TBD Meeting (3388-21)

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

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

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

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

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

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

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

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

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

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

Study details

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Study details

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Study details

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pandemic presented ‘perfect storm’

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

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

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

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

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

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

Rheumatology practice changed practically overnight

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

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

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

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

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

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

Different approach taken in CONTAIN Study

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

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

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

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

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

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

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

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

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

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

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

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

No other relevant conflicts of interested were declared.
 

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

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

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

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

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

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

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

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

Pandemic presented ‘perfect storm’

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

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

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

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

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

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

Rheumatology practice changed practically overnight

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

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

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

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

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

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

Different approach taken in CONTAIN Study

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

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

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

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

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

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

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

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

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

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

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

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

No other relevant conflicts of interested were declared.
 

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

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

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

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

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

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

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

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

Pandemic presented ‘perfect storm’

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

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

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

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

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

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

Rheumatology practice changed practically overnight

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

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

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

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

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

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

Different approach taken in CONTAIN Study

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

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

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

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

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

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

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

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

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

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

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

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

No other relevant conflicts of interested were declared.
 

Around three-quarters of patients remained on treatment with baricitinib (Olumiant) for rheumatoid arthritis after their first 6-month assessment in an independent analysis of British Society for Rheumatology Biologics Register (BSRBR) data.

The rate of continuation was even higher, at almost 85%, in patients who had not previously been treated with a biologic or targeted synthetic disease-modifying antirheumatic drug (b/ts DMARD) before being given baricitinib. The 6-month continuation rate was also higher, at 80%, in patients who received baricitinib without additional DMARDs or steroid therapy.

Overall, the Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) score was reduced from a baseline of 5.7 to 3.4, with similar reductions seen among the subgroups of patients who had received baricitinib as monotherapy, after prior b/tsDMARDs, or no prior b/tsDMARDs.

“We’ve looked at an RA study population using data from the BSR biologics registry, to try and have a look at how patients with baricitinib are being treated and how they’re doing in this real-world setting, within the U.K.,” explained consultant rheumatologist Christopher J. Edwards, MD, of University Hospital Southampton (England) at the British Society for Rheumatology annual conference.

“Overall, effectiveness and tolerability seem to be pretty good indeed,” he said. “Sample size, of course, was small and it will be nice to see a little bit more data collected over time that allow us to be more confident in any conclusions.”

‘Getting to grips’ with baricitinib

Baricitinib is a drug that clinicians in the United Kingdom are “just getting to grips with,” observed Jon Packham, BM, DM, a consultant rheumatologist at Haywood Hospital in Stoke-on-Trent (England) who was not involved in the analysis.

“We look forward to when we’ve got a few more patients through that 6-month hurdle and we were getting even more data coming through,” Dr. Packham said.

Baricitinib was given marketing authorization in Europe for the treatment of moderate to severe RA in 2017 and so is a relatively new addition into the BSRBR-RA, which has been running for the past 20 years. It includes data on patients with RA who are newly starting a bDMARD or tsDMARD, and patients are followed up every 6 months for the first 3 years of their treatment and then annually thereafter.

Dr. Edwards presented data on some of the baseline characteristics and status of patients at the first 6-month follow-up of the BSRBR-RA. He was clear that this analysis was done independently of the BSRBR-RA study team and performed under an agreement between Eli Lilly and the BSR to allow access to the data.

Between Jan. 1, 2018, and March 31, 2019, there were 409 patients who were just starting baricitinib treatment and who were entered into the BSRBR-RA. The mean age of patients was 61 years, and the majority (76%) was female. On average, patients starting baricitinib had been diagnosed with RA for 11 years, and 62% had previously been treated with a biologic.

As per the European label, most patients were being treated with baricitinib in combination with a conventional synthetic DMARD (61%), with 40% of patients receiving it in combination with methotrexate. Around 38% of patients received baricitinib as monotherapy, and just under 30% were receiving concomitant glucocorticoids.

The majority (84%) were prescribed a 4-mg daily dose of baricitinib, with the remainder on a daily dose of 2 mg.

There were 163 patients with data available at the first 6-month follow up, and of those, 103 had prior experience of being treated with a b/ts DMARD, 59 did not, and 65 had been given baricitinib as monotherapy.
 

Reasons for discontinuation

Overall, around a quarter of patients discontinued treatment with baricitinib, and “the reasons for this were lack of efficacy in approximately a quarter and adverse events in about two-thirds of the patients,” Dr. Edwards said.

Breaking down the types of adverse events was not part of this analysis, and that information is likely to come from the BSRBR-RA study team directly.

“We have some experience in our practice in Southampton,” Dr. Edwards observed. This experience was outlined in a separate abstract at the meeting and presented by Dr. May Nwe Lwin, a clinical research fellow within Dr. Edwards’ group.

Dr. Lwin presented data on 83 patients who had received baricitinib at University Hospital Southampton between October 2017 and July 2020, 55 (65.2%) of whom remain on treatment to date, with mean follow-up of 17 months. Of the 28 patients who stopped baricitinib, 21 stopped within 12 months.

“Patients who continued on baricitinib appeared more likely to be older and female,” Dr. Lwin said.

The mean age of patients who continued on treatment after 12 months was 61.5 years but was 49 years for those who stopped earlier. The percentage of women continuing treatment at 12 months versus those stopping earlier were a respective 82% and 67%. Both findings were significant (P < .001) but “could mean nothing, or could be very interesting data to explore more,” Dr. Lwin suggested.

“However, there was no significant difference in discontinuation rates for those using mono or combination therapy, and also no effect of disease duration or seropositivity,” Dr. Lwin said.

“Most people stopped baricitinib in the first 3 months of their treatment,” Dr. Lwin reported, noting that the most common reason was a lack of efficacy in 64% of patients, with 28.5% of patients discontinuing because of side effects.

“When you look at the adverse events, the reasons for discontinuation are quite variable,” Dr. Lwin said. These included infections (one urinary tract infection, two chest infections, and a urinary tract infection), and one case each of discitis, deranged liver function, lymphoma, and personality change.

Update on the long-term safety profile

Also at the BSR annual conference, an update on the long-term safety profile of baricitinib seen in clinical trials was presented, using data from the ‘All-BARI-RA’ dataset. This includes data from nine clinical trials and one long-term extension study.

“We recently published a long-term safety analysis of this molecule involving 3,700-plus patients with exposure up to 7 years,” said Kevin L. Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health Sciences University in Portland.

Dr. Winthrop provided an update on this, adding in another 13,148 patient-years of follow-up and giving data on the safety experience with baricitinib with up to 8.4 years of exposure for some patients.

