Lupus & Connective Tissue Diseases

A revolutionary treatment for cancers may also be able to treat and reset the immune system to provide long-term remission or possibly even cure certain autoimmune diseases.

Chimeric antigen receptor (CAR) T-cell therapy has offered a novel approach to treating hematologic cancers since 2017, but there are early signs that these cellular immunotherapies could be repurposed for B-cell mediated autoimmune diseases.

In September of last year, researchers in Germany reported that five patients with refractory systemic lupus erythematosus (SLE) treated with CAR T-cell therapy all achieved drug-free remission. At the time of publication, no patients had relapsed for up to 17 months after treatment. The authors described seroconversion of antinuclear antibodies in two patients with the longest follow-up, “indicating that abrogation of autoimmune B-cell clones may lead to a more widespread correction of autoimmunity,” the researchers write.

In another case study published in June, researchers used CD-19 targeted CAR-T cells to treat a 41-year-old man with refractory antisynthetase syndrome with progressive myositis and interstitial lung disease. Six months after treatment, there were no signs of myositis on MRI and a chest CT scan showed full regression of alveolitis.

John Hopkins Medicine

Since then, two biotechnology companies – Cabaletta Bio in Philadelphia and Kyverna Therapeutics in Emeryville, Calif. – have already been granted fast-track designations from the U.S. Food and Drug Administration for CAR T-cell therapy for SLE and lupus nephritis. Bristol-Myers Squibb is also conducting a phase 1 trial in patients with severe, refractory SLE. Several biotechnology companies and hospitals in China are also conducting clinical trials for SLE. But this is only the tip of the iceberg regarding cellular therapies for autoimmune disease, said Max Konig, MD, PhD, an assistant professor of medicine in the division of rheumatology at Johns Hopkins University, Baltimore.

“It’s an incredibly exciting time. It’s unprecedented in the history of autoimmunity,” he noted.
 

A ‘reboot’ for the immune system

B-cell targeted therapies have been around since the early 2000s with drugs like rituximab, a monoclonal antibody medication that targets CD20, an antigen expressed on the surface of B cells. The CAR T cells currently available target another surface antigen, CD19, and are a much more potent therapy. Both are effective at depleting B cells in blood, but these engineered CD19-targeted T cells can reach B cells sitting in tissues in a way that antibody therapies cannot, Dr. Konig explained.

“If you have a patient with myositis, for example, where autoreactive B cells are sitting in the inflamed muscle, or a patient with rheumatoid arthritis, where you have disease-relevant B cells in hard-to-reach tissues like the synovium, those cells are much harder to deplete with an antibody, compared to a T cell that evolved to surveil and effectively kill in all tissues,” he explained.

In this process, T cells are collected from patients via leukapheresis and then re-engineered to express chimeric antigen receptors. A few days before these modified T cells are infused back into the patient, the patients are given a low-dose chemotherapy (lymphodepletion) regimen to help increase the effectiveness of the therapy. The one-time infusion is generally given on an inpatient basis, and patients are then monitored in hospital for side effects.

Once B cells are depleted, disease symptoms improve. But in the case studies published to date, once B cells re-emerge, they are naïve and no longer producing autoreactive B cells.
 

“Maybe it’s like a tabula rasa: You wipe [the B cells] out and start with a clean slate. Then, the immune system reboots, and now it’s working, whereas before it was messed up,” said Carl June, MD, who directs the Center for Cellular Immunotherapies at the at the University of Pennsylvania, Philadelphia. Dr. June and his research team led the development of CAR T-cell therapies for blood cancers.

The findings suggest that autoantibodies “might not be hardwired into the immune system,” he said.

But Dr. Konig stressed that we are still in the early days of clinical trials, and more research is necessary to understand the safety and efficacy of these therapies.

“There’s an incredible buzz around CAR T cells at the moment in rheumatology, which is great because I think that’s where the future is,” he said. “But we still need to learn how to appropriately apply these therapies in randomized, controlled trials.”

So far, the evidence behind CD19 CAR T-cell therapies in autoimmune disease is from case studies and phase 1 trials in a very small number of selected patients. (The upcoming Cabaletta and Kyverna trials in lupus will also be small, consisting of 12 patients each.)
 

Risks of intensive therapy

But while these therapies show promise, the process is very intensive. The lymphodepleting regimen increases the risk for infection and patients are commonly hospitalized for a week or more following infusion for toxicity monitoring. Serious adverse events such as cytokine release syndrome (CRS) can occur days to weeks after CAR T-cell infusion. In the five-patient case series reported in 2022, patients were hospitalized for 10 days following treatment.

The patient with antisynthetase syndrome, as well as three of five patients in the SLE case series study experienced mild CRS following infusion. Patients are also at a high risk for infection, as the engineered T cells target all B cells, not just the autoreactive immune cells.

The inability to differentiate between disease-causing and protective immune cells is an issue for all currently available drugs treating autoimmune disease, Dr. Konig said. But scientists are already working on how to make these potent cellular therapies safer and more precise.
 

Alternatives to standard CAR T-cell therapies

Engineering T cells with RNA is a new approach to limit the side effects and toxicity of CAR T-cell therapy, said Chris Jewell, PhD, the chief scientific officer at Cartesian Therapeutics, a biotechnology company based in Gaithersburg, Md. The company’s RNA CAR T-cell (rCAR-T) therapy – called DESCARTES-08 – is in phase 2 clinical trials for treatment of myasthenia gravis. Once these rCAR-T cells are infused in patients, as they divide, the RNAnaturally decays, he explained, meaning that after a certain point, the CAR is no longer expressed.

Cartesian Therapeutics

DESCARTES-08 targets B-cell maturation antigen (BCMA), which is primarily expressed on plasma cells, rather than all B cells, Dr. Jewell said.

“Targeting BCMA, we actually have a more selective profile,” he explained. “We are targeting the cells primarily responsible for the pathogenicity; many plasma cells – such as long-lived plasma cells – also take a long time to repopulate.”

This therapy also does not require lymphodepletion prior to infusion and can be done in an outpatient setting. The therapy is given in multiple infusions, once per week.

In the most recent clinical trial, patients with myasthenia gravis received six infusions over 6 weeks and experienced notable decreases in myasthenia gravis severity scale at up to 9 months of follow-up.

Abata Therapeutics

While standard CAR T-cell therapies under clinical investigational up to now all use effector T cells, regulatory T cells (Tregs) can also be engineered to target autoimmune disease. Abata Therapeutics, based in Boston, is using this approach for therapies for progressive multiple sclerosis and type 1 diabetes. These engineered Tregs express a T-cell receptor (TCR) that recognizes tissue-specific antigens and suppress inflammation at the site of the disease. “Treg-based cell therapies are really harnessing the natural power of regulatory cells to reset immune tolerance and recalibrate the immune system,” said their chief medical officer, Leonard Dragone, MD, PhD.

These therapies are derived from terminally differentiated cells that have limited capacity to produce pro-inflammatory cytokines including interleukin-2 or interferon gamma, Dr. Dragone explained. “CRS is difficult to envision from engineered Treg products and hasn’t been observed in any clinical experience with polyclonal Tregs,” he said.

This approach also does not require lymphodepletion prior to treatment. The company’s Treg cellular therapy for progressive MS is currently in investigational new drug-enabling studies, and they aim to dose their first patients in 2024.
 

Precision immunotherapy

For B-cell driven autoimmune diseases where the autoantibody is known, researchers have begun to re-engineer T cells to recognize only autoreactive B cells. While CD19 CAR T cells act more like a sledgehammer, these precision cellular immunotherapies are “like a razor’s strike,” Dr. June said.

University of Pennsylvania

“The chimeric autoantibody receptor (CAAR) approach targets autoantibodies that are expressed only on the surface of autoimmune B cells and are not expressed on normal B cells, which ideally should lead to precision targeting of just the cells that cause autoimmune disease,” explained Aimee Payne, MD, PhD, professor of dermatology and director of the Penn Clinical Autoimmunity Center of Excellence at the University of Pennsylvania, Philadelphia.

She and her research team used this approach to develop a treatment for mucosal pemphigus vulgaris, an autoimmune blistering disease of mucous membranes driven by autoantibodies against desmoglein 3.

“The current standard of care for pemphigus is to treat with steroids and rituximab, an infusion therapy that results in global, but temporary, B-cell depletion,” she said. “By expressing desmoglein 3 (DSG3) on the surface of the CAAR T-cell therapy, we target just the anti-DSG3 B cells that cause disease in mucosal pemphigus vulgaris and spare the healthy B cells.”

The therapy – called DSG3-CAART – is being developed by Cabaletta Bio and is now in phase 1 clinical trials. The approach is also being investigated to treat certain types of myasthenia gravis and membranous nephropathy.

Dr. Konig’s lab at Johns Hopkins developed and is now exploring a new precision cellular immunotherapy approach, chimeric autoantigen-T cell receptor (CATCR) T-cell therapy, to treat antiphospholipid syndrome, which is in preclinical stages. In this approach, Dr. Konig and his team are “re-engineering the natural T-cell receptor to selectively kill disease-causing B cells that drive antiphospholipid syndrome,” he explained.

He anticipates the CD19 CAR T-cell therapies currently in clinical trials will help to pave the way for this new generation of precision cellular therapies. The ultimate goal of these therapies, he said, is to uncouple therapeutic potency from infection risk.

“That’s really the holy grail in the treatment of autoimmune diseases. It’s tantalizingly close, but we’re not there yet.”

Dr. June is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. Dr. June is a scientific founder of Tmunity Therapeutics and Capstan Therapeutics and is a member of the scientific advisory boards of AC Immune SA, Alaunos, BlueSphere Bio, Cabaletta, Carisma, Cartography Biosciences, Cellares, Celldex, Decheng Capital, Poseida, Verismo, and WIRB-Copernicus Group. Dr. Konig is a consultant for argenx and Revel and is listed as inventor for patent applications filed by John Hopkins University. Dr. Payne holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen.

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

A revolutionary treatment for cancers may also be able to treat and reset the immune system to provide long-term remission or possibly even cure certain autoimmune diseases.

Chimeric antigen receptor (CAR) T-cell therapy has offered a novel approach to treating hematologic cancers since 2017, but there are early signs that these cellular immunotherapies could be repurposed for B-cell mediated autoimmune diseases.

In September of last year, researchers in Germany reported that five patients with refractory systemic lupus erythematosus (SLE) treated with CAR T-cell therapy all achieved drug-free remission. At the time of publication, no patients had relapsed for up to 17 months after treatment. The authors described seroconversion of antinuclear antibodies in two patients with the longest follow-up, “indicating that abrogation of autoimmune B-cell clones may lead to a more widespread correction of autoimmunity,” the researchers write.

In another case study published in June, researchers used CD-19 targeted CAR-T cells to treat a 41-year-old man with refractory antisynthetase syndrome with progressive myositis and interstitial lung disease. Six months after treatment, there were no signs of myositis on MRI and a chest CT scan showed full regression of alveolitis.

John Hopkins Medicine

Since then, two biotechnology companies – Cabaletta Bio in Philadelphia and Kyverna Therapeutics in Emeryville, Calif. – have already been granted fast-track designations from the U.S. Food and Drug Administration for CAR T-cell therapy for SLE and lupus nephritis. Bristol-Myers Squibb is also conducting a phase 1 trial in patients with severe, refractory SLE. Several biotechnology companies and hospitals in China are also conducting clinical trials for SLE. But this is only the tip of the iceberg regarding cellular therapies for autoimmune disease, said Max Konig, MD, PhD, an assistant professor of medicine in the division of rheumatology at Johns Hopkins University, Baltimore.

“It’s an incredibly exciting time. It’s unprecedented in the history of autoimmunity,” he noted.
 

A ‘reboot’ for the immune system

B-cell targeted therapies have been around since the early 2000s with drugs like rituximab, a monoclonal antibody medication that targets CD20, an antigen expressed on the surface of B cells. The CAR T cells currently available target another surface antigen, CD19, and are a much more potent therapy. Both are effective at depleting B cells in blood, but these engineered CD19-targeted T cells can reach B cells sitting in tissues in a way that antibody therapies cannot, Dr. Konig explained.

“If you have a patient with myositis, for example, where autoreactive B cells are sitting in the inflamed muscle, or a patient with rheumatoid arthritis, where you have disease-relevant B cells in hard-to-reach tissues like the synovium, those cells are much harder to deplete with an antibody, compared to a T cell that evolved to surveil and effectively kill in all tissues,” he explained.

In this process, T cells are collected from patients via leukapheresis and then re-engineered to express chimeric antigen receptors. A few days before these modified T cells are infused back into the patient, the patients are given a low-dose chemotherapy (lymphodepletion) regimen to help increase the effectiveness of the therapy. The one-time infusion is generally given on an inpatient basis, and patients are then monitored in hospital for side effects.

Once B cells are depleted, disease symptoms improve. But in the case studies published to date, once B cells re-emerge, they are naïve and no longer producing autoreactive B cells.
 

“Maybe it’s like a tabula rasa: You wipe [the B cells] out and start with a clean slate. Then, the immune system reboots, and now it’s working, whereas before it was messed up,” said Carl June, MD, who directs the Center for Cellular Immunotherapies at the at the University of Pennsylvania, Philadelphia. Dr. June and his research team led the development of CAR T-cell therapies for blood cancers.

