Sara Freeman

As might be expected, the “EULAR [European League Against Rheumatism] provisional recommendations for the management of rheumatic and musculoskeletal diseases [RMDs] in the context of SARS-CoV-2” concur with much of the guidance already released on how best to manage patients during the current pandemic.

Highlights of the five overarching principles are that, contrary to earlier expectations, “there is no indication that patients with RMDs have an additional, or have a higher, risk of contracting the virus, or that they fare a worse course” than the general population, said the task force convener Robert Landewé, MD, PhD, professor of rheumatology at the University of Amsterdam.

“The second pertinent highlight is that, when it comes to managerial discussions, whether or not to stop or to start treatment for RMDs, rheumatologists should definitely be involved,” Dr. Landewé said during a live session at the annual European Congress of Rheumatology, held online this year due to COVID-19. “In practice, something that happens very often is that immunosuppressive drugs are stopped by medical specialists involved in the care of COVID but without any expertise in treating patients with rheumatic diseases. We should try to avoid that situation.”

The third highlight, something many rheumatologists may already be well aware of, is that rheumatology drugs are being used to treat COVID-19 patients without RMDs and a shortage of disease-modifying antirheumatic drugs (DMARDs) agents is a real possibility. As such, the fifth overarching highlight states that the availability of both synthetic and biologic DMARDs is “a delicate societal responsibility” and that “the off-label use of DMARDs in COVID-19 outside the context of clinical trials should be discouraged.”

The EULAR recommendation are now published online in Annals of the Rheumatic Diseases and they are “what you could call an unprecedented set of recommendations,” Dr. Landewé said. “We have never done this before,” he added, referring to the speed and way in which they had to be put together, remotely, and with little scientific evidence currently available. “Three months ago we hadn’t even heard about the virus.”

From the first patient being identified in the Hubei province of China in November 2019, to the first U.S. patient in the state of Washington on Jan. 20, 2020, and to the first European patient identified a little over 10 days later, the COVID-19 pandemic has taken the world by storm. It was only declared a pandemic on March 11, 2020, however, and Dr. Landewé noted that the response to the pandemic had been very variable – some countries locking down their borders early, while others took their time to make an appropriate response, if at all.

The rheumatology community was particularly concerned, Dr. Landewé said, because people with autoimmune diseases who were taking immunosuppressant drugs might be at higher risk for becoming infected with SARS-CoV-2, and may be at higher risk than others for a worse disease course. Thankfully, that seems not to be the case according to data that are emerging from new registries that have been set up, including EULAR’s own COVID-19 registry.

There are 13 recommendations that cover 4 themes: general measures and prevention of SARS-CoV-2 infection; the management of RMD patients during the pandemic; the management of RMD patients who have COVID-19; and the prevention of other pulmonary infections in RMD patients.

Highlighting the first three general recommendations, Dr. Landewé said: “Follow the regular guidelines in your country; if a patient with RMD does not have symptoms of COVID-19, simply continue RMD treatments,” albeit with a couple of exceptions.

The next four recommendation highlights are to avoid visits to the hospital or to the office; use remote monitoring via the telephone, for example; and if visits cannot be avoided, then take appropriate precautions. Finally, if you suspect a patient has COVID-19, do a test.

If patients test positive, then the next four recommendations cover what to do, such as continuing use of RMD treatments, but in the case of glucocorticoids this should be the lowest possible dose necessary. There is no consensus on what to do in cases of mild symptoms; the recommendation is to “decide on a case-by-case basis,” said Dr. Landewé. If a patient’s symptoms worsen, then “seek expert advice immediately and follow local treatment recommendations. The rheumatologist is not the expert to treat COVID-19,” he added. That responsibility lies with the pulmonologist, infectious disease specialist, or maybe the intensive care specialist, depending on local situations.

On the whole, the EULAR recommendations are pretty similar to those already released by the American College of Rheumatology, said Ted Mikuls, MD, of the University of Nebraska Medical Center, Omaha. The ACR recommendations are “slightly more prescriptive”, he suggested, with 25 final guidance statements. For example, general statements focused not only on the use of glucocorticoids, but also other medicines, such as antihypertensives.

“There’s really not a [lot of], I would say, major differences in the two efforts and that’s ... somewhat reassuring that we’re approaching the unknown from very different parts of the world, and driving in a very similar place,” commented Dr. Mikuls, who is a member of the ACR COVID-19 recommendations task force.

“I think one of the very important similarities that I would highlight is that, in the absence of known exposure, in the absence of COVID-19 infection, our panel felt very strongly about the importance of continuing rheumatic disease treatments,” Dr. Mikuls observed. The ACR guidelines also touch upon societal perspectives, including “some statements that were made very specific to lupus, and the use of antimalarials, given supply chain issues that we have encountered.”

Dr. Mikuls also said that the American recommendations emphasized that “you really have to manage active inflammatory rheumatic disease. Even in the context of the COVID-19 pandemic, given what we saw as the potential risk of unchecked inflammation and unchecked rheumatic disease.”

One notable difference, however, is that the European recommendations advise on immunizations and pneumonia prophylaxis, saying that all patients without COVID-19 symptoms should make sure they are up to date with any recommended vaccinations, “with a particular focus on pneumococcal and influenza vaccinations,” Dr. Landewé said.

Another difference is that the ACR recommendations are a living document and could potentially be updated monthly if the evidence arrives to allow that. In that sense, the American guidance is more agile, with EULAR expecting to update its recommendations every 3 months.

“The current evidence is extremely sparse and fragmented,” Dr. Landewé said. “We, as a task force are essentially flying blindly. We also have to cover many jurisdictions within Europe, with many conflicting opinions. So the last word to say is that updates are truly necessary, but we have to wait a while.”

SOURCE: Landewé RB et al. Ann Rheum Dis. 2020 Jun 5. doi: 10.1136/annrheumdis-2020-217877.

As might be expected, the “EULAR [European League Against Rheumatism] provisional recommendations for the management of rheumatic and musculoskeletal diseases [RMDs] in the context of SARS-CoV-2” concur with much of the guidance already released on how best to manage patients during the current pandemic.

Highlights of the five overarching principles are that, contrary to earlier expectations, “there is no indication that patients with RMDs have an additional, or have a higher, risk of contracting the virus, or that they fare a worse course” than the general population, said the task force convener Robert Landewé, MD, PhD, professor of rheumatology at the University of Amsterdam.

“The second pertinent highlight is that, when it comes to managerial discussions, whether or not to stop or to start treatment for RMDs, rheumatologists should definitely be involved,” Dr. Landewé said during a live session at the annual European Congress of Rheumatology, held online this year due to COVID-19. “In practice, something that happens very often is that immunosuppressive drugs are stopped by medical specialists involved in the care of COVID but without any expertise in treating patients with rheumatic diseases. We should try to avoid that situation.”

The third highlight, something many rheumatologists may already be well aware of, is that rheumatology drugs are being used to treat COVID-19 patients without RMDs and a shortage of disease-modifying antirheumatic drugs (DMARDs) agents is a real possibility. As such, the fifth overarching highlight states that the availability of both synthetic and biologic DMARDs is “a delicate societal responsibility” and that “the off-label use of DMARDs in COVID-19 outside the context of clinical trials should be discouraged.”

The EULAR recommendation are now published online in Annals of the Rheumatic Diseases and they are “what you could call an unprecedented set of recommendations,” Dr. Landewé said. “We have never done this before,” he added, referring to the speed and way in which they had to be put together, remotely, and with little scientific evidence currently available. “Three months ago we hadn’t even heard about the virus.”

From the first patient being identified in the Hubei province of China in November 2019, to the first U.S. patient in the state of Washington on Jan. 20, 2020, and to the first European patient identified a little over 10 days later, the COVID-19 pandemic has taken the world by storm. It was only declared a pandemic on March 11, 2020, however, and Dr. Landewé noted that the response to the pandemic had been very variable – some countries locking down their borders early, while others took their time to make an appropriate response, if at all.

The rheumatology community was particularly concerned, Dr. Landewé said, because people with autoimmune diseases who were taking immunosuppressant drugs might be at higher risk for becoming infected with SARS-CoV-2, and may be at higher risk than others for a worse disease course. Thankfully, that seems not to be the case according to data that are emerging from new registries that have been set up, including EULAR’s own COVID-19 registry.

There are 13 recommendations that cover 4 themes: general measures and prevention of SARS-CoV-2 infection; the management of RMD patients during the pandemic; the management of RMD patients who have COVID-19; and the prevention of other pulmonary infections in RMD patients.

Highlighting the first three general recommendations, Dr. Landewé said: “Follow the regular guidelines in your country; if a patient with RMD does not have symptoms of COVID-19, simply continue RMD treatments,” albeit with a couple of exceptions.

The next four recommendation highlights are to avoid visits to the hospital or to the office; use remote monitoring via the telephone, for example; and if visits cannot be avoided, then take appropriate precautions. Finally, if you suspect a patient has COVID-19, do a test.

If patients test positive, then the next four recommendations cover what to do, such as continuing use of RMD treatments, but in the case of glucocorticoids this should be the lowest possible dose necessary. There is no consensus on what to do in cases of mild symptoms; the recommendation is to “decide on a case-by-case basis,” said Dr. Landewé. If a patient’s symptoms worsen, then “seek expert advice immediately and follow local treatment recommendations. The rheumatologist is not the expert to treat COVID-19,” he added. That responsibility lies with the pulmonologist, infectious disease specialist, or maybe the intensive care specialist, depending on local situations.

On the whole, the EULAR recommendations are pretty similar to those already released by the American College of Rheumatology, said Ted Mikuls, MD, of the University of Nebraska Medical Center, Omaha. The ACR recommendations are “slightly more prescriptive”, he suggested, with 25 final guidance statements. For example, general statements focused not only on the use of glucocorticoids, but also other medicines, such as antihypertensives.

“There’s really not a [lot of], I would say, major differences in the two efforts and that’s ... somewhat reassuring that we’re approaching the unknown from very different parts of the world, and driving in a very similar place,” commented Dr. Mikuls, who is a member of the ACR COVID-19 recommendations task force.

“I think one of the very important similarities that I would highlight is that, in the absence of known exposure, in the absence of COVID-19 infection, our panel felt very strongly about the importance of continuing rheumatic disease treatments,” Dr. Mikuls observed. The ACR guidelines also touch upon societal perspectives, including “some statements that were made very specific to lupus, and the use of antimalarials, given supply chain issues that we have encountered.”

Dr. Mikuls also said that the American recommendations emphasized that “you really have to manage active inflammatory rheumatic disease. Even in the context of the COVID-19 pandemic, given what we saw as the potential risk of unchecked inflammation and unchecked rheumatic disease.”

One notable difference, however, is that the European recommendations advise on immunizations and pneumonia prophylaxis, saying that all patients without COVID-19 symptoms should make sure they are up to date with any recommended vaccinations, “with a particular focus on pneumococcal and influenza vaccinations,” Dr. Landewé said.

Another difference is that the ACR recommendations are a living document and could potentially be updated monthly if the evidence arrives to allow that. In that sense, the American guidance is more agile, with EULAR expecting to update its recommendations every 3 months.

“The current evidence is extremely sparse and fragmented,” Dr. Landewé said. “We, as a task force are essentially flying blindly. We also have to cover many jurisdictions within Europe, with many conflicting opinions. So the last word to say is that updates are truly necessary, but we have to wait a while.”

SOURCE: Landewé RB et al. Ann Rheum Dis. 2020 Jun 5. doi: 10.1136/annrheumdis-2020-217877.

As might be expected, the “EULAR [European League Against Rheumatism] provisional recommendations for the management of rheumatic and musculoskeletal diseases [RMDs] in the context of SARS-CoV-2” concur with much of the guidance already released on how best to manage patients during the current pandemic.

Highlights of the five overarching principles are that, contrary to earlier expectations, “there is no indication that patients with RMDs have an additional, or have a higher, risk of contracting the virus, or that they fare a worse course” than the general population, said the task force convener Robert Landewé, MD, PhD, professor of rheumatology at the University of Amsterdam.

“The second pertinent highlight is that, when it comes to managerial discussions, whether or not to stop or to start treatment for RMDs, rheumatologists should definitely be involved,” Dr. Landewé said during a live session at the annual European Congress of Rheumatology, held online this year due to COVID-19. “In practice, something that happens very often is that immunosuppressive drugs are stopped by medical specialists involved in the care of COVID but without any expertise in treating patients with rheumatic diseases. We should try to avoid that situation.”

The third highlight, something many rheumatologists may already be well aware of, is that rheumatology drugs are being used to treat COVID-19 patients without RMDs and a shortage of disease-modifying antirheumatic drugs (DMARDs) agents is a real possibility. As such, the fifth overarching highlight states that the availability of both synthetic and biologic DMARDs is “a delicate societal responsibility” and that “the off-label use of DMARDs in COVID-19 outside the context of clinical trials should be discouraged.”

The EULAR recommendation are now published online in Annals of the Rheumatic Diseases and they are “what you could call an unprecedented set of recommendations,” Dr. Landewé said. “We have never done this before,” he added, referring to the speed and way in which they had to be put together, remotely, and with little scientific evidence currently available. “Three months ago we hadn’t even heard about the virus.”

From the first patient being identified in the Hubei province of China in November 2019, to the first U.S. patient in the state of Washington on Jan. 20, 2020, and to the first European patient identified a little over 10 days later, the COVID-19 pandemic has taken the world by storm. It was only declared a pandemic on March 11, 2020, however, and Dr. Landewé noted that the response to the pandemic had been very variable – some countries locking down their borders early, while others took their time to make an appropriate response, if at all.

The rheumatology community was particularly concerned, Dr. Landewé said, because people with autoimmune diseases who were taking immunosuppressant drugs might be at higher risk for becoming infected with SARS-CoV-2, and may be at higher risk than others for a worse disease course. Thankfully, that seems not to be the case according to data that are emerging from new registries that have been set up, including EULAR’s own COVID-19 registry.

There are 13 recommendations that cover 4 themes: general measures and prevention of SARS-CoV-2 infection; the management of RMD patients during the pandemic; the management of RMD patients who have COVID-19; and the prevention of other pulmonary infections in RMD patients.

Highlighting the first three general recommendations, Dr. Landewé said: “Follow the regular guidelines in your country; if a patient with RMD does not have symptoms of COVID-19, simply continue RMD treatments,” albeit with a couple of exceptions.

The next four recommendation highlights are to avoid visits to the hospital or to the office; use remote monitoring via the telephone, for example; and if visits cannot be avoided, then take appropriate precautions. Finally, if you suspect a patient has COVID-19, do a test.

If patients test positive, then the next four recommendations cover what to do, such as continuing use of RMD treatments, but in the case of glucocorticoids this should be the lowest possible dose necessary. There is no consensus on what to do in cases of mild symptoms; the recommendation is to “decide on a case-by-case basis,” said Dr. Landewé. If a patient’s symptoms worsen, then “seek expert advice immediately and follow local treatment recommendations. The rheumatologist is not the expert to treat COVID-19,” he added. That responsibility lies with the pulmonologist, infectious disease specialist, or maybe the intensive care specialist, depending on local situations.

On the whole, the EULAR recommendations are pretty similar to those already released by the American College of Rheumatology, said Ted Mikuls, MD, of the University of Nebraska Medical Center, Omaha. The ACR recommendations are “slightly more prescriptive”, he suggested, with 25 final guidance statements. For example, general statements focused not only on the use of glucocorticoids, but also other medicines, such as antihypertensives.

“There’s really not a [lot of], I would say, major differences in the two efforts and that’s ... somewhat reassuring that we’re approaching the unknown from very different parts of the world, and driving in a very similar place,” commented Dr. Mikuls, who is a member of the ACR COVID-19 recommendations task force.

“I think one of the very important similarities that I would highlight is that, in the absence of known exposure, in the absence of COVID-19 infection, our panel felt very strongly about the importance of continuing rheumatic disease treatments,” Dr. Mikuls observed. The ACR guidelines also touch upon societal perspectives, including “some statements that were made very specific to lupus, and the use of antimalarials, given supply chain issues that we have encountered.”

Dr. Mikuls also said that the American recommendations emphasized that “you really have to manage active inflammatory rheumatic disease. Even in the context of the COVID-19 pandemic, given what we saw as the potential risk of unchecked inflammation and unchecked rheumatic disease.”

One notable difference, however, is that the European recommendations advise on immunizations and pneumonia prophylaxis, saying that all patients without COVID-19 symptoms should make sure they are up to date with any recommended vaccinations, “with a particular focus on pneumococcal and influenza vaccinations,” Dr. Landewé said.

Another difference is that the ACR recommendations are a living document and could potentially be updated monthly if the evidence arrives to allow that. In that sense, the American guidance is more agile, with EULAR expecting to update its recommendations every 3 months.

“The current evidence is extremely sparse and fragmented,” Dr. Landewé said. “We, as a task force are essentially flying blindly. We also have to cover many jurisdictions within Europe, with many conflicting opinions. So the last word to say is that updates are truly necessary, but we have to wait a while.”

SOURCE: Landewé RB et al. Ann Rheum Dis. 2020 Jun 5. doi: 10.1136/annrheumdis-2020-217877.

Being aged older than 65 years was associated with the highest risk of people with rheumatic and musculoskeletal diseases (RMDs) needing hospital treatment for COVID-19, according to the first results to be reported from ReCoVery, the German national COVID-19 registry.

Older patients with RMDs were five times more likely than younger patients to be hospitalized if they tested positive for SARS‑CoV‑2 and developed COVID-19 (odds ratio, 5.1; 95% confidence interval, 2.3-11.4).

The likelihood of hospitalization was also significantly increased by the current or prior use of glucocorticoids (OR, 2.59; 95% CI, 1.2-5.4) and by the presence of cardiovascular disease (OR, 2.27; 95% CI, 1.2-5.4).

“The register is a joint initiative of the German Society for Rheumatology and the Justus Liebig University in Giessen,” explained Anne Regierer, MD, during a live session of the annual European Congress of Rheumatology, held online this year due to COVID-19.

“The current pandemic has changed all of our lives. For patients it brought a lot of uncertainty and fears,” said Dr. Regierer, of the German Rheumatism Research Center Berlin.

“The risk of SARS-CoV-2 infection in patients with inflammatory rheumatic diseases [IRD] is still largely unknown. We still don’t know whether they have a high risk of getting the infection or whether they have a higher risk of a severer case ... therefore there’s an urgent need to have data to generate evidence for the management of our patients.”

Launched at the end of March 2020, the German registry now includes data on 251 patients – 194 of whom have recovered – provided by more than 200 registered rheumatologists. The registry data have now been integrated into the EULAR COVID-19 Database, which is itself part of a global effort to better understand and optimally manage RMD patients during the pandemic.

“The data presented by Dr. Regierer looked at similar outcomes and found quite similar results, which is reassuring,” Kimme Hyrich, MD, PhD, professor of epidemiology at the University of Manchester (England) and a consultant rheumatologist in the Kellgren Centre for Rheumatology at Manchester University Hospitals NHS Foundation Trust, said in an interview.

“We are very grateful for this collaboration [with the German society and others]. Our first publication has looked at hospitalization, but with more data we may have the opportunity to look at less-common outcomes [e.g. death, other COVID complications] or within individual diseases or treatments. So far I don’t think we will come to a different conclusion,” observed Dr. Hyrich, who is on the steering committee for the EULAR COVID-19 Database.

“These initial data are reassuring in that the majority of cases of COVID reported to our database have recovered, including those who were hospitalized,” she said.

Current EULAR advice is to continue treatment with glucocorticoids in patients who are being chronically treated, but to use them at the lowest possible dose.

The objectives of this first analysis of the German registry was to provide a description of the patients who did and did not require hospitalization and those who needed ventilation, as well as look at possible risk factors for hospitalization.

Dr. Regierer reported that, of 192 patients they included – all with a positive lab test for SARS-CoV-2 – 128 (67%) did not require hospital admission. Of those that did (n = 64), 43 (22%) did not need ventilation and 21 (11%) did. Fifteen patients died, all of whom had been hospitalized, and all but one of them had needed ventilation.