“In short, not much has changed,” Dr. Winthrop said, noting that event rates have remained stable.

The overall major adverse cardiovascular event (MACE) and overall deep vein thrombosis/pulmonary embolism event rate were both 0.5 per 100 patient-years. Referring to the latter, Dr. Winthrop called them “rock solid stable” and “it’s been that way really all the way through the development program.”

Overall, event rates per 100 patient-years for serious infections, herpes zoster, and tuberculosis were a respective 2.7, 3.0, and 0.2. Serious infection rates over time have remained similar, but “clearly age is a risk factor for infection,” Dr. Winthrop said. “I would just say it’s similar to what we see with all biologics and small molecules in this setting.”

Malignancy and death rates were also higher in older patients, but after age adjustment, these had been stable across the different analysis points.

“Malignancy overall, excluding NMSC [nonmelanoma skin cancer], the event rate is 0.9 per 100 patient-years, very similar to what we’ve seen in the prior data cuts,” he said. “The same is true for lymphoma,” he added, with an overall event rate of 0.1 per 100 patient-years.

This updated analysis, Dr. Winthrop concluded, “suggests a safety profile really very similar to what was published recently.”Dr. Edwards has received research and educational grants and advisory panel and speaker fees from Eli Lilly and from multiple other pharmaceutical companies. The analysis of BSRBR-RA data he presented was sponsored by Eli Lilly and performed independently of the BSRBR-RA study team. Dr. Packham reported no conflicts of interest; he chaired the oral abstracts sessions in which Dr. Edwards presented his findings.

Dr. Lwin did not report having any disclosures.

Dr. Winthrop has acted as a consultant to Eli Lilly and several other pharmaceutical companies and had received research or grant support from Bristol-Myers Squibb and Pfizer. The work he presented was sponsored by Eli Lilly.

Around three-quarters of patients remained on treatment with baricitinib (Olumiant) for rheumatoid arthritis after their first 6-month assessment in an independent analysis of British Society for Rheumatology Biologics Register (BSRBR) data.

The rate of continuation was even higher, at almost 85%, in patients who had not previously been treated with a biologic or targeted synthetic disease-modifying antirheumatic drug (b/ts DMARD) before being given baricitinib. The 6-month continuation rate was also higher, at 80%, in patients who received baricitinib without additional DMARDs or steroid therapy.

Overall, the Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) score was reduced from a baseline of 5.7 to 3.4, with similar reductions seen among the subgroups of patients who had received baricitinib as monotherapy, after prior b/tsDMARDs, or no prior b/tsDMARDs.

“We’ve looked at an RA study population using data from the BSR biologics registry, to try and have a look at how patients with baricitinib are being treated and how they’re doing in this real-world setting, within the U.K.,” explained consultant rheumatologist Christopher J. Edwards, MD, of University Hospital Southampton (England) at the British Society for Rheumatology annual conference.

“Overall, effectiveness and tolerability seem to be pretty good indeed,” he said. “Sample size, of course, was small and it will be nice to see a little bit more data collected over time that allow us to be more confident in any conclusions.”

‘Getting to grips’ with baricitinib

Baricitinib is a drug that clinicians in the United Kingdom are “just getting to grips with,” observed Jon Packham, BM, DM, a consultant rheumatologist at Haywood Hospital in Stoke-on-Trent (England) who was not involved in the analysis.

“We look forward to when we’ve got a few more patients through that 6-month hurdle and we were getting even more data coming through,” Dr. Packham said.

Baricitinib was given marketing authorization in Europe for the treatment of moderate to severe RA in 2017 and so is a relatively new addition into the BSRBR-RA, which has been running for the past 20 years. It includes data on patients with RA who are newly starting a bDMARD or tsDMARD, and patients are followed up every 6 months for the first 3 years of their treatment and then annually thereafter.

Dr. Edwards presented data on some of the baseline characteristics and status of patients at the first 6-month follow-up of the BSRBR-RA. He was clear that this analysis was done independently of the BSRBR-RA study team and performed under an agreement between Eli Lilly and the BSR to allow access to the data.

Between Jan. 1, 2018, and March 31, 2019, there were 409 patients who were just starting baricitinib treatment and who were entered into the BSRBR-RA. The mean age of patients was 61 years, and the majority (76%) was female. On average, patients starting baricitinib had been diagnosed with RA for 11 years, and 62% had previously been treated with a biologic.

As per the European label, most patients were being treated with baricitinib in combination with a conventional synthetic DMARD (61%), with 40% of patients receiving it in combination with methotrexate. Around 38% of patients received baricitinib as monotherapy, and just under 30% were receiving concomitant glucocorticoids.

The majority (84%) were prescribed a 4-mg daily dose of baricitinib, with the remainder on a daily dose of 2 mg.

There were 163 patients with data available at the first 6-month follow up, and of those, 103 had prior experience of being treated with a b/ts DMARD, 59 did not, and 65 had been given baricitinib as monotherapy.
 

Reasons for discontinuation

Overall, around a quarter of patients discontinued treatment with baricitinib, and “the reasons for this were lack of efficacy in approximately a quarter and adverse events in about two-thirds of the patients,” Dr. Edwards said.

Breaking down the types of adverse events was not part of this analysis, and that information is likely to come from the BSRBR-RA study team directly.

“We have some experience in our practice in Southampton,” Dr. Edwards observed. This experience was outlined in a separate abstract at the meeting and presented by Dr. May Nwe Lwin, a clinical research fellow within Dr. Edwards’ group.

Dr. Lwin presented data on 83 patients who had received baricitinib at University Hospital Southampton between October 2017 and July 2020, 55 (65.2%) of whom remain on treatment to date, with mean follow-up of 17 months. Of the 28 patients who stopped baricitinib, 21 stopped within 12 months.

“Patients who continued on baricitinib appeared more likely to be older and female,” Dr. Lwin said.

The mean age of patients who continued on treatment after 12 months was 61.5 years but was 49 years for those who stopped earlier. The percentage of women continuing treatment at 12 months versus those stopping earlier were a respective 82% and 67%. Both findings were significant (P < .001) but “could mean nothing, or could be very interesting data to explore more,” Dr. Lwin suggested.

“However, there was no significant difference in discontinuation rates for those using mono or combination therapy, and also no effect of disease duration or seropositivity,” Dr. Lwin said.

“Most people stopped baricitinib in the first 3 months of their treatment,” Dr. Lwin reported, noting that the most common reason was a lack of efficacy in 64% of patients, with 28.5% of patients discontinuing because of side effects.

“When you look at the adverse events, the reasons for discontinuation are quite variable,” Dr. Lwin said. These included infections (one urinary tract infection, two chest infections, and a urinary tract infection), and one case each of discitis, deranged liver function, lymphoma, and personality change.

