, Dr. Silverman said.
The NYU study was funded in part by grants from the National Institutes of Health and the Lupus Research Alliance. Dr. Silverman disclosed that NYU has filed a patent application for an antibody test to detect serum antibodies to the lipoglycan made by some strains of R. gnavus. Dr. Kriegel disclosed that he holds a patent at Yale related to the Enterococcus bacteria he studies, and that he consults for Roche, Enterome, and Eligo Biosciences.
Flares of systemic lupus erythematosus (SLE), particularly those involving severe kidney disease, were associated with growth spikes of the gut bacteria Ruminococcus blautia gnavus in a small, 4-year observational study that also demonstrated an underlying, inherent instability in the gut microbiome of patients with SLE.
Of 16 patients with SLE studied during the provision of routine care and monitoring, 5 had R. gnavus blooms that were “strikingly concordant with periods of raised disease activity,” Gregg J. Silverman, MD, of NYU Grossman School of Medicine, New York, and coinvestigators reported in Annals of the Rheumatic Diseases.
Four of the five patients with flare-associated R. gnavus blooms had lupus nephritis (LN); the other had a flare involving inflammation in multiple joints. The four patients with concurrent LN and spikes in R. gnavus also represented almost half of patients who had LN disease flares (four of nine) during the study period. The nine patients in the study with renal involvement, and the four with concurrent R. gnavus spikes and flares, represented different races and ethnicities.
The findings build upon research published by the NYU group several years ago showing that patients with SLE had more R. gnavus in the gut than similar patients without the disease, and that flares closely tracked major increases in R. gnavus growth. Evidence of R. gnavus expansions in patients with SLE now comes from several cohorts in the United States as well as cohorts in Europe and China, the researchers noted in their new paper.
An underlying, unstable microbiome
The new study at NYU took a “deeper dive” than previous research, looking at individuals over a longer period of time, Dr. Silverman, the study’s senior investigator and associate director of rheumatology at NYU Langone Health, said in an interview. Blood and a total of 44 stool samples from the 16 patients were analyzed, as were a total of 72 stool samples from 22 healthy control volunteers.
Importantly, he said, the gut microbiome in patients with SLE was found to be inherently unstable over time, compared with the microbiota communities of the controls. “There was an instability, a shifting dynamic composition of the microbiome [in patients with lupus]. ... Healthy individuals had more of a balance, with small changes over time” and a stable, low abundance of R. gnavus, Dr. Silverman said.
Transient expansions of several pathogenic species occurred in some of the patients with lupus (and not in controls), but blooms of R. gnavus were the most common. The researchers said in their paper that they “speculate that susceptibility for specific clinical features during R. gnavus blooms reflect in part differences in genetic susceptibility of the patient.”
Patients on cytotoxic agents or antibiotics were excluded from the study, but the study was not designed to disentangle the potential influence of diet or prior antibiotic exposure, they noted. Larger studies are needed that are better controlled and that include more frequent assessments, Dr. Silverman added.
A sure association and probable cause
“There seems to be a special connection [of R. gnavus] to lupus nephritis, which is an important, major subset of disease,” said Martin Kriegel, MD, PhD, chief or rheumatology and clinical immunology at the University of Munster (Germany). Dr. Kriegel also researches the gut microbiome in lupus and was asked to comment on the new findings from NYU.
The “difficult question is, is the bug driving the flare [as the NYU paper proposes], or is it the lupus nephritis that leads to overgrowth?” he said, noting that it “is well known that kidney disease, whether from lupus or other causes, creates disturbances in the microbiome.”
It’s “likely the case” that the pathobiome – with R. gnavus being an important pathobiont – helps to drive flares, he said. The new research shows only an association, but studies done in mice – including prior research by Dr. Silverman – support a mechanistic link, said Dr. Kriegel, also adjunct associate professor of immunobiology and of medicine at Yale University, New Haven, Conn.
Investigators in the microbiome space are moving toward more strain-level analysis – “not only measuring what organisms are there, but culturing them and sequencing them,” Dr. Kriegel noted, and the new study does just this.
The R. gnavus strains isolated during lupus flares were distinguishable from strains found in healthy people – and from strains found by other researchers in patients with inflammatory bowel disease – by their common expression of a novel type of cell membrane–associated lipoglycan. The lipoglycans were recognized by specific serum IgG2 antibodies that were detected concurrently with R. gnavus blooms and lupus flares, Dr. Silverman and his colleagues reported.
Dr. Silverman and Dr. Kriegel both study the paradigm of a gut-barrier breach, whereby pathogenic bacteria cause intestinal permeability, allowing bacterial leakages that trigger inflammation and immune responses. “We think that in lupus and other rheumatic diseases like rheumatoid arthritis, a leaky gut barrier is an important mechanism, even though these patients don’t have gastrointestinal symptoms,” said Dr. Kriegel, who has studied the role of another potentially pathogenic bacteria, Enterococcus gallinarum, in SLE.
Strengthening the gut barrier may be a plausible, general approach to reducing the severity of diseases like SLE and RA until more personalized approaches targeting individuals’ microbiome are developed, he noted.
Future treatments involving antibacterial agents, probiotics or dietary regimens that prevent imbalances in the gut microbiome would be “benign,” compared with currently utilized immunosuppressive medications, Dr. Silverman said.
The NYU study was funded in part by grants from the National Institutes of Health and the Lupus Research Alliance. Dr. Silverman disclosed that NYU has filed a patent application for an antibody test to detect serum antibodies to the lipoglycan made by some strains of R. gnavus. Dr. Kriegel disclosed that he holds a patent at Yale related to the Enterococcus bacteria he studies, and that he consults for Roche, Enterome, and Eligo Biosciences.
FROM ANNALS OF THE RHEUMATIC DISEASES
New guidelines for MTX use in pediatric inflammatory skin disease unveiled
While the typical dose of methotrexate (MTX) for inflammatory disease in pediatric patients varies in published studies, the maximum dose is considered to be 1 mg/kg and not to exceed 25 mg/week. In addition, test doses are not necessary for pediatric patients starting low dose (1 mg/kg or less) MTX for inflammatory skin disease, and the onset of efficacy with MTX may take 8-16 weeks.
and published online in Pediatric Dermatology.
“Methotrexate is a cost-effective, readily accessible, well-tolerated, useful, and time-honored option for children with a spectrum of inflammatory skin diseases,” project cochair Elaine C. Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, told this news organization. “Although considered an ‘immune suppressant’ by some, it is more accurately classified as an immune modulator and has been widely used for more than 50 years, and remains the standard of care when administered at very high doses and intrathecally in children with acute lymphoblastic leukemia – a practice that supports safety. But many details that support optimized treatment are not widely appreciated.”
In their guidelines document, Dr. Siegfried and her 22 coauthors noted that Food and Drug Administration labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata. “Furthermore, some clinicians may be unfamiliar or uncomfortable prescribing medications off label for pediatric patients, causing delayed initiation, premature drug discontinuation, or use of less advantageous alternatives,” they wrote.