The findings suggest that autoantibodies “might not be hardwired into the immune system,” he said.

But Dr. Konig stressed that we are still in the early days of clinical trials, and more research is necessary to understand the safety and efficacy of these therapies.

“There’s an incredible buzz around CAR T cells at the moment in rheumatology, which is great because I think that’s where the future is,” he said. “But we still need to learn how to appropriately apply these therapies in randomized, controlled trials.”

So far, the evidence behind CD19 CAR T-cell therapies in autoimmune disease is from case studies and phase 1 trials in a very small number of selected patients. (The upcoming Cabaletta and Kyverna trials in lupus will also be small, consisting of 12 patients each.)
 

Risks of intensive therapy

But while these therapies show promise, the process is very intensive. The lymphodepleting regimen increases the risk for infection and patients are commonly hospitalized for a week or more following infusion for toxicity monitoring. Serious adverse events such as cytokine release syndrome (CRS) can occur days to weeks after CAR T-cell infusion. In the five-patient case series reported in 2022, patients were hospitalized for 10 days following treatment.

The patient with antisynthetase syndrome, as well as three of five patients in the SLE case series study experienced mild CRS following infusion. Patients are also at a high risk for infection, as the engineered T cells target all B cells, not just the autoreactive immune cells.

The inability to differentiate between disease-causing and protective immune cells is an issue for all currently available drugs treating autoimmune disease, Dr. Konig said. But scientists are already working on how to make these potent cellular therapies safer and more precise.
 

Alternatives to standard CAR T-cell therapies

Engineering T cells with RNA is a new approach to limit the side effects and toxicity of CAR T-cell therapy, said Chris Jewell, PhD, the chief scientific officer at Cartesian Therapeutics, a biotechnology company based in Gaithersburg, Md. The company’s RNA CAR T-cell (rCAR-T) therapy – called DESCARTES-08 – is in phase 2 clinical trials for treatment of myasthenia gravis. Once these rCAR-T cells are infused in patients, as they divide, the RNAnaturally decays, he explained, meaning that after a certain point, the CAR is no longer expressed.

Cartesian Therapeutics

DESCARTES-08 targets B-cell maturation antigen (BCMA), which is primarily expressed on plasma cells, rather than all B cells, Dr. Jewell said.

“Targeting BCMA, we actually have a more selective profile,” he explained. “We are targeting the cells primarily responsible for the pathogenicity; many plasma cells – such as long-lived plasma cells – also take a long time to repopulate.”

This therapy also does not require lymphodepletion prior to infusion and can be done in an outpatient setting. The therapy is given in multiple infusions, once per week.

In the most recent clinical trial, patients with myasthenia gravis received six infusions over 6 weeks and experienced notable decreases in myasthenia gravis severity scale at up to 9 months of follow-up.

Abata Therapeutics

While standard CAR T-cell therapies under clinical investigational up to now all use effector T cells, regulatory T cells (Tregs) can also be engineered to target autoimmune disease. Abata Therapeutics, based in Boston, is using this approach for therapies for progressive multiple sclerosis and type 1 diabetes. These engineered Tregs express a T-cell receptor (TCR) that recognizes tissue-specific antigens and suppress inflammation at the site of the disease. “Treg-based cell therapies are really harnessing the natural power of regulatory cells to reset immune tolerance and recalibrate the immune system,” said their chief medical officer, Leonard Dragone, MD, PhD.

These therapies are derived from terminally differentiated cells that have limited capacity to produce pro-inflammatory cytokines including interleukin-2 or interferon gamma, Dr. Dragone explained. “CRS is difficult to envision from engineered Treg products and hasn’t been observed in any clinical experience with polyclonal Tregs,” he said.

This approach also does not require lymphodepletion prior to treatment. The company’s Treg cellular therapy for progressive MS is currently in investigational new drug-enabling studies, and they aim to dose their first patients in 2024.
 

Precision immunotherapy

For B-cell driven autoimmune diseases where the autoantibody is known, researchers have begun to re-engineer T cells to recognize only autoreactive B cells. While CD19 CAR T cells act more like a sledgehammer, these precision cellular immunotherapies are “like a razor’s strike,” Dr. June said.

University of Pennsylvania

“The chimeric autoantibody receptor (CAAR) approach targets autoantibodies that are expressed only on the surface of autoimmune B cells and are not expressed on normal B cells, which ideally should lead to precision targeting of just the cells that cause autoimmune disease,” explained Aimee Payne, MD, PhD, professor of dermatology and director of the Penn Clinical Autoimmunity Center of Excellence at the University of Pennsylvania, Philadelphia.

She and her research team used this approach to develop a treatment for mucosal pemphigus vulgaris, an autoimmune blistering disease of mucous membranes driven by autoantibodies against desmoglein 3.

“The current standard of care for pemphigus is to treat with steroids and rituximab, an infusion therapy that results in global, but temporary, B-cell depletion,” she said. “By expressing desmoglein 3 (DSG3) on the surface of the CAAR T-cell therapy, we target just the anti-DSG3 B cells that cause disease in mucosal pemphigus vulgaris and spare the healthy B cells.”

The therapy – called DSG3-CAART – is being developed by Cabaletta Bio and is now in phase 1 clinical trials. The approach is also being investigated to treat certain types of myasthenia gravis and membranous nephropathy.

Dr. Konig’s lab at Johns Hopkins developed and is now exploring a new precision cellular immunotherapy approach, chimeric autoantigen-T cell receptor (CATCR) T-cell therapy, to treat antiphospholipid syndrome, which is in preclinical stages. In this approach, Dr. Konig and his team are “re-engineering the natural T-cell receptor to selectively kill disease-causing B cells that drive antiphospholipid syndrome,” he explained.

He anticipates the CD19 CAR T-cell therapies currently in clinical trials will help to pave the way for this new generation of precision cellular therapies. The ultimate goal of these therapies, he said, is to uncouple therapeutic potency from infection risk.

“That’s really the holy grail in the treatment of autoimmune diseases. It’s tantalizingly close, but we’re not there yet.”

Dr. June is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. Dr. June is a scientific founder of Tmunity Therapeutics and Capstan Therapeutics and is a member of the scientific advisory boards of AC Immune SA, Alaunos, BlueSphere Bio, Cabaletta, Carisma, Cartography Biosciences, Cellares, Celldex, Decheng Capital, Poseida, Verismo, and WIRB-Copernicus Group. Dr. Konig is a consultant for argenx and Revel and is listed as inventor for patent applications filed by John Hopkins University. Dr. Payne holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen.

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

A revolutionary treatment for cancers may also be able to treat and reset the immune system to provide long-term remission or possibly even cure certain autoimmune diseases.

Chimeric antigen receptor (CAR) T-cell therapy has offered a novel approach to treating hematologic cancers since 2017, but there are early signs that these cellular immunotherapies could be repurposed for B-cell mediated autoimmune diseases.

In September of last year, researchers in Germany reported that five patients with refractory systemic lupus erythematosus (SLE) treated with CAR T-cell therapy all achieved drug-free remission. At the time of publication, no patients had relapsed for up to 17 months after treatment. The authors described seroconversion of antinuclear antibodies in two patients with the longest follow-up, “indicating that abrogation of autoimmune B-cell clones may lead to a more widespread correction of autoimmunity,” the researchers write.

In another case study published in June, researchers used CD-19 targeted CAR-T cells to treat a 41-year-old man with refractory antisynthetase syndrome with progressive myositis and interstitial lung disease. Six months after treatment, there were no signs of myositis on MRI and a chest CT scan showed full regression of alveolitis.

John Hopkins Medicine

Since then, two biotechnology companies – Cabaletta Bio in Philadelphia and Kyverna Therapeutics in Emeryville, Calif. – have already been granted fast-track designations from the U.S. Food and Drug Administration for CAR T-cell therapy for SLE and lupus nephritis. Bristol-Myers Squibb is also conducting a phase 1 trial in patients with severe, refractory SLE. Several biotechnology companies and hospitals in China are also conducting clinical trials for SLE. But this is only the tip of the iceberg regarding cellular therapies for autoimmune disease, said Max Konig, MD, PhD, an assistant professor of medicine in the division of rheumatology at Johns Hopkins University, Baltimore.

“It’s an incredibly exciting time. It’s unprecedented in the history of autoimmunity,” he noted.
 

A ‘reboot’ for the immune system

B-cell targeted therapies have been around since the early 2000s with drugs like rituximab, a monoclonal antibody medication that targets CD20, an antigen expressed on the surface of B cells. The CAR T cells currently available target another surface antigen, CD19, and are a much more potent therapy. Both are effective at depleting B cells in blood, but these engineered CD19-targeted T cells can reach B cells sitting in tissues in a way that antibody therapies cannot, Dr. Konig explained.

“If you have a patient with myositis, for example, where autoreactive B cells are sitting in the inflamed muscle, or a patient with rheumatoid arthritis, where you have disease-relevant B cells in hard-to-reach tissues like the synovium, those cells are much harder to deplete with an antibody, compared to a T cell that evolved to surveil and effectively kill in all tissues,” he explained.

In this process, T cells are collected from patients via leukapheresis and then re-engineered to express chimeric antigen receptors. A few days before these modified T cells are infused back into the patient, the patients are given a low-dose chemotherapy (lymphodepletion) regimen to help increase the effectiveness of the therapy. The one-time infusion is generally given on an inpatient basis, and patients are then monitored in hospital for side effects.

Once B cells are depleted, disease symptoms improve. But in the case studies published to date, once B cells re-emerge, they are naïve and no longer producing autoreactive B cells.
 

“Maybe it’s like a tabula rasa: You wipe [the B cells] out and start with a clean slate. Then, the immune system reboots, and now it’s working, whereas before it was messed up,” said Carl June, MD, who directs the Center for Cellular Immunotherapies at the at the University of Pennsylvania, Philadelphia. Dr. June and his research team led the development of CAR T-cell therapies for blood cancers.

The findings suggest that autoantibodies “might not be hardwired into the immune system,” he said.

But Dr. Konig stressed that we are still in the early days of clinical trials, and more research is necessary to understand the safety and efficacy of these therapies.

“There’s an incredible buzz around CAR T cells at the moment in rheumatology, which is great because I think that’s where the future is,” he said. “But we still need to learn how to appropriately apply these therapies in randomized, controlled trials.”

So far, the evidence behind CD19 CAR T-cell therapies in autoimmune disease is from case studies and phase 1 trials in a very small number of selected patients. (The upcoming Cabaletta and Kyverna trials in lupus will also be small, consisting of 12 patients each.)
 

Risks of intensive therapy

But while these therapies show promise, the process is very intensive. The lymphodepleting regimen increases the risk for infection and patients are commonly hospitalized for a week or more following infusion for toxicity monitoring. Serious adverse events such as cytokine release syndrome (CRS) can occur days to weeks after CAR T-cell infusion. In the five-patient case series reported in 2022, patients were hospitalized for 10 days following treatment.

The patient with antisynthetase syndrome, as well as three of five patients in the SLE case series study experienced mild CRS following infusion. Patients are also at a high risk for infection, as the engineered T cells target all B cells, not just the autoreactive immune cells.

The inability to differentiate between disease-causing and protective immune cells is an issue for all currently available drugs treating autoimmune disease, Dr. Konig said. But scientists are already working on how to make these potent cellular therapies safer and more precise.
 

Alternatives to standard CAR T-cell therapies

Engineering T cells with RNA is a new approach to limit the side effects and toxicity of CAR T-cell therapy, said Chris Jewell, PhD, the chief scientific officer at Cartesian Therapeutics, a biotechnology company based in Gaithersburg, Md. The company’s RNA CAR T-cell (rCAR-T) therapy – called DESCARTES-08 – is in phase 2 clinical trials for treatment of myasthenia gravis. Once these rCAR-T cells are infused in patients, as they divide, the RNAnaturally decays, he explained, meaning that after a certain point, the CAR is no longer expressed.

Cartesian Therapeutics

DESCARTES-08 targets B-cell maturation antigen (BCMA), which is primarily expressed on plasma cells, rather than all B cells, Dr. Jewell said.

“Targeting BCMA, we actually have a more selective profile,” he explained. “We are targeting the cells primarily responsible for the pathogenicity; many plasma cells – such as long-lived plasma cells – also take a long time to repopulate.”

This therapy also does not require lymphodepletion prior to infusion and can be done in an outpatient setting. The therapy is given in multiple infusions, once per week.

In the most recent clinical trial, patients with myasthenia gravis received six infusions over 6 weeks and experienced notable decreases in myasthenia gravis severity scale at up to 9 months of follow-up.

Abata Therapeutics

While standard CAR T-cell therapies under clinical investigational up to now all use effector T cells, regulatory T cells (Tregs) can also be engineered to target autoimmune disease. Abata Therapeutics, based in Boston, is using this approach for therapies for progressive multiple sclerosis and type 1 diabetes. These engineered Tregs express a T-cell receptor (TCR) that recognizes tissue-specific antigens and suppress inflammation at the site of the disease. “Treg-based cell therapies are really harnessing the natural power of regulatory cells to reset immune tolerance and recalibrate the immune system,” said their chief medical officer, Leonard Dragone, MD, PhD.

