Rheumatoid Arthritis

Among patients with immune-mediated inflammatory diseases (IMIDs) who get COVID-19, the risk for hospitalization and death is lower if they are receiving tumor necrosis factor (TNF) inhibitor monotherapy, compared with receiving most other common drugs for these conditions, with or without TNF inhibitors, according to a study published in JAMA Network Open The only combination not associated with an increased risk for hospitalization or death was TNF inhibitor therapy with methotrexate.

“These findings support the continued use of TNF inhibitor monotherapy during the pandemic and warrant further research investigating the association of other biologic therapies with COVID-19 outcomes,” write Zara Izadi, MPharm, of the University of California, San Francisco, and her colleagues. “Treatment with TNF inhibitor combination therapy was associated with a more favorable safety profile when methotrexate rather than azathioprine/6-mercaptopurine was used, suggesting that clinicians would benefit from weighing the risks versus benefits of deescalating treatment or changing medications when a patient is receiving concomitant TNF inhibitors and azathioprine/6-mercaptopurine,” they write.
 

Findings mirror those seen in other settings

These findings are in line with what has been found in other settings, according to Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, Philadelphia.

“In the beginning of the pandemic, there was concern about use of immune-modulating treatments, and many patients self-discontinued treatments like TNF inhibitors,” Dr. Gelfand, who was not involved in the study, told this news organization. “This has ultimately proved unnecessary and unfortunately resulted in harm to many patients due to flaring of their underlying disease.”

Dr. Gelfand emphasized the importance of vaccinating patients against COVID-19 as soon as possible and of getting a third dose for those who are already fully vaccinated with the Pfizer or Moderna shots, as recommended by the Centers for Disease Control and Prevention.

“I typically recommend this third dose be taken 6 months after the second dose,” Dr. Gelfand said. “The good news is that TNF inhibitors do not seem to meaningfully impact response to mRNA vaccines.”
 

Study details

The researchers analyzed data from three international registries of adults with rheumatic diseases, inflammatory bowel disease, and psoriasis who had COVID-19 between March 12, 2020, and Feb. 1, 2021. The registries included the Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry, the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), and the physician-reported registry from the Global Rheumatology Alliance (GRA).

The population included 6,077 patients from 74 countries. About half of the cohort (52.9%) were from Europe; more than half were women (58.6%). The average age was 48 years. A little over one-third of the patients (35.3%) had rheumatoid arthritis, 25.3% had Crohn’s disease, 12.5% had ulcerative colitis, 10.3% had spondyloarthritis, and 9.3% had psoriatic arthritis. Smaller percentages had psoriasis (4.9%), another type of arthritis or multiple types (1.7%), or another inflammatory bowel disease (0.6%).

One in five patients (21.3%) were hospitalized, and 3.1% died. The researchers compared outcomes for those who were receiving TNF inhibitor therapy alone to outcomes for those who were taking azathioprine/6-mercaptopurine therapy (alone or with a TNF inhibitor), methotrexate (alone or with a TNF inhibitor), and Janus kinase (JAK) inhibitors. They adjusted their analysis to account for active disease and common comorbidities, as well as geography and the period during the pandemic in which the person was admitted, because treatment regimens and hospitalization indications have varied over time.

All of the therapies except the combination of TNF inhibitors and methotrexate were associated with higher odds of hospitalization and death than TNF inhibitor monotherapy.

The researchers explored several possible explanations for the findings, including the possibility that high serum TNF concentrations may have been associated with more organ damage at the time of COVID-19 admission, owing to interaction with SARS-CoV-2–associated hyperinflammation.

“Therefore, blocking TNF could inhibit this detrimental immune response,” the authors write. “Multiple case series reporting favorable outcomes among patients receiving TNF inhibitor therapy support this assertion.”

Another possibility relates to the effects of taking non–TNF inhibitor medications for immunosuppression. The authors note that thiopurine medications are linked to a greater risk for opportunistic viral infections and that JAK inhibitors may reduce the body’s ability to clear the virus because of its suppression of innate immune response.

The authors also postulate that methotrexate may lower the likelihood of cytokine storm linked to COVID-19, even though methotrexate monotherapy was associated with poorer outcomes. “This association could mean that TNF inhibitor therapy is exerting a protective benefit or that methotrexate therapy is exerting a harmful consequence,” the authors write.

 

Caution needed in interpreting uncontrolled, registry-based data

The findings were not surprising to Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, who was not involved in the research.

Northwestern University

“We’ve been monitoring IBD [inflammatory bowel disease] patients through the Secure registry similar to the rheumatologic and dermatologic societies and have not identified a signal of harm from any international groups,” Dr. Hanauer told this news organization. He noted that these registries also have not shown an increased risk for COVID-19 complications among patients receiving TNF inhibitors, antiadhesion therapies, or anti–IL12/23 inhibitors, compared with the general population not taking these therapies.

The study’s size and the diversity of patients strengthen its findings. However, the registries’ use of convenience sampling increases the potential for reporting bias, although the results remained similar after a sensitivity analysis. The study also lacked a control group, and the registries did not collect data uniformly.

“These are databases that rely on reporting from investigators and are not comprehensive prospective studies,” Dr. Hanauer noted as another study limitation.

Dr. Gelfand similarly advised caution in interpreting these findings, inasmuch as the study is a “collection of spontaneous reports” that should be viewed as hypothesis-generating rather than testing.

“Fortunately, more rigorous studies have been conducted, typically in large medical record systems, and have confirmed the hypothesis that TNF inhibitors are associated with a lower risk of poor COVID-19 outcomes, compared to other treatments,” Dr. Gelfand said.

Previous smaller studies similarly found better outcomes among patients taking TNF inhibitors, compared with other therapies, but their participants were predominantly from North America and Europe, noted Licio A. Velloso, MD, PhD, of the University of Campinas, in São Paulo, in an accompanying commentary.

On the basis of the findings of this study, “which included a much larger sample comprising distinct diseases and patients with a multitude of genetic backgrounds, the evidence in favor of the continued use of TNF inhibitor monotherapy for patients with IMIDs during the COVID-19 pandemic has become more substantial,” Dr. Velloso writes. “The finding that maintenance of TNF inhibitor monotherapy is associated with reductions in the risk of severe COVID-19 among patients with IMIDs offers new perspective that may guide health care professionals in the difficult decisions regarding therapeutic approaches among this specific group of patients.”

The research was funded by the American College of Rheumatology, the European Alliance of Associations for Rheumatology, the United Kingdom’s National Institute for Health Research Biomedical Research Center, and the Psoriasis Association. Many authors reported receiving grants and/or personal fees from a variety of pharmaceutical companies. Dr. Velloso has disclosed no relevant financial relationships. Dr. Hanauer has served as a consultant to companies that market TNF inhibitors. Dr. Gelfand has consulted for and received research grants from companies that market TNF inhibitors.

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

Among patients with immune-mediated inflammatory diseases (IMIDs) who get COVID-19, the risk for hospitalization and death is lower if they are receiving tumor necrosis factor (TNF) inhibitor monotherapy, compared with receiving most other common drugs for these conditions, with or without TNF inhibitors, according to a study published in JAMA Network Open The only combination not associated with an increased risk for hospitalization or death was TNF inhibitor therapy with methotrexate.

“These findings support the continued use of TNF inhibitor monotherapy during the pandemic and warrant further research investigating the association of other biologic therapies with COVID-19 outcomes,” write Zara Izadi, MPharm, of the University of California, San Francisco, and her colleagues. “Treatment with TNF inhibitor combination therapy was associated with a more favorable safety profile when methotrexate rather than azathioprine/6-mercaptopurine was used, suggesting that clinicians would benefit from weighing the risks versus benefits of deescalating treatment or changing medications when a patient is receiving concomitant TNF inhibitors and azathioprine/6-mercaptopurine,” they write.
 

Findings mirror those seen in other settings

These findings are in line with what has been found in other settings, according to Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, Philadelphia.

“In the beginning of the pandemic, there was concern about use of immune-modulating treatments, and many patients self-discontinued treatments like TNF inhibitors,” Dr. Gelfand, who was not involved in the study, told this news organization. “This has ultimately proved unnecessary and unfortunately resulted in harm to many patients due to flaring of their underlying disease.”

Dr. Gelfand emphasized the importance of vaccinating patients against COVID-19 as soon as possible and of getting a third dose for those who are already fully vaccinated with the Pfizer or Moderna shots, as recommended by the Centers for Disease Control and Prevention.

“I typically recommend this third dose be taken 6 months after the second dose,” Dr. Gelfand said. “The good news is that TNF inhibitors do not seem to meaningfully impact response to mRNA vaccines.”
 

Study details

The researchers analyzed data from three international registries of adults with rheumatic diseases, inflammatory bowel disease, and psoriasis who had COVID-19 between March 12, 2020, and Feb. 1, 2021. The registries included the Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry, the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), and the physician-reported registry from the Global Rheumatology Alliance (GRA).

The population included 6,077 patients from 74 countries. About half of the cohort (52.9%) were from Europe; more than half were women (58.6%). The average age was 48 years. A little over one-third of the patients (35.3%) had rheumatoid arthritis, 25.3% had Crohn’s disease, 12.5% had ulcerative colitis, 10.3% had spondyloarthritis, and 9.3% had psoriatic arthritis. Smaller percentages had psoriasis (4.9%), another type of arthritis or multiple types (1.7%), or another inflammatory bowel disease (0.6%).

One in five patients (21.3%) were hospitalized, and 3.1% died. The researchers compared outcomes for those who were receiving TNF inhibitor therapy alone to outcomes for those who were taking azathioprine/6-mercaptopurine therapy (alone or with a TNF inhibitor), methotrexate (alone or with a TNF inhibitor), and Janus kinase (JAK) inhibitors. They adjusted their analysis to account for active disease and common comorbidities, as well as geography and the period during the pandemic in which the person was admitted, because treatment regimens and hospitalization indications have varied over time.

All of the therapies except the combination of TNF inhibitors and methotrexate were associated with higher odds of hospitalization and death than TNF inhibitor monotherapy.

The researchers explored several possible explanations for the findings, including the possibility that high serum TNF concentrations may have been associated with more organ damage at the time of COVID-19 admission, owing to interaction with SARS-CoV-2–associated hyperinflammation.

“Therefore, blocking TNF could inhibit this detrimental immune response,” the authors write. “Multiple case series reporting favorable outcomes among patients receiving TNF inhibitor therapy support this assertion.”

Another possibility relates to the effects of taking non–TNF inhibitor medications for immunosuppression. The authors note that thiopurine medications are linked to a greater risk for opportunistic viral infections and that JAK inhibitors may reduce the body’s ability to clear the virus because of its suppression of innate immune response.

The authors also postulate that methotrexate may lower the likelihood of cytokine storm linked to COVID-19, even though methotrexate monotherapy was associated with poorer outcomes. “This association could mean that TNF inhibitor therapy is exerting a protective benefit or that methotrexate therapy is exerting a harmful consequence,” the authors write.

 

Caution needed in interpreting uncontrolled, registry-based data

The findings were not surprising to Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, who was not involved in the research.

Northwestern University

“We’ve been monitoring IBD [inflammatory bowel disease] patients through the Secure registry similar to the rheumatologic and dermatologic societies and have not identified a signal of harm from any international groups,” Dr. Hanauer told this news organization. He noted that these registries also have not shown an increased risk for COVID-19 complications among patients receiving TNF inhibitors, antiadhesion therapies, or anti–IL12/23 inhibitors, compared with the general population not taking these therapies.

The study’s size and the diversity of patients strengthen its findings. However, the registries’ use of convenience sampling increases the potential for reporting bias, although the results remained similar after a sensitivity analysis. The study also lacked a control group, and the registries did not collect data uniformly.

“These are databases that rely on reporting from investigators and are not comprehensive prospective studies,” Dr. Hanauer noted as another study limitation.

Dr. Gelfand similarly advised caution in interpreting these findings, inasmuch as the study is a “collection of spontaneous reports” that should be viewed as hypothesis-generating rather than testing.

“Fortunately, more rigorous studies have been conducted, typically in large medical record systems, and have confirmed the hypothesis that TNF inhibitors are associated with a lower risk of poor COVID-19 outcomes, compared to other treatments,” Dr. Gelfand said.

Previous smaller studies similarly found better outcomes among patients taking TNF inhibitors, compared with other therapies, but their participants were predominantly from North America and Europe, noted Licio A. Velloso, MD, PhD, of the University of Campinas, in São Paulo, in an accompanying commentary.

On the basis of the findings of this study, “which included a much larger sample comprising distinct diseases and patients with a multitude of genetic backgrounds, the evidence in favor of the continued use of TNF inhibitor monotherapy for patients with IMIDs during the COVID-19 pandemic has become more substantial,” Dr. Velloso writes. “The finding that maintenance of TNF inhibitor monotherapy is associated with reductions in the risk of severe COVID-19 among patients with IMIDs offers new perspective that may guide health care professionals in the difficult decisions regarding therapeutic approaches among this specific group of patients.”

The research was funded by the American College of Rheumatology, the European Alliance of Associations for Rheumatology, the United Kingdom’s National Institute for Health Research Biomedical Research Center, and the Psoriasis Association. Many authors reported receiving grants and/or personal fees from a variety of pharmaceutical companies. Dr. Velloso has disclosed no relevant financial relationships. Dr. Hanauer has served as a consultant to companies that market TNF inhibitors. Dr. Gelfand has consulted for and received research grants from companies that market TNF inhibitors.

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

Among patients with immune-mediated inflammatory diseases (IMIDs) who get COVID-19, the risk for hospitalization and death is lower if they are receiving tumor necrosis factor (TNF) inhibitor monotherapy, compared with receiving most other common drugs for these conditions, with or without TNF inhibitors, according to a study published in JAMA Network Open The only combination not associated with an increased risk for hospitalization or death was TNF inhibitor therapy with methotrexate.

“These findings support the continued use of TNF inhibitor monotherapy during the pandemic and warrant further research investigating the association of other biologic therapies with COVID-19 outcomes,” write Zara Izadi, MPharm, of the University of California, San Francisco, and her colleagues. “Treatment with TNF inhibitor combination therapy was associated with a more favorable safety profile when methotrexate rather than azathioprine/6-mercaptopurine was used, suggesting that clinicians would benefit from weighing the risks versus benefits of deescalating treatment or changing medications when a patient is receiving concomitant TNF inhibitors and azathioprine/6-mercaptopurine,” they write.
 

Findings mirror those seen in other settings

These findings are in line with what has been found in other settings, according to Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, Philadelphia.

“In the beginning of the pandemic, there was concern about use of immune-modulating treatments, and many patients self-discontinued treatments like TNF inhibitors,” Dr. Gelfand, who was not involved in the study, told this news organization. “This has ultimately proved unnecessary and unfortunately resulted in harm to many patients due to flaring of their underlying disease.”

Dr. Gelfand emphasized the importance of vaccinating patients against COVID-19 as soon as possible and of getting a third dose for those who are already fully vaccinated with the Pfizer or Moderna shots, as recommended by the Centers for Disease Control and Prevention.

“I typically recommend this third dose be taken 6 months after the second dose,” Dr. Gelfand said. “The good news is that TNF inhibitors do not seem to meaningfully impact response to mRNA vaccines.”
 

Study details

The researchers analyzed data from three international registries of adults with rheumatic diseases, inflammatory bowel disease, and psoriasis who had COVID-19 between March 12, 2020, and Feb. 1, 2021. The registries included the Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry, the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), and the physician-reported registry from the Global Rheumatology Alliance (GRA).