Concerning the characteristics of the patients, those who needed hospital treatment with and without ventilation were older than those who were not admitted (70 vs. 65 vs. 54 years, respectively).

“Looking at the sexes, the gender distribution is also interesting. We see 69% females in the nonhospitalized patients, 65% of the inpatients without ventilation, but only 43% females in the ventilated patients. So in this group, the male patients are the majority,” Dr. Regierer observed.

Just over half of all patients in the nonhospitalized and the hospitalized without ventilation groups had IRD in remission, but those in the hospitalized with ventilation group less than one-fifth had their IRD under control.

“Of course we have to keep in mind the small sample sizes,” Dr. Regierer said, but the distribution of patients by disease type was “what you’d expect in clinical care.” The majority of patients in each of the three groups had RA (47%, 56%, and 57%), followed by psoriatic arthritis (19%, 7%, and 14%), axial spondyloarthritis (11%, 5%, and 0%), systemic lupus erythematosus (6%, 2%, and 0%), and vasculitis (1%, 5%, and 5%).

Patients who were hospitalized with and without ventilation were more likely to have more than one comorbidity than those who were not hospitalized with COVID-19.

“The most frequent comorbidity was cardiovascular disease with 58% and 76% in the inpatient groups,” Dr. Regierer reported. One-third of the nonhospitalized patients had a cardiovascular comorbidity.

“If we look at pulmonary disease, we see that 38% of the ventilator patients had an underlying pulmonary disease,” she added. This was in comparison with 19% of the hospitalized without ventilation and 13% of the nonhospitalized patients. Diabetes was another common comorbidity in hospitalized patients with (16%) and without (19%) ventilation versus just 2% of nonhospitalized patients. While these and other comorbidities such as chronic renal insufficiency were associated with higher odds ratios in the multivariate risk factor analysis, they did not reach statistical significance.

With regard to RMD treatments, more than 60% of patients in the hospitalized group had received treatment with glucocorticoids versus 37% of those who did not get admitted. No differences were seen for the other treatments.

Interestingly, “female sex, remission, and use of NSAIDs have an odds ratio smaller than 1. So there might be a lower risk of hospitalization associated with these factors,” Dr. Regierer said.

Dr. Regierer has received grant support and is part of speaker’s bureaus for a variety of pharmaceutical companies. Dr. Hyrich disclosed grant income from Bristol-Myers Squibb, UCB, and Pfizer, and receiving speaker fees from AbbVie.

Being aged older than 65 years was associated with the highest risk of people with rheumatic and musculoskeletal diseases (RMDs) needing hospital treatment for COVID-19, according to the first results to be reported from ReCoVery, the German national COVID-19 registry.

Older patients with RMDs were five times more likely than younger patients to be hospitalized if they tested positive for SARS‑CoV‑2 and developed COVID-19 (odds ratio, 5.1; 95% confidence interval, 2.3-11.4).

The likelihood of hospitalization was also significantly increased by the current or prior use of glucocorticoids (OR, 2.59; 95% CI, 1.2-5.4) and by the presence of cardiovascular disease (OR, 2.27; 95% CI, 1.2-5.4).

“The register is a joint initiative of the German Society for Rheumatology and the Justus Liebig University in Giessen,” explained Anne Regierer, MD, during a live session of the annual European Congress of Rheumatology, held online this year due to COVID-19.

“The current pandemic has changed all of our lives. For patients it brought a lot of uncertainty and fears,” said Dr. Regierer, of the German Rheumatism Research Center Berlin.

“The risk of SARS-CoV-2 infection in patients with inflammatory rheumatic diseases [IRD] is still largely unknown. We still don’t know whether they have a high risk of getting the infection or whether they have a higher risk of a severer case ... therefore there’s an urgent need to have data to generate evidence for the management of our patients.”

Launched at the end of March 2020, the German registry now includes data on 251 patients – 194 of whom have recovered – provided by more than 200 registered rheumatologists. The registry data have now been integrated into the EULAR COVID-19 Database, which is itself part of a global effort to better understand and optimally manage RMD patients during the pandemic.

“The data presented by Dr. Regierer looked at similar outcomes and found quite similar results, which is reassuring,” Kimme Hyrich, MD, PhD, professor of epidemiology at the University of Manchester (England) and a consultant rheumatologist in the Kellgren Centre for Rheumatology at Manchester University Hospitals NHS Foundation Trust, said in an interview.

“We are very grateful for this collaboration [with the German society and others]. Our first publication has looked at hospitalization, but with more data we may have the opportunity to look at less-common outcomes [e.g. death, other COVID complications] or within individual diseases or treatments. So far I don’t think we will come to a different conclusion,” observed Dr. Hyrich, who is on the steering committee for the EULAR COVID-19 Database.

“These initial data are reassuring in that the majority of cases of COVID reported to our database have recovered, including those who were hospitalized,” she said.

Current EULAR advice is to continue treatment with glucocorticoids in patients who are being chronically treated, but to use them at the lowest possible dose.

The objectives of this first analysis of the German registry was to provide a description of the patients who did and did not require hospitalization and those who needed ventilation, as well as look at possible risk factors for hospitalization.

Dr. Regierer reported that, of 192 patients they included – all with a positive lab test for SARS-CoV-2 – 128 (67%) did not require hospital admission. Of those that did (n = 64), 43 (22%) did not need ventilation and 21 (11%) did. Fifteen patients died, all of whom had been hospitalized, and all but one of them had needed ventilation.

Concerning the characteristics of the patients, those who needed hospital treatment with and without ventilation were older than those who were not admitted (70 vs. 65 vs. 54 years, respectively).

“Looking at the sexes, the gender distribution is also interesting. We see 69% females in the nonhospitalized patients, 65% of the inpatients without ventilation, but only 43% females in the ventilated patients. So in this group, the male patients are the majority,” Dr. Regierer observed.

Just over half of all patients in the nonhospitalized and the hospitalized without ventilation groups had IRD in remission, but those in the hospitalized with ventilation group less than one-fifth had their IRD under control.

“Of course we have to keep in mind the small sample sizes,” Dr. Regierer said, but the distribution of patients by disease type was “what you’d expect in clinical care.” The majority of patients in each of the three groups had RA (47%, 56%, and 57%), followed by psoriatic arthritis (19%, 7%, and 14%), axial spondyloarthritis (11%, 5%, and 0%), systemic lupus erythematosus (6%, 2%, and 0%), and vasculitis (1%, 5%, and 5%).

Patients who were hospitalized with and without ventilation were more likely to have more than one comorbidity than those who were not hospitalized with COVID-19.

“The most frequent comorbidity was cardiovascular disease with 58% and 76% in the inpatient groups,” Dr. Regierer reported. One-third of the nonhospitalized patients had a cardiovascular comorbidity.

“If we look at pulmonary disease, we see that 38% of the ventilator patients had an underlying pulmonary disease,” she added. This was in comparison with 19% of the hospitalized without ventilation and 13% of the nonhospitalized patients. Diabetes was another common comorbidity in hospitalized patients with (16%) and without (19%) ventilation versus just 2% of nonhospitalized patients. While these and other comorbidities such as chronic renal insufficiency were associated with higher odds ratios in the multivariate risk factor analysis, they did not reach statistical significance.

With regard to RMD treatments, more than 60% of patients in the hospitalized group had received treatment with glucocorticoids versus 37% of those who did not get admitted. No differences were seen for the other treatments.

Interestingly, “female sex, remission, and use of NSAIDs have an odds ratio smaller than 1. So there might be a lower risk of hospitalization associated with these factors,” Dr. Regierer said.

Dr. Regierer has received grant support and is part of speaker’s bureaus for a variety of pharmaceutical companies. Dr. Hyrich disclosed grant income from Bristol-Myers Squibb, UCB, and Pfizer, and receiving speaker fees from AbbVie.

Being aged older than 65 years was associated with the highest risk of people with rheumatic and musculoskeletal diseases (RMDs) needing hospital treatment for COVID-19, according to the first results to be reported from ReCoVery, the German national COVID-19 registry.

Older patients with RMDs were five times more likely than younger patients to be hospitalized if they tested positive for SARS‑CoV‑2 and developed COVID-19 (odds ratio, 5.1; 95% confidence interval, 2.3-11.4).

The likelihood of hospitalization was also significantly increased by the current or prior use of glucocorticoids (OR, 2.59; 95% CI, 1.2-5.4) and by the presence of cardiovascular disease (OR, 2.27; 95% CI, 1.2-5.4).

“The register is a joint initiative of the German Society for Rheumatology and the Justus Liebig University in Giessen,” explained Anne Regierer, MD, during a live session of the annual European Congress of Rheumatology, held online this year due to COVID-19.

“The current pandemic has changed all of our lives. For patients it brought a lot of uncertainty and fears,” said Dr. Regierer, of the German Rheumatism Research Center Berlin.

“The risk of SARS-CoV-2 infection in patients with inflammatory rheumatic diseases [IRD] is still largely unknown. We still don’t know whether they have a high risk of getting the infection or whether they have a higher risk of a severer case ... therefore there’s an urgent need to have data to generate evidence for the management of our patients.”

Launched at the end of March 2020, the German registry now includes data on 251 patients – 194 of whom have recovered – provided by more than 200 registered rheumatologists. The registry data have now been integrated into the EULAR COVID-19 Database, which is itself part of a global effort to better understand and optimally manage RMD patients during the pandemic.

“The data presented by Dr. Regierer looked at similar outcomes and found quite similar results, which is reassuring,” Kimme Hyrich, MD, PhD, professor of epidemiology at the University of Manchester (England) and a consultant rheumatologist in the Kellgren Centre for Rheumatology at Manchester University Hospitals NHS Foundation Trust, said in an interview.

“We are very grateful for this collaboration [with the German society and others]. Our first publication has looked at hospitalization, but with more data we may have the opportunity to look at less-common outcomes [e.g. death, other COVID complications] or within individual diseases or treatments. So far I don’t think we will come to a different conclusion,” observed Dr. Hyrich, who is on the steering committee for the EULAR COVID-19 Database.

“These initial data are reassuring in that the majority of cases of COVID reported to our database have recovered, including those who were hospitalized,” she said.

Current EULAR advice is to continue treatment with glucocorticoids in patients who are being chronically treated, but to use them at the lowest possible dose.

The objectives of this first analysis of the German registry was to provide a description of the patients who did and did not require hospitalization and those who needed ventilation, as well as look at possible risk factors for hospitalization.

Dr. Regierer reported that, of 192 patients they included – all with a positive lab test for SARS-CoV-2 – 128 (67%) did not require hospital admission. Of those that did (n = 64), 43 (22%) did not need ventilation and 21 (11%) did. Fifteen patients died, all of whom had been hospitalized, and all but one of them had needed ventilation.

Concerning the characteristics of the patients, those who needed hospital treatment with and without ventilation were older than those who were not admitted (70 vs. 65 vs. 54 years, respectively).

“Looking at the sexes, the gender distribution is also interesting. We see 69% females in the nonhospitalized patients, 65% of the inpatients without ventilation, but only 43% females in the ventilated patients. So in this group, the male patients are the majority,” Dr. Regierer observed.

Just over half of all patients in the nonhospitalized and the hospitalized without ventilation groups had IRD in remission, but those in the hospitalized with ventilation group less than one-fifth had their IRD under control.

“Of course we have to keep in mind the small sample sizes,” Dr. Regierer said, but the distribution of patients by disease type was “what you’d expect in clinical care.” The majority of patients in each of the three groups had RA (47%, 56%, and 57%), followed by psoriatic arthritis (19%, 7%, and 14%), axial spondyloarthritis (11%, 5%, and 0%), systemic lupus erythematosus (6%, 2%, and 0%), and vasculitis (1%, 5%, and 5%).

Patients who were hospitalized with and without ventilation were more likely to have more than one comorbidity than those who were not hospitalized with COVID-19.

“The most frequent comorbidity was cardiovascular disease with 58% and 76% in the inpatient groups,” Dr. Regierer reported. One-third of the nonhospitalized patients had a cardiovascular comorbidity.

“If we look at pulmonary disease, we see that 38% of the ventilator patients had an underlying pulmonary disease,” she added. This was in comparison with 19% of the hospitalized without ventilation and 13% of the nonhospitalized patients. Diabetes was another common comorbidity in hospitalized patients with (16%) and without (19%) ventilation versus just 2% of nonhospitalized patients. While these and other comorbidities such as chronic renal insufficiency were associated with higher odds ratios in the multivariate risk factor analysis, they did not reach statistical significance.

With regard to RMD treatments, more than 60% of patients in the hospitalized group had received treatment with glucocorticoids versus 37% of those who did not get admitted. No differences were seen for the other treatments.

Interestingly, “female sex, remission, and use of NSAIDs have an odds ratio smaller than 1. So there might be a lower risk of hospitalization associated with these factors,” Dr. Regierer said.

Dr. Regierer has received grant support and is part of speaker’s bureaus for a variety of pharmaceutical companies. Dr. Hyrich disclosed grant income from Bristol-Myers Squibb, UCB, and Pfizer, and receiving speaker fees from AbbVie.

Patients with rheumatoid arthritis (RA) who are treated with Janus kinase (JAK) inhibitors had the highest risk of developing herpes zoster among newer disease-modifying antirheumatic drugs (DMARDs), according to data released from the German biologics registry.

These are believed to be the first European data on the risk of herpes zoster with JAK inhibitors and showed that the crude incidence rate of herpes zoster per 1,000 patient-years was 24.9 with JAK inhibitors, compared with just 5.8 for controls taking conventional synthetic (cs) DMARDs.

The risk of herpes zoster was also increased with other biologic (b) and targeted synthetic (ts) DMARDs that were assessed, with crude rates per 1,000 patient-years of 10.4 for monoclonal tumor necrosis factor inhibitors (TNFi), 10.5 for B-cell targeted therapies, 9.4 for T-cell costimulation modulators, 9.0 for soluble TNF receptors, and 8.5 for interleukin (IL)-6 inhibitors.

Overall, JAK inhibitor treatment was associated with a fivefold higher risk of herpes zoster (hazard ratio, 5.0; P < .0001), compared with the control csDMARD population after adjustment using an inverse probability weights (IPW) method.

“The general risk of herpes zoster is [twofold] higher in patients with rheumatoid arthritis when you compare it with the general population,” said Anja Strangfeld, MD of the German Research Center, Berlin, and one of the three RABBIT [Rheumatoide Arthritis: Biobachtung der Biologika-Therapie] principal investigators.

“If you think of all the treatments that RA patients get, then the risk is further increased with bDMARD and [JAK inhibitor] treatments,” she added in an interview. While the risk was highest with JAK inhibitors, “we also saw that monoclonal TNF antibodies as well as all the other biologic DMARD treatments have a higher risk of herpes zoster in RA patients, compared to csDMARD therapy,” Dr. Strangfeld said.

Adjusted IPW HR for the other RA treatments showed an increased herpes zoster risk for all but the soluble TNF receptor agents, at 1.6 for IL-6 inhibitors (P = .0045) and monoclonal TNFi antibodies (P = .0003), and 1.7 for B-cell targeted therapies (P = .00026) and T-cell costimulation modulators (P = .0048).

Dr. Strangfeld presented these data during the annual European Congress of Rheumatology, held online this year due to COVID-19. The analysis included 12,470 patients with RA enrolled in RABBIT from 2007 onward and who had been treated with monoclonal TNF inhibitor antibodies, cell-targeted therapies, and tsDMARDs such as JAK inhibitors. In all, at the data cutoff at the end of April 2019, 452 cases of herpes zoster were recorded in 433 patients, of which 52 cases were serious.

“The reactivation of the varicella zoster virus causing the herpes zoster is triggered by a decline of cellular immunity. This can be due to aging or immune suppression of any kind,” Dr. Strangfeld said in her presentation.

“The Cox regression [analysis] revealed that higher age and intake of glucocorticoids were associated with an increased risk of herpes zoster,” she reported, with a dose dependent increase with glucocorticoids. IPW HR for age per 10 years was 1.3 (P < .0001) and 1.9 (P = .0022) for higher doses of glucocorticoids (>10 vs. 0 mg/day).

Commenting on the study, rheumatologist and epidemiologist Loreto Carmona, MD, PhD, said: “This is a very interesting study. The results are confident and precise. The frequency of herpes zoster infection [based on crude incidence rate estimates] is very high. However, we must focus on the [multivariable with IPW] analysis after taking into account baseline risk.”

Dr. Carmona, who is the chair of the congress’s Abstract Selection Committee and is the scientific director of the Instituto de Salud Musculoesquelética in Madrid, added: “Having a disease with high levels of activity or a disease refractory to treatments [both of which were very likely used in creating the IPW] levels off the risk a bit. Also, because RA by itself, glucocorticoids, and age all increase the risk. Still, jakinibs [JAK inhibitors] stand out as the treatment related to higher risk of herpes zoster infection.”

Dr. Strangfeld and fellow RABBIT investigators have previously looked at the risk of herpes zoster in patients treated with anti–TNF-alpha agents (JAMA. 2009;301[7]:737-44). They found that monoclonal anti–TNF-alpha agents may be associated with increased risk of herpes zoster, which is now confirmed by the current analysis. The reason for looking at herpes zoster risk again is that since that first analysis, many more therapies have become available for RA during the past 10 years, notably the tsDMARDs.

Herpes zoster may not always be a serious event, Dr. Strangfeld said in the interview, “but it diminishes your quality of life; it can also be associated with pain and may be followed by postherpetic neuralgia, which is very painful.” With new herpes zoster vaccinations available, it is now possible to vaccinate patients more easily. “This is advisable for all kinds of treatments,” she said.

“What we found was quite in agreement with the data that we know from the U.S., from the observational studies, for example from the Corrona database,” Dr. Strangfeld stated. The key finding is that the risk of herpes zoster is increased to some level, almost regardless of which drug is chosen, she said. “This gives a clear message that systematic herpes zoster vaccination should be done in patients with RA,” she suggested.

The German biologics registry RABBIT is supported by a joint unconditional grant from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Hexal, Lilly, Merck Sharp & Dohme, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld has received speaker fees from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, Sanofi-Aventis, and UCB. Dr. Carmona had no relevant conflicts of interest to disclose.

SOURCE: Strangfeld A et al. Ann Rheum Dis. 2020;79[suppl 1]:150. Abstract OP0238.

Patients with rheumatoid arthritis (RA) who are treated with Janus kinase (JAK) inhibitors had the highest risk of developing herpes zoster among newer disease-modifying antirheumatic drugs (DMARDs), according to data released from the German biologics registry.

These are believed to be the first European data on the risk of herpes zoster with JAK inhibitors and showed that the crude incidence rate of herpes zoster per 1,000 patient-years was 24.9 with JAK inhibitors, compared with just 5.8 for controls taking conventional synthetic (cs) DMARDs.

The risk of herpes zoster was also increased with other biologic (b) and targeted synthetic (ts) DMARDs that were assessed, with crude rates per 1,000 patient-years of 10.4 for monoclonal tumor necrosis factor inhibitors (TNFi), 10.5 for B-cell targeted therapies, 9.4 for T-cell costimulation modulators, 9.0 for soluble TNF receptors, and 8.5 for interleukin (IL)-6 inhibitors.

Overall, JAK inhibitor treatment was associated with a fivefold higher risk of herpes zoster (hazard ratio, 5.0; P < .0001), compared with the control csDMARD population after adjustment using an inverse probability weights (IPW) method.

“The general risk of herpes zoster is [twofold] higher in patients with rheumatoid arthritis when you compare it with the general population,” said Anja Strangfeld, MD of the German Research Center, Berlin, and one of the three RABBIT [Rheumatoide Arthritis: Biobachtung der Biologika-Therapie] principal investigators.

“If you think of all the treatments that RA patients get, then the risk is further increased with bDMARD and [JAK inhibitor] treatments,” she added in an interview. While the risk was highest with JAK inhibitors, “we also saw that monoclonal TNF antibodies as well as all the other biologic DMARD treatments have a higher risk of herpes zoster in RA patients, compared to csDMARD therapy,” Dr. Strangfeld said.