To address this unmet need, Dr. Siegfried and the other committee members used a modified Delphi process to reach agreement on recommendations related to five key topic areas: indications and contraindications, dosing, interactions with immunizations and medications, potential for and management of adverse effects, and monitoring needs. Consensus was predefined as at least 70% of participants rating a statement as 7-9 on the Likert scale. The effort to develop 46 recommendations has been a work in progress for almost 5 years, “somewhat delayed by the pandemic,” Dr. Siegfried, past president and director of the American Board of Dermatology, said in an interview. “But it remains relevant, despite the emergence of biologics and JAK inhibitors for treating inflammatory skin conditions in children. Although the mechanism-of-action of low-dose MTX is not clear, it may overlap with the newer small molecules.”
The guidelines contain several pearls to guide optimal dosing, including the following key points:
- MTX can be discontinued abruptly without adverse effects, other than the risk of disease worsening.
- Folic acid supplementation (starting at 1 mg/day, regardless of weight) is an effective approach to minimizing associated gastrointestinal adverse effects.
- Concomitant use of MTX and antibiotics (including trimethoprim-sulfamethoxazole) and NSAIDS are not contraindicated for most pediatric patients treated for inflammatory skin disease.
- Live virus vaccine boosters such as varicella-zoster virus (VZV) and measles, mumps, and rubella (MMR) are not contraindicated in patients taking MTX; there are insufficient data to make recommendations for or against primary immunization with MMR vaccine in patients taking MTX; inactivated vaccines should be given to patients taking MTX.
- Routine surveillance laboratory monitoring (i.e., CBC with differential, alanine transaminase, aspartate aminotransferase, creatinine) is recommended at baseline, after 1 month of treatment, and every 3-4 months thereafter.
- Transient transaminase elevation (≤ 3 upper limit normal for < 3 months) is not uncommon with low-dose MTX and does not usually require interruption of MTX. The most likely causes are concomitant viral infection, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (such as acetaminophen), and/or recent alcohol consumption.
- Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX.
According to Dr. Siegfried, consensus of the committee members was lowest on the need for a test dose of MTX.
Overall, she said in the interview, helping to craft the guidelines caused her to reflect on how her approach to using MTX has evolved over the past 35 years, after treating “many hundreds” of patients. “I was gratified to confirm similar practice patterns among my colleagues,” she added.
The project’s other cochair was Heather Brandling-Bennett, MD, a dermatologist at Seattle Children’s Hospital. This work was supported by a grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association and the National Psoriasis Foundation. Dr. Siegfried disclosed ties with AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica. She has participated in contracted research for AI Therapeutics, and has served as principal investigator for Janssen. Many of the guideline coauthors disclosed having received grant support and other funding from pharmaceutical companies.
While the typical dose of methotrexate (MTX) for inflammatory disease in pediatric patients varies in published studies, the maximum dose is considered to be 1 mg/kg and not to exceed 25 mg/week. In addition, test doses are not necessary for pediatric patients starting low dose (1 mg/kg or less) MTX for inflammatory skin disease, and the onset of efficacy with MTX may take 8-16 weeks.
and published online in Pediatric Dermatology.
“Methotrexate is a cost-effective, readily accessible, well-tolerated, useful, and time-honored option for children with a spectrum of inflammatory skin diseases,” project cochair Elaine C. Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, told this news organization. “Although considered an ‘immune suppressant’ by some, it is more accurately classified as an immune modulator and has been widely used for more than 50 years, and remains the standard of care when administered at very high doses and intrathecally in children with acute lymphoblastic leukemia – a practice that supports safety. But many details that support optimized treatment are not widely appreciated.”
In their guidelines document, Dr. Siegfried and her 22 coauthors noted that Food and Drug Administration labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata. “Furthermore, some clinicians may be unfamiliar or uncomfortable prescribing medications off label for pediatric patients, causing delayed initiation, premature drug discontinuation, or use of less advantageous alternatives,” they wrote.
To address this unmet need, Dr. Siegfried and the other committee members used a modified Delphi process to reach agreement on recommendations related to five key topic areas: indications and contraindications, dosing, interactions with immunizations and medications, potential for and management of adverse effects, and monitoring needs. Consensus was predefined as at least 70% of participants rating a statement as 7-9 on the Likert scale. The effort to develop 46 recommendations has been a work in progress for almost 5 years, “somewhat delayed by the pandemic,” Dr. Siegfried, past president and director of the American Board of Dermatology, said in an interview. “But it remains relevant, despite the emergence of biologics and JAK inhibitors for treating inflammatory skin conditions in children. Although the mechanism-of-action of low-dose MTX is not clear, it may overlap with the newer small molecules.”
The guidelines contain several pearls to guide optimal dosing, including the following key points:
- MTX can be discontinued abruptly without adverse effects, other than the risk of disease worsening.
- Folic acid supplementation (starting at 1 mg/day, regardless of weight) is an effective approach to minimizing associated gastrointestinal adverse effects.
- Concomitant use of MTX and antibiotics (including trimethoprim-sulfamethoxazole) and NSAIDS are not contraindicated for most pediatric patients treated for inflammatory skin disease.
- Live virus vaccine boosters such as varicella-zoster virus (VZV) and measles, mumps, and rubella (MMR) are not contraindicated in patients taking MTX; there are insufficient data to make recommendations for or against primary immunization with MMR vaccine in patients taking MTX; inactivated vaccines should be given to patients taking MTX.
- Routine surveillance laboratory monitoring (i.e., CBC with differential, alanine transaminase, aspartate aminotransferase, creatinine) is recommended at baseline, after 1 month of treatment, and every 3-4 months thereafter.
- Transient transaminase elevation (≤ 3 upper limit normal for < 3 months) is not uncommon with low-dose MTX and does not usually require interruption of MTX. The most likely causes are concomitant viral infection, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (such as acetaminophen), and/or recent alcohol consumption.
- Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX.
According to Dr. Siegfried, consensus of the committee members was lowest on the need for a test dose of MTX.
Overall, she said in the interview, helping to craft the guidelines caused her to reflect on how her approach to using MTX has evolved over the past 35 years, after treating “many hundreds” of patients. “I was gratified to confirm similar practice patterns among my colleagues,” she added.
The project’s other cochair was Heather Brandling-Bennett, MD, a dermatologist at Seattle Children’s Hospital. This work was supported by a grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association and the National Psoriasis Foundation. Dr. Siegfried disclosed ties with AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica. She has participated in contracted research for AI Therapeutics, and has served as principal investigator for Janssen. Many of the guideline coauthors disclosed having received grant support and other funding from pharmaceutical companies.
