Rheumatology News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients taking long-term, low-dose glucocorticoids for rheumatoid arthritis over 2 years had a very modest relative weight gain but no relative increase in blood pressure when compared with patients who did not take the drugs, according to findings from a combined study of randomized, controlled trials (RCTs).

“This pooled analysis of five RCTs in RA found that 2 years of low-dose glucocorticoid treatment [at 7.5 mg/day or less] leads to a modest weight gain of about 1 kg but has no effect on blood pressure,” lead study author Andriko Palmowski, MD, a physician and researcher in rheumatology and clinical immunology at Charité-Universitätsmedizin Berlin, and colleagues wrote in the study, published in Annals of Internal Medicine.

“Many clinicians fear using even low-dose glucocorticoids because of the adverse effects associated with their long-term use at higher doses,” noted Leslie J. Crofford, MD, professor of medicine, pathology, microbiology, and immunology, and director of the division of rheumatology and immunology at Vanderbilt University, Nashville, Tenn.

“Indeed, long-term use of even these low doses increases risk for many significant adverse effects, including osteoporosis and cataracts in observational cohorts,” added Dr. Crofford, who was not involved in the study.

Studies were combined for stronger results

Observational studies are prone to confounding, and the RCTs in the literature have been small, resulting in low statistical power, the authors explained.

To overcome these limitations, Dr. Palmowski and associates combined individual participant data from five RCTs of glucocorticoid treatment for RA in 12 countries in Europe. The 1,112 participants had early and established RA, averaged 61.4 years of age, and 68% were women. The GLORIA trial, an RCT that contributed about 40% of the overall study population, “explicitly included elderly patients and patients with multimorbidity who are often excluded from RA trials,” the authors wrote.

Participants in the intervention group took low-dose glucocorticoids (prednisone equivalent, ≤ 7.5 mg/day; three trials used a dose of 5 mg prednisone equivalent per day); and patients in the control groups took placebo, disease-modifying antirheumatic drugs, or both. The researchers compared change over 2 years in body weight and mean arterial pressure between the groups.

At 2 years, both groups gained weight, but participants who took glucocorticoids gained an average of 1.1 kg (P < .001) more than the controls. Mean arterial pressure increased by around 2 mm Hg in both groups, with a –0.4 mm Hg between-group difference (P = .187).

Daniel G. Arkfeld MD, DDS, professor of clinical medicine in the division of rheumatology at the University of Southern California, Los Angeles, found this “a fascinating analysis” and called the lack of change in blood pressure important.

“Steroids are used less in RA due to perceived side effects. Yet many patients have ongoing synovitis and need steroids to enable them to work and perform other activities,” said Dr. Arkfeld, who also was not involved in the study. “NSAIDs are more of an issue, with up to 10% raising blood pressure. Should we be using more steroids and less NSAIDs?”

Dr. Arkfeld also was concerned that the small 2-year weight gain may become significant over time.

Kim Marie Huffman, MD, PhD, associate professor of medicine at Duke University, Durham, N.C., agreed.

“More investigations and longer (or shorter) time periods may have yielded additional findings,” said Dr. Huffman, who also was not involved in the study. “Efforts should be made to minimize long-term prednisone use to minimize impact on weight gain and resulting consequences.”
 

Are these results applicable to U.S. patients?

“Low-dose prednisone is commonly used in the U.S.,” Dr. Huffman said. “Extrapolating the results to a U.S. population is probably fine.”

Dr. Arkfeld agreed that the results can be used to treat U.S. patients because of the large number of study participants.

According to Rebecca B. Blank, MD, PhD, rheumatologist and instructor of medicine at NYU Langone Health, New York, this is an important study. But she cautioned that the literature does not contain good data for other potential harmful effects of long-term, low-dose glucocorticoid use. “Therefore, as per both ACR [American College of Rheumatology] and EULAR [European Alliance of Associations for Rheumatology] recommendations, we should still try to limit glucocorticoids to the lowest dose and shortest duration possible in our RA patients,” advised Dr. Blank, who was not an author in the study.
 