These therapies are derived from terminally differentiated cells that have limited capacity to produce pro-inflammatory cytokines including interleukin-2 or interferon gamma, Dr. Dragone explained. “CRS is difficult to envision from engineered Treg products and hasn’t been observed in any clinical experience with polyclonal Tregs,” he said.

This approach also does not require lymphodepletion prior to treatment. The company’s Treg cellular therapy for progressive MS is currently in investigational new drug-enabling studies, and they aim to dose their first patients in 2024.
 

Precision immunotherapy

For B-cell driven autoimmune diseases where the autoantibody is known, researchers have begun to re-engineer T cells to recognize only autoreactive B cells. While CD19 CAR T cells act more like a sledgehammer, these precision cellular immunotherapies are “like a razor’s strike,” Dr. June said.

University of Pennsylvania

“The chimeric autoantibody receptor (CAAR) approach targets autoantibodies that are expressed only on the surface of autoimmune B cells and are not expressed on normal B cells, which ideally should lead to precision targeting of just the cells that cause autoimmune disease,” explained Aimee Payne, MD, PhD, professor of dermatology and director of the Penn Clinical Autoimmunity Center of Excellence at the University of Pennsylvania, Philadelphia.

She and her research team used this approach to develop a treatment for mucosal pemphigus vulgaris, an autoimmune blistering disease of mucous membranes driven by autoantibodies against desmoglein 3.

“The current standard of care for pemphigus is to treat with steroids and rituximab, an infusion therapy that results in global, but temporary, B-cell depletion,” she said. “By expressing desmoglein 3 (DSG3) on the surface of the CAAR T-cell therapy, we target just the anti-DSG3 B cells that cause disease in mucosal pemphigus vulgaris and spare the healthy B cells.”

The therapy – called DSG3-CAART – is being developed by Cabaletta Bio and is now in phase 1 clinical trials. The approach is also being investigated to treat certain types of myasthenia gravis and membranous nephropathy.

Dr. Konig’s lab at Johns Hopkins developed and is now exploring a new precision cellular immunotherapy approach, chimeric autoantigen-T cell receptor (CATCR) T-cell therapy, to treat antiphospholipid syndrome, which is in preclinical stages. In this approach, Dr. Konig and his team are “re-engineering the natural T-cell receptor to selectively kill disease-causing B cells that drive antiphospholipid syndrome,” he explained.

He anticipates the CD19 CAR T-cell therapies currently in clinical trials will help to pave the way for this new generation of precision cellular therapies. The ultimate goal of these therapies, he said, is to uncouple therapeutic potency from infection risk.

“That’s really the holy grail in the treatment of autoimmune diseases. It’s tantalizingly close, but we’re not there yet.”

Dr. June is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives license revenue from such licenses. Dr. June is a scientific founder of Tmunity Therapeutics and Capstan Therapeutics and is a member of the scientific advisory boards of AC Immune SA, Alaunos, BlueSphere Bio, Cabaletta, Carisma, Cartography Biosciences, Cellares, Celldex, Decheng Capital, Poseida, Verismo, and WIRB-Copernicus Group. Dr. Konig is a consultant for argenx and Revel and is listed as inventor for patent applications filed by John Hopkins University. Dr. Payne holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen.

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

TOPLINE:

Blood samples from healthy adults show an inhibition of neutrophil extracellular trap formation (NET) after 1 week of daily ginger supplements.

METHODOLOGY:

• Researchers recruited nine healthy adults aged 18-38 years to receive a 100-mg oral ginger supplement daily for 7 consecutive days.
• Blood samples were collected at baseline and on days 7 and 14, with isolation of neutrophils, peripheral blood mononuclear cells, and plasma.
• The researchers measured NET formation (NETosis) as a way to show the effect of ginger on inflammation.

TAKEAWAY:

• Measures of neutrophil cyclic AMP (cAMP) were significantly higher after 7 days of ginger supplements, compared with baseline levels, although these levels returned to near baseline by 1 week after discontinuing ginger consumption.
• Oral ginger supplements reduced neutrophil phosphodiesterase (PDE) activity by 40% from baseline, similar to results seen with synthetic PDE4 inhibitors.
• The results build on previous studies showing inhibition of neutrophil hyperactivity in mice with antiphospholipid syndrome and lupus after injection with a purified ginger preparation.
• Researchers replicated the results showing effects of oral ginger on neutrophils in eight additional healthy adults who also showed reduced NETosis and increased cAMP after 1 week of ginger supplements.

IN PRACTICE:

The results show biologic support for the potential of ginger to affect neutrophil function in humans; therefore, “ginger may have a real ability to complement treatment programs that are already underway,” said corresponding author Jason Knight, MD, of the University of Michigan, Ann Arbor, in a press release.

SOURCE:

First author Ramadan A. Ali, MD, of the University of Michigan, Ann Arbor, and colleagues reported their study in JCI Insight.

LIMITATIONS:

More research is needed in humans with inflammatory and autoimmune diseases to confirm the findings and explore ginger as an adjuvant therapeutic intervention.

DISCLOSURES:

The study received no outside funding. The researchers report no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Blood samples from healthy adults show an inhibition of neutrophil extracellular trap formation (NET) after 1 week of daily ginger supplements.

METHODOLOGY:

• Researchers recruited nine healthy adults aged 18-38 years to receive a 100-mg oral ginger supplement daily for 7 consecutive days.
• Blood samples were collected at baseline and on days 7 and 14, with isolation of neutrophils, peripheral blood mononuclear cells, and plasma.
• The researchers measured NET formation (NETosis) as a way to show the effect of ginger on inflammation.

TAKEAWAY:

• Measures of neutrophil cyclic AMP (cAMP) were significantly higher after 7 days of ginger supplements, compared with baseline levels, although these levels returned to near baseline by 1 week after discontinuing ginger consumption.
• Oral ginger supplements reduced neutrophil phosphodiesterase (PDE) activity by 40% from baseline, similar to results seen with synthetic PDE4 inhibitors.
• The results build on previous studies showing inhibition of neutrophil hyperactivity in mice with antiphospholipid syndrome and lupus after injection with a purified ginger preparation.
• Researchers replicated the results showing effects of oral ginger on neutrophils in eight additional healthy adults who also showed reduced NETosis and increased cAMP after 1 week of ginger supplements.

IN PRACTICE:

The results show biologic support for the potential of ginger to affect neutrophil function in humans; therefore, “ginger may have a real ability to complement treatment programs that are already underway,” said corresponding author Jason Knight, MD, of the University of Michigan, Ann Arbor, in a press release.

SOURCE:

First author Ramadan A. Ali, MD, of the University of Michigan, Ann Arbor, and colleagues reported their study in JCI Insight.

LIMITATIONS:

More research is needed in humans with inflammatory and autoimmune diseases to confirm the findings and explore ginger as an adjuvant therapeutic intervention.

DISCLOSURES:

The study received no outside funding. The researchers report no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Blood samples from healthy adults show an inhibition of neutrophil extracellular trap formation (NET) after 1 week of daily ginger supplements.

METHODOLOGY:

• Researchers recruited nine healthy adults aged 18-38 years to receive a 100-mg oral ginger supplement daily for 7 consecutive days.
• Blood samples were collected at baseline and on days 7 and 14, with isolation of neutrophils, peripheral blood mononuclear cells, and plasma.
• The researchers measured NET formation (NETosis) as a way to show the effect of ginger on inflammation.

TAKEAWAY:

• Measures of neutrophil cyclic AMP (cAMP) were significantly higher after 7 days of ginger supplements, compared with baseline levels, although these levels returned to near baseline by 1 week after discontinuing ginger consumption.
• Oral ginger supplements reduced neutrophil phosphodiesterase (PDE) activity by 40% from baseline, similar to results seen with synthetic PDE4 inhibitors.
• The results build on previous studies showing inhibition of neutrophil hyperactivity in mice with antiphospholipid syndrome and lupus after injection with a purified ginger preparation.
• Researchers replicated the results showing effects of oral ginger on neutrophils in eight additional healthy adults who also showed reduced NETosis and increased cAMP after 1 week of ginger supplements.

IN PRACTICE:

The results show biologic support for the potential of ginger to affect neutrophil function in humans; therefore, “ginger may have a real ability to complement treatment programs that are already underway,” said corresponding author Jason Knight, MD, of the University of Michigan, Ann Arbor, in a press release.

SOURCE:

First author Ramadan A. Ali, MD, of the University of Michigan, Ann Arbor, and colleagues reported their study in JCI Insight.

LIMITATIONS:

More research is needed in humans with inflammatory and autoimmune diseases to confirm the findings and explore ginger as an adjuvant therapeutic intervention.

DISCLOSURES:

The study received no outside funding. The researchers report no relevant financial relationships.

A version of this article appeared on Medscape.com.

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

TOPLINE:

Patients with both systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are more likely to be female, Black, and diagnosed with limited cutaneous SSc.

METHODOLOGY:

• Researchers used the 2019 SLE classification criteria from the European Alliance of Associations for Rheumatology and American College of Rheumatology to identify patients with SSc who also met criteria for SLE at a single academic center.
• The study population included 402 adults with SSc.
• The researchers compared demographics, laboratory data, clinical features, and mortality between patients with SSc-SLE and patients with SSc only.

TAKEAWAY:

• Among the 402 patients with SSc who were analyzed, 40 (10%) met the 2019 EULAR/ACR Classification Criteria for SLE.
• Patients with both SSc and SLE were significantly more likely to be female and Black, which is consistent with previous studies; patients with both conditions also were more likely than those with SSc alone to have limited cutaneous SSc (75% vs. 52.2%; P = .006).
• The prevalence of anti-U1-RNP antibody positivity, a classic marker for mixed connective tissue disease, was 30% in SSc-SLE patients and 6.6% in those with SSc only (P < .001).
• Mortality was similar between the two groups, and similar rates were also seen between the two for severe SSc-related end-organ damage, including pulmonary fibrosis, pulmonary hypertension, and scleroderma renal crisis.

IN PRACTICE:

The results highlight the need for clinicians to recognize the SSc-SLE overlap syndrome and to watch for scleroderma organ involvement in patients with features of SLE, Raynaud syndrome, anti-U1-RNP antibody positivity, or an isolated nucleolar pattern of antinuclear antibodies.

SOURCE:

First author Ronald D. Bass, MD, MBA, of Georgetown University, Washington, and colleagues published their report online in Arthritis Care & Research.

LIMITATIONS:

The primary cohort was designed to compare Black to non-Black patients with SSc, and the process of matching these patients may have introduced unmeasured selection bias. Also, since the study was based on classification criteria and not diagnostic criteria, the overlapping patients may not reflect patients with true overlapping of both conditions.

DISCLOSURES:

No outside funding source was listed by the authors. The researchers report no relevant financial relationships.

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

TOPLINE:

Patients with both systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are more likely to be female, Black, and diagnosed with limited cutaneous SSc.

METHODOLOGY:

• Researchers used the 2019 SLE classification criteria from the European Alliance of Associations for Rheumatology and American College of Rheumatology to identify patients with SSc who also met criteria for SLE at a single academic center.
• The study population included 402 adults with SSc.
• The researchers compared demographics, laboratory data, clinical features, and mortality between patients with SSc-SLE and patients with SSc only.

TAKEAWAY:

• Among the 402 patients with SSc who were analyzed, 40 (10%) met the 2019 EULAR/ACR Classification Criteria for SLE.
• Patients with both SSc and SLE were significantly more likely to be female and Black, which is consistent with previous studies; patients with both conditions also were more likely than those with SSc alone to have limited cutaneous SSc (75% vs. 52.2%; P = .006).
• The prevalence of anti-U1-RNP antibody positivity, a classic marker for mixed connective tissue disease, was 30% in SSc-SLE patients and 6.6% in those with SSc only (P < .001).
• Mortality was similar between the two groups, and similar rates were also seen between the two for severe SSc-related end-organ damage, including pulmonary fibrosis, pulmonary hypertension, and scleroderma renal crisis.

IN PRACTICE:

The results highlight the need for clinicians to recognize the SSc-SLE overlap syndrome and to watch for scleroderma organ involvement in patients with features of SLE, Raynaud syndrome, anti-U1-RNP antibody positivity, or an isolated nucleolar pattern of antinuclear antibodies.

SOURCE:

First author Ronald D. Bass, MD, MBA, of Georgetown University, Washington, and colleagues published their report online in Arthritis Care & Research.

LIMITATIONS:

The primary cohort was designed to compare Black to non-Black patients with SSc, and the process of matching these patients may have introduced unmeasured selection bias. Also, since the study was based on classification criteria and not diagnostic criteria, the overlapping patients may not reflect patients with true overlapping of both conditions.

DISCLOSURES:

No outside funding source was listed by the authors. The researchers report no relevant financial relationships.

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

TOPLINE:

Patients with both systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are more likely to be female, Black, and diagnosed with limited cutaneous SSc.