While the typical dose of methotrexate (MTX) for inflammatory disease in pediatric patients varies in published studies, the maximum dose is considered to be 1 mg/kg and not to exceed 25 mg/week. In addition, test doses are not necessary for pediatric patients starting low dose (1 mg/kg or less) MTX for inflammatory skin disease, and the onset of efficacy with MTX may take 8-16 weeks.
and published online in Pediatric Dermatology.
“Methotrexate is a cost-effective, readily accessible, well-tolerated, useful, and time-honored option for children with a spectrum of inflammatory skin diseases,” project cochair Elaine C. Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, told this news organization. “Although considered an ‘immune suppressant’ by some, it is more accurately classified as an immune modulator and has been widely used for more than 50 years, and remains the standard of care when administered at very high doses and intrathecally in children with acute lymphoblastic leukemia – a practice that supports safety. But many details that support optimized treatment are not widely appreciated.”
In their guidelines document, Dr. Siegfried and her 22 coauthors noted that Food and Drug Administration labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata. “Furthermore, some clinicians may be unfamiliar or uncomfortable prescribing medications off label for pediatric patients, causing delayed initiation, premature drug discontinuation, or use of less advantageous alternatives,” they wrote.
To address this unmet need, Dr. Siegfried and the other committee members used a modified Delphi process to reach agreement on recommendations related to five key topic areas: indications and contraindications, dosing, interactions with immunizations and medications, potential for and management of adverse effects, and monitoring needs. Consensus was predefined as at least 70% of participants rating a statement as 7-9 on the Likert scale. The effort to develop 46 recommendations has been a work in progress for almost 5 years, “somewhat delayed by the pandemic,” Dr. Siegfried, past president and director of the American Board of Dermatology, said in an interview. “But it remains relevant, despite the emergence of biologics and JAK inhibitors for treating inflammatory skin conditions in children. Although the mechanism-of-action of low-dose MTX is not clear, it may overlap with the newer small molecules.”
The guidelines contain several pearls to guide optimal dosing, including the following key points:
- MTX can be discontinued abruptly without adverse effects, other than the risk of disease worsening.
- Folic acid supplementation (starting at 1 mg/day, regardless of weight) is an effective approach to minimizing associated gastrointestinal adverse effects.
- Concomitant use of MTX and antibiotics (including trimethoprim-sulfamethoxazole) and NSAIDS are not contraindicated for most pediatric patients treated for inflammatory skin disease.
- Live virus vaccine boosters such as varicella-zoster virus (VZV) and measles, mumps, and rubella (MMR) are not contraindicated in patients taking MTX; there are insufficient data to make recommendations for or against primary immunization with MMR vaccine in patients taking MTX; inactivated vaccines should be given to patients taking MTX.
- Routine surveillance laboratory monitoring (i.e., CBC with differential, alanine transaminase, aspartate aminotransferase, creatinine) is recommended at baseline, after 1 month of treatment, and every 3-4 months thereafter.
- Transient transaminase elevation (≤ 3 upper limit normal for < 3 months) is not uncommon with low-dose MTX and does not usually require interruption of MTX. The most likely causes are concomitant viral infection, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (such as acetaminophen), and/or recent alcohol consumption.
- Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX.
According to Dr. Siegfried, consensus of the committee members was lowest on the need for a test dose of MTX.
Overall, she said in the interview, helping to craft the guidelines caused her to reflect on how her approach to using MTX has evolved over the past 35 years, after treating “many hundreds” of patients. “I was gratified to confirm similar practice patterns among my colleagues,” she added.
The project’s other cochair was Heather Brandling-Bennett, MD, a dermatologist at Seattle Children’s Hospital. This work was supported by a grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association and the National Psoriasis Foundation. Dr. Siegfried disclosed ties with AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica. She has participated in contracted research for AI Therapeutics, and has served as principal investigator for Janssen. Many of the guideline coauthors disclosed having received grant support and other funding from pharmaceutical companies.
FROM PEDIATRIC DERMATOLOGY
Does colchicine have a role in treating excess ASCVD risk in patients with chronic inflammatory conditions?
The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.
Potential in rheumatology
The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.
The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.
She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.
However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.
“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”
However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.
Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.
Possibilities in dermatology
The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.
Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.
“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”
Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.
The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.
Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
Would side effects bar use in gastroenterology?
Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.
“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.
Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.
Potential in rheumatology
The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.
The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.
She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.
However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.
“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”
However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.
Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.
Possibilities in dermatology
The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.
Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.
“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”
Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.
The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.
Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
Would side effects bar use in gastroenterology?
Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.
“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.
Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.
Potential in rheumatology
The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.
The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.
She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.
However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.
“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”
However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.
Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.
Possibilities in dermatology
The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.
Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.
“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”
Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.
The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.
Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
Would side effects bar use in gastroenterology?
Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.
“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.
Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
New EULAR lupus recommendations advise using biologics, tapering steroids
MILAN – Treatment of systemic lupus erythematosus with biologics may enable steroid tapering while ensuring the achievement of remission or low disease activity in more patients with fewer flares and less organ damage, as well as leading to better responses if used early, according to the latest recommendations on the management of SLE from the European Alliance of Associations for Rheumatology (EULAR).
Dimitrios Boumpas, MD, president of the Athens Medical Society and chair of the European Task force on SLE, presented the recommendations at the annual European Congress of Rheumatology. “Although steroids save lives, it is at the expense of excessive collateral damage. They are better for short-term use as a rescue or bridging therapy but may be used in some patients at 5 mg/day of prednisone or less, rather than the previous 7.5 mg/day,” he emphasized.
The 2023 recommendations cover new treatment strategies with more ambitious goals, new data on adverse effects of chronic glucocorticoid use, and newly approved agents and combination therapies.
“Most importantly, we sourced help from experts from all over the world,” said Dr. Boumpas, describing the task force that included 35 rheumatologists, 5 nephrologists, 2 methodologists, 2 patient representatives, and 2 fellows, all brought together from across Europe, North America, Asia, and Australia.
Over 7,000 papers were reviewed, with 437 included in the systematic literature review to inform the updated recommendations.
Session moderator Robert Landewé, MD, PhD, professor of clinical immunology and rheumatology at the University of Amsterdam, said that “the underlying heterogeneity and multisystem involvement of SLE can make it difficult to demonstrate and know which drugs work in the condition. However, these latest recommendations should encourage greater confidence to taper steroids early on and perhaps consider new biologic drugs, so that more patients can achieve better results sooner to prevent flares and organ damage, improve prognosis, and enhance their quality of life.”
Dr. Boumpas provided a summary of the overarching principles that guide the recommendations. These say that SLE requires multidisciplinary individualized management; disease activity should be assessed at each visit; nonpharmacologic interventions such as sun protection, smoking cessation, and following a healthy diet are all important for improving long-term outcomes; pharmacologic interventions are to be directed by patient characteristics, type and severity of organ involvement, treatment-related harms, and patient preferences, among other factors; and early SLE diagnosis is essential to prevent flares and organ damage, improve prognosis, and enhance quality of life.