The population included 6,077 patients from 74 countries. About half of the cohort (52.9%) were from Europe; more than half were women (58.6%). The average age was 48 years. A little over one-third of the patients (35.3%) had rheumatoid arthritis, 25.3% had Crohn’s disease, 12.5% had ulcerative colitis, 10.3% had spondyloarthritis, and 9.3% had psoriatic arthritis. Smaller percentages had psoriasis (4.9%), another type of arthritis or multiple types (1.7%), or another inflammatory bowel disease (0.6%).

One in five patients (21.3%) were hospitalized, and 3.1% died. The researchers compared outcomes for those who were receiving TNF inhibitor therapy alone to outcomes for those who were taking azathioprine/6-mercaptopurine therapy (alone or with a TNF inhibitor), methotrexate (alone or with a TNF inhibitor), and Janus kinase (JAK) inhibitors. They adjusted their analysis to account for active disease and common comorbidities, as well as geography and the period during the pandemic in which the person was admitted, because treatment regimens and hospitalization indications have varied over time.

All of the therapies except the combination of TNF inhibitors and methotrexate were associated with higher odds of hospitalization and death than TNF inhibitor monotherapy.

The researchers explored several possible explanations for the findings, including the possibility that high serum TNF concentrations may have been associated with more organ damage at the time of COVID-19 admission, owing to interaction with SARS-CoV-2–associated hyperinflammation.

“Therefore, blocking TNF could inhibit this detrimental immune response,” the authors write. “Multiple case series reporting favorable outcomes among patients receiving TNF inhibitor therapy support this assertion.”

Another possibility relates to the effects of taking non–TNF inhibitor medications for immunosuppression. The authors note that thiopurine medications are linked to a greater risk for opportunistic viral infections and that JAK inhibitors may reduce the body’s ability to clear the virus because of its suppression of innate immune response.

The authors also postulate that methotrexate may lower the likelihood of cytokine storm linked to COVID-19, even though methotrexate monotherapy was associated with poorer outcomes. “This association could mean that TNF inhibitor therapy is exerting a protective benefit or that methotrexate therapy is exerting a harmful consequence,” the authors write.

 

Caution needed in interpreting uncontrolled, registry-based data

The findings were not surprising to Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, who was not involved in the research.

Northwestern University

“We’ve been monitoring IBD [inflammatory bowel disease] patients through the Secure registry similar to the rheumatologic and dermatologic societies and have not identified a signal of harm from any international groups,” Dr. Hanauer told this news organization. He noted that these registries also have not shown an increased risk for COVID-19 complications among patients receiving TNF inhibitors, antiadhesion therapies, or anti–IL12/23 inhibitors, compared with the general population not taking these therapies.

The study’s size and the diversity of patients strengthen its findings. However, the registries’ use of convenience sampling increases the potential for reporting bias, although the results remained similar after a sensitivity analysis. The study also lacked a control group, and the registries did not collect data uniformly.

“These are databases that rely on reporting from investigators and are not comprehensive prospective studies,” Dr. Hanauer noted as another study limitation.

Dr. Gelfand similarly advised caution in interpreting these findings, inasmuch as the study is a “collection of spontaneous reports” that should be viewed as hypothesis-generating rather than testing.

“Fortunately, more rigorous studies have been conducted, typically in large medical record systems, and have confirmed the hypothesis that TNF inhibitors are associated with a lower risk of poor COVID-19 outcomes, compared to other treatments,” Dr. Gelfand said.

Previous smaller studies similarly found better outcomes among patients taking TNF inhibitors, compared with other therapies, but their participants were predominantly from North America and Europe, noted Licio A. Velloso, MD, PhD, of the University of Campinas, in São Paulo, in an accompanying commentary.

On the basis of the findings of this study, “which included a much larger sample comprising distinct diseases and patients with a multitude of genetic backgrounds, the evidence in favor of the continued use of TNF inhibitor monotherapy for patients with IMIDs during the COVID-19 pandemic has become more substantial,” Dr. Velloso writes. “The finding that maintenance of TNF inhibitor monotherapy is associated with reductions in the risk of severe COVID-19 among patients with IMIDs offers new perspective that may guide health care professionals in the difficult decisions regarding therapeutic approaches among this specific group of patients.”

The research was funded by the American College of Rheumatology, the European Alliance of Associations for Rheumatology, the United Kingdom’s National Institute for Health Research Biomedical Research Center, and the Psoriasis Association. Many authors reported receiving grants and/or personal fees from a variety of pharmaceutical companies. Dr. Velloso has disclosed no relevant financial relationships. Dr. Hanauer has served as a consultant to companies that market TNF inhibitors. Dr. Gelfand has consulted for and received research grants from companies that market TNF inhibitors.

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

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.

Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published Oct. 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)

Higher risk of adverse outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
 

Potential for confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
 

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

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.

Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published Oct. 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)

Higher risk of adverse outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
 

Potential for confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
 

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

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.

Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published Oct. 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)

Higher risk of adverse outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
 

Potential for confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
 

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

Nearly a quarter of adults in the United States have been diagnosed with various forms of arthritis, new federal estimates report. The disorders limit the activities of 43.9% of them. Researchers also report that adults with poorer mental or physical health and those who are more disadvantaged socially are most vulnerable to arthritis.

“There is a substantial unmet need for existing, evidence-based, arthritis-appropriate interventions for people with arthritis to minimize activity limitations,” study coauthor and Centers for Disease Control and Prevention epidemiologist Kristina Theis, PhD, MPH, told this news organization. “Our findings show that interventions addressing self-management, education, physical activity, workplace accommodations, and mental health, among other areas, are all indicated for people with arthritis.”

The CDC report was published Oct. 8 in Morbidity and Mortality Weekly Report. Researchers estimated the number of arthritis cases on the basis of in-person interviews conducted with tens of thousands of U.S. adults as part of the National Health Interview Survey during 2016-2018. In the report, the researchers considered arthritis to include general arthritis, rheumatoid arthritis, gout, lupus, and fibromyalgia.
 

Activity limitations rose faster than predicted

According to the report, an estimated 58.5 million U.S. adults (23.7%; 21.5% age-standardized) told interviewers that they had been diagnosed with arthritis conditions. Of those, 25.7 million (43.9%; 40.8% age-standardized) had arthritis-attributable activity limitations (AAALs), which represents 10.4% of all adults.

The number of adults who reported having arthritis rose by 4.1 million from previous estimates for the years 2013-2015, a number that’s on pace with predictions. The number in the AAAL category rose by 2 million, a jump that’s higher than what had been predicted.

“The aging of the population is one factor in the increasing number of people with arthritis, even though arthritis is not an inevitable part of aging,” Dr. Theis said. “Individual factors, such as body mass index or other health conditions, and societal factors, such as educational and economic opportunities, likely play a role.”

Arthritis was especially common among those aged ≥ 65 years (50.4%), those who were unable to work or were disabled (52.3%), and those who self-reported fair/poor health (51.2%) or joint symptoms in the past 30 days (52.2%). The rate of arthritis was also high among those whose activities of daily living (ADL) were limited (54.8%) and those whose instrumental activities of daily living (IADL) were limited (55.9%).

The researchers report that the percentage of AAAL was also high among the following groups: “adults with joint symptoms in the past 30 days (51.6%), adults who were unable to work or disabled (54.7%), adults of other/multiple races (54.5%) or non-Hispanic American Indian or Alaska Natives (60.7%), adults with low income (53.3%) or poor/near poor income-to-poverty ratios (63.3%), or with moderate psychological distress (59.5%). AAAL was reported by a high proportion of adults with arthritis who had an ADL disability (82.6%), IADL disability (80.4%), serious psychological distress (76.3%), or fair/poor self-rated health (72.6%).”

The researchers found that among all adults with arthritis, the percentage of adults with arthritis was high among women (59.3%), those with obesity or overweight (74.2%), and those who weren’t sufficiently active (58%).

Comments on latest findings

Michael LaValley, PhD, biostatistician at the Boston University School of Public Health, who has studied arthritis statistics, told this news organization that the findings “fall right in line with the trends that have been observed in arthritis over the past 20 years. The prevalence is increasing, which certainly seems to be influenced by the aging population in the U.S.”

As for specific conditions, he said the rate of osteoarthritis may be influenced by older Americans and by those with obesity and sedentary behavior. “There is also some thinking that there may be environmental factors increasing the risk for some types of arthritis, but nothing conclusive. There also may be more clinical attention paid to arthritic conditions, leading to more people being diagnosed or even just suspecting that they have arthritis.”

It’s difficult to disentangle connections between arthritis and risk factors such as poverty, he said. “There almost certainly are occupational exposures that put people at risk of osteoarthritis – having to kneel, stoop, and lift heavy things – or other musculoskeletal conditions like lower back pain. These exposures are most likely in jobs that would predominantly go to people with few other options because of lower levels of income and education. People in these jobs would also be more likely to have financial stresses that lead to increased psychological distress and less time to take care of their health.”

Also, he said, “There is probably some reverse causation with the occupational results, self-related health, and psychological distress. These could all be affected by a person’s arthritis. Having arthritis may interfere with getting a better-paying job, and arthritis could certainly reduce someone’s self-reported health and induce psychological distress.”

The authors and LaValley have disclosed no relevant financial relationships.

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

Nearly a quarter of adults in the United States have been diagnosed with various forms of arthritis, new federal estimates report. The disorders limit the activities of 43.9% of them. Researchers also report that adults with poorer mental or physical health and those who are more disadvantaged socially are most vulnerable to arthritis.

“There is a substantial unmet need for existing, evidence-based, arthritis-appropriate interventions for people with arthritis to minimize activity limitations,” study coauthor and Centers for Disease Control and Prevention epidemiologist Kristina Theis, PhD, MPH, told this news organization. “Our findings show that interventions addressing self-management, education, physical activity, workplace accommodations, and mental health, among other areas, are all indicated for people with arthritis.”

The CDC report was published Oct. 8 in Morbidity and Mortality Weekly Report. Researchers estimated the number of arthritis cases on the basis of in-person interviews conducted with tens of thousands of U.S. adults as part of the National Health Interview Survey during 2016-2018. In the report, the researchers considered arthritis to include general arthritis, rheumatoid arthritis, gout, lupus, and fibromyalgia.
 

Activity limitations rose faster than predicted

According to the report, an estimated 58.5 million U.S. adults (23.7%; 21.5% age-standardized) told interviewers that they had been diagnosed with arthritis conditions. Of those, 25.7 million (43.9%; 40.8% age-standardized) had arthritis-attributable activity limitations (AAALs), which represents 10.4% of all adults.

The number of adults who reported having arthritis rose by 4.1 million from previous estimates for the years 2013-2015, a number that’s on pace with predictions. The number in the AAAL category rose by 2 million, a jump that’s higher than what had been predicted.

“The aging of the population is one factor in the increasing number of people with arthritis, even though arthritis is not an inevitable part of aging,” Dr. Theis said. “Individual factors, such as body mass index or other health conditions, and societal factors, such as educational and economic opportunities, likely play a role.”

Arthritis was especially common among those aged ≥ 65 years (50.4%), those who were unable to work or were disabled (52.3%), and those who self-reported fair/poor health (51.2%) or joint symptoms in the past 30 days (52.2%). The rate of arthritis was also high among those whose activities of daily living (ADL) were limited (54.8%) and those whose instrumental activities of daily living (IADL) were limited (55.9%).

The researchers report that the percentage of AAAL was also high among the following groups: “adults with joint symptoms in the past 30 days (51.6%), adults who were unable to work or disabled (54.7%), adults of other/multiple races (54.5%) or non-Hispanic American Indian or Alaska Natives (60.7%), adults with low income (53.3%) or poor/near poor income-to-poverty ratios (63.3%), or with moderate psychological distress (59.5%). AAAL was reported by a high proportion of adults with arthritis who had an ADL disability (82.6%), IADL disability (80.4%), serious psychological distress (76.3%), or fair/poor self-rated health (72.6%).”

The researchers found that among all adults with arthritis, the percentage of adults with arthritis was high among women (59.3%), those with obesity or overweight (74.2%), and those who weren’t sufficiently active (58%).

Comments on latest findings

Michael LaValley, PhD, biostatistician at the Boston University School of Public Health, who has studied arthritis statistics, told this news organization that the findings “fall right in line with the trends that have been observed in arthritis over the past 20 years. The prevalence is increasing, which certainly seems to be influenced by the aging population in the U.S.”

As for specific conditions, he said the rate of osteoarthritis may be influenced by older Americans and by those with obesity and sedentary behavior. “There is also some thinking that there may be environmental factors increasing the risk for some types of arthritis, but nothing conclusive. There also may be more clinical attention paid to arthritic conditions, leading to more people being diagnosed or even just suspecting that they have arthritis.”

It’s difficult to disentangle connections between arthritis and risk factors such as poverty, he said. “There almost certainly are occupational exposures that put people at risk of osteoarthritis – having to kneel, stoop, and lift heavy things – or other musculoskeletal conditions like lower back pain. These exposures are most likely in jobs that would predominantly go to people with few other options because of lower levels of income and education. People in these jobs would also be more likely to have financial stresses that lead to increased psychological distress and less time to take care of their health.”

Also, he said, “There is probably some reverse causation with the occupational results, self-related health, and psychological distress. These could all be affected by a person’s arthritis. Having arthritis may interfere with getting a better-paying job, and arthritis could certainly reduce someone’s self-reported health and induce psychological distress.”

The authors and LaValley have disclosed no relevant financial relationships.

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

Nearly a quarter of adults in the United States have been diagnosed with various forms of arthritis, new federal estimates report. The disorders limit the activities of 43.9% of them. Researchers also report that adults with poorer mental or physical health and those who are more disadvantaged socially are most vulnerable to arthritis.

“There is a substantial unmet need for existing, evidence-based, arthritis-appropriate interventions for people with arthritis to minimize activity limitations,” study coauthor and Centers for Disease Control and Prevention epidemiologist Kristina Theis, PhD, MPH, told this news organization. “Our findings show that interventions addressing self-management, education, physical activity, workplace accommodations, and mental health, among other areas, are all indicated for people with arthritis.”

The CDC report was published Oct. 8 in Morbidity and Mortality Weekly Report. Researchers estimated the number of arthritis cases on the basis of in-person interviews conducted with tens of thousands of U.S. adults as part of the National Health Interview Survey during 2016-2018. In the report, the researchers considered arthritis to include general arthritis, rheumatoid arthritis, gout, lupus, and fibromyalgia.
 

Activity limitations rose faster than predicted

According to the report, an estimated 58.5 million U.S. adults (23.7%; 21.5% age-standardized) told interviewers that they had been diagnosed with arthritis conditions. Of those, 25.7 million (43.9%; 40.8% age-standardized) had arthritis-attributable activity limitations (AAALs), which represents 10.4% of all adults.

The number of adults who reported having arthritis rose by 4.1 million from previous estimates for the years 2013-2015, a number that’s on pace with predictions. The number in the AAAL category rose by 2 million, a jump that’s higher than what had been predicted.

“The aging of the population is one factor in the increasing number of people with arthritis, even though arthritis is not an inevitable part of aging,” Dr. Theis said. “Individual factors, such as body mass index or other health conditions, and societal factors, such as educational and economic opportunities, likely play a role.”

Arthritis was especially common among those aged ≥ 65 years (50.4%), those who were unable to work or were disabled (52.3%), and those who self-reported fair/poor health (51.2%) or joint symptoms in the past 30 days (52.2%). The rate of arthritis was also high among those whose activities of daily living (ADL) were limited (54.8%) and those whose instrumental activities of daily living (IADL) were limited (55.9%).