Strengths, weaknesses, and thoughts on further research

“Pooling trials can be tricky, but these investigators used individual-level data, which increases the rigor of the analyses,” Dr. Crofford noted. “There were differences in patient populations and with the glucocorticoid doses and routes of administration. The fact that the patients in each of the studies were randomized is very important in determining if the outcomes can be attributed to the drugs or could be the results of other exposures.”

Dr. Arkfeld would like to know whether early versus late RA patients may have different results because they may have different pathophysiologies.

Dr. Huffman is interested in low-dose glucocorticoids’ impacts on glucose homeostasis, bone density, infection, and other common adverse effects.

In an accompanying editorial, David Fernandez, MD, PhD, of Hospital for Special Surgery, New York, wrote: “These findings provide a more quantifiable assessment of the potential adverse effects of steroid therapy than had existed previously and will be helpful to providers and patients as they decide on the relative risks and benefits of glucocorticoids as part of their therapy plan in rheumatoid arthritis.”

The study received no specific funding. Four of the study’s 13 authors reported financial relationships with pharmaceutical companies. Dr. Fernandez and all outside experts who commented on the study reported no relevant financial relationships.

Patients taking long-term, low-dose glucocorticoids for rheumatoid arthritis over 2 years had a very modest relative weight gain but no relative increase in blood pressure when compared with patients who did not take the drugs, according to findings from a combined study of randomized, controlled trials (RCTs).

“This pooled analysis of five RCTs in RA found that 2 years of low-dose glucocorticoid treatment [at 7.5 mg/day or less] leads to a modest weight gain of about 1 kg but has no effect on blood pressure,” lead study author Andriko Palmowski, MD, a physician and researcher in rheumatology and clinical immunology at Charité-Universitätsmedizin Berlin, and colleagues wrote in the study, published in Annals of Internal Medicine.

“Many clinicians fear using even low-dose glucocorticoids because of the adverse effects associated with their long-term use at higher doses,” noted Leslie J. Crofford, MD, professor of medicine, pathology, microbiology, and immunology, and director of the division of rheumatology and immunology at Vanderbilt University, Nashville, Tenn.

“Indeed, long-term use of even these low doses increases risk for many significant adverse effects, including osteoporosis and cataracts in observational cohorts,” added Dr. Crofford, who was not involved in the study.

Studies were combined for stronger results

Observational studies are prone to confounding, and the RCTs in the literature have been small, resulting in low statistical power, the authors explained.

To overcome these limitations, Dr. Palmowski and associates combined individual participant data from five RCTs of glucocorticoid treatment for RA in 12 countries in Europe. The 1,112 participants had early and established RA, averaged 61.4 years of age, and 68% were women. The GLORIA trial, an RCT that contributed about 40% of the overall study population, “explicitly included elderly patients and patients with multimorbidity who are often excluded from RA trials,” the authors wrote.

Participants in the intervention group took low-dose glucocorticoids (prednisone equivalent, ≤ 7.5 mg/day; three trials used a dose of 5 mg prednisone equivalent per day); and patients in the control groups took placebo, disease-modifying antirheumatic drugs, or both. The researchers compared change over 2 years in body weight and mean arterial pressure between the groups.

At 2 years, both groups gained weight, but participants who took glucocorticoids gained an average of 1.1 kg (P < .001) more than the controls. Mean arterial pressure increased by around 2 mm Hg in both groups, with a –0.4 mm Hg between-group difference (P = .187).

Daniel G. Arkfeld MD, DDS, professor of clinical medicine in the division of rheumatology at the University of Southern California, Los Angeles, found this “a fascinating analysis” and called the lack of change in blood pressure important.

“Steroids are used less in RA due to perceived side effects. Yet many patients have ongoing synovitis and need steroids to enable them to work and perform other activities,” said Dr. Arkfeld, who also was not involved in the study. “NSAIDs are more of an issue, with up to 10% raising blood pressure. Should we be using more steroids and less NSAIDs?”

Dr. Arkfeld also was concerned that the small 2-year weight gain may become significant over time.

Kim Marie Huffman, MD, PhD, associate professor of medicine at Duke University, Durham, N.C., agreed.

