Sara Freeman

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has included more drugs and data and is moving toward a slightly more stepped approach to treating some forms of psoriatic disease in the latest iteration of their recommendations.

“There’s been an explosion over the last few years in terms of the number of medications,” available to treat psoriasis and psoriatic arthritis, Laura C. Coates, MBChB, PhD, said in an interview ahead of presenting the draft recommendations at the annual European Congress of Rheumatology.

“The good thing about having more drugs is you’ve got more choice, but actually it makes these recommendations even more important because it becomes more complicated to choose optimal treatment for individuals,” added Dr. Coates, a senior clinical research fellow at the University of Oxford (England).

“We’ve been waiting for a while now for the new GRAPPA recommendations,” Laure Gossec, MD, PhD, of Sorbonne University and Pitié-Salpêtrière Hospital in Paris, said in a separate interview.

New overarching principle and position statements

The goal of the recommendations hasn’t really changed since the first iteration of the guidelines in 2009, Dr. Coates noted in her presentation. They are intended to provide clinicians with recommendations “based on the best available evidence” for the management of patients with psoriatic disease.

To that end, a through process was followed, starting with the setting of PICO (Patient/population/problem; intervention; comparison; outcome) questions followed by systematic literature searches, data extraction, and review that assess the quality of evidence and then grade it accordingly before using it to inform the recommendation statements.

There is a new overarching principle that says: “These recommendations, which include the most current data concerning the optimal assessment of and therapeutic approached to psoriatic arthritis, present contextual considerations to empower shared decision making.”

The other overarching principles remain the same as in the 2015 version, with “minor wording changes particularly around the comorbidities overarching principle,” Dr. Coates said.

Also new are two position statements. “One of them is specifically around biosimilars, because that’s been a big shift since 2015,” Dr. Coates said. “It has basic rules about what evidence there should be, what we should consider when we’re using them, and patient involvement and decision making.”

The second statement covers “similar advice on tapering or discontinuing therapy – what we do when people are doing really well, how we should stop or taper, and which drugs we should choose to stop along with shared decision making with patients.”

GRAPPA intentionally gives clinicians more freedom

While there may be data to show differences in efficacy and side effects between the various drugs cited in the recommendations, “GRAPPA makes the choice to not prioritize one drug over another,” Dr. Gossec said. This decision gives “a lot of freedom then to the physician to make the decision.”

One important change according to Dr. Gossec is that oral “NSAIDs have clearly been put back as first-line treatment, before going on to disease-modifying drugs for most of the musculoskeletal manifestations. She added that for skin manifestations, topical NSAIDs were recommended, but that NSAIDs were more recommended for IBD and uveitis of course.

“I feel that’s a big step towards more of a step-up approach,” Dr. Gossec said. “The old recommendations were not clear that you would precede an NSAID before moving on to a disease-modifying drug. So, I think that makes it a little bit more similar to the 2019 EULAR recommendations.” The use of csDMARDs such as methotrexate has also been “pushed up a notch” in peripheral arthritis, she said.

What’s next?

There are a few fine tunings still to be made before the final recommendations are published. They also have to be discussed at the meeting of the GRAPPA task force, which consists of rheumatologists, dermatologists, and patient representatives.

Besides the recommendations manuscript, there will be individual papers detailing the evidence underpinning the recommendations in each of the eight domains, Dr. Coates noted. Those “will look at relative efficacy in detail,” she said. “There will be a lot more discussion/evidence summary included” to help with drug selection.

“We also plan to have some case studies to illustrate how the recommendations can be used, similar to that included in the 2015 recommendations,” she added.

Paul Studenic, MD, PhD, of the Karolinska Institute in Stockholm and Medical University of Vienna, tweeted that the GRAPPA recommendations showed treatment “needs to be tailored to the patient” taking “comorbidities as well as the heterogeneity of features of the clinical presentation into account.”

He said in an interview: “The third edition of the GRAPPA is a huge collaborative effort.” The new overarching principle put the recommendations in the context of shared decision making and, he added, they emphasize an “integrated management plan taking not only ‘classical’-related manifestations like uveitis into account but [also] a spectrum of comorbidities and reproductive health.”

GRAPPA is a not-for-profit organization and receives funding from multiple pharmaceutical companies. Currently this includes AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Eli Lilly, Novartis, Pfizer, UCB, and Sun Pharma with Galapagos and Nordic Bioscience as Innovation Partners. Dr. Coates acknowledged receiving research funding, honoraria, speaker fees or all of these from most of the aforementioned companies.

Dr. Gossec has received research funding or other support from numerous pharmaceutical companies and is a member of GRAPPA and the task force that developed the EULAR guidelines on the pharmacological management of psoriatic arthritis.

Dr. Studenic had nothing to disclose.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has included more drugs and data and is moving toward a slightly more stepped approach to treating some forms of psoriatic disease in the latest iteration of their recommendations.

“There’s been an explosion over the last few years in terms of the number of medications,” available to treat psoriasis and psoriatic arthritis, Laura C. Coates, MBChB, PhD, said in an interview ahead of presenting the draft recommendations at the annual European Congress of Rheumatology.

“The good thing about having more drugs is you’ve got more choice, but actually it makes these recommendations even more important because it becomes more complicated to choose optimal treatment for individuals,” added Dr. Coates, a senior clinical research fellow at the University of Oxford (England).

“We’ve been waiting for a while now for the new GRAPPA recommendations,” Laure Gossec, MD, PhD, of Sorbonne University and Pitié-Salpêtrière Hospital in Paris, said in a separate interview.

New overarching principle and position statements

The goal of the recommendations hasn’t really changed since the first iteration of the guidelines in 2009, Dr. Coates noted in her presentation. They are intended to provide clinicians with recommendations “based on the best available evidence” for the management of patients with psoriatic disease.

To that end, a through process was followed, starting with the setting of PICO (Patient/population/problem; intervention; comparison; outcome) questions followed by systematic literature searches, data extraction, and review that assess the quality of evidence and then grade it accordingly before using it to inform the recommendation statements.

There is a new overarching principle that says: “These recommendations, which include the most current data concerning the optimal assessment of and therapeutic approached to psoriatic arthritis, present contextual considerations to empower shared decision making.”

The other overarching principles remain the same as in the 2015 version, with “minor wording changes particularly around the comorbidities overarching principle,” Dr. Coates said.

Also new are two position statements. “One of them is specifically around biosimilars, because that’s been a big shift since 2015,” Dr. Coates said. “It has basic rules about what evidence there should be, what we should consider when we’re using them, and patient involvement and decision making.”

The second statement covers “similar advice on tapering or discontinuing therapy – what we do when people are doing really well, how we should stop or taper, and which drugs we should choose to stop along with shared decision making with patients.”

GRAPPA intentionally gives clinicians more freedom

While there may be data to show differences in efficacy and side effects between the various drugs cited in the recommendations, “GRAPPA makes the choice to not prioritize one drug over another,” Dr. Gossec said. This decision gives “a lot of freedom then to the physician to make the decision.”

One important change according to Dr. Gossec is that oral “NSAIDs have clearly been put back as first-line treatment, before going on to disease-modifying drugs for most of the musculoskeletal manifestations. She added that for skin manifestations, topical NSAIDs were recommended, but that NSAIDs were more recommended for IBD and uveitis of course.

“I feel that’s a big step towards more of a step-up approach,” Dr. Gossec said. “The old recommendations were not clear that you would precede an NSAID before moving on to a disease-modifying drug. So, I think that makes it a little bit more similar to the 2019 EULAR recommendations.” The use of csDMARDs such as methotrexate has also been “pushed up a notch” in peripheral arthritis, she said.

What’s next?

There are a few fine tunings still to be made before the final recommendations are published. They also have to be discussed at the meeting of the GRAPPA task force, which consists of rheumatologists, dermatologists, and patient representatives.

Besides the recommendations manuscript, there will be individual papers detailing the evidence underpinning the recommendations in each of the eight domains, Dr. Coates noted. Those “will look at relative efficacy in detail,” she said. “There will be a lot more discussion/evidence summary included” to help with drug selection.

“We also plan to have some case studies to illustrate how the recommendations can be used, similar to that included in the 2015 recommendations,” she added.

Paul Studenic, MD, PhD, of the Karolinska Institute in Stockholm and Medical University of Vienna, tweeted that the GRAPPA recommendations showed treatment “needs to be tailored to the patient” taking “comorbidities as well as the heterogeneity of features of the clinical presentation into account.”

He said in an interview: “The third edition of the GRAPPA is a huge collaborative effort.” The new overarching principle put the recommendations in the context of shared decision making and, he added, they emphasize an “integrated management plan taking not only ‘classical’-related manifestations like uveitis into account but [also] a spectrum of comorbidities and reproductive health.”

GRAPPA is a not-for-profit organization and receives funding from multiple pharmaceutical companies. Currently this includes AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Eli Lilly, Novartis, Pfizer, UCB, and Sun Pharma with Galapagos and Nordic Bioscience as Innovation Partners. Dr. Coates acknowledged receiving research funding, honoraria, speaker fees or all of these from most of the aforementioned companies.

Dr. Gossec has received research funding or other support from numerous pharmaceutical companies and is a member of GRAPPA and the task force that developed the EULAR guidelines on the pharmacological management of psoriatic arthritis.

Dr. Studenic had nothing to disclose.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has included more drugs and data and is moving toward a slightly more stepped approach to treating some forms of psoriatic disease in the latest iteration of their recommendations.

“There’s been an explosion over the last few years in terms of the number of medications,” available to treat psoriasis and psoriatic arthritis, Laura C. Coates, MBChB, PhD, said in an interview ahead of presenting the draft recommendations at the annual European Congress of Rheumatology.

“The good thing about having more drugs is you’ve got more choice, but actually it makes these recommendations even more important because it becomes more complicated to choose optimal treatment for individuals,” added Dr. Coates, a senior clinical research fellow at the University of Oxford (England).

“We’ve been waiting for a while now for the new GRAPPA recommendations,” Laure Gossec, MD, PhD, of Sorbonne University and Pitié-Salpêtrière Hospital in Paris, said in a separate interview.

New overarching principle and position statements

The goal of the recommendations hasn’t really changed since the first iteration of the guidelines in 2009, Dr. Coates noted in her presentation. They are intended to provide clinicians with recommendations “based on the best available evidence” for the management of patients with psoriatic disease.

To that end, a through process was followed, starting with the setting of PICO (Patient/population/problem; intervention; comparison; outcome) questions followed by systematic literature searches, data extraction, and review that assess the quality of evidence and then grade it accordingly before using it to inform the recommendation statements.

There is a new overarching principle that says: “These recommendations, which include the most current data concerning the optimal assessment of and therapeutic approached to psoriatic arthritis, present contextual considerations to empower shared decision making.”

The other overarching principles remain the same as in the 2015 version, with “minor wording changes particularly around the comorbidities overarching principle,” Dr. Coates said.

Also new are two position statements. “One of them is specifically around biosimilars, because that’s been a big shift since 2015,” Dr. Coates said. “It has basic rules about what evidence there should be, what we should consider when we’re using them, and patient involvement and decision making.”

The second statement covers “similar advice on tapering or discontinuing therapy – what we do when people are doing really well, how we should stop or taper, and which drugs we should choose to stop along with shared decision making with patients.”

GRAPPA intentionally gives clinicians more freedom

While there may be data to show differences in efficacy and side effects between the various drugs cited in the recommendations, “GRAPPA makes the choice to not prioritize one drug over another,” Dr. Gossec said. This decision gives “a lot of freedom then to the physician to make the decision.”

One important change according to Dr. Gossec is that oral “NSAIDs have clearly been put back as first-line treatment, before going on to disease-modifying drugs for most of the musculoskeletal manifestations. She added that for skin manifestations, topical NSAIDs were recommended, but that NSAIDs were more recommended for IBD and uveitis of course.

“I feel that’s a big step towards more of a step-up approach,” Dr. Gossec said. “The old recommendations were not clear that you would precede an NSAID before moving on to a disease-modifying drug. So, I think that makes it a little bit more similar to the 2019 EULAR recommendations.” The use of csDMARDs such as methotrexate has also been “pushed up a notch” in peripheral arthritis, she said.

What’s next?

There are a few fine tunings still to be made before the final recommendations are published. They also have to be discussed at the meeting of the GRAPPA task force, which consists of rheumatologists, dermatologists, and patient representatives.

Besides the recommendations manuscript, there will be individual papers detailing the evidence underpinning the recommendations in each of the eight domains, Dr. Coates noted. Those “will look at relative efficacy in detail,” she said. “There will be a lot more discussion/evidence summary included” to help with drug selection.

“We also plan to have some case studies to illustrate how the recommendations can be used, similar to that included in the 2015 recommendations,” she added.

Paul Studenic, MD, PhD, of the Karolinska Institute in Stockholm and Medical University of Vienna, tweeted that the GRAPPA recommendations showed treatment “needs to be tailored to the patient” taking “comorbidities as well as the heterogeneity of features of the clinical presentation into account.”

He said in an interview: “The third edition of the GRAPPA is a huge collaborative effort.” The new overarching principle put the recommendations in the context of shared decision making and, he added, they emphasize an “integrated management plan taking not only ‘classical’-related manifestations like uveitis into account but [also] a spectrum of comorbidities and reproductive health.”

GRAPPA is a not-for-profit organization and receives funding from multiple pharmaceutical companies. Currently this includes AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Eli Lilly, Novartis, Pfizer, UCB, and Sun Pharma with Galapagos and Nordic Bioscience as Innovation Partners. Dr. Coates acknowledged receiving research funding, honoraria, speaker fees or all of these from most of the aforementioned companies.

Dr. Gossec has received research funding or other support from numerous pharmaceutical companies and is a member of GRAPPA and the task force that developed the EULAR guidelines on the pharmacological management of psoriatic arthritis.

Dr. Studenic had nothing to disclose.

Using belimumab after rituximab to treat patients with systemic lupus erythematosus (SLE) refractory to conventional therapy not only significantly decreased levels of serum IgG anti-dsDNA antibody levels but also prolonged the time before severe flares of disease occurred in the phase 2b BEAT-LUPUS (Belimumab after B cell depletion in SLE) study.

The trial’s primary outcome of serum IgG anti-dsDNA antibody levels showed a decline from a geometric mean of 162 IU/mL at baseline to 69 IU/mL at 24 weeks and 47 IU/mL at 1 year in patients treated with belimumab (Benlysta) after rituximab (Rituxan and biosimilars). These reductions were significantly lower than the values seen in the placebo after rituximab arm (a respective 121 IU/mL, 99 IU/mL, and 103 IU/mL; P < .001).

Just 3 patients who received belimumab versus 10 who received placebo after rituximab experienced a severe BILAG (British Isles Lupus Assessment Group) index A flare by the end of the study at 52 weeks. The hazard ratio (HR) for the flare reduction was 0.27 (P = .03), indicating a 73% reduction.

The use of belimumab rather than a placebo also led to a small reduction in total serum IgG, and significantly suppressed B-cell repopulation (P = .03).