The researchers report that the percentage of AAAL was also high among the following groups: “adults with joint symptoms in the past 30 days (51.6%), adults who were unable to work or disabled (54.7%), adults of other/multiple races (54.5%) or non-Hispanic American Indian or Alaska Natives (60.7%), adults with low income (53.3%) or poor/near poor income-to-poverty ratios (63.3%), or with moderate psychological distress (59.5%). AAAL was reported by a high proportion of adults with arthritis who had an ADL disability (82.6%), IADL disability (80.4%), serious psychological distress (76.3%), or fair/poor self-rated health (72.6%).”

The researchers found that among all adults with arthritis, the percentage of adults with arthritis was high among women (59.3%), those with obesity or overweight (74.2%), and those who weren’t sufficiently active (58%).

Comments on latest findings

Michael LaValley, PhD, biostatistician at the Boston University School of Public Health, who has studied arthritis statistics, told this news organization that the findings “fall right in line with the trends that have been observed in arthritis over the past 20 years. The prevalence is increasing, which certainly seems to be influenced by the aging population in the U.S.”

As for specific conditions, he said the rate of osteoarthritis may be influenced by older Americans and by those with obesity and sedentary behavior. “There is also some thinking that there may be environmental factors increasing the risk for some types of arthritis, but nothing conclusive. There also may be more clinical attention paid to arthritic conditions, leading to more people being diagnosed or even just suspecting that they have arthritis.”

It’s difficult to disentangle connections between arthritis and risk factors such as poverty, he said. “There almost certainly are occupational exposures that put people at risk of osteoarthritis – having to kneel, stoop, and lift heavy things – or other musculoskeletal conditions like lower back pain. These exposures are most likely in jobs that would predominantly go to people with few other options because of lower levels of income and education. People in these jobs would also be more likely to have financial stresses that lead to increased psychological distress and less time to take care of their health.”

Also, he said, “There is probably some reverse causation with the occupational results, self-related health, and psychological distress. These could all be affected by a person’s arthritis. Having arthritis may interfere with getting a better-paying job, and arthritis could certainly reduce someone’s self-reported health and induce psychological distress.”

The authors and LaValley have disclosed no relevant financial relationships.

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

Patients who are being treated with Janus kinase (JAK) inhibitors overall show a high immune response rate to COVID-19 vaccination, one that matches the rates seen in patients on other immunosuppressants, a new study has found.

The patients taking a JAK inhibitor who are most at risk of a diminished response may be those on upadacitinib (Rinvoq) and anyone 65 years or older, wrote Raphaèle Seror, MD, PhD, of Paris-Saclay (France) University and coauthors. The study was published in The Lancet Rheumatology.

To gauge the effectiveness of COVID-19 vaccines in this subset of immunosuppressed patients, the researchers analyzed 113 participants in the MAJIK-SFR Registry, a multicenter study of French patients with rheumatoid or psoriatic arthritis. The participants were treated at 13 centers throughout France; their mean age was 61.8 years (standard deviation, 12.5), and 72% were female. A total of 56 were taking baricitinib (Olumiant), 30 were taking tofacitinib (Xeljanz), and 27 were taking upadacitinib.

Serologic assessment was performed an average of 8.7 weeks (SD, 5.2) after the last dose of vaccine. The overall response rate – defined as the proportion of patients with detectable anti-spike antibodies per manufacturer’s cutoff values – was 88% (100 of 113). The nonresponse rate was higher with upadacitinib (7 of 27 patients, 26%) than with baricitinib (5 of 56, 9%) or tofacitinib (1 of 30, 3%). The only nonresponders who were not age 65 or older were four of the seven who received upadacitinib. The interval between the last vaccine dose and serologic assessment was somewhat longer in nonresponders (11.3 weeks) than in responders (8.3 weeks).

Earlier this year, the American College of Rheumatology recommended withholding JAK inhibitors for 1 week after each vaccine dose because of “concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response Only two patients in the study had treatment with JAK inhibitors stopped before or after vaccination.

Questions about antibody levels remain difficult to answer

“This study does further confirm a big point,” said Alfred Kim, MD, PhD, of Washington University, St. Louis, in an interview. “Most people on any sort of immunosuppression, with rare exceptions, can mount responses to COVID-19 vaccination.”

“What level of response is going to be sufficient, of course, is not clear,” he added. “Even though most people generate responses, at the population level those responses seem lower than those in nonimmunosuppressed people. Particularly for those on upadacitinib, which is lower than patients on the other JAK inhibitors. Is that problematic? We don’t know yet.”

Dr. Kim, who was part of a separate, earlier study that assessed vaccine response in patients with chronic inflammatory disease who were being treated with immunosuppressive medications, noted that many of the questions patients are asking about their antibody levels cannot yet be answered.

“It’s kind of the Wild West of serologic testing out there right now,” he said. “Even though we’re recommending that people still don’t check their antibody levels because their results are largely inactionable, everyone is still getting them anyway. But each of these tests are slightly different, and the results and the interpretation are further clouded because of those slight performance differences between each platform.”

Dr. Kim highlighted the number of different tests as one of this study’s notable limitations: 11 different assays were used to determine patients’ immune responses. “The authors made the argument that these tests are FDA approved, and that’s true, but that doesn’t necessarily mean much. Approval does translate to technical reliability but not to comparisons between the tests.”

As for next steps, both the authors and Dr. Kim recognized the need for a prospective trial. “To do a vaccine effectiveness–type study and show clinical protection against either infection or hospitalization – those are going to take a while, simply because of the nature of how many people you need for each of these studies,” he said. “Time will tell whether or not the data that are being presented here will translate literally into protective outcomes downstream.”

The MAJIK Registry is supported by the French Rheumatology Society. The authors acknowledged numerous potential conflicts of interest, including receiving consulting fees, research support, and honoraria from various pharmaceutical companies.

Patients who are being treated with Janus kinase (JAK) inhibitors overall show a high immune response rate to COVID-19 vaccination, one that matches the rates seen in patients on other immunosuppressants, a new study has found.

The patients taking a JAK inhibitor who are most at risk of a diminished response may be those on upadacitinib (Rinvoq) and anyone 65 years or older, wrote Raphaèle Seror, MD, PhD, of Paris-Saclay (France) University and coauthors. The study was published in The Lancet Rheumatology.

To gauge the effectiveness of COVID-19 vaccines in this subset of immunosuppressed patients, the researchers analyzed 113 participants in the MAJIK-SFR Registry, a multicenter study of French patients with rheumatoid or psoriatic arthritis. The participants were treated at 13 centers throughout France; their mean age was 61.8 years (standard deviation, 12.5), and 72% were female. A total of 56 were taking baricitinib (Olumiant), 30 were taking tofacitinib (Xeljanz), and 27 were taking upadacitinib.

Serologic assessment was performed an average of 8.7 weeks (SD, 5.2) after the last dose of vaccine. The overall response rate – defined as the proportion of patients with detectable anti-spike antibodies per manufacturer’s cutoff values – was 88% (100 of 113). The nonresponse rate was higher with upadacitinib (7 of 27 patients, 26%) than with baricitinib (5 of 56, 9%) or tofacitinib (1 of 30, 3%). The only nonresponders who were not age 65 or older were four of the seven who received upadacitinib. The interval between the last vaccine dose and serologic assessment was somewhat longer in nonresponders (11.3 weeks) than in responders (8.3 weeks).

Earlier this year, the American College of Rheumatology recommended withholding JAK inhibitors for 1 week after each vaccine dose because of “concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response Only two patients in the study had treatment with JAK inhibitors stopped before or after vaccination.

Questions about antibody levels remain difficult to answer

“This study does further confirm a big point,” said Alfred Kim, MD, PhD, of Washington University, St. Louis, in an interview. “Most people on any sort of immunosuppression, with rare exceptions, can mount responses to COVID-19 vaccination.”

“What level of response is going to be sufficient, of course, is not clear,” he added. “Even though most people generate responses, at the population level those responses seem lower than those in nonimmunosuppressed people. Particularly for those on upadacitinib, which is lower than patients on the other JAK inhibitors. Is that problematic? We don’t know yet.”

Dr. Kim, who was part of a separate, earlier study that assessed vaccine response in patients with chronic inflammatory disease who were being treated with immunosuppressive medications, noted that many of the questions patients are asking about their antibody levels cannot yet be answered.

“It’s kind of the Wild West of serologic testing out there right now,” he said. “Even though we’re recommending that people still don’t check their antibody levels because their results are largely inactionable, everyone is still getting them anyway. But each of these tests are slightly different, and the results and the interpretation are further clouded because of those slight performance differences between each platform.”

Dr. Kim highlighted the number of different tests as one of this study’s notable limitations: 11 different assays were used to determine patients’ immune responses. “The authors made the argument that these tests are FDA approved, and that’s true, but that doesn’t necessarily mean much. Approval does translate to technical reliability but not to comparisons between the tests.”

As for next steps, both the authors and Dr. Kim recognized the need for a prospective trial. “To do a vaccine effectiveness–type study and show clinical protection against either infection or hospitalization – those are going to take a while, simply because of the nature of how many people you need for each of these studies,” he said. “Time will tell whether or not the data that are being presented here will translate literally into protective outcomes downstream.”

The MAJIK Registry is supported by the French Rheumatology Society. The authors acknowledged numerous potential conflicts of interest, including receiving consulting fees, research support, and honoraria from various pharmaceutical companies.

Patients who are being treated with Janus kinase (JAK) inhibitors overall show a high immune response rate to COVID-19 vaccination, one that matches the rates seen in patients on other immunosuppressants, a new study has found.

The patients taking a JAK inhibitor who are most at risk of a diminished response may be those on upadacitinib (Rinvoq) and anyone 65 years or older, wrote Raphaèle Seror, MD, PhD, of Paris-Saclay (France) University and coauthors. The study was published in The Lancet Rheumatology.

To gauge the effectiveness of COVID-19 vaccines in this subset of immunosuppressed patients, the researchers analyzed 113 participants in the MAJIK-SFR Registry, a multicenter study of French patients with rheumatoid or psoriatic arthritis. The participants were treated at 13 centers throughout France; their mean age was 61.8 years (standard deviation, 12.5), and 72% were female. A total of 56 were taking baricitinib (Olumiant), 30 were taking tofacitinib (Xeljanz), and 27 were taking upadacitinib.

Serologic assessment was performed an average of 8.7 weeks (SD, 5.2) after the last dose of vaccine. The overall response rate – defined as the proportion of patients with detectable anti-spike antibodies per manufacturer’s cutoff values – was 88% (100 of 113). The nonresponse rate was higher with upadacitinib (7 of 27 patients, 26%) than with baricitinib (5 of 56, 9%) or tofacitinib (1 of 30, 3%). The only nonresponders who were not age 65 or older were four of the seven who received upadacitinib. The interval between the last vaccine dose and serologic assessment was somewhat longer in nonresponders (11.3 weeks) than in responders (8.3 weeks).

Earlier this year, the American College of Rheumatology recommended withholding JAK inhibitors for 1 week after each vaccine dose because of “concern related to the effects of this medication class on interferon signaling that may result in a diminished vaccine response Only two patients in the study had treatment with JAK inhibitors stopped before or after vaccination.

Questions about antibody levels remain difficult to answer

“This study does further confirm a big point,” said Alfred Kim, MD, PhD, of Washington University, St. Louis, in an interview. “Most people on any sort of immunosuppression, with rare exceptions, can mount responses to COVID-19 vaccination.”

“What level of response is going to be sufficient, of course, is not clear,” he added. “Even though most people generate responses, at the population level those responses seem lower than those in nonimmunosuppressed people. Particularly for those on upadacitinib, which is lower than patients on the other JAK inhibitors. Is that problematic? We don’t know yet.”

Dr. Kim, who was part of a separate, earlier study that assessed vaccine response in patients with chronic inflammatory disease who were being treated with immunosuppressive medications, noted that many of the questions patients are asking about their antibody levels cannot yet be answered.

“It’s kind of the Wild West of serologic testing out there right now,” he said. “Even though we’re recommending that people still don’t check their antibody levels because their results are largely inactionable, everyone is still getting them anyway. But each of these tests are slightly different, and the results and the interpretation are further clouded because of those slight performance differences between each platform.”

Dr. Kim highlighted the number of different tests as one of this study’s notable limitations: 11 different assays were used to determine patients’ immune responses. “The authors made the argument that these tests are FDA approved, and that’s true, but that doesn’t necessarily mean much. Approval does translate to technical reliability but not to comparisons between the tests.”

As for next steps, both the authors and Dr. Kim recognized the need for a prospective trial. “To do a vaccine effectiveness–type study and show clinical protection against either infection or hospitalization – those are going to take a while, simply because of the nature of how many people you need for each of these studies,” he said. “Time will tell whether or not the data that are being presented here will translate literally into protective outcomes downstream.”

The MAJIK Registry is supported by the French Rheumatology Society. The authors acknowledged numerous potential conflicts of interest, including receiving consulting fees, research support, and honoraria from various pharmaceutical companies.

The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.

The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.

The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.

Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.

The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.

Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.

jevans@mdedge.com

The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.

The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.

The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.

Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.

The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.

Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.

jevans@mdedge.com

The Food and Drug Administration approved a supplement to the biologics license application of the adalimumab biosimilar drug Cyltezo (adalimumab-adbm) that makes it the first interchangeable biosimilar with Humira (adalimumab), the original branded version of the drug, its manufacturer Boehringer Ingelheim announced Oct. 15.

The FDA originally approved Cyltezo in 2017 for the treatment of multiple chronic inflammatory diseases, including seven of Humira’s nine indications for adults and pediatric patients: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis.

The interchangeability designation means that Cyltezo was tested in an additional clinical trial in which patients were successfully switched back and forth multiple times from Humira to Cyltezo and allows pharmacists to autosubstitute Humira with Cyltezo. In these cases, individual state laws control how and whether physicians will be notified of this switch.

Cyltezo is just the second biosimilar to be designated as interchangeable with its originator biologic product. The first approval, announced July 28, was for the interchangeability of Semglee (insulin glargine-yfgn) with the originator Lantus.

The agency based its decision on positive data from the VOLTAIRE-X study of 238 patients with moderate to severe chronic plaque psoriasis in which Cyltezo had no meaningful clinical differences from Humira in pharmacokinetics, efficacy, immunogenicity, and safety between the switching and continuous treatment groups.

Cyltezo will not be commercially available in the United States until July 1, 2023, according to Boehringer Ingelheim.

jevans@mdedge.com

About half of patients with rheumatoid arthritis who taper or stop disease-modifying antirheumatic drugs (DMARDs) retain stable remission after 12 months, and a majority of those who do relapse regain remission when back on their original treatments, according to data from the open-label, randomized Rheumatoid Arthritis in Ongoing Remission (RETRO) study.

“Currently, 40%-50% of patients with rheumatoid arthritis reach stable remission,” as a result of factors including earlier diagnosis and a wider range of treatments, Koray Tascilar, MD, of Friedrich Alexander University Erlangen-Nuremberg (Germany) and colleagues wrote in their publication of the RETRO trial results in Lancet Rheumatology.

Previous studies have suggested that patients with RA in sustained remission may be able to taper or withdraw treatment, but data from randomized trials are limited, the researchers said.

In the RETRO trial, researchers compared three strategies for RA patients in remission, which was defined as <2.6 on the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR). They randomized 100 adults to continue DMARDs and glucocorticoids, 102 to taper DMARDs and glucocorticoids to half their prior doses, and 101 to reduce the doses to half for 6 months and then stop DMARDs. Patients were enrolled between May 26, 2010, and May 29, 2018, from 14 treatment centers in Germany. The final analysis included 282 patients; 92 in the continuation group, 93 in the taper group, and 96 in the stop group. The mean age of the patients was 56.5 years, and 59% were women. The mean duration of RA was 7.4 years, and the mean duration of remission was 20 months.