Referring to each recommendation statement in turn, Dr. Boumpas provided a detailed description of each, and highlighted any changes since the 2019 recommendations.
Hydroxychloroquine, glucocorticoids as bridging therapy, and biologics
Referring to statement 1, Dr. Boumpas reported that hydroxychloroquine should be a first-line therapy at a dose of 5 mg/kg, but this dose should be individualized based on risk of flare and retinal toxicity. “There was some discussion about monitoring blood levels, but this was to ensure adherence only,” said Dr. Boumpas.
Continuing to statement 2, he added, “here is one change. With chronic use of glucocorticoids, the maintenance dose is 5 mg/day or less or prednisone equivalent. This pertains to both new onset and relapsing disease.” Previous recommendations advised a maintenance dose of 7.5 mg/day or less.
But he pointed out that “we are discussing using glucocorticoids in lupus as a bridging therapy only, for short, limited periods of time. We should shy away from chronic use of glucocorticoids and only use them for 3 months, and to do this we need to use glucocorticoid-sparing strategies.”
This led to statement 3, which refers to glucocorticoid-sparing strategies. Dr. Boumpas explained that, in patients who are not responding to hydroxychloroquine or unable to reduce glucocorticoids further during chronic use, add immunosuppressive agents, such as methotrexate and/or biologics (for example, belimumab [Benlysta] or anifrolumab [Saphnelo]).
“To allow flexibility for patients and clinicians, it isn’t necessary to use DMARDs [disease-modifying antirheumatic drugs] first if you prefer biologics,” he continued. “We are becoming more liberal with the use of biologics because there are new data that confirm the efficacy of belimumab in extrarenal SLE, plus good data with 3-year extension with anifrolumab.”
Statement 4 says that for patients with organ- or life-threatening disease, intravenous cyclophosphamide, “our old friend,” should be considered, while in refractory cases, rituximab may be considered, Dr. Boumpas said. “It’s okay to use cyclophosphamide. It isn’t a sin.”
Statement 5 refers to skin disease, and Dr. Boumpas explained that good data suggested that biologics help, including both belimumab and anifrolumab.
Nothing has changed with statement 6 concerning neuropsychiatric lupus, said Dr. Boumpas. “Glucocorticoids, immunosuppressive, and antithrombotic therapies should be considered.”
Regarding hematologic disease (statement 7), he said, “the new kid on the block is MMF [mycophenolate mofetil]. For acute treatment, still use the same drugs, including rituximab, but for maintenance you may use rituximab, azathioprine, MMF, or cyclosporine.”
Lupus nephritis
Turning to what Dr. Boumpas described as the “reason you had all come here, and what you had been waiting for ... what’s changing with lupus nephritis?” he said.
Statement 8 describes initial therapy in active lupus nephritis. Dr. Boumpas said that low-dose, intravenous cyclophosphamide or mycophenolate should be considered, but also that belimumab or a calcineurin inhibitor (CNI) should be considered at the start. The changes were based on two successful phase 3 trials of belimumab and voclosporin, with belimumab being associated with a reduced flare rate and estimated glomerular filtration rate (eGFR).
“Changes from 2019 include that there is no distinction between classes III/IV and V, which is heretical,” he stressed. Belimumab and CNIs/voclosporin should be considered in all patents as an add-on therapy from the start. “Lupus nephritis has high morbidity, and it’s difficult to predict outcomes at the beginning, but there are clear benefits of add-on therapies. CNIs, although they can be used for all patients, might be more appropriate for membranous or nephrotic-range proteinuria.”
He went on to announce that the “million-dollar question” was whether to use belimumab or voclosporin (or other CNIs), and that this was “a question of gentle, compared with forceful, power and collateral damage.
“For me, voclosporin works very fast, but you worry about side effects, while belimumab is gentle and the response is sustained, preventing flares and organ damage,” he said, adding that “our expert panel discussions showed that nephrologists were more eager to support steroid-free regimens.”
Moving on to statement 9, Dr. Boumpas explained that after initial therapy and renal response, subsequent therapy should continue for at least 3 years. If treated with MMF alone or in combination with belimumab, then these drugs should continue. However, MMF should replace cyclophosphamide if the latter is used initially.
Regarding treat-to-target in lupus nephritis, he said that EULAR now advises to aim for a 25% drop in urine protein/creatinine ratio by 3 months, a 50% drop by 6 months, and a UPCR of less than 0.5-0.7, plus normal eGFR, by 12 months, Dr. Boumpas said.
Statement 10 advises considering high-dose intravenous cyclophosphamide in combination with pulse intravenous methylprednisolone for patients at high risk of renal failure.
Tapering drugs in sustained remission, managing antiphospholipid syndrome, giving immunizations
Statement 11 suggests to consider tapering immunosuppressive agents and glucocorticoids in patients achieving sustained remission, starting with glucocorticoids first.
There was no change to statement 12, which recommends that thrombotic antiphospholipid syndrome associated with SLE be treated with long-term vitamin K antagonists.
Statement 13 addresses immunizations and adjunct therapies. In addition to conventional immunizations, Dr. Boumpas said that renoprotection should receive attention in case of proteinuria and/or hypertension.
“With [sodium-glucose cotransporter 2] inhibitors, it’s a bit early. They’re promising, and you may consider them, although there are no data for patients with eGFR below 60 mL/min per 1.73 m2,” he remarked, completing his detailed discussion of the updated recommendations.
Dr. Boumpas reported no relevant financial relationships. Dr. Landewé served as past chair of EULAR’s Quality of Care Committee, which develops recommendations.
MILAN – Treatment of systemic lupus erythematosus with biologics may enable steroid tapering while ensuring the achievement of remission or low disease activity in more patients with fewer flares and less organ damage, as well as leading to better responses if used early, according to the latest recommendations on the management of SLE from the European Alliance of Associations for Rheumatology (EULAR).
Dimitrios Boumpas, MD, president of the Athens Medical Society and chair of the European Task force on SLE, presented the recommendations at the annual European Congress of Rheumatology. “Although steroids save lives, it is at the expense of excessive collateral damage. They are better for short-term use as a rescue or bridging therapy but may be used in some patients at 5 mg/day of prednisone or less, rather than the previous 7.5 mg/day,” he emphasized.
The 2023 recommendations cover new treatment strategies with more ambitious goals, new data on adverse effects of chronic glucocorticoid use, and newly approved agents and combination therapies.
“Most importantly, we sourced help from experts from all over the world,” said Dr. Boumpas, describing the task force that included 35 rheumatologists, 5 nephrologists, 2 methodologists, 2 patient representatives, and 2 fellows, all brought together from across Europe, North America, Asia, and Australia.
Over 7,000 papers were reviewed, with 437 included in the systematic literature review to inform the updated recommendations.