METHODOLOGY:

• Researchers used the 2019 SLE classification criteria from the European Alliance of Associations for Rheumatology and American College of Rheumatology to identify patients with SSc who also met criteria for SLE at a single academic center.
• The study population included 402 adults with SSc.
• The researchers compared demographics, laboratory data, clinical features, and mortality between patients with SSc-SLE and patients with SSc only.

TAKEAWAY:

• Among the 402 patients with SSc who were analyzed, 40 (10%) met the 2019 EULAR/ACR Classification Criteria for SLE.
• Patients with both SSc and SLE were significantly more likely to be female and Black, which is consistent with previous studies; patients with both conditions also were more likely than those with SSc alone to have limited cutaneous SSc (75% vs. 52.2%; P = .006).
• The prevalence of anti-U1-RNP antibody positivity, a classic marker for mixed connective tissue disease, was 30% in SSc-SLE patients and 6.6% in those with SSc only (P < .001).
• Mortality was similar between the two groups, and similar rates were also seen between the two for severe SSc-related end-organ damage, including pulmonary fibrosis, pulmonary hypertension, and scleroderma renal crisis.

IN PRACTICE:

The results highlight the need for clinicians to recognize the SSc-SLE overlap syndrome and to watch for scleroderma organ involvement in patients with features of SLE, Raynaud syndrome, anti-U1-RNP antibody positivity, or an isolated nucleolar pattern of antinuclear antibodies.

SOURCE:

First author Ronald D. Bass, MD, MBA, of Georgetown University, Washington, and colleagues published their report online in Arthritis Care & Research.

LIMITATIONS:

The primary cohort was designed to compare Black to non-Black patients with SSc, and the process of matching these patients may have introduced unmeasured selection bias. Also, since the study was based on classification criteria and not diagnostic criteria, the overlapping patients may not reflect patients with true overlapping of both conditions.

DISCLOSURES:

No outside funding source was listed by the authors. The researchers report no relevant financial relationships.

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

A single monthly injection of benralizumab (Fasenra) was noninferior to a series of three injections per month of mepolizumab (Nucala) for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA), based on data from 140 individuals.

The unpublished topline results of the phase 3 MANDARA study were shared in a press release from benralizumab’s manufacturer, AstraZeneca. More detailed findings are scheduled to be presented at a future medical meeting, according to the company.

EGPA, although rare, can damage multiple organs including the heart, lungs, gastrointestinal tract, skin, and nerves, and can be fatal if left untreated, but treatment options are limited, and mepolizumab, an anti-interleukin (IL)-5 monoclonal antibody, is the only currently approved treatment.

In the study, adults with EGPA were randomized to a single 30-mg subcutaneous injection of benralizumab or three separate 100-mg subcutaneous injections of mepolizumab once every 4 weeks. The primary endpoint was remission rates after 36 and 48 weeks of treatment. Remission was defined as a Birmingham Vasculitis Activity Score of 0 and use of 4 mg/day or less of oral corticosteroids.

At 36 weeks and 48 weeks, remission rates for benralizumab were noninferior to mepolizumab. According to Clinicaltrials.gov, the study is scheduled to last for 52 weeks to compare the remission rates with the two treatments, and collect data from an extension that allows each patient at least 1 year of treatment in an open-label format.

Benralizumab, also a monoclonal antibody, differs in action from mepolizumab by binding directly to the IL-5 receptor alpha on eosinophils.

“This trial demonstrates that a biologic medicine given in a single monthly injection could help patients achieve remission rates comparable to the current standard of care, adding to the importance of benralizumab as a potential treatment option for eosinophilic granulomatosis with polyangiitis,” Michael Wechsler, MD, principal investigator on the MANDARA study, said in the press release.

The safety and tolerability of benralizumab in the MANDARA study were consistent with drug’s known profile, according to the company.

Benralizumab is currently approved as an add-on maintenance treatment for severe eosinophilic asthma in the United States, the European Union, and Japan, among other countries, and for self-administration in the United States, the European Union, and other countries, according to the company.

Benralizumab also is in development for other eosinophilic diseases, including chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, and hypereosinophilic syndrome, and received an Orphan Drug Designation from the U.S. Food and Drug Administration in 2018, according to the company.
 

A single monthly injection of benralizumab (Fasenra) was noninferior to a series of three injections per month of mepolizumab (Nucala) for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA), based on data from 140 individuals.

The unpublished topline results of the phase 3 MANDARA study were shared in a press release from benralizumab’s manufacturer, AstraZeneca. More detailed findings are scheduled to be presented at a future medical meeting, according to the company.

EGPA, although rare, can damage multiple organs including the heart, lungs, gastrointestinal tract, skin, and nerves, and can be fatal if left untreated, but treatment options are limited, and mepolizumab, an anti-interleukin (IL)-5 monoclonal antibody, is the only currently approved treatment.

In the study, adults with EGPA were randomized to a single 30-mg subcutaneous injection of benralizumab or three separate 100-mg subcutaneous injections of mepolizumab once every 4 weeks. The primary endpoint was remission rates after 36 and 48 weeks of treatment. Remission was defined as a Birmingham Vasculitis Activity Score of 0 and use of 4 mg/day or less of oral corticosteroids.

At 36 weeks and 48 weeks, remission rates for benralizumab were noninferior to mepolizumab. According to Clinicaltrials.gov, the study is scheduled to last for 52 weeks to compare the remission rates with the two treatments, and collect data from an extension that allows each patient at least 1 year of treatment in an open-label format.

Benralizumab, also a monoclonal antibody, differs in action from mepolizumab by binding directly to the IL-5 receptor alpha on eosinophils.

“This trial demonstrates that a biologic medicine given in a single monthly injection could help patients achieve remission rates comparable to the current standard of care, adding to the importance of benralizumab as a potential treatment option for eosinophilic granulomatosis with polyangiitis,” Michael Wechsler, MD, principal investigator on the MANDARA study, said in the press release.

The safety and tolerability of benralizumab in the MANDARA study were consistent with drug’s known profile, according to the company.

Benralizumab is currently approved as an add-on maintenance treatment for severe eosinophilic asthma in the United States, the European Union, and Japan, among other countries, and for self-administration in the United States, the European Union, and other countries, according to the company.

Benralizumab also is in development for other eosinophilic diseases, including chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, and hypereosinophilic syndrome, and received an Orphan Drug Designation from the U.S. Food and Drug Administration in 2018, according to the company.
 

A single monthly injection of benralizumab (Fasenra) was noninferior to a series of three injections per month of mepolizumab (Nucala) for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA), based on data from 140 individuals.

The unpublished topline results of the phase 3 MANDARA study were shared in a press release from benralizumab’s manufacturer, AstraZeneca. More detailed findings are scheduled to be presented at a future medical meeting, according to the company.

EGPA, although rare, can damage multiple organs including the heart, lungs, gastrointestinal tract, skin, and nerves, and can be fatal if left untreated, but treatment options are limited, and mepolizumab, an anti-interleukin (IL)-5 monoclonal antibody, is the only currently approved treatment.

In the study, adults with EGPA were randomized to a single 30-mg subcutaneous injection of benralizumab or three separate 100-mg subcutaneous injections of mepolizumab once every 4 weeks. The primary endpoint was remission rates after 36 and 48 weeks of treatment. Remission was defined as a Birmingham Vasculitis Activity Score of 0 and use of 4 mg/day or less of oral corticosteroids.

At 36 weeks and 48 weeks, remission rates for benralizumab were noninferior to mepolizumab. According to Clinicaltrials.gov, the study is scheduled to last for 52 weeks to compare the remission rates with the two treatments, and collect data from an extension that allows each patient at least 1 year of treatment in an open-label format.

Benralizumab, also a monoclonal antibody, differs in action from mepolizumab by binding directly to the IL-5 receptor alpha on eosinophils.

“This trial demonstrates that a biologic medicine given in a single monthly injection could help patients achieve remission rates comparable to the current standard of care, adding to the importance of benralizumab as a potential treatment option for eosinophilic granulomatosis with polyangiitis,” Michael Wechsler, MD, principal investigator on the MANDARA study, said in the press release.

The safety and tolerability of benralizumab in the MANDARA study were consistent with drug’s known profile, according to the company.

Benralizumab is currently approved as an add-on maintenance treatment for severe eosinophilic asthma in the United States, the European Union, and Japan, among other countries, and for self-administration in the United States, the European Union, and other countries, according to the company.

Benralizumab also is in development for other eosinophilic diseases, including chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, and hypereosinophilic syndrome, and received an Orphan Drug Designation from the U.S. Food and Drug Administration in 2018, according to the company.
 

A blood-level reference range of 750-1,200 ng/mL of hydroxychloroquine (HCQ) has been linked with 71% lower odds of active lupus, new research suggests.

AlexLMX/iStock/Getty Images

Researchers, led by Shivani Garg, MD, assistant professor of rheumatology at the University of Wisconsin–Madison, also found that maintaining levels within that range lowered the odds for flares by 26% over 9 months of follow-up.

The findings, published in Arthritis Care & Research, could help clinicians personalize HCQ doses to maximize efficacy for each patient.

UW Health

HCQ levels in whole blood and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were measured during a baseline visit and again during a routine follow-up visit.

Among 158 baseline patient visits, 19% of the patients had active lupus. Researchers longitudinally followed 42 patients using convenience sampling, and among those patients, 7 (17%) had flares at the follow-up visit.

Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center in Baltimore, called the findings that suggest upper and lower efficacy and safety boundaries “very important.”

The findings highlight that guidelines for dosing don’t match efficacy needs, said Dr. Petri, who was not involved with the study.

“HCQ dosing has been under threat by guidelines insisting that the dose should be < 5 mg/kg even though this does not correlate with efficacy,” she said. “Basically, if we dose too low, the patient loses efficacy. If we dose too high, the risk of retinopathy increases, so this paper hones down the sweet spot.”

A 2014 study identified a higher eye toxicity risk with HCQ doses > 5 mg/kg per day, and the American Academy of Ophthalmology followed with guidelines for HCQ retinopathy screening that recommended reducing HCQ to ≤ 5 mg/kg per day.

Dr. Petri said that the range Dr. Garg and colleagues identified corroborates findings in one of her team’s studies.

That paper showed that thrombotic events dropped by 69% in patients with average HCQ blood levels ≥ 1,068 ng/mL vs. those with levels < 648 ng/mL (relative risk, 0.31; 95% confidence interval, 0.11-0.86; P = .024).

Dr. Garg and colleagues write that current lupus treatment guidelines do not universally recommend blood level monitoring for HCQ “as different cut-points have been used to define therapeutic HCQ blood levels and an effective range of HCQ levels with upper and lower bounds for efficacy has not been extensively examined.”
 

When to start checking levels

Blood levels of HCQ can be checked for any patient, although 1-3 months after starting the medication may be best to get steady levels, Dr. Garg told this news organization.

Dr. Petri said that she recommends HCQ whole blood levels be checked routinely for maximum dosing efficacy “but also to identify patients who are missing so many doses that they are subtherapeutic.”

She noted that nonadherence is a major issue among patients with systemic lupus erythematosus, especially among those who are younger and newly diagnosed.

Dr. Garg and Dr. Petri both said that insurance does not automatically cover the costs of checking HCQ levels in the blood, which has been a consistent frustration in the field.

“Having more data validates the reason to do it,” Dr. Garg said.

She added that “HCQ blood levels are still not done routinely in all patients, and at times the test needs to be sent to outside laboratories.”
 

Importance for patients with CKD

Many patient factors can affect how the body absorbs HCQ, Dr. Garg said, so finding the right level that is safe and maximizes benefit individually is important.

The findings are particularly important for patients with chronic kidney disease (CKD) of stage 3 or higher, Dr. Garg said.

The authors write that because kidneys clear more than half of all HCQ, impaired kidney function could boost HCQ blood levels, risking toxicity.

“Our study found a sixfold higher odds of having supratherapeutic HCQ blood levels in patients with CKD stage ≥ 3,” they write.

Dr. Garg added that if blood levels cannot be analyzed in all patients, they could be prioritized in patients with CKD stage 3 or above because these patients are at “higher risk of being underdosed with arbitrary reductions in HCQ doses and carry higher risk of toxicity if HCQ doses are not adjusted.”

More research will uncover other high-risk groups who would benefit most from close monitoring of HCQ blood levels, she said.

The study was supported by an award from the University of Wisconsin–Madison, and by an award to the institution from the National Institutes of Health National Center for Advancing Translational Sciences. Dr. Garg and coauthors as well as Dr. Petri report no relevant financial relationships.

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

A blood-level reference range of 750-1,200 ng/mL of hydroxychloroquine (HCQ) has been linked with 71% lower odds of active lupus, new research suggests.

AlexLMX/iStock/Getty Images

Researchers, led by Shivani Garg, MD, assistant professor of rheumatology at the University of Wisconsin–Madison, also found that maintaining levels within that range lowered the odds for flares by 26% over 9 months of follow-up.

The findings, published in Arthritis Care & Research, could help clinicians personalize HCQ doses to maximize efficacy for each patient.

UW Health

HCQ levels in whole blood and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were measured during a baseline visit and again during a routine follow-up visit.

Among 158 baseline patient visits, 19% of the patients had active lupus. Researchers longitudinally followed 42 patients using convenience sampling, and among those patients, 7 (17%) had flares at the follow-up visit.

Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center in Baltimore, called the findings that suggest upper and lower efficacy and safety boundaries “very important.”

The findings highlight that guidelines for dosing don’t match efficacy needs, said Dr. Petri, who was not involved with the study.

“HCQ dosing has been under threat by guidelines insisting that the dose should be < 5 mg/kg even though this does not correlate with efficacy,” she said. “Basically, if we dose too low, the patient loses efficacy. If we dose too high, the risk of retinopathy increases, so this paper hones down the sweet spot.”

A 2014 study identified a higher eye toxicity risk with HCQ doses > 5 mg/kg per day, and the American Academy of Ophthalmology followed with guidelines for HCQ retinopathy screening that recommended reducing HCQ to ≤ 5 mg/kg per day.

Dr. Petri said that the range Dr. Garg and colleagues identified corroborates findings in one of her team’s studies.

That paper showed that thrombotic events dropped by 69% in patients with average HCQ blood levels ≥ 1,068 ng/mL vs. those with levels < 648 ng/mL (relative risk, 0.31; 95% confidence interval, 0.11-0.86; P = .024).

Dr. Garg and colleagues write that current lupus treatment guidelines do not universally recommend blood level monitoring for HCQ “as different cut-points have been used to define therapeutic HCQ blood levels and an effective range of HCQ levels with upper and lower bounds for efficacy has not been extensively examined.”
 

When to start checking levels

Blood levels of HCQ can be checked for any patient, although 1-3 months after starting the medication may be best to get steady levels, Dr. Garg told this news organization.

Dr. Petri said that she recommends HCQ whole blood levels be checked routinely for maximum dosing efficacy “but also to identify patients who are missing so many doses that they are subtherapeutic.”

She noted that nonadherence is a major issue among patients with systemic lupus erythematosus, especially among those who are younger and newly diagnosed.

Dr. Garg and Dr. Petri both said that insurance does not automatically cover the costs of checking HCQ levels in the blood, which has been a consistent frustration in the field.

“Having more data validates the reason to do it,” Dr. Garg said.

She added that “HCQ blood levels are still not done routinely in all patients, and at times the test needs to be sent to outside laboratories.”
 

Importance for patients with CKD

Many patient factors can affect how the body absorbs HCQ, Dr. Garg said, so finding the right level that is safe and maximizes benefit individually is important.

The findings are particularly important for patients with chronic kidney disease (CKD) of stage 3 or higher, Dr. Garg said.

The authors write that because kidneys clear more than half of all HCQ, impaired kidney function could boost HCQ blood levels, risking toxicity.

“Our study found a sixfold higher odds of having supratherapeutic HCQ blood levels in patients with CKD stage ≥ 3,” they write.

Dr. Garg added that if blood levels cannot be analyzed in all patients, they could be prioritized in patients with CKD stage 3 or above because these patients are at “higher risk of being underdosed with arbitrary reductions in HCQ doses and carry higher risk of toxicity if HCQ doses are not adjusted.”

More research will uncover other high-risk groups who would benefit most from close monitoring of HCQ blood levels, she said.

The study was supported by an award from the University of Wisconsin–Madison, and by an award to the institution from the National Institutes of Health National Center for Advancing Translational Sciences. Dr. Garg and coauthors as well as Dr. Petri report no relevant financial relationships.

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

A blood-level reference range of 750-1,200 ng/mL of hydroxychloroquine (HCQ) has been linked with 71% lower odds of active lupus, new research suggests.

AlexLMX/iStock/Getty Images

Researchers, led by Shivani Garg, MD, assistant professor of rheumatology at the University of Wisconsin–Madison, also found that maintaining levels within that range lowered the odds for flares by 26% over 9 months of follow-up.

The findings, published in Arthritis Care & Research, could help clinicians personalize HCQ doses to maximize efficacy for each patient.

UW Health

HCQ levels in whole blood and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were measured during a baseline visit and again during a routine follow-up visit.

Among 158 baseline patient visits, 19% of the patients had active lupus. Researchers longitudinally followed 42 patients using convenience sampling, and among those patients, 7 (17%) had flares at the follow-up visit.

Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center in Baltimore, called the findings that suggest upper and lower efficacy and safety boundaries “very important.”

The findings highlight that guidelines for dosing don’t match efficacy needs, said Dr. Petri, who was not involved with the study.

“HCQ dosing has been under threat by guidelines insisting that the dose should be < 5 mg/kg even though this does not correlate with efficacy,” she said. “Basically, if we dose too low, the patient loses efficacy. If we dose too high, the risk of retinopathy increases, so this paper hones down the sweet spot.”

A 2014 study identified a higher eye toxicity risk with HCQ doses > 5 mg/kg per day, and the American Academy of Ophthalmology followed with guidelines for HCQ retinopathy screening that recommended reducing HCQ to ≤ 5 mg/kg per day.

Dr. Petri said that the range Dr. Garg and colleagues identified corroborates findings in one of her team’s studies.

That paper showed that thrombotic events dropped by 69% in patients with average HCQ blood levels ≥ 1,068 ng/mL vs. those with levels < 648 ng/mL (relative risk, 0.31; 95% confidence interval, 0.11-0.86; P = .024).

Dr. Garg and colleagues write that current lupus treatment guidelines do not universally recommend blood level monitoring for HCQ “as different cut-points have been used to define therapeutic HCQ blood levels and an effective range of HCQ levels with upper and lower bounds for efficacy has not been extensively examined.”
 

When to start checking levels

Blood levels of HCQ can be checked for any patient, although 1-3 months after starting the medication may be best to get steady levels, Dr. Garg told this news organization.

Dr. Petri said that she recommends HCQ whole blood levels be checked routinely for maximum dosing efficacy “but also to identify patients who are missing so many doses that they are subtherapeutic.”

She noted that nonadherence is a major issue among patients with systemic lupus erythematosus, especially among those who are younger and newly diagnosed.

Dr. Garg and Dr. Petri both said that insurance does not automatically cover the costs of checking HCQ levels in the blood, which has been a consistent frustration in the field.

“Having more data validates the reason to do it,” Dr. Garg said.

She added that “HCQ blood levels are still not done routinely in all patients, and at times the test needs to be sent to outside laboratories.”
 

Importance for patients with CKD

Many patient factors can affect how the body absorbs HCQ, Dr. Garg said, so finding the right level that is safe and maximizes benefit individually is important.

The findings are particularly important for patients with chronic kidney disease (CKD) of stage 3 or higher, Dr. Garg said.

The authors write that because kidneys clear more than half of all HCQ, impaired kidney function could boost HCQ blood levels, risking toxicity.

“Our study found a sixfold higher odds of having supratherapeutic HCQ blood levels in patients with CKD stage ≥ 3,” they write.

Dr. Garg added that if blood levels cannot be analyzed in all patients, they could be prioritized in patients with CKD stage 3 or above because these patients are at “higher risk of being underdosed with arbitrary reductions in HCQ doses and carry higher risk of toxicity if HCQ doses are not adjusted.”

More research will uncover other high-risk groups who would benefit most from close monitoring of HCQ blood levels, she said.

The study was supported by an award from the University of Wisconsin–Madison, and by an award to the institution from the National Institutes of Health National Center for Advancing Translational Sciences. Dr. Garg and coauthors as well as Dr. Petri report no relevant financial relationships.

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

The American College of Rheumatology has released a summary of upcoming guidelines on screening, monitoring, and treatment for interstitial lung disease (ILD) in patients with systemic autoimmune rheumatic disease.

The recommendations apply to adults with rheumatic diseases at greater risk for ILD: rheumatoid arthritis, systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren’s disease (SjD), and idiopathic inflammatory myopathies (IIM).

“Interstitial lung disease is a major cause of morbidity and mortality across several systemic autoimmune rheumatic diseases,” Sindhu R. Johnson, MD, PhD, lead author of the new guidelines and director of the clinical epidemiology and health care research program at the University of Toronto, said in an ACR press release. “Guidance was needed for which tests to use for screening and monitoring this particular disease.”

The two documents are summaries of part of a larger manuscript currently awaiting peer review, according to the ACR, and the final guidelines are anticipated to be published by early 2024.

The recommendations were developed using “the best available evidence and consensus across a range of expert opinions and incorporated patient values and preferences,” according to the press release.

Highlights of recommendations for screening and monitoring ILD are:

• Providers can screen patients at higher risk for ILD with pulmonary function tests (PFTs) and high-resolution CT of the chest.
• PFTs, chest high-resolution CT, and ambulatory desaturation testing are conditionally recommended for monitoring ILD progression.
• It is conditionally recommended that providers do not use 6-minute walk test distance, chest radiography, or bronchoscopy for screening or monitoring disease.
• It is suggested that patients with IIM-ILD and SSc-ILD receive PFTs for monitoring every 3-6 months during the first year, then less frequently once stable.
• It is suggested that patients with RA-ILD, SjD-ILD, and MCTD-ILD receive PFTs every 3-12 months for the first year, then less frequently once stable.

Suggestions on how often to screen for ILD were not present in the summary documents, but will be made available in the larger manuscript, said Elana Bernstein, MD, director of the Columbia University Medical Center/New York–Presbyterian Hospital scleroderma program, New York. She is co–first author of the guidelines.

Nearly all recommendations are conditional, primarily because the certainty of evidence behind many of these recommendations is low or very low, she said in an interview. More clinical data on ILD in patients with rheumatic disease would help strengthen evidence, she said, particularly for best practices in frequency of testing. “We need more research on how often patients should be screened for ILD and how often they should be monitored for ILD progression,” she said. “That would enable us to provide recommendations, rather than just suggestions.”

Highlights of recommendations for ILD treatment are:

• The guidelines strongly recommend against using glucocorticoids for first-line ILD treatment in patients with SSc-ILD.
• Short-term glucocorticoids are conditionally recommended as a first-line ILD treatment for patients with systemic autoimmune rheumatic disease–related ILD (SARD-ILD), excluding SSc-ILD.
• Mycophenolate, azathioprine, rituximab, and cyclophosphamide are all potential first-line ILD treatment options for patients with SARD-ILD.
• It is conditionally recommended that patients with SARD-ILD do not receive leflunomide, methotrexate, tumor necrosis factor inhibitors, or abatacept as first-line ILD treatment.
• If SARD-ILD progresses despite first-line therapy, mycophenolate, rituximab, cyclophosphamide, and nintedanib are potential secondary treatment options.
• If RA-ILD progresses following initial therapy, pirfenidone is a treatment option.
• The guidelines conditionally recommend against pirfenidone as a secondary treatment option for SARD-ILD other than RA-ILD.

These summary guidelines appear “comprehensive,” but there has yet to be information published on the basis of these recommendations, Elizabeth Volkmann, MD, said in an interview.

“It’s important to understand that we don’t know whether most of these recommendations were just driven by expert opinion versus actual evidence from randomized, controlled clinical trials,” said Dr. Volkmann, who codirects the connective tissue disease–related interstitial lung disease program at the University of California, Los Angeles. She was not involved with creating the guidelines.

She expects that many of the recommendations for first- and second-line ILD treatment options were based on expert opinion, as there have been no randomized clinical trials looking at that specific topic, she said. For example, nintedanib is conditionally recommended as a first-line treatment option for SSc-ILD, but as a second-line treatment for SjD-ILD, IIM-ILD, and MCTD-ILD. “There’s no literature to support one or the other – whether nintedanib is first-line or second-line [treatment].”

The decision to publish the summary recommendations online prior to peer review is unusual, she said, as these recommendations could be altered during that process; however, Dr. Bernstein noted that was not likely.

By releasing the summary guideline now, the ACR can “get the needed information to clinicians earlier as the manuscript goes through its remaining stages and is finalized,” an ACR representative explained.

Prior to the expected publication of these guidelines in early 2024, Dr. Volkmann noted that the American Thoracic Society will be publishing guidelines on the treatment of SSc-ILD in the American Journal of Respiratory and Critical Care Medicine in September.

Dr. Bernstein reported grants/contracts with the Department of Defense, the Scleroderma Research Foundation, the National Institutes of Health, Eicos, Boehringer Ingelheim, Kadmon, and Pfizer. Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and GlaxoSmithKline and institutional support for performing studies on systemic sclerosis for Kadmon, Boehringer Ingelheim, Horizon, and Prometheus.

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

The American College of Rheumatology has released a summary of upcoming guidelines on screening, monitoring, and treatment for interstitial lung disease (ILD) in patients with systemic autoimmune rheumatic disease.

The recommendations apply to adults with rheumatic diseases at greater risk for ILD: rheumatoid arthritis, systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren’s disease (SjD), and idiopathic inflammatory myopathies (IIM).

“Interstitial lung disease is a major cause of morbidity and mortality across several systemic autoimmune rheumatic diseases,” Sindhu R. Johnson, MD, PhD, lead author of the new guidelines and director of the clinical epidemiology and health care research program at the University of Toronto, said in an ACR press release. “Guidance was needed for which tests to use for screening and monitoring this particular disease.”

The two documents are summaries of part of a larger manuscript currently awaiting peer review, according to the ACR, and the final guidelines are anticipated to be published by early 2024.