These results need confirming in a larger, phase 3 trial, the trial’s principal investigator, Michael Ehrenstein, PhD, said at the annual European Congress of Rheumatology. They are “clearly encouraging” and “support the hypothesis that BAFF [B-cell–activating factor] can drive flares after rituximab,” he said.

Although B-cell depletion with rituximab is recommended by national and international guidelines to treat some patients with SLE who are refractory to conventional therapy, its use is not licensed.

“Certainly, rituximab is a controversial drug in lupus,” Dr. Ehrenstein, a consultant rheumatologist based at University College London, said in an interview. Although there is real-world evidence from registries and open-label studies suggesting that it is widely used and effective in some patients, the randomized, controlled trials conducted with rituximab about 10 years ago failed to meet their primary endpoints.

“A lot has been written about why that was, but probably the biggest reason was the high dose of steroids in both groups,” Dr. Ehrenstein said. To try to avoid muddying the waters of the BEAT-LUPUS trial findings, the maximum dose of prednisolone allowed to be used as background therapy was 20 mg/day. The trial’s investigators were also encouraged to reduce the baseline steroid dose to at least 50% by the trial’s 6-month halfway point.

“We tried to reflect what was going on in the U.K.,” Dr. Ehrenstein said, noting that the inspiration for the trial was a patient who had received sequential rituximab treatment. Although she got better with each cycle of rituximab, when her disease flared it would be worse than the time before, with increasingly higher anti-dsDNA levels recorded. The reason for this seemed to be because of increasing BAFF levels, and so the hypothesis was that if rituximab was associated with increased BAFF levels, then co-targeting BAFF with belimumab should be able to prevent those flares from happening.

The BEAT-LUPUS trial has been a huge collaborative effort and was conducted across 16 U.K. centers. From initial funding to the data analysis, it has taken 6 years to complete and was made possible by a unique partnership between Versus Arthritis, University College London Hospitals Biomedical Research Center, the National Institute for Health Research UK Musculoskeletal Translational Research Collaboration, and GlaxoSmithKline (GSK). GSK provided belimumab free of charge, as well as additional funding, but had no role in the design of the study and will not have any role going forward.

From an initial 172 patients assessed for eligibility, 52 patients were finally enrolled into the trial and received rituximab as two infusions given 2 weeks apart. Patients were then randomized in a double-blind manner to receive either belimumab (n = 26) or placebo (n = 26) 4-8 weeks after their first dose of rituximab. The intention-to-treat population consisted of 43 patients.

The use of belimumab after rituximab did not increase the risk for infection – serious or otherwise – or adverse effects, Dr. Ehrenstein reported. Serious adverse events were reported in six (23%) patients in each arm, and serious infections were seen in two (8%) of the belimumab- and four (15%) of the placebo-treated patients.

“I think the take-home message is that it seems that belimumab can reduce the number of severe flares that occur after rituximab therapy,” Dr. Ehrenstein said. “It’s promising, but not definitive,” he added. The next step is of course to publish these data and to perform a phase 3 trial.

In the discussion time following the presentation, session moderator Xavier Mariette, MD, PhD, of Bicêtre Hospital, Paris-Saclay University, asked why not give belimumab first before rituximab if using belimumab afterward works?

“Our strategy was driven by the observation that BAFF levels surged after rituximab, and therefore it’s logical to give the belimumab to block that BAFF surge,” he answered.

“Certainly, there are ideas that belimumab releases mature B cells into the circulation and rituximab can target that,” he added. That strategy is under investigation in the BLISS-BELIEVE trial, which should also report by the end of this year. It’s a much larger, phase 3 trial, involving nearly 300 patients and is sponsored by GSK.

“Clearly, this is a combination treatment [but] whether you give one before the other is uncertain,” Dr. Ehrenstein observed.

Another member of the viewing audience asked whether it would have been a fairer comparison if another dose of rituximab had been given to patients at week 24 instead of no treatment. Dr. Ehrenstein noted that it was a “good point” to make, but the investigators mainly wanted to answer whether giving belimumab after rituximab would target BAFF and thereby drop serum anti-dsDNA antibody levels. He said that a full trial of rituximab for patients with SLE, perhaps adding this extra dose, needs to be conducted.

Dr. Ehrenstein disclosed receiving research funding and educational grants from GSK and participating in advisory panels for the company.

Using belimumab after rituximab to treat patients with systemic lupus erythematosus (SLE) refractory to conventional therapy not only significantly decreased levels of serum IgG anti-dsDNA antibody levels but also prolonged the time before severe flares of disease occurred in the phase 2b BEAT-LUPUS (Belimumab after B cell depletion in SLE) study.

The trial’s primary outcome of serum IgG anti-dsDNA antibody levels showed a decline from a geometric mean of 162 IU/mL at baseline to 69 IU/mL at 24 weeks and 47 IU/mL at 1 year in patients treated with belimumab (Benlysta) after rituximab (Rituxan and biosimilars). These reductions were significantly lower than the values seen in the placebo after rituximab arm (a respective 121 IU/mL, 99 IU/mL, and 103 IU/mL; P < .001).

Just 3 patients who received belimumab versus 10 who received placebo after rituximab experienced a severe BILAG (British Isles Lupus Assessment Group) index A flare by the end of the study at 52 weeks. The hazard ratio (HR) for the flare reduction was 0.27 (P = .03), indicating a 73% reduction.

The use of belimumab rather than a placebo also led to a small reduction in total serum IgG, and significantly suppressed B-cell repopulation (P = .03).

These results need confirming in a larger, phase 3 trial, the trial’s principal investigator, Michael Ehrenstein, PhD, said at the annual European Congress of Rheumatology. They are “clearly encouraging” and “support the hypothesis that BAFF [B-cell–activating factor] can drive flares after rituximab,” he said.

Although B-cell depletion with rituximab is recommended by national and international guidelines to treat some patients with SLE who are refractory to conventional therapy, its use is not licensed.

“Certainly, rituximab is a controversial drug in lupus,” Dr. Ehrenstein, a consultant rheumatologist based at University College London, said in an interview. Although there is real-world evidence from registries and open-label studies suggesting that it is widely used and effective in some patients, the randomized, controlled trials conducted with rituximab about 10 years ago failed to meet their primary endpoints.

“A lot has been written about why that was, but probably the biggest reason was the high dose of steroids in both groups,” Dr. Ehrenstein said. To try to avoid muddying the waters of the BEAT-LUPUS trial findings, the maximum dose of prednisolone allowed to be used as background therapy was 20 mg/day. The trial’s investigators were also encouraged to reduce the baseline steroid dose to at least 50% by the trial’s 6-month halfway point.

“We tried to reflect what was going on in the U.K.,” Dr. Ehrenstein said, noting that the inspiration for the trial was a patient who had received sequential rituximab treatment. Although she got better with each cycle of rituximab, when her disease flared it would be worse than the time before, with increasingly higher anti-dsDNA levels recorded. The reason for this seemed to be because of increasing BAFF levels, and so the hypothesis was that if rituximab was associated with increased BAFF levels, then co-targeting BAFF with belimumab should be able to prevent those flares from happening.

The BEAT-LUPUS trial has been a huge collaborative effort and was conducted across 16 U.K. centers. From initial funding to the data analysis, it has taken 6 years to complete and was made possible by a unique partnership between Versus Arthritis, University College London Hospitals Biomedical Research Center, the National Institute for Health Research UK Musculoskeletal Translational Research Collaboration, and GlaxoSmithKline (GSK). GSK provided belimumab free of charge, as well as additional funding, but had no role in the design of the study and will not have any role going forward.

From an initial 172 patients assessed for eligibility, 52 patients were finally enrolled into the trial and received rituximab as two infusions given 2 weeks apart. Patients were then randomized in a double-blind manner to receive either belimumab (n = 26) or placebo (n = 26) 4-8 weeks after their first dose of rituximab. The intention-to-treat population consisted of 43 patients.

The use of belimumab after rituximab did not increase the risk for infection – serious or otherwise – or adverse effects, Dr. Ehrenstein reported. Serious adverse events were reported in six (23%) patients in each arm, and serious infections were seen in two (8%) of the belimumab- and four (15%) of the placebo-treated patients.

“I think the take-home message is that it seems that belimumab can reduce the number of severe flares that occur after rituximab therapy,” Dr. Ehrenstein said. “It’s promising, but not definitive,” he added. The next step is of course to publish these data and to perform a phase 3 trial.

In the discussion time following the presentation, session moderator Xavier Mariette, MD, PhD, of Bicêtre Hospital, Paris-Saclay University, asked why not give belimumab first before rituximab if using belimumab afterward works?

“Our strategy was driven by the observation that BAFF levels surged after rituximab, and therefore it’s logical to give the belimumab to block that BAFF surge,” he answered.

“Certainly, there are ideas that belimumab releases mature B cells into the circulation and rituximab can target that,” he added. That strategy is under investigation in the BLISS-BELIEVE trial, which should also report by the end of this year. It’s a much larger, phase 3 trial, involving nearly 300 patients and is sponsored by GSK.

“Clearly, this is a combination treatment [but] whether you give one before the other is uncertain,” Dr. Ehrenstein observed.

Another member of the viewing audience asked whether it would have been a fairer comparison if another dose of rituximab had been given to patients at week 24 instead of no treatment. Dr. Ehrenstein noted that it was a “good point” to make, but the investigators mainly wanted to answer whether giving belimumab after rituximab would target BAFF and thereby drop serum anti-dsDNA antibody levels. He said that a full trial of rituximab for patients with SLE, perhaps adding this extra dose, needs to be conducted.

Dr. Ehrenstein disclosed receiving research funding and educational grants from GSK and participating in advisory panels for the company.

Using belimumab after rituximab to treat patients with systemic lupus erythematosus (SLE) refractory to conventional therapy not only significantly decreased levels of serum IgG anti-dsDNA antibody levels but also prolonged the time before severe flares of disease occurred in the phase 2b BEAT-LUPUS (Belimumab after B cell depletion in SLE) study.

The trial’s primary outcome of serum IgG anti-dsDNA antibody levels showed a decline from a geometric mean of 162 IU/mL at baseline to 69 IU/mL at 24 weeks and 47 IU/mL at 1 year in patients treated with belimumab (Benlysta) after rituximab (Rituxan and biosimilars). These reductions were significantly lower than the values seen in the placebo after rituximab arm (a respective 121 IU/mL, 99 IU/mL, and 103 IU/mL; P < .001).

Just 3 patients who received belimumab versus 10 who received placebo after rituximab experienced a severe BILAG (British Isles Lupus Assessment Group) index A flare by the end of the study at 52 weeks. The hazard ratio (HR) for the flare reduction was 0.27 (P = .03), indicating a 73% reduction.

The use of belimumab rather than a placebo also led to a small reduction in total serum IgG, and significantly suppressed B-cell repopulation (P = .03).

These results need confirming in a larger, phase 3 trial, the trial’s principal investigator, Michael Ehrenstein, PhD, said at the annual European Congress of Rheumatology. They are “clearly encouraging” and “support the hypothesis that BAFF [B-cell–activating factor] can drive flares after rituximab,” he said.

Although B-cell depletion with rituximab is recommended by national and international guidelines to treat some patients with SLE who are refractory to conventional therapy, its use is not licensed.

“Certainly, rituximab is a controversial drug in lupus,” Dr. Ehrenstein, a consultant rheumatologist based at University College London, said in an interview. Although there is real-world evidence from registries and open-label studies suggesting that it is widely used and effective in some patients, the randomized, controlled trials conducted with rituximab about 10 years ago failed to meet their primary endpoints.

“A lot has been written about why that was, but probably the biggest reason was the high dose of steroids in both groups,” Dr. Ehrenstein said. To try to avoid muddying the waters of the BEAT-LUPUS trial findings, the maximum dose of prednisolone allowed to be used as background therapy was 20 mg/day. The trial’s investigators were also encouraged to reduce the baseline steroid dose to at least 50% by the trial’s 6-month halfway point.

“We tried to reflect what was going on in the U.K.,” Dr. Ehrenstein said, noting that the inspiration for the trial was a patient who had received sequential rituximab treatment. Although she got better with each cycle of rituximab, when her disease flared it would be worse than the time before, with increasingly higher anti-dsDNA levels recorded. The reason for this seemed to be because of increasing BAFF levels, and so the hypothesis was that if rituximab was associated with increased BAFF levels, then co-targeting BAFF with belimumab should be able to prevent those flares from happening.

The BEAT-LUPUS trial has been a huge collaborative effort and was conducted across 16 U.K. centers. From initial funding to the data analysis, it has taken 6 years to complete and was made possible by a unique partnership between Versus Arthritis, University College London Hospitals Biomedical Research Center, the National Institute for Health Research UK Musculoskeletal Translational Research Collaboration, and GlaxoSmithKline (GSK). GSK provided belimumab free of charge, as well as additional funding, but had no role in the design of the study and will not have any role going forward.

From an initial 172 patients assessed for eligibility, 52 patients were finally enrolled into the trial and received rituximab as two infusions given 2 weeks apart. Patients were then randomized in a double-blind manner to receive either belimumab (n = 26) or placebo (n = 26) 4-8 weeks after their first dose of rituximab. The intention-to-treat population consisted of 43 patients.

The use of belimumab after rituximab did not increase the risk for infection – serious or otherwise – or adverse effects, Dr. Ehrenstein reported. Serious adverse events were reported in six (23%) patients in each arm, and serious infections were seen in two (8%) of the belimumab- and four (15%) of the placebo-treated patients.

“I think the take-home message is that it seems that belimumab can reduce the number of severe flares that occur after rituximab therapy,” Dr. Ehrenstein said. “It’s promising, but not definitive,” he added. The next step is of course to publish these data and to perform a phase 3 trial.

In the discussion time following the presentation, session moderator Xavier Mariette, MD, PhD, of Bicêtre Hospital, Paris-Saclay University, asked why not give belimumab first before rituximab if using belimumab afterward works?

“Our strategy was driven by the observation that BAFF levels surged after rituximab, and therefore it’s logical to give the belimumab to block that BAFF surge,” he answered.

“Certainly, there are ideas that belimumab releases mature B cells into the circulation and rituximab can target that,” he added. That strategy is under investigation in the BLISS-BELIEVE trial, which should also report by the end of this year. It’s a much larger, phase 3 trial, involving nearly 300 patients and is sponsored by GSK.

“Clearly, this is a combination treatment [but] whether you give one before the other is uncertain,” Dr. Ehrenstein observed.

Another member of the viewing audience asked whether it would have been a fairer comparison if another dose of rituximab had been given to patients at week 24 instead of no treatment. Dr. Ehrenstein noted that it was a “good point” to make, but the investigators mainly wanted to answer whether giving belimumab after rituximab would target BAFF and thereby drop serum anti-dsDNA antibody levels. He said that a full trial of rituximab for patients with SLE, perhaps adding this extra dose, needs to be conducted.

Dr. Ehrenstein disclosed receiving research funding and educational grants from GSK and participating in advisory panels for the company.

The European Alliance of Associations for Rheumatology has started the process of updating their recommendations on how to manage patients with rheumatic and musculoskeletal diseases (RMDs) in the context of the SARS-CoV-2 pandemic.