Session moderator Robert Landewé, MD, PhD, professor of clinical immunology and rheumatology at the University of Amsterdam, said that “the underlying heterogeneity and multisystem involvement of SLE can make it difficult to demonstrate and know which drugs work in the condition. However, these latest recommendations should encourage greater confidence to taper steroids early on and perhaps consider new biologic drugs, so that more patients can achieve better results sooner to prevent flares and organ damage, improve prognosis, and enhance their quality of life.”
Dr. Boumpas provided a summary of the overarching principles that guide the recommendations. These say that SLE requires multidisciplinary individualized management; disease activity should be assessed at each visit; nonpharmacologic interventions such as sun protection, smoking cessation, and following a healthy diet are all important for improving long-term outcomes; pharmacologic interventions are to be directed by patient characteristics, type and severity of organ involvement, treatment-related harms, and patient preferences, among other factors; and early SLE diagnosis is essential to prevent flares and organ damage, improve prognosis, and enhance quality of life.
Referring to each recommendation statement in turn, Dr. Boumpas provided a detailed description of each, and highlighted any changes since the 2019 recommendations.
Hydroxychloroquine, glucocorticoids as bridging therapy, and biologics
Referring to statement 1, Dr. Boumpas reported that hydroxychloroquine should be a first-line therapy at a dose of 5 mg/kg, but this dose should be individualized based on risk of flare and retinal toxicity. “There was some discussion about monitoring blood levels, but this was to ensure adherence only,” said Dr. Boumpas.
Continuing to statement 2, he added, “here is one change. With chronic use of glucocorticoids, the maintenance dose is 5 mg/day or less or prednisone equivalent. This pertains to both new onset and relapsing disease.” Previous recommendations advised a maintenance dose of 7.5 mg/day or less.
But he pointed out that “we are discussing using glucocorticoids in lupus as a bridging therapy only, for short, limited periods of time. We should shy away from chronic use of glucocorticoids and only use them for 3 months, and to do this we need to use glucocorticoid-sparing strategies.”
This led to statement 3, which refers to glucocorticoid-sparing strategies. Dr. Boumpas explained that, in patients who are not responding to hydroxychloroquine or unable to reduce glucocorticoids further during chronic use, add immunosuppressive agents, such as methotrexate and/or biologics (for example, belimumab [Benlysta] or anifrolumab [Saphnelo]).
“To allow flexibility for patients and clinicians, it isn’t necessary to use DMARDs [disease-modifying antirheumatic drugs] first if you prefer biologics,” he continued. “We are becoming more liberal with the use of biologics because there are new data that confirm the efficacy of belimumab in extrarenal SLE, plus good data with 3-year extension with anifrolumab.”
Statement 4 says that for patients with organ- or life-threatening disease, intravenous cyclophosphamide, “our old friend,” should be considered, while in refractory cases, rituximab may be considered, Dr. Boumpas said. “It’s okay to use cyclophosphamide. It isn’t a sin.”
Statement 5 refers to skin disease, and Dr. Boumpas explained that good data suggested that biologics help, including both belimumab and anifrolumab.
Nothing has changed with statement 6 concerning neuropsychiatric lupus, said Dr. Boumpas. “Glucocorticoids, immunosuppressive, and antithrombotic therapies should be considered.”
Regarding hematologic disease (statement 7), he said, “the new kid on the block is MMF [mycophenolate mofetil]. For acute treatment, still use the same drugs, including rituximab, but for maintenance you may use rituximab, azathioprine, MMF, or cyclosporine.”
Lupus nephritis
Turning to what Dr. Boumpas described as the “reason you had all come here, and what you had been waiting for ... what’s changing with lupus nephritis?” he said.
Statement 8 describes initial therapy in active lupus nephritis. Dr. Boumpas said that low-dose, intravenous cyclophosphamide or mycophenolate should be considered, but also that belimumab or a calcineurin inhibitor (CNI) should be considered at the start. The changes were based on two successful phase 3 trials of belimumab and voclosporin, with belimumab being associated with a reduced flare rate and estimated glomerular filtration rate (eGFR).
“Changes from 2019 include that there is no distinction between classes III/IV and V, which is heretical,” he stressed. Belimumab and CNIs/voclosporin should be considered in all patents as an add-on therapy from the start. “Lupus nephritis has high morbidity, and it’s difficult to predict outcomes at the beginning, but there are clear benefits of add-on therapies. CNIs, although they can be used for all patients, might be more appropriate for membranous or nephrotic-range proteinuria.”
He went on to announce that the “million-dollar question” was whether to use belimumab or voclosporin (or other CNIs), and that this was “a question of gentle, compared with forceful, power and collateral damage.
“For me, voclosporin works very fast, but you worry about side effects, while belimumab is gentle and the response is sustained, preventing flares and organ damage,” he said, adding that “our expert panel discussions showed that nephrologists were more eager to support steroid-free regimens.”
Moving on to statement 9, Dr. Boumpas explained that after initial therapy and renal response, subsequent therapy should continue for at least 3 years. If treated with MMF alone or in combination with belimumab, then these drugs should continue. However, MMF should replace cyclophosphamide if the latter is used initially.
Regarding treat-to-target in lupus nephritis, he said that EULAR now advises to aim for a 25% drop in urine protein/creatinine ratio by 3 months, a 50% drop by 6 months, and a UPCR of less than 0.5-0.7, plus normal eGFR, by 12 months, Dr. Boumpas said.
Statement 10 advises considering high-dose intravenous cyclophosphamide in combination with pulse intravenous methylprednisolone for patients at high risk of renal failure.
Tapering drugs in sustained remission, managing antiphospholipid syndrome, giving immunizations
Statement 11 suggests to consider tapering immunosuppressive agents and glucocorticoids in patients achieving sustained remission, starting with glucocorticoids first.
There was no change to statement 12, which recommends that thrombotic antiphospholipid syndrome associated with SLE be treated with long-term vitamin K antagonists.
Statement 13 addresses immunizations and adjunct therapies. In addition to conventional immunizations, Dr. Boumpas said that renoprotection should receive attention in case of proteinuria and/or hypertension.
“With [sodium-glucose cotransporter 2] inhibitors, it’s a bit early. They’re promising, and you may consider them, although there are no data for patients with eGFR below 60 mL/min per 1.73 m2,” he remarked, completing his detailed discussion of the updated recommendations.
Dr. Boumpas reported no relevant financial relationships. Dr. Landewé served as past chair of EULAR’s Quality of Care Committee, which develops recommendations.
MILAN – Treatment of systemic lupus erythematosus with biologics may enable steroid tapering while ensuring the achievement of remission or low disease activity in more patients with fewer flares and less organ damage, as well as leading to better responses if used early, according to the latest recommendations on the management of SLE from the European Alliance of Associations for Rheumatology (EULAR).
Dimitrios Boumpas, MD, president of the Athens Medical Society and chair of the European Task force on SLE, presented the recommendations at the annual European Congress of Rheumatology. “Although steroids save lives, it is at the expense of excessive collateral damage. They are better for short-term use as a rescue or bridging therapy but may be used in some patients at 5 mg/day of prednisone or less, rather than the previous 7.5 mg/day,” he emphasized.