The recommendations were developed using “the best available evidence and consensus across a range of expert opinions and incorporated patient values and preferences,” according to the press release.

Highlights of recommendations for screening and monitoring ILD are:

• Providers can screen patients at higher risk for ILD with pulmonary function tests (PFTs) and high-resolution CT of the chest.
• PFTs, chest high-resolution CT, and ambulatory desaturation testing are conditionally recommended for monitoring ILD progression.
• It is conditionally recommended that providers do not use 6-minute walk test distance, chest radiography, or bronchoscopy for screening or monitoring disease.
• It is suggested that patients with IIM-ILD and SSc-ILD receive PFTs for monitoring every 3-6 months during the first year, then less frequently once stable.
• It is suggested that patients with RA-ILD, SjD-ILD, and MCTD-ILD receive PFTs every 3-12 months for the first year, then less frequently once stable.

Suggestions on how often to screen for ILD were not present in the summary documents, but will be made available in the larger manuscript, said Elana Bernstein, MD, director of the Columbia University Medical Center/New York–Presbyterian Hospital scleroderma program, New York. She is co–first author of the guidelines.

Nearly all recommendations are conditional, primarily because the certainty of evidence behind many of these recommendations is low or very low, she said in an interview. More clinical data on ILD in patients with rheumatic disease would help strengthen evidence, she said, particularly for best practices in frequency of testing. “We need more research on how often patients should be screened for ILD and how often they should be monitored for ILD progression,” she said. “That would enable us to provide recommendations, rather than just suggestions.”

Highlights of recommendations for ILD treatment are:

• The guidelines strongly recommend against using glucocorticoids for first-line ILD treatment in patients with SSc-ILD.
• Short-term glucocorticoids are conditionally recommended as a first-line ILD treatment for patients with systemic autoimmune rheumatic disease–related ILD (SARD-ILD), excluding SSc-ILD.
• Mycophenolate, azathioprine, rituximab, and cyclophosphamide are all potential first-line ILD treatment options for patients with SARD-ILD.
• It is conditionally recommended that patients with SARD-ILD do not receive leflunomide, methotrexate, tumor necrosis factor inhibitors, or abatacept as first-line ILD treatment.
• If SARD-ILD progresses despite first-line therapy, mycophenolate, rituximab, cyclophosphamide, and nintedanib are potential secondary treatment options.
• If RA-ILD progresses following initial therapy, pirfenidone is a treatment option.
• The guidelines conditionally recommend against pirfenidone as a secondary treatment option for SARD-ILD other than RA-ILD.

These summary guidelines appear “comprehensive,” but there has yet to be information published on the basis of these recommendations, Elizabeth Volkmann, MD, said in an interview.

“It’s important to understand that we don’t know whether most of these recommendations were just driven by expert opinion versus actual evidence from randomized, controlled clinical trials,” said Dr. Volkmann, who codirects the connective tissue disease–related interstitial lung disease program at the University of California, Los Angeles. She was not involved with creating the guidelines.

She expects that many of the recommendations for first- and second-line ILD treatment options were based on expert opinion, as there have been no randomized clinical trials looking at that specific topic, she said. For example, nintedanib is conditionally recommended as a first-line treatment option for SSc-ILD, but as a second-line treatment for SjD-ILD, IIM-ILD, and MCTD-ILD. “There’s no literature to support one or the other – whether nintedanib is first-line or second-line [treatment].”

The decision to publish the summary recommendations online prior to peer review is unusual, she said, as these recommendations could be altered during that process; however, Dr. Bernstein noted that was not likely.

By releasing the summary guideline now, the ACR can “get the needed information to clinicians earlier as the manuscript goes through its remaining stages and is finalized,” an ACR representative explained.

Prior to the expected publication of these guidelines in early 2024, Dr. Volkmann noted that the American Thoracic Society will be publishing guidelines on the treatment of SSc-ILD in the American Journal of Respiratory and Critical Care Medicine in September.

Dr. Bernstein reported grants/contracts with the Department of Defense, the Scleroderma Research Foundation, the National Institutes of Health, Eicos, Boehringer Ingelheim, Kadmon, and Pfizer. Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and GlaxoSmithKline and institutional support for performing studies on systemic sclerosis for Kadmon, Boehringer Ingelheim, Horizon, and Prometheus.

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

The American College of Rheumatology has released a summary of upcoming guidelines on screening, monitoring, and treatment for interstitial lung disease (ILD) in patients with systemic autoimmune rheumatic disease.

The recommendations apply to adults with rheumatic diseases at greater risk for ILD: rheumatoid arthritis, systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren’s disease (SjD), and idiopathic inflammatory myopathies (IIM).

“Interstitial lung disease is a major cause of morbidity and mortality across several systemic autoimmune rheumatic diseases,” Sindhu R. Johnson, MD, PhD, lead author of the new guidelines and director of the clinical epidemiology and health care research program at the University of Toronto, said in an ACR press release. “Guidance was needed for which tests to use for screening and monitoring this particular disease.”

The two documents are summaries of part of a larger manuscript currently awaiting peer review, according to the ACR, and the final guidelines are anticipated to be published by early 2024.

The recommendations were developed using “the best available evidence and consensus across a range of expert opinions and incorporated patient values and preferences,” according to the press release.

Highlights of recommendations for screening and monitoring ILD are:

• Providers can screen patients at higher risk for ILD with pulmonary function tests (PFTs) and high-resolution CT of the chest.
• PFTs, chest high-resolution CT, and ambulatory desaturation testing are conditionally recommended for monitoring ILD progression.
• It is conditionally recommended that providers do not use 6-minute walk test distance, chest radiography, or bronchoscopy for screening or monitoring disease.
• It is suggested that patients with IIM-ILD and SSc-ILD receive PFTs for monitoring every 3-6 months during the first year, then less frequently once stable.
• It is suggested that patients with RA-ILD, SjD-ILD, and MCTD-ILD receive PFTs every 3-12 months for the first year, then less frequently once stable.

Suggestions on how often to screen for ILD were not present in the summary documents, but will be made available in the larger manuscript, said Elana Bernstein, MD, director of the Columbia University Medical Center/New York–Presbyterian Hospital scleroderma program, New York. She is co–first author of the guidelines.

Nearly all recommendations are conditional, primarily because the certainty of evidence behind many of these recommendations is low or very low, she said in an interview. More clinical data on ILD in patients with rheumatic disease would help strengthen evidence, she said, particularly for best practices in frequency of testing. “We need more research on how often patients should be screened for ILD and how often they should be monitored for ILD progression,” she said. “That would enable us to provide recommendations, rather than just suggestions.”

Highlights of recommendations for ILD treatment are:

• The guidelines strongly recommend against using glucocorticoids for first-line ILD treatment in patients with SSc-ILD.
• Short-term glucocorticoids are conditionally recommended as a first-line ILD treatment for patients with systemic autoimmune rheumatic disease–related ILD (SARD-ILD), excluding SSc-ILD.
• Mycophenolate, azathioprine, rituximab, and cyclophosphamide are all potential first-line ILD treatment options for patients with SARD-ILD.
• It is conditionally recommended that patients with SARD-ILD do not receive leflunomide, methotrexate, tumor necrosis factor inhibitors, or abatacept as first-line ILD treatment.
• If SARD-ILD progresses despite first-line therapy, mycophenolate, rituximab, cyclophosphamide, and nintedanib are potential secondary treatment options.
• If RA-ILD progresses following initial therapy, pirfenidone is a treatment option.
• The guidelines conditionally recommend against pirfenidone as a secondary treatment option for SARD-ILD other than RA-ILD.

These summary guidelines appear “comprehensive,” but there has yet to be information published on the basis of these recommendations, Elizabeth Volkmann, MD, said in an interview.

“It’s important to understand that we don’t know whether most of these recommendations were just driven by expert opinion versus actual evidence from randomized, controlled clinical trials,” said Dr. Volkmann, who codirects the connective tissue disease–related interstitial lung disease program at the University of California, Los Angeles. She was not involved with creating the guidelines.

She expects that many of the recommendations for first- and second-line ILD treatment options were based on expert opinion, as there have been no randomized clinical trials looking at that specific topic, she said. For example, nintedanib is conditionally recommended as a first-line treatment option for SSc-ILD, but as a second-line treatment for SjD-ILD, IIM-ILD, and MCTD-ILD. “There’s no literature to support one or the other – whether nintedanib is first-line or second-line [treatment].”

The decision to publish the summary recommendations online prior to peer review is unusual, she said, as these recommendations could be altered during that process; however, Dr. Bernstein noted that was not likely.

By releasing the summary guideline now, the ACR can “get the needed information to clinicians earlier as the manuscript goes through its remaining stages and is finalized,” an ACR representative explained.

Prior to the expected publication of these guidelines in early 2024, Dr. Volkmann noted that the American Thoracic Society will be publishing guidelines on the treatment of SSc-ILD in the American Journal of Respiratory and Critical Care Medicine in September.

Dr. Bernstein reported grants/contracts with the Department of Defense, the Scleroderma Research Foundation, the National Institutes of Health, Eicos, Boehringer Ingelheim, Kadmon, and Pfizer. Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and GlaxoSmithKline and institutional support for performing studies on systemic sclerosis for Kadmon, Boehringer Ingelheim, Horizon, and Prometheus.

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

Systemic sclerosis patients with both interstitial lung disease and pulmonary hypertension had worse survival than those without both conditions, based on data from more than 3,000 individuals.

Pulmonary complications are now the most common causes of death in adults with systemic sclerosis (SSc), but the impact of patient characteristics and risk factors such as interstitial lung disease (ILD) and pulmonary hypertension (PH) on SSc outcomes remains unclear, wrote Pia Moinzadeh, MD, of University Hospital Cologne (Germany) and colleagues.

Although the role of ILD and PH in different SSc subtypes has been studied, larger studies of the effects of ILD and combining ILD and PH on outcomes are needed, since survival rates can change over time with new classification criteria, diagnostic tools, and improved therapies, they said.

In a study published in the journal Chest, the researchers reviewed data from 3,257 adults aged 18 years and older with SSc over a mean follow-up of 3.45 years. Participants were part of the German Network for Systemic Sclerosis (DNSS) that included 25 clinical centers in Germany. The participants were divided into SSc subsets: 54.2% with limited cutaneous SSc (lcSSc), 31.4% with diffuse cutaneous SSc (dcSSc), and 14.4% SSc overlapping syndromes.

The baseline prevalence of ILD was 34.5%, including 200 patients with ILD-PH and 923 with ILD but without PH. The baseline prevalence of PH without ILD was 4.5%. ILD was defined as SSc associated when other causes were excluded. PH was defined as an increase in mean arterial pressure of at least 25 mm Hg at rest, and also was defined by an estimated right ventricular systolic pressure greater than 35 mm Hg based on echocardiography.

By the end of the study period, 47.6% of SSc patients had ILD, 15.2% had ILD-PH, and 6.5% had pulmonary arterial hypertension (PAH). Of the SSc patients with ILD, 57.3% had dcSSc; the prevalence of PAH was not significantly different between the SSc subtypes. Patients with dcSSc were more likely to develop ILD-PH (52.2%) and ILD without PH (52.1%); patients with lcSSc were more likely to have PAH (64.9%) or no pulmonary involvement (64.1%).

“For all subsets, a significant increase in the frequency of SSc-ILD was observed during follow-ups,” the researchers noted.

Overall survival at 5 years was worst for patients with both ILD and PH (79.1%). Five-year OS for patients with PAH was 85.0%. OS at 5 years was significantly better for patients with ILD without PH (92.8%) and those with no pulmonary involvement (96.4%), compared with the ILD and PH patients (P < 0.001).

In a multivariate analysis, the risk of death was more than five times higher for patients with ILD-PH, compared with the reference group of patients without pulmonary involvement (hazard ratio, 5.3). Factors associated with reduced risk of death included female sex (HR, 0.3), higher body mass index (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide (HR, 0.98).

The findings were limited by several factors including the incomplete data for patients enrolled early in the registry, lack of complete radiology data, and the inability to determine whether the association between pulmonary involvement and survival was related to ILD or to pulmonary vascular disease, the researchers noted.

However, the results suggest that a combination of ILD and PH is the main predictor of death in patients with SSc and ILD, although the overall survival for SSc patients with and without pulmonary involvement has improved in recent decades thanks to improved therapies, multidisciplinary care, and greater attention to the disease worldwide, they concluded.

The study received no outside funding. Dr. Moinzadeh disclosed lecture fees from Boehringer Ingelheim.

Systemic sclerosis patients with both interstitial lung disease and pulmonary hypertension had worse survival than those without both conditions, based on data from more than 3,000 individuals.

Pulmonary complications are now the most common causes of death in adults with systemic sclerosis (SSc), but the impact of patient characteristics and risk factors such as interstitial lung disease (ILD) and pulmonary hypertension (PH) on SSc outcomes remains unclear, wrote Pia Moinzadeh, MD, of University Hospital Cologne (Germany) and colleagues.

Although the role of ILD and PH in different SSc subtypes has been studied, larger studies of the effects of ILD and combining ILD and PH on outcomes are needed, since survival rates can change over time with new classification criteria, diagnostic tools, and improved therapies, they said.