Overall, at 12 months, 61% of the patients remained in remission without relapse; 81.2% of the continuation group, 58.6% of the taper group, and 43.3% of the stop group. Relapses occurred in 17%, 43%, and 55% of patients in the continuation, taper, and stop groups, respectively. The median times to relapse in the three groups were 30.6 weeks, 24.3 weeks, and 26.1 weeks, respectively.

Most of the relapses occurred between weeks 24 and 36 after stopping treatment, the researchers wrote. Corresponding hazard ratios for relapse were 3.02 for the taper group and 4.34 for the stop group, compared with the continuation group. In comparison to continuing treatment, the number needed to treat for one more relapse to occur during the 12-month observation period was four for tapering and three for stopping, they noted.

The study protocol called for a return to baseline treatment for any patients who relapsed in the taper and stop groups, and most patients who relapsed regained remission after restarting their baseline treatments. Among patients who had a follow-up visit after a relapse, 10 (63%) of 16 patients in the continuation group reachieved remission before the end of the study, as did 21 (62%) of 34 in the taper group and 35 (76%) of 46 in the stop group.

The most common treatments at baseline were methotrexate (76%) and tumor necrosis factor (TNF) inhibitors (32%).

The researchers also identified several baseline characteristics associated with relapse. Overall, relapse occurred more often in biologic DMARD users than in participants treated with other drugs, more often in women than men, and more often in those with a longer disease duration, higher baseline DAS28-ESR and Health Assessment Questionnaire scores, and in those who were positive for rheumatoid factor or anti–citrullinated protein antibodies.

A total of 38 serious adverse events occurred in 29 participants during the study period, but none were deemed treatment related, and none led to study withdrawal.

The study findings were limited by several factors including the lack of masking of patients and assessors and potential underestimation of disease activity, the researchers noted. Also, the study did not include radiographic data that might have been used to confirm progression; however, such data could have produced a null result and were not feasible in the study population, they wrote.

“If RETRO had been a trial to test the superiority of 100% dose continuation, compared with tapering plus rescue treatment or stopping plus rescue treatment, we would not be able to show that continuation is superior to tapering or stopping,” the researchers noted.

The study results support “an increasingly dynamic management approach in patients with rheumatoid arthritis in stable remission,” given the changing nature of RA management, that may help reduce overtreatment in many RA patients, the researchers concluded. “Furthermore, the observation that most of the patients regained remission after reintroduction of antirheumatic treatments is helpful with regard to the benefit-risk aspect of treatment reduction.”

Real-world setting serves as starting point

The RETRO study is unique in that it tried to reflect a real-life setting by enrolling patients on baseline treatment with combinations of conventional synthetic DMARDs and biologic DMARDs seen in clinical practice rather than only patients taking biologic DMARDs – primarily TNF inhibitors – as done in previous studies of tapering and stopping DMARDs, wrote Catherine L. Hill, MD, of the University of Adelaide (Australia), in an accompanying editorial. It is also “used a simple, pragmatic one-size-fits-all treatment-tapering strategy,” she wrote.

However, she emphasized that answers are needed to questions about what relapse rates are acceptable, what duration of treatment-free time is ideal, and whether benefits to the patient outweigh risks.

Dr. Hill also highlighted the issue of identifying patients who are appropriate candidates for tapering or withdrawal. Stricter remission criteria may not be feasible in routine practice, and so “the development of algorithms to guide patient selection is likely to be the most practical way forward for clinicians and patients,” she wrote.

“Contemplation of treatment tapering or discontinuation in some patients with rheumatoid arthritis is remarkable and a measure of how far treatments have advanced,” Dr. Hill wrote. “However, further work to address outstanding questions on who should taper and how best to do it is still required,” she concluded.

The study received no outside funding. Lead author Dr. Tascilar disclosed lecture fees from Gilead and Union Chimique Belge; several coauthors disclosed relationships with multiple companies outside the current study. Dr. Hill had no financial conflicts to disclose.

About half of patients with rheumatoid arthritis who taper or stop disease-modifying antirheumatic drugs (DMARDs) retain stable remission after 12 months, and a majority of those who do relapse regain remission when back on their original treatments, according to data from the open-label, randomized Rheumatoid Arthritis in Ongoing Remission (RETRO) study.

“Currently, 40%-50% of patients with rheumatoid arthritis reach stable remission,” as a result of factors including earlier diagnosis and a wider range of treatments, Koray Tascilar, MD, of Friedrich Alexander University Erlangen-Nuremberg (Germany) and colleagues wrote in their publication of the RETRO trial results in Lancet Rheumatology.

Previous studies have suggested that patients with RA in sustained remission may be able to taper or withdraw treatment, but data from randomized trials are limited, the researchers said.

In the RETRO trial, researchers compared three strategies for RA patients in remission, which was defined as <2.6 on the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR). They randomized 100 adults to continue DMARDs and glucocorticoids, 102 to taper DMARDs and glucocorticoids to half their prior doses, and 101 to reduce the doses to half for 6 months and then stop DMARDs. Patients were enrolled between May 26, 2010, and May 29, 2018, from 14 treatment centers in Germany. The final analysis included 282 patients; 92 in the continuation group, 93 in the taper group, and 96 in the stop group. The mean age of the patients was 56.5 years, and 59% were women. The mean duration of RA was 7.4 years, and the mean duration of remission was 20 months.

Overall, at 12 months, 61% of the patients remained in remission without relapse; 81.2% of the continuation group, 58.6% of the taper group, and 43.3% of the stop group. Relapses occurred in 17%, 43%, and 55% of patients in the continuation, taper, and stop groups, respectively. The median times to relapse in the three groups were 30.6 weeks, 24.3 weeks, and 26.1 weeks, respectively.

Most of the relapses occurred between weeks 24 and 36 after stopping treatment, the researchers wrote. Corresponding hazard ratios for relapse were 3.02 for the taper group and 4.34 for the stop group, compared with the continuation group. In comparison to continuing treatment, the number needed to treat for one more relapse to occur during the 12-month observation period was four for tapering and three for stopping, they noted.

The study protocol called for a return to baseline treatment for any patients who relapsed in the taper and stop groups, and most patients who relapsed regained remission after restarting their baseline treatments. Among patients who had a follow-up visit after a relapse, 10 (63%) of 16 patients in the continuation group reachieved remission before the end of the study, as did 21 (62%) of 34 in the taper group and 35 (76%) of 46 in the stop group.

The most common treatments at baseline were methotrexate (76%) and tumor necrosis factor (TNF) inhibitors (32%).

The researchers also identified several baseline characteristics associated with relapse. Overall, relapse occurred more often in biologic DMARD users than in participants treated with other drugs, more often in women than men, and more often in those with a longer disease duration, higher baseline DAS28-ESR and Health Assessment Questionnaire scores, and in those who were positive for rheumatoid factor or anti–citrullinated protein antibodies.

A total of 38 serious adverse events occurred in 29 participants during the study period, but none were deemed treatment related, and none led to study withdrawal.

The study findings were limited by several factors including the lack of masking of patients and assessors and potential underestimation of disease activity, the researchers noted. Also, the study did not include radiographic data that might have been used to confirm progression; however, such data could have produced a null result and were not feasible in the study population, they wrote.

“If RETRO had been a trial to test the superiority of 100% dose continuation, compared with tapering plus rescue treatment or stopping plus rescue treatment, we would not be able to show that continuation is superior to tapering or stopping,” the researchers noted.

The study results support “an increasingly dynamic management approach in patients with rheumatoid arthritis in stable remission,” given the changing nature of RA management, that may help reduce overtreatment in many RA patients, the researchers concluded. “Furthermore, the observation that most of the patients regained remission after reintroduction of antirheumatic treatments is helpful with regard to the benefit-risk aspect of treatment reduction.”

Real-world setting serves as starting point

The RETRO study is unique in that it tried to reflect a real-life setting by enrolling patients on baseline treatment with combinations of conventional synthetic DMARDs and biologic DMARDs seen in clinical practice rather than only patients taking biologic DMARDs – primarily TNF inhibitors – as done in previous studies of tapering and stopping DMARDs, wrote Catherine L. Hill, MD, of the University of Adelaide (Australia), in an accompanying editorial. It is also “used a simple, pragmatic one-size-fits-all treatment-tapering strategy,” she wrote.

However, she emphasized that answers are needed to questions about what relapse rates are acceptable, what duration of treatment-free time is ideal, and whether benefits to the patient outweigh risks.

Dr. Hill also highlighted the issue of identifying patients who are appropriate candidates for tapering or withdrawal. Stricter remission criteria may not be feasible in routine practice, and so “the development of algorithms to guide patient selection is likely to be the most practical way forward for clinicians and patients,” she wrote.

“Contemplation of treatment tapering or discontinuation in some patients with rheumatoid arthritis is remarkable and a measure of how far treatments have advanced,” Dr. Hill wrote. “However, further work to address outstanding questions on who should taper and how best to do it is still required,” she concluded.

The study received no outside funding. Lead author Dr. Tascilar disclosed lecture fees from Gilead and Union Chimique Belge; several coauthors disclosed relationships with multiple companies outside the current study. Dr. Hill had no financial conflicts to disclose.

About half of patients with rheumatoid arthritis who taper or stop disease-modifying antirheumatic drugs (DMARDs) retain stable remission after 12 months, and a majority of those who do relapse regain remission when back on their original treatments, according to data from the open-label, randomized Rheumatoid Arthritis in Ongoing Remission (RETRO) study.

“Currently, 40%-50% of patients with rheumatoid arthritis reach stable remission,” as a result of factors including earlier diagnosis and a wider range of treatments, Koray Tascilar, MD, of Friedrich Alexander University Erlangen-Nuremberg (Germany) and colleagues wrote in their publication of the RETRO trial results in Lancet Rheumatology.

Previous studies have suggested that patients with RA in sustained remission may be able to taper or withdraw treatment, but data from randomized trials are limited, the researchers said.

In the RETRO trial, researchers compared three strategies for RA patients in remission, which was defined as <2.6 on the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR). They randomized 100 adults to continue DMARDs and glucocorticoids, 102 to taper DMARDs and glucocorticoids to half their prior doses, and 101 to reduce the doses to half for 6 months and then stop DMARDs. Patients were enrolled between May 26, 2010, and May 29, 2018, from 14 treatment centers in Germany. The final analysis included 282 patients; 92 in the continuation group, 93 in the taper group, and 96 in the stop group. The mean age of the patients was 56.5 years, and 59% were women. The mean duration of RA was 7.4 years, and the mean duration of remission was 20 months.

Overall, at 12 months, 61% of the patients remained in remission without relapse; 81.2% of the continuation group, 58.6% of the taper group, and 43.3% of the stop group. Relapses occurred in 17%, 43%, and 55% of patients in the continuation, taper, and stop groups, respectively. The median times to relapse in the three groups were 30.6 weeks, 24.3 weeks, and 26.1 weeks, respectively.

Most of the relapses occurred between weeks 24 and 36 after stopping treatment, the researchers wrote. Corresponding hazard ratios for relapse were 3.02 for the taper group and 4.34 for the stop group, compared with the continuation group. In comparison to continuing treatment, the number needed to treat for one more relapse to occur during the 12-month observation period was four for tapering and three for stopping, they noted.

The study protocol called for a return to baseline treatment for any patients who relapsed in the taper and stop groups, and most patients who relapsed regained remission after restarting their baseline treatments. Among patients who had a follow-up visit after a relapse, 10 (63%) of 16 patients in the continuation group reachieved remission before the end of the study, as did 21 (62%) of 34 in the taper group and 35 (76%) of 46 in the stop group.

The most common treatments at baseline were methotrexate (76%) and tumor necrosis factor (TNF) inhibitors (32%).

The researchers also identified several baseline characteristics associated with relapse. Overall, relapse occurred more often in biologic DMARD users than in participants treated with other drugs, more often in women than men, and more often in those with a longer disease duration, higher baseline DAS28-ESR and Health Assessment Questionnaire scores, and in those who were positive for rheumatoid factor or anti–citrullinated protein antibodies.

A total of 38 serious adverse events occurred in 29 participants during the study period, but none were deemed treatment related, and none led to study withdrawal.

The study findings were limited by several factors including the lack of masking of patients and assessors and potential underestimation of disease activity, the researchers noted. Also, the study did not include radiographic data that might have been used to confirm progression; however, such data could have produced a null result and were not feasible in the study population, they wrote.

“If RETRO had been a trial to test the superiority of 100% dose continuation, compared with tapering plus rescue treatment or stopping plus rescue treatment, we would not be able to show that continuation is superior to tapering or stopping,” the researchers noted.

The study results support “an increasingly dynamic management approach in patients with rheumatoid arthritis in stable remission,” given the changing nature of RA management, that may help reduce overtreatment in many RA patients, the researchers concluded. “Furthermore, the observation that most of the patients regained remission after reintroduction of antirheumatic treatments is helpful with regard to the benefit-risk aspect of treatment reduction.”

Real-world setting serves as starting point

The RETRO study is unique in that it tried to reflect a real-life setting by enrolling patients on baseline treatment with combinations of conventional synthetic DMARDs and biologic DMARDs seen in clinical practice rather than only patients taking biologic DMARDs – primarily TNF inhibitors – as done in previous studies of tapering and stopping DMARDs, wrote Catherine L. Hill, MD, of the University of Adelaide (Australia), in an accompanying editorial. It is also “used a simple, pragmatic one-size-fits-all treatment-tapering strategy,” she wrote.

However, she emphasized that answers are needed to questions about what relapse rates are acceptable, what duration of treatment-free time is ideal, and whether benefits to the patient outweigh risks.

Dr. Hill also highlighted the issue of identifying patients who are appropriate candidates for tapering or withdrawal. Stricter remission criteria may not be feasible in routine practice, and so “the development of algorithms to guide patient selection is likely to be the most practical way forward for clinicians and patients,” she wrote.

“Contemplation of treatment tapering or discontinuation in some patients with rheumatoid arthritis is remarkable and a measure of how far treatments have advanced,” Dr. Hill wrote. “However, further work to address outstanding questions on who should taper and how best to do it is still required,” she concluded.

The study received no outside funding. Lead author Dr. Tascilar disclosed lecture fees from Gilead and Union Chimique Belge; several coauthors disclosed relationships with multiple companies outside the current study. Dr. Hill had no financial conflicts to disclose.

After many years at the University of California, San Francisco, Lindsey A. Criswell, MD, MPH, DSc, began a new chapter in February 2021 as the director of the National Institute of Arthritis and Musculoskeletal and Skin Disease, part of the National Institutes of Health. NIH Director Francis S. Collins, MD, PhD, selected her for the post.

“Dr. Criswell has rich experience as a clinician, researcher, and administrator,” Dr. Collins said in a prepared statement. “Her ability to oversee the research program of one of the country’s top research-intensive medical schools, and her expertise in autoimmune diseases, including rheumatoid arthritis and lupus, make her well positioned to direct NIAMS.” Dr. Criswell, a rheumatologist, was named a full professor of medicine at UCSF in 2007 and had served as vice chancellor of research at the university since 2017. She has authored more than 250 peer-reviewed scientific papers, and her efforts have contributed to the identification of more than 30 genes linked to autoimmune disorders. In her first media interview, Dr. Criswell opens up about her mentors, operational challenges posed by the COVID-19 pandemic, and highlights many NIAMS research projects underway.

Who inspired you most early in your career as a physician scientist? I have had great opportunities to work with fabulous mentors. Wallace (Wally) Epstein, MD, was my mentor when I was a rheumatology fellow and junior faculty member at UCSF. He was broadly admired for the breadth of his experience as a clinician and a researcher, and he was noteworthy at that time for his strong support for women and students of color. One of the many things I appreciated about him was his diverse range of interests outside of work, which included cello playing and woodworking.