Adjusted IPW HR for the other RA treatments showed an increased herpes zoster risk for all but the soluble TNF receptor agents, at 1.6 for IL-6 inhibitors (P = .0045) and monoclonal TNFi antibodies (P = .0003), and 1.7 for B-cell targeted therapies (P = .00026) and T-cell costimulation modulators (P = .0048).

Dr. Strangfeld presented these data during the annual European Congress of Rheumatology, held online this year due to COVID-19. The analysis included 12,470 patients with RA enrolled in RABBIT from 2007 onward and who had been treated with monoclonal TNF inhibitor antibodies, cell-targeted therapies, and tsDMARDs such as JAK inhibitors. In all, at the data cutoff at the end of April 2019, 452 cases of herpes zoster were recorded in 433 patients, of which 52 cases were serious.

“The reactivation of the varicella zoster virus causing the herpes zoster is triggered by a decline of cellular immunity. This can be due to aging or immune suppression of any kind,” Dr. Strangfeld said in her presentation.

“The Cox regression [analysis] revealed that higher age and intake of glucocorticoids were associated with an increased risk of herpes zoster,” she reported, with a dose dependent increase with glucocorticoids. IPW HR for age per 10 years was 1.3 (P < .0001) and 1.9 (P = .0022) for higher doses of glucocorticoids (>10 vs. 0 mg/day).

Commenting on the study, rheumatologist and epidemiologist Loreto Carmona, MD, PhD, said: “This is a very interesting study. The results are confident and precise. The frequency of herpes zoster infection [based on crude incidence rate estimates] is very high. However, we must focus on the [multivariable with IPW] analysis after taking into account baseline risk.”

Dr. Carmona, who is the chair of the congress’s Abstract Selection Committee and is the scientific director of the Instituto de Salud Musculoesquelética in Madrid, added: “Having a disease with high levels of activity or a disease refractory to treatments [both of which were very likely used in creating the IPW] levels off the risk a bit. Also, because RA by itself, glucocorticoids, and age all increase the risk. Still, jakinibs [JAK inhibitors] stand out as the treatment related to higher risk of herpes zoster infection.”

Dr. Strangfeld and fellow RABBIT investigators have previously looked at the risk of herpes zoster in patients treated with anti–TNF-alpha agents (JAMA. 2009;301[7]:737-44). They found that monoclonal anti–TNF-alpha agents may be associated with increased risk of herpes zoster, which is now confirmed by the current analysis. The reason for looking at herpes zoster risk again is that since that first analysis, many more therapies have become available for RA during the past 10 years, notably the tsDMARDs.

Herpes zoster may not always be a serious event, Dr. Strangfeld said in the interview, “but it diminishes your quality of life; it can also be associated with pain and may be followed by postherpetic neuralgia, which is very painful.” With new herpes zoster vaccinations available, it is now possible to vaccinate patients more easily. “This is advisable for all kinds of treatments,” she said.

“What we found was quite in agreement with the data that we know from the U.S., from the observational studies, for example from the Corrona database,” Dr. Strangfeld stated. The key finding is that the risk of herpes zoster is increased to some level, almost regardless of which drug is chosen, she said. “This gives a clear message that systematic herpes zoster vaccination should be done in patients with RA,” she suggested.

The German biologics registry RABBIT is supported by a joint unconditional grant from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Hexal, Lilly, Merck Sharp & Dohme, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld has received speaker fees from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, Sanofi-Aventis, and UCB. Dr. Carmona had no relevant conflicts of interest to disclose.

SOURCE: Strangfeld A et al. Ann Rheum Dis. 2020;79[suppl 1]:150. Abstract OP0238.

Patients with rheumatoid arthritis (RA) who are treated with Janus kinase (JAK) inhibitors had the highest risk of developing herpes zoster among newer disease-modifying antirheumatic drugs (DMARDs), according to data released from the German biologics registry.

These are believed to be the first European data on the risk of herpes zoster with JAK inhibitors and showed that the crude incidence rate of herpes zoster per 1,000 patient-years was 24.9 with JAK inhibitors, compared with just 5.8 for controls taking conventional synthetic (cs) DMARDs.

The risk of herpes zoster was also increased with other biologic (b) and targeted synthetic (ts) DMARDs that were assessed, with crude rates per 1,000 patient-years of 10.4 for monoclonal tumor necrosis factor inhibitors (TNFi), 10.5 for B-cell targeted therapies, 9.4 for T-cell costimulation modulators, 9.0 for soluble TNF receptors, and 8.5 for interleukin (IL)-6 inhibitors.

Overall, JAK inhibitor treatment was associated with a fivefold higher risk of herpes zoster (hazard ratio, 5.0; P < .0001), compared with the control csDMARD population after adjustment using an inverse probability weights (IPW) method.

“The general risk of herpes zoster is [twofold] higher in patients with rheumatoid arthritis when you compare it with the general population,” said Anja Strangfeld, MD of the German Research Center, Berlin, and one of the three RABBIT [Rheumatoide Arthritis: Biobachtung der Biologika-Therapie] principal investigators.

“If you think of all the treatments that RA patients get, then the risk is further increased with bDMARD and [JAK inhibitor] treatments,” she added in an interview. While the risk was highest with JAK inhibitors, “we also saw that monoclonal TNF antibodies as well as all the other biologic DMARD treatments have a higher risk of herpes zoster in RA patients, compared to csDMARD therapy,” Dr. Strangfeld said.

Adjusted IPW HR for the other RA treatments showed an increased herpes zoster risk for all but the soluble TNF receptor agents, at 1.6 for IL-6 inhibitors (P = .0045) and monoclonal TNFi antibodies (P = .0003), and 1.7 for B-cell targeted therapies (P = .00026) and T-cell costimulation modulators (P = .0048).

Dr. Strangfeld presented these data during the annual European Congress of Rheumatology, held online this year due to COVID-19. The analysis included 12,470 patients with RA enrolled in RABBIT from 2007 onward and who had been treated with monoclonal TNF inhibitor antibodies, cell-targeted therapies, and tsDMARDs such as JAK inhibitors. In all, at the data cutoff at the end of April 2019, 452 cases of herpes zoster were recorded in 433 patients, of which 52 cases were serious.

“The reactivation of the varicella zoster virus causing the herpes zoster is triggered by a decline of cellular immunity. This can be due to aging or immune suppression of any kind,” Dr. Strangfeld said in her presentation.

“The Cox regression [analysis] revealed that higher age and intake of glucocorticoids were associated with an increased risk of herpes zoster,” she reported, with a dose dependent increase with glucocorticoids. IPW HR for age per 10 years was 1.3 (P < .0001) and 1.9 (P = .0022) for higher doses of glucocorticoids (>10 vs. 0 mg/day).

Commenting on the study, rheumatologist and epidemiologist Loreto Carmona, MD, PhD, said: “This is a very interesting study. The results are confident and precise. The frequency of herpes zoster infection [based on crude incidence rate estimates] is very high. However, we must focus on the [multivariable with IPW] analysis after taking into account baseline risk.”

Dr. Carmona, who is the chair of the congress’s Abstract Selection Committee and is the scientific director of the Instituto de Salud Musculoesquelética in Madrid, added: “Having a disease with high levels of activity or a disease refractory to treatments [both of which were very likely used in creating the IPW] levels off the risk a bit. Also, because RA by itself, glucocorticoids, and age all increase the risk. Still, jakinibs [JAK inhibitors] stand out as the treatment related to higher risk of herpes zoster infection.”

Dr. Strangfeld and fellow RABBIT investigators have previously looked at the risk of herpes zoster in patients treated with anti–TNF-alpha agents (JAMA. 2009;301[7]:737-44). They found that monoclonal anti–TNF-alpha agents may be associated with increased risk of herpes zoster, which is now confirmed by the current analysis. The reason for looking at herpes zoster risk again is that since that first analysis, many more therapies have become available for RA during the past 10 years, notably the tsDMARDs.

Herpes zoster may not always be a serious event, Dr. Strangfeld said in the interview, “but it diminishes your quality of life; it can also be associated with pain and may be followed by postherpetic neuralgia, which is very painful.” With new herpes zoster vaccinations available, it is now possible to vaccinate patients more easily. “This is advisable for all kinds of treatments,” she said.

“What we found was quite in agreement with the data that we know from the U.S., from the observational studies, for example from the Corrona database,” Dr. Strangfeld stated. The key finding is that the risk of herpes zoster is increased to some level, almost regardless of which drug is chosen, she said. “This gives a clear message that systematic herpes zoster vaccination should be done in patients with RA,” she suggested.

The German biologics registry RABBIT is supported by a joint unconditional grant from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Hexal, Lilly, Merck Sharp & Dohme, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld has received speaker fees from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, Sanofi-Aventis, and UCB. Dr. Carmona had no relevant conflicts of interest to disclose.

SOURCE: Strangfeld A et al. Ann Rheum Dis. 2020;79[suppl 1]:150. Abstract OP0238.

Patients with OA treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs, according to the results of a large, population-based study performed in British Columbia.

Within 1 year of starting treatment, 296 of 13,798 patients treated with tramadol had died, compared with 246 of 13,798 treated with naproxen, giving a death rate of 21.5 versus 17.8 per 1,000 person-years, and representing a 20% increase in all-cause mortality versus the NSAID (hazard ratio, 1.2).

Similar results were seen comparing tramadol with diclofenac and tramadol with cyclooxygenase (COX)-2 inhibitors, but with increasing death rates of 24.8 versus 19.5 per 1,000 person-years (HR, 1.3) and 23.6 versus 15.7 per 1,000 person-years (HR, 1.5), respectively.

However, all-cause mortality was lower with tramadol than with the opiate painkiller, codeine (21.5 vs. 25.5 per 1,000 person-years; HR, 0.8), reported Ms. Lingyi Li, a PhD student from the University of British Columbia, Vancouver, at the annual European Congress of Rheumatology, held online this year due to COVID-19.

This is not the first time that tramadol’s excess mortality risk has been highlighted. Indeed, just last year (JAMA. 2019;321[10]:969-82), researchers using The Health Improvement Network database reported found that tramadol was associated with higher all-cause mortality than two COX-2 inhibitors, celecoxib (31.2 versus 18.4 per 1,000 person-years) and etoricoxib (25.7 versus 12.8 per 1,000 person-years).

Ms. Li and associates’ data not only now add further weight to those findings, but also go a step further by also looking at other serious risks associated with tramadol’s use among patients with OA. “The objective of this study is to compare tramadol with other commonly prescribed pain relief medications on the risk of several severe outcomes, including mortality, cardiovascular diseases [CVD], venous thromboembolism [VTE], and hip fracture,” Ms. Li said during her virtual presentation.

Using sequential propensity score matching, the researchers compared data on patients in British Columbia during 2005-2014 with a first prescription of tramadol (56,325), the NSAIDs naproxen (n = 13,798) or diclofenac (n = 17,675), COX-2 inhibitors (17,039), or codeine (n = 7,813).

“For CVD, we found that there is a higher risk among tramadol users, compared with diclofenac [HR, 1.2] and COX-2 inhibitors [HR, 1.2], but not with naproxen [HR, 1.0] and codeine [HR, 0.9] users,” Ms. Li reported.

Similarly, the 1-year risk of VTE was significantly higher among tramadol users only when compared with diclofenac (HR, 1.5) and COX-2 inhibitors (HR, 1.7).

“For hip fractures, tramadol initiation was associated with an increased risk of hip fractures, compared with all NSAIDs, but not with codeine,” Ms. Li said. The risk of hip fractures was 40%-50% higher with tramadol versus naproxen (HR, 1.4), diclofenac and COX-2 inhibitors (both HR, 1.5).

“Our results suggest an unfavorable safety profile of tramadol use,” Ms. Li said, suggesting that “several guidelines on tramadol use in clinical practice might need to be revisited.”

According to a recent Cochrane review there is “moderate-quality evidence” that tramadol “has no important benefit on mean pain or function in people with osteoarthritis.” The authors of the review wrote that, while some patients might glean a benefit from treatment, the evidence suggests that “adverse events probably cause substantially more participants to stop taking tramadol.”

Current guidance on the use of tramadol varies. The American Academy of Orthopaedic Surgeons guidelines recommend its use in patients with symptomatic knee OA on a par with NSAIDs while the American College of Rheumatology guidance (Arthritis Care Res. 2020;72[2]:149-62) conditionally recommends that it be used only if there is no real alternative, such as a contraindication to NSAIDs or pain relief is ineffective.

Patients with rheumatic disease are increasingly taking opioid painkillers such as tramadol, with other data reported at the EULAR 2020 E-Congress showing a rise from 15% in 2007 to 25% in 2016 in the Catalonia region of Spain alone. A rise from 5% to 10% has previously been reported in the United States from 2003 to 2009.

With increasing rates of tramadol prescribing, the worry is that perhaps tramadol is not as safe a people think it is, as Thomas Schwenk, MD, pointed out when he reviewed the previous research showing excess mortality with tramadol (NEJM Journal Watch, March 2019).

“The opioid agonist tramadol often is prescribed for patients with osteoarthritis pain because it is thought to be safer than opioids or nonsteroidal anti-inflammatory drugs,” he observed. Dr. Schwenk, who is dean of the University of Nevada, Reno, added that the “results [of that study] suggest that tramadol is not as safe as some people believe.”

He suggested cautious prescribing: “Tramadol might be an option for patients in whom NSAIDs are contraindicated, but it should be prescribed as judiciously as traditional opioids.”

Responsible prescribing to avoid opioid misuse in patients with rheumatic diseases was also advocated in a EULAR press release from the congress. A study from Iceland was highlighted that found patients with inflammatory arthritis frequently did not stop taking opioids after the source of their pain had gone; in fact, their use went up despite being treated with tumor necrosis factor inhibitors.

“We would like to raise awareness of a responsible approach both by the prescribers and also the patients,” said John Isaacs, PhD, of the University of Newcastle (England). “In order to alleviate chronic pain, medications should in any case only be part of a comprehensive therapy program, in which doctors, psychologists, and physiotherapists work together.”

The study authors had no conflicts of interest.

SOURCE: Li L et al. Ann Rheum Dis. 2020;79[suppl 1]:118, Abstract OP0191.

Patients with OA treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs, according to the results of a large, population-based study performed in British Columbia.

Within 1 year of starting treatment, 296 of 13,798 patients treated with tramadol had died, compared with 246 of 13,798 treated with naproxen, giving a death rate of 21.5 versus 17.8 per 1,000 person-years, and representing a 20% increase in all-cause mortality versus the NSAID (hazard ratio, 1.2).

Similar results were seen comparing tramadol with diclofenac and tramadol with cyclooxygenase (COX)-2 inhibitors, but with increasing death rates of 24.8 versus 19.5 per 1,000 person-years (HR, 1.3) and 23.6 versus 15.7 per 1,000 person-years (HR, 1.5), respectively.

However, all-cause mortality was lower with tramadol than with the opiate painkiller, codeine (21.5 vs. 25.5 per 1,000 person-years; HR, 0.8), reported Ms. Lingyi Li, a PhD student from the University of British Columbia, Vancouver, at the annual European Congress of Rheumatology, held online this year due to COVID-19.

This is not the first time that tramadol’s excess mortality risk has been highlighted. Indeed, just last year (JAMA. 2019;321[10]:969-82), researchers using The Health Improvement Network database reported found that tramadol was associated with higher all-cause mortality than two COX-2 inhibitors, celecoxib (31.2 versus 18.4 per 1,000 person-years) and etoricoxib (25.7 versus 12.8 per 1,000 person-years).

Ms. Li and associates’ data not only now add further weight to those findings, but also go a step further by also looking at other serious risks associated with tramadol’s use among patients with OA. “The objective of this study is to compare tramadol with other commonly prescribed pain relief medications on the risk of several severe outcomes, including mortality, cardiovascular diseases [CVD], venous thromboembolism [VTE], and hip fracture,” Ms. Li said during her virtual presentation.

Using sequential propensity score matching, the researchers compared data on patients in British Columbia during 2005-2014 with a first prescription of tramadol (56,325), the NSAIDs naproxen (n = 13,798) or diclofenac (n = 17,675), COX-2 inhibitors (17,039), or codeine (n = 7,813).

“For CVD, we found that there is a higher risk among tramadol users, compared with diclofenac [HR, 1.2] and COX-2 inhibitors [HR, 1.2], but not with naproxen [HR, 1.0] and codeine [HR, 0.9] users,” Ms. Li reported.

Similarly, the 1-year risk of VTE was significantly higher among tramadol users only when compared with diclofenac (HR, 1.5) and COX-2 inhibitors (HR, 1.7).

“For hip fractures, tramadol initiation was associated with an increased risk of hip fractures, compared with all NSAIDs, but not with codeine,” Ms. Li said. The risk of hip fractures was 40%-50% higher with tramadol versus naproxen (HR, 1.4), diclofenac and COX-2 inhibitors (both HR, 1.5).

“Our results suggest an unfavorable safety profile of tramadol use,” Ms. Li said, suggesting that “several guidelines on tramadol use in clinical practice might need to be revisited.”

According to a recent Cochrane review there is “moderate-quality evidence” that tramadol “has no important benefit on mean pain or function in people with osteoarthritis.” The authors of the review wrote that, while some patients might glean a benefit from treatment, the evidence suggests that “adverse events probably cause substantially more participants to stop taking tramadol.”

Current guidance on the use of tramadol varies. The American Academy of Orthopaedic Surgeons guidelines recommend its use in patients with symptomatic knee OA on a par with NSAIDs while the American College of Rheumatology guidance (Arthritis Care Res. 2020;72[2]:149-62) conditionally recommends that it be used only if there is no real alternative, such as a contraindication to NSAIDs or pain relief is ineffective.

Patients with rheumatic disease are increasingly taking opioid painkillers such as tramadol, with other data reported at the EULAR 2020 E-Congress showing a rise from 15% in 2007 to 25% in 2016 in the Catalonia region of Spain alone. A rise from 5% to 10% has previously been reported in the United States from 2003 to 2009.

With increasing rates of tramadol prescribing, the worry is that perhaps tramadol is not as safe a people think it is, as Thomas Schwenk, MD, pointed out when he reviewed the previous research showing excess mortality with tramadol (NEJM Journal Watch, March 2019).

“The opioid agonist tramadol often is prescribed for patients with osteoarthritis pain because it is thought to be safer than opioids or nonsteroidal anti-inflammatory drugs,” he observed. Dr. Schwenk, who is dean of the University of Nevada, Reno, added that the “results [of that study] suggest that tramadol is not as safe as some people believe.”

He suggested cautious prescribing: “Tramadol might be an option for patients in whom NSAIDs are contraindicated, but it should be prescribed as judiciously as traditional opioids.”

Responsible prescribing to avoid opioid misuse in patients with rheumatic diseases was also advocated in a EULAR press release from the congress. A study from Iceland was highlighted that found patients with inflammatory arthritis frequently did not stop taking opioids after the source of their pain had gone; in fact, their use went up despite being treated with tumor necrosis factor inhibitors.

“We would like to raise awareness of a responsible approach both by the prescribers and also the patients,” said John Isaacs, PhD, of the University of Newcastle (England). “In order to alleviate chronic pain, medications should in any case only be part of a comprehensive therapy program, in which doctors, psychologists, and physiotherapists work together.”

The study authors had no conflicts of interest.

SOURCE: Li L et al. Ann Rheum Dis. 2020;79[suppl 1]:118, Abstract OP0191.

Patients with OA treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs, according to the results of a large, population-based study performed in British Columbia.

Within 1 year of starting treatment, 296 of 13,798 patients treated with tramadol had died, compared with 246 of 13,798 treated with naproxen, giving a death rate of 21.5 versus 17.8 per 1,000 person-years, and representing a 20% increase in all-cause mortality versus the NSAID (hazard ratio, 1.2).

Similar results were seen comparing tramadol with diclofenac and tramadol with cyclooxygenase (COX)-2 inhibitors, but with increasing death rates of 24.8 versus 19.5 per 1,000 person-years (HR, 1.3) and 23.6 versus 15.7 per 1,000 person-years (HR, 1.5), respectively.