Update on the long-term safety profile

Also at the BSR annual conference, an update on the long-term safety profile of baricitinib seen in clinical trials was presented, using data from the ‘All-BARI-RA’ dataset. This includes data from nine clinical trials and one long-term extension study.

“We recently published a long-term safety analysis of this molecule involving 3,700-plus patients with exposure up to 7 years,” said Kevin L. Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health Sciences University in Portland.

Dr. Winthrop provided an update on this, adding in another 13,148 patient-years of follow-up and giving data on the safety experience with baricitinib with up to 8.4 years of exposure for some patients.

“In short, not much has changed,” Dr. Winthrop said, noting that event rates have remained stable.

The overall major adverse cardiovascular event (MACE) and overall deep vein thrombosis/pulmonary embolism event rate were both 0.5 per 100 patient-years. Referring to the latter, Dr. Winthrop called them “rock solid stable” and “it’s been that way really all the way through the development program.”

Overall, event rates per 100 patient-years for serious infections, herpes zoster, and tuberculosis were a respective 2.7, 3.0, and 0.2. Serious infection rates over time have remained similar, but “clearly age is a risk factor for infection,” Dr. Winthrop said. “I would just say it’s similar to what we see with all biologics and small molecules in this setting.”

Malignancy and death rates were also higher in older patients, but after age adjustment, these had been stable across the different analysis points.

“Malignancy overall, excluding NMSC [nonmelanoma skin cancer], the event rate is 0.9 per 100 patient-years, very similar to what we’ve seen in the prior data cuts,” he said. “The same is true for lymphoma,” he added, with an overall event rate of 0.1 per 100 patient-years.

This updated analysis, Dr. Winthrop concluded, “suggests a safety profile really very similar to what was published recently.”Dr. Edwards has received research and educational grants and advisory panel and speaker fees from Eli Lilly and from multiple other pharmaceutical companies. The analysis of BSRBR-RA data he presented was sponsored by Eli Lilly and performed independently of the BSRBR-RA study team. Dr. Packham reported no conflicts of interest; he chaired the oral abstracts sessions in which Dr. Edwards presented his findings.

Dr. Lwin did not report having any disclosures.

Dr. Winthrop has acted as a consultant to Eli Lilly and several other pharmaceutical companies and had received research or grant support from Bristol-Myers Squibb and Pfizer. The work he presented was sponsored by Eli Lilly.

Around three-quarters of patients remained on treatment with baricitinib (Olumiant) for rheumatoid arthritis after their first 6-month assessment in an independent analysis of British Society for Rheumatology Biologics Register (BSRBR) data.

The rate of continuation was even higher, at almost 85%, in patients who had not previously been treated with a biologic or targeted synthetic disease-modifying antirheumatic drug (b/ts DMARD) before being given baricitinib. The 6-month continuation rate was also higher, at 80%, in patients who received baricitinib without additional DMARDs or steroid therapy.

Overall, the Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) score was reduced from a baseline of 5.7 to 3.4, with similar reductions seen among the subgroups of patients who had received baricitinib as monotherapy, after prior b/tsDMARDs, or no prior b/tsDMARDs.

“We’ve looked at an RA study population using data from the BSR biologics registry, to try and have a look at how patients with baricitinib are being treated and how they’re doing in this real-world setting, within the U.K.,” explained consultant rheumatologist Christopher J. Edwards, MD, of University Hospital Southampton (England) at the British Society for Rheumatology annual conference.

“Overall, effectiveness and tolerability seem to be pretty good indeed,” he said. “Sample size, of course, was small and it will be nice to see a little bit more data collected over time that allow us to be more confident in any conclusions.”

‘Getting to grips’ with baricitinib

Baricitinib is a drug that clinicians in the United Kingdom are “just getting to grips with,” observed Jon Packham, BM, DM, a consultant rheumatologist at Haywood Hospital in Stoke-on-Trent (England) who was not involved in the analysis.

“We look forward to when we’ve got a few more patients through that 6-month hurdle and we were getting even more data coming through,” Dr. Packham said.

Baricitinib was given marketing authorization in Europe for the treatment of moderate to severe RA in 2017 and so is a relatively new addition into the BSRBR-RA, which has been running for the past 20 years. It includes data on patients with RA who are newly starting a bDMARD or tsDMARD, and patients are followed up every 6 months for the first 3 years of their treatment and then annually thereafter.

Dr. Edwards presented data on some of the baseline characteristics and status of patients at the first 6-month follow-up of the BSRBR-RA. He was clear that this analysis was done independently of the BSRBR-RA study team and performed under an agreement between Eli Lilly and the BSR to allow access to the data.

Between Jan. 1, 2018, and March 31, 2019, there were 409 patients who were just starting baricitinib treatment and who were entered into the BSRBR-RA. The mean age of patients was 61 years, and the majority (76%) was female. On average, patients starting baricitinib had been diagnosed with RA for 11 years, and 62% had previously been treated with a biologic.

As per the European label, most patients were being treated with baricitinib in combination with a conventional synthetic DMARD (61%), with 40% of patients receiving it in combination with methotrexate. Around 38% of patients received baricitinib as monotherapy, and just under 30% were receiving concomitant glucocorticoids.

The majority (84%) were prescribed a 4-mg daily dose of baricitinib, with the remainder on a daily dose of 2 mg.

There were 163 patients with data available at the first 6-month follow up, and of those, 103 had prior experience of being treated with a b/ts DMARD, 59 did not, and 65 had been given baricitinib as monotherapy.
 

Reasons for discontinuation

Overall, around a quarter of patients discontinued treatment with baricitinib, and “the reasons for this were lack of efficacy in approximately a quarter and adverse events in about two-thirds of the patients,” Dr. Edwards said.

Breaking down the types of adverse events was not part of this analysis, and that information is likely to come from the BSRBR-RA study team directly.

“We have some experience in our practice in Southampton,” Dr. Edwards observed. This experience was outlined in a separate abstract at the meeting and presented by Dr. May Nwe Lwin, a clinical research fellow within Dr. Edwards’ group.

Dr. Lwin presented data on 83 patients who had received baricitinib at University Hospital Southampton between October 2017 and July 2020, 55 (65.2%) of whom remain on treatment to date, with mean follow-up of 17 months. Of the 28 patients who stopped baricitinib, 21 stopped within 12 months.

“Patients who continued on baricitinib appeared more likely to be older and female,” Dr. Lwin said.