In a study published in the journal Chest, the researchers reviewed data from 3,257 adults aged 18 years and older with SSc over a mean follow-up of 3.45 years. Participants were part of the German Network for Systemic Sclerosis (DNSS) that included 25 clinical centers in Germany. The participants were divided into SSc subsets: 54.2% with limited cutaneous SSc (lcSSc), 31.4% with diffuse cutaneous SSc (dcSSc), and 14.4% SSc overlapping syndromes.

The baseline prevalence of ILD was 34.5%, including 200 patients with ILD-PH and 923 with ILD but without PH. The baseline prevalence of PH without ILD was 4.5%. ILD was defined as SSc associated when other causes were excluded. PH was defined as an increase in mean arterial pressure of at least 25 mm Hg at rest, and also was defined by an estimated right ventricular systolic pressure greater than 35 mm Hg based on echocardiography.

By the end of the study period, 47.6% of SSc patients had ILD, 15.2% had ILD-PH, and 6.5% had pulmonary arterial hypertension (PAH). Of the SSc patients with ILD, 57.3% had dcSSc; the prevalence of PAH was not significantly different between the SSc subtypes. Patients with dcSSc were more likely to develop ILD-PH (52.2%) and ILD without PH (52.1%); patients with lcSSc were more likely to have PAH (64.9%) or no pulmonary involvement (64.1%).

“For all subsets, a significant increase in the frequency of SSc-ILD was observed during follow-ups,” the researchers noted.

Overall survival at 5 years was worst for patients with both ILD and PH (79.1%). Five-year OS for patients with PAH was 85.0%. OS at 5 years was significantly better for patients with ILD without PH (92.8%) and those with no pulmonary involvement (96.4%), compared with the ILD and PH patients (P < 0.001).

In a multivariate analysis, the risk of death was more than five times higher for patients with ILD-PH, compared with the reference group of patients without pulmonary involvement (hazard ratio, 5.3). Factors associated with reduced risk of death included female sex (HR, 0.3), higher body mass index (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide (HR, 0.98).

The findings were limited by several factors including the incomplete data for patients enrolled early in the registry, lack of complete radiology data, and the inability to determine whether the association between pulmonary involvement and survival was related to ILD or to pulmonary vascular disease, the researchers noted.

However, the results suggest that a combination of ILD and PH is the main predictor of death in patients with SSc and ILD, although the overall survival for SSc patients with and without pulmonary involvement has improved in recent decades thanks to improved therapies, multidisciplinary care, and greater attention to the disease worldwide, they concluded.

The study received no outside funding. Dr. Moinzadeh disclosed lecture fees from Boehringer Ingelheim.

Systemic sclerosis patients with both interstitial lung disease and pulmonary hypertension had worse survival than those without both conditions, based on data from more than 3,000 individuals.

Pulmonary complications are now the most common causes of death in adults with systemic sclerosis (SSc), but the impact of patient characteristics and risk factors such as interstitial lung disease (ILD) and pulmonary hypertension (PH) on SSc outcomes remains unclear, wrote Pia Moinzadeh, MD, of University Hospital Cologne (Germany) and colleagues.

Although the role of ILD and PH in different SSc subtypes has been studied, larger studies of the effects of ILD and combining ILD and PH on outcomes are needed, since survival rates can change over time with new classification criteria, diagnostic tools, and improved therapies, they said.

In a study published in the journal Chest, the researchers reviewed data from 3,257 adults aged 18 years and older with SSc over a mean follow-up of 3.45 years. Participants were part of the German Network for Systemic Sclerosis (DNSS) that included 25 clinical centers in Germany. The participants were divided into SSc subsets: 54.2% with limited cutaneous SSc (lcSSc), 31.4% with diffuse cutaneous SSc (dcSSc), and 14.4% SSc overlapping syndromes.

The baseline prevalence of ILD was 34.5%, including 200 patients with ILD-PH and 923 with ILD but without PH. The baseline prevalence of PH without ILD was 4.5%. ILD was defined as SSc associated when other causes were excluded. PH was defined as an increase in mean arterial pressure of at least 25 mm Hg at rest, and also was defined by an estimated right ventricular systolic pressure greater than 35 mm Hg based on echocardiography.

By the end of the study period, 47.6% of SSc patients had ILD, 15.2% had ILD-PH, and 6.5% had pulmonary arterial hypertension (PAH). Of the SSc patients with ILD, 57.3% had dcSSc; the prevalence of PAH was not significantly different between the SSc subtypes. Patients with dcSSc were more likely to develop ILD-PH (52.2%) and ILD without PH (52.1%); patients with lcSSc were more likely to have PAH (64.9%) or no pulmonary involvement (64.1%).

“For all subsets, a significant increase in the frequency of SSc-ILD was observed during follow-ups,” the researchers noted.

Overall survival at 5 years was worst for patients with both ILD and PH (79.1%). Five-year OS for patients with PAH was 85.0%. OS at 5 years was significantly better for patients with ILD without PH (92.8%) and those with no pulmonary involvement (96.4%), compared with the ILD and PH patients (P < 0.001).

In a multivariate analysis, the risk of death was more than five times higher for patients with ILD-PH, compared with the reference group of patients without pulmonary involvement (hazard ratio, 5.3). Factors associated with reduced risk of death included female sex (HR, 0.3), higher body mass index (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide (HR, 0.98).

The findings were limited by several factors including the incomplete data for patients enrolled early in the registry, lack of complete radiology data, and the inability to determine whether the association between pulmonary involvement and survival was related to ILD or to pulmonary vascular disease, the researchers noted.

However, the results suggest that a combination of ILD and PH is the main predictor of death in patients with SSc and ILD, although the overall survival for SSc patients with and without pulmonary involvement has improved in recent decades thanks to improved therapies, multidisciplinary care, and greater attention to the disease worldwide, they concluded.

The study received no outside funding. Dr. Moinzadeh disclosed lecture fees from Boehringer Ingelheim.

Clinical trials of treatments for rheumatologic conditions appear especially vulnerable to inadvertent unblinding, because of noticeable side effects of some drugs and subjective outcome measures, according to a new analysis.

Until more is known about the potential for unblinding, clinicians need to keep in mind that patients and physicians could often guess accurately who was getting placebo or active drug, first author Cody Bruggemeyer, MD, a resident at the Medical College of Wisconsin, Milwaukee, said in an interview.

Dr. Bruggemeyer

“It’s important that rheumatologists be aware of this potential issue and use their clinical reasoning and their ability to critically assess papers to evaluate the study design” of research on treatments, he said in an interview.

Dr. Bruggemeyer and coauthors at the Medical College of Wisconsin presented their assessment of the potential for unblinding in a Viewpoint article in The Lancet Rheumatology.
 

A sample of pivotal clinical trials

The authors selected a sample of pivotal studies of 14 commonly prescribed drugs for rheumatic conditions for which double-blind randomized controlled trials (RCTs) that compared the active ingredient with a placebo were available.

The 14 trials involved treatments classified as disease-modifying antirheumatic drugs (DMARDs), some of which were likely to produce side effects that placebos would not mimic, such as injection site and infusion reactions and difference in readings in lab reports, the authors wrote.

In their analysis, Dr. Bruggemeyer and colleagues evaluated discrepancies in the rates of adverse events reported between active drugs and placebos and classified the 14 studies as follows:

• High unblinding risk: Nine studies had a high estimated risk of unblinding, including trials of adalimumab with citrate (Humira), anakinra (Kineret), anifrolumab (Saphnelo), apremilast (Otezla), ixekizumab (Taltz), leflunomide (Arava), methotrexate, risankizumab (Skyrizi) and tofacitinib (Xeljanz).
• Moderate unblinding risk: Three studies had a moderate estimated risk of unblinding, including trials of azathioprine (Imuran), mycophenolate mofetil and tocilizumab (Actemra).
• Low unblinding risk: Two studies had a low estimated risk of unblinding. These involved tests of belimumab (Benlysta) and rituximab (Rituxan).

Many of the effectiveness measurements of treatments used in rheumatology depend on patients’ reports of relief of pain and other disease symptoms. For example, the widely used American College of Rheumatology 20% response for rheumatoid arthritis includes components that rely on patient and physician assessment of disease activity.
 

Unblinding risk to clinical trial validity

CTs are the highest level of evidence to establish efficacy, because the study design aims to mask whether the experimental treatment is a drug or placebo. In cases where patients and physicians are more likely to correctly detect use of an active drug, there can be biases that skew results toward reports of symptom improvement. Other patients’ views of their treatment may be distorted by accurate guesses that they have been given placebo, Dr. Bruggemeyer and coauthors wrote.

“The degree of these effects cannot be predicted, but they tend to erroneously inflate the perceived benefit of novel interventions,” they wrote.

The consequences of this unblinding may be minimal in cases where there’s a clear difference between the placebo and active drug, they said. As an example, they cited trials of interleukin-23 inhibitors for psoriasis, where skin clearance as measured by the Psoriatic Area and Severity Index 75 differed by more than 50% in absolute terms between the treatment and placebo groups.

But in other cases, there needs to be more attention paid to the potential role of unblinding, they wrote.

“Studies where effect sizes were small, contradictory, or dependent on subgroup analyses might be especially problematic, but commentary rarely reflects this issue or acknowledges the potential influence of unblinding,” they wrote.

In the paper, they call for more analysis of previous trials to look for unreported assessments of unblinding, while also asking that researchers consider surveying participants in future trials to evaluate the degree to which unblinding occurs.

“Advocacy from professional societies and the U.S. Food and Drug Administration itself might be necessary, but in the interim, rheumatologists should assume unblinding has occurred to some degree in most trials,” they wrote.
 

Unblinding measure needs validation

In an interview, Roy M. Fleischmann, MD, co–medical director of the Metroplex Clinical Research Center in Dallas, raised some objections to the paper. The paper addresses an interesting question about unblinding, but there should have been more work done, such as finding “a measure that is validated that can say whether you’ve been unblinded or not.”

He added that he was surprised the paper on unblinding in rheumatology trials was published in its current form.

“I would have sent it for a major rewrite” if asked to review this paper before publication, said Dr. Fleischmann, who as a reviewer for Lancet Rheumatology. “I would have said: ‘Okay, 90% of this paper is okay, but your gist is not correct.’ It should be: ‘Is this a problem?’ ”

Dr. Fleischmann said he would have recommended a different perspective to the paper. “That is, this could occur. Should we be looking at this, and how would we look at this?”

In the paper, the authors acknowledge their approach has not been validated, “but it highlights the potential effect of idiosyncratic adverse events,” they wrote.

There’s less funding in general for meta-research than for studies involving treatments, so researchers look for approaches that can be handled without requiring significant funding, and much of the research on the quality of research is conducted like this analysis of rheumatology trials, Michael Putman, MD, the corresponding author and is a rheumatologist and an assistant professor at the Medical College of Wisconsin, said in an interview.

“You’re mostly doing on a shoestring budget with yourself and trainees,” he said. Dr. Putman is an associate editor at the journal Rheumatology and also involved in meta-research, or efforts to understand how studies and trials answer questions about how medical treatments work.

In an Aug. 16 tweet, Dr. Putman said this issue of unintentional unblinding with rheumatology trials was something he’d “been ruminating about for awhile; took two all star trainees to push it over the top!”

One of the barriers to funding of meta-research is a tendency for major funding for medical studies to be focused on specific diseases or targets. With meta-research, it may be more difficult to explain how a specific project will advance efforts to treat or prevent a certain disease, Dr. Putman said.

“It’s a little more esoteric and maybe not quite as clear how these projects will move things forward,” Dr. Putman said.

In addition, the nature of meta-research is to question and often be critical of work that’s already been published, adding another hurdle in attempts to secure funding, he said.

Dr. Putman is supported by a Rheumatology Research Foundation Scientist Development Grant, receives research funding related to clinical trials by AbbVie and AstraZeneca, and consulting fees from Novartis. The other authors declared no competing interests.

Clinical trials of treatments for rheumatologic conditions appear especially vulnerable to inadvertent unblinding, because of noticeable side effects of some drugs and subjective outcome measures, according to a new analysis.

Until more is known about the potential for unblinding, clinicians need to keep in mind that patients and physicians could often guess accurately who was getting placebo or active drug, first author Cody Bruggemeyer, MD, a resident at the Medical College of Wisconsin, Milwaukee, said in an interview.

Dr. Bruggemeyer

“It’s important that rheumatologists be aware of this potential issue and use their clinical reasoning and their ability to critically assess papers to evaluate the study design” of research on treatments, he said in an interview.

Dr. Bruggemeyer and coauthors at the Medical College of Wisconsin presented their assessment of the potential for unblinding in a Viewpoint article in The Lancet Rheumatology.
 

A sample of pivotal clinical trials

The authors selected a sample of pivotal studies of 14 commonly prescribed drugs for rheumatic conditions for which double-blind randomized controlled trials (RCTs) that compared the active ingredient with a placebo were available.

The 14 trials involved treatments classified as disease-modifying antirheumatic drugs (DMARDs), some of which were likely to produce side effects that placebos would not mimic, such as injection site and infusion reactions and difference in readings in lab reports, the authors wrote.