However, all-cause mortality was lower with tramadol than with the opiate painkiller, codeine (21.5 vs. 25.5 per 1,000 person-years; HR, 0.8), reported Ms. Lingyi Li, a PhD student from the University of British Columbia, Vancouver, at the annual European Congress of Rheumatology, held online this year due to COVID-19.

This is not the first time that tramadol’s excess mortality risk has been highlighted. Indeed, just last year (JAMA. 2019;321[10]:969-82), researchers using The Health Improvement Network database reported found that tramadol was associated with higher all-cause mortality than two COX-2 inhibitors, celecoxib (31.2 versus 18.4 per 1,000 person-years) and etoricoxib (25.7 versus 12.8 per 1,000 person-years).

Ms. Li and associates’ data not only now add further weight to those findings, but also go a step further by also looking at other serious risks associated with tramadol’s use among patients with OA. “The objective of this study is to compare tramadol with other commonly prescribed pain relief medications on the risk of several severe outcomes, including mortality, cardiovascular diseases [CVD], venous thromboembolism [VTE], and hip fracture,” Ms. Li said during her virtual presentation.

Using sequential propensity score matching, the researchers compared data on patients in British Columbia during 2005-2014 with a first prescription of tramadol (56,325), the NSAIDs naproxen (n = 13,798) or diclofenac (n = 17,675), COX-2 inhibitors (17,039), or codeine (n = 7,813).

“For CVD, we found that there is a higher risk among tramadol users, compared with diclofenac [HR, 1.2] and COX-2 inhibitors [HR, 1.2], but not with naproxen [HR, 1.0] and codeine [HR, 0.9] users,” Ms. Li reported.

Similarly, the 1-year risk of VTE was significantly higher among tramadol users only when compared with diclofenac (HR, 1.5) and COX-2 inhibitors (HR, 1.7).

“For hip fractures, tramadol initiation was associated with an increased risk of hip fractures, compared with all NSAIDs, but not with codeine,” Ms. Li said. The risk of hip fractures was 40%-50% higher with tramadol versus naproxen (HR, 1.4), diclofenac and COX-2 inhibitors (both HR, 1.5).

“Our results suggest an unfavorable safety profile of tramadol use,” Ms. Li said, suggesting that “several guidelines on tramadol use in clinical practice might need to be revisited.”

According to a recent Cochrane review there is “moderate-quality evidence” that tramadol “has no important benefit on mean pain or function in people with osteoarthritis.” The authors of the review wrote that, while some patients might glean a benefit from treatment, the evidence suggests that “adverse events probably cause substantially more participants to stop taking tramadol.”

Current guidance on the use of tramadol varies. The American Academy of Orthopaedic Surgeons guidelines recommend its use in patients with symptomatic knee OA on a par with NSAIDs while the American College of Rheumatology guidance (Arthritis Care Res. 2020;72[2]:149-62) conditionally recommends that it be used only if there is no real alternative, such as a contraindication to NSAIDs or pain relief is ineffective.

Patients with rheumatic disease are increasingly taking opioid painkillers such as tramadol, with other data reported at the EULAR 2020 E-Congress showing a rise from 15% in 2007 to 25% in 2016 in the Catalonia region of Spain alone. A rise from 5% to 10% has previously been reported in the United States from 2003 to 2009.

With increasing rates of tramadol prescribing, the worry is that perhaps tramadol is not as safe a people think it is, as Thomas Schwenk, MD, pointed out when he reviewed the previous research showing excess mortality with tramadol (NEJM Journal Watch, March 2019).

“The opioid agonist tramadol often is prescribed for patients with osteoarthritis pain because it is thought to be safer than opioids or nonsteroidal anti-inflammatory drugs,” he observed. Dr. Schwenk, who is dean of the University of Nevada, Reno, added that the “results [of that study] suggest that tramadol is not as safe as some people believe.”

He suggested cautious prescribing: “Tramadol might be an option for patients in whom NSAIDs are contraindicated, but it should be prescribed as judiciously as traditional opioids.”

Responsible prescribing to avoid opioid misuse in patients with rheumatic diseases was also advocated in a EULAR press release from the congress. A study from Iceland was highlighted that found patients with inflammatory arthritis frequently did not stop taking opioids after the source of their pain had gone; in fact, their use went up despite being treated with tumor necrosis factor inhibitors.

“We would like to raise awareness of a responsible approach both by the prescribers and also the patients,” said John Isaacs, PhD, of the University of Newcastle (England). “In order to alleviate chronic pain, medications should in any case only be part of a comprehensive therapy program, in which doctors, psychologists, and physiotherapists work together.”

The study authors had no conflicts of interest.

SOURCE: Li L et al. Ann Rheum Dis. 2020;79[suppl 1]:118, Abstract OP0191.

When COVID-19 is suspected or confirmed in a patient with a rheumatic disease, treatment with hydroxychloroquine may be continued, but other treatments may need to be stopped or held temporarily, according to new guidance issued by the American College of Rheumatology.

That includes disease-modifying treatment with antirheumatic drugs such as sulfasalazine, methotrexate, leflunomide, and the Janus kinase (JAK) inhibitors, as well as immunosuppressants and non-interleukin (IL)-6 biologics, and this is regardless of how severe the COVID-19 illness is. NSAIDs should also be stopped if there are respiratory symptoms.

The advice is slightly less drastic if someone with stable rheumatic disease has probably been exposed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or are asymptomatic. In those patients, DMARDs may be continued, although there is uncertainty over whether there is a need to temporarily stop methotrexate or leflunomide. Interruption of immunosuppressive, non–IL-6, and JAK inhibitor treatment is advised pending a negative SARS-CoV-2 test result, assuming the patient’s rheumatic disease is stable.
 

Impetus for ACR COVID-19 guidance

“One of the earliest challenges for rheumatologists during the COVID-19 pandemic was determining how to advise our patients who were taking immunosuppressive medications and were concerned as to whether or not to discontinue their therapy,” ACR President Ellen Gravallese, MD, said in an interview about the ACR Clinical Guidance Document, which is published online in Arthritis & Rheumatology.

“A second challenge was keeping our patients safe from exposure to the virus, while still seeing those patients in person who required office visits,” added Dr. Gravallese, who is chief of the division of rheumatology, inflammation, and immunity at Brigham and Women’s Hospital in Boston.

She continued: “The ACR Clinical Guidance Document was prepared in order to assist rheumatologists with decisions as to how to handle current medications during different phases of a patient’s exposure to the SARS-CoV-2 virus.”

But with very little evidence available on how to manage COVID-19 patients generally, let alone specifically in those with rheumatic diseases, “it became evident that any recommendations made would need to be done in a thoughtful and organized manner, evaluating the evidence that was available and obtaining the advice of experts in infectious disease, epidemiology, and in the use of biologic and nonbiologic agents for rheumatic disease,” she said.

As such, the ACR convened a task force of 10 rheumatologists and 4 infectious disease specialists from North America to look at how best to manage patients with rheumatic disease during the COVID-19 pandemic.

“Our charge was to develop a guidance document for the care of adult rheumatic disease patients in the context of COVID-19 and not per se to provide guidance for the treatment of COVID-19,” explained task force member and the corresponding author for the guidance, Ted R. Mikuls, MD, MSPH, of the University of Nebraska Medical Center, Omaha.

Dr. Mikuls, who was speaking at a virtual town hall meeting hosted by the ACR on May 6, noted that the guidance was obviously based on the best consensus of the available data and as such represented a “living document” that “would change and be added to” as necessary.
 

General recommendations for adult rheumatic disease management

In terms of general recommendations for the management of adult rheumatic disease patients, Dr. Mikuls said that six statements had been made “specific to risk assessment, prevention of infection, and best practices related to glucocorticoid use and the use of ACE [angiotensin-converting enzyme] inhibitors and ARBs [angiotensin II receptor blockers] during the pandemic.”

For example, general advice is to counsel patients to keep up general preventive measures such as social distancing and regular hand washing, reducing the number of in-person health care visits, and undertaking other means to try to prevent potential SARS-CoV-2 exposure. As for general treatment advice, glucocorticoids should be used at their lowest doses possible and should not be abruptly stopped, and antihypertensive treatment should be used as indicated.

Additional guidance statements include those that address the treatment of patients with stable rheumatic disease in the absence of infection or known exposure to SARS-CoV-2, with guidance specific to the treatment of systemic lupus erythematosus (SLE), and those with newly diagnosed or active rheumatic disease.
 

SLE and inflammatory arthritis recommendations

“There are several sections within the guidance document that address the treatment of patients with systemic lupus erythematosus during this pandemic,” Dr. Gravallese pointed out. “In general, it is recommended that lupus patients who are currently taking hydroxychloroquine can remain on the therapy prior to and during infection and that newly diagnosed patients with lupus can be placed on this medication at full dose. It is recommended that pregnant patients with lupus remain on therapy with this drug.”

She also observed that, for the treatment of active inflammatory arthritis, “the recommendations were written to address specific medications that could be used in this setting. In general, the task force recommendations were guided by the importance of controlling inflammation prior to exposure to the virus, even during this pandemic.
 

Guidance raises questions

During the ACR’s town hall meeting, the task force answered several questions raised by the guidance, such as the reasoning behind recommending that the use of traditional DMARDs be discontinued in patients with confirmed SARS-CoV-2 infection.

Dr. Mikuls observed: “Maybe if you just read the guidance statements it isn’t terribly intuitive.” There was a lot of discussion about whether or not conventional DMARDs were immunosuppressive, and even though they may not have such effects, it was decided to err on the side of caution.

“I think the task force felt that, with a COVID-19–positive patient, there is a concern of potentially confusing adverse effects related to medicines or conflate those with problems from the infection,” he said. Although rare, examples of those issues could be drug-induced hypersensitivity, hypersensitivity pneumonitis, or gastrointestinal side effects of hepatitis, all of which have been described in COVID-19. “Not only could it cause confusion, but it could maybe worsen those sequalae of COVID-19,” he said.

“I think the other part of this answer was that the panel really felt that the risk in terms of the flaring of the underlying rheumatic disease was likely to be pretty low given the finite time frame you’d be taking about – usually a time frame of 2-3 weeks you’d be holding the agent – so I think that is really why the task force ended up with that recommendation.”

Similarly, for the JAK inhibitors, the decision was to err on the side of caution when COVID-19 was suspected or confirmed. “Not so much because of the risk of thromboembolic disease, but concerns over immunosuppression that these drugs carry with them and also the fact the JAK inhibitors are probably inhibitors of type 1 interferons, which play a significant role in viral immunity and could potentially have a negative impact,” said Stanley Cohen, MD, who practices rheumatology in the Dallas area.

“On the flipside, there is interest in some of the JAK inhibitors as a potential treatment for COVID-19,” Dr. Cohen said, referring to anecdotal evidence for baricitinib (Olumiant).

Michael Weinblatt, MD, of Brigham and Women’s Hospital, addressed the recent concern over the use of NSAIDs by the public.

“There’s been a lot in the lay press that NSAIDs – because of the effects on receptors in the lung – could lead to deleterious outcomes in patients with COVID and there’s very little data to support this.

“We did recommend that NSAIDs be held in the hospitalized patient and that wasn’t because of the COVID-19 issue, it really was just medical practice, and we didn’t want to confound the care of these really sick patients with potential toxicities from NSAIDs. But as far as routine rheumatological care in your outpatients, we did not recommend that nonsteroidals be stopped if they were tolerated.”

One part of the guidance that might already need revision is the recommendation on the continued use of hydroxychloroquine in patients who develop COVID-19.

“Our guidance document says it’s OK; we were all in very strong agreement to continue hydroxychloroquine in our patients with COVID-19 because at that point, just a couple of weeks ago, we thought it was part of the potential treatment,” Karen Costenbader, MD, MPH, of Brigham and Women’s Hospital, said during the town hall meeting.

“Now the pendulum has swung the other way, and we’re worried about maybe we shouldn’t be continuing it because COVID-19 patients will be getting many other medications,” Dr. Costenbader said, and these may affect the QT-interval. “They will not be getting azithromycin because the pendulum swung the other way on that one too, but definitely on many other medications when they are sick.”

Potentially, she added, “if the rheumatic disease is under good control the inpatient physicians could decide whether they should continue [hydroxychloroquine] or not. If the COVID-19 is a mild disease, I would say we probably could continue in accordance with what we put in the document, but we will have to revisit this as well.”
 

Guidance is a ‘living document’

“We will be providing updates to the Clinical Guidance Document as the need arises,” Dr. Gravallese emphasized. While the general recommendations are unlikely to change very much, “the task force will be interested in seeing the results of all new data, but the results of randomized, clinical trials will be particularly important as they become available,” she said. In particular, randomized, controlled trials of glucocorticoids and IL-6 receptor blockade for use in COVID-19 will be of great importance.

“In this initial document, we could not take on all of the medical scenarios our members will face. For example, we could not take on recommendations for the pediatric population as this group of patients has a very different response than adults to the SARS-CoV-2 virus,” Dr. Gravallese acknowledged. The plan is to provide guidance for that group of patients soon.

In addition, the ACR Executive Committee has appointed a Practice and Advocacy Task Force that will “address issues rheumatologists face on the practice side, including advice regarding how to effectively use telemedicine, address the frequency and safety of infusions, determine urgent versus nonurgent issues that would or would not require face-to-face visits, and help with financial challenges.”

The American College of Rheumatology supported the guidance-development process. Dr. Mikuls, Dr. Weinblatt, Dr. Cohen, and Dr. Costenbader each disclosed research support or consultancies with multiple pharmaceutical companies. Dr. Gravallese had no disclosures.

SOURCE: Mikuls TR et al. Arthritis Rheumatol. 2020 Apr 29. doi: 10.1002/art.41301.

When COVID-19 is suspected or confirmed in a patient with a rheumatic disease, treatment with hydroxychloroquine may be continued, but other treatments may need to be stopped or held temporarily, according to new guidance issued by the American College of Rheumatology.

That includes disease-modifying treatment with antirheumatic drugs such as sulfasalazine, methotrexate, leflunomide, and the Janus kinase (JAK) inhibitors, as well as immunosuppressants and non-interleukin (IL)-6 biologics, and this is regardless of how severe the COVID-19 illness is. NSAIDs should also be stopped if there are respiratory symptoms.

The advice is slightly less drastic if someone with stable rheumatic disease has probably been exposed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or are asymptomatic. In those patients, DMARDs may be continued, although there is uncertainty over whether there is a need to temporarily stop methotrexate or leflunomide. Interruption of immunosuppressive, non–IL-6, and JAK inhibitor treatment is advised pending a negative SARS-CoV-2 test result, assuming the patient’s rheumatic disease is stable.
 

Impetus for ACR COVID-19 guidance

“One of the earliest challenges for rheumatologists during the COVID-19 pandemic was determining how to advise our patients who were taking immunosuppressive medications and were concerned as to whether or not to discontinue their therapy,” ACR President Ellen Gravallese, MD, said in an interview about the ACR Clinical Guidance Document, which is published online in Arthritis & Rheumatology.

“A second challenge was keeping our patients safe from exposure to the virus, while still seeing those patients in person who required office visits,” added Dr. Gravallese, who is chief of the division of rheumatology, inflammation, and immunity at Brigham and Women’s Hospital in Boston.

She continued: “The ACR Clinical Guidance Document was prepared in order to assist rheumatologists with decisions as to how to handle current medications during different phases of a patient’s exposure to the SARS-CoV-2 virus.”

But with very little evidence available on how to manage COVID-19 patients generally, let alone specifically in those with rheumatic diseases, “it became evident that any recommendations made would need to be done in a thoughtful and organized manner, evaluating the evidence that was available and obtaining the advice of experts in infectious disease, epidemiology, and in the use of biologic and nonbiologic agents for rheumatic disease,” she said.

As such, the ACR convened a task force of 10 rheumatologists and 4 infectious disease specialists from North America to look at how best to manage patients with rheumatic disease during the COVID-19 pandemic.

“Our charge was to develop a guidance document for the care of adult rheumatic disease patients in the context of COVID-19 and not per se to provide guidance for the treatment of COVID-19,” explained task force member and the corresponding author for the guidance, Ted R. Mikuls, MD, MSPH, of the University of Nebraska Medical Center, Omaha.

Dr. Mikuls, who was speaking at a virtual town hall meeting hosted by the ACR on May 6, noted that the guidance was obviously based on the best consensus of the available data and as such represented a “living document” that “would change and be added to” as necessary.
 

General recommendations for adult rheumatic disease management

In terms of general recommendations for the management of adult rheumatic disease patients, Dr. Mikuls said that six statements had been made “specific to risk assessment, prevention of infection, and best practices related to glucocorticoid use and the use of ACE [angiotensin-converting enzyme] inhibitors and ARBs [angiotensin II receptor blockers] during the pandemic.”

For example, general advice is to counsel patients to keep up general preventive measures such as social distancing and regular hand washing, reducing the number of in-person health care visits, and undertaking other means to try to prevent potential SARS-CoV-2 exposure. As for general treatment advice, glucocorticoids should be used at their lowest doses possible and should not be abruptly stopped, and antihypertensive treatment should be used as indicated.

Additional guidance statements include those that address the treatment of patients with stable rheumatic disease in the absence of infection or known exposure to SARS-CoV-2, with guidance specific to the treatment of systemic lupus erythematosus (SLE), and those with newly diagnosed or active rheumatic disease.
 

SLE and inflammatory arthritis recommendations

“There are several sections within the guidance document that address the treatment of patients with systemic lupus erythematosus during this pandemic,” Dr. Gravallese pointed out. “In general, it is recommended that lupus patients who are currently taking hydroxychloroquine can remain on the therapy prior to and during infection and that newly diagnosed patients with lupus can be placed on this medication at full dose. It is recommended that pregnant patients with lupus remain on therapy with this drug.”

She also observed that, for the treatment of active inflammatory arthritis, “the recommendations were written to address specific medications that could be used in this setting. In general, the task force recommendations were guided by the importance of controlling inflammation prior to exposure to the virus, even during this pandemic.
 

Guidance raises questions

During the ACR’s town hall meeting, the task force answered several questions raised by the guidance, such as the reasoning behind recommending that the use of traditional DMARDs be discontinued in patients with confirmed SARS-CoV-2 infection.

Dr. Mikuls observed: “Maybe if you just read the guidance statements it isn’t terribly intuitive.” There was a lot of discussion about whether or not conventional DMARDs were immunosuppressive, and even though they may not have such effects, it was decided to err on the side of caution.

“I think the task force felt that, with a COVID-19–positive patient, there is a concern of potentially confusing adverse effects related to medicines or conflate those with problems from the infection,” he said. Although rare, examples of those issues could be drug-induced hypersensitivity, hypersensitivity pneumonitis, or gastrointestinal side effects of hepatitis, all of which have been described in COVID-19. “Not only could it cause confusion, but it could maybe worsen those sequalae of COVID-19,” he said.

“I think the other part of this answer was that the panel really felt that the risk in terms of the flaring of the underlying rheumatic disease was likely to be pretty low given the finite time frame you’d be taking about – usually a time frame of 2-3 weeks you’d be holding the agent – so I think that is really why the task force ended up with that recommendation.”

Similarly, for the JAK inhibitors, the decision was to err on the side of caution when COVID-19 was suspected or confirmed. “Not so much because of the risk of thromboembolic disease, but concerns over immunosuppression that these drugs carry with them and also the fact the JAK inhibitors are probably inhibitors of type 1 interferons, which play a significant role in viral immunity and could potentially have a negative impact,” said Stanley Cohen, MD, who practices rheumatology in the Dallas area.

“On the flipside, there is interest in some of the JAK inhibitors as a potential treatment for COVID-19,” Dr. Cohen said, referring to anecdotal evidence for baricitinib (Olumiant).

Michael Weinblatt, MD, of Brigham and Women’s Hospital, addressed the recent concern over the use of NSAIDs by the public.