Another mentor was Ephraim (Eph) Engleman, MD, the first academic rheumatologist in California. Eph continued to see patients beyond the age of 100. Perhaps his most important contributions were his efforts towards advocacy for funding for research and education in rheumatology. A prodigy violinist, he too had a broad range of personal interests.

What research into the genetics and epidemiology of human autoimmune disease that you have been a part of has most surprised you, in term of its ultimate clinical impact? Some of my most rewarding and impactful work has focused on the shared genetic basis of autoimmune diseases. We’ve identified dozens of genes that contribute to the risk and outcome of rheumatoid arthritis, lupus, and other autoimmune disorders. These discoveries regarding shared genes and pathways among such a diverse set of conditions have helped to inform optimal therapeutic target and treatment strategies across multiple diseases. For example, exploration of RA genes and pathways has revealed that approved agents for other conditions, such as cancer, may be appropriately repurposed for the treatment of RA. These are critical observations that have the potential to dramatically accelerate progress in developing new therapies for autoimmune diseases, such as RA.

Did you have much interaction with Stephen I. Katz, MD, PhD, your longtime predecessor who passed away unexpectedly in 2018? If so, what do you remember most about him? I regret that I had very little interaction with Steve, but I am well aware of the impact he had on NIAMS, NIH, and the research enterprise overall. He inspired so many people in a personal way, and I am energized by the legacy that he left behind.

What are your goals for the early part of your tenure as the new director of NIAMS? An important goal is getting to know the NIAMS community and expanding my knowledge of the Institute’s musculoskeletal and skin portfolios. I am also conducting outreach to Institute/Center directors and other NIH leadership to increase opportunities for input and advice. In doing this, I am identifying shared research interests, best practices, and potential partners for possible future collaborations. Another important goal is to increase NIAMS’ visibility within and beyond NIH. Ultimately, I want to contribute to the great work of the Institute and improve the lives of people with rheumatic, musculoskeletal, and skin diseases.

How would you characterize your management style? I like to lead with a flat hierarchy and work collectively to address opportunities and challenges. I value team building and tend to tap a variety of perspectives and expertise at all levels to achieve consensus, where possible.

The Accelerating Medicines Partnership (AMP) program was launched in 2014, with projects in three disease areas including the autoimmune disorders RA and lupus. What are some recent highlights from this program with respect to RA and lupus? AMP RA/SLE was dedicated to identifying promising therapeutic targets for RA and systemic lupus erythematosus. AMP-funded researchers have applied cutting-edge technologies to study cells from the synovial tissues of the joints of people with RA, and from the kidneys of people with lupus nephritis. In 2014, studying tissues in patients where the disease is active was a novel approach, since most research was conducted in mouse models or human blood samples.

The AMP RA/SLE Network developed a rich dataset that is available to the research community. Investigators are now using the data to facilitate RA and lupus research. For example, using AMP data, NIAMS-supported researchers identified potential biomarkers that could help predict an imminent RA flare. Work from another NIAMS-supported group suggests that targeting the regulatory transcription factor HIF-1, which drives inflammation and tissue damage, might be an effective approach for treating renal injury in lupus.

The data generated are accessible to the scientific community through two NIH websites: the database of Genotypes and Phenotypes (dbGaP) and the Immunology Database and Analysis Portal (IMMPORT).

Given the success of AMP RA/SLE, NIH plans to launch an “AMP 2.0” later in 2021. The AMP Autoimmune and Immune-Mediated Diseases (AMP AIM) program will provide an opportunity to leverage the accomplishments of AMP RA/SLE to new conditions, including psoriatic spectrum diseases and Sjögren’s syndrome.

What are some recent highlights from NIAMS-supported research in skin diseases? NIAMS-supported investigators continue to make significant strides in our understanding of skin biology and disease. For example, researchers recently demonstrated that imiquimod, a drug used to treat precancerous skin lesions, can help mouse ear wounds heal without scarring.

Another team addressed the safety and potential benefit of Staphylococcus hominis A9, a bacterium isolated from healthy human skin, as a topical therapy for atopic dermatitis.

Moving forward, AMP AIM will refine and extend the single-cell analysis of tissues to additional diseases, including psoriasis, setting the stage for the discovery of new therapeutic targets for the disease.

How has the COVID-19 pandemic changed the landscape of research, at least for the short term? This is a once-in-a-century pandemic that none of us were fully prepared for. We understand that it has been particularly challenging for women scientists, scientists with young children, and trainees and junior faculty who are at critically important and vulnerable stages of their careers. There isn’t a lab or clinical setting that hasn’t been negatively impacted in some way.

During the pandemic, the NIH instituted administrative flexibilities to support the grantee community, including extensions in time. In addition, the agency has issued several funding opportunities specific to COVID-19, some of which involve NIAMS participation.

What is NIAMS doing to help early/young investigators as well as female investigators and those from minority groups? Structural racism in biomedical research is a heightened concern. Earlier this year, Dr. Collins established the UNITE initiative to address structural racism and promote racial equity and inclusion at the NIH and within the larger biomedical community that we support. NIAMS is fully committed to this effort. One example is the Diversity Supplement Program, which is designed to attract and encourage eligible individuals from underrepresented populations to research careers.

Early-stage investigators are another top priority. In a tribute to the beloved former NIAMS director, NIH recently established the Stephen I. Katz Early Stage Investigator Research Grant Program. The R01 award provides support for a project unrelated to an early investigator’s area of postdoctoral study. (No preliminary data are allowed.) This award mechanism is a unique opportunity for early-stage investigators to take their research in a completely new direction.

Managing work and family life is an important concern, particularly for female investigators. Many NIH grant awards allow for reimbursement of actual, allowable costs incurred for childcare and parental leave. The NIH is exploring initiatives to promote research continuity and retention of eligible investigators facing major life events, such as pregnancy, childbirth, and adoption, at vulnerable career stages.

Who inspires you most in your work today? I am inspired by the ongoing struggles of our patients, junior investigators, and by the committed staff members on my team.

dbrunk@mdedge.com

After many years at the University of California, San Francisco, Lindsey A. Criswell, MD, MPH, DSc, began a new chapter in February 2021 as the director of the National Institute of Arthritis and Musculoskeletal and Skin Disease, part of the National Institutes of Health. NIH Director Francis S. Collins, MD, PhD, selected her for the post.

“Dr. Criswell has rich experience as a clinician, researcher, and administrator,” Dr. Collins said in a prepared statement. “Her ability to oversee the research program of one of the country’s top research-intensive medical schools, and her expertise in autoimmune diseases, including rheumatoid arthritis and lupus, make her well positioned to direct NIAMS.” Dr. Criswell, a rheumatologist, was named a full professor of medicine at UCSF in 2007 and had served as vice chancellor of research at the university since 2017. She has authored more than 250 peer-reviewed scientific papers, and her efforts have contributed to the identification of more than 30 genes linked to autoimmune disorders. In her first media interview, Dr. Criswell opens up about her mentors, operational challenges posed by the COVID-19 pandemic, and highlights many NIAMS research projects underway.

Who inspired you most early in your career as a physician scientist? I have had great opportunities to work with fabulous mentors. Wallace (Wally) Epstein, MD, was my mentor when I was a rheumatology fellow and junior faculty member at UCSF. He was broadly admired for the breadth of his experience as a clinician and a researcher, and he was noteworthy at that time for his strong support for women and students of color. One of the many things I appreciated about him was his diverse range of interests outside of work, which included cello playing and woodworking.

Another mentor was Ephraim (Eph) Engleman, MD, the first academic rheumatologist in California. Eph continued to see patients beyond the age of 100. Perhaps his most important contributions were his efforts towards advocacy for funding for research and education in rheumatology. A prodigy violinist, he too had a broad range of personal interests.

What research into the genetics and epidemiology of human autoimmune disease that you have been a part of has most surprised you, in term of its ultimate clinical impact? Some of my most rewarding and impactful work has focused on the shared genetic basis of autoimmune diseases. We’ve identified dozens of genes that contribute to the risk and outcome of rheumatoid arthritis, lupus, and other autoimmune disorders. These discoveries regarding shared genes and pathways among such a diverse set of conditions have helped to inform optimal therapeutic target and treatment strategies across multiple diseases. For example, exploration of RA genes and pathways has revealed that approved agents for other conditions, such as cancer, may be appropriately repurposed for the treatment of RA. These are critical observations that have the potential to dramatically accelerate progress in developing new therapies for autoimmune diseases, such as RA.

Did you have much interaction with Stephen I. Katz, MD, PhD, your longtime predecessor who passed away unexpectedly in 2018? If so, what do you remember most about him? I regret that I had very little interaction with Steve, but I am well aware of the impact he had on NIAMS, NIH, and the research enterprise overall. He inspired so many people in a personal way, and I am energized by the legacy that he left behind.

What are your goals for the early part of your tenure as the new director of NIAMS? An important goal is getting to know the NIAMS community and expanding my knowledge of the Institute’s musculoskeletal and skin portfolios. I am also conducting outreach to Institute/Center directors and other NIH leadership to increase opportunities for input and advice. In doing this, I am identifying shared research interests, best practices, and potential partners for possible future collaborations. Another important goal is to increase NIAMS’ visibility within and beyond NIH. Ultimately, I want to contribute to the great work of the Institute and improve the lives of people with rheumatic, musculoskeletal, and skin diseases.

How would you characterize your management style? I like to lead with a flat hierarchy and work collectively to address opportunities and challenges. I value team building and tend to tap a variety of perspectives and expertise at all levels to achieve consensus, where possible.

The Accelerating Medicines Partnership (AMP) program was launched in 2014, with projects in three disease areas including the autoimmune disorders RA and lupus. What are some recent highlights from this program with respect to RA and lupus? AMP RA/SLE was dedicated to identifying promising therapeutic targets for RA and systemic lupus erythematosus. AMP-funded researchers have applied cutting-edge technologies to study cells from the synovial tissues of the joints of people with RA, and from the kidneys of people with lupus nephritis. In 2014, studying tissues in patients where the disease is active was a novel approach, since most research was conducted in mouse models or human blood samples.

The AMP RA/SLE Network developed a rich dataset that is available to the research community. Investigators are now using the data to facilitate RA and lupus research. For example, using AMP data, NIAMS-supported researchers identified potential biomarkers that could help predict an imminent RA flare. Work from another NIAMS-supported group suggests that targeting the regulatory transcription factor HIF-1, which drives inflammation and tissue damage, might be an effective approach for treating renal injury in lupus.

The data generated are accessible to the scientific community through two NIH websites: the database of Genotypes and Phenotypes (dbGaP) and the Immunology Database and Analysis Portal (IMMPORT).

Given the success of AMP RA/SLE, NIH plans to launch an “AMP 2.0” later in 2021. The AMP Autoimmune and Immune-Mediated Diseases (AMP AIM) program will provide an opportunity to leverage the accomplishments of AMP RA/SLE to new conditions, including psoriatic spectrum diseases and Sjögren’s syndrome.

What are some recent highlights from NIAMS-supported research in skin diseases? NIAMS-supported investigators continue to make significant strides in our understanding of skin biology and disease. For example, researchers recently demonstrated that imiquimod, a drug used to treat precancerous skin lesions, can help mouse ear wounds heal without scarring.

Another team addressed the safety and potential benefit of Staphylococcus hominis A9, a bacterium isolated from healthy human skin, as a topical therapy for atopic dermatitis.

Moving forward, AMP AIM will refine and extend the single-cell analysis of tissues to additional diseases, including psoriasis, setting the stage for the discovery of new therapeutic targets for the disease.

How has the COVID-19 pandemic changed the landscape of research, at least for the short term? This is a once-in-a-century pandemic that none of us were fully prepared for. We understand that it has been particularly challenging for women scientists, scientists with young children, and trainees and junior faculty who are at critically important and vulnerable stages of their careers. There isn’t a lab or clinical setting that hasn’t been negatively impacted in some way.

During the pandemic, the NIH instituted administrative flexibilities to support the grantee community, including extensions in time. In addition, the agency has issued several funding opportunities specific to COVID-19, some of which involve NIAMS participation.

What is NIAMS doing to help early/young investigators as well as female investigators and those from minority groups? Structural racism in biomedical research is a heightened concern. Earlier this year, Dr. Collins established the UNITE initiative to address structural racism and promote racial equity and inclusion at the NIH and within the larger biomedical community that we support. NIAMS is fully committed to this effort. One example is the Diversity Supplement Program, which is designed to attract and encourage eligible individuals from underrepresented populations to research careers.

Early-stage investigators are another top priority. In a tribute to the beloved former NIAMS director, NIH recently established the Stephen I. Katz Early Stage Investigator Research Grant Program. The R01 award provides support for a project unrelated to an early investigator’s area of postdoctoral study. (No preliminary data are allowed.) This award mechanism is a unique opportunity for early-stage investigators to take their research in a completely new direction.

Managing work and family life is an important concern, particularly for female investigators. Many NIH grant awards allow for reimbursement of actual, allowable costs incurred for childcare and parental leave. The NIH is exploring initiatives to promote research continuity and retention of eligible investigators facing major life events, such as pregnancy, childbirth, and adoption, at vulnerable career stages.

Who inspires you most in your work today? I am inspired by the ongoing struggles of our patients, junior investigators, and by the committed staff members on my team.

dbrunk@mdedge.com

After many years at the University of California, San Francisco, Lindsey A. Criswell, MD, MPH, DSc, began a new chapter in February 2021 as the director of the National Institute of Arthritis and Musculoskeletal and Skin Disease, part of the National Institutes of Health. NIH Director Francis S. Collins, MD, PhD, selected her for the post.

“Dr. Criswell has rich experience as a clinician, researcher, and administrator,” Dr. Collins said in a prepared statement. “Her ability to oversee the research program of one of the country’s top research-intensive medical schools, and her expertise in autoimmune diseases, including rheumatoid arthritis and lupus, make her well positioned to direct NIAMS.” Dr. Criswell, a rheumatologist, was named a full professor of medicine at UCSF in 2007 and had served as vice chancellor of research at the university since 2017. She has authored more than 250 peer-reviewed scientific papers, and her efforts have contributed to the identification of more than 30 genes linked to autoimmune disorders. In her first media interview, Dr. Criswell opens up about her mentors, operational challenges posed by the COVID-19 pandemic, and highlights many NIAMS research projects underway.

Who inspired you most early in your career as a physician scientist? I have had great opportunities to work with fabulous mentors. Wallace (Wally) Epstein, MD, was my mentor when I was a rheumatology fellow and junior faculty member at UCSF. He was broadly admired for the breadth of his experience as a clinician and a researcher, and he was noteworthy at that time for his strong support for women and students of color. One of the many things I appreciated about him was his diverse range of interests outside of work, which included cello playing and woodworking.

Another mentor was Ephraim (Eph) Engleman, MD, the first academic rheumatologist in California. Eph continued to see patients beyond the age of 100. Perhaps his most important contributions were his efforts towards advocacy for funding for research and education in rheumatology. A prodigy violinist, he too had a broad range of personal interests.

What research into the genetics and epidemiology of human autoimmune disease that you have been a part of has most surprised you, in term of its ultimate clinical impact? Some of my most rewarding and impactful work has focused on the shared genetic basis of autoimmune diseases. We’ve identified dozens of genes that contribute to the risk and outcome of rheumatoid arthritis, lupus, and other autoimmune disorders. These discoveries regarding shared genes and pathways among such a diverse set of conditions have helped to inform optimal therapeutic target and treatment strategies across multiple diseases. For example, exploration of RA genes and pathways has revealed that approved agents for other conditions, such as cancer, may be appropriately repurposed for the treatment of RA. These are critical observations that have the potential to dramatically accelerate progress in developing new therapies for autoimmune diseases, such as RA.