So far, the first part of the systematic literature review has been performed and the conclusions that have been drawn appear to back up the recommendations that have already been made. It’s “hard to say” if there will need to be changes, said Robert B.M. Landewé, MD, PhD, at the annual European Congress of Rheumatology, as the next phase will be for the task force members to meet and discuss the implications of the literature research.“I think there will only be minor modifications and a few novel recommendations, but that is personal opinion,” speculated Dr. Landewé, who is professor of rheumatology at the Amsterdam Medical Center, University of Amsterdam.

The recommendations, which were developed a little over a year ago and published in Annals of the Rheumatic Diseases, set out provisional guidance covering four themes: infection prevention, managing patients when social distancing measures are in effect, managing patients with RMDs who develop COVID-19, and the prevention of infections other than SARS-CoV-2.
 

Emphasis on quality of evidence

According to EULAR’s standard operating procedures “updates should only be done if the evolving evidence mandates to do so,” and be based on “rational arguments,” Dr. Landewé said. “The last year was a bit unprecedented in that regard as we didn’t have those rational arguments before we designed our first set of recommendations and, as you can expect, that is totally due to the character of the pandemic.”

So much has been published on COVID-19 since then it was time to reappraise the situation. The task force behind the recommendations met in January 2021 to discuss the results of the literature search that was centered around five main research questions.

• Do patients with RMDs face more risk of contracting SARS-CoV-2 than the general population?
• If patients contract the virus, do they have a worse prognosis?
• Are antirheumatic medications associated with a worse outcome in people with RMDs?
• Should patients continue their antirheumatic medications?
• What evidence informs the use of vaccination against SARS-CoV-2 in patients with RMDs?

The latter research question is pending discussion since there were no studies to review at the time as the various vaccines had only just started to be widely available.

“We put a lot of emphasis on the quality of evidence,” Dr. Landewé said. In addition to making sure that patients did indeed have COVID-19 and checking that hospitalization and death records were caused by the disease, the task force team also looked to see if there was a control group being used. An extensive risk of bias assessment was undertaken, the results of which are pending.

Of 6,665 records identified during the literature search, just 113 full-text articles were assessed for eligibility. Of those, 60% were rejected as they did not pass the quality assessment, leaving 49 articles for consideration. The majority of these looked at the incidence of COVID-19, with others focusing on risk factors or both.
 

Literature search findings on main research questions

Dr. Landewé observed that the task force concluded that “current literature provides no evidence that patients with RMDs face more risk of contracting SARS-CoV-2 than individuals without RMDs.” They also concluded that patients with RMDs who do contract COVID-19 do not have a worse prognosis either, even though there have been a few studies suggesting a higher rate of hospitalization.

Both findings are reassuring as they fit with the existing recommendation to follow the same preventive and control measures in patients with RMDs as for the general population, but the task force is yet to determine if that recommendation should be amended.

There did not appear to be any hard evidence of any unique demographic feature or comorbidity that puts people with RMDs at more risk for severe COVID-19 than the general population. Think older age, male gender, high bodyweight, cardiovascular disease, diabetes, and chronic lung disease, Dr. Landewé said.

He noted, however, that there were some single-center reports suggesting that moderate or high levels of disease activity could put people with RMDs at greater risk for COVID-related death, “which is an intriguing finding in the context of discontinuing antirheumatic medication.” That is likely something the task force will be discussing when they decide how to update their recommendations.

The type of RMD may also be important, but again only single-center evidence to show that there might be an increased hospitalization risk in patients with autoinflammatory disease or risk for severe COVID-19 in those with certain connective tissue diseases. “These associations were not consistently found in other studies,” so it’s an open question how the task force decides to incorporate this into the updated guidance.

As for antirheumatic medications, conclusions from the literature review suggest that there doesn’t appear to be an increased or decreased risk for severe COVID-19 among users of NSAIDs or antimalarials.

That’s not the case for glucocorticoids. There appears to be an increased risk for hospitalization and COVID-19–related death, notably among those using higher (>10 mg) daily doses. “This is, so to say, the elephant in the room,” Dr. Landewé said. The current recommendation states that chronic users of glucocorticoids should continue their treatment. “The reports of additional risk could be due to glucocorticoids or to biases such as confounding by indication. So, the conclusion that we draw [is] not completely clear.”

In response to a question, he clarified this a little further: “We think ‘glucocorticoid use’ is a determinant of worse health, as is the case in many RMDs. Be aware that finding a positive association between [glucocorticoid] use and bad outcome does not mean that if you reduce [glucocorticoids], your patient will have a better outcome.”

The jury is also out on rituximab, which has been reported to increase the risk of severe COVID-19 and COVID-related death in two studies. There are also equivocal data on whether not using disease-modifying antirheumatic drugs increases the risk for these worse outcomes.

Asked about the absence of a recommendation on the use of the interleukin-6 inhibitor tocilizumab, Dr. Landewé responded: “We are caught up by evolving evidence. That is a generic problem in a dynamic field of COVID-19, I am afraid. What you recommend today is sometimes ‘old history’ tomorrow.”

Dr. Landewé had no relevant disclosures to make.

The European Alliance of Associations for Rheumatology has started the process of updating their recommendations on how to manage patients with rheumatic and musculoskeletal diseases (RMDs) in the context of the SARS-CoV-2 pandemic.

So far, the first part of the systematic literature review has been performed and the conclusions that have been drawn appear to back up the recommendations that have already been made. It’s “hard to say” if there will need to be changes, said Robert B.M. Landewé, MD, PhD, at the annual European Congress of Rheumatology, as the next phase will be for the task force members to meet and discuss the implications of the literature research.“I think there will only be minor modifications and a few novel recommendations, but that is personal opinion,” speculated Dr. Landewé, who is professor of rheumatology at the Amsterdam Medical Center, University of Amsterdam.

The recommendations, which were developed a little over a year ago and published in Annals of the Rheumatic Diseases, set out provisional guidance covering four themes: infection prevention, managing patients when social distancing measures are in effect, managing patients with RMDs who develop COVID-19, and the prevention of infections other than SARS-CoV-2.
 

Emphasis on quality of evidence

According to EULAR’s standard operating procedures “updates should only be done if the evolving evidence mandates to do so,” and be based on “rational arguments,” Dr. Landewé said. “The last year was a bit unprecedented in that regard as we didn’t have those rational arguments before we designed our first set of recommendations and, as you can expect, that is totally due to the character of the pandemic.”

So much has been published on COVID-19 since then it was time to reappraise the situation. The task force behind the recommendations met in January 2021 to discuss the results of the literature search that was centered around five main research questions.

• Do patients with RMDs face more risk of contracting SARS-CoV-2 than the general population?
• If patients contract the virus, do they have a worse prognosis?
• Are antirheumatic medications associated with a worse outcome in people with RMDs?
• Should patients continue their antirheumatic medications?
• What evidence informs the use of vaccination against SARS-CoV-2 in patients with RMDs?

The latter research question is pending discussion since there were no studies to review at the time as the various vaccines had only just started to be widely available.

“We put a lot of emphasis on the quality of evidence,” Dr. Landewé said. In addition to making sure that patients did indeed have COVID-19 and checking that hospitalization and death records were caused by the disease, the task force team also looked to see if there was a control group being used. An extensive risk of bias assessment was undertaken, the results of which are pending.

Of 6,665 records identified during the literature search, just 113 full-text articles were assessed for eligibility. Of those, 60% were rejected as they did not pass the quality assessment, leaving 49 articles for consideration. The majority of these looked at the incidence of COVID-19, with others focusing on risk factors or both.
 

Literature search findings on main research questions

Dr. Landewé observed that the task force concluded that “current literature provides no evidence that patients with RMDs face more risk of contracting SARS-CoV-2 than individuals without RMDs.” They also concluded that patients with RMDs who do contract COVID-19 do not have a worse prognosis either, even though there have been a few studies suggesting a higher rate of hospitalization.

Both findings are reassuring as they fit with the existing recommendation to follow the same preventive and control measures in patients with RMDs as for the general population, but the task force is yet to determine if that recommendation should be amended.

There did not appear to be any hard evidence of any unique demographic feature or comorbidity that puts people with RMDs at more risk for severe COVID-19 than the general population. Think older age, male gender, high bodyweight, cardiovascular disease, diabetes, and chronic lung disease, Dr. Landewé said.

He noted, however, that there were some single-center reports suggesting that moderate or high levels of disease activity could put people with RMDs at greater risk for COVID-related death, “which is an intriguing finding in the context of discontinuing antirheumatic medication.” That is likely something the task force will be discussing when they decide how to update their recommendations.

The type of RMD may also be important, but again only single-center evidence to show that there might be an increased hospitalization risk in patients with autoinflammatory disease or risk for severe COVID-19 in those with certain connective tissue diseases. “These associations were not consistently found in other studies,” so it’s an open question how the task force decides to incorporate this into the updated guidance.

As for antirheumatic medications, conclusions from the literature review suggest that there doesn’t appear to be an increased or decreased risk for severe COVID-19 among users of NSAIDs or antimalarials.

That’s not the case for glucocorticoids. There appears to be an increased risk for hospitalization and COVID-19–related death, notably among those using higher (>10 mg) daily doses. “This is, so to say, the elephant in the room,” Dr. Landewé said. The current recommendation states that chronic users of glucocorticoids should continue their treatment. “The reports of additional risk could be due to glucocorticoids or to biases such as confounding by indication. So, the conclusion that we draw [is] not completely clear.”

In response to a question, he clarified this a little further: “We think ‘glucocorticoid use’ is a determinant of worse health, as is the case in many RMDs. Be aware that finding a positive association between [glucocorticoid] use and bad outcome does not mean that if you reduce [glucocorticoids], your patient will have a better outcome.”

The jury is also out on rituximab, which has been reported to increase the risk of severe COVID-19 and COVID-related death in two studies. There are also equivocal data on whether not using disease-modifying antirheumatic drugs increases the risk for these worse outcomes.

Asked about the absence of a recommendation on the use of the interleukin-6 inhibitor tocilizumab, Dr. Landewé responded: “We are caught up by evolving evidence. That is a generic problem in a dynamic field of COVID-19, I am afraid. What you recommend today is sometimes ‘old history’ tomorrow.”

Dr. Landewé had no relevant disclosures to make.

The European Alliance of Associations for Rheumatology has started the process of updating their recommendations on how to manage patients with rheumatic and musculoskeletal diseases (RMDs) in the context of the SARS-CoV-2 pandemic.

So far, the first part of the systematic literature review has been performed and the conclusions that have been drawn appear to back up the recommendations that have already been made. It’s “hard to say” if there will need to be changes, said Robert B.M. Landewé, MD, PhD, at the annual European Congress of Rheumatology, as the next phase will be for the task force members to meet and discuss the implications of the literature research.“I think there will only be minor modifications and a few novel recommendations, but that is personal opinion,” speculated Dr. Landewé, who is professor of rheumatology at the Amsterdam Medical Center, University of Amsterdam.

The recommendations, which were developed a little over a year ago and published in Annals of the Rheumatic Diseases, set out provisional guidance covering four themes: infection prevention, managing patients when social distancing measures are in effect, managing patients with RMDs who develop COVID-19, and the prevention of infections other than SARS-CoV-2.
 

Emphasis on quality of evidence

According to EULAR’s standard operating procedures “updates should only be done if the evolving evidence mandates to do so,” and be based on “rational arguments,” Dr. Landewé said. “The last year was a bit unprecedented in that regard as we didn’t have those rational arguments before we designed our first set of recommendations and, as you can expect, that is totally due to the character of the pandemic.”

So much has been published on COVID-19 since then it was time to reappraise the situation. The task force behind the recommendations met in January 2021 to discuss the results of the literature search that was centered around five main research questions.

• Do patients with RMDs face more risk of contracting SARS-CoV-2 than the general population?
• If patients contract the virus, do they have a worse prognosis?
• Are antirheumatic medications associated with a worse outcome in people with RMDs?
• Should patients continue their antirheumatic medications?
• What evidence informs the use of vaccination against SARS-CoV-2 in patients with RMDs?

The latter research question is pending discussion since there were no studies to review at the time as the various vaccines had only just started to be widely available.

“We put a lot of emphasis on the quality of evidence,” Dr. Landewé said. In addition to making sure that patients did indeed have COVID-19 and checking that hospitalization and death records were caused by the disease, the task force team also looked to see if there was a control group being used. An extensive risk of bias assessment was undertaken, the results of which are pending.

Of 6,665 records identified during the literature search, just 113 full-text articles were assessed for eligibility. Of those, 60% were rejected as they did not pass the quality assessment, leaving 49 articles for consideration. The majority of these looked at the incidence of COVID-19, with others focusing on risk factors or both.
 

Literature search findings on main research questions

Dr. Landewé observed that the task force concluded that “current literature provides no evidence that patients with RMDs face more risk of contracting SARS-CoV-2 than individuals without RMDs.” They also concluded that patients with RMDs who do contract COVID-19 do not have a worse prognosis either, even though there have been a few studies suggesting a higher rate of hospitalization.

Both findings are reassuring as they fit with the existing recommendation to follow the same preventive and control measures in patients with RMDs as for the general population, but the task force is yet to determine if that recommendation should be amended.

There did not appear to be any hard evidence of any unique demographic feature or comorbidity that puts people with RMDs at more risk for severe COVID-19 than the general population. Think older age, male gender, high bodyweight, cardiovascular disease, diabetes, and chronic lung disease, Dr. Landewé said.

He noted, however, that there were some single-center reports suggesting that moderate or high levels of disease activity could put people with RMDs at greater risk for COVID-related death, “which is an intriguing finding in the context of discontinuing antirheumatic medication.” That is likely something the task force will be discussing when they decide how to update their recommendations.

The type of RMD may also be important, but again only single-center evidence to show that there might be an increased hospitalization risk in patients with autoinflammatory disease or risk for severe COVID-19 in those with certain connective tissue diseases. “These associations were not consistently found in other studies,” so it’s an open question how the task force decides to incorporate this into the updated guidance.

As for antirheumatic medications, conclusions from the literature review suggest that there doesn’t appear to be an increased or decreased risk for severe COVID-19 among users of NSAIDs or antimalarials.

That’s not the case for glucocorticoids. There appears to be an increased risk for hospitalization and COVID-19–related death, notably among those using higher (>10 mg) daily doses. “This is, so to say, the elephant in the room,” Dr. Landewé said. The current recommendation states that chronic users of glucocorticoids should continue their treatment. “The reports of additional risk could be due to glucocorticoids or to biases such as confounding by indication. So, the conclusion that we draw [is] not completely clear.”

In response to a question, he clarified this a little further: “We think ‘glucocorticoid use’ is a determinant of worse health, as is the case in many RMDs. Be aware that finding a positive association between [glucocorticoid] use and bad outcome does not mean that if you reduce [glucocorticoids], your patient will have a better outcome.”

The jury is also out on rituximab, which has been reported to increase the risk of severe COVID-19 and COVID-related death in two studies. There are also equivocal data on whether not using disease-modifying antirheumatic drugs increases the risk for these worse outcomes.