The mean age of patients who continued on treatment after 12 months was 61.5 years but was 49 years for those who stopped earlier. The percentage of women continuing treatment at 12 months versus those stopping earlier were a respective 82% and 67%. Both findings were significant (P < .001) but “could mean nothing, or could be very interesting data to explore more,” Dr. Lwin suggested.

“However, there was no significant difference in discontinuation rates for those using mono or combination therapy, and also no effect of disease duration or seropositivity,” Dr. Lwin said.

“Most people stopped baricitinib in the first 3 months of their treatment,” Dr. Lwin reported, noting that the most common reason was a lack of efficacy in 64% of patients, with 28.5% of patients discontinuing because of side effects.

“When you look at the adverse events, the reasons for discontinuation are quite variable,” Dr. Lwin said. These included infections (one urinary tract infection, two chest infections, and a urinary tract infection), and one case each of discitis, deranged liver function, lymphoma, and personality change.

Update on the long-term safety profile

Also at the BSR annual conference, an update on the long-term safety profile of baricitinib seen in clinical trials was presented, using data from the ‘All-BARI-RA’ dataset. This includes data from nine clinical trials and one long-term extension study.

“We recently published a long-term safety analysis of this molecule involving 3,700-plus patients with exposure up to 7 years,” said Kevin L. Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health Sciences University in Portland.

Dr. Winthrop provided an update on this, adding in another 13,148 patient-years of follow-up and giving data on the safety experience with baricitinib with up to 8.4 years of exposure for some patients.

“In short, not much has changed,” Dr. Winthrop said, noting that event rates have remained stable.

The overall major adverse cardiovascular event (MACE) and overall deep vein thrombosis/pulmonary embolism event rate were both 0.5 per 100 patient-years. Referring to the latter, Dr. Winthrop called them “rock solid stable” and “it’s been that way really all the way through the development program.”

Overall, event rates per 100 patient-years for serious infections, herpes zoster, and tuberculosis were a respective 2.7, 3.0, and 0.2. Serious infection rates over time have remained similar, but “clearly age is a risk factor for infection,” Dr. Winthrop said. “I would just say it’s similar to what we see with all biologics and small molecules in this setting.”

Malignancy and death rates were also higher in older patients, but after age adjustment, these had been stable across the different analysis points.

“Malignancy overall, excluding NMSC [nonmelanoma skin cancer], the event rate is 0.9 per 100 patient-years, very similar to what we’ve seen in the prior data cuts,” he said. “The same is true for lymphoma,” he added, with an overall event rate of 0.1 per 100 patient-years.

This updated analysis, Dr. Winthrop concluded, “suggests a safety profile really very similar to what was published recently.”Dr. Edwards has received research and educational grants and advisory panel and speaker fees from Eli Lilly and from multiple other pharmaceutical companies. The analysis of BSRBR-RA data he presented was sponsored by Eli Lilly and performed independently of the BSRBR-RA study team. Dr. Packham reported no conflicts of interest; he chaired the oral abstracts sessions in which Dr. Edwards presented his findings.

Dr. Lwin did not report having any disclosures.

Dr. Winthrop has acted as a consultant to Eli Lilly and several other pharmaceutical companies and had received research or grant support from Bristol-Myers Squibb and Pfizer. The work he presented was sponsored by Eli Lilly.

Patients with neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) seem to benefit from rituximab (Rituxan) therapy, according to data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR).

Indeed, the percentage of patients with active disease, as scored by the BILAG-2004 index or SLEDAI-2K (SLE Disease Activity Index 2000), fell significantly (P < .0001) when comparing pre- and postrituximab treatment scores. There was also a reduction in the dose of oral steroids used.

Interestingly, the use of concomitant cyclophosphamide might enhance the level of improvement seen in some patients, Trixy David, MBBS, reported during an abstract session at the British Society for Rheumatology annual conference.

“Larger-scale studies are warranted to establish the effectiveness of rituximab alone, or in combination with cyclophosphamide, in the treatment neuropsychiatric lupus,” said Dr. David, a clinical research fellow at the University of Manchester (England) and specialist registrar in rheumatology at the Manchester University National Health Service Foundation Trust.

Neil Basu, MBChB, PhD, who chaired the virtual session, called the findings “enlightening” and “descriptive.”

The study “provides some interesting data, which should be tested in a robust, randomized clinical trial,” he agreed, and not that clinicians should now start using rituximab for their NPSLE cases.

Dr. Basu, who is a clinical senior lecturer in rheumatology and honorary consultant rheumatologist at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, added: “It is really important that we do these studies to help support a rationale for such a trial, which are obviously very expensive and require strong evidence before we go down that track. I think these data have really been quite enlightening in that respect.”

Rationale for rituximab in neuropsychiatric lupus

Managing patients with NPSLE remains an area of substantial unmet need. According to a recent review in Rheumatology, “there is a dearth of controlled clinical trials to guide management” and “therapeutic options include symptomatic, antithrombotic, and immunosuppressive agents that are supported by observational cohort studies.”

Despite being seen in at least half of all patients with SLE, neuropsychiatric disease “is not very well studied in patients with lupus, as a lot of large-scale trials tend to exclude patients with active neurological disease,” Dr. David said.

Although it is unclear why neuropsychiatric disease occurs in SLE, it could be “as a result of vascular injury or disruption of the blood brain barrier, thereby allowing the passive diffusion of autoantibodies and cytokines across through the cerebral spinal fluid, thereby generating a proinflammatory response,” Dr. David suggested.

“We know B cells are involved in the pathogenesis of lupus, and rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells and mediates transient B-cell depletion,” she said. Notably, there have been some small studies suggesting that rituximab may be effective in neuropsychiatric lupus, and it is currently widely used to treat refractory lupus in the United Kingdom.
 

About the BILAG-BR and results

“Our aim was to describe the baseline characteristics and short-term effectiveness of rituximab in patients treated for neuropsychiatric lupus within the BILAG-BR,” Dr. David explained.

Started in 2009, the BILAG-BR now contains information on more than 1,400 individuals with SLE who have been recruited at 62 centers in the United Kingdom. Its purpose is to evaluate the long-term safety and effectiveness of biologic drugs versus standard immunosuppressive therapy such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine. To date, 1,229 patients have been treated with biologics, of whom 1,056 have received rituximab.

A total of 74 rituximab-treated patients were identified as having active neuropsychiatric disease, making this “the largest prospective observational cohort to date, to our knowledge,” Dr. David said.

The median age of patients was 45.5 years, the majority was female (82%) and White (74%). The median disease duration was 11.5 years.

A total of 96% had multiple organ involvement and not just neuropsychiatric disease, and 91% were positive for antineutrophil antibodies.