“There’s been a lot in the lay press that NSAIDs – because of the effects on receptors in the lung – could lead to deleterious outcomes in patients with COVID and there’s very little data to support this.

“We did recommend that NSAIDs be held in the hospitalized patient and that wasn’t because of the COVID-19 issue, it really was just medical practice, and we didn’t want to confound the care of these really sick patients with potential toxicities from NSAIDs. But as far as routine rheumatological care in your outpatients, we did not recommend that nonsteroidals be stopped if they were tolerated.”

One part of the guidance that might already need revision is the recommendation on the continued use of hydroxychloroquine in patients who develop COVID-19.

“Our guidance document says it’s OK; we were all in very strong agreement to continue hydroxychloroquine in our patients with COVID-19 because at that point, just a couple of weeks ago, we thought it was part of the potential treatment,” Karen Costenbader, MD, MPH, of Brigham and Women’s Hospital, said during the town hall meeting.

“Now the pendulum has swung the other way, and we’re worried about maybe we shouldn’t be continuing it because COVID-19 patients will be getting many other medications,” Dr. Costenbader said, and these may affect the QT-interval. “They will not be getting azithromycin because the pendulum swung the other way on that one too, but definitely on many other medications when they are sick.”

Potentially, she added, “if the rheumatic disease is under good control the inpatient physicians could decide whether they should continue [hydroxychloroquine] or not. If the COVID-19 is a mild disease, I would say we probably could continue in accordance with what we put in the document, but we will have to revisit this as well.”
 

Guidance is a ‘living document’

“We will be providing updates to the Clinical Guidance Document as the need arises,” Dr. Gravallese emphasized. While the general recommendations are unlikely to change very much, “the task force will be interested in seeing the results of all new data, but the results of randomized, clinical trials will be particularly important as they become available,” she said. In particular, randomized, controlled trials of glucocorticoids and IL-6 receptor blockade for use in COVID-19 will be of great importance.

“In this initial document, we could not take on all of the medical scenarios our members will face. For example, we could not take on recommendations for the pediatric population as this group of patients has a very different response than adults to the SARS-CoV-2 virus,” Dr. Gravallese acknowledged. The plan is to provide guidance for that group of patients soon.

In addition, the ACR Executive Committee has appointed a Practice and Advocacy Task Force that will “address issues rheumatologists face on the practice side, including advice regarding how to effectively use telemedicine, address the frequency and safety of infusions, determine urgent versus nonurgent issues that would or would not require face-to-face visits, and help with financial challenges.”

The American College of Rheumatology supported the guidance-development process. Dr. Mikuls, Dr. Weinblatt, Dr. Cohen, and Dr. Costenbader each disclosed research support or consultancies with multiple pharmaceutical companies. Dr. Gravallese had no disclosures.

SOURCE: Mikuls TR et al. Arthritis Rheumatol. 2020 Apr 29. doi: 10.1002/art.41301.

When COVID-19 is suspected or confirmed in a patient with a rheumatic disease, treatment with hydroxychloroquine may be continued, but other treatments may need to be stopped or held temporarily, according to new guidance issued by the American College of Rheumatology.

That includes disease-modifying treatment with antirheumatic drugs such as sulfasalazine, methotrexate, leflunomide, and the Janus kinase (JAK) inhibitors, as well as immunosuppressants and non-interleukin (IL)-6 biologics, and this is regardless of how severe the COVID-19 illness is. NSAIDs should also be stopped if there are respiratory symptoms.

The advice is slightly less drastic if someone with stable rheumatic disease has probably been exposed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or are asymptomatic. In those patients, DMARDs may be continued, although there is uncertainty over whether there is a need to temporarily stop methotrexate or leflunomide. Interruption of immunosuppressive, non–IL-6, and JAK inhibitor treatment is advised pending a negative SARS-CoV-2 test result, assuming the patient’s rheumatic disease is stable.
 

Impetus for ACR COVID-19 guidance

“One of the earliest challenges for rheumatologists during the COVID-19 pandemic was determining how to advise our patients who were taking immunosuppressive medications and were concerned as to whether or not to discontinue their therapy,” ACR President Ellen Gravallese, MD, said in an interview about the ACR Clinical Guidance Document, which is published online in Arthritis & Rheumatology.

“A second challenge was keeping our patients safe from exposure to the virus, while still seeing those patients in person who required office visits,” added Dr. Gravallese, who is chief of the division of rheumatology, inflammation, and immunity at Brigham and Women’s Hospital in Boston.

She continued: “The ACR Clinical Guidance Document was prepared in order to assist rheumatologists with decisions as to how to handle current medications during different phases of a patient’s exposure to the SARS-CoV-2 virus.”

But with very little evidence available on how to manage COVID-19 patients generally, let alone specifically in those with rheumatic diseases, “it became evident that any recommendations made would need to be done in a thoughtful and organized manner, evaluating the evidence that was available and obtaining the advice of experts in infectious disease, epidemiology, and in the use of biologic and nonbiologic agents for rheumatic disease,” she said.

As such, the ACR convened a task force of 10 rheumatologists and 4 infectious disease specialists from North America to look at how best to manage patients with rheumatic disease during the COVID-19 pandemic.

“Our charge was to develop a guidance document for the care of adult rheumatic disease patients in the context of COVID-19 and not per se to provide guidance for the treatment of COVID-19,” explained task force member and the corresponding author for the guidance, Ted R. Mikuls, MD, MSPH, of the University of Nebraska Medical Center, Omaha.

Dr. Mikuls, who was speaking at a virtual town hall meeting hosted by the ACR on May 6, noted that the guidance was obviously based on the best consensus of the available data and as such represented a “living document” that “would change and be added to” as necessary.
 

General recommendations for adult rheumatic disease management

In terms of general recommendations for the management of adult rheumatic disease patients, Dr. Mikuls said that six statements had been made “specific to risk assessment, prevention of infection, and best practices related to glucocorticoid use and the use of ACE [angiotensin-converting enzyme] inhibitors and ARBs [angiotensin II receptor blockers] during the pandemic.”

For example, general advice is to counsel patients to keep up general preventive measures such as social distancing and regular hand washing, reducing the number of in-person health care visits, and undertaking other means to try to prevent potential SARS-CoV-2 exposure. As for general treatment advice, glucocorticoids should be used at their lowest doses possible and should not be abruptly stopped, and antihypertensive treatment should be used as indicated.

Additional guidance statements include those that address the treatment of patients with stable rheumatic disease in the absence of infection or known exposure to SARS-CoV-2, with guidance specific to the treatment of systemic lupus erythematosus (SLE), and those with newly diagnosed or active rheumatic disease.
 

SLE and inflammatory arthritis recommendations

“There are several sections within the guidance document that address the treatment of patients with systemic lupus erythematosus during this pandemic,” Dr. Gravallese pointed out. “In general, it is recommended that lupus patients who are currently taking hydroxychloroquine can remain on the therapy prior to and during infection and that newly diagnosed patients with lupus can be placed on this medication at full dose. It is recommended that pregnant patients with lupus remain on therapy with this drug.”

She also observed that, for the treatment of active inflammatory arthritis, “the recommendations were written to address specific medications that could be used in this setting. In general, the task force recommendations were guided by the importance of controlling inflammation prior to exposure to the virus, even during this pandemic.
 

Guidance raises questions

During the ACR’s town hall meeting, the task force answered several questions raised by the guidance, such as the reasoning behind recommending that the use of traditional DMARDs be discontinued in patients with confirmed SARS-CoV-2 infection.

Dr. Mikuls observed: “Maybe if you just read the guidance statements it isn’t terribly intuitive.” There was a lot of discussion about whether or not conventional DMARDs were immunosuppressive, and even though they may not have such effects, it was decided to err on the side of caution.

“I think the task force felt that, with a COVID-19–positive patient, there is a concern of potentially confusing adverse effects related to medicines or conflate those with problems from the infection,” he said. Although rare, examples of those issues could be drug-induced hypersensitivity, hypersensitivity pneumonitis, or gastrointestinal side effects of hepatitis, all of which have been described in COVID-19. “Not only could it cause confusion, but it could maybe worsen those sequalae of COVID-19,” he said.

“I think the other part of this answer was that the panel really felt that the risk in terms of the flaring of the underlying rheumatic disease was likely to be pretty low given the finite time frame you’d be taking about – usually a time frame of 2-3 weeks you’d be holding the agent – so I think that is really why the task force ended up with that recommendation.”

Similarly, for the JAK inhibitors, the decision was to err on the side of caution when COVID-19 was suspected or confirmed. “Not so much because of the risk of thromboembolic disease, but concerns over immunosuppression that these drugs carry with them and also the fact the JAK inhibitors are probably inhibitors of type 1 interferons, which play a significant role in viral immunity and could potentially have a negative impact,” said Stanley Cohen, MD, who practices rheumatology in the Dallas area.

“On the flipside, there is interest in some of the JAK inhibitors as a potential treatment for COVID-19,” Dr. Cohen said, referring to anecdotal evidence for baricitinib (Olumiant).

Michael Weinblatt, MD, of Brigham and Women’s Hospital, addressed the recent concern over the use of NSAIDs by the public.

“There’s been a lot in the lay press that NSAIDs – because of the effects on receptors in the lung – could lead to deleterious outcomes in patients with COVID and there’s very little data to support this.

“We did recommend that NSAIDs be held in the hospitalized patient and that wasn’t because of the COVID-19 issue, it really was just medical practice, and we didn’t want to confound the care of these really sick patients with potential toxicities from NSAIDs. But as far as routine rheumatological care in your outpatients, we did not recommend that nonsteroidals be stopped if they were tolerated.”

One part of the guidance that might already need revision is the recommendation on the continued use of hydroxychloroquine in patients who develop COVID-19.

“Our guidance document says it’s OK; we were all in very strong agreement to continue hydroxychloroquine in our patients with COVID-19 because at that point, just a couple of weeks ago, we thought it was part of the potential treatment,” Karen Costenbader, MD, MPH, of Brigham and Women’s Hospital, said during the town hall meeting.

“Now the pendulum has swung the other way, and we’re worried about maybe we shouldn’t be continuing it because COVID-19 patients will be getting many other medications,” Dr. Costenbader said, and these may affect the QT-interval. “They will not be getting azithromycin because the pendulum swung the other way on that one too, but definitely on many other medications when they are sick.”

Potentially, she added, “if the rheumatic disease is under good control the inpatient physicians could decide whether they should continue [hydroxychloroquine] or not. If the COVID-19 is a mild disease, I would say we probably could continue in accordance with what we put in the document, but we will have to revisit this as well.”
 

Guidance is a ‘living document’

“We will be providing updates to the Clinical Guidance Document as the need arises,” Dr. Gravallese emphasized. While the general recommendations are unlikely to change very much, “the task force will be interested in seeing the results of all new data, but the results of randomized, clinical trials will be particularly important as they become available,” she said. In particular, randomized, controlled trials of glucocorticoids and IL-6 receptor blockade for use in COVID-19 will be of great importance.

“In this initial document, we could not take on all of the medical scenarios our members will face. For example, we could not take on recommendations for the pediatric population as this group of patients has a very different response than adults to the SARS-CoV-2 virus,” Dr. Gravallese acknowledged. The plan is to provide guidance for that group of patients soon.

In addition, the ACR Executive Committee has appointed a Practice and Advocacy Task Force that will “address issues rheumatologists face on the practice side, including advice regarding how to effectively use telemedicine, address the frequency and safety of infusions, determine urgent versus nonurgent issues that would or would not require face-to-face visits, and help with financial challenges.”

The American College of Rheumatology supported the guidance-development process. Dr. Mikuls, Dr. Weinblatt, Dr. Cohen, and Dr. Costenbader each disclosed research support or consultancies with multiple pharmaceutical companies. Dr. Gravallese had no disclosures.

SOURCE: Mikuls TR et al. Arthritis Rheumatol. 2020 Apr 29. doi: 10.1002/art.41301.

LONDON – Advances in cell- and gene-based research are paving the way towards the possibility of a cure for the rare inherited skin disorder, recessive dystrophic epidermolysis bullosa (RDEB), several experts said at the first EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Sara Freeman/MDedge News

“I think there is a palpable sense that we are close to some breakthroughs for EB,” which may include “a cure for this intractable disease,” said Jouni Uitto, MD, PhD, in welcoming delegates to the meeting, held in January 2020.

Dr. Uitto, professor of dermatology and cutaneous biology, and biochemistry and molecular biology, at Sidney Kimmel Medical College, Philadelphia, said that the “breadth of academia-based basic science has been tremendous over the past 3 decades. We can now identify 21 different genes harboring mutations associated with different EB phenotypes, and we have a pretty good understanding how those mutations actually explain the phenotypic spectrum of different forms of EB.”

Importantly, “there are now perhaps as many as a dozen different clinical trials that are in the early stages of trying to find a permanent cure for this disease,” Dr. Uitto said, with some that are looking at fixing the underlying defect once and for all, or at the very least, counteracting subsequent complications. “The spectrum varies from attempting to enhance wound healing to gene repair, gene replacement, protein replacement therapies, cell-based therapies. There is a whole spectrum of often complementary approaches that we believe will lead to a cure and treatment for this disease. We look forward to developing therapies which will be helpful to the benefit of all the patients with EB,” said Dr. Uitto, who is also chair of the department of dermatology and cutaneous biology at Sidney Kimmel Medical College.
 

EB research is gathering ‘momentum’

John McGrath, MD, professor of molecular dermatology, King’s College, London, chaired a session on the latest in cell manipulation research and made the following comment: “A few years ago, we were making progress, but we were chatting about a lot of the same things; but now, suddenly there seems to be momentum, re-energy, rediscovery, real progress.”

Dr. McGrath noted that gene and cell research, and preclinical development, were culminating in clinical trials and potentially products that could change the way clinicians thought about managing patients with EB. “That prospect of getting closer and closer to real treatments, and maybe even a cure” is becoming more of a reality, he said.

Dr. McGrath is also head of the genetic skin disease group at King’s College London, and an honorary consultant dermatologist at St. John’s Institute of Dermatology, part of the Guy’s and St. Thomas’ NHS Foundation Trust in London. He has been a principal investigator for clinical trials of fibroblast cell therapy and allogeneic intravenous mesenchymal stromal cells (MSCs) therapy.

“It has been a joy for me to see the benefits of those clinical trials. There is nothing like it as an investigator when you see an intervention make a difference to a patient,” Dr. McGrath said. “For me, it was just a real eye opener when I saw the skin changes in a child that received intravenous allogeneic MSCs. The skin changed dramatically, it went from red and inflamed to calm and pink, [giving a] first glimpse into something that might be reversible, treatable, not just papering over the cracks.”
 

Correcting the genetic defect

The most severe form of RDEB is caused by mutations in COL7A1, the gene for collagen type 7 (COL7), the major connective component of the skin, anchoring the epidermis to the dermis. Its absence results in skin that can be so fragile it has been likened to the wings of a butterfly and results in severe blistering after very little trauma.

There is a lot of research on how to correct the underlying genetic defect, either by replacing COL7A1 entirely, repairing the gene, or editing the gene so that COL 7 can be produced in situ and prevent the formation of wounds and heal those that might already be present.

“The excitement is obvious,” said Jakub Tolar, MD, PhD, professor in the department of pediatrics, blood and marrow transplantation, and dean of the University of Minnesota Medical School, Minneapolis, who chaired a session on gene and gene manipulation therapies. “If one can go and correct that information, it follows that everything else is going to be okay,” he said. “Only it’s not. I think that it’s pretty clear that more than gene correction is needed.”

Some of the approaches to replace the faulty gene discussed at the meeting involved taking skin biopsy samples from a healthy area of skin from a patient with RDEB, isolating specific skin cells (fibroblasts, keratinocytes, or both), transferring a healthy copy of the COL7A1 gene into those cells – then expanding the population to form sheets of cells that can be grafted onto the wounds of the same patient.

Clinical trials of gene therapy for RDEB

Clinical trials with these novel gene-corrected, tissue-engineered grafts have already started, including EBGraft, a phase 1/2 open, nonrandomized, proof-of-concept trial using genetically corrected sheets of fibroblasts and keratinocytes, conducted by Alain Hovnanian, MD, PhD, Necker-Enfants Malades Hospital in Paris, and associates.

Then there is the phase 3 VIITAL trial being conducted at Stanford (Calif.) University by Jean Tang, MD, PhD, and colleagues. Recruitment in this open trial, which will enroll 10-15 patients with RDEB, has just started. The aim of the study is to investigate the efficacy and safety of EB-101, an autologous cell therapy that corrects COL7A1 in keratinocytes.

Positive findings from a phase 1/2 study with EB-101 were presented in a poster at the meeting by Emily Gorell, DO, a postdoctoral medical fellow in dermatology, at Stanford University and her associates. The trial included seven patients with RDEB who were treated and followed for 3 to 6 years. Data from that study showed that there were no serious adverse events and 95% of patients’ wounds that were treated (36/38) were healed by at least 50%, based on an Investigator Global Assessment at 6 months. In comparison, none of the untreated wounds had healed by that time point. “There was evidence of C7 [collagen 7] restoration at 2 years in two participants,” and wound healing was associated with both reduced pain and itch, the investigators wrote in the poster.

Another approach to this so-called ‘ex-vivo’ gene therapy is to take the patient’s cells via a small skin biopsy, genetically modify them, expand the population of these modified cells, and then inject them back into the patient. This approach was described by Peter Marinkovich, MD, of the department of dermatology at Stanford University, during an oral presentation and in a poster at the meeting.

Dr. Marinkovich discussed the results of an ongoing phase 1/2 study in which six subjects with RDEB – five adults and one child ­­– were treated intradermally with genetically modified fibroblasts in a preparation currently known as FCX-007.

“Before we had to graft the cells, take the patients into the OR [operating room], with the risks of general anesthesia, but here we don’t have to take the patients to the OR, we just take them into the hospital for a day, inject their wounds and then send them on their way,” Dr. Marinkovich said. Interim findings show that the patients have tolerated the therapy very well up to 52 weeks, he noted.

A greater percentage of wounds were healed by more than 50% following treatment with FCX-007 than those left untreated at weeks 4 (80% versus 20%), 12 (90% versus 44%), 25 (75% versus 50%), and 52 (83% versus 33%).

These results have been used to inform the design of the upcoming phase 3 study, DEFI-RDEB. The multicenter intrapatient randomized, controlled, open-label study is evaluating FCX-007 in the treatment of persistent nonhealing wounds in about 20 people with RDEB.
 

The promise of ‘off-the-shelf’ topical gene therapy

Another study Dr. Marinkovich is involved with is a phase 1/2 study of beremagene geperpavec (B-VEC), an “in-vivo” gene therapy. B-VEC is a topically administered therapy containing a replication-deficient, nonintegrating viral vector that contains two functional COL7A1 genes. The concept is that, when applied directly onto the skin, the virus gets into the skin and carries with it the healthy gene copies; these get taken up by the skin cells, which then produce COL7.

Initially, two patients with generalized severe RDEB were studied. B-VEC was applied to one of two wounds and a placebo to the other wound in each patient. Another four patients were then enrolled and studied for 3 months. Nine of 10 wounds closed completely after initial administration of B-VEC, with an average time to 100% wound closure of 17.4 days. The average duration of wound closure has been 113 days so far.
 

“One chronic wound that was originally open for over 4 years closed completely following B-VEC readministration. The wound has remained closed for 100 days,” Dr. Marinkovich and associates reported in a poster at the meeting. A postimaging study showed that COL7 was being produced from 48 hours to up to 90 days later.

“I’m really excited about this type of therapy,” Dr. Marinkovich said during an oral presentation. Unlike the ex-vivo gene therapy approach, where each patient’s cells have to be taken by a biopsy, altered, engineered, and expanded, which takes specialized facilities that can vary by country and location, this in-vivo gene therapy can be considered an “off-the shelf” treatment that can be shipped all over the world and could reach many patients. “It’s another weapon in our armamentarium against this deadly disease that we are all fighting against together,” Dr. Marinkovich added.