Asked about the absence of a recommendation on the use of the interleukin-6 inhibitor tocilizumab, Dr. Landewé responded: “We are caught up by evolving evidence. That is a generic problem in a dynamic field of COVID-19, I am afraid. What you recommend today is sometimes ‘old history’ tomorrow.”

Dr. Landewé had no relevant disclosures to make.

Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).

That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.

Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.

Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.

The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”

He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
 

ILD occurs with other cancer drugs

ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.

That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.

“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
 

Investigating ILD in T-DXd trials

T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.

It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.

“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.

To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).

In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
 

Dealing with lung toxicity

“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.

“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.

Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.

The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”

Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
 

ILD also seen in monarchE trial with abemaciclib

Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.

Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
 

So who’s at risk?

The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.

“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”

Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”

While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.

As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”

While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.

These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”

The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.

Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.

Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).

That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.

Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.

Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.

The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”

He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
 

ILD occurs with other cancer drugs

ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.

That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.

“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
 

Investigating ILD in T-DXd trials

T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.

It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.

“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.

To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).

In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
 

Dealing with lung toxicity

“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.

“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.

Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.

The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”

Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
 

ILD also seen in monarchE trial with abemaciclib

Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.

Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
 

So who’s at risk?

The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.

“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”

Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”

While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.

As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”

While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.

These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”

The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.

Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.

Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).

That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.

Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.

Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.

The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”

He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
 

ILD occurs with other cancer drugs

ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.

That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.

“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
 

Investigating ILD in T-DXd trials

T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.

It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.

“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.

To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).

In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
 

Dealing with lung toxicity

“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.

“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.

Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.

The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”

Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
 

ILD also seen in monarchE trial with abemaciclib

Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.

Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
 

So who’s at risk?

The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.

“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”

Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”

While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.

As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”

While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.

These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”

The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.

Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.

The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).

Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.

“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.

Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.

“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.

However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”

As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
 

Study details and results

The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.

Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.

We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.

Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).

After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).

Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.

A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).

Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.

“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.

“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.

The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.

The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).

Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.

“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.

Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.

“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.

However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”

As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
 

Study details and results

The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.

Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.

We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.

Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).

After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).

Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.

A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).

Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.

“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.

“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.

The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.

The long-term benefits of endocrine therapy in premenopausal breast cancer appear to differ according to whether patients are categorized as high or low molecular risk using the 70-gene signature (MammaPrint).

Based upon data from patients who had participated in the Stockholm tamoxifen (STO-5) trial, high-risk patients significantly benefited from goserelin treatment, whereas low-risk patients benefited more from tamoxifen treatment when compared with no endocrine therapy.

“Goserelin, tamoxifen, and the combination of the two, reduced the 20-year risk of distant occurrences and fatal breast cancer, compared to no endocrine therapy,” Annelie Johansson, MSc, said at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Our findings indicate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification and thus tumor characteristics,” she added.

Ms. Johansson, a postdoctoral researcher in genomic breast cancer at the Karolinska Institutet in Stockholm, reported the results of the analysis as a late-breaking abstract at the meeting.

“I think this is an innovative translational study trying to use the multigene assay results to look at differential endocrine therapy effects,” said Prudence Francis, MD, the invited discussant for study.

However, there are relatively few patients in the various subgroups being tested, she added. “We’ve also got short duration of tamoxifen, only 2 years, we’ve got prior chemotherapy in some patients and absence of HER2 therapy, all of which might influence outcomes.”

As a result, Dr. Francis, who is head of medical oncology at the Peter MacCallum Cancer Centre and a consultant Medical Oncologist at St. Vincent’s Hospital Melbourne, called the findings purely “hypothesis generating.”
 

Study details and results

The analysis was based on data from the STO-5 trial, which had recruited just over 900 patients between 1990 and 1997. Patients were stratified according to their lymph node status and some received chemotherapy with or without locoregional radiotherapy before being randomized to one of four study arms: goserelin alone, tamoxifen alone, the combination of the two, or no endocrine therapy.

Ms. Johansson noted that they were able to obtain the primary tumor blocks from 729 patients in the past year, of whom 610 were estrogen receptor positive. The analysis according to the 70-gene signature was then based on data from 465 patients: 131 had been treated with goserelin, 105 with tamoxifen, 120 with both, and 109 had received no endocrine treatment.

We have complete 20-year follow-up from high-quality Swedish National registries,” Ms. Johansson said, observing that the median age in the trial was 46 years.

Before stratifying patients into high and low risk using the 70-gene signature, the risk for having a distant recurrence, compared with no endocrine therapy was reduced by 52% with goserelin (hazard ratio, .48), 41% with tamoxifen (HR, 0.59), and 33% with both in combination (HR, 0.67).

After stratification, however, goserelin was associated with a 78% reduction of distant recurrence versus no endocrine treatment in high-risk patients (HR, 0.22) and a 20% reduction in low-risk patients (HR, 0.80).

Results in high- and low-risk patients with tamoxifen versus no endocrine treatment were a respective 31% reduction (HR, 0.69) and 62% reduction (HR, 0.38), and a respective 36% (HR, 0.64) and 28% (HR, 0.72) for the combination.

A further analysis was performed to compare between the active treatment arms, and this suggested a greater benefit of goserelin in patients at high risk when compared with both tamoxifen (HR, 0.30) and the combination (HR, 0.33).

Dr. Francis commented: “it is a bit surprising to find that goserelin appeared to be also better than the combination,” and it is something that the research team is looking into.

“One hypothesis might be if you look how the different treatments are working,” Ms. Johansson said. “Goserelin is very efficient in lowering the estrogen levels in premenopausal patients, suppressing the ovarian production of estrogen whereas tamoxifen can act both as an antagonist and agonist.

“So, we are thinking that maybe the addition of tamoxifen, with the agonistic properties of tamoxifen, might then make the goserelin not as efficient. But that’s of course, just a hypothesis right now and we need to look into this further,” she said.

The work was funded by The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare, and the Swedish Cancer Society (Cancerfonden). Ms. Johansson had no personal disclosures; one of the coauthors was a coinventor of MammaPrint. Dr. Francis disclosed receiving travel support for overseas lectures from Ipsen and Novartis and acting as a medical oncology editor for Elsevier.

The PD-L1 inhibitor atezolizumab (Tecentriq) combined with carboplatin has shown signs of clinical activity in women with metastatic invasive lobular breast cancer (ILC) according to the first results to come from the ongoing GELATO trial.

The 6-month objective response rate was 19%, based on 4 of 21 patients who could be evaluated exhibiting a partial response to the chemoimmunotherapy. A further two (10%) patients had stable disease, meaning that clinical benefit rate was 29%.

GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer) is a phase 2 trial being conducted at four Dutch centers. The primary premise of the study is that “there’s an immune-related subtype of ILC,” researcher Leonie Voorwerk, BSc, reported at the European Society for Medical Oncology: Breast Cancer virtual meeting (Abstract LBA3).

This ILC subtype is “characterized by high expression of immune-related genes and high levels of TILs [tumor-infiltrating lymphocytes] and PDL-1,” said Ms. Voorwerk, a PhD student working with medical oncologist Marleen Kok, MD, PhD, at the Netherlands Cancer Institute in Amsterdam.

Furthermore, she added, in vitro data suggest sensitivity of immune-related-ILCs to platinum and there is preclinical work showing that there is synergy between platinum-based chemotherapy and checkpoint blockade.
 

First chemoimmunotherapy trial in lobular cancer setting

GELATO is a significant trial as it is “the first chemoimmunotherapy trial in metastatic lobular breast cancer,” said Sylvia Adams, MD, professor of medicine and director of the Breast Cancer Center at NYU Langone Health in New York City.

“Of note, the further research should include the immune-related genes and TMB [tumor mutational burden],” proposed Dr. Adams, who was not involved in the trial.

“We should look to tumor mutational burden because while it is not typically high in early disease, metastatic lesions can have higher TMB,” she explained. “Also, metastatic ILC is known to have higher tumor mutational burden compared to IDC [invasive ductal carcinoma], so this is an important thing along with the clinical factors as described in looking at outcomes.”
 

Trial design and patient characteristics

GELATO is a single-arm, nonrandomized trial in which 37 patients with metastatic ILC were screened for inclusion between November 2017 and January 2021. A total of 26 of these patients were registered for the trial, and 23 have so far received at least one cycle of atezolizumab.

Prerequisites for entry into the trial were that patients had to have negative or aberrant E-cadherin, a characteristic feature of ILC. Patients with estrogen receptor (ER)-positive (ER+) disease could be included, but they had to be proven to be resistant to endocrine therapies. No more than two prior lines of palliative chemotherapy were allowed, and all participants had to have lactose dehydrogenase levels of less than 2 times the upper limit of normal.

Patients were then treated with up to 12 cycles of weekly carboplatin (AUC = 1.5 mg/mL/min), with atezolizumab (1,200 mg) added in from cycle 3 onward. Treatment was continued until disease progression or unacceptable toxicity occurred.

“Baseline characteristics were mainly as expected for this patient population,” Ms. Voorwerk stated. Patients were aged 45-89 years, with a median of 60 years. Around half each had a WHO performance status of 0 or 1, and around half each had one to two or three or more metastatic sites; 78% had liver metastases.

“But I want to highlight that we included five patients with the triple-negative ILC,” said Ms. Voorwerk, also highlighting that approximately 50% of patients had received prior palliative chemotherapy. Later in her presentation she noted that four out of the six patients that showed any clinical benefit had triple negative disease.
 

Key findings and next steps

The primary endpoint was progression-free survival (PFS) at 6 months, with secondary endpoints of the best overall response rate, PFS at 1 year, overall survival, and safety.

While details of the latter three endpoints are yet to be reported, Ms. Voorwerk noted that there was a median duration of response of 12 weeks and the median PFS was 15 weeks. The primary endpoint of PFS was met as four patients were free of progression at 6 months and the statistical method used called for patients to be progression free at this time point.

“We observed that stromal TILs and CD8+ cells were not associated with clinical benefits,” said Ms. Voorwerk. There was, however, “a slight trend” toward higher PD-L1 expression in responding patients.

“Further translational research is needed to provide the rationale for new strategies to improve checkpoint blockade in patients with lobular breast cancer,” she concluded.

Dr. Adams concurred, adding that a future research question was whether either atezolizumab or carboplatin was contributing to the response. This is “difficult to tell as the study was a single arm trial.”

Another question, said Dr. Adams, is are “anti-CDK 4/6 inhibitors helpful in improving response rates and durability?” In the trial, 70% of patients had prior exposure to CDK 4/6 inhibitors.

The GELATO trial was sponsored by the Netherlands Cancer Institute with funding from Roche Pharma AG. Ms. Voorwerk had nothing to disclose. Dr. Adams disclosed uncompensated consulting or advisory roles with Bristol-Myers Squibb, Genentech, and Merck from whom she has received research funding. Dr. Adams also disclosed research funding from Amgen, Celgene, and Novartis.

The PD-L1 inhibitor atezolizumab (Tecentriq) combined with carboplatin has shown signs of clinical activity in women with metastatic invasive lobular breast cancer (ILC) according to the first results to come from the ongoing GELATO trial.

The 6-month objective response rate was 19%, based on 4 of 21 patients who could be evaluated exhibiting a partial response to the chemoimmunotherapy. A further two (10%) patients had stable disease, meaning that clinical benefit rate was 29%.

GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer) is a phase 2 trial being conducted at four Dutch centers. The primary premise of the study is that “there’s an immune-related subtype of ILC,” researcher Leonie Voorwerk, BSc, reported at the European Society for Medical Oncology: Breast Cancer virtual meeting (Abstract LBA3).

This ILC subtype is “characterized by high expression of immune-related genes and high levels of TILs [tumor-infiltrating lymphocytes] and PDL-1,” said Ms. Voorwerk, a PhD student working with medical oncologist Marleen Kok, MD, PhD, at the Netherlands Cancer Institute in Amsterdam.

Furthermore, she added, in vitro data suggest sensitivity of immune-related-ILCs to platinum and there is preclinical work showing that there is synergy between platinum-based chemotherapy and checkpoint blockade.
 

First chemoimmunotherapy trial in lobular cancer setting

GELATO is a significant trial as it is “the first chemoimmunotherapy trial in metastatic lobular breast cancer,” said Sylvia Adams, MD, professor of medicine and director of the Breast Cancer Center at NYU Langone Health in New York City.

“Of note, the further research should include the immune-related genes and TMB [tumor mutational burden],” proposed Dr. Adams, who was not involved in the trial.

“We should look to tumor mutational burden because while it is not typically high in early disease, metastatic lesions can have higher TMB,” she explained. “Also, metastatic ILC is known to have higher tumor mutational burden compared to IDC [invasive ductal carcinoma], so this is an important thing along with the clinical factors as described in looking at outcomes.”
 

Trial design and patient characteristics

GELATO is a single-arm, nonrandomized trial in which 37 patients with metastatic ILC were screened for inclusion between November 2017 and January 2021. A total of 26 of these patients were registered for the trial, and 23 have so far received at least one cycle of atezolizumab.

Prerequisites for entry into the trial were that patients had to have negative or aberrant E-cadherin, a characteristic feature of ILC. Patients with estrogen receptor (ER)-positive (ER+) disease could be included, but they had to be proven to be resistant to endocrine therapies. No more than two prior lines of palliative chemotherapy were allowed, and all participants had to have lactose dehydrogenase levels of less than 2 times the upper limit of normal.

Patients were then treated with up to 12 cycles of weekly carboplatin (AUC = 1.5 mg/mL/min), with atezolizumab (1,200 mg) added in from cycle 3 onward. Treatment was continued until disease progression or unacceptable toxicity occurred.

“Baseline characteristics were mainly as expected for this patient population,” Ms. Voorwerk stated. Patients were aged 45-89 years, with a median of 60 years. Around half each had a WHO performance status of 0 or 1, and around half each had one to two or three or more metastatic sites; 78% had liver metastases.

“But I want to highlight that we included five patients with the triple-negative ILC,” said Ms. Voorwerk, also highlighting that approximately 50% of patients had received prior palliative chemotherapy. Later in her presentation she noted that four out of the six patients that showed any clinical benefit had triple negative disease.
 

Key findings and next steps

The primary endpoint was progression-free survival (PFS) at 6 months, with secondary endpoints of the best overall response rate, PFS at 1 year, overall survival, and safety.

While details of the latter three endpoints are yet to be reported, Ms. Voorwerk noted that there was a median duration of response of 12 weeks and the median PFS was 15 weeks. The primary endpoint of PFS was met as four patients were free of progression at 6 months and the statistical method used called for patients to be progression free at this time point.

“We observed that stromal TILs and CD8+ cells were not associated with clinical benefits,” said Ms. Voorwerk. There was, however, “a slight trend” toward higher PD-L1 expression in responding patients.

“Further translational research is needed to provide the rationale for new strategies to improve checkpoint blockade in patients with lobular breast cancer,” she concluded.

Dr. Adams concurred, adding that a future research question was whether either atezolizumab or carboplatin was contributing to the response. This is “difficult to tell as the study was a single arm trial.”