Did you have much interaction with Stephen I. Katz, MD, PhD, your longtime predecessor who passed away unexpectedly in 2018? If so, what do you remember most about him? I regret that I had very little interaction with Steve, but I am well aware of the impact he had on NIAMS, NIH, and the research enterprise overall. He inspired so many people in a personal way, and I am energized by the legacy that he left behind.

What are your goals for the early part of your tenure as the new director of NIAMS? An important goal is getting to know the NIAMS community and expanding my knowledge of the Institute’s musculoskeletal and skin portfolios. I am also conducting outreach to Institute/Center directors and other NIH leadership to increase opportunities for input and advice. In doing this, I am identifying shared research interests, best practices, and potential partners for possible future collaborations. Another important goal is to increase NIAMS’ visibility within and beyond NIH. Ultimately, I want to contribute to the great work of the Institute and improve the lives of people with rheumatic, musculoskeletal, and skin diseases.

How would you characterize your management style? I like to lead with a flat hierarchy and work collectively to address opportunities and challenges. I value team building and tend to tap a variety of perspectives and expertise at all levels to achieve consensus, where possible.

The Accelerating Medicines Partnership (AMP) program was launched in 2014, with projects in three disease areas including the autoimmune disorders RA and lupus. What are some recent highlights from this program with respect to RA and lupus? AMP RA/SLE was dedicated to identifying promising therapeutic targets for RA and systemic lupus erythematosus. AMP-funded researchers have applied cutting-edge technologies to study cells from the synovial tissues of the joints of people with RA, and from the kidneys of people with lupus nephritis. In 2014, studying tissues in patients where the disease is active was a novel approach, since most research was conducted in mouse models or human blood samples.

The AMP RA/SLE Network developed a rich dataset that is available to the research community. Investigators are now using the data to facilitate RA and lupus research. For example, using AMP data, NIAMS-supported researchers identified potential biomarkers that could help predict an imminent RA flare. Work from another NIAMS-supported group suggests that targeting the regulatory transcription factor HIF-1, which drives inflammation and tissue damage, might be an effective approach for treating renal injury in lupus.

The data generated are accessible to the scientific community through two NIH websites: the database of Genotypes and Phenotypes (dbGaP) and the Immunology Database and Analysis Portal (IMMPORT).

Given the success of AMP RA/SLE, NIH plans to launch an “AMP 2.0” later in 2021. The AMP Autoimmune and Immune-Mediated Diseases (AMP AIM) program will provide an opportunity to leverage the accomplishments of AMP RA/SLE to new conditions, including psoriatic spectrum diseases and Sjögren’s syndrome.

What are some recent highlights from NIAMS-supported research in skin diseases? NIAMS-supported investigators continue to make significant strides in our understanding of skin biology and disease. For example, researchers recently demonstrated that imiquimod, a drug used to treat precancerous skin lesions, can help mouse ear wounds heal without scarring.

Another team addressed the safety and potential benefit of Staphylococcus hominis A9, a bacterium isolated from healthy human skin, as a topical therapy for atopic dermatitis.

Moving forward, AMP AIM will refine and extend the single-cell analysis of tissues to additional diseases, including psoriasis, setting the stage for the discovery of new therapeutic targets for the disease.

How has the COVID-19 pandemic changed the landscape of research, at least for the short term? This is a once-in-a-century pandemic that none of us were fully prepared for. We understand that it has been particularly challenging for women scientists, scientists with young children, and trainees and junior faculty who are at critically important and vulnerable stages of their careers. There isn’t a lab or clinical setting that hasn’t been negatively impacted in some way.

During the pandemic, the NIH instituted administrative flexibilities to support the grantee community, including extensions in time. In addition, the agency has issued several funding opportunities specific to COVID-19, some of which involve NIAMS participation.

What is NIAMS doing to help early/young investigators as well as female investigators and those from minority groups? Structural racism in biomedical research is a heightened concern. Earlier this year, Dr. Collins established the UNITE initiative to address structural racism and promote racial equity and inclusion at the NIH and within the larger biomedical community that we support. NIAMS is fully committed to this effort. One example is the Diversity Supplement Program, which is designed to attract and encourage eligible individuals from underrepresented populations to research careers.

Early-stage investigators are another top priority. In a tribute to the beloved former NIAMS director, NIH recently established the Stephen I. Katz Early Stage Investigator Research Grant Program. The R01 award provides support for a project unrelated to an early investigator’s area of postdoctoral study. (No preliminary data are allowed.) This award mechanism is a unique opportunity for early-stage investigators to take their research in a completely new direction.

Managing work and family life is an important concern, particularly for female investigators. Many NIH grant awards allow for reimbursement of actual, allowable costs incurred for childcare and parental leave. The NIH is exploring initiatives to promote research continuity and retention of eligible investigators facing major life events, such as pregnancy, childbirth, and adoption, at vulnerable career stages.

Who inspires you most in your work today? I am inspired by the ongoing struggles of our patients, junior investigators, and by the committed staff members on my team.

dbrunk@mdedge.com

It took years for Elle Moxley to get a diagnosis that explained her crippling gastrointestinal pain, digestion problems, fatigue, and hot, red rashes. And after learning in 2016 that she had Crohn’s disease, a chronic inflammation of the digestive tract, she spent more than 4 years trying medications before getting her disease under control with a biologic drug called Remicade.

So Ms. Moxley, 33, was dismayed to receive a notice from her insurer in January that Remicade would no longer be covered as a preferred drug on her plan. Another drug, Inflectra, which the Food and Drug Administration says has no meaningful clinical differences from Remicade, is now preferred. It is a “biosimilar” drug.

“I felt very powerless,” said Ms. Moxley, who recently started a job as a public relations coordinator for Kansas City (Mo.) Public Schools. “I have this decision being made for me and my doctor that’s not in my best interest, and it might knock me out of remission.”

After Ms. Moxley’s first Inflectra infusion in July, she developed a painful rash. It went away after a few days, but she said she continues to feel extremely fatigued and experiences gastrointestinal pain, constipation, diarrhea and nausea.

Many medical professionals look to biosimilar drugs as a way to increase competition and give consumers cheaper options, much as generic drugs do, and they point to the more robust use of these products in Europe to cut costs.

Yet the United States has been slower to adopt biosimilar drugs since the first such medicine was approved in 2015. That’s partly because of concerns raised by patients like Moxley and their doctors, but also because brand-name biologics have kept biosimilars from entering the market. The companies behind the brand-name drugs have used legal actions to extend the life of their patents and incentives that make offering the brand biologic more attractive than offering a biosimilar on a formulary, listing which drugs are covered on an insurance plan.

“It distorts the market and makes it so that patients can’t get access,” said Jinoos Yazdany, MD, MPH, a professor of medicine and chief of the rheumatology division at Zuckerberg San Francisco General Hospital.

The FDA has approved 31 biosimilar medications since 2015, but only about 60% have made it to market, according to an analysis by NORC, a research organization at the University of Chicago.

Remicade’s manufacturer, Johnson & Johnson, and Pfizer, which makes the Remicade biosimilar Inflectra, have been embroiled in a long-running lawsuit over Pfizer’s claims that Johnson & Johnson tried to choke off competition through exclusionary contracts with insurers and other anticompetitive actions. In July, the companies settled the case on undisclosed terms.

In a statement, Pfizer said it would continue to sell Inflectra in the United States but noted ongoing challenges: “Pfizer has begun to see progress in the overall biosimilars marketplace in the U.S. However, changes in policy at a government level and acceptance of biosimilars among key stakeholders are critical to deliver more meaningful uptake so patients and the health care system at large can benefit from the cost savings these medicines may deliver.”

Johnson & Johnson said it is committed to making Remicade available to patients who choose it, which “compels us to compete responsibly on both price and value.”

Biologic medicines, which are generally grown from living organisms such as animal cells or bacteria, are more complex and expensive to manufacture than drugs made from chemicals. In recent years, biologic drugs have become a mainstay of treatment for autoimmune conditions like Crohn’s disease and rheumatoid arthritis, as well as certain cancers and diabetes, among other conditions.

Other drugmakers can’t exactly reproduce these biologic drugs by following chemical recipes as they do for generic versions of conventional drugs.

Instead, biosimilar versions of biologic drugs are generally made from the same types of materials as the original biologics and must be “highly similar” to them to be approved by the FDA. They must have no clinically meaningful differences from the biologic drug, and be just as safe, pure and potent. More than a decade after Congress created an approval pathway for biosimilars, they are widely accepted as safe and effective alternatives to brand biologics.

Medical experts hope that as biosimilars become more widely used they will increasingly provide a brake on drug spending.

From 2015 to 2019, drug spending overall grew 6.1%, while spending on biologics grew more than twice as much – 14.6% – according to a report by IQVIA, a health care analytics company. In 2019, biologics accounted for 43% of drug spending in the United States

Biosimilars provide a roughly 30% discount over brand biologics in the United States but have the potential to reduce spending by more than $100 billion in the next 5 years, the IQVIA analysis found.

In a survey of 602 physicians who prescribe biologic medications, more than three-quarters said they believed biosimilars are just as safe and effective as their biologic counterparts, according to NORC.

But they were less comfortable with switching patients from a brand biologic to a biosimilar. While about half said they were very likely to prescribe a biosimilar to a patient just starting biologic therapy, only 31% said they were very likely to prescribe a biosimilar to a patient already doing well on a brand biologic.

It can be challenging to find a treatment regimen that works for patients with complicated chronic conditions, and physicians and patients often don’t want to rock the boat once that is achieved.

In Ms. Moxley’s case, for example, before her condition stabilized on Remicade, she tried a conventional pill called Lialda, the biologic drug Humira and a lower dose of Remicade.

Some doctors and patients raise concerns that switching between these drugs might cause patients to develop antibodies that cause the drugs to lose effectiveness. They want to see more research about the effects of such switches.

“We haven’t seen enough studies about patients going from the biologic to the biosimilar and bouncing back and forth,” said Marcus Snow, MD, chair of the American College of Rheumatology’s Committee on Rheumatologic Care. “We don’t want our patients to be guinea pigs.”

Manufacturers of biologic and biosimilar drugs have participated in advertising, exhibit or sponsorship opportunities with the American College of Rheumatology, according to ACR spokesperson Jocelyn Givens.

But studies show a one-time switch from Remicade to a biosimilar like Inflectra does not cause side effects or the development of antibodies, said Ross Maltz, MD, a pediatric gastroenterologist at Nationwide Children’s Hospital in Columbus, Ohio, and former member of the Crohn’s & Colitis Foundation’s National Scientific Advisory Committee. Studies may be conducted by researchers with extensive ties to the industry and funded by drugmakers.

Situations like Ms. Moxley’s are unusual, said Kristine Grow, senior vice president of communications at AHIP, an insurer trade group.

“For patients who have been taking a brand-name biologic for some time, health insurance providers do not typically encourage them to switch to a biosimilar because of a formulary change, and most plans exclude these patients from any changes in cost sharing due to formulary changes,” she said.

Drugmakers can seek approval from the FDA of their biosimilar as interchangeable with a biologic drug, allowing pharmacists, subject to state law, to switch a physician’s prescription from the brand drug, as they often do with generic drugs.

However, the FDA has approved only one biosimilar (Semglee, a form of insulin) as interchangeable with a biologic (Lantus).

Like Ms. Moxley, many other patients using biologics get copay assistance from drug companies, but the money often isn’t enough to cover the full cost. In her old job as a radio reporter, Ms. Moxley said, she hit the $7,000 maximum annual out-of-pocket spending limit for her plan by May.

In her new job, Ms. Moxley has an individual plan with a $4,000 maximum out-of-pocket limit, which she expects to blow past once again within months.

But she received good news recently: Her new plan will cover Remicade.

“I’m still concerned that I will have developed antibodies since my last dose,” she said. “But it feels like a step in the direction of good health again.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

It took years for Elle Moxley to get a diagnosis that explained her crippling gastrointestinal pain, digestion problems, fatigue, and hot, red rashes. And after learning in 2016 that she had Crohn’s disease, a chronic inflammation of the digestive tract, she spent more than 4 years trying medications before getting her disease under control with a biologic drug called Remicade.

So Ms. Moxley, 33, was dismayed to receive a notice from her insurer in January that Remicade would no longer be covered as a preferred drug on her plan. Another drug, Inflectra, which the Food and Drug Administration says has no meaningful clinical differences from Remicade, is now preferred. It is a “biosimilar” drug.

“I felt very powerless,” said Ms. Moxley, who recently started a job as a public relations coordinator for Kansas City (Mo.) Public Schools. “I have this decision being made for me and my doctor that’s not in my best interest, and it might knock me out of remission.”

After Ms. Moxley’s first Inflectra infusion in July, she developed a painful rash. It went away after a few days, but she said she continues to feel extremely fatigued and experiences gastrointestinal pain, constipation, diarrhea and nausea.

Many medical professionals look to biosimilar drugs as a way to increase competition and give consumers cheaper options, much as generic drugs do, and they point to the more robust use of these products in Europe to cut costs.

Yet the United States has been slower to adopt biosimilar drugs since the first such medicine was approved in 2015. That’s partly because of concerns raised by patients like Moxley and their doctors, but also because brand-name biologics have kept biosimilars from entering the market. The companies behind the brand-name drugs have used legal actions to extend the life of their patents and incentives that make offering the brand biologic more attractive than offering a biosimilar on a formulary, listing which drugs are covered on an insurance plan.

“It distorts the market and makes it so that patients can’t get access,” said Jinoos Yazdany, MD, MPH, a professor of medicine and chief of the rheumatology division at Zuckerberg San Francisco General Hospital.

The FDA has approved 31 biosimilar medications since 2015, but only about 60% have made it to market, according to an analysis by NORC, a research organization at the University of Chicago.

Remicade’s manufacturer, Johnson & Johnson, and Pfizer, which makes the Remicade biosimilar Inflectra, have been embroiled in a long-running lawsuit over Pfizer’s claims that Johnson & Johnson tried to choke off competition through exclusionary contracts with insurers and other anticompetitive actions. In July, the companies settled the case on undisclosed terms.

In a statement, Pfizer said it would continue to sell Inflectra in the United States but noted ongoing challenges: “Pfizer has begun to see progress in the overall biosimilars marketplace in the U.S. However, changes in policy at a government level and acceptance of biosimilars among key stakeholders are critical to deliver more meaningful uptake so patients and the health care system at large can benefit from the cost savings these medicines may deliver.”

Johnson & Johnson said it is committed to making Remicade available to patients who choose it, which “compels us to compete responsibly on both price and value.”

Biologic medicines, which are generally grown from living organisms such as animal cells or bacteria, are more complex and expensive to manufacture than drugs made from chemicals. In recent years, biologic drugs have become a mainstay of treatment for autoimmune conditions like Crohn’s disease and rheumatoid arthritis, as well as certain cancers and diabetes, among other conditions.

Other drugmakers can’t exactly reproduce these biologic drugs by following chemical recipes as they do for generic versions of conventional drugs.

Instead, biosimilar versions of biologic drugs are generally made from the same types of materials as the original biologics and must be “highly similar” to them to be approved by the FDA. They must have no clinically meaningful differences from the biologic drug, and be just as safe, pure and potent. More than a decade after Congress created an approval pathway for biosimilars, they are widely accepted as safe and effective alternatives to brand biologics.

Medical experts hope that as biosimilars become more widely used they will increasingly provide a brake on drug spending.

From 2015 to 2019, drug spending overall grew 6.1%, while spending on biologics grew more than twice as much – 14.6% – according to a report by IQVIA, a health care analytics company. In 2019, biologics accounted for 43% of drug spending in the United States

Biosimilars provide a roughly 30% discount over brand biologics in the United States but have the potential to reduce spending by more than $100 billion in the next 5 years, the IQVIA analysis found.