EBGRAFT is supported by Cure EB. The VIITAL trial is sponsored by Abeona Therapeutics. The phase 1/2 trials of EB-101 were funded by grants from the National Institutes of Health, EB Research Partnership, EM Medical Research Foundation, and Abeona Therapeutics. The FCX-007 phase 1/2 study was supported by Fibrocell Technologies. The upcoming phase 3 will be funded by Fibrocell Technologies in collaboration with Castle Creek Pharmaceuticals. The B-VEC study is supported by Krystal Biotech.

Dr. Uitto and Dr. McGrath had no potential conflicts of interest to report. Dr. Tolar has received funding from the National Institutes of Health, various EB charities and the Richard M. Schulze Family Foundation (RMSFF). He disclosed receiving honoraria or consultation fees from Ticeba/RHEACELL GmbH and Taiga Biosciences. Dr. Marinkovich disclosed being an investigator working on RDEB-related research projects in collaboration with Krystal Biotech, Fibrocell Technologies, Abeona Therapeutics, and Wings (formerly ProQR).

SOURCES: Gorell E et al. EB 2020, Poster 124; Marinkovich MP et al. EB 2020, Poster 123; Marinkovich MP et al. EB 2020, Poster 52.

LONDON – Advances in cell- and gene-based research are paving the way towards the possibility of a cure for the rare inherited skin disorder, recessive dystrophic epidermolysis bullosa (RDEB), several experts said at the first EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Sara Freeman/MDedge News

“I think there is a palpable sense that we are close to some breakthroughs for EB,” which may include “a cure for this intractable disease,” said Jouni Uitto, MD, PhD, in welcoming delegates to the meeting, held in January 2020.

Dr. Uitto, professor of dermatology and cutaneous biology, and biochemistry and molecular biology, at Sidney Kimmel Medical College, Philadelphia, said that the “breadth of academia-based basic science has been tremendous over the past 3 decades. We can now identify 21 different genes harboring mutations associated with different EB phenotypes, and we have a pretty good understanding how those mutations actually explain the phenotypic spectrum of different forms of EB.”

Importantly, “there are now perhaps as many as a dozen different clinical trials that are in the early stages of trying to find a permanent cure for this disease,” Dr. Uitto said, with some that are looking at fixing the underlying defect once and for all, or at the very least, counteracting subsequent complications. “The spectrum varies from attempting to enhance wound healing to gene repair, gene replacement, protein replacement therapies, cell-based therapies. There is a whole spectrum of often complementary approaches that we believe will lead to a cure and treatment for this disease. We look forward to developing therapies which will be helpful to the benefit of all the patients with EB,” said Dr. Uitto, who is also chair of the department of dermatology and cutaneous biology at Sidney Kimmel Medical College.
 

EB research is gathering ‘momentum’

John McGrath, MD, professor of molecular dermatology, King’s College, London, chaired a session on the latest in cell manipulation research and made the following comment: “A few years ago, we were making progress, but we were chatting about a lot of the same things; but now, suddenly there seems to be momentum, re-energy, rediscovery, real progress.”

Dr. McGrath noted that gene and cell research, and preclinical development, were culminating in clinical trials and potentially products that could change the way clinicians thought about managing patients with EB. “That prospect of getting closer and closer to real treatments, and maybe even a cure” is becoming more of a reality, he said.

Dr. McGrath is also head of the genetic skin disease group at King’s College London, and an honorary consultant dermatologist at St. John’s Institute of Dermatology, part of the Guy’s and St. Thomas’ NHS Foundation Trust in London. He has been a principal investigator for clinical trials of fibroblast cell therapy and allogeneic intravenous mesenchymal stromal cells (MSCs) therapy.

“It has been a joy for me to see the benefits of those clinical trials. There is nothing like it as an investigator when you see an intervention make a difference to a patient,” Dr. McGrath said. “For me, it was just a real eye opener when I saw the skin changes in a child that received intravenous allogeneic MSCs. The skin changed dramatically, it went from red and inflamed to calm and pink, [giving a] first glimpse into something that might be reversible, treatable, not just papering over the cracks.”
 

Correcting the genetic defect

The most severe form of RDEB is caused by mutations in COL7A1, the gene for collagen type 7 (COL7), the major connective component of the skin, anchoring the epidermis to the dermis. Its absence results in skin that can be so fragile it has been likened to the wings of a butterfly and results in severe blistering after very little trauma.

There is a lot of research on how to correct the underlying genetic defect, either by replacing COL7A1 entirely, repairing the gene, or editing the gene so that COL 7 can be produced in situ and prevent the formation of wounds and heal those that might already be present.

“The excitement is obvious,” said Jakub Tolar, MD, PhD, professor in the department of pediatrics, blood and marrow transplantation, and dean of the University of Minnesota Medical School, Minneapolis, who chaired a session on gene and gene manipulation therapies. “If one can go and correct that information, it follows that everything else is going to be okay,” he said. “Only it’s not. I think that it’s pretty clear that more than gene correction is needed.”

Some of the approaches to replace the faulty gene discussed at the meeting involved taking skin biopsy samples from a healthy area of skin from a patient with RDEB, isolating specific skin cells (fibroblasts, keratinocytes, or both), transferring a healthy copy of the COL7A1 gene into those cells – then expanding the population to form sheets of cells that can be grafted onto the wounds of the same patient.

Clinical trials of gene therapy for RDEB

Clinical trials with these novel gene-corrected, tissue-engineered grafts have already started, including EBGraft, a phase 1/2 open, nonrandomized, proof-of-concept trial using genetically corrected sheets of fibroblasts and keratinocytes, conducted by Alain Hovnanian, MD, PhD, Necker-Enfants Malades Hospital in Paris, and associates.

Then there is the phase 3 VIITAL trial being conducted at Stanford (Calif.) University by Jean Tang, MD, PhD, and colleagues. Recruitment in this open trial, which will enroll 10-15 patients with RDEB, has just started. The aim of the study is to investigate the efficacy and safety of EB-101, an autologous cell therapy that corrects COL7A1 in keratinocytes.

Positive findings from a phase 1/2 study with EB-101 were presented in a poster at the meeting by Emily Gorell, DO, a postdoctoral medical fellow in dermatology, at Stanford University and her associates. The trial included seven patients with RDEB who were treated and followed for 3 to 6 years. Data from that study showed that there were no serious adverse events and 95% of patients’ wounds that were treated (36/38) were healed by at least 50%, based on an Investigator Global Assessment at 6 months. In comparison, none of the untreated wounds had healed by that time point. “There was evidence of C7 [collagen 7] restoration at 2 years in two participants,” and wound healing was associated with both reduced pain and itch, the investigators wrote in the poster.

Another approach to this so-called ‘ex-vivo’ gene therapy is to take the patient’s cells via a small skin biopsy, genetically modify them, expand the population of these modified cells, and then inject them back into the patient. This approach was described by Peter Marinkovich, MD, of the department of dermatology at Stanford University, during an oral presentation and in a poster at the meeting.

Dr. Marinkovich discussed the results of an ongoing phase 1/2 study in which six subjects with RDEB – five adults and one child ­­– were treated intradermally with genetically modified fibroblasts in a preparation currently known as FCX-007.

“Before we had to graft the cells, take the patients into the OR [operating room], with the risks of general anesthesia, but here we don’t have to take the patients to the OR, we just take them into the hospital for a day, inject their wounds and then send them on their way,” Dr. Marinkovich said. Interim findings show that the patients have tolerated the therapy very well up to 52 weeks, he noted.

A greater percentage of wounds were healed by more than 50% following treatment with FCX-007 than those left untreated at weeks 4 (80% versus 20%), 12 (90% versus 44%), 25 (75% versus 50%), and 52 (83% versus 33%).

These results have been used to inform the design of the upcoming phase 3 study, DEFI-RDEB. The multicenter intrapatient randomized, controlled, open-label study is evaluating FCX-007 in the treatment of persistent nonhealing wounds in about 20 people with RDEB.
 

The promise of ‘off-the-shelf’ topical gene therapy

Another study Dr. Marinkovich is involved with is a phase 1/2 study of beremagene geperpavec (B-VEC), an “in-vivo” gene therapy. B-VEC is a topically administered therapy containing a replication-deficient, nonintegrating viral vector that contains two functional COL7A1 genes. The concept is that, when applied directly onto the skin, the virus gets into the skin and carries with it the healthy gene copies; these get taken up by the skin cells, which then produce COL7.

Initially, two patients with generalized severe RDEB were studied. B-VEC was applied to one of two wounds and a placebo to the other wound in each patient. Another four patients were then enrolled and studied for 3 months. Nine of 10 wounds closed completely after initial administration of B-VEC, with an average time to 100% wound closure of 17.4 days. The average duration of wound closure has been 113 days so far.
 

“One chronic wound that was originally open for over 4 years closed completely following B-VEC readministration. The wound has remained closed for 100 days,” Dr. Marinkovich and associates reported in a poster at the meeting. A postimaging study showed that COL7 was being produced from 48 hours to up to 90 days later.

“I’m really excited about this type of therapy,” Dr. Marinkovich said during an oral presentation. Unlike the ex-vivo gene therapy approach, where each patient’s cells have to be taken by a biopsy, altered, engineered, and expanded, which takes specialized facilities that can vary by country and location, this in-vivo gene therapy can be considered an “off-the shelf” treatment that can be shipped all over the world and could reach many patients. “It’s another weapon in our armamentarium against this deadly disease that we are all fighting against together,” Dr. Marinkovich added.

EBGRAFT is supported by Cure EB. The VIITAL trial is sponsored by Abeona Therapeutics. The phase 1/2 trials of EB-101 were funded by grants from the National Institutes of Health, EB Research Partnership, EM Medical Research Foundation, and Abeona Therapeutics. The FCX-007 phase 1/2 study was supported by Fibrocell Technologies. The upcoming phase 3 will be funded by Fibrocell Technologies in collaboration with Castle Creek Pharmaceuticals. The B-VEC study is supported by Krystal Biotech.

Dr. Uitto and Dr. McGrath had no potential conflicts of interest to report. Dr. Tolar has received funding from the National Institutes of Health, various EB charities and the Richard M. Schulze Family Foundation (RMSFF). He disclosed receiving honoraria or consultation fees from Ticeba/RHEACELL GmbH and Taiga Biosciences. Dr. Marinkovich disclosed being an investigator working on RDEB-related research projects in collaboration with Krystal Biotech, Fibrocell Technologies, Abeona Therapeutics, and Wings (formerly ProQR).

SOURCES: Gorell E et al. EB 2020, Poster 124; Marinkovich MP et al. EB 2020, Poster 123; Marinkovich MP et al. EB 2020, Poster 52.

LONDON – Advances in cell- and gene-based research are paving the way towards the possibility of a cure for the rare inherited skin disorder, recessive dystrophic epidermolysis bullosa (RDEB), several experts said at the first EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Sara Freeman/MDedge News

“I think there is a palpable sense that we are close to some breakthroughs for EB,” which may include “a cure for this intractable disease,” said Jouni Uitto, MD, PhD, in welcoming delegates to the meeting, held in January 2020.

Dr. Uitto, professor of dermatology and cutaneous biology, and biochemistry and molecular biology, at Sidney Kimmel Medical College, Philadelphia, said that the “breadth of academia-based basic science has been tremendous over the past 3 decades. We can now identify 21 different genes harboring mutations associated with different EB phenotypes, and we have a pretty good understanding how those mutations actually explain the phenotypic spectrum of different forms of EB.”

Importantly, “there are now perhaps as many as a dozen different clinical trials that are in the early stages of trying to find a permanent cure for this disease,” Dr. Uitto said, with some that are looking at fixing the underlying defect once and for all, or at the very least, counteracting subsequent complications. “The spectrum varies from attempting to enhance wound healing to gene repair, gene replacement, protein replacement therapies, cell-based therapies. There is a whole spectrum of often complementary approaches that we believe will lead to a cure and treatment for this disease. We look forward to developing therapies which will be helpful to the benefit of all the patients with EB,” said Dr. Uitto, who is also chair of the department of dermatology and cutaneous biology at Sidney Kimmel Medical College.
 

EB research is gathering ‘momentum’

John McGrath, MD, professor of molecular dermatology, King’s College, London, chaired a session on the latest in cell manipulation research and made the following comment: “A few years ago, we were making progress, but we were chatting about a lot of the same things; but now, suddenly there seems to be momentum, re-energy, rediscovery, real progress.”

Dr. McGrath noted that gene and cell research, and preclinical development, were culminating in clinical trials and potentially products that could change the way clinicians thought about managing patients with EB. “That prospect of getting closer and closer to real treatments, and maybe even a cure” is becoming more of a reality, he said.

Dr. McGrath is also head of the genetic skin disease group at King’s College London, and an honorary consultant dermatologist at St. John’s Institute of Dermatology, part of the Guy’s and St. Thomas’ NHS Foundation Trust in London. He has been a principal investigator for clinical trials of fibroblast cell therapy and allogeneic intravenous mesenchymal stromal cells (MSCs) therapy.

“It has been a joy for me to see the benefits of those clinical trials. There is nothing like it as an investigator when you see an intervention make a difference to a patient,” Dr. McGrath said. “For me, it was just a real eye opener when I saw the skin changes in a child that received intravenous allogeneic MSCs. The skin changed dramatically, it went from red and inflamed to calm and pink, [giving a] first glimpse into something that might be reversible, treatable, not just papering over the cracks.”
 

Correcting the genetic defect

The most severe form of RDEB is caused by mutations in COL7A1, the gene for collagen type 7 (COL7), the major connective component of the skin, anchoring the epidermis to the dermis. Its absence results in skin that can be so fragile it has been likened to the wings of a butterfly and results in severe blistering after very little trauma.

There is a lot of research on how to correct the underlying genetic defect, either by replacing COL7A1 entirely, repairing the gene, or editing the gene so that COL 7 can be produced in situ and prevent the formation of wounds and heal those that might already be present.

“The excitement is obvious,” said Jakub Tolar, MD, PhD, professor in the department of pediatrics, blood and marrow transplantation, and dean of the University of Minnesota Medical School, Minneapolis, who chaired a session on gene and gene manipulation therapies. “If one can go and correct that information, it follows that everything else is going to be okay,” he said. “Only it’s not. I think that it’s pretty clear that more than gene correction is needed.”

Some of the approaches to replace the faulty gene discussed at the meeting involved taking skin biopsy samples from a healthy area of skin from a patient with RDEB, isolating specific skin cells (fibroblasts, keratinocytes, or both), transferring a healthy copy of the COL7A1 gene into those cells – then expanding the population to form sheets of cells that can be grafted onto the wounds of the same patient.

Clinical trials of gene therapy for RDEB

Clinical trials with these novel gene-corrected, tissue-engineered grafts have already started, including EBGraft, a phase 1/2 open, nonrandomized, proof-of-concept trial using genetically corrected sheets of fibroblasts and keratinocytes, conducted by Alain Hovnanian, MD, PhD, Necker-Enfants Malades Hospital in Paris, and associates.

Then there is the phase 3 VIITAL trial being conducted at Stanford (Calif.) University by Jean Tang, MD, PhD, and colleagues. Recruitment in this open trial, which will enroll 10-15 patients with RDEB, has just started. The aim of the study is to investigate the efficacy and safety of EB-101, an autologous cell therapy that corrects COL7A1 in keratinocytes.

Positive findings from a phase 1/2 study with EB-101 were presented in a poster at the meeting by Emily Gorell, DO, a postdoctoral medical fellow in dermatology, at Stanford University and her associates. The trial included seven patients with RDEB who were treated and followed for 3 to 6 years. Data from that study showed that there were no serious adverse events and 95% of patients’ wounds that were treated (36/38) were healed by at least 50%, based on an Investigator Global Assessment at 6 months. In comparison, none of the untreated wounds had healed by that time point. “There was evidence of C7 [collagen 7] restoration at 2 years in two participants,” and wound healing was associated with both reduced pain and itch, the investigators wrote in the poster.

Another approach to this so-called ‘ex-vivo’ gene therapy is to take the patient’s cells via a small skin biopsy, genetically modify them, expand the population of these modified cells, and then inject them back into the patient. This approach was described by Peter Marinkovich, MD, of the department of dermatology at Stanford University, during an oral presentation and in a poster at the meeting.

Dr. Marinkovich discussed the results of an ongoing phase 1/2 study in which six subjects with RDEB – five adults and one child ­­– were treated intradermally with genetically modified fibroblasts in a preparation currently known as FCX-007.

“Before we had to graft the cells, take the patients into the OR [operating room], with the risks of general anesthesia, but here we don’t have to take the patients to the OR, we just take them into the hospital for a day, inject their wounds and then send them on their way,” Dr. Marinkovich said. Interim findings show that the patients have tolerated the therapy very well up to 52 weeks, he noted.

A greater percentage of wounds were healed by more than 50% following treatment with FCX-007 than those left untreated at weeks 4 (80% versus 20%), 12 (90% versus 44%), 25 (75% versus 50%), and 52 (83% versus 33%).

These results have been used to inform the design of the upcoming phase 3 study, DEFI-RDEB. The multicenter intrapatient randomized, controlled, open-label study is evaluating FCX-007 in the treatment of persistent nonhealing wounds in about 20 people with RDEB.
 

The promise of ‘off-the-shelf’ topical gene therapy

Another study Dr. Marinkovich is involved with is a phase 1/2 study of beremagene geperpavec (B-VEC), an “in-vivo” gene therapy. B-VEC is a topically administered therapy containing a replication-deficient, nonintegrating viral vector that contains two functional COL7A1 genes. The concept is that, when applied directly onto the skin, the virus gets into the skin and carries with it the healthy gene copies; these get taken up by the skin cells, which then produce COL7.

Initially, two patients with generalized severe RDEB were studied. B-VEC was applied to one of two wounds and a placebo to the other wound in each patient. Another four patients were then enrolled and studied for 3 months. Nine of 10 wounds closed completely after initial administration of B-VEC, with an average time to 100% wound closure of 17.4 days. The average duration of wound closure has been 113 days so far.
 

“One chronic wound that was originally open for over 4 years closed completely following B-VEC readministration. The wound has remained closed for 100 days,” Dr. Marinkovich and associates reported in a poster at the meeting. A postimaging study showed that COL7 was being produced from 48 hours to up to 90 days later.

“I’m really excited about this type of therapy,” Dr. Marinkovich said during an oral presentation. Unlike the ex-vivo gene therapy approach, where each patient’s cells have to be taken by a biopsy, altered, engineered, and expanded, which takes specialized facilities that can vary by country and location, this in-vivo gene therapy can be considered an “off-the shelf” treatment that can be shipped all over the world and could reach many patients. “It’s another weapon in our armamentarium against this deadly disease that we are all fighting against together,” Dr. Marinkovich added.

EBGRAFT is supported by Cure EB. The VIITAL trial is sponsored by Abeona Therapeutics. The phase 1/2 trials of EB-101 were funded by grants from the National Institutes of Health, EB Research Partnership, EM Medical Research Foundation, and Abeona Therapeutics. The FCX-007 phase 1/2 study was supported by Fibrocell Technologies. The upcoming phase 3 will be funded by Fibrocell Technologies in collaboration with Castle Creek Pharmaceuticals. The B-VEC study is supported by Krystal Biotech.

Dr. Uitto and Dr. McGrath had no potential conflicts of interest to report. Dr. Tolar has received funding from the National Institutes of Health, various EB charities and the Richard M. Schulze Family Foundation (RMSFF). He disclosed receiving honoraria or consultation fees from Ticeba/RHEACELL GmbH and Taiga Biosciences. Dr. Marinkovich disclosed being an investigator working on RDEB-related research projects in collaboration with Krystal Biotech, Fibrocell Technologies, Abeona Therapeutics, and Wings (formerly ProQR).

SOURCES: Gorell E et al. EB 2020, Poster 124; Marinkovich MP et al. EB 2020, Poster 123; Marinkovich MP et al. EB 2020, Poster 52.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

With health care systems becoming increasingly stretched as the COVID-19 pandemic sweeps the globe, the European Society for Medical Oncology (ESMO) has produced practical recommendations for prioritizing the management of cancer patients, including those with gynecologic cancers.