Another question, said Dr. Adams, is are “anti-CDK 4/6 inhibitors helpful in improving response rates and durability?” In the trial, 70% of patients had prior exposure to CDK 4/6 inhibitors.

The GELATO trial was sponsored by the Netherlands Cancer Institute with funding from Roche Pharma AG. Ms. Voorwerk had nothing to disclose. Dr. Adams disclosed uncompensated consulting or advisory roles with Bristol-Myers Squibb, Genentech, and Merck from whom she has received research funding. Dr. Adams also disclosed research funding from Amgen, Celgene, and Novartis.

The PD-L1 inhibitor atezolizumab (Tecentriq) combined with carboplatin has shown signs of clinical activity in women with metastatic invasive lobular breast cancer (ILC) according to the first results to come from the ongoing GELATO trial.

The 6-month objective response rate was 19%, based on 4 of 21 patients who could be evaluated exhibiting a partial response to the chemoimmunotherapy. A further two (10%) patients had stable disease, meaning that clinical benefit rate was 29%.

GELATO (AssessinG Efficacy of Carboplatin and ATezOlizumab in Metastatic Lobular Breast Cancer) is a phase 2 trial being conducted at four Dutch centers. The primary premise of the study is that “there’s an immune-related subtype of ILC,” researcher Leonie Voorwerk, BSc, reported at the European Society for Medical Oncology: Breast Cancer virtual meeting (Abstract LBA3).

This ILC subtype is “characterized by high expression of immune-related genes and high levels of TILs [tumor-infiltrating lymphocytes] and PDL-1,” said Ms. Voorwerk, a PhD student working with medical oncologist Marleen Kok, MD, PhD, at the Netherlands Cancer Institute in Amsterdam.

Furthermore, she added, in vitro data suggest sensitivity of immune-related-ILCs to platinum and there is preclinical work showing that there is synergy between platinum-based chemotherapy and checkpoint blockade.
 

First chemoimmunotherapy trial in lobular cancer setting

GELATO is a significant trial as it is “the first chemoimmunotherapy trial in metastatic lobular breast cancer,” said Sylvia Adams, MD, professor of medicine and director of the Breast Cancer Center at NYU Langone Health in New York City.

“Of note, the further research should include the immune-related genes and TMB [tumor mutational burden],” proposed Dr. Adams, who was not involved in the trial.

“We should look to tumor mutational burden because while it is not typically high in early disease, metastatic lesions can have higher TMB,” she explained. “Also, metastatic ILC is known to have higher tumor mutational burden compared to IDC [invasive ductal carcinoma], so this is an important thing along with the clinical factors as described in looking at outcomes.”
 

Trial design and patient characteristics

GELATO is a single-arm, nonrandomized trial in which 37 patients with metastatic ILC were screened for inclusion between November 2017 and January 2021. A total of 26 of these patients were registered for the trial, and 23 have so far received at least one cycle of atezolizumab.

Prerequisites for entry into the trial were that patients had to have negative or aberrant E-cadherin, a characteristic feature of ILC. Patients with estrogen receptor (ER)-positive (ER+) disease could be included, but they had to be proven to be resistant to endocrine therapies. No more than two prior lines of palliative chemotherapy were allowed, and all participants had to have lactose dehydrogenase levels of less than 2 times the upper limit of normal.

Patients were then treated with up to 12 cycles of weekly carboplatin (AUC = 1.5 mg/mL/min), with atezolizumab (1,200 mg) added in from cycle 3 onward. Treatment was continued until disease progression or unacceptable toxicity occurred.

“Baseline characteristics were mainly as expected for this patient population,” Ms. Voorwerk stated. Patients were aged 45-89 years, with a median of 60 years. Around half each had a WHO performance status of 0 or 1, and around half each had one to two or three or more metastatic sites; 78% had liver metastases.

“But I want to highlight that we included five patients with the triple-negative ILC,” said Ms. Voorwerk, also highlighting that approximately 50% of patients had received prior palliative chemotherapy. Later in her presentation she noted that four out of the six patients that showed any clinical benefit had triple negative disease.
 

Key findings and next steps

The primary endpoint was progression-free survival (PFS) at 6 months, with secondary endpoints of the best overall response rate, PFS at 1 year, overall survival, and safety.

While details of the latter three endpoints are yet to be reported, Ms. Voorwerk noted that there was a median duration of response of 12 weeks and the median PFS was 15 weeks. The primary endpoint of PFS was met as four patients were free of progression at 6 months and the statistical method used called for patients to be progression free at this time point.

“We observed that stromal TILs and CD8+ cells were not associated with clinical benefits,” said Ms. Voorwerk. There was, however, “a slight trend” toward higher PD-L1 expression in responding patients.

“Further translational research is needed to provide the rationale for new strategies to improve checkpoint blockade in patients with lobular breast cancer,” she concluded.

Dr. Adams concurred, adding that a future research question was whether either atezolizumab or carboplatin was contributing to the response. This is “difficult to tell as the study was a single arm trial.”

Another question, said Dr. Adams, is are “anti-CDK 4/6 inhibitors helpful in improving response rates and durability?” In the trial, 70% of patients had prior exposure to CDK 4/6 inhibitors.

The GELATO trial was sponsored by the Netherlands Cancer Institute with funding from Roche Pharma AG. Ms. Voorwerk had nothing to disclose. Dr. Adams disclosed uncompensated consulting or advisory roles with Bristol-Myers Squibb, Genentech, and Merck from whom she has received research funding. Dr. Adams also disclosed research funding from Amgen, Celgene, and Novartis.

Three-year survival rates were similarly high among postmenopausal women with high-risk early luminal breast cancer who were treated with either the neoadjuvant combination of letrozole and palbociclib (Ibrance) or standard neoadjuvant chemotherapy in the phase 2 NeoPAL study.

Progression-free survival (PFS) was a respective 86.7% and 87.2%, with a hazard ratio (HR) of 1.01 (P = .98) comparing the endocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitor combination versus FEC/taxane chemotherapy.

There were also no differences between the two treatment arms in terms of invasive disease-free survival (iDFS, HR = 0.83, P = .71) or breast cancer–specific survival (BCSS), although the latter was an exploratory endpoint alongside overall survival (OS).

“The lack of difference is impressive,” said Hope S. Rugo, MD, FASCO, who commented independently on the study’s findings after their presentation at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Overall survival in patients who received chemotherapy appears to be better, but the very small numbers here make interpretation of this difference impossible,” observed Dr. Rugo, professor of medicine at the University of California San Francisco’s Helen Diller Family Comprehensive Cancer Center.

“Unfortunately, this study is underpowered for definitive conclusions,” acknowledged study investigator Suzette Delaloge, MD, associate professor of medical oncology at Institut Gustave Roussy in Villejuif, France.

However, “it shows that the nonchemotherapy, preoperative letrozole/palbociclib approach deserves further exploration and could be an option for a chemotherapy-free regimen in some specific cases.”
 

Primary data already reported

The NeoPAL study was an open-label, randomized study conducted in 27 centers throughout France that compared the preoperative use of letrozole plus palbociclib to neoadjuvant chemotherapy in 106 postmenopausal patients with either luminal A or B node-positive disease.

Patients were considered for inclusion in the trial if they had been newly diagnosed with estrogen receptor (ER)-positive, HER2-negative stage I-III breast cancer and were not candidates for breast conservation. Genetic testing was used to confirm that only those with luminal B, or luminal A and who were node positive were recruited.

Neoadjuvant treatment consisted of either letrozole (2.5 mg/day) and palbociclib (125 mg daily for 3 weeks out of 4 weeks) for 19 weeks or three 21-day cycles of 5-fluorouracil (500 mg/m²), epirubicin (100 mg/m²), and cyclophosphamide (500 mg/m²), followed by three 21-day cycles of docetaxel (100 mg/m²).

The primary endpoint was the pathological complete response (pCR), defined as a residual cancer burden (RCB) of 0 to 1. Results, which have already been reported, showed equivalent, but perhaps disappointingly low, pathological responses in both the letrozole/palbociclib and chemotherapy arms (3.8% and 5.9%, respectively).

There were, however, identical clinical responses (at around 75%) and “encouraging biomarker responses in the Prosigna-defined high risk luminal breast cancer population,” Dr. Delaloge said.

The NeoPAL findings were on par with those of the CORALLEEN study, Dr. Delaloge suggested. That trial, as Dr. Rugo has also pointed out, was conducted in 106 patients with luminal B early breast cancer and used a combination of letrozole and the CDK 4/6 inhibitor ribociclib (Kisquali).
 

Future studies needed

NeoPAL “is a small study with relatively short follow-up even for hormone receptor-positive, high-risk disease,” Dr. Rugo observed. However, she qualified “this short follow-up can be very meaningful in high-risk disease.” as shown by other CDK 4/6 inhibitor trials.

Dr. Rugo also noted: “Short-term biologic endpoints are clearly more informative following and during neoadjuvant endocrine therapy than pCR and this trial, as well as the data from previous studies, indicates that this is the case.”

Further, Dr. Rugo said: “Antiproliferative response is enhanced with CDK 4/6 inhibitors, but this doesn’t seem to translate into a difference in pCR. The lack of impact on longer term, outcome to date, provides support for ongoing trials.”

Two such trials are already underway. The 200-patient CARABELA trial started recruitment in March last year and is comparing endocrine therapy with letrozole plus the CDK 4/6 inhibitor abemaciclib (Verzenio) to standard chemotherapy in patients with hormone receptor–positive, high-risk Ki67 disease.

Then there is the ADAPTcycle trial, a large open-label, phase 3 trial that is randomizing patients based on Ki67 and recurrence score after a short preoperative induction with endocrine therapy to postoperative chemotherapy or to 2 years of endocrine therapy plus ribociclib, with both arms receiving a standard course of 5 years of endocrine therapy.

“These two studies have provided interesting information that will help us design studies in the future,” said Dr. Rugo.

Not only that, but they will also help “investigate the subgroups of patients that benefit the most from CDK 4/6 inhibitors and better study neoadjuvant endocrine therapy which is an important option for patients that can be evaluated in terms of its efficacy by short term measures of antiproliferative response.”

NeoPAL was sponsored by UNICANCER with funding from Pfizer and NanoString Technologies. Dr. Delaloge disclosed receiving research grants or funding via her institution from Pfizer, AstraZeneca, Roche, Merck, Sanofi, Lilly, Novartis, BMS, Orion, Daiichi, Puma, and Pierre Fabre. Dr. Rugo reported receipt of grants via her institution to perform clinical trials from Pfizer and multiple other companies. She disclosed receiving honoraria from PUMA, Samsung, and Mylan.

Three-year survival rates were similarly high among postmenopausal women with high-risk early luminal breast cancer who were treated with either the neoadjuvant combination of letrozole and palbociclib (Ibrance) or standard neoadjuvant chemotherapy in the phase 2 NeoPAL study.

Progression-free survival (PFS) was a respective 86.7% and 87.2%, with a hazard ratio (HR) of 1.01 (P = .98) comparing the endocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitor combination versus FEC/taxane chemotherapy.

There were also no differences between the two treatment arms in terms of invasive disease-free survival (iDFS, HR = 0.83, P = .71) or breast cancer–specific survival (BCSS), although the latter was an exploratory endpoint alongside overall survival (OS).

“The lack of difference is impressive,” said Hope S. Rugo, MD, FASCO, who commented independently on the study’s findings after their presentation at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Overall survival in patients who received chemotherapy appears to be better, but the very small numbers here make interpretation of this difference impossible,” observed Dr. Rugo, professor of medicine at the University of California San Francisco’s Helen Diller Family Comprehensive Cancer Center.

“Unfortunately, this study is underpowered for definitive conclusions,” acknowledged study investigator Suzette Delaloge, MD, associate professor of medical oncology at Institut Gustave Roussy in Villejuif, France.

However, “it shows that the nonchemotherapy, preoperative letrozole/palbociclib approach deserves further exploration and could be an option for a chemotherapy-free regimen in some specific cases.”
 

Primary data already reported

The NeoPAL study was an open-label, randomized study conducted in 27 centers throughout France that compared the preoperative use of letrozole plus palbociclib to neoadjuvant chemotherapy in 106 postmenopausal patients with either luminal A or B node-positive disease.

Patients were considered for inclusion in the trial if they had been newly diagnosed with estrogen receptor (ER)-positive, HER2-negative stage I-III breast cancer and were not candidates for breast conservation. Genetic testing was used to confirm that only those with luminal B, or luminal A and who were node positive were recruited.

Neoadjuvant treatment consisted of either letrozole (2.5 mg/day) and palbociclib (125 mg daily for 3 weeks out of 4 weeks) for 19 weeks or three 21-day cycles of 5-fluorouracil (500 mg/m²), epirubicin (100 mg/m²), and cyclophosphamide (500 mg/m²), followed by three 21-day cycles of docetaxel (100 mg/m²).

The primary endpoint was the pathological complete response (pCR), defined as a residual cancer burden (RCB) of 0 to 1. Results, which have already been reported, showed equivalent, but perhaps disappointingly low, pathological responses in both the letrozole/palbociclib and chemotherapy arms (3.8% and 5.9%, respectively).

There were, however, identical clinical responses (at around 75%) and “encouraging biomarker responses in the Prosigna-defined high risk luminal breast cancer population,” Dr. Delaloge said.

The NeoPAL findings were on par with those of the CORALLEEN study, Dr. Delaloge suggested. That trial, as Dr. Rugo has also pointed out, was conducted in 106 patients with luminal B early breast cancer and used a combination of letrozole and the CDK 4/6 inhibitor ribociclib (Kisquali).
 

Future studies needed

NeoPAL “is a small study with relatively short follow-up even for hormone receptor-positive, high-risk disease,” Dr. Rugo observed. However, she qualified “this short follow-up can be very meaningful in high-risk disease.” as shown by other CDK 4/6 inhibitor trials.

Dr. Rugo also noted: “Short-term biologic endpoints are clearly more informative following and during neoadjuvant endocrine therapy than pCR and this trial, as well as the data from previous studies, indicates that this is the case.”

Further, Dr. Rugo said: “Antiproliferative response is enhanced with CDK 4/6 inhibitors, but this doesn’t seem to translate into a difference in pCR. The lack of impact on longer term, outcome to date, provides support for ongoing trials.”

Two such trials are already underway. The 200-patient CARABELA trial started recruitment in March last year and is comparing endocrine therapy with letrozole plus the CDK 4/6 inhibitor abemaciclib (Verzenio) to standard chemotherapy in patients with hormone receptor–positive, high-risk Ki67 disease.

Then there is the ADAPTcycle trial, a large open-label, phase 3 trial that is randomizing patients based on Ki67 and recurrence score after a short preoperative induction with endocrine therapy to postoperative chemotherapy or to 2 years of endocrine therapy plus ribociclib, with both arms receiving a standard course of 5 years of endocrine therapy.

“These two studies have provided interesting information that will help us design studies in the future,” said Dr. Rugo.

Not only that, but they will also help “investigate the subgroups of patients that benefit the most from CDK 4/6 inhibitors and better study neoadjuvant endocrine therapy which is an important option for patients that can be evaluated in terms of its efficacy by short term measures of antiproliferative response.”