In a survey of 602 physicians who prescribe biologic medications, more than three-quarters said they believed biosimilars are just as safe and effective as their biologic counterparts, according to NORC.

But they were less comfortable with switching patients from a brand biologic to a biosimilar. While about half said they were very likely to prescribe a biosimilar to a patient just starting biologic therapy, only 31% said they were very likely to prescribe a biosimilar to a patient already doing well on a brand biologic.

It can be challenging to find a treatment regimen that works for patients with complicated chronic conditions, and physicians and patients often don’t want to rock the boat once that is achieved.

In Ms. Moxley’s case, for example, before her condition stabilized on Remicade, she tried a conventional pill called Lialda, the biologic drug Humira and a lower dose of Remicade.

Some doctors and patients raise concerns that switching between these drugs might cause patients to develop antibodies that cause the drugs to lose effectiveness. They want to see more research about the effects of such switches.

“We haven’t seen enough studies about patients going from the biologic to the biosimilar and bouncing back and forth,” said Marcus Snow, MD, chair of the American College of Rheumatology’s Committee on Rheumatologic Care. “We don’t want our patients to be guinea pigs.”

Manufacturers of biologic and biosimilar drugs have participated in advertising, exhibit or sponsorship opportunities with the American College of Rheumatology, according to ACR spokesperson Jocelyn Givens.

But studies show a one-time switch from Remicade to a biosimilar like Inflectra does not cause side effects or the development of antibodies, said Ross Maltz, MD, a pediatric gastroenterologist at Nationwide Children’s Hospital in Columbus, Ohio, and former member of the Crohn’s & Colitis Foundation’s National Scientific Advisory Committee. Studies may be conducted by researchers with extensive ties to the industry and funded by drugmakers.

Situations like Ms. Moxley’s are unusual, said Kristine Grow, senior vice president of communications at AHIP, an insurer trade group.

“For patients who have been taking a brand-name biologic for some time, health insurance providers do not typically encourage them to switch to a biosimilar because of a formulary change, and most plans exclude these patients from any changes in cost sharing due to formulary changes,” she said.

Drugmakers can seek approval from the FDA of their biosimilar as interchangeable with a biologic drug, allowing pharmacists, subject to state law, to switch a physician’s prescription from the brand drug, as they often do with generic drugs.

However, the FDA has approved only one biosimilar (Semglee, a form of insulin) as interchangeable with a biologic (Lantus).

Like Ms. Moxley, many other patients using biologics get copay assistance from drug companies, but the money often isn’t enough to cover the full cost. In her old job as a radio reporter, Ms. Moxley said, she hit the $7,000 maximum annual out-of-pocket spending limit for her plan by May.

In her new job, Ms. Moxley has an individual plan with a $4,000 maximum out-of-pocket limit, which she expects to blow past once again within months.

But she received good news recently: Her new plan will cover Remicade.

“I’m still concerned that I will have developed antibodies since my last dose,” she said. “But it feels like a step in the direction of good health again.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

It took years for Elle Moxley to get a diagnosis that explained her crippling gastrointestinal pain, digestion problems, fatigue, and hot, red rashes. And after learning in 2016 that she had Crohn’s disease, a chronic inflammation of the digestive tract, she spent more than 4 years trying medications before getting her disease under control with a biologic drug called Remicade.

So Ms. Moxley, 33, was dismayed to receive a notice from her insurer in January that Remicade would no longer be covered as a preferred drug on her plan. Another drug, Inflectra, which the Food and Drug Administration says has no meaningful clinical differences from Remicade, is now preferred. It is a “biosimilar” drug.

“I felt very powerless,” said Ms. Moxley, who recently started a job as a public relations coordinator for Kansas City (Mo.) Public Schools. “I have this decision being made for me and my doctor that’s not in my best interest, and it might knock me out of remission.”

After Ms. Moxley’s first Inflectra infusion in July, she developed a painful rash. It went away after a few days, but she said she continues to feel extremely fatigued and experiences gastrointestinal pain, constipation, diarrhea and nausea.

Many medical professionals look to biosimilar drugs as a way to increase competition and give consumers cheaper options, much as generic drugs do, and they point to the more robust use of these products in Europe to cut costs.

Yet the United States has been slower to adopt biosimilar drugs since the first such medicine was approved in 2015. That’s partly because of concerns raised by patients like Moxley and their doctors, but also because brand-name biologics have kept biosimilars from entering the market. The companies behind the brand-name drugs have used legal actions to extend the life of their patents and incentives that make offering the brand biologic more attractive than offering a biosimilar on a formulary, listing which drugs are covered on an insurance plan.

“It distorts the market and makes it so that patients can’t get access,” said Jinoos Yazdany, MD, MPH, a professor of medicine and chief of the rheumatology division at Zuckerberg San Francisco General Hospital.

The FDA has approved 31 biosimilar medications since 2015, but only about 60% have made it to market, according to an analysis by NORC, a research organization at the University of Chicago.

Remicade’s manufacturer, Johnson & Johnson, and Pfizer, which makes the Remicade biosimilar Inflectra, have been embroiled in a long-running lawsuit over Pfizer’s claims that Johnson & Johnson tried to choke off competition through exclusionary contracts with insurers and other anticompetitive actions. In July, the companies settled the case on undisclosed terms.

In a statement, Pfizer said it would continue to sell Inflectra in the United States but noted ongoing challenges: “Pfizer has begun to see progress in the overall biosimilars marketplace in the U.S. However, changes in policy at a government level and acceptance of biosimilars among key stakeholders are critical to deliver more meaningful uptake so patients and the health care system at large can benefit from the cost savings these medicines may deliver.”

Johnson & Johnson said it is committed to making Remicade available to patients who choose it, which “compels us to compete responsibly on both price and value.”

Biologic medicines, which are generally grown from living organisms such as animal cells or bacteria, are more complex and expensive to manufacture than drugs made from chemicals. In recent years, biologic drugs have become a mainstay of treatment for autoimmune conditions like Crohn’s disease and rheumatoid arthritis, as well as certain cancers and diabetes, among other conditions.

Other drugmakers can’t exactly reproduce these biologic drugs by following chemical recipes as they do for generic versions of conventional drugs.

Instead, biosimilar versions of biologic drugs are generally made from the same types of materials as the original biologics and must be “highly similar” to them to be approved by the FDA. They must have no clinically meaningful differences from the biologic drug, and be just as safe, pure and potent. More than a decade after Congress created an approval pathway for biosimilars, they are widely accepted as safe and effective alternatives to brand biologics.

Medical experts hope that as biosimilars become more widely used they will increasingly provide a brake on drug spending.

From 2015 to 2019, drug spending overall grew 6.1%, while spending on biologics grew more than twice as much – 14.6% – according to a report by IQVIA, a health care analytics company. In 2019, biologics accounted for 43% of drug spending in the United States

Biosimilars provide a roughly 30% discount over brand biologics in the United States but have the potential to reduce spending by more than $100 billion in the next 5 years, the IQVIA analysis found.

In a survey of 602 physicians who prescribe biologic medications, more than three-quarters said they believed biosimilars are just as safe and effective as their biologic counterparts, according to NORC.

But they were less comfortable with switching patients from a brand biologic to a biosimilar. While about half said they were very likely to prescribe a biosimilar to a patient just starting biologic therapy, only 31% said they were very likely to prescribe a biosimilar to a patient already doing well on a brand biologic.

It can be challenging to find a treatment regimen that works for patients with complicated chronic conditions, and physicians and patients often don’t want to rock the boat once that is achieved.

In Ms. Moxley’s case, for example, before her condition stabilized on Remicade, she tried a conventional pill called Lialda, the biologic drug Humira and a lower dose of Remicade.

Some doctors and patients raise concerns that switching between these drugs might cause patients to develop antibodies that cause the drugs to lose effectiveness. They want to see more research about the effects of such switches.

“We haven’t seen enough studies about patients going from the biologic to the biosimilar and bouncing back and forth,” said Marcus Snow, MD, chair of the American College of Rheumatology’s Committee on Rheumatologic Care. “We don’t want our patients to be guinea pigs.”

Manufacturers of biologic and biosimilar drugs have participated in advertising, exhibit or sponsorship opportunities with the American College of Rheumatology, according to ACR spokesperson Jocelyn Givens.

But studies show a one-time switch from Remicade to a biosimilar like Inflectra does not cause side effects or the development of antibodies, said Ross Maltz, MD, a pediatric gastroenterologist at Nationwide Children’s Hospital in Columbus, Ohio, and former member of the Crohn’s & Colitis Foundation’s National Scientific Advisory Committee. Studies may be conducted by researchers with extensive ties to the industry and funded by drugmakers.

Situations like Ms. Moxley’s are unusual, said Kristine Grow, senior vice president of communications at AHIP, an insurer trade group.

“For patients who have been taking a brand-name biologic for some time, health insurance providers do not typically encourage them to switch to a biosimilar because of a formulary change, and most plans exclude these patients from any changes in cost sharing due to formulary changes,” she said.

Drugmakers can seek approval from the FDA of their biosimilar as interchangeable with a biologic drug, allowing pharmacists, subject to state law, to switch a physician’s prescription from the brand drug, as they often do with generic drugs.

However, the FDA has approved only one biosimilar (Semglee, a form of insulin) as interchangeable with a biologic (Lantus).

Like Ms. Moxley, many other patients using biologics get copay assistance from drug companies, but the money often isn’t enough to cover the full cost. In her old job as a radio reporter, Ms. Moxley said, she hit the $7,000 maximum annual out-of-pocket spending limit for her plan by May.

In her new job, Ms. Moxley has an individual plan with a $4,000 maximum out-of-pocket limit, which she expects to blow past once again within months.

But she received good news recently: Her new plan will cover Remicade.

“I’m still concerned that I will have developed antibodies since my last dose,” she said. “But it feels like a step in the direction of good health again.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Cigarette smoking is a well-known modifiable risk factor for the development of rheumatoid arthritis (RA). Studies have suggested not only an elevated risk but possible pathogenetic role in the development of autoantibodies, as well as effects on disease outcomes. Passive cigarette smoking has also been proposed as a potential risk factor for RA, though studies are harder to evaluate. This review of prospective data from the Nurses Health Study (NHS) by Yoshida et al looks at incident RA among women enrolled in the study and the influence of in utero, childhood, and adulthood exposure to cigarettes. Childhood exposure to parental smoking was associated with seropositive RA (hazard ratio 1.75) even after controlling for adult personal smoking, and maternal smoking during pregnancy was associated with RA, though the latter effect was not seen after controlling for subsequent smoking exposure. As the authors point out, verifiable prospective data is difficult to obtain regarding exposure to smoking in utero or in childhood and recall bias is possible in obtaining historical information in this prospective study given the use of questionnaires, though it remains plausible given prior studies on the association of personal smoking with RA.

The involvement of gut microbiota in development of autoimmunity has also been postulated but not well-explained. Several recent studies have examined the impact of antibiotic use on the development of RA, including a recent large UK-based case-control study suggesting an increase in RA incidence in people with antibiotic exposure. While a systematic review is ongoing, this prospective cohort study by Liu et al also examines data from NHSI and NHSII and RA risk in patients exposed to antibiotics, stratified by duration of use (none, ≤14 days, ≥15 days). It is reassuring that in this study neither short term (≤14 days) nor long term (≥15 days) antibiotic use was associated with RA risk. Comparison with prior studies with prescription data, however, is limited given the use of questionnaires to establish duration of recent antibiotic exposure.

Fatigue is a common symptom of RA and has a high impact on quality of life in terms of function. The study by Holten et al examines data from the ARCTIC trial in terms of associations between disease activity and fatigue in early RA, as well as change in fatigue with therapy for RA. Fatigue was measured via a visual analog scale (VAS) and did decrease with therapy from baseline; 80% of patients in the study had moderate or high disease activity based on disease activity score (DAS) at baseline and 69% of patients reported fatigue, while 9% of patients had moderate or high disease activity based on DAS at  24 months and 38% reported fatigue. Interestingly, patients who were in remission (per DAS) at 6 months had a reduced risk of fatigue at 24 months. It is hard to interpret this information in a granular way as fatigue is not measured in a standardized way across clinical studies and the only instrument of measure in the ARCTIC trial was the VAS. An alternate view, for example examining the impact of baseline fatigue on response to therapy, may also be reasonable, or fatigue may be a residual symptom similar to chronic myofascial or “non-inflammatory” pain not responsive to treatment in RA.

Finally, another associated extra-articular manifestation of RA is bronchiectasis. Martin et al performed a systematic review and meta-analysis of the literature and found that the prevalence of bronchiectasis was about 18% in RA patients, suggesting that it is more common than previously thought. However, inclusion of CT imaging may detect subclinical bronchiectasis and other secondary causes were not determined. Still, given the effects on quality of life and mortality, further research into causes and risk factors for bronchiectasis in RA is warranted.

Cigarette smoking is a well-known modifiable risk factor for the development of rheumatoid arthritis (RA). Studies have suggested not only an elevated risk but possible pathogenetic role in the development of autoantibodies, as well as effects on disease outcomes. Passive cigarette smoking has also been proposed as a potential risk factor for RA, though studies are harder to evaluate. This review of prospective data from the Nurses Health Study (NHS) by Yoshida et al looks at incident RA among women enrolled in the study and the influence of in utero, childhood, and adulthood exposure to cigarettes. Childhood exposure to parental smoking was associated with seropositive RA (hazard ratio 1.75) even after controlling for adult personal smoking, and maternal smoking during pregnancy was associated with RA, though the latter effect was not seen after controlling for subsequent smoking exposure. As the authors point out, verifiable prospective data is difficult to obtain regarding exposure to smoking in utero or in childhood and recall bias is possible in obtaining historical information in this prospective study given the use of questionnaires, though it remains plausible given prior studies on the association of personal smoking with RA.

The involvement of gut microbiota in development of autoimmunity has also been postulated but not well-explained. Several recent studies have examined the impact of antibiotic use on the development of RA, including a recent large UK-based case-control study suggesting an increase in RA incidence in people with antibiotic exposure. While a systematic review is ongoing, this prospective cohort study by Liu et al also examines data from NHSI and NHSII and RA risk in patients exposed to antibiotics, stratified by duration of use (none, ≤14 days, ≥15 days). It is reassuring that in this study neither short term (≤14 days) nor long term (≥15 days) antibiotic use was associated with RA risk. Comparison with prior studies with prescription data, however, is limited given the use of questionnaires to establish duration of recent antibiotic exposure.

Fatigue is a common symptom of RA and has a high impact on quality of life in terms of function. The study by Holten et al examines data from the ARCTIC trial in terms of associations between disease activity and fatigue in early RA, as well as change in fatigue with therapy for RA. Fatigue was measured via a visual analog scale (VAS) and did decrease with therapy from baseline; 80% of patients in the study had moderate or high disease activity based on disease activity score (DAS) at baseline and 69% of patients reported fatigue, while 9% of patients had moderate or high disease activity based on DAS at  24 months and 38% reported fatigue. Interestingly, patients who were in remission (per DAS) at 6 months had a reduced risk of fatigue at 24 months. It is hard to interpret this information in a granular way as fatigue is not measured in a standardized way across clinical studies and the only instrument of measure in the ARCTIC trial was the VAS. An alternate view, for example examining the impact of baseline fatigue on response to therapy, may also be reasonable, or fatigue may be a residual symptom similar to chronic myofascial or “non-inflammatory” pain not responsive to treatment in RA.