The top six neuropsychiatric manifestations were cognitive dysfunction and lupus headache (both affecting 27.5% of patients); acute confessional state or mononeuropathy (each seen in 10% of patients); and seizure disorder and polyneuropathy, seen in a respective 8.6% and 8.7% of patients. These findings are in line with a 2011 meta-analysis, Dr. David pointed out.

BILAG-2004 scores before and after rituximab treatment were available for 50 patients. The number of patients with a BILAG A score dropped from 24 (48%) at baseline to 7 (14%) after treatment with rituximab, and the number with a BILAG B score declined from 26 (52%) at baseline to 4 (8%) after rituximab (both P < .0001).

There was also a reduction following rituximab treatment in the percentage of patients categorized as having mainly central nervous system disease (70% vs. 11%), peripheral nervous system disease (19% vs. 6%), or both (11% vs. 8%).

Total SLEDAI-2K scores were also reduced following rituximab treatment, from a median of 12 at baseline to 2 (P < .0001).

Pre- and postrituximab oral prednisolone doses were a median of 15 mg and 10 mg (P = .009).

Limitations

“Our data are from a real-world setting of patients who had active neuropsychiatric disease and were treated with rituximab,” Dr. David said. There are of course many limitations that go hand in hand with observational studies.

“There was the issue of missing data,” Dr. David said. It was difficult or not possible to determine what doses of steroids patients were taking after rituximab therapy, particularly in terms of intravenous steroids, and what doses of any other concomitant disease-modifying therapy might have been around the time that patients initiated or stopped rituximab treatment.

“These could have acted as potential confounders,” she acknowledged.

Dr. Basu noted: “My major haziness from it is the uncertainty of knowing why these patients improved. Yes, they had rituximab, but I’m sure also that they probably received high doses of steroids if they had quite severe CNS lupus which was categorized as a BILAG-A or a B.”

Patients may also be given methylprednisolone when clinicians are really concerned, he continued, and “as was quite clearly pointed out,” there was quite a lot of missing data from a steroid perspective.

Dr. David and coinvestigators reported having no conflicts of interest. The BILAG-BR is supported by funding from Lupus UK, GlaxoSmithKline, and Roche. Dr. Basu did not state having any disclosures.

Patients with neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) seem to benefit from rituximab (Rituxan) therapy, according to data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR).

Indeed, the percentage of patients with active disease, as scored by the BILAG-2004 index or SLEDAI-2K (SLE Disease Activity Index 2000), fell significantly (P < .0001) when comparing pre- and postrituximab treatment scores. There was also a reduction in the dose of oral steroids used.

Interestingly, the use of concomitant cyclophosphamide might enhance the level of improvement seen in some patients, Trixy David, MBBS, reported during an abstract session at the British Society for Rheumatology annual conference.

“Larger-scale studies are warranted to establish the effectiveness of rituximab alone, or in combination with cyclophosphamide, in the treatment neuropsychiatric lupus,” said Dr. David, a clinical research fellow at the University of Manchester (England) and specialist registrar in rheumatology at the Manchester University National Health Service Foundation Trust.

Neil Basu, MBChB, PhD, who chaired the virtual session, called the findings “enlightening” and “descriptive.”

The study “provides some interesting data, which should be tested in a robust, randomized clinical trial,” he agreed, and not that clinicians should now start using rituximab for their NPSLE cases.

Dr. Basu, who is a clinical senior lecturer in rheumatology and honorary consultant rheumatologist at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, added: “It is really important that we do these studies to help support a rationale for such a trial, which are obviously very expensive and require strong evidence before we go down that track. I think these data have really been quite enlightening in that respect.”

Rationale for rituximab in neuropsychiatric lupus

Managing patients with NPSLE remains an area of substantial unmet need. According to a recent review in Rheumatology, “there is a dearth of controlled clinical trials to guide management” and “therapeutic options include symptomatic, antithrombotic, and immunosuppressive agents that are supported by observational cohort studies.”

Despite being seen in at least half of all patients with SLE, neuropsychiatric disease “is not very well studied in patients with lupus, as a lot of large-scale trials tend to exclude patients with active neurological disease,” Dr. David said.

Although it is unclear why neuropsychiatric disease occurs in SLE, it could be “as a result of vascular injury or disruption of the blood brain barrier, thereby allowing the passive diffusion of autoantibodies and cytokines across through the cerebral spinal fluid, thereby generating a proinflammatory response,” Dr. David suggested.

“We know B cells are involved in the pathogenesis of lupus, and rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells and mediates transient B-cell depletion,” she said. Notably, there have been some small studies suggesting that rituximab may be effective in neuropsychiatric lupus, and it is currently widely used to treat refractory lupus in the United Kingdom.
 

About the BILAG-BR and results

“Our aim was to describe the baseline characteristics and short-term effectiveness of rituximab in patients treated for neuropsychiatric lupus within the BILAG-BR,” Dr. David explained.

Started in 2009, the BILAG-BR now contains information on more than 1,400 individuals with SLE who have been recruited at 62 centers in the United Kingdom. Its purpose is to evaluate the long-term safety and effectiveness of biologic drugs versus standard immunosuppressive therapy such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine. To date, 1,229 patients have been treated with biologics, of whom 1,056 have received rituximab.

A total of 74 rituximab-treated patients were identified as having active neuropsychiatric disease, making this “the largest prospective observational cohort to date, to our knowledge,” Dr. David said.

The median age of patients was 45.5 years, the majority was female (82%) and White (74%). The median disease duration was 11.5 years.

A total of 96% had multiple organ involvement and not just neuropsychiatric disease, and 91% were positive for antineutrophil antibodies.

The top six neuropsychiatric manifestations were cognitive dysfunction and lupus headache (both affecting 27.5% of patients); acute confessional state or mononeuropathy (each seen in 10% of patients); and seizure disorder and polyneuropathy, seen in a respective 8.6% and 8.7% of patients. These findings are in line with a 2011 meta-analysis, Dr. David pointed out.

BILAG-2004 scores before and after rituximab treatment were available for 50 patients. The number of patients with a BILAG A score dropped from 24 (48%) at baseline to 7 (14%) after treatment with rituximab, and the number with a BILAG B score declined from 26 (52%) at baseline to 4 (8%) after rituximab (both P < .0001).

There was also a reduction following rituximab treatment in the percentage of patients categorized as having mainly central nervous system disease (70% vs. 11%), peripheral nervous system disease (19% vs. 6%), or both (11% vs. 8%).

Total SLEDAI-2K scores were also reduced following rituximab treatment, from a median of 12 at baseline to 2 (P < .0001).

Pre- and postrituximab oral prednisolone doses were a median of 15 mg and 10 mg (P = .009).