NeoPAL was sponsored by UNICANCER with funding from Pfizer and NanoString Technologies. Dr. Delaloge disclosed receiving research grants or funding via her institution from Pfizer, AstraZeneca, Roche, Merck, Sanofi, Lilly, Novartis, BMS, Orion, Daiichi, Puma, and Pierre Fabre. Dr. Rugo reported receipt of grants via her institution to perform clinical trials from Pfizer and multiple other companies. She disclosed receiving honoraria from PUMA, Samsung, and Mylan.

Three-year survival rates were similarly high among postmenopausal women with high-risk early luminal breast cancer who were treated with either the neoadjuvant combination of letrozole and palbociclib (Ibrance) or standard neoadjuvant chemotherapy in the phase 2 NeoPAL study.

Progression-free survival (PFS) was a respective 86.7% and 87.2%, with a hazard ratio (HR) of 1.01 (P = .98) comparing the endocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitor combination versus FEC/taxane chemotherapy.

There were also no differences between the two treatment arms in terms of invasive disease-free survival (iDFS, HR = 0.83, P = .71) or breast cancer–specific survival (BCSS), although the latter was an exploratory endpoint alongside overall survival (OS).

“The lack of difference is impressive,” said Hope S. Rugo, MD, FASCO, who commented independently on the study’s findings after their presentation at the European Society for Medical Oncology: Breast Cancer virtual meeting.

“Overall survival in patients who received chemotherapy appears to be better, but the very small numbers here make interpretation of this difference impossible,” observed Dr. Rugo, professor of medicine at the University of California San Francisco’s Helen Diller Family Comprehensive Cancer Center.

“Unfortunately, this study is underpowered for definitive conclusions,” acknowledged study investigator Suzette Delaloge, MD, associate professor of medical oncology at Institut Gustave Roussy in Villejuif, France.

However, “it shows that the nonchemotherapy, preoperative letrozole/palbociclib approach deserves further exploration and could be an option for a chemotherapy-free regimen in some specific cases.”
 

Primary data already reported

The NeoPAL study was an open-label, randomized study conducted in 27 centers throughout France that compared the preoperative use of letrozole plus palbociclib to neoadjuvant chemotherapy in 106 postmenopausal patients with either luminal A or B node-positive disease.

Patients were considered for inclusion in the trial if they had been newly diagnosed with estrogen receptor (ER)-positive, HER2-negative stage I-III breast cancer and were not candidates for breast conservation. Genetic testing was used to confirm that only those with luminal B, or luminal A and who were node positive were recruited.

Neoadjuvant treatment consisted of either letrozole (2.5 mg/day) and palbociclib (125 mg daily for 3 weeks out of 4 weeks) for 19 weeks or three 21-day cycles of 5-fluorouracil (500 mg/m²), epirubicin (100 mg/m²), and cyclophosphamide (500 mg/m²), followed by three 21-day cycles of docetaxel (100 mg/m²).

The primary endpoint was the pathological complete response (pCR), defined as a residual cancer burden (RCB) of 0 to 1. Results, which have already been reported, showed equivalent, but perhaps disappointingly low, pathological responses in both the letrozole/palbociclib and chemotherapy arms (3.8% and 5.9%, respectively).

There were, however, identical clinical responses (at around 75%) and “encouraging biomarker responses in the Prosigna-defined high risk luminal breast cancer population,” Dr. Delaloge said.

The NeoPAL findings were on par with those of the CORALLEEN study, Dr. Delaloge suggested. That trial, as Dr. Rugo has also pointed out, was conducted in 106 patients with luminal B early breast cancer and used a combination of letrozole and the CDK 4/6 inhibitor ribociclib (Kisquali).
 

Future studies needed

NeoPAL “is a small study with relatively short follow-up even for hormone receptor-positive, high-risk disease,” Dr. Rugo observed. However, she qualified “this short follow-up can be very meaningful in high-risk disease.” as shown by other CDK 4/6 inhibitor trials.

Dr. Rugo also noted: “Short-term biologic endpoints are clearly more informative following and during neoadjuvant endocrine therapy than pCR and this trial, as well as the data from previous studies, indicates that this is the case.”

Further, Dr. Rugo said: “Antiproliferative response is enhanced with CDK 4/6 inhibitors, but this doesn’t seem to translate into a difference in pCR. The lack of impact on longer term, outcome to date, provides support for ongoing trials.”

Two such trials are already underway. The 200-patient CARABELA trial started recruitment in March last year and is comparing endocrine therapy with letrozole plus the CDK 4/6 inhibitor abemaciclib (Verzenio) to standard chemotherapy in patients with hormone receptor–positive, high-risk Ki67 disease.

Then there is the ADAPTcycle trial, a large open-label, phase 3 trial that is randomizing patients based on Ki67 and recurrence score after a short preoperative induction with endocrine therapy to postoperative chemotherapy or to 2 years of endocrine therapy plus ribociclib, with both arms receiving a standard course of 5 years of endocrine therapy.

“These two studies have provided interesting information that will help us design studies in the future,” said Dr. Rugo.

Not only that, but they will also help “investigate the subgroups of patients that benefit the most from CDK 4/6 inhibitors and better study neoadjuvant endocrine therapy which is an important option for patients that can be evaluated in terms of its efficacy by short term measures of antiproliferative response.”

NeoPAL was sponsored by UNICANCER with funding from Pfizer and NanoString Technologies. Dr. Delaloge disclosed receiving research grants or funding via her institution from Pfizer, AstraZeneca, Roche, Merck, Sanofi, Lilly, Novartis, BMS, Orion, Daiichi, Puma, and Pierre Fabre. Dr. Rugo reported receipt of grants via her institution to perform clinical trials from Pfizer and multiple other companies. She disclosed receiving honoraria from PUMA, Samsung, and Mylan.

Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.

After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).

Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.

Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.

BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.

“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.

Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”

Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.

That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.

“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.

The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
 

BERENICE study design

BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.

Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.

Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.

Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.

The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.

The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
 

Discussion points

Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.

“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”

Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.

“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”

The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.

Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.

After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).

Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.

Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.

BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.

“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.

Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”

Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.

That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.

“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.

The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
 

BERENICE study design

BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.

Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.

Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.

Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.

The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.

The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
 

Discussion points

Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.

“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”

Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.

“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”

The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.

Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.

After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).

Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.

Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.

BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.

“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.

Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”

Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.

That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.

“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.

The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
 

BERENICE study design

BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.

Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.

Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.

Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.

The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.

The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
 

Discussion points

Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.

“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”

Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.

“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”

The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.

The serious infection risk associated with rituximab treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is high but can be offset by co-prescribing co-trimoxazole, data from a single-center, retrospective study reaffirm.

Over the course of a 3-year study period, 14 (28%) of 50 patients with AAV treated with rituximab experienced at latest one severe infection defined as a grade 3 or higher event. The incidence of severe infections was 15.4 per 100 person-years.

However, a lower rate of infections was seen in patients who had been co-prescribed co-trimoxazole (trimethoprim and sulfamethoxazole), Francesco Dernie, a fifth-year medical student at the University of Oxford (England), reported at the British Society for Rheumatology annual conference.

“In the case of rituximab, the depletion of B cells and associated immune suppression is a double-edged sword, allowing effective disease control, but also leaving the body vulnerable to opportunistic and severe infections,” Mr. Dernie said at the meeting.

Of the patients who developed a severe infection on rituximab, just 7% had been treated with co-trimoxazole. In comparison, 44% of those who did not get a severe infection had received co-trimoxazole. Multivariate analysis confirmed that co-trimoxazole use was an influencing factor, with an odds ratio (OR) of 0.096 (95% confidence interval, 0.009–0.996; P = .05).

Another finding was that patients with low immunoglobulin G levels (less than 6 g/L) were more likely to develop a severe infection than were those with higher IgG levels. Indeed, the OR for hypogammaglobulinemia and the risk for infection was 8.782 (95% CI, 1.19–64.6; P = .033).

“Our results support the monitoring of IgG levels to identify patients who may be more susceptible to infection, as well as the prescription of prophylactic co-trimoxazole to reduce overall severe infection risk,” Mr. Dernie and associates concluded in their abstract.

It’s a “really important message around co-trimoxazole,” observed Neil Basu, MBChB, a clinical senior lecturer and honorary consultant at the Institute of Infection, Immunity & Inflammation, University of Glasgow (Scotland).

“It still frustrates me when I see that patients haven’t received that while receiving rituximab. Of course, co-trimoxazole can have its problems,” said Dr. Basu, who was not involved in the study. “It’s not uncommon for patients to develop reactions or be intolerant to the drug.”

Raashid Luqmani, DM, a senior coauthor of the work and professor of rheumatology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, said: “The tolerance of co-trimoxazole has been remarkably good in this cohort.” If there was a problem with using co-trimoxazole, then “our standard would be to go with trimethoprim alone as the next in line and follow that with inhaled pentamidine. So, it’s kind of following what we would all generally do,” Dr. Luqmani said.

Study details

To look at the characteristics of and risk factors for serious infections associated with rituximab use in AAV, Mr. Dernie and associates retrospectively examined the electronic records of patients who had been treated between August 2016 and August 2019. Follow-up was until August 2020.

Of the 50 patients identified, nearly half (48%) were men. The average age was 60 years, ranging from 25 to 90 years. Most (n = 36; 72%) patients had a diagnosis of granulomatosis with polyangiitis, while another 2 (4%) had microscopic polyangiitis, 1 (2%) had eosinophilic granulomatosis with polyangiitis, and 11 (22%) had an overlapping type of vasculitis or undefined AAV.

Of the 18 severe infection events recorded, most (56%) involved the respiratory tract. Less than one-third (28%) were sepsis or neutropenic sepsis events, and there was one case each (6%) of cellulitis, complicated urinary tract infection, and recurrent wound infection.

There were “small numbers of individual comorbidities that were not sufficient to enter into our regression analysis,” Mr. Dernie noted. “It’s likely that comorbid conditions such as COPD [chronic obstructive pulmonary disease] also contribute to an individual’s risk of developing severe infections, and thus should factor into their individualized management.”

Mr. Dernie acknowledged in discussion: “One of the limitations of the study was we just looked at patients in a time when they were receiving rituximab, so they may have historically been exposed to other treatment options.” However, he added, “they weren’t having any other major DMARDs or immunosuppressive treatments at the time.”

Dr. Luqmani observed: “If you look at Francesco’s data on the hypogammaglobulinemia at the start of rituximab, that probably gives you a good idea of just how immunosuppressed these patients were already before we got to this point.”

Dr. Luqmani added: “I suspect that’s in keeping with a lot of other centers that have started using rituximab an awful lot for patients who previously had episodes of vasculitis treated with other disease-modifying therapies, particularly cyclophosphamide.”

But for how long should co-trimoxazole be given after the last rituximab dose? asked the chair of the session, Richard Watts, DM, of Norwich (England) Medical School. These data are purely observational, so it’s not possible to say, Mr. Dernie noted: “The patients that we included as having co-trimoxazole seem to be on it more or less consistently, permanently,” he said.

What about the best dose? “It’s a tricky one,” Dr. Luqmani said, as “we not only use co-trimoxazole for prophylaxis, but we often also want to use it for treatment of the vasculitis itself.”

It’s very likely that there was a mix of patients in the analysis that had received co-trimoxazole as either a treatment or prophylaxis, which means different doses, he said.

“It might be interesting to know whether there was a difference” between doses used and the prevention of infection, added Dr. Luqmani, “but I suspect the numbers are too small to tell.”

Mr. Dernie, Dr. Luqmani, and the other coauthors had no disclosures.

The serious infection risk associated with rituximab treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is high but can be offset by co-prescribing co-trimoxazole, data from a single-center, retrospective study reaffirm.

Over the course of a 3-year study period, 14 (28%) of 50 patients with AAV treated with rituximab experienced at latest one severe infection defined as a grade 3 or higher event. The incidence of severe infections was 15.4 per 100 person-years.

However, a lower rate of infections was seen in patients who had been co-prescribed co-trimoxazole (trimethoprim and sulfamethoxazole), Francesco Dernie, a fifth-year medical student at the University of Oxford (England), reported at the British Society for Rheumatology annual conference.

“In the case of rituximab, the depletion of B cells and associated immune suppression is a double-edged sword, allowing effective disease control, but also leaving the body vulnerable to opportunistic and severe infections,” Mr. Dernie said at the meeting.

Of the patients who developed a severe infection on rituximab, just 7% had been treated with co-trimoxazole. In comparison, 44% of those who did not get a severe infection had received co-trimoxazole. Multivariate analysis confirmed that co-trimoxazole use was an influencing factor, with an odds ratio (OR) of 0.096 (95% confidence interval, 0.009–0.996; P = .05).

Another finding was that patients with low immunoglobulin G levels (less than 6 g/L) were more likely to develop a severe infection than were those with higher IgG levels. Indeed, the OR for hypogammaglobulinemia and the risk for infection was 8.782 (95% CI, 1.19–64.6; P = .033).

“Our results support the monitoring of IgG levels to identify patients who may be more susceptible to infection, as well as the prescription of prophylactic co-trimoxazole to reduce overall severe infection risk,” Mr. Dernie and associates concluded in their abstract.

It’s a “really important message around co-trimoxazole,” observed Neil Basu, MBChB, a clinical senior lecturer and honorary consultant at the Institute of Infection, Immunity & Inflammation, University of Glasgow (Scotland).

“It still frustrates me when I see that patients haven’t received that while receiving rituximab. Of course, co-trimoxazole can have its problems,” said Dr. Basu, who was not involved in the study. “It’s not uncommon for patients to develop reactions or be intolerant to the drug.”

Raashid Luqmani, DM, a senior coauthor of the work and professor of rheumatology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, said: “The tolerance of co-trimoxazole has been remarkably good in this cohort.” If there was a problem with using co-trimoxazole, then “our standard would be to go with trimethoprim alone as the next in line and follow that with inhaled pentamidine. So, it’s kind of following what we would all generally do,” Dr. Luqmani said.

Study details

To look at the characteristics of and risk factors for serious infections associated with rituximab use in AAV, Mr. Dernie and associates retrospectively examined the electronic records of patients who had been treated between August 2016 and August 2019. Follow-up was until August 2020.

Of the 50 patients identified, nearly half (48%) were men. The average age was 60 years, ranging from 25 to 90 years. Most (n = 36; 72%) patients had a diagnosis of granulomatosis with polyangiitis, while another 2 (4%) had microscopic polyangiitis, 1 (2%) had eosinophilic granulomatosis with polyangiitis, and 11 (22%) had an overlapping type of vasculitis or undefined AAV.

Of the 18 severe infection events recorded, most (56%) involved the respiratory tract. Less than one-third (28%) were sepsis or neutropenic sepsis events, and there was one case each (6%) of cellulitis, complicated urinary tract infection, and recurrent wound infection.

There were “small numbers of individual comorbidities that were not sufficient to enter into our regression analysis,” Mr. Dernie noted. “It’s likely that comorbid conditions such as COPD [chronic obstructive pulmonary disease] also contribute to an individual’s risk of developing severe infections, and thus should factor into their individualized management.”