The 2023 recommendations cover new treatment strategies with more ambitious goals, new data on adverse effects of chronic glucocorticoid use, and newly approved agents and combination therapies.
“Most importantly, we sourced help from experts from all over the world,” said Dr. Boumpas, describing the task force that included 35 rheumatologists, 5 nephrologists, 2 methodologists, 2 patient representatives, and 2 fellows, all brought together from across Europe, North America, Asia, and Australia.
Over 7,000 papers were reviewed, with 437 included in the systematic literature review to inform the updated recommendations.
Session moderator Robert Landewé, MD, PhD, professor of clinical immunology and rheumatology at the University of Amsterdam, said that “the underlying heterogeneity and multisystem involvement of SLE can make it difficult to demonstrate and know which drugs work in the condition. However, these latest recommendations should encourage greater confidence to taper steroids early on and perhaps consider new biologic drugs, so that more patients can achieve better results sooner to prevent flares and organ damage, improve prognosis, and enhance their quality of life.”
Dr. Boumpas provided a summary of the overarching principles that guide the recommendations. These say that SLE requires multidisciplinary individualized management; disease activity should be assessed at each visit; nonpharmacologic interventions such as sun protection, smoking cessation, and following a healthy diet are all important for improving long-term outcomes; pharmacologic interventions are to be directed by patient characteristics, type and severity of organ involvement, treatment-related harms, and patient preferences, among other factors; and early SLE diagnosis is essential to prevent flares and organ damage, improve prognosis, and enhance quality of life.
Referring to each recommendation statement in turn, Dr. Boumpas provided a detailed description of each, and highlighted any changes since the 2019 recommendations.
Hydroxychloroquine, glucocorticoids as bridging therapy, and biologics
Referring to statement 1, Dr. Boumpas reported that hydroxychloroquine should be a first-line therapy at a dose of 5 mg/kg, but this dose should be individualized based on risk of flare and retinal toxicity. “There was some discussion about monitoring blood levels, but this was to ensure adherence only,” said Dr. Boumpas.
Continuing to statement 2, he added, “here is one change. With chronic use of glucocorticoids, the maintenance dose is 5 mg/day or less or prednisone equivalent. This pertains to both new onset and relapsing disease.” Previous recommendations advised a maintenance dose of 7.5 mg/day or less.
But he pointed out that “we are discussing using glucocorticoids in lupus as a bridging therapy only, for short, limited periods of time. We should shy away from chronic use of glucocorticoids and only use them for 3 months, and to do this we need to use glucocorticoid-sparing strategies.”
This led to statement 3, which refers to glucocorticoid-sparing strategies. Dr. Boumpas explained that, in patients who are not responding to hydroxychloroquine or unable to reduce glucocorticoids further during chronic use, add immunosuppressive agents, such as methotrexate and/or biologics (for example, belimumab [Benlysta] or anifrolumab [Saphnelo]).
“To allow flexibility for patients and clinicians, it isn’t necessary to use DMARDs [disease-modifying antirheumatic drugs] first if you prefer biologics,” he continued. “We are becoming more liberal with the use of biologics because there are new data that confirm the efficacy of belimumab in extrarenal SLE, plus good data with 3-year extension with anifrolumab.”
Statement 4 says that for patients with organ- or life-threatening disease, intravenous cyclophosphamide, “our old friend,” should be considered, while in refractory cases, rituximab may be considered, Dr. Boumpas said. “It’s okay to use cyclophosphamide. It isn’t a sin.”
Statement 5 refers to skin disease, and Dr. Boumpas explained that good data suggested that biologics help, including both belimumab and anifrolumab.
Nothing has changed with statement 6 concerning neuropsychiatric lupus, said Dr. Boumpas. “Glucocorticoids, immunosuppressive, and antithrombotic therapies should be considered.”
Regarding hematologic disease (statement 7), he said, “the new kid on the block is MMF [mycophenolate mofetil]. For acute treatment, still use the same drugs, including rituximab, but for maintenance you may use rituximab, azathioprine, MMF, or cyclosporine.”
Lupus nephritis
Turning to what Dr. Boumpas described as the “reason you had all come here, and what you had been waiting for ... what’s changing with lupus nephritis?” he said.
Statement 8 describes initial therapy in active lupus nephritis. Dr. Boumpas said that low-dose, intravenous cyclophosphamide or mycophenolate should be considered, but also that belimumab or a calcineurin inhibitor (CNI) should be considered at the start. The changes were based on two successful phase 3 trials of belimumab and voclosporin, with belimumab being associated with a reduced flare rate and estimated glomerular filtration rate (eGFR).
“Changes from 2019 include that there is no distinction between classes III/IV and V, which is heretical,” he stressed. Belimumab and CNIs/voclosporin should be considered in all patents as an add-on therapy from the start. “Lupus nephritis has high morbidity, and it’s difficult to predict outcomes at the beginning, but there are clear benefits of add-on therapies. CNIs, although they can be used for all patients, might be more appropriate for membranous or nephrotic-range proteinuria.”
He went on to announce that the “million-dollar question” was whether to use belimumab or voclosporin (or other CNIs), and that this was “a question of gentle, compared with forceful, power and collateral damage.
“For me, voclosporin works very fast, but you worry about side effects, while belimumab is gentle and the response is sustained, preventing flares and organ damage,” he said, adding that “our expert panel discussions showed that nephrologists were more eager to support steroid-free regimens.”
Moving on to statement 9, Dr. Boumpas explained that after initial therapy and renal response, subsequent therapy should continue for at least 3 years. If treated with MMF alone or in combination with belimumab, then these drugs should continue. However, MMF should replace cyclophosphamide if the latter is used initially.
Regarding treat-to-target in lupus nephritis, he said that EULAR now advises to aim for a 25% drop in urine protein/creatinine ratio by 3 months, a 50% drop by 6 months, and a UPCR of less than 0.5-0.7, plus normal eGFR, by 12 months, Dr. Boumpas said.
Statement 10 advises considering high-dose intravenous cyclophosphamide in combination with pulse intravenous methylprednisolone for patients at high risk of renal failure.
Tapering drugs in sustained remission, managing antiphospholipid syndrome, giving immunizations
Statement 11 suggests to consider tapering immunosuppressive agents and glucocorticoids in patients achieving sustained remission, starting with glucocorticoids first.
There was no change to statement 12, which recommends that thrombotic antiphospholipid syndrome associated with SLE be treated with long-term vitamin K antagonists.
Statement 13 addresses immunizations and adjunct therapies. In addition to conventional immunizations, Dr. Boumpas said that renoprotection should receive attention in case of proteinuria and/or hypertension.