Limitations

“Our data are from a real-world setting of patients who had active neuropsychiatric disease and were treated with rituximab,” Dr. David said. There are of course many limitations that go hand in hand with observational studies.

“There was the issue of missing data,” Dr. David said. It was difficult or not possible to determine what doses of steroids patients were taking after rituximab therapy, particularly in terms of intravenous steroids, and what doses of any other concomitant disease-modifying therapy might have been around the time that patients initiated or stopped rituximab treatment.

“These could have acted as potential confounders,” she acknowledged.

Dr. Basu noted: “My major haziness from it is the uncertainty of knowing why these patients improved. Yes, they had rituximab, but I’m sure also that they probably received high doses of steroids if they had quite severe CNS lupus which was categorized as a BILAG-A or a B.”

Patients may also be given methylprednisolone when clinicians are really concerned, he continued, and “as was quite clearly pointed out,” there was quite a lot of missing data from a steroid perspective.

Dr. David and coinvestigators reported having no conflicts of interest. The BILAG-BR is supported by funding from Lupus UK, GlaxoSmithKline, and Roche. Dr. Basu did not state having any disclosures.

Patients with neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) seem to benefit from rituximab (Rituxan) therapy, according to data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR).

Indeed, the percentage of patients with active disease, as scored by the BILAG-2004 index or SLEDAI-2K (SLE Disease Activity Index 2000), fell significantly (P < .0001) when comparing pre- and postrituximab treatment scores. There was also a reduction in the dose of oral steroids used.

Interestingly, the use of concomitant cyclophosphamide might enhance the level of improvement seen in some patients, Trixy David, MBBS, reported during an abstract session at the British Society for Rheumatology annual conference.

“Larger-scale studies are warranted to establish the effectiveness of rituximab alone, or in combination with cyclophosphamide, in the treatment neuropsychiatric lupus,” said Dr. David, a clinical research fellow at the University of Manchester (England) and specialist registrar in rheumatology at the Manchester University National Health Service Foundation Trust.

Neil Basu, MBChB, PhD, who chaired the virtual session, called the findings “enlightening” and “descriptive.”

The study “provides some interesting data, which should be tested in a robust, randomized clinical trial,” he agreed, and not that clinicians should now start using rituximab for their NPSLE cases.

Dr. Basu, who is a clinical senior lecturer in rheumatology and honorary consultant rheumatologist at the Institute of Infection, Immunity and Inflammation at the University of Glasgow, added: “It is really important that we do these studies to help support a rationale for such a trial, which are obviously very expensive and require strong evidence before we go down that track. I think these data have really been quite enlightening in that respect.”

Rationale for rituximab in neuropsychiatric lupus

Managing patients with NPSLE remains an area of substantial unmet need. According to a recent review in Rheumatology, “there is a dearth of controlled clinical trials to guide management” and “therapeutic options include symptomatic, antithrombotic, and immunosuppressive agents that are supported by observational cohort studies.”

Despite being seen in at least half of all patients with SLE, neuropsychiatric disease “is not very well studied in patients with lupus, as a lot of large-scale trials tend to exclude patients with active neurological disease,” Dr. David said.

Although it is unclear why neuropsychiatric disease occurs in SLE, it could be “as a result of vascular injury or disruption of the blood brain barrier, thereby allowing the passive diffusion of autoantibodies and cytokines across through the cerebral spinal fluid, thereby generating a proinflammatory response,” Dr. David suggested.

“We know B cells are involved in the pathogenesis of lupus, and rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells and mediates transient B-cell depletion,” she said. Notably, there have been some small studies suggesting that rituximab may be effective in neuropsychiatric lupus, and it is currently widely used to treat refractory lupus in the United Kingdom.
 

About the BILAG-BR and results

“Our aim was to describe the baseline characteristics and short-term effectiveness of rituximab in patients treated for neuropsychiatric lupus within the BILAG-BR,” Dr. David explained.

Started in 2009, the BILAG-BR now contains information on more than 1,400 individuals with SLE who have been recruited at 62 centers in the United Kingdom. Its purpose is to evaluate the long-term safety and effectiveness of biologic drugs versus standard immunosuppressive therapy such as azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporine. To date, 1,229 patients have been treated with biologics, of whom 1,056 have received rituximab.

A total of 74 rituximab-treated patients were identified as having active neuropsychiatric disease, making this “the largest prospective observational cohort to date, to our knowledge,” Dr. David said.

The median age of patients was 45.5 years, the majority was female (82%) and White (74%). The median disease duration was 11.5 years.

A total of 96% had multiple organ involvement and not just neuropsychiatric disease, and 91% were positive for antineutrophil antibodies.

The top six neuropsychiatric manifestations were cognitive dysfunction and lupus headache (both affecting 27.5% of patients); acute confessional state or mononeuropathy (each seen in 10% of patients); and seizure disorder and polyneuropathy, seen in a respective 8.6% and 8.7% of patients. These findings are in line with a 2011 meta-analysis, Dr. David pointed out.

BILAG-2004 scores before and after rituximab treatment were available for 50 patients. The number of patients with a BILAG A score dropped from 24 (48%) at baseline to 7 (14%) after treatment with rituximab, and the number with a BILAG B score declined from 26 (52%) at baseline to 4 (8%) after rituximab (both P < .0001).

There was also a reduction following rituximab treatment in the percentage of patients categorized as having mainly central nervous system disease (70% vs. 11%), peripheral nervous system disease (19% vs. 6%), or both (11% vs. 8%).

Total SLEDAI-2K scores were also reduced following rituximab treatment, from a median of 12 at baseline to 2 (P < .0001).

Pre- and postrituximab oral prednisolone doses were a median of 15 mg and 10 mg (P = .009).

Limitations

“Our data are from a real-world setting of patients who had active neuropsychiatric disease and were treated with rituximab,” Dr. David said. There are of course many limitations that go hand in hand with observational studies.

“There was the issue of missing data,” Dr. David said. It was difficult or not possible to determine what doses of steroids patients were taking after rituximab therapy, particularly in terms of intravenous steroids, and what doses of any other concomitant disease-modifying therapy might have been around the time that patients initiated or stopped rituximab treatment.

“These could have acted as potential confounders,” she acknowledged.

Dr. Basu noted: “My major haziness from it is the uncertainty of knowing why these patients improved. Yes, they had rituximab, but I’m sure also that they probably received high doses of steroids if they had quite severe CNS lupus which was categorized as a BILAG-A or a B.”

Patients may also be given methylprednisolone when clinicians are really concerned, he continued, and “as was quite clearly pointed out,” there was quite a lot of missing data from a steroid perspective.