Mr. Dernie acknowledged in discussion: “One of the limitations of the study was we just looked at patients in a time when they were receiving rituximab, so they may have historically been exposed to other treatment options.” However, he added, “they weren’t having any other major DMARDs or immunosuppressive treatments at the time.”

Dr. Luqmani observed: “If you look at Francesco’s data on the hypogammaglobulinemia at the start of rituximab, that probably gives you a good idea of just how immunosuppressed these patients were already before we got to this point.”

Dr. Luqmani added: “I suspect that’s in keeping with a lot of other centers that have started using rituximab an awful lot for patients who previously had episodes of vasculitis treated with other disease-modifying therapies, particularly cyclophosphamide.”

But for how long should co-trimoxazole be given after the last rituximab dose? asked the chair of the session, Richard Watts, DM, of Norwich (England) Medical School. These data are purely observational, so it’s not possible to say, Mr. Dernie noted: “The patients that we included as having co-trimoxazole seem to be on it more or less consistently, permanently,” he said.

What about the best dose? “It’s a tricky one,” Dr. Luqmani said, as “we not only use co-trimoxazole for prophylaxis, but we often also want to use it for treatment of the vasculitis itself.”

It’s very likely that there was a mix of patients in the analysis that had received co-trimoxazole as either a treatment or prophylaxis, which means different doses, he said.

“It might be interesting to know whether there was a difference” between doses used and the prevention of infection, added Dr. Luqmani, “but I suspect the numbers are too small to tell.”

Mr. Dernie, Dr. Luqmani, and the other coauthors had no disclosures.

The serious infection risk associated with rituximab treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is high but can be offset by co-prescribing co-trimoxazole, data from a single-center, retrospective study reaffirm.

Over the course of a 3-year study period, 14 (28%) of 50 patients with AAV treated with rituximab experienced at latest one severe infection defined as a grade 3 or higher event. The incidence of severe infections was 15.4 per 100 person-years.

However, a lower rate of infections was seen in patients who had been co-prescribed co-trimoxazole (trimethoprim and sulfamethoxazole), Francesco Dernie, a fifth-year medical student at the University of Oxford (England), reported at the British Society for Rheumatology annual conference.

“In the case of rituximab, the depletion of B cells and associated immune suppression is a double-edged sword, allowing effective disease control, but also leaving the body vulnerable to opportunistic and severe infections,” Mr. Dernie said at the meeting.

Of the patients who developed a severe infection on rituximab, just 7% had been treated with co-trimoxazole. In comparison, 44% of those who did not get a severe infection had received co-trimoxazole. Multivariate analysis confirmed that co-trimoxazole use was an influencing factor, with an odds ratio (OR) of 0.096 (95% confidence interval, 0.009–0.996; P = .05).

Another finding was that patients with low immunoglobulin G levels (less than 6 g/L) were more likely to develop a severe infection than were those with higher IgG levels. Indeed, the OR for hypogammaglobulinemia and the risk for infection was 8.782 (95% CI, 1.19–64.6; P = .033).

“Our results support the monitoring of IgG levels to identify patients who may be more susceptible to infection, as well as the prescription of prophylactic co-trimoxazole to reduce overall severe infection risk,” Mr. Dernie and associates concluded in their abstract.

It’s a “really important message around co-trimoxazole,” observed Neil Basu, MBChB, a clinical senior lecturer and honorary consultant at the Institute of Infection, Immunity & Inflammation, University of Glasgow (Scotland).

“It still frustrates me when I see that patients haven’t received that while receiving rituximab. Of course, co-trimoxazole can have its problems,” said Dr. Basu, who was not involved in the study. “It’s not uncommon for patients to develop reactions or be intolerant to the drug.”

Raashid Luqmani, DM, a senior coauthor of the work and professor of rheumatology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, said: “The tolerance of co-trimoxazole has been remarkably good in this cohort.” If there was a problem with using co-trimoxazole, then “our standard would be to go with trimethoprim alone as the next in line and follow that with inhaled pentamidine. So, it’s kind of following what we would all generally do,” Dr. Luqmani said.

Study details

To look at the characteristics of and risk factors for serious infections associated with rituximab use in AAV, Mr. Dernie and associates retrospectively examined the electronic records of patients who had been treated between August 2016 and August 2019. Follow-up was until August 2020.

Of the 50 patients identified, nearly half (48%) were men. The average age was 60 years, ranging from 25 to 90 years. Most (n = 36; 72%) patients had a diagnosis of granulomatosis with polyangiitis, while another 2 (4%) had microscopic polyangiitis, 1 (2%) had eosinophilic granulomatosis with polyangiitis, and 11 (22%) had an overlapping type of vasculitis or undefined AAV.

Of the 18 severe infection events recorded, most (56%) involved the respiratory tract. Less than one-third (28%) were sepsis or neutropenic sepsis events, and there was one case each (6%) of cellulitis, complicated urinary tract infection, and recurrent wound infection.

There were “small numbers of individual comorbidities that were not sufficient to enter into our regression analysis,” Mr. Dernie noted. “It’s likely that comorbid conditions such as COPD [chronic obstructive pulmonary disease] also contribute to an individual’s risk of developing severe infections, and thus should factor into their individualized management.”

Mr. Dernie acknowledged in discussion: “One of the limitations of the study was we just looked at patients in a time when they were receiving rituximab, so they may have historically been exposed to other treatment options.” However, he added, “they weren’t having any other major DMARDs or immunosuppressive treatments at the time.”

Dr. Luqmani observed: “If you look at Francesco’s data on the hypogammaglobulinemia at the start of rituximab, that probably gives you a good idea of just how immunosuppressed these patients were already before we got to this point.”

Dr. Luqmani added: “I suspect that’s in keeping with a lot of other centers that have started using rituximab an awful lot for patients who previously had episodes of vasculitis treated with other disease-modifying therapies, particularly cyclophosphamide.”

But for how long should co-trimoxazole be given after the last rituximab dose? asked the chair of the session, Richard Watts, DM, of Norwich (England) Medical School. These data are purely observational, so it’s not possible to say, Mr. Dernie noted: “The patients that we included as having co-trimoxazole seem to be on it more or less consistently, permanently,” he said.

What about the best dose? “It’s a tricky one,” Dr. Luqmani said, as “we not only use co-trimoxazole for prophylaxis, but we often also want to use it for treatment of the vasculitis itself.”

It’s very likely that there was a mix of patients in the analysis that had received co-trimoxazole as either a treatment or prophylaxis, which means different doses, he said.

“It might be interesting to know whether there was a difference” between doses used and the prevention of infection, added Dr. Luqmani, “but I suspect the numbers are too small to tell.”

Mr. Dernie, Dr. Luqmani, and the other coauthors had no disclosures.

Reduced access to medical care, increased mental health issues, poor lifestyle habits, and concern over future care are just some of the patient-reported problems associated with the early phases of the COVID-19 pandemic, according to the results of multiple studies.

Data from the Europe-based REUMAVID study, which surveyed more 1,800 patients between April and July last year, have revealed that 58% of patients with rheumatic and musculoskeletal diseases (RMDs) had their appointments with their rheumatologists canceled, 42% could not get in touch with their primary care physicians, and 52% experienced interrupted visits to mental health specialists.

Not surprisingly, this took a toll on patients’ self-perceived health, with nearly two-thirds stating that they had fair to very poor health, and 47% reporting that their health had worsened. Furthermore, 57% of respondents reported high levels of anxiety, almost 46% were at risk for depression, and 49% reported having poor well-being overall.

“The COVID-19 pandemic has had tremendous impact,” Marco Garrido-Cumbrera, PhD, of the University of Seville, Spain, said at the British Society for Rheumatology annual conference.

Dr. Garrido-Cumbrera, who is key player in the REUMAVID initiative, explained that the project was conceived to respond to concerns raised by the president of the Spanish Federation of Spondyloarthritis Associations (CEADE) about providing the right information to their members.

“First in Italy and then in Spain, it was really difficult to deal with the pandemic and there was a lot of uncertainty from a patient perspective,” Dr. Garrido-Cumbrera said.

Victoria Navarro-Compán, MD, PhD, of La Paz University Hospital, Madrid, who was not involved in the study, observed: “I think this reflects how important collaboration between patient organizations is in order to gather relevant data, and to do it in record time.”

The REUMAVID project was the result of initial collaboration between the Health and Territory Research Group at the University of Seville and CEADE but also involved patient organizations from six other European countries: the National Axial Spondyloarthritis Society, National Rheumatoid Arthritis Society, and Arthritis Action in the United Kingdom; the French Association for the Fight against Rheumatism (AFLAR; L’Association Française de Lutte Anti-Rhumatismale); the National Association of People with Rheumatological and Rare Diseases (APMARR; Associazione Nazionale Persone con Malattie Reumatologiche e Rare) in Italy; Portuguese League Against Rheumatic Diseases (LPCDR; Liga Portuguesa contra as Doenças Reumáticas) in Portugal; the Hellenic League Against Rheumatism (ELEANA) in Greece; and the Cyprus League Against Rheumatism.
 

Pandemic presented ‘perfect storm’

“We’ve never been so well-communicated as we are now,” said Helena Marzo-Ortega, MD, PhD, a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust in England who participated the REUMAVID project. The beginning of the pandemic was “the perfect storm” in that everybody jumped in to try to do something. This resulted in a myriad of research publications, surveys, and attempts to try to understand and make sense of what was happening.

“Research is being conducted in a more structured manner, and it’s given us a lot of very insightful information,” Dr. Marzo-Ortega added. Obviously, patients are important stakeholders to consult when conducting research into how the pandemic has affected them, she added, as they are the ones who had their lives turned upside down.

“A pandemic knows no boundaries, has no limits, everybody can be affected equally. But patients with rheumatic conditions were at particular risk because of the treatments,” she said. “You can remember how worried we all were initially, and thinking about the potential impact of immunosuppressants and many other aspects of these conditions.”

One of the many positives to come out of the pandemic is the “possibility of doing collaborative research at a worldwide level, not just European,” Dr. Marzo-Ortega said, referring to how the EULAR COVID-19 registries are part of the COVID-19 Global Rheumatology Alliance.

Furthermore, Dr. Marzo-Ortega believes the rheumatology community is now better prepared for any upsurges in COVID-19 or any new potentially pandemic-causing viruses.

“What we know now is that we have to be alert, and we know how to respond. We also know how to communicate effectively in order to be able to improve outcomes, not only for the health of the whole population, but also to protect patients such as ours,” she said.
 

Rheumatology practice changed practically overnight

The REUMAVID study is not alone in looking at the impact that the COVID-19 pandemic has had on RMD patients’ health and well-being, particularly during periods of lockdown or where patients were advised to “shield.”

There were “near overnight changes to rheumatology practice,” said Chris Wincup, MBBS, a clinical research fellow at University College London (UCL), who presented the findings of another large-scale survey that looked at the early effects of the pandemic nationally in the United Kingdom.

“The recovery of those services has taken time and, speaking with patients, this varies between different locations,” Dr. Wincup noted. “Unfortunately, access to care does remain a major area of unmet need [and] is something that we’re going to need to think about when planning services in the future,” he added.

Between September and October last year, Dr. Wincup and fellow UCL researchers conducted an online survey among 2,054 patients attending U.K. rheumatology clinics. As in the REUMAVID study, accessing care was difficult or very difficult for a substantial proportion of patients. However, getting medication and monitoring “were generally well maintained” despite lockdown measures.

Many patients (57%) had “extremely high levels of worry about their future care being negatively impacted as a result of the pandemic,” Dr. Wincup said, with 44% saying that their current care was worse than before the pandemic and 41% being dissatisfied with the services they were able to access.

While 48% of patients welcomed a more hybrid approach to their care, 69% thought face-to-face appointments with their rheumatologists were important and 49% wanted only face-to-face appointments. “A possible more hybrid approach, compared with pure face-to-face, is going to be something that may be required,” he said.
 

Different approach taken in CONTAIN Study

A different approach to assessing the impact of the COVID pandemic was taken by researchers at the University of Aberdeen in Scotland, observed Gary Macfarlane, MBChB, PhD.

In the COVID-19 and Musculoskeletal Heath During Lockdown (CONTAIN) study, three well-defined populations of patients from existing cohort studies were looked at prospectively. This included patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) participating in two separate British Society for Rheumatology registries, and patients at high risk for developing chronic widespread pain who had been part of the MAmMOTH (Maintaining Musculoskeletal Health) study.

“Our aim was to quantify the changes from the previous prepandemic assessment, focusing on quality of life, changes in lifestyle, and recording what has happened to their musculoskeletal health, including symptoms and disease-specific measures,” Dr. Macfarlane said.

Patients had been invited to participate in June 2020 and were reminded in October 2020 and could respond online or via a postal questionnaire. Some patients were invited to participate in in-depth interviews.

Although the participation rate was low, at 29%, this was typical of studies being conducted at this time due to “survey fatigue,” Dr. Macfarlane said. The CONTAIN study population still included a good number of patients, however, with 596 having AS, 162 PsA, and 296 at risk for chronic widespread pain.

According to Dr. Macfarlane, the CONTAIN study results were “generally reassuring.” Although there was a significant decrease in quality of life as measured by the five-level EQ-5D instrument overall, and in every subgroup population studied, “the magnitude of the decrease was small.” There was no change in disease-specific quality of life in patients with AS, for example.

Levels of pain, anxiety, or depression did increase somewhat, he reported, but the factors that influenced quality of life remained the same before and during the pandemic, such as high levels of deprivation, living in an urban location, low levels of physical activity, and sleep problems.

“Rather surprisingly, sleep problems significantly decreased overall,” Dr. Macfarlane reported. Again, it was only a small change, but “the benefit in terms of the improvement in sleep strengthened with later periods in the follow-up.”

There was also some evidence of increased low-level and high-level physical activity in patients with psoriatic arthritis.

“Mental health is a key issue not just in maintaining musculoskeletal health but also, in terms of the likelihood responding to therapy,” Dr. Macfarlane acknowledged. “Focusing on addressing anxiety is important,” he added.

“Providing enhanced support for self-management, including in relation to pain, is likely to be a priority in the absence of normal health care being available,” he suggested. Importantly, regardless of circumstances, “all patients can be affected.”

The REUMAVID study is conducted by the Health & Territory Research of the University of Seville, with the support of Novartis Pharma AG. The CONTAIN study is supported by the British Society for Rheumatology and Versus Arthritis.

No other relevant conflicts of interested were declared.
 

Reduced access to medical care, increased mental health issues, poor lifestyle habits, and concern over future care are just some of the patient-reported problems associated with the early phases of the COVID-19 pandemic, according to the results of multiple studies.

Data from the Europe-based REUMAVID study, which surveyed more 1,800 patients between April and July last year, have revealed that 58% of patients with rheumatic and musculoskeletal diseases (RMDs) had their appointments with their rheumatologists canceled, 42% could not get in touch with their primary care physicians, and 52% experienced interrupted visits to mental health specialists.