“More investigations and longer (or shorter) time periods may have yielded additional findings,” said Dr. Huffman, who also was not involved in the study. “Efforts should be made to minimize long-term prednisone use to minimize impact on weight gain and resulting consequences.”
 

Are these results applicable to U.S. patients?

“Low-dose prednisone is commonly used in the U.S.,” Dr. Huffman said. “Extrapolating the results to a U.S. population is probably fine.”

Dr. Arkfeld agreed that the results can be used to treat U.S. patients because of the large number of study participants.

According to Rebecca B. Blank, MD, PhD, rheumatologist and instructor of medicine at NYU Langone Health, New York, this is an important study. But she cautioned that the literature does not contain good data for other potential harmful effects of long-term, low-dose glucocorticoid use. “Therefore, as per both ACR [American College of Rheumatology] and EULAR [European Alliance of Associations for Rheumatology] recommendations, we should still try to limit glucocorticoids to the lowest dose and shortest duration possible in our RA patients,” advised Dr. Blank, who was not an author in the study.
 

Strengths, weaknesses, and thoughts on further research

“Pooling trials can be tricky, but these investigators used individual-level data, which increases the rigor of the analyses,” Dr. Crofford noted. “There were differences in patient populations and with the glucocorticoid doses and routes of administration. The fact that the patients in each of the studies were randomized is very important in determining if the outcomes can be attributed to the drugs or could be the results of other exposures.”

Dr. Arkfeld would like to know whether early versus late RA patients may have different results because they may have different pathophysiologies.

Dr. Huffman is interested in low-dose glucocorticoids’ impacts on glucose homeostasis, bone density, infection, and other common adverse effects.

In an accompanying editorial, David Fernandez, MD, PhD, of Hospital for Special Surgery, New York, wrote: “These findings provide a more quantifiable assessment of the potential adverse effects of steroid therapy than had existed previously and will be helpful to providers and patients as they decide on the relative risks and benefits of glucocorticoids as part of their therapy plan in rheumatoid arthritis.”

The study received no specific funding. Four of the study’s 13 authors reported financial relationships with pharmaceutical companies. Dr. Fernandez and all outside experts who commented on the study reported no relevant financial relationships.

Patients taking long-term, low-dose glucocorticoids for rheumatoid arthritis over 2 years had a very modest relative weight gain but no relative increase in blood pressure when compared with patients who did not take the drugs, according to findings from a combined study of randomized, controlled trials (RCTs).

“This pooled analysis of five RCTs in RA found that 2 years of low-dose glucocorticoid treatment [at 7.5 mg/day or less] leads to a modest weight gain of about 1 kg but has no effect on blood pressure,” lead study author Andriko Palmowski, MD, a physician and researcher in rheumatology and clinical immunology at Charité-Universitätsmedizin Berlin, and colleagues wrote in the study, published in Annals of Internal Medicine.

“Many clinicians fear using even low-dose glucocorticoids because of the adverse effects associated with their long-term use at higher doses,” noted Leslie J. Crofford, MD, professor of medicine, pathology, microbiology, and immunology, and director of the division of rheumatology and immunology at Vanderbilt University, Nashville, Tenn.

“Indeed, long-term use of even these low doses increases risk for many significant adverse effects, including osteoporosis and cataracts in observational cohorts,” added Dr. Crofford, who was not involved in the study.

Studies were combined for stronger results

Observational studies are prone to confounding, and the RCTs in the literature have been small, resulting in low statistical power, the authors explained.

To overcome these limitations, Dr. Palmowski and associates combined individual participant data from five RCTs of glucocorticoid treatment for RA in 12 countries in Europe. The 1,112 participants had early and established RA, averaged 61.4 years of age, and 68% were women. The GLORIA trial, an RCT that contributed about 40% of the overall study population, “explicitly included elderly patients and patients with multimorbidity who are often excluded from RA trials,” the authors wrote.

Participants in the intervention group took low-dose glucocorticoids (prednisone equivalent, ≤ 7.5 mg/day; three trials used a dose of 5 mg prednisone equivalent per day); and patients in the control groups took placebo, disease-modifying antirheumatic drugs, or both. The researchers compared change over 2 years in body weight and mean arterial pressure between the groups.