Dr. David and coinvestigators reported having no conflicts of interest. The BILAG-BR is supported by funding from Lupus UK, GlaxoSmithKline, and Roche. Dr. Basu did not state having any disclosures.

The order in which tocilizumab (Actemra) is used in the sequence of treatments for rheumatoid arthritis could be muddying the waters when it comes to evaluating patients’ risk for serious infection.

According to new data emerging from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA), the line of therapy is a confounding factor when examining the risk for serious infection with not only tocilizumab but also other biologic agents.

The good news for patients, however, is that there doesn’t appear to be any overall greater risk for serious infection with one biologic over another when the line of therapy is taken into account.

“We don’t have any strong signal that there is an increased risk of serious infections with tocilizumab, compared to TNF inhibitors,” rheumatologist Kim Lauper, MD, of Geneva University Hospitals, said in an interview after presenting the data at the annual conference of the British Society for Rheumatology.

This is in contrast to studies where an increased risk of infections with tocilizumab has been seen when compared to TNF inhibitors. However, those studies did not account for the line of therapy, explained Dr. Lauper, who is also a clinical research fellow in the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), where the BSRBR-RA is managed.

“Tocilizumab is a treatment that we often give to patients after several other treatments, so they’re really different patients,” Dr. Lauper observed. Indeed, in the “real-world” setting, patients taking tocilizumab tend to be older, have longer disease duration, and have worse functional status than do those who might receive other biologics.

To look at the effect of line of therapy on the serious infection risk associated with commonly used biologic drugs, Dr. Lauper and associates examined data on more than 33,000 treatment courses, representing more than 62,500 patient-years.

Using etanercept as the comparator – because it represents the largest group of patients in the BSRBR-RA – the serious infection risk for tocilizumab, rituximab, adalimumab, infliximab, certolizumab pegol, and abatacept were calculated as an overall rate, and for their use as first-, second-, third-, fourth-, or fifth-line therapy.

The researchers adjusted their analysis for some clear baseline differences between the treatment groups, including age, prior treatment, disease duration, and comorbidities. Seropositivity, smoking status, general health status, and disease activity scores were also adjusted for in the analysis.

Crude hazard ratios (HRs), compared with etanercept, before and after adjusting for these already-known confounding factors were 1.0 and 1.2 for tocilizumab, 1.1 and 1.1 for adalimumab, 1.4 and 1.3 for infliximab, 0.6 and 0.8 for certolizumab pegol, 0.9 and 1.0 for rituximab, and 0.9 and 1.2 for abatacept.

Stratifying by line of therapy, however, changed the results: HRs were no longer significantly different, compared with etanercept, for tocilizumab, adalimumab, and infliximab for most lines of therapy.

Indeed, while the risk for serious infection occurring with tocilizumab was 20% higher overall, compared with etanercept, that risk was actually lower if tocilizumab had been used as first- or fifth-line therapy (HRs for both, 0.9) but higher if it had been used as a third- or fourth-line therapy (HR of 1.4 for both).

“We often use tocilizumab as a second-line, third-line, or even fourth-line therapy, and if we don’t adjust for anything, we can have the impression that there are more infections with tocilizumab. But then, when we adjust for confounding factors and the line of therapy, we don’t have this anymore,” Dr. Lauper said.

“Line of therapy in itself is not a risk for serious infections,” she said in qualifying the conclusions that could be drawn from the study. “It may be a marker of the disease or some patient characteristic that is associated with a higher risk of infections.” Nevertheless, it should be taken into account when evaluating serious outcomes and possibly other safety and effectiveness outcomes.

“I understand concentrating on the hospitalized infections because the data are so much more robust,” observed consultant rheumatologist Jon Packham, BM, DM, of Haywood Hospital in Stoke-on-Trent, England, who chaired the session. He queried if there were any data on milder or just antibiotic-treated infections. At present, there aren’t those data to look at, Dr. Lauper responded, as this is something that’s difficult for registers to capture because doctors often do not log them in the databases.

There are also too few data on Janus kinase (JAK) inhibitors currently in the BSRBR-RA at present to be able to look at their rate of serious infection by line of therapy, Dr. Lauper noted. Because JAK inhibitors act on cytokines different from those affected by biologics for RA, there may be a difference there, but more data are needed on the JAK inhibitors before that question can be analyzed.

Dr. Lauper did not state having any disclosures. The BSRBR-RA is funded by the BSR via restricted income grants from several U.K. pharmaceutical companies, which has included or currently includes AbbVie, Celltrion, Hospira, Pfizer, UCB, Roche, Swedish Orphan Biovitrum, and Merck.

The order in which tocilizumab (Actemra) is used in the sequence of treatments for rheumatoid arthritis could be muddying the waters when it comes to evaluating patients’ risk for serious infection.

According to new data emerging from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA), the line of therapy is a confounding factor when examining the risk for serious infection with not only tocilizumab but also other biologic agents.

The good news for patients, however, is that there doesn’t appear to be any overall greater risk for serious infection with one biologic over another when the line of therapy is taken into account.

“We don’t have any strong signal that there is an increased risk of serious infections with tocilizumab, compared to TNF inhibitors,” rheumatologist Kim Lauper, MD, of Geneva University Hospitals, said in an interview after presenting the data at the annual conference of the British Society for Rheumatology.

This is in contrast to studies where an increased risk of infections with tocilizumab has been seen when compared to TNF inhibitors. However, those studies did not account for the line of therapy, explained Dr. Lauper, who is also a clinical research fellow in the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), where the BSRBR-RA is managed.

“Tocilizumab is a treatment that we often give to patients after several other treatments, so they’re really different patients,” Dr. Lauper observed. Indeed, in the “real-world” setting, patients taking tocilizumab tend to be older, have longer disease duration, and have worse functional status than do those who might receive other biologics.

To look at the effect of line of therapy on the serious infection risk associated with commonly used biologic drugs, Dr. Lauper and associates examined data on more than 33,000 treatment courses, representing more than 62,500 patient-years.

Using etanercept as the comparator – because it represents the largest group of patients in the BSRBR-RA – the serious infection risk for tocilizumab, rituximab, adalimumab, infliximab, certolizumab pegol, and abatacept were calculated as an overall rate, and for their use as first-, second-, third-, fourth-, or fifth-line therapy.

The researchers adjusted their analysis for some clear baseline differences between the treatment groups, including age, prior treatment, disease duration, and comorbidities. Seropositivity, smoking status, general health status, and disease activity scores were also adjusted for in the analysis.