Finally, another associated extra-articular manifestation of RA is bronchiectasis. Martin et al performed a systematic review and meta-analysis of the literature and found that the prevalence of bronchiectasis was about 18% in RA patients, suggesting that it is more common than previously thought. However, inclusion of CT imaging may detect subclinical bronchiectasis and other secondary causes were not determined. Still, given the effects on quality of life and mortality, further research into causes and risk factors for bronchiectasis in RA is warranted.

Cigarette smoking is a well-known modifiable risk factor for the development of rheumatoid arthritis (RA). Studies have suggested not only an elevated risk but possible pathogenetic role in the development of autoantibodies, as well as effects on disease outcomes. Passive cigarette smoking has also been proposed as a potential risk factor for RA, though studies are harder to evaluate. This review of prospective data from the Nurses Health Study (NHS) by Yoshida et al looks at incident RA among women enrolled in the study and the influence of in utero, childhood, and adulthood exposure to cigarettes. Childhood exposure to parental smoking was associated with seropositive RA (hazard ratio 1.75) even after controlling for adult personal smoking, and maternal smoking during pregnancy was associated with RA, though the latter effect was not seen after controlling for subsequent smoking exposure. As the authors point out, verifiable prospective data is difficult to obtain regarding exposure to smoking in utero or in childhood and recall bias is possible in obtaining historical information in this prospective study given the use of questionnaires, though it remains plausible given prior studies on the association of personal smoking with RA.

The involvement of gut microbiota in development of autoimmunity has also been postulated but not well-explained. Several recent studies have examined the impact of antibiotic use on the development of RA, including a recent large UK-based case-control study suggesting an increase in RA incidence in people with antibiotic exposure. While a systematic review is ongoing, this prospective cohort study by Liu et al also examines data from NHSI and NHSII and RA risk in patients exposed to antibiotics, stratified by duration of use (none, ≤14 days, ≥15 days). It is reassuring that in this study neither short term (≤14 days) nor long term (≥15 days) antibiotic use was associated with RA risk. Comparison with prior studies with prescription data, however, is limited given the use of questionnaires to establish duration of recent antibiotic exposure.

Fatigue is a common symptom of RA and has a high impact on quality of life in terms of function. The study by Holten et al examines data from the ARCTIC trial in terms of associations between disease activity and fatigue in early RA, as well as change in fatigue with therapy for RA. Fatigue was measured via a visual analog scale (VAS) and did decrease with therapy from baseline; 80% of patients in the study had moderate or high disease activity based on disease activity score (DAS) at baseline and 69% of patients reported fatigue, while 9% of patients had moderate or high disease activity based on DAS at  24 months and 38% reported fatigue. Interestingly, patients who were in remission (per DAS) at 6 months had a reduced risk of fatigue at 24 months. It is hard to interpret this information in a granular way as fatigue is not measured in a standardized way across clinical studies and the only instrument of measure in the ARCTIC trial was the VAS. An alternate view, for example examining the impact of baseline fatigue on response to therapy, may also be reasonable, or fatigue may be a residual symptom similar to chronic myofascial or “non-inflammatory” pain not responsive to treatment in RA.

Finally, another associated extra-articular manifestation of RA is bronchiectasis. Martin et al performed a systematic review and meta-analysis of the literature and found that the prevalence of bronchiectasis was about 18% in RA patients, suggesting that it is more common than previously thought. However, inclusion of CT imaging may detect subclinical bronchiectasis and other secondary causes were not determined. Still, given the effects on quality of life and mortality, further research into causes and risk factors for bronchiectasis in RA is warranted.

Patients with rheumatoid arthritis who were taking glucocorticoids and received short-term denosumab (Prolia) had lost any gains in bone mineral density at the spine or hip as well as any improvements in bone turnover markers a year later, according to findings from a post-hoc analysis of a phase 2 trial.

That is, stopping denosumab after a 12-month course resulted in a gradual increase in bone turnover markers and a concurrent return to baseline lumbar spine and total hip bone mineral density, Kenneth G. Saag, MD, professor of medicine and division director of clinical immunology and rheumatology at the University of Alabama at Birmingham, and colleagues reported in an article published online Sept. 17, 2021 in Arthritis & Rheumatology.

“These results provide further support for recommendations that patients discontinuing denosumab should transition to follow-on osteoporosis therapy to prevent or minimize remodeling-induced bone loss,” they concluded.

Like all nonbisphosphonate medications for osteoporosis, Dr. Saag and colleagues wrote, the pharmacologic effects of denosumab are readily reversible after discontinuation.

The current findings in glucocorticoid-treated patients are consistent with those observed in postmenopausal women 2 years after discontinuing denosumab therapy for osteoporosis. Denosumab is typically given for a longer time in such patients, compared with patients receiving glucocorticoids.

Invited to comment, Karen E. Hansen, MD, a rheumatologist and associate professor at the University of Wisconsin, Madison, who was not involved with the study, agreed that the results “highlight the need to prescribe another osteoporosis medication after stopping denosumab, in hopes of preventing loss of bone mineral density.”

Dr. Hansen, a coauthor of a review and meta-analysis of denosumab in the treatment of glucocorticoid-induced osteoporosis, noted that the American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis suggests the use of denosumab as fourth-line therapy, after oral bisphosphonates, intravenous bisphosphonates, and teriparatide (Forteo).

“Its use is particularly relevant in patients who have contraindications or side effects from bisphosphonates or anabolic therapy, or when patient compliance must be ensured,” she said in an interview.

“The type, timing, and effect of therapy after denosumab discontinuation, however, remain controversial,” Dr. Saag and colleagues noted.

However, ongoing trials that are investigating the optimal medication and dosing needed to prevent such losses in bone mineral density after stopping denosumab should provide greater insight, Dr. Hansen said.

Bone health after stopping denosumab

Patients with rheumatoid arthritis often have bone loss that can be worsened by their frequent use of glucocorticoids, leading to an increased risk of fragility fractures.

Denosumab, a monoclonal antibody that inhibits receptor activator of nuclear factor kappaB ligand (RANKL), was approved by the Food and Drug Administration in 2018 for treating patients with glucocorticoid-induced osteoporosis and a high risk of fracture.

Dr. Saag and colleagues performed a post-hoc analysis of a subgroup of 82 patients receiving glucocorticoids who were part of a larger phase 2 clinical trial of 218 patients with rheumatoid arthritis.

The patients had been randomized to receive placebo (n = 26), 60 mg denosumab (the approved dose, n = 27), or 180 mg denosumab (n = 29), given as two subcutaneous 6-month injections at baseline and 6 months, followed by 12 months without any bone-loss prevention therapy.

The patients had a mean age of 55, and 62% were women.

While receiving denosumab, their serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) and the bone formation marker procollagen type I N-terminal propeptide (P1NP) decreased significantly from baseline.

In patients who received the 60-mg dose of denosumab, CTX levels had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 0.16% lower than baseline and 15% higher than baseline at 6 months and 12 months after denosumab was stopped, respectively.

In patients who received the 180-mg dose of denosumab, CTX levels also had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 9% and 76% higher than baseline levels, at 6 months and 12 months after denosumab was stopped, respectively.

Bone mineral density at the lumbar spine and total hip increased during the 12 months of denosumab treatment and then returned to baseline after 12 months of discontinuation of both doses of denosumab.

No osteoporotic fractures were reported during the 12-month denosumab treatment or the 12-month follow-up.

The study was funded by Amgen, which markets denosumab. Dr. Saag is an investigator with Amgen, Mereo, and Radius, and a consultant for Amgen and Roche. Four coauthors are employees of Amgen. The other six coauthors all reported a financial relationship with Amgen.

Patients with rheumatoid arthritis who were taking glucocorticoids and received short-term denosumab (Prolia) had lost any gains in bone mineral density at the spine or hip as well as any improvements in bone turnover markers a year later, according to findings from a post-hoc analysis of a phase 2 trial.

That is, stopping denosumab after a 12-month course resulted in a gradual increase in bone turnover markers and a concurrent return to baseline lumbar spine and total hip bone mineral density, Kenneth G. Saag, MD, professor of medicine and division director of clinical immunology and rheumatology at the University of Alabama at Birmingham, and colleagues reported in an article published online Sept. 17, 2021 in Arthritis & Rheumatology.

“These results provide further support for recommendations that patients discontinuing denosumab should transition to follow-on osteoporosis therapy to prevent or minimize remodeling-induced bone loss,” they concluded.

Like all nonbisphosphonate medications for osteoporosis, Dr. Saag and colleagues wrote, the pharmacologic effects of denosumab are readily reversible after discontinuation.

The current findings in glucocorticoid-treated patients are consistent with those observed in postmenopausal women 2 years after discontinuing denosumab therapy for osteoporosis. Denosumab is typically given for a longer time in such patients, compared with patients receiving glucocorticoids.

Invited to comment, Karen E. Hansen, MD, a rheumatologist and associate professor at the University of Wisconsin, Madison, who was not involved with the study, agreed that the results “highlight the need to prescribe another osteoporosis medication after stopping denosumab, in hopes of preventing loss of bone mineral density.”

Dr. Hansen, a coauthor of a review and meta-analysis of denosumab in the treatment of glucocorticoid-induced osteoporosis, noted that the American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis suggests the use of denosumab as fourth-line therapy, after oral bisphosphonates, intravenous bisphosphonates, and teriparatide (Forteo).

“Its use is particularly relevant in patients who have contraindications or side effects from bisphosphonates or anabolic therapy, or when patient compliance must be ensured,” she said in an interview.

“The type, timing, and effect of therapy after denosumab discontinuation, however, remain controversial,” Dr. Saag and colleagues noted.

However, ongoing trials that are investigating the optimal medication and dosing needed to prevent such losses in bone mineral density after stopping denosumab should provide greater insight, Dr. Hansen said.

Bone health after stopping denosumab

Patients with rheumatoid arthritis often have bone loss that can be worsened by their frequent use of glucocorticoids, leading to an increased risk of fragility fractures.

Denosumab, a monoclonal antibody that inhibits receptor activator of nuclear factor kappaB ligand (RANKL), was approved by the Food and Drug Administration in 2018 for treating patients with glucocorticoid-induced osteoporosis and a high risk of fracture.

Dr. Saag and colleagues performed a post-hoc analysis of a subgroup of 82 patients receiving glucocorticoids who were part of a larger phase 2 clinical trial of 218 patients with rheumatoid arthritis.

The patients had been randomized to receive placebo (n = 26), 60 mg denosumab (the approved dose, n = 27), or 180 mg denosumab (n = 29), given as two subcutaneous 6-month injections at baseline and 6 months, followed by 12 months without any bone-loss prevention therapy.

The patients had a mean age of 55, and 62% were women.

While receiving denosumab, their serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) and the bone formation marker procollagen type I N-terminal propeptide (P1NP) decreased significantly from baseline.

In patients who received the 60-mg dose of denosumab, CTX levels had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 0.16% lower than baseline and 15% higher than baseline at 6 months and 12 months after denosumab was stopped, respectively.

In patients who received the 180-mg dose of denosumab, CTX levels also had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 9% and 76% higher than baseline levels, at 6 months and 12 months after denosumab was stopped, respectively.

Bone mineral density at the lumbar spine and total hip increased during the 12 months of denosumab treatment and then returned to baseline after 12 months of discontinuation of both doses of denosumab.

No osteoporotic fractures were reported during the 12-month denosumab treatment or the 12-month follow-up.

The study was funded by Amgen, which markets denosumab. Dr. Saag is an investigator with Amgen, Mereo, and Radius, and a consultant for Amgen and Roche. Four coauthors are employees of Amgen. The other six coauthors all reported a financial relationship with Amgen.

Patients with rheumatoid arthritis who were taking glucocorticoids and received short-term denosumab (Prolia) had lost any gains in bone mineral density at the spine or hip as well as any improvements in bone turnover markers a year later, according to findings from a post-hoc analysis of a phase 2 trial.

That is, stopping denosumab after a 12-month course resulted in a gradual increase in bone turnover markers and a concurrent return to baseline lumbar spine and total hip bone mineral density, Kenneth G. Saag, MD, professor of medicine and division director of clinical immunology and rheumatology at the University of Alabama at Birmingham, and colleagues reported in an article published online Sept. 17, 2021 in Arthritis & Rheumatology.

“These results provide further support for recommendations that patients discontinuing denosumab should transition to follow-on osteoporosis therapy to prevent or minimize remodeling-induced bone loss,” they concluded.

Like all nonbisphosphonate medications for osteoporosis, Dr. Saag and colleagues wrote, the pharmacologic effects of denosumab are readily reversible after discontinuation.

The current findings in glucocorticoid-treated patients are consistent with those observed in postmenopausal women 2 years after discontinuing denosumab therapy for osteoporosis. Denosumab is typically given for a longer time in such patients, compared with patients receiving glucocorticoids.

Invited to comment, Karen E. Hansen, MD, a rheumatologist and associate professor at the University of Wisconsin, Madison, who was not involved with the study, agreed that the results “highlight the need to prescribe another osteoporosis medication after stopping denosumab, in hopes of preventing loss of bone mineral density.”

Dr. Hansen, a coauthor of a review and meta-analysis of denosumab in the treatment of glucocorticoid-induced osteoporosis, noted that the American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis suggests the use of denosumab as fourth-line therapy, after oral bisphosphonates, intravenous bisphosphonates, and teriparatide (Forteo).

“Its use is particularly relevant in patients who have contraindications or side effects from bisphosphonates or anabolic therapy, or when patient compliance must be ensured,” she said in an interview.

“The type, timing, and effect of therapy after denosumab discontinuation, however, remain controversial,” Dr. Saag and colleagues noted.

However, ongoing trials that are investigating the optimal medication and dosing needed to prevent such losses in bone mineral density after stopping denosumab should provide greater insight, Dr. Hansen said.

Bone health after stopping denosumab

Patients with rheumatoid arthritis often have bone loss that can be worsened by their frequent use of glucocorticoids, leading to an increased risk of fragility fractures.

Denosumab, a monoclonal antibody that inhibits receptor activator of nuclear factor kappaB ligand (RANKL), was approved by the Food and Drug Administration in 2018 for treating patients with glucocorticoid-induced osteoporosis and a high risk of fracture.

Dr. Saag and colleagues performed a post-hoc analysis of a subgroup of 82 patients receiving glucocorticoids who were part of a larger phase 2 clinical trial of 218 patients with rheumatoid arthritis.

The patients had been randomized to receive placebo (n = 26), 60 mg denosumab (the approved dose, n = 27), or 180 mg denosumab (n = 29), given as two subcutaneous 6-month injections at baseline and 6 months, followed by 12 months without any bone-loss prevention therapy.

The patients had a mean age of 55, and 62% were women.

While receiving denosumab, their serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) and the bone formation marker procollagen type I N-terminal propeptide (P1NP) decreased significantly from baseline.

In patients who received the 60-mg dose of denosumab, CTX levels had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 0.16% lower than baseline and 15% higher than baseline at 6 months and 12 months after denosumab was stopped, respectively.

In patients who received the 180-mg dose of denosumab, CTX levels also had returned to baseline levels 6 months and 12 months after denosumab was discontinued.

Median levels of P1NP in these patients were 9% and 76% higher than baseline levels, at 6 months and 12 months after denosumab was stopped, respectively.

Bone mineral density at the lumbar spine and total hip increased during the 12 months of denosumab treatment and then returned to baseline after 12 months of discontinuation of both doses of denosumab.

No osteoporotic fractures were reported during the 12-month denosumab treatment or the 12-month follow-up.

The study was funded by Amgen, which markets denosumab. Dr. Saag is an investigator with Amgen, Mereo, and Radius, and a consultant for Amgen and Roche. Four coauthors are employees of Amgen. The other six coauthors all reported a financial relationship with Amgen.