At 2 years, both groups gained weight, but participants who took glucocorticoids gained an average of 1.1 kg (P < .001) more than the controls. Mean arterial pressure increased by around 2 mm Hg in both groups, with a –0.4 mm Hg between-group difference (P = .187).

Daniel G. Arkfeld MD, DDS, professor of clinical medicine in the division of rheumatology at the University of Southern California, Los Angeles, found this “a fascinating analysis” and called the lack of change in blood pressure important.

“Steroids are used less in RA due to perceived side effects. Yet many patients have ongoing synovitis and need steroids to enable them to work and perform other activities,” said Dr. Arkfeld, who also was not involved in the study. “NSAIDs are more of an issue, with up to 10% raising blood pressure. Should we be using more steroids and less NSAIDs?”

Dr. Arkfeld also was concerned that the small 2-year weight gain may become significant over time.

Kim Marie Huffman, MD, PhD, associate professor of medicine at Duke University, Durham, N.C., agreed.

“More investigations and longer (or shorter) time periods may have yielded additional findings,” said Dr. Huffman, who also was not involved in the study. “Efforts should be made to minimize long-term prednisone use to minimize impact on weight gain and resulting consequences.”
 

Are these results applicable to U.S. patients?

“Low-dose prednisone is commonly used in the U.S.,” Dr. Huffman said. “Extrapolating the results to a U.S. population is probably fine.”

Dr. Arkfeld agreed that the results can be used to treat U.S. patients because of the large number of study participants.

According to Rebecca B. Blank, MD, PhD, rheumatologist and instructor of medicine at NYU Langone Health, New York, this is an important study. But she cautioned that the literature does not contain good data for other potential harmful effects of long-term, low-dose glucocorticoid use. “Therefore, as per both ACR [American College of Rheumatology] and EULAR [European Alliance of Associations for Rheumatology] recommendations, we should still try to limit glucocorticoids to the lowest dose and shortest duration possible in our RA patients,” advised Dr. Blank, who was not an author in the study.
 

Strengths, weaknesses, and thoughts on further research

“Pooling trials can be tricky, but these investigators used individual-level data, which increases the rigor of the analyses,” Dr. Crofford noted. “There were differences in patient populations and with the glucocorticoid doses and routes of administration. The fact that the patients in each of the studies were randomized is very important in determining if the outcomes can be attributed to the drugs or could be the results of other exposures.”

Dr. Arkfeld would like to know whether early versus late RA patients may have different results because they may have different pathophysiologies.

Dr. Huffman is interested in low-dose glucocorticoids’ impacts on glucose homeostasis, bone density, infection, and other common adverse effects.

In an accompanying editorial, David Fernandez, MD, PhD, of Hospital for Special Surgery, New York, wrote: “These findings provide a more quantifiable assessment of the potential adverse effects of steroid therapy than had existed previously and will be helpful to providers and patients as they decide on the relative risks and benefits of glucocorticoids as part of their therapy plan in rheumatoid arthritis.”

The study received no specific funding. Four of the study’s 13 authors reported financial relationships with pharmaceutical companies. Dr. Fernandez and all outside experts who commented on the study reported no relevant financial relationships.

Severe COVID infections may lead to lasting damage to the immune system, new research finds.

The small study, published in Cell and funded by the National Institutes of Health, details how immune cells were analyzed through blood samples collected from 38 patients recovering from severe COVID and other critical illnesses, and from 19 healthy people. Researchers from Weill Cornell Medicine, New York, and The Jackson Laboratory for Genomic Medicine, Farmington, Conn., found through isolating hematopoietic stem cells that people recovering from severe bouts of COVID had changes to their DNA that were passed down to offspring cells.

The research team, led by Steven Josefowicz, PhD, of Weill Cornell’s pathology department, and Duygu Ucar, PhD, associate professor at The Jackson Laboratory for Genomic Medicine, discovered that this chain reaction of stem cell changes caused a boost in the production of monocytes. The authors found that, due to the innate cellular changes from a severe case of COVID, patients in recovery ended up producing a larger amount of inflammatory cytokines, rather than monocytes – distinct from samples collected from healthy patients and those recovering from other critical illnesses.