ESMO’s guidelines for cervical, endometrial, and epithelial ovarian cancer delineate which patients should be prioritized for treatment in the face of reduced resources and despite the risk of SARS-CoV-2 infection.

“Many European countries have already sorted their own guidelines, either nationally or through their own societies,” said Jonathan Ledermann, MD, a professor of medical oncology at the University College London Cancer Institute who was involved in developing ESMO’s recommendations for gynecologic cancers.

Dr. Ledermann noted that the British Gynaecological Cancer Society, for example, has published guidance on COVID-19 that reflects U.K. practice.

“ESMO obviously feels a responsibility, from the European perspective, to give some guidance to their membership about the COVID-19 situation in the same way that they would put out guidelines if a new drug became available,” Dr. Ledermann said.
 

Prioritizing care

All of the ESMO COVID-19 guidelines group cancer patients into high-, medium-, or low-priority categories to ensure that patients who may need the most care will be seen first as hospital services become affected by the pandemic.

Those in the high-priority category are patients whose condition is either immediately life-threatening or clinically unstable or who may benefit greatly from intervention. Those in the low-priority group are patients who may be stable enough to have treatment delayed while the COVID-19 pandemic is ongoing or for whom the benefit of the intervention is low, compared with the risks of SARS-CoV-2 infection.

Those in the medium-priority group are patients whose treatment is noncritical, but for whom delaying treatment for more than 6 weeks could potentially impact the overall outcome or care of the patient.

For all gynecologic cancers covered, the guidelines stress that decisions made by the multidisciplinary team need to be documented, taking the patient’s condition into account, assessing who may be the most vulnerable, and considering the available resources.
 

High-priority visits

Examples of patients with cervical cancer who are a high priority for outpatient visits, according to the guidelines, include patients who have acute abdominal symptoms, renal obstruction, or complications after surgery or radiotherapy. Persistent and severe symptomatic pelvic or vaginal bleeding is another reason to be categorized as high priority for an outpatient visit, alongside anuria or symptoms of deep vein thrombosis.

New patients with histologically confirmed cervical changes should also be seen as a high priority to stage their cancer, but the guidelines stress that any blood tests and imaging should be done as close to the patient’s home as possible.

Similar recommendations are made for women with endometrial cancer, with those who have potentially unstable symptoms, severe bleeding from their tumors, and signs of venous thromboembolism or anuria being at the highest priority for outpatient visits.

Women with potentially unstable epithelial ovarian cancer – who have acute abdominal pain, intestinal obstruction, or complications after surgery – are also a high priority for an outpatient visit, as are new patients who have symptomatic ascites, pleural effusion, or intestinal obstruction.
 

Applying guidelines in practice

Knowing that ESMO and other organizations have carefully considered the management of cancer patients specifically in relation to COVID-19 could offer oncologists “a feeling of support and some security when they make difficult decisions,” Dr. Ledermann said.

“With all guidelines, particularly in this sort of situation, we have to be very careful in terms of their interpretation, because what fits one country may not fit another, and what fits one hospital may not necessarily fit another. So they should be taken as guidance rather than prescriptive documents,” Dr. Ledermann said.

As vice president of the European Society for Gynecologic Oncology, Dr. Ledermann noted that ESGO has taken a slightly different approach than ESMO. ESGO decided to collect and post links to existing COVID-19 resources on its website rather than create its own specific recommendations.

ESGO is also producing an expert webinar series, which has, so far, covered the management of ovarian and uterine cancers, giving clinicians the chance to learn from those who have experienced dramatic changes to their services during the COVID-19 pandemic.

Dr. Ledermann has no conflicts of interest.

With health care systems becoming increasingly stretched as the COVID-19 pandemic sweeps the globe, the European Society for Medical Oncology (ESMO) has produced practical recommendations for prioritizing the management of cancer patients, including those with gynecologic cancers.

ESMO’s guidelines for cervical, endometrial, and epithelial ovarian cancer delineate which patients should be prioritized for treatment in the face of reduced resources and despite the risk of SARS-CoV-2 infection.

“Many European countries have already sorted their own guidelines, either nationally or through their own societies,” said Jonathan Ledermann, MD, a professor of medical oncology at the University College London Cancer Institute who was involved in developing ESMO’s recommendations for gynecologic cancers.

Dr. Ledermann noted that the British Gynaecological Cancer Society, for example, has published guidance on COVID-19 that reflects U.K. practice.

“ESMO obviously feels a responsibility, from the European perspective, to give some guidance to their membership about the COVID-19 situation in the same way that they would put out guidelines if a new drug became available,” Dr. Ledermann said.
 

Prioritizing care

All of the ESMO COVID-19 guidelines group cancer patients into high-, medium-, or low-priority categories to ensure that patients who may need the most care will be seen first as hospital services become affected by the pandemic.

Those in the high-priority category are patients whose condition is either immediately life-threatening or clinically unstable or who may benefit greatly from intervention. Those in the low-priority group are patients who may be stable enough to have treatment delayed while the COVID-19 pandemic is ongoing or for whom the benefit of the intervention is low, compared with the risks of SARS-CoV-2 infection.

Those in the medium-priority group are patients whose treatment is noncritical, but for whom delaying treatment for more than 6 weeks could potentially impact the overall outcome or care of the patient.

For all gynecologic cancers covered, the guidelines stress that decisions made by the multidisciplinary team need to be documented, taking the patient’s condition into account, assessing who may be the most vulnerable, and considering the available resources.
 

High-priority visits

Examples of patients with cervical cancer who are a high priority for outpatient visits, according to the guidelines, include patients who have acute abdominal symptoms, renal obstruction, or complications after surgery or radiotherapy. Persistent and severe symptomatic pelvic or vaginal bleeding is another reason to be categorized as high priority for an outpatient visit, alongside anuria or symptoms of deep vein thrombosis.

New patients with histologically confirmed cervical changes should also be seen as a high priority to stage their cancer, but the guidelines stress that any blood tests and imaging should be done as close to the patient’s home as possible.

Similar recommendations are made for women with endometrial cancer, with those who have potentially unstable symptoms, severe bleeding from their tumors, and signs of venous thromboembolism or anuria being at the highest priority for outpatient visits.

Women with potentially unstable epithelial ovarian cancer – who have acute abdominal pain, intestinal obstruction, or complications after surgery – are also a high priority for an outpatient visit, as are new patients who have symptomatic ascites, pleural effusion, or intestinal obstruction.
 

Applying guidelines in practice

Knowing that ESMO and other organizations have carefully considered the management of cancer patients specifically in relation to COVID-19 could offer oncologists “a feeling of support and some security when they make difficult decisions,” Dr. Ledermann said.

“With all guidelines, particularly in this sort of situation, we have to be very careful in terms of their interpretation, because what fits one country may not fit another, and what fits one hospital may not necessarily fit another. So they should be taken as guidance rather than prescriptive documents,” Dr. Ledermann said.

As vice president of the European Society for Gynecologic Oncology, Dr. Ledermann noted that ESGO has taken a slightly different approach than ESMO. ESGO decided to collect and post links to existing COVID-19 resources on its website rather than create its own specific recommendations.

ESGO is also producing an expert webinar series, which has, so far, covered the management of ovarian and uterine cancers, giving clinicians the chance to learn from those who have experienced dramatic changes to their services during the COVID-19 pandemic.

Dr. Ledermann has no conflicts of interest.

With health care systems becoming increasingly stretched as the COVID-19 pandemic sweeps the globe, the European Society for Medical Oncology (ESMO) has produced practical recommendations for prioritizing the management of cancer patients, including those with gynecologic cancers.

ESMO’s guidelines for cervical, endometrial, and epithelial ovarian cancer delineate which patients should be prioritized for treatment in the face of reduced resources and despite the risk of SARS-CoV-2 infection.

“Many European countries have already sorted their own guidelines, either nationally or through their own societies,” said Jonathan Ledermann, MD, a professor of medical oncology at the University College London Cancer Institute who was involved in developing ESMO’s recommendations for gynecologic cancers.

Dr. Ledermann noted that the British Gynaecological Cancer Society, for example, has published guidance on COVID-19 that reflects U.K. practice.

“ESMO obviously feels a responsibility, from the European perspective, to give some guidance to their membership about the COVID-19 situation in the same way that they would put out guidelines if a new drug became available,” Dr. Ledermann said.
 

Prioritizing care

All of the ESMO COVID-19 guidelines group cancer patients into high-, medium-, or low-priority categories to ensure that patients who may need the most care will be seen first as hospital services become affected by the pandemic.

Those in the high-priority category are patients whose condition is either immediately life-threatening or clinically unstable or who may benefit greatly from intervention. Those in the low-priority group are patients who may be stable enough to have treatment delayed while the COVID-19 pandemic is ongoing or for whom the benefit of the intervention is low, compared with the risks of SARS-CoV-2 infection.

Those in the medium-priority group are patients whose treatment is noncritical, but for whom delaying treatment for more than 6 weeks could potentially impact the overall outcome or care of the patient.

For all gynecologic cancers covered, the guidelines stress that decisions made by the multidisciplinary team need to be documented, taking the patient’s condition into account, assessing who may be the most vulnerable, and considering the available resources.
 

High-priority visits

Examples of patients with cervical cancer who are a high priority for outpatient visits, according to the guidelines, include patients who have acute abdominal symptoms, renal obstruction, or complications after surgery or radiotherapy. Persistent and severe symptomatic pelvic or vaginal bleeding is another reason to be categorized as high priority for an outpatient visit, alongside anuria or symptoms of deep vein thrombosis.

New patients with histologically confirmed cervical changes should also be seen as a high priority to stage their cancer, but the guidelines stress that any blood tests and imaging should be done as close to the patient’s home as possible.

Similar recommendations are made for women with endometrial cancer, with those who have potentially unstable symptoms, severe bleeding from their tumors, and signs of venous thromboembolism or anuria being at the highest priority for outpatient visits.

Women with potentially unstable epithelial ovarian cancer – who have acute abdominal pain, intestinal obstruction, or complications after surgery – are also a high priority for an outpatient visit, as are new patients who have symptomatic ascites, pleural effusion, or intestinal obstruction.
 

Applying guidelines in practice

Knowing that ESMO and other organizations have carefully considered the management of cancer patients specifically in relation to COVID-19 could offer oncologists “a feeling of support and some security when they make difficult decisions,” Dr. Ledermann said.

“With all guidelines, particularly in this sort of situation, we have to be very careful in terms of their interpretation, because what fits one country may not fit another, and what fits one hospital may not necessarily fit another. So they should be taken as guidance rather than prescriptive documents,” Dr. Ledermann said.

As vice president of the European Society for Gynecologic Oncology, Dr. Ledermann noted that ESGO has taken a slightly different approach than ESMO. ESGO decided to collect and post links to existing COVID-19 resources on its website rather than create its own specific recommendations.

ESGO is also producing an expert webinar series, which has, so far, covered the management of ovarian and uterine cancers, giving clinicians the chance to learn from those who have experienced dramatic changes to their services during the COVID-19 pandemic.

Dr. Ledermann has no conflicts of interest.

To manage patients with gynecologic cancers, oncologists in the United States and Europe are recommending reducing outpatient visits, delaying surgeries, prolonging chemotherapy regimens, and generally trying to keep cancer patients away from those who have tested positive for COVID-19.

“We recognize that, in this special situation, we must continue to provide our gynecologic oncology patients with the highest quality of medical services,” Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center in Houston and associates wrote in an editorial published in the International Journal of Gynecological Cancer.

At the same time, the authors added, the safety of patients, their families, and medical staff needs to be assured.

Dr. Ramirez and colleagues’ editorial includes recommendations on how to optimize the care of patients with gynecologic cancers while prioritizing safety and minimizing the burden to the healthcare system. The group’s recommendations outline when surgery, radiotherapy, and other treatments might be safely postponed and when they need to proceed out of urgency.

Some authors of the editorial also described their experiences with COVID-19 during a webinar on managing patients with advanced ovarian cancer, which was hosted by the European Society of Gynaecological Oncology (ESGO).
 

A lack of resources

In Spain, health resources “are collapsed” by the pandemic, editorial author Luis Chiva, MD, said during the webinar.

At his institution, the Clínica Universidad de Navarra in Madrid, 98% of the 1,500 intensive care beds were occupied by COVID-19 patients at the end of March. So the hope was to be able to refer their patients to other communities where there may still be some capacity.

Another problem in Spain is the high percentage of health workers infected with SARS-CoV-2, the virus behind COVID-19. More than 15,000 health workers were recently reported to be sick or self-isolating, which is around 14% of the health care workforce in the country.

Dr. Chiva noted that this puts those treating gynecologic cancers in a difficult position. On the one hand, surgery to remove a high-risk ovarian mass should not be delayed, but the majority of hospitals in Spain simply cannot perform this type of surgery during the pandemic.

“Unfortunately, due to this specific situation, almost, I would say in 80%-90% of hospitals, we are only able to carry out emergency surgical procedures,” Dr. Chiva said. That’s general emergency procedures such as appendectomies, removing blockages, and dealing with hemorrhages, not gynecologic surgeries. “It’s almost impossible to schedule the typical oncological cases,” he said.

Even with the Hospital IFEMA now set up at the Feria de Madrid, which is usually used to host large-scale events, there are “minimal options for performing standard oncological surgery,” Dr. Chiva said. He estimated that just 5% of hospitals in Spain are able to perform oncologic surgeries as normal, with maybe 15% able to offer surgery without the backup of postsurgical intensive care.
 

‘Ring-fencing’

“This is really an unusual time for us,” commented Jonathan Ledermann, MD, vice president of ESGO and a professor of medical oncology at University College London, who moderated the webinar.

“This is affecting the way in which we diagnose our patients and have access to care,” he said. “It compromises the way in which we treat patients. We have to adjust our treatment pathways. We have to look at the risks of coronavirus infection in cancer patients and how we manage patients in a socially distancing environment. We also need to think about managing gynecological oncology departments in the face of disease amongst staff, the risks of transmission, and the reduced clinical service.”

Dr. Ledermann noted that “ring-fencing” a few hospitals to deal only with patients free of COVID-19 might be a way forward. This approach has been used in Northern Italy and was recently started in London.

“We try to divide and have separate access between COVID-positive and -negative patients,” said Anna Fagotti, MD, an assistant professor at Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome and another coauthor of the editorial.

“We are trying to divide the work flow of patients and try to ensure treatment to cancer patients as much as we can,” she explained. “This means that it’s a very difficult situation, and, every time, you have to deal with the number of places available as some places have been taken by other patients from the emergency room. We are still trying to have a number of beds and intensive care unit beds available for our patients.”

Setting up dedicated hospitals is a good idea, but it has to be done before the “tsunami” of cases hits and there are no more intensive care beds or ventilators, according to Antonio González-Martín, MD, of Clínica Universidad de Navarra in Madrid, another coauthor of the editorial.
 

Limiting hospital visits

Strategies to limit the number of times patients need to come into hospital for appointments and treatment is key to getting through the pandemic, Sandro Pignata, MD, of Instituto Nazionale Tumori IRCCS Fondazione G. Pascale in Naples, Italy, said during the webinar.

“It will be imperative to explore options that reduce the number of procedures or surgical interventions that may be associated with prolonged operative time, risk of major blood loss, necessitating blood products, risk of infection to the medical personnel, or admission to intensive care units,” Dr. Ramirez and colleagues wrote in their editorial.

“In considering management of disease, we must recognize that, in many centers, access to routine visits and surgery may be either completely restricted or significantly reduced. We must, therefore, consider options that may still offer our patients a treatment plan that addresses their disease while at the same time limiting risk of exposure,” the authors wrote.

The authors declared no competing interests or specific funding in relation to their work, and the webinar participants had no conflicts of interest.

SOURCE: Ramirez PT et al. Int J Gynecol Cancer. 2020 Mar 27. doi: 10.1136/ijgc-2020-001419.
 

To manage patients with gynecologic cancers, oncologists in the United States and Europe are recommending reducing outpatient visits, delaying surgeries, prolonging chemotherapy regimens, and generally trying to keep cancer patients away from those who have tested positive for COVID-19.

“We recognize that, in this special situation, we must continue to provide our gynecologic oncology patients with the highest quality of medical services,” Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center in Houston and associates wrote in an editorial published in the International Journal of Gynecological Cancer.

At the same time, the authors added, the safety of patients, their families, and medical staff needs to be assured.

Dr. Ramirez and colleagues’ editorial includes recommendations on how to optimize the care of patients with gynecologic cancers while prioritizing safety and minimizing the burden to the healthcare system. The group’s recommendations outline when surgery, radiotherapy, and other treatments might be safely postponed and when they need to proceed out of urgency.

Some authors of the editorial also described their experiences with COVID-19 during a webinar on managing patients with advanced ovarian cancer, which was hosted by the European Society of Gynaecological Oncology (ESGO).
 

A lack of resources

In Spain, health resources “are collapsed” by the pandemic, editorial author Luis Chiva, MD, said during the webinar.

At his institution, the Clínica Universidad de Navarra in Madrid, 98% of the 1,500 intensive care beds were occupied by COVID-19 patients at the end of March. So the hope was to be able to refer their patients to other communities where there may still be some capacity.

Another problem in Spain is the high percentage of health workers infected with SARS-CoV-2, the virus behind COVID-19. More than 15,000 health workers were recently reported to be sick or self-isolating, which is around 14% of the health care workforce in the country.

Dr. Chiva noted that this puts those treating gynecologic cancers in a difficult position. On the one hand, surgery to remove a high-risk ovarian mass should not be delayed, but the majority of hospitals in Spain simply cannot perform this type of surgery during the pandemic.

“Unfortunately, due to this specific situation, almost, I would say in 80%-90% of hospitals, we are only able to carry out emergency surgical procedures,” Dr. Chiva said. That’s general emergency procedures such as appendectomies, removing blockages, and dealing with hemorrhages, not gynecologic surgeries. “It’s almost impossible to schedule the typical oncological cases,” he said.

Even with the Hospital IFEMA now set up at the Feria de Madrid, which is usually used to host large-scale events, there are “minimal options for performing standard oncological surgery,” Dr. Chiva said. He estimated that just 5% of hospitals in Spain are able to perform oncologic surgeries as normal, with maybe 15% able to offer surgery without the backup of postsurgical intensive care.
 

‘Ring-fencing’

“This is really an unusual time for us,” commented Jonathan Ledermann, MD, vice president of ESGO and a professor of medical oncology at University College London, who moderated the webinar.

“This is affecting the way in which we diagnose our patients and have access to care,” he said. “It compromises the way in which we treat patients. We have to adjust our treatment pathways. We have to look at the risks of coronavirus infection in cancer patients and how we manage patients in a socially distancing environment. We also need to think about managing gynecological oncology departments in the face of disease amongst staff, the risks of transmission, and the reduced clinical service.”

Dr. Ledermann noted that “ring-fencing” a few hospitals to deal only with patients free of COVID-19 might be a way forward. This approach has been used in Northern Italy and was recently started in London.

“We try to divide and have separate access between COVID-positive and -negative patients,” said Anna Fagotti, MD, an assistant professor at Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome and another coauthor of the editorial.

“We are trying to divide the work flow of patients and try to ensure treatment to cancer patients as much as we can,” she explained. “This means that it’s a very difficult situation, and, every time, you have to deal with the number of places available as some places have been taken by other patients from the emergency room. We are still trying to have a number of beds and intensive care unit beds available for our patients.”

Setting up dedicated hospitals is a good idea, but it has to be done before the “tsunami” of cases hits and there are no more intensive care beds or ventilators, according to Antonio González-Martín, MD, of Clínica Universidad de Navarra in Madrid, another coauthor of the editorial.
 

Limiting hospital visits

Strategies to limit the number of times patients need to come into hospital for appointments and treatment is key to getting through the pandemic, Sandro Pignata, MD, of Instituto Nazionale Tumori IRCCS Fondazione G. Pascale in Naples, Italy, said during the webinar.