Not surprisingly, this took a toll on patients’ self-perceived health, with nearly two-thirds stating that they had fair to very poor health, and 47% reporting that their health had worsened. Furthermore, 57% of respondents reported high levels of anxiety, almost 46% were at risk for depression, and 49% reported having poor well-being overall.

“The COVID-19 pandemic has had tremendous impact,” Marco Garrido-Cumbrera, PhD, of the University of Seville, Spain, said at the British Society for Rheumatology annual conference.

Dr. Garrido-Cumbrera, who is key player in the REUMAVID initiative, explained that the project was conceived to respond to concerns raised by the president of the Spanish Federation of Spondyloarthritis Associations (CEADE) about providing the right information to their members.

“First in Italy and then in Spain, it was really difficult to deal with the pandemic and there was a lot of uncertainty from a patient perspective,” Dr. Garrido-Cumbrera said.

Victoria Navarro-Compán, MD, PhD, of La Paz University Hospital, Madrid, who was not involved in the study, observed: “I think this reflects how important collaboration between patient organizations is in order to gather relevant data, and to do it in record time.”

The REUMAVID project was the result of initial collaboration between the Health and Territory Research Group at the University of Seville and CEADE but also involved patient organizations from six other European countries: the National Axial Spondyloarthritis Society, National Rheumatoid Arthritis Society, and Arthritis Action in the United Kingdom; the French Association for the Fight against Rheumatism (AFLAR; L’Association Française de Lutte Anti-Rhumatismale); the National Association of People with Rheumatological and Rare Diseases (APMARR; Associazione Nazionale Persone con Malattie Reumatologiche e Rare) in Italy; Portuguese League Against Rheumatic Diseases (LPCDR; Liga Portuguesa contra as Doenças Reumáticas) in Portugal; the Hellenic League Against Rheumatism (ELEANA) in Greece; and the Cyprus League Against Rheumatism.
 

Pandemic presented ‘perfect storm’

“We’ve never been so well-communicated as we are now,” said Helena Marzo-Ortega, MD, PhD, a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust in England who participated the REUMAVID project. The beginning of the pandemic was “the perfect storm” in that everybody jumped in to try to do something. This resulted in a myriad of research publications, surveys, and attempts to try to understand and make sense of what was happening.

“Research is being conducted in a more structured manner, and it’s given us a lot of very insightful information,” Dr. Marzo-Ortega added. Obviously, patients are important stakeholders to consult when conducting research into how the pandemic has affected them, she added, as they are the ones who had their lives turned upside down.

“A pandemic knows no boundaries, has no limits, everybody can be affected equally. But patients with rheumatic conditions were at particular risk because of the treatments,” she said. “You can remember how worried we all were initially, and thinking about the potential impact of immunosuppressants and many other aspects of these conditions.”

One of the many positives to come out of the pandemic is the “possibility of doing collaborative research at a worldwide level, not just European,” Dr. Marzo-Ortega said, referring to how the EULAR COVID-19 registries are part of the COVID-19 Global Rheumatology Alliance.

Furthermore, Dr. Marzo-Ortega believes the rheumatology community is now better prepared for any upsurges in COVID-19 or any new potentially pandemic-causing viruses.

“What we know now is that we have to be alert, and we know how to respond. We also know how to communicate effectively in order to be able to improve outcomes, not only for the health of the whole population, but also to protect patients such as ours,” she said.
 

Rheumatology practice changed practically overnight

The REUMAVID study is not alone in looking at the impact that the COVID-19 pandemic has had on RMD patients’ health and well-being, particularly during periods of lockdown or where patients were advised to “shield.”

There were “near overnight changes to rheumatology practice,” said Chris Wincup, MBBS, a clinical research fellow at University College London (UCL), who presented the findings of another large-scale survey that looked at the early effects of the pandemic nationally in the United Kingdom.

“The recovery of those services has taken time and, speaking with patients, this varies between different locations,” Dr. Wincup noted. “Unfortunately, access to care does remain a major area of unmet need [and] is something that we’re going to need to think about when planning services in the future,” he added.

Between September and October last year, Dr. Wincup and fellow UCL researchers conducted an online survey among 2,054 patients attending U.K. rheumatology clinics. As in the REUMAVID study, accessing care was difficult or very difficult for a substantial proportion of patients. However, getting medication and monitoring “were generally well maintained” despite lockdown measures.

Many patients (57%) had “extremely high levels of worry about their future care being negatively impacted as a result of the pandemic,” Dr. Wincup said, with 44% saying that their current care was worse than before the pandemic and 41% being dissatisfied with the services they were able to access.

While 48% of patients welcomed a more hybrid approach to their care, 69% thought face-to-face appointments with their rheumatologists were important and 49% wanted only face-to-face appointments. “A possible more hybrid approach, compared with pure face-to-face, is going to be something that may be required,” he said.
 

Different approach taken in CONTAIN Study

A different approach to assessing the impact of the COVID pandemic was taken by researchers at the University of Aberdeen in Scotland, observed Gary Macfarlane, MBChB, PhD.

In the COVID-19 and Musculoskeletal Heath During Lockdown (CONTAIN) study, three well-defined populations of patients from existing cohort studies were looked at prospectively. This included patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) participating in two separate British Society for Rheumatology registries, and patients at high risk for developing chronic widespread pain who had been part of the MAmMOTH (Maintaining Musculoskeletal Health) study.

“Our aim was to quantify the changes from the previous prepandemic assessment, focusing on quality of life, changes in lifestyle, and recording what has happened to their musculoskeletal health, including symptoms and disease-specific measures,” Dr. Macfarlane said.

Patients had been invited to participate in June 2020 and were reminded in October 2020 and could respond online or via a postal questionnaire. Some patients were invited to participate in in-depth interviews.

Although the participation rate was low, at 29%, this was typical of studies being conducted at this time due to “survey fatigue,” Dr. Macfarlane said. The CONTAIN study population still included a good number of patients, however, with 596 having AS, 162 PsA, and 296 at risk for chronic widespread pain.

According to Dr. Macfarlane, the CONTAIN study results were “generally reassuring.” Although there was a significant decrease in quality of life as measured by the five-level EQ-5D instrument overall, and in every subgroup population studied, “the magnitude of the decrease was small.” There was no change in disease-specific quality of life in patients with AS, for example.

Levels of pain, anxiety, or depression did increase somewhat, he reported, but the factors that influenced quality of life remained the same before and during the pandemic, such as high levels of deprivation, living in an urban location, low levels of physical activity, and sleep problems.

“Rather surprisingly, sleep problems significantly decreased overall,” Dr. Macfarlane reported. Again, it was only a small change, but “the benefit in terms of the improvement in sleep strengthened with later periods in the follow-up.”

There was also some evidence of increased low-level and high-level physical activity in patients with psoriatic arthritis.

“Mental health is a key issue not just in maintaining musculoskeletal health but also, in terms of the likelihood responding to therapy,” Dr. Macfarlane acknowledged. “Focusing on addressing anxiety is important,” he added.

“Providing enhanced support for self-management, including in relation to pain, is likely to be a priority in the absence of normal health care being available,” he suggested. Importantly, regardless of circumstances, “all patients can be affected.”

The REUMAVID study is conducted by the Health & Territory Research of the University of Seville, with the support of Novartis Pharma AG. The CONTAIN study is supported by the British Society for Rheumatology and Versus Arthritis.

No other relevant conflicts of interested were declared.
 

Reduced access to medical care, increased mental health issues, poor lifestyle habits, and concern over future care are just some of the patient-reported problems associated with the early phases of the COVID-19 pandemic, according to the results of multiple studies.

Data from the Europe-based REUMAVID study, which surveyed more 1,800 patients between April and July last year, have revealed that 58% of patients with rheumatic and musculoskeletal diseases (RMDs) had their appointments with their rheumatologists canceled, 42% could not get in touch with their primary care physicians, and 52% experienced interrupted visits to mental health specialists.

Not surprisingly, this took a toll on patients’ self-perceived health, with nearly two-thirds stating that they had fair to very poor health, and 47% reporting that their health had worsened. Furthermore, 57% of respondents reported high levels of anxiety, almost 46% were at risk for depression, and 49% reported having poor well-being overall.

“The COVID-19 pandemic has had tremendous impact,” Marco Garrido-Cumbrera, PhD, of the University of Seville, Spain, said at the British Society for Rheumatology annual conference.

Dr. Garrido-Cumbrera, who is key player in the REUMAVID initiative, explained that the project was conceived to respond to concerns raised by the president of the Spanish Federation of Spondyloarthritis Associations (CEADE) about providing the right information to their members.

“First in Italy and then in Spain, it was really difficult to deal with the pandemic and there was a lot of uncertainty from a patient perspective,” Dr. Garrido-Cumbrera said.

Victoria Navarro-Compán, MD, PhD, of La Paz University Hospital, Madrid, who was not involved in the study, observed: “I think this reflects how important collaboration between patient organizations is in order to gather relevant data, and to do it in record time.”

The REUMAVID project was the result of initial collaboration between the Health and Territory Research Group at the University of Seville and CEADE but also involved patient organizations from six other European countries: the National Axial Spondyloarthritis Society, National Rheumatoid Arthritis Society, and Arthritis Action in the United Kingdom; the French Association for the Fight against Rheumatism (AFLAR; L’Association Française de Lutte Anti-Rhumatismale); the National Association of People with Rheumatological and Rare Diseases (APMARR; Associazione Nazionale Persone con Malattie Reumatologiche e Rare) in Italy; Portuguese League Against Rheumatic Diseases (LPCDR; Liga Portuguesa contra as Doenças Reumáticas) in Portugal; the Hellenic League Against Rheumatism (ELEANA) in Greece; and the Cyprus League Against Rheumatism.
 

Pandemic presented ‘perfect storm’

“We’ve never been so well-communicated as we are now,” said Helena Marzo-Ortega, MD, PhD, a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust in England who participated the REUMAVID project. The beginning of the pandemic was “the perfect storm” in that everybody jumped in to try to do something. This resulted in a myriad of research publications, surveys, and attempts to try to understand and make sense of what was happening.

“Research is being conducted in a more structured manner, and it’s given us a lot of very insightful information,” Dr. Marzo-Ortega added. Obviously, patients are important stakeholders to consult when conducting research into how the pandemic has affected them, she added, as they are the ones who had their lives turned upside down.

“A pandemic knows no boundaries, has no limits, everybody can be affected equally. But patients with rheumatic conditions were at particular risk because of the treatments,” she said. “You can remember how worried we all were initially, and thinking about the potential impact of immunosuppressants and many other aspects of these conditions.”

One of the many positives to come out of the pandemic is the “possibility of doing collaborative research at a worldwide level, not just European,” Dr. Marzo-Ortega said, referring to how the EULAR COVID-19 registries are part of the COVID-19 Global Rheumatology Alliance.

Furthermore, Dr. Marzo-Ortega believes the rheumatology community is now better prepared for any upsurges in COVID-19 or any new potentially pandemic-causing viruses.

“What we know now is that we have to be alert, and we know how to respond. We also know how to communicate effectively in order to be able to improve outcomes, not only for the health of the whole population, but also to protect patients such as ours,” she said.
 

Rheumatology practice changed practically overnight

The REUMAVID study is not alone in looking at the impact that the COVID-19 pandemic has had on RMD patients’ health and well-being, particularly during periods of lockdown or where patients were advised to “shield.”

There were “near overnight changes to rheumatology practice,” said Chris Wincup, MBBS, a clinical research fellow at University College London (UCL), who presented the findings of another large-scale survey that looked at the early effects of the pandemic nationally in the United Kingdom.

“The recovery of those services has taken time and, speaking with patients, this varies between different locations,” Dr. Wincup noted. “Unfortunately, access to care does remain a major area of unmet need [and] is something that we’re going to need to think about when planning services in the future,” he added.

Between September and October last year, Dr. Wincup and fellow UCL researchers conducted an online survey among 2,054 patients attending U.K. rheumatology clinics. As in the REUMAVID study, accessing care was difficult or very difficult for a substantial proportion of patients. However, getting medication and monitoring “were generally well maintained” despite lockdown measures.

Many patients (57%) had “extremely high levels of worry about their future care being negatively impacted as a result of the pandemic,” Dr. Wincup said, with 44% saying that their current care was worse than before the pandemic and 41% being dissatisfied with the services they were able to access.

While 48% of patients welcomed a more hybrid approach to their care, 69% thought face-to-face appointments with their rheumatologists were important and 49% wanted only face-to-face appointments. “A possible more hybrid approach, compared with pure face-to-face, is going to be something that may be required,” he said.
 

Different approach taken in CONTAIN Study

A different approach to assessing the impact of the COVID pandemic was taken by researchers at the University of Aberdeen in Scotland, observed Gary Macfarlane, MBChB, PhD.

In the COVID-19 and Musculoskeletal Heath During Lockdown (CONTAIN) study, three well-defined populations of patients from existing cohort studies were looked at prospectively. This included patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) participating in two separate British Society for Rheumatology registries, and patients at high risk for developing chronic widespread pain who had been part of the MAmMOTH (Maintaining Musculoskeletal Health) study.

“Our aim was to quantify the changes from the previous prepandemic assessment, focusing on quality of life, changes in lifestyle, and recording what has happened to their musculoskeletal health, including symptoms and disease-specific measures,” Dr. Macfarlane said.

Patients had been invited to participate in June 2020 and were reminded in October 2020 and could respond online or via a postal questionnaire. Some patients were invited to participate in in-depth interviews.

Although the participation rate was low, at 29%, this was typical of studies being conducted at this time due to “survey fatigue,” Dr. Macfarlane said. The CONTAIN study population still included a good number of patients, however, with 596 having AS, 162 PsA, and 296 at risk for chronic widespread pain.

According to Dr. Macfarlane, the CONTAIN study results were “generally reassuring.” Although there was a significant decrease in quality of life as measured by the five-level EQ-5D instrument overall, and in every subgroup population studied, “the magnitude of the decrease was small.” There was no change in disease-specific quality of life in patients with AS, for example.

Levels of pain, anxiety, or depression did increase somewhat, he reported, but the factors that influenced quality of life remained the same before and during the pandemic, such as high levels of deprivation, living in an urban location, low levels of physical activity, and sleep problems.

“Rather surprisingly, sleep problems significantly decreased overall,” Dr. Macfarlane reported. Again, it was only a small change, but “the benefit in terms of the improvement in sleep strengthened with later periods in the follow-up.”

There was also some evidence of increased low-level and high-level physical activity in patients with psoriatic arthritis.

“Mental health is a key issue not just in maintaining musculoskeletal health but also, in terms of the likelihood responding to therapy,” Dr. Macfarlane acknowledged. “Focusing on addressing anxiety is important,” he added.

“Providing enhanced support for self-management, including in relation to pain, is likely to be a priority in the absence of normal health care being available,” he suggested. Importantly, regardless of circumstances, “all patients can be affected.”

The REUMAVID study is conducted by the Health & Territory Research of the University of Seville, with the support of Novartis Pharma AG. The CONTAIN study is supported by the British Society for Rheumatology and Versus Arthritis.

No other relevant conflicts of interested were declared.