“With [sodium-glucose cotransporter 2] inhibitors, it’s a bit early. They’re promising, and you may consider them, although there are no data for patients with eGFR below 60 mL/min per 1.73 m2,” he remarked, completing his detailed discussion of the updated recommendations.
Dr. Boumpas reported no relevant financial relationships. Dr. Landewé served as past chair of EULAR’s Quality of Care Committee, which develops recommendations.
AT EULAR 2023
Patient selection key to lowering placebo response rates in lupus clinical trials
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.
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.
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.
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.
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.
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.
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.
AT LUPUS 2023
Strategies for complete B-cell depletion evolve for patients with lupus nephritis
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.
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.
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.
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.
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.
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.
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.
AT LUPUS 2023
Dazodalibep may mitigate Sjögren’s syndrome, but more data are needed
MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.
Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.
Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
Patients with moderate to high systemic disease activity
The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).
A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
Patients with unacceptable symptom burden but limited systemic involvement
Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.
In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.
Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
Dazodalibep safety
“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.
However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.
Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.
“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.
Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.
A version of this article first appeared on Medscape.com.
MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.
Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.
Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
Patients with moderate to high systemic disease activity
The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).
A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
Patients with unacceptable symptom burden but limited systemic involvement
Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.
In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.
Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
Dazodalibep safety
“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.
However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.
Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.
“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.
Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.
A version of this article first appeared on Medscape.com.
MILAN – Dazodalibep, an intravenously administered inhibitor of CD40 ligand, shows promise in reducing disease activity and alleviating key subjective symptoms of Sjögren’s syndrome, compared with placebo. These preliminary findings are from the initial phase of the ALISS trial, a phase 2 randomized, double-blind, placebo-controlled, crossover clinical trial presented at the annul European Congress of Rheumatology.
Over the course of the 169-day trial, both the disease activity score and the patient-reported symptom score dropped significantly for patients who were treated with dazodalibep, also known as VIB4920 or HZN4920, compared with those treated with placebo, meeting both primary endpoints. This benefit was particularly evident for patients who had limited systemic organ involvement but substantial symptom burden.
Dazodalibep is a fusion protein that functions as an inhibitor by blocking the interaction between T cells and CD40-expressing B cells. This inhibition effectively suppresses costimulatory signaling between immune cells. Unlike previous CD40-targeting biologics, dazodalibep does not belong to the antibody class. According to Horizon Thereapeutics, this distinction is expected to help mitigate safety concerns, particularly those related to blood clot formation that were encountered with antibody-based biologics such as ruplizumab, according to Horizon, which acquired the trial’s sponsor, Viela Bio.
Patients with moderate to high systemic disease activity
The trial investigated dazodalibep in two patient populations. Wan-Fai Ng, MBBCh, PhD, professor of rheumatology at Newcastle University and honorary consultant rheumatologist at Newcastle upon Tyne Hospitals NHS Foundation Trust, England, presented results from the first group, which comprised 74 adult patients with Sjögren’s syndrome with moderate to high systemic disease activity. Disease activity was defined as a score of ≥ 5 on the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).
A post hoc responder analysis demonstrated that dazodalibep outperformed placebo in patients who achieved a 5- or 6-point improvement on the ESSDAI. Response rates for these patients was 61.1% and 60.0%, respectively, compared with 35.1% and 34.3% for patients who received placebo. Patients who received dazodalibep experienced a reduction of –6.3 ± 0.6 points in ESSDAI score, whereas the placebo group experienced a reduction of –4.1 ± 0.6 points, a difference of –2.2 (P = .0167). However, there was no significant change in any symptom-related score in this population.
Patients with unacceptable symptom burden but limited systemic involvement
Also at EULAR 2023, Chiara Baldini, MD, of the University of Pisa, Italy, reported the results from the second group of 109 adult patients with Sjögren’s syndrome who had notable symptom burden but limited systemic organ involvement. “These patients represent a significant portion of individuals with reduced quality of life who are largely excluded from other clinical trials,” Dr. Baldini said in an interview. The study population was defined by having a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and, in contrast to the previous group, an ESSDAI score < 5.
In this case, treatment with dazodalibep correlated with a substantial reduction in symptom burden, compared with placebo. Among the patients who received dazodalibep, 66.7% achieved ≥ 1 point or ≥ 15% reduction in symptoms, as measured by ESSPRI, compared with 32.7% in the placebo group. The ESSPRI score decreased by –1.80 ± 0.23 points in the dazodalibep group, while it decreased by –0.53 ± 0.23 points in the placebo group, a difference of −1.27 ± 0.33 points favoring dazodalibep (P = .0002). The reduction in symptoms in the dazodalibep group was evident from the first data point on day 29 and was statistically significant for each of the three symptom components included in the ESSPRI score: dryness, pain, and fatigue.
Additionally, a significant improvement was observed in one of the secondary endpoints, namely, a reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score. The dazodalibep group exhibited a considerably greater reduction (+8.1 ± 1.4, compared with baseline) than did the placebo group (+2.8 ± 1.4; P = .0095).
Dazodalibep safety
“Dazodalibep therapy was generally safe and well tolerated,” Dr. Baldini said in her presentation. Adverse events that were reported for both investigations were generally mild and occurred with similar frequency between the treatment groups. The most commonly reported adverse events, each occurring in more than 5% of patients who received dazodalibep, were COVID-19, diarrhea, anemia, dizziness, ligament sprain, upper respiratory tract infection, and nasopharyngitis. The incidence of COVID-19 and nasopharyngitis was comparable between the treatment and placebo arms.
However, in the patient group with moderate to high systemic disease activity, one patient who was treated with dazodalibep experienced two serious adverse events: a grade 3 SARS-CoV-2 infection, and subsequent death from an unknown cause, which occurred 46 days after the last administration of dazodalibep (12 days after COVID-19 diagnosis). Additionally, there was one case of herpes zoster in a patient treated with dazodalibep. In the group with limited systemic organ involvement, three serious adverse events were reported in the dazodalibep group (pneumonia influenza, postacute COVID-19 syndrome [long COVID], and gammopathy); one serious adverse event (neutropenia) was reported in the placebo group. One patient in the dazodalibep group discontinued participation in the study because of an adverse event, compared with two in the placebo group. Investigators determined that, thus far, all serious adverse events in both populations have been unrelated to the medication.
Throughout the trial, eligible participants in both populations were randomly assigned in a 1:1 ratio to receive either intravenous dazodalibep 1,500 mg or placebo every 2 weeks for three doses, followed by every 4 weeks for an additional four doses, up to day 169. The majority of participants in all populations and treatment arms were women (> 90%). Key inclusion criteria were being aged 18 years or older, meeting the 2016 American College of Rheumatology–EULAR classification criteria for Sjögren’s syndrome, and testing positive for anti-SSA and/or rheumatoid factors. Exclusion criteria were having a medical history of thrombosis or anticoagulant use, as well as prior treatment with B cell–depleting therapies. The proportions of patients who received glucocorticoids, antimalarials, or disease-modifying antirheumatic drugs were consistent between both arms of each population.