Crude hazard ratios (HRs), compared with etanercept, before and after adjusting for these already-known confounding factors were 1.0 and 1.2 for tocilizumab, 1.1 and 1.1 for adalimumab, 1.4 and 1.3 for infliximab, 0.6 and 0.8 for certolizumab pegol, 0.9 and 1.0 for rituximab, and 0.9 and 1.2 for abatacept.

Stratifying by line of therapy, however, changed the results: HRs were no longer significantly different, compared with etanercept, for tocilizumab, adalimumab, and infliximab for most lines of therapy.

Indeed, while the risk for serious infection occurring with tocilizumab was 20% higher overall, compared with etanercept, that risk was actually lower if tocilizumab had been used as first- or fifth-line therapy (HRs for both, 0.9) but higher if it had been used as a third- or fourth-line therapy (HR of 1.4 for both).

“We often use tocilizumab as a second-line, third-line, or even fourth-line therapy, and if we don’t adjust for anything, we can have the impression that there are more infections with tocilizumab. But then, when we adjust for confounding factors and the line of therapy, we don’t have this anymore,” Dr. Lauper said.

“Line of therapy in itself is not a risk for serious infections,” she said in qualifying the conclusions that could be drawn from the study. “It may be a marker of the disease or some patient characteristic that is associated with a higher risk of infections.” Nevertheless, it should be taken into account when evaluating serious outcomes and possibly other safety and effectiveness outcomes.

“I understand concentrating on the hospitalized infections because the data are so much more robust,” observed consultant rheumatologist Jon Packham, BM, DM, of Haywood Hospital in Stoke-on-Trent, England, who chaired the session. He queried if there were any data on milder or just antibiotic-treated infections. At present, there aren’t those data to look at, Dr. Lauper responded, as this is something that’s difficult for registers to capture because doctors often do not log them in the databases.

There are also too few data on Janus kinase (JAK) inhibitors currently in the BSRBR-RA at present to be able to look at their rate of serious infection by line of therapy, Dr. Lauper noted. Because JAK inhibitors act on cytokines different from those affected by biologics for RA, there may be a difference there, but more data are needed on the JAK inhibitors before that question can be analyzed.

Dr. Lauper did not state having any disclosures. The BSRBR-RA is funded by the BSR via restricted income grants from several U.K. pharmaceutical companies, which has included or currently includes AbbVie, Celltrion, Hospira, Pfizer, UCB, Roche, Swedish Orphan Biovitrum, and Merck.

The order in which tocilizumab (Actemra) is used in the sequence of treatments for rheumatoid arthritis could be muddying the waters when it comes to evaluating patients’ risk for serious infection.

According to new data emerging from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA), the line of therapy is a confounding factor when examining the risk for serious infection with not only tocilizumab but also other biologic agents.

The good news for patients, however, is that there doesn’t appear to be any overall greater risk for serious infection with one biologic over another when the line of therapy is taken into account.

“We don’t have any strong signal that there is an increased risk of serious infections with tocilizumab, compared to TNF inhibitors,” rheumatologist Kim Lauper, MD, of Geneva University Hospitals, said in an interview after presenting the data at the annual conference of the British Society for Rheumatology.

This is in contrast to studies where an increased risk of infections with tocilizumab has been seen when compared to TNF inhibitors. However, those studies did not account for the line of therapy, explained Dr. Lauper, who is also a clinical research fellow in the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), where the BSRBR-RA is managed.

“Tocilizumab is a treatment that we often give to patients after several other treatments, so they’re really different patients,” Dr. Lauper observed. Indeed, in the “real-world” setting, patients taking tocilizumab tend to be older, have longer disease duration, and have worse functional status than do those who might receive other biologics.

To look at the effect of line of therapy on the serious infection risk associated with commonly used biologic drugs, Dr. Lauper and associates examined data on more than 33,000 treatment courses, representing more than 62,500 patient-years.

Using etanercept as the comparator – because it represents the largest group of patients in the BSRBR-RA – the serious infection risk for tocilizumab, rituximab, adalimumab, infliximab, certolizumab pegol, and abatacept were calculated as an overall rate, and for their use as first-, second-, third-, fourth-, or fifth-line therapy.

The researchers adjusted their analysis for some clear baseline differences between the treatment groups, including age, prior treatment, disease duration, and comorbidities. Seropositivity, smoking status, general health status, and disease activity scores were also adjusted for in the analysis.

Crude hazard ratios (HRs), compared with etanercept, before and after adjusting for these already-known confounding factors were 1.0 and 1.2 for tocilizumab, 1.1 and 1.1 for adalimumab, 1.4 and 1.3 for infliximab, 0.6 and 0.8 for certolizumab pegol, 0.9 and 1.0 for rituximab, and 0.9 and 1.2 for abatacept.

Stratifying by line of therapy, however, changed the results: HRs were no longer significantly different, compared with etanercept, for tocilizumab, adalimumab, and infliximab for most lines of therapy.

Indeed, while the risk for serious infection occurring with tocilizumab was 20% higher overall, compared with etanercept, that risk was actually lower if tocilizumab had been used as first- or fifth-line therapy (HRs for both, 0.9) but higher if it had been used as a third- or fourth-line therapy (HR of 1.4 for both).

“We often use tocilizumab as a second-line, third-line, or even fourth-line therapy, and if we don’t adjust for anything, we can have the impression that there are more infections with tocilizumab. But then, when we adjust for confounding factors and the line of therapy, we don’t have this anymore,” Dr. Lauper said.

“Line of therapy in itself is not a risk for serious infections,” she said in qualifying the conclusions that could be drawn from the study. “It may be a marker of the disease or some patient characteristic that is associated with a higher risk of infections.” Nevertheless, it should be taken into account when evaluating serious outcomes and possibly other safety and effectiveness outcomes.

“I understand concentrating on the hospitalized infections because the data are so much more robust,” observed consultant rheumatologist Jon Packham, BM, DM, of Haywood Hospital in Stoke-on-Trent, England, who chaired the session. He queried if there were any data on milder or just antibiotic-treated infections. At present, there aren’t those data to look at, Dr. Lauper responded, as this is something that’s difficult for registers to capture because doctors often do not log them in the databases.

There are also too few data on Janus kinase (JAK) inhibitors currently in the BSRBR-RA at present to be able to look at their rate of serious infection by line of therapy, Dr. Lauper noted. Because JAK inhibitors act on cytokines different from those affected by biologics for RA, there may be a difference there, but more data are needed on the JAK inhibitors before that question can be analyzed.

Dr. Lauper did not state having any disclosures. The BSRBR-RA is funded by the BSR via restricted income grants from several U.K. pharmaceutical companies, which has included or currently includes AbbVie, Celltrion, Hospira, Pfizer, UCB, Roche, Swedish Orphan Biovitrum, and Merck.