These changes to patients’ epigenetic landscapes were observed even a year after the initial COVID-19 infection. While the small participant pool meant that the research team could not establish a direct line between these innate changes and any ensuing health outcomes, the research provides us with clues as to why patients continue to struggle with inflammation and long COVID symptoms well after they recover.

While the authors reiterate the study’s limitations and hesitate to make any clear-cut associations between the results and long-term health outcomes, Wolfgang Leitner, PhD, from the NIH’s National Institute of Allergy and Infectious Diseases, predicts that long COVID can, at least in part, be explained by the changes in innate immune responses.

“Ideally, the authors would have had cells from each patient before they got infected, as a comparator, to see what the epigenetic landscape was before COVID changed it,” said Dr. Leitner. “Clear links between the severity of COVID and genetics were discovered already early in the pandemic and this paper should prompt follow-up studies that link mutations in immune genes with the epigenetic changes described here.”

Dr. Leitner said he had some initial predictions about the long-term impact of COVID-19, but he had not anticipated some of what the study’s findings now show.

“Unlike in the case of, for example, influenza, where the lungs go into ‘repair mode’ after the infection has been resolved – which leaves people susceptible to secondary infections for up to several months – this study shows that after severe COVID, the immune system remains in ‘emergency mode’ and in a heightened state of inflammation,” said Dr. Leitner.

“That further aggravates the problem the initial strong inflammation causes: even higher risk of autoimmune disease, but also, cancer.”

Commenting on the findings, Eric Topol, MD, editor-in-chief of Medscape Medical News, said the study presents “evidence that a key line of immune cells are essentially irrevocably, epigenetically altered and activated.

“You do not want to have this [COVID],” he added.

The study also highlights the researchers’ novel approach to isolating hematopoietic stem cells, found largely in bone marrow. This type of research has been limited in the past because of how costly and invasive it can be to analyze cells in bone marrow. But, by isolating and enriching hematopoietic stem cells, the team can decipher the full cellular diversity of the cells’ bone marrow counterparts.

“This revelation opened the doors to study, at single-cell resolution, how stem cells are affected upon infection and vaccination with a simple blood draw,” representatives from the Jackson lab said in a press release.

A version of this article appeared on Medscape.com.

Severe COVID infections may lead to lasting damage to the immune system, new research finds.

The small study, published in Cell and funded by the National Institutes of Health, details how immune cells were analyzed through blood samples collected from 38 patients recovering from severe COVID and other critical illnesses, and from 19 healthy people. Researchers from Weill Cornell Medicine, New York, and The Jackson Laboratory for Genomic Medicine, Farmington, Conn., found through isolating hematopoietic stem cells that people recovering from severe bouts of COVID had changes to their DNA that were passed down to offspring cells.

The research team, led by Steven Josefowicz, PhD, of Weill Cornell’s pathology department, and Duygu Ucar, PhD, associate professor at The Jackson Laboratory for Genomic Medicine, discovered that this chain reaction of stem cell changes caused a boost in the production of monocytes. The authors found that, due to the innate cellular changes from a severe case of COVID, patients in recovery ended up producing a larger amount of inflammatory cytokines, rather than monocytes – distinct from samples collected from healthy patients and those recovering from other critical illnesses.

These changes to patients’ epigenetic landscapes were observed even a year after the initial COVID-19 infection. While the small participant pool meant that the research team could not establish a direct line between these innate changes and any ensuing health outcomes, the research provides us with clues as to why patients continue to struggle with inflammation and long COVID symptoms well after they recover.

While the authors reiterate the study’s limitations and hesitate to make any clear-cut associations between the results and long-term health outcomes, Wolfgang Leitner, PhD, from the NIH’s National Institute of Allergy and Infectious Diseases, predicts that long COVID can, at least in part, be explained by the changes in innate immune responses.