In their analysis, Dr. Bruggemeyer and colleagues evaluated discrepancies in the rates of adverse events reported between active drugs and placebos and classified the 14 studies as follows:

• High unblinding risk: Nine studies had a high estimated risk of unblinding, including trials of adalimumab with citrate (Humira), anakinra (Kineret), anifrolumab (Saphnelo), apremilast (Otezla), ixekizumab (Taltz), leflunomide (Arava), methotrexate, risankizumab (Skyrizi) and tofacitinib (Xeljanz).
• Moderate unblinding risk: Three studies had a moderate estimated risk of unblinding, including trials of azathioprine (Imuran), mycophenolate mofetil and tocilizumab (Actemra).
• Low unblinding risk: Two studies had a low estimated risk of unblinding. These involved tests of belimumab (Benlysta) and rituximab (Rituxan).

Many of the effectiveness measurements of treatments used in rheumatology depend on patients’ reports of relief of pain and other disease symptoms. For example, the widely used American College of Rheumatology 20% response for rheumatoid arthritis includes components that rely on patient and physician assessment of disease activity.
 

Unblinding risk to clinical trial validity

CTs are the highest level of evidence to establish efficacy, because the study design aims to mask whether the experimental treatment is a drug or placebo. In cases where patients and physicians are more likely to correctly detect use of an active drug, there can be biases that skew results toward reports of symptom improvement. Other patients’ views of their treatment may be distorted by accurate guesses that they have been given placebo, Dr. Bruggemeyer and coauthors wrote.

“The degree of these effects cannot be predicted, but they tend to erroneously inflate the perceived benefit of novel interventions,” they wrote.

The consequences of this unblinding may be minimal in cases where there’s a clear difference between the placebo and active drug, they said. As an example, they cited trials of interleukin-23 inhibitors for psoriasis, where skin clearance as measured by the Psoriatic Area and Severity Index 75 differed by more than 50% in absolute terms between the treatment and placebo groups.

But in other cases, there needs to be more attention paid to the potential role of unblinding, they wrote.

“Studies where effect sizes were small, contradictory, or dependent on subgroup analyses might be especially problematic, but commentary rarely reflects this issue or acknowledges the potential influence of unblinding,” they wrote.

In the paper, they call for more analysis of previous trials to look for unreported assessments of unblinding, while also asking that researchers consider surveying participants in future trials to evaluate the degree to which unblinding occurs.

“Advocacy from professional societies and the U.S. Food and Drug Administration itself might be necessary, but in the interim, rheumatologists should assume unblinding has occurred to some degree in most trials,” they wrote.
 

Unblinding measure needs validation

In an interview, Roy M. Fleischmann, MD, co–medical director of the Metroplex Clinical Research Center in Dallas, raised some objections to the paper. The paper addresses an interesting question about unblinding, but there should have been more work done, such as finding “a measure that is validated that can say whether you’ve been unblinded or not.”

He added that he was surprised the paper on unblinding in rheumatology trials was published in its current form.

“I would have sent it for a major rewrite” if asked to review this paper before publication, said Dr. Fleischmann, who as a reviewer for Lancet Rheumatology. “I would have said: ‘Okay, 90% of this paper is okay, but your gist is not correct.’ It should be: ‘Is this a problem?’ ”

Dr. Fleischmann said he would have recommended a different perspective to the paper. “That is, this could occur. Should we be looking at this, and how would we look at this?”

In the paper, the authors acknowledge their approach has not been validated, “but it highlights the potential effect of idiosyncratic adverse events,” they wrote.

There’s less funding in general for meta-research than for studies involving treatments, so researchers look for approaches that can be handled without requiring significant funding, and much of the research on the quality of research is conducted like this analysis of rheumatology trials, Michael Putman, MD, the corresponding author and is a rheumatologist and an assistant professor at the Medical College of Wisconsin, said in an interview.

“You’re mostly doing on a shoestring budget with yourself and trainees,” he said. Dr. Putman is an associate editor at the journal Rheumatology and also involved in meta-research, or efforts to understand how studies and trials answer questions about how medical treatments work.

In an Aug. 16 tweet, Dr. Putman said this issue of unintentional unblinding with rheumatology trials was something he’d “been ruminating about for awhile; took two all star trainees to push it over the top!”

One of the barriers to funding of meta-research is a tendency for major funding for medical studies to be focused on specific diseases or targets. With meta-research, it may be more difficult to explain how a specific project will advance efforts to treat or prevent a certain disease, Dr. Putman said.

“It’s a little more esoteric and maybe not quite as clear how these projects will move things forward,” Dr. Putman said.

In addition, the nature of meta-research is to question and often be critical of work that’s already been published, adding another hurdle in attempts to secure funding, he said.

Dr. Putman is supported by a Rheumatology Research Foundation Scientist Development Grant, receives research funding related to clinical trials by AbbVie and AstraZeneca, and consulting fees from Novartis. The other authors declared no competing interests.

Clinical trials of treatments for rheumatologic conditions appear especially vulnerable to inadvertent unblinding, because of noticeable side effects of some drugs and subjective outcome measures, according to a new analysis.

Until more is known about the potential for unblinding, clinicians need to keep in mind that patients and physicians could often guess accurately who was getting placebo or active drug, first author Cody Bruggemeyer, MD, a resident at the Medical College of Wisconsin, Milwaukee, said in an interview.

Dr. Bruggemeyer

“It’s important that rheumatologists be aware of this potential issue and use their clinical reasoning and their ability to critically assess papers to evaluate the study design” of research on treatments, he said in an interview.

Dr. Bruggemeyer and coauthors at the Medical College of Wisconsin presented their assessment of the potential for unblinding in a Viewpoint article in The Lancet Rheumatology.
 

A sample of pivotal clinical trials

The authors selected a sample of pivotal studies of 14 commonly prescribed drugs for rheumatic conditions for which double-blind randomized controlled trials (RCTs) that compared the active ingredient with a placebo were available.

The 14 trials involved treatments classified as disease-modifying antirheumatic drugs (DMARDs), some of which were likely to produce side effects that placebos would not mimic, such as injection site and infusion reactions and difference in readings in lab reports, the authors wrote.

In their analysis, Dr. Bruggemeyer and colleagues evaluated discrepancies in the rates of adverse events reported between active drugs and placebos and classified the 14 studies as follows:

• High unblinding risk: Nine studies had a high estimated risk of unblinding, including trials of adalimumab with citrate (Humira), anakinra (Kineret), anifrolumab (Saphnelo), apremilast (Otezla), ixekizumab (Taltz), leflunomide (Arava), methotrexate, risankizumab (Skyrizi) and tofacitinib (Xeljanz).
• Moderate unblinding risk: Three studies had a moderate estimated risk of unblinding, including trials of azathioprine (Imuran), mycophenolate mofetil and tocilizumab (Actemra).
• Low unblinding risk: Two studies had a low estimated risk of unblinding. These involved tests of belimumab (Benlysta) and rituximab (Rituxan).

Many of the effectiveness measurements of treatments used in rheumatology depend on patients’ reports of relief of pain and other disease symptoms. For example, the widely used American College of Rheumatology 20% response for rheumatoid arthritis includes components that rely on patient and physician assessment of disease activity.
 

Unblinding risk to clinical trial validity

CTs are the highest level of evidence to establish efficacy, because the study design aims to mask whether the experimental treatment is a drug or placebo. In cases where patients and physicians are more likely to correctly detect use of an active drug, there can be biases that skew results toward reports of symptom improvement. Other patients’ views of their treatment may be distorted by accurate guesses that they have been given placebo, Dr. Bruggemeyer and coauthors wrote.

“The degree of these effects cannot be predicted, but they tend to erroneously inflate the perceived benefit of novel interventions,” they wrote.

The consequences of this unblinding may be minimal in cases where there’s a clear difference between the placebo and active drug, they said. As an example, they cited trials of interleukin-23 inhibitors for psoriasis, where skin clearance as measured by the Psoriatic Area and Severity Index 75 differed by more than 50% in absolute terms between the treatment and placebo groups.

But in other cases, there needs to be more attention paid to the potential role of unblinding, they wrote.

“Studies where effect sizes were small, contradictory, or dependent on subgroup analyses might be especially problematic, but commentary rarely reflects this issue or acknowledges the potential influence of unblinding,” they wrote.

In the paper, they call for more analysis of previous trials to look for unreported assessments of unblinding, while also asking that researchers consider surveying participants in future trials to evaluate the degree to which unblinding occurs.

“Advocacy from professional societies and the U.S. Food and Drug Administration itself might be necessary, but in the interim, rheumatologists should assume unblinding has occurred to some degree in most trials,” they wrote.
 

Unblinding measure needs validation

In an interview, Roy M. Fleischmann, MD, co–medical director of the Metroplex Clinical Research Center in Dallas, raised some objections to the paper. The paper addresses an interesting question about unblinding, but there should have been more work done, such as finding “a measure that is validated that can say whether you’ve been unblinded or not.”

He added that he was surprised the paper on unblinding in rheumatology trials was published in its current form.

“I would have sent it for a major rewrite” if asked to review this paper before publication, said Dr. Fleischmann, who as a reviewer for Lancet Rheumatology. “I would have said: ‘Okay, 90% of this paper is okay, but your gist is not correct.’ It should be: ‘Is this a problem?’ ”

Dr. Fleischmann said he would have recommended a different perspective to the paper. “That is, this could occur. Should we be looking at this, and how would we look at this?”

In the paper, the authors acknowledge their approach has not been validated, “but it highlights the potential effect of idiosyncratic adverse events,” they wrote.

There’s less funding in general for meta-research than for studies involving treatments, so researchers look for approaches that can be handled without requiring significant funding, and much of the research on the quality of research is conducted like this analysis of rheumatology trials, Michael Putman, MD, the corresponding author and is a rheumatologist and an assistant professor at the Medical College of Wisconsin, said in an interview.

“You’re mostly doing on a shoestring budget with yourself and trainees,” he said. Dr. Putman is an associate editor at the journal Rheumatology and also involved in meta-research, or efforts to understand how studies and trials answer questions about how medical treatments work.

In an Aug. 16 tweet, Dr. Putman said this issue of unintentional unblinding with rheumatology trials was something he’d “been ruminating about for awhile; took two all star trainees to push it over the top!”

One of the barriers to funding of meta-research is a tendency for major funding for medical studies to be focused on specific diseases or targets. With meta-research, it may be more difficult to explain how a specific project will advance efforts to treat or prevent a certain disease, Dr. Putman said.

“It’s a little more esoteric and maybe not quite as clear how these projects will move things forward,” Dr. Putman said.

In addition, the nature of meta-research is to question and often be critical of work that’s already been published, adding another hurdle in attempts to secure funding, he said.

Dr. Putman is supported by a Rheumatology Research Foundation Scientist Development Grant, receives research funding related to clinical trials by AbbVie and AstraZeneca, and consulting fees from Novartis. The other authors declared no competing interests.

Antigephyrin autoantibodies have been tied to lower gastrointestinal dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

University of Texas Health Science Center at Houston

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told this news organization in an email. Dr. McMahan is co–first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Md.

Hospital for Special Surgery

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medicine and a rheumatologist at Hospital for Special Surgery, New York, called the study “interesting and novel.”

“Not only did [antigephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Dr. Lakin, who was not involved with the research.

The study was published online in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

Dr. McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had antigephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in antigephyrin antibody–positive patients, compared with antibody-negative patients (46% vs. 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher antigephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio, 4.74; P = .010) to be antigephyrin antibody–positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said Dr. McMahan, who is associate professor in the division of rheumatology and codirector of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (e.g., an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Dr. Lakin report no relevant financial relationships.
 

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

Antigephyrin autoantibodies have been tied to lower gastrointestinal dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

University of Texas Health Science Center at Houston

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told this news organization in an email. Dr. McMahan is co–first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Md.

Hospital for Special Surgery

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medicine and a rheumatologist at Hospital for Special Surgery, New York, called the study “interesting and novel.”

“Not only did [antigephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Dr. Lakin, who was not involved with the research.

The study was published online in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

Dr. McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had antigephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in antigephyrin antibody–positive patients, compared with antibody-negative patients (46% vs. 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher antigephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio, 4.74; P = .010) to be antigephyrin antibody–positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said Dr. McMahan, who is associate professor in the division of rheumatology and codirector of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (e.g., an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Dr. Lakin report no relevant financial relationships.
 

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

Antigephyrin autoantibodies have been tied to lower gastrointestinal dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

University of Texas Health Science Center at Houston

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told this news organization in an email. Dr. McMahan is co–first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Md.

Hospital for Special Surgery

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medicine and a rheumatologist at Hospital for Special Surgery, New York, called the study “interesting and novel.”

“Not only did [antigephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Dr. Lakin, who was not involved with the research.

The study was published online in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

Dr. McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had antigephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in antigephyrin antibody–positive patients, compared with antibody-negative patients (46% vs. 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher antigephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio, 4.74; P = .010) to be antigephyrin antibody–positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said Dr. McMahan, who is associate professor in the division of rheumatology and codirector of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (e.g., an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Dr. Lakin report no relevant financial relationships.
 

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