“It will be imperative to explore options that reduce the number of procedures or surgical interventions that may be associated with prolonged operative time, risk of major blood loss, necessitating blood products, risk of infection to the medical personnel, or admission to intensive care units,” Dr. Ramirez and colleagues wrote in their editorial.

“In considering management of disease, we must recognize that, in many centers, access to routine visits and surgery may be either completely restricted or significantly reduced. We must, therefore, consider options that may still offer our patients a treatment plan that addresses their disease while at the same time limiting risk of exposure,” the authors wrote.

The authors declared no competing interests or specific funding in relation to their work, and the webinar participants had no conflicts of interest.

SOURCE: Ramirez PT et al. Int J Gynecol Cancer. 2020 Mar 27. doi: 10.1136/ijgc-2020-001419.
 

To manage patients with gynecologic cancers, oncologists in the United States and Europe are recommending reducing outpatient visits, delaying surgeries, prolonging chemotherapy regimens, and generally trying to keep cancer patients away from those who have tested positive for COVID-19.

“We recognize that, in this special situation, we must continue to provide our gynecologic oncology patients with the highest quality of medical services,” Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center in Houston and associates wrote in an editorial published in the International Journal of Gynecological Cancer.

At the same time, the authors added, the safety of patients, their families, and medical staff needs to be assured.

Dr. Ramirez and colleagues’ editorial includes recommendations on how to optimize the care of patients with gynecologic cancers while prioritizing safety and minimizing the burden to the healthcare system. The group’s recommendations outline when surgery, radiotherapy, and other treatments might be safely postponed and when they need to proceed out of urgency.

Some authors of the editorial also described their experiences with COVID-19 during a webinar on managing patients with advanced ovarian cancer, which was hosted by the European Society of Gynaecological Oncology (ESGO).
 

A lack of resources

In Spain, health resources “are collapsed” by the pandemic, editorial author Luis Chiva, MD, said during the webinar.

At his institution, the Clínica Universidad de Navarra in Madrid, 98% of the 1,500 intensive care beds were occupied by COVID-19 patients at the end of March. So the hope was to be able to refer their patients to other communities where there may still be some capacity.

Another problem in Spain is the high percentage of health workers infected with SARS-CoV-2, the virus behind COVID-19. More than 15,000 health workers were recently reported to be sick or self-isolating, which is around 14% of the health care workforce in the country.

Dr. Chiva noted that this puts those treating gynecologic cancers in a difficult position. On the one hand, surgery to remove a high-risk ovarian mass should not be delayed, but the majority of hospitals in Spain simply cannot perform this type of surgery during the pandemic.

“Unfortunately, due to this specific situation, almost, I would say in 80%-90% of hospitals, we are only able to carry out emergency surgical procedures,” Dr. Chiva said. That’s general emergency procedures such as appendectomies, removing blockages, and dealing with hemorrhages, not gynecologic surgeries. “It’s almost impossible to schedule the typical oncological cases,” he said.

Even with the Hospital IFEMA now set up at the Feria de Madrid, which is usually used to host large-scale events, there are “minimal options for performing standard oncological surgery,” Dr. Chiva said. He estimated that just 5% of hospitals in Spain are able to perform oncologic surgeries as normal, with maybe 15% able to offer surgery without the backup of postsurgical intensive care.
 

‘Ring-fencing’

“This is really an unusual time for us,” commented Jonathan Ledermann, MD, vice president of ESGO and a professor of medical oncology at University College London, who moderated the webinar.

“This is affecting the way in which we diagnose our patients and have access to care,” he said. “It compromises the way in which we treat patients. We have to adjust our treatment pathways. We have to look at the risks of coronavirus infection in cancer patients and how we manage patients in a socially distancing environment. We also need to think about managing gynecological oncology departments in the face of disease amongst staff, the risks of transmission, and the reduced clinical service.”

Dr. Ledermann noted that “ring-fencing” a few hospitals to deal only with patients free of COVID-19 might be a way forward. This approach has been used in Northern Italy and was recently started in London.

“We try to divide and have separate access between COVID-positive and -negative patients,” said Anna Fagotti, MD, an assistant professor at Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome and another coauthor of the editorial.

“We are trying to divide the work flow of patients and try to ensure treatment to cancer patients as much as we can,” she explained. “This means that it’s a very difficult situation, and, every time, you have to deal with the number of places available as some places have been taken by other patients from the emergency room. We are still trying to have a number of beds and intensive care unit beds available for our patients.”

Setting up dedicated hospitals is a good idea, but it has to be done before the “tsunami” of cases hits and there are no more intensive care beds or ventilators, according to Antonio González-Martín, MD, of Clínica Universidad de Navarra in Madrid, another coauthor of the editorial.
 

Limiting hospital visits

Strategies to limit the number of times patients need to come into hospital for appointments and treatment is key to getting through the pandemic, Sandro Pignata, MD, of Instituto Nazionale Tumori IRCCS Fondazione G. Pascale in Naples, Italy, said during the webinar.

“It will be imperative to explore options that reduce the number of procedures or surgical interventions that may be associated with prolonged operative time, risk of major blood loss, necessitating blood products, risk of infection to the medical personnel, or admission to intensive care units,” Dr. Ramirez and colleagues wrote in their editorial.

“In considering management of disease, we must recognize that, in many centers, access to routine visits and surgery may be either completely restricted or significantly reduced. We must, therefore, consider options that may still offer our patients a treatment plan that addresses their disease while at the same time limiting risk of exposure,” the authors wrote.

The authors declared no competing interests or specific funding in relation to their work, and the webinar participants had no conflicts of interest.

SOURCE: Ramirez PT et al. Int J Gynecol Cancer. 2020 Mar 27. doi: 10.1136/ijgc-2020-001419.
 

LONDON – The larger the wound caused by epidermolysis bullosa (EB), the worse someone’s quality of life (QoL) is likely to be, according to the results of a global survey.

Of 85 patients with the recessive dystrophic type of EB (RDEB) who were surveyed through the EBCare Registry, 39 had available data from the validated quality of life in EB (QOLEB) questionnaire. Those with the largest wounds (7.5 cm or greater) had an average QOLEB score of 27, compared with 22.5 for those with wounds ranging from 2.5 to 7.5 cm in size, and a score of 14 for those with wounds less than 2.5 cm in size. The maximum score on the 17-item questionnaire is 51, with the higher the number, the greater the impact on quality of life.

“Large wound areas were seen more frequently in chronic open wounds, similar to findings in separate studies,” Emily S. Gorell, DO, a postdoctoral clinical research fellow in dermatology at Stanford (Calif.) University, and associates reported in a poster presentation at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association.

“Larger wounds correlate with self-reported disease severity and key clinical manifestations,” they said, which includes history of squamous cell carcinoma (P = .04), anemia (P less than.01), osteoporosis (P = .03), and gastrostomy tube use (P = .02).

In total, 28 adults and 37 children and adolescents were surveyed; the majority (59%) were from North America, with the remainder from Europe (26%) or other countries (15%). Just over half of respondents were female (53%), and about 38% of surveys were completed by the individual rather than a parent or care giver (62%).

Dr. Gorell is working with Jean Y. Tang, MD, PhD, professor of dermatology at Stanford. During an oral presentation at the meeting, Dr. Tang observed that wounds could be defined as being recurrent or chronic open wounds. These two types of wounds behave differently, she said, with the latter never fully healing.

Indeed, in the survey, data on 1,226 wounds were collated, with 937 (76%) classified as recurrent – and healing within 12 weeks – but 289 (24%) remaining chronic open wounds, which did not heal for 12 weeks or longer. Some patients have had open wounds for more than 6 years, Dr. Tang noted.

“In our natural history study … you can see that chronic open wounds never reached 100% closure, they hardly ever reached 50% closure,” she said. In contrast, recurrent wounds have a more dynamic nature, healing completely, then reopening time after time. This is important when considering suitable endpoints for clinical trials, she said, as it could make or break some of the novel treatment approaches currently being tested. For instance, the placebo response in phase 3 trials of the topical therapy allantoin might have been high because recurrent wounds were being studied and were more likely to heal with or without active treatment.

“We’ve done a lot of work, it’s been 2 years, and we have benefited tremendously from these data in our negotiations with the FDA [Food and Drug Administration],” Dr. Tang said. “I am glad we did our homework … we were able to convince the FDA that, for a chronic open wound, a meaningful outcome is 50% healing, not 100%.”

Dr. Tang and Dr. Gorell are part of a team looking at gene-corrected autologous cell therapy (EB-101) to help heal large wounds caused by RDEB. The premise is that by replacing the faulty COL7A1 gene in keratinocytes taken from an individual, these skin cells will be able to produce collagen type VII (COL7). After being grown in culture to form epidermal sheets that look like a plastic film, the sheets can then be grafted over an individuals’ wounds.

Dr. Tang noted that the work was the culmination of 17 years’ of hard work by a small group of committed scientists. Preclinical studies started in 2003, when, she said, “the only funding we could get was through the NIH and thankfully some of the patient organizations.”

Initial results with the EB-101 therapy have been promising. Data on the first four subjects included in a seven-patient phase 1/2 study were published 4 years ago (JAMA. 2016;316[17]:1808-17), and the complete data were recently released (JCI Insight. 2019;4. doi: 10.1172/jci.insight.130554). Each trial subject had an EB-101 graft of approximately 35 cm² (5 cm x 7 cm) transplanted onto three wounds, with three similar wounds used as controls.

At 6 months, 95% of treated wounds had healed by 50% or more, compared with none of the untreated control wounds (P less than .0001). Healing rates at 1 year and 2 years, respectively, were 68% vs. 17% (P = .025) and 71% vs. 17% (P = .019). All grafts were well tolerated and molecular correction was seen to last for up to 2 years in two patients.

EB-101 therapy will be evaluated in a phase 3 study, the VIITAL study, a multicenter, randomized trial involving 10-15 individuals with RDEB; 50% wound healing at 3 months is the trial’s primary endpoint. The trial, funded by Abeona Therapeutics, was given the go ahead by the FDA in December 2019 and has an estimated completion date of March 2021.

Dr. Gorell did not provide a conflict of interest statement. Dr. Tang disclosed receipt of honoraria or consultation fees from Abeona and Menlo Therapeutics and being a stock shareholder in PellePharm and BridgeBio. Dr. Tang also acknowledged receiving research grants from the EB Research Partnership, the Epidermolysis Medical Research Foundation, and the California Institute for Regenerative Medicine.

SOURCES: Gorell ES et al. EB World Congress, poster 29. Tang JYl. EB World Congress, oral presentation.

LONDON – The larger the wound caused by epidermolysis bullosa (EB), the worse someone’s quality of life (QoL) is likely to be, according to the results of a global survey.

Of 85 patients with the recessive dystrophic type of EB (RDEB) who were surveyed through the EBCare Registry, 39 had available data from the validated quality of life in EB (QOLEB) questionnaire. Those with the largest wounds (7.5 cm or greater) had an average QOLEB score of 27, compared with 22.5 for those with wounds ranging from 2.5 to 7.5 cm in size, and a score of 14 for those with wounds less than 2.5 cm in size. The maximum score on the 17-item questionnaire is 51, with the higher the number, the greater the impact on quality of life.

“Large wound areas were seen more frequently in chronic open wounds, similar to findings in separate studies,” Emily S. Gorell, DO, a postdoctoral clinical research fellow in dermatology at Stanford (Calif.) University, and associates reported in a poster presentation at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association.

“Larger wounds correlate with self-reported disease severity and key clinical manifestations,” they said, which includes history of squamous cell carcinoma (P = .04), anemia (P less than.01), osteoporosis (P = .03), and gastrostomy tube use (P = .02).

In total, 28 adults and 37 children and adolescents were surveyed; the majority (59%) were from North America, with the remainder from Europe (26%) or other countries (15%). Just over half of respondents were female (53%), and about 38% of surveys were completed by the individual rather than a parent or care giver (62%).

Dr. Gorell is working with Jean Y. Tang, MD, PhD, professor of dermatology at Stanford. During an oral presentation at the meeting, Dr. Tang observed that wounds could be defined as being recurrent or chronic open wounds. These two types of wounds behave differently, she said, with the latter never fully healing.

Indeed, in the survey, data on 1,226 wounds were collated, with 937 (76%) classified as recurrent – and healing within 12 weeks – but 289 (24%) remaining chronic open wounds, which did not heal for 12 weeks or longer. Some patients have had open wounds for more than 6 years, Dr. Tang noted.

“In our natural history study … you can see that chronic open wounds never reached 100% closure, they hardly ever reached 50% closure,” she said. In contrast, recurrent wounds have a more dynamic nature, healing completely, then reopening time after time. This is important when considering suitable endpoints for clinical trials, she said, as it could make or break some of the novel treatment approaches currently being tested. For instance, the placebo response in phase 3 trials of the topical therapy allantoin might have been high because recurrent wounds were being studied and were more likely to heal with or without active treatment.

“We’ve done a lot of work, it’s been 2 years, and we have benefited tremendously from these data in our negotiations with the FDA [Food and Drug Administration],” Dr. Tang said. “I am glad we did our homework … we were able to convince the FDA that, for a chronic open wound, a meaningful outcome is 50% healing, not 100%.”

Dr. Tang and Dr. Gorell are part of a team looking at gene-corrected autologous cell therapy (EB-101) to help heal large wounds caused by RDEB. The premise is that by replacing the faulty COL7A1 gene in keratinocytes taken from an individual, these skin cells will be able to produce collagen type VII (COL7). After being grown in culture to form epidermal sheets that look like a plastic film, the sheets can then be grafted over an individuals’ wounds.

Dr. Tang noted that the work was the culmination of 17 years’ of hard work by a small group of committed scientists. Preclinical studies started in 2003, when, she said, “the only funding we could get was through the NIH and thankfully some of the patient organizations.”

Initial results with the EB-101 therapy have been promising. Data on the first four subjects included in a seven-patient phase 1/2 study were published 4 years ago (JAMA. 2016;316[17]:1808-17), and the complete data were recently released (JCI Insight. 2019;4. doi: 10.1172/jci.insight.130554). Each trial subject had an EB-101 graft of approximately 35 cm² (5 cm x 7 cm) transplanted onto three wounds, with three similar wounds used as controls.

At 6 months, 95% of treated wounds had healed by 50% or more, compared with none of the untreated control wounds (P less than .0001). Healing rates at 1 year and 2 years, respectively, were 68% vs. 17% (P = .025) and 71% vs. 17% (P = .019). All grafts were well tolerated and molecular correction was seen to last for up to 2 years in two patients.

EB-101 therapy will be evaluated in a phase 3 study, the VIITAL study, a multicenter, randomized trial involving 10-15 individuals with RDEB; 50% wound healing at 3 months is the trial’s primary endpoint. The trial, funded by Abeona Therapeutics, was given the go ahead by the FDA in December 2019 and has an estimated completion date of March 2021.

Dr. Gorell did not provide a conflict of interest statement. Dr. Tang disclosed receipt of honoraria or consultation fees from Abeona and Menlo Therapeutics and being a stock shareholder in PellePharm and BridgeBio. Dr. Tang also acknowledged receiving research grants from the EB Research Partnership, the Epidermolysis Medical Research Foundation, and the California Institute for Regenerative Medicine.

SOURCES: Gorell ES et al. EB World Congress, poster 29. Tang JYl. EB World Congress, oral presentation.

LONDON – The larger the wound caused by epidermolysis bullosa (EB), the worse someone’s quality of life (QoL) is likely to be, according to the results of a global survey.

Of 85 patients with the recessive dystrophic type of EB (RDEB) who were surveyed through the EBCare Registry, 39 had available data from the validated quality of life in EB (QOLEB) questionnaire. Those with the largest wounds (7.5 cm or greater) had an average QOLEB score of 27, compared with 22.5 for those with wounds ranging from 2.5 to 7.5 cm in size, and a score of 14 for those with wounds less than 2.5 cm in size. The maximum score on the 17-item questionnaire is 51, with the higher the number, the greater the impact on quality of life.

“Large wound areas were seen more frequently in chronic open wounds, similar to findings in separate studies,” Emily S. Gorell, DO, a postdoctoral clinical research fellow in dermatology at Stanford (Calif.) University, and associates reported in a poster presentation at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association.

“Larger wounds correlate with self-reported disease severity and key clinical manifestations,” they said, which includes history of squamous cell carcinoma (P = .04), anemia (P less than.01), osteoporosis (P = .03), and gastrostomy tube use (P = .02).

In total, 28 adults and 37 children and adolescents were surveyed; the majority (59%) were from North America, with the remainder from Europe (26%) or other countries (15%). Just over half of respondents were female (53%), and about 38% of surveys were completed by the individual rather than a parent or care giver (62%).

Dr. Gorell is working with Jean Y. Tang, MD, PhD, professor of dermatology at Stanford. During an oral presentation at the meeting, Dr. Tang observed that wounds could be defined as being recurrent or chronic open wounds. These two types of wounds behave differently, she said, with the latter never fully healing.

Indeed, in the survey, data on 1,226 wounds were collated, with 937 (76%) classified as recurrent – and healing within 12 weeks – but 289 (24%) remaining chronic open wounds, which did not heal for 12 weeks or longer. Some patients have had open wounds for more than 6 years, Dr. Tang noted.

“In our natural history study … you can see that chronic open wounds never reached 100% closure, they hardly ever reached 50% closure,” she said. In contrast, recurrent wounds have a more dynamic nature, healing completely, then reopening time after time. This is important when considering suitable endpoints for clinical trials, she said, as it could make or break some of the novel treatment approaches currently being tested. For instance, the placebo response in phase 3 trials of the topical therapy allantoin might have been high because recurrent wounds were being studied and were more likely to heal with or without active treatment.

“We’ve done a lot of work, it’s been 2 years, and we have benefited tremendously from these data in our negotiations with the FDA [Food and Drug Administration],” Dr. Tang said. “I am glad we did our homework … we were able to convince the FDA that, for a chronic open wound, a meaningful outcome is 50% healing, not 100%.”

Dr. Tang and Dr. Gorell are part of a team looking at gene-corrected autologous cell therapy (EB-101) to help heal large wounds caused by RDEB. The premise is that by replacing the faulty COL7A1 gene in keratinocytes taken from an individual, these skin cells will be able to produce collagen type VII (COL7). After being grown in culture to form epidermal sheets that look like a plastic film, the sheets can then be grafted over an individuals’ wounds.

Dr. Tang noted that the work was the culmination of 17 years’ of hard work by a small group of committed scientists. Preclinical studies started in 2003, when, she said, “the only funding we could get was through the NIH and thankfully some of the patient organizations.”

Initial results with the EB-101 therapy have been promising. Data on the first four subjects included in a seven-patient phase 1/2 study were published 4 years ago (JAMA. 2016;316[17]:1808-17), and the complete data were recently released (JCI Insight. 2019;4. doi: 10.1172/jci.insight.130554). Each trial subject had an EB-101 graft of approximately 35 cm² (5 cm x 7 cm) transplanted onto three wounds, with three similar wounds used as controls.

At 6 months, 95% of treated wounds had healed by 50% or more, compared with none of the untreated control wounds (P less than .0001). Healing rates at 1 year and 2 years, respectively, were 68% vs. 17% (P = .025) and 71% vs. 17% (P = .019). All grafts were well tolerated and molecular correction was seen to last for up to 2 years in two patients.

EB-101 therapy will be evaluated in a phase 3 study, the VIITAL study, a multicenter, randomized trial involving 10-15 individuals with RDEB; 50% wound healing at 3 months is the trial’s primary endpoint. The trial, funded by Abeona Therapeutics, was given the go ahead by the FDA in December 2019 and has an estimated completion date of March 2021.

Dr. Gorell did not provide a conflict of interest statement. Dr. Tang disclosed receipt of honoraria or consultation fees from Abeona and Menlo Therapeutics and being a stock shareholder in PellePharm and BridgeBio. Dr. Tang also acknowledged receiving research grants from the EB Research Partnership, the Epidermolysis Medical Research Foundation, and the California Institute for Regenerative Medicine.

SOURCES: Gorell ES et al. EB World Congress, poster 29. Tang JYl. EB World Congress, oral presentation.