“Larger clinical trials are necessary to validate the clinical effectiveness and safety of dazodalibep therapy in this specific subgroup of patients,” Dr. Baldini concluded. Currently, dazodalibep is being studied for the treatment of rheumatoid arthritis and renal transplant rejection, and Horizon Therapeutics has plans to explore its use in focal segmental glomerulosclerosis.
Dr. Ng has served as a consultant to Novartis, GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Sanofi, MedImmune, Resolves Therapeutics, Janssen, and UCB. Dr. Baldini has served as a consultant to GlaxoSmithKline and Sanofi.
A version of this article first appeared on Medscape.com.
AT EULAR 2023
EULAR systemic sclerosis recommendations now include immunosuppressants
MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.
Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.
“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.
“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.
The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.
“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.
Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.
In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.
A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.
“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.
He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”
“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.
The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.
Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.
Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.
“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.
Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”
Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”
Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”
Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.
MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.
Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.
“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.
“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.
The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.
“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.
Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.
In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.
A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.
“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.
He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”
“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.
The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.
Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.
Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.
“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.
Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”
Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”
Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”
Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.
MILAN – Targeted synthetic and biologic therapies are recommended as disease-modifying agents for key fibrotic manifestations of systemic sclerosis for the first time in the 2023 update of European Alliance of Associations for Rheumatology recommendations for the treatment of systemic sclerosis.
Reflecting important advances over the past 8 years, mostly relating to the use of new treatments being made available to patients, the recommendations provide an update on the 2017 recommendations, which relied on evidence published through 2014. Of note, these include the use of immunosuppressive agents, for example, the monoclonal antibody rituximab (Rituxan) for skin and lung fibrosis.
“For the first time, synthetic and targeted treatments are recommended for the treatment of systemic sclerosis–interstitial lung disease, including mycophenolate mofetil [Cellcept], nintedanib [Ofev], rituximab, and tocilizumab [Actemra]. None of these were present in 2017. Mycophenolate mofetil is also recommended for the treatment of skin fibrosis, and this was not present in 2017,” Francesco Del Galdo, MD, rheumatology consultant at Leeds Teaching Hospital NHS Trust, Leeds, England, and member of the 2023 recommendations task force, said in an interview. He gave an overview of the preliminary recommendations at the annual European Congress of Rheumatology.
“Phosphodiesterase-5 [PDE-5] inhibitors and endothelin receptor antagonist [ERA] monotherapy are also recommended for up-front combination use for digital ulcers and pulmonary hypertension, and this is new for 2023 and was not present in the 2017 recommendations,” Dr. Del Galdo added.
The new recommendations also note that iloprost is categorized as having grade A evidence for use in Raynaud’s phenomenon and digital ulcers, while it has grade B evidence for pulmonary hypertension.
“We are not allowed to share the final table [of recommendations] today because the wording has only very recently been agreed” upon, Dr. Del Galdo said, but he provided a summary representation and reflected on some changes, noting that the task force is aiming to publish the 2023 recommendations by the end of the year.
Consideration and discussion of both established and new evidence highlighted a need for more evidence on the use of immunosuppressive agents in vascular manifestations of systemic sclerosis, as well as for gastrointestinal and musculoskeletal ones.
In this update to the 2017 recommendations, high-grade evidence was identified for use of immunosuppressants in skin and lung fibrosis. Grade A evidence has been accepted for the use of rituximab in skin fibrosis; for interstitial lung disease, rituximab, cyclophosphamide, and nintedanib also have grade A evidence, which is a change from the 2017 recommendations.
A total of 20 updated recommendations were agreed on, an increase from 16 in 2017. These were grouped into eight disease domains: Raynaud’s phenomenon, digital ulcers, pulmonary arterial hypertension, skin fibrosis, interstitial lung disease, musculoskeletal and gastrointestinal manifestations, and renal crisis. Interventions were then graded A-D based on the evidence reviewed.
“This approach allowed us to see clearly that there were patterns of similar recommendations in different organ manifestations, reflecting an understanding of common pathogenic pathways,” said Dr. Del Galdo.
He also noted that the development of the recommendations highlighted certain gaps in research that limit treatment options. “By grouping the recommendations in blocks – for example, skin fibrosis or vascular [manifestations] – we show that immunosuppressive treatments have only been studied in skin and lung, while vascular manifestations have very little evidence for immunosuppression. They might be effective but there’s no evidence yet [hence no recommendation in vascular manifestations].”
“Also, there’s no grade A evidence at all for musculoskeletal and gastrointestinal manifestations, and this should help to define the research agenda going forward,” Dr. Del Galdo said.
The 2023 recommendations task force comprised 28 members from 14 countries, including 18 rheumatologists, 1 EULAR methodologist, 1 health professional representative, 5 rheumatology fellows, 1 librarian, and 2 patient representatives. They used a consensual approach incorporating the views of 101 European Scleroderma Trials and Research group (EUSTAR) centers, sourced via a survey in which questions were advanced to an extensive systematic review if there was 70% or greater agreement.
Eventually, 31 questions on interventions were chosen, and the task force reviewed 12,500 abstracts (up to December 2022) related to interventions and outcomes that were either included in the 2017 recommendations or were totally new.
Dr. Del Galdo said that the three vascular manifestations of scleroderma – Raynaud’s, pulmonary arterial hypertension, and digital ulcers – were treated with the same drugs, all with a similar grade of evidence. “This suggests two things – firstly there’s a vascular disease continuum in the disease, and secondly, we’ve borrowed these drugs from vascular community, but we have not yet tested synthetic and biologic targeted treatments in these manifestations, and we should.
“Treating one manifestation may benefit the other, and this is important time wise because pulmonary hypertension usually comes around 10 years after the first phenomena so by treating digital ulcers and Raynaud’s phenomena, we may prevent pulmonary hypertension, but a study is needed,” added Dr. Del Galdo, who is also president of EUSTAR.
Finally, he pointed out that research remains particularly open for nonpharmacologic treatments for digital ulcers and severe gastrointestinal involvement. “Patients can now ask for studies into this because of the current lack of evidence.”
Moderator Ariane Herrick, PhD, professor of rheumatology at the University of Manchester (England), shared her thoughts on the guidelines. “These recommendations have been long awaited by the scleroderma community because there has been some exciting progress in recent years, and the new recommendations reflect these new developments.”
Commenting on the paucity of evidence in some areas, she added that “there do remain some huge areas of unmet need that are difficult to address, and these are musculoskeletal, gastrointestinal, and calcinosis, for which there have been no trials at all.”
Dr. Del Galdo declared disclosures relating to AstraZeneca, Janssen, Boehringer Ingelheim, Capella, Chemomab, GlaxoSmithKline, and Mitsubishi-Tanabe. Dr. Herrick disclosed serving as a consultant for Boehringer Ingelheim and Janssen.
AT EULAR 2023