“Ideally, the authors would have had cells from each patient before they got infected, as a comparator, to see what the epigenetic landscape was before COVID changed it,” said Dr. Leitner. “Clear links between the severity of COVID and genetics were discovered already early in the pandemic and this paper should prompt follow-up studies that link mutations in immune genes with the epigenetic changes described here.”

Dr. Leitner said he had some initial predictions about the long-term impact of COVID-19, but he had not anticipated some of what the study’s findings now show.

“Unlike in the case of, for example, influenza, where the lungs go into ‘repair mode’ after the infection has been resolved – which leaves people susceptible to secondary infections for up to several months – this study shows that after severe COVID, the immune system remains in ‘emergency mode’ and in a heightened state of inflammation,” said Dr. Leitner.

“That further aggravates the problem the initial strong inflammation causes: even higher risk of autoimmune disease, but also, cancer.”

Commenting on the findings, Eric Topol, MD, editor-in-chief of Medscape Medical News, said the study presents “evidence that a key line of immune cells are essentially irrevocably, epigenetically altered and activated.

“You do not want to have this [COVID],” he added.

The study also highlights the researchers’ novel approach to isolating hematopoietic stem cells, found largely in bone marrow. This type of research has been limited in the past because of how costly and invasive it can be to analyze cells in bone marrow. But, by isolating and enriching hematopoietic stem cells, the team can decipher the full cellular diversity of the cells’ bone marrow counterparts.

“This revelation opened the doors to study, at single-cell resolution, how stem cells are affected upon infection and vaccination with a simple blood draw,” representatives from the Jackson lab said in a press release.

A version of this article appeared on Medscape.com.

Severe COVID infections may lead to lasting damage to the immune system, new research finds.

The small study, published in Cell and funded by the National Institutes of Health, details how immune cells were analyzed through blood samples collected from 38 patients recovering from severe COVID and other critical illnesses, and from 19 healthy people. Researchers from Weill Cornell Medicine, New York, and The Jackson Laboratory for Genomic Medicine, Farmington, Conn., found through isolating hematopoietic stem cells that people recovering from severe bouts of COVID had changes to their DNA that were passed down to offspring cells.

The research team, led by Steven Josefowicz, PhD, of Weill Cornell’s pathology department, and Duygu Ucar, PhD, associate professor at The Jackson Laboratory for Genomic Medicine, discovered that this chain reaction of stem cell changes caused a boost in the production of monocytes. The authors found that, due to the innate cellular changes from a severe case of COVID, patients in recovery ended up producing a larger amount of inflammatory cytokines, rather than monocytes – distinct from samples collected from healthy patients and those recovering from other critical illnesses.

These changes to patients’ epigenetic landscapes were observed even a year after the initial COVID-19 infection. While the small participant pool meant that the research team could not establish a direct line between these innate changes and any ensuing health outcomes, the research provides us with clues as to why patients continue to struggle with inflammation and long COVID symptoms well after they recover.

While the authors reiterate the study’s limitations and hesitate to make any clear-cut associations between the results and long-term health outcomes, Wolfgang Leitner, PhD, from the NIH’s National Institute of Allergy and Infectious Diseases, predicts that long COVID can, at least in part, be explained by the changes in innate immune responses.

“Ideally, the authors would have had cells from each patient before they got infected, as a comparator, to see what the epigenetic landscape was before COVID changed it,” said Dr. Leitner. “Clear links between the severity of COVID and genetics were discovered already early in the pandemic and this paper should prompt follow-up studies that link mutations in immune genes with the epigenetic changes described here.”

Dr. Leitner said he had some initial predictions about the long-term impact of COVID-19, but he had not anticipated some of what the study’s findings now show.

“Unlike in the case of, for example, influenza, where the lungs go into ‘repair mode’ after the infection has been resolved – which leaves people susceptible to secondary infections for up to several months – this study shows that after severe COVID, the immune system remains in ‘emergency mode’ and in a heightened state of inflammation,” said Dr. Leitner.

“That further aggravates the problem the initial strong inflammation causes: even higher risk of autoimmune disease, but also, cancer.”

Commenting on the findings, Eric Topol, MD, editor-in-chief of Medscape Medical News, said the study presents “evidence that a key line of immune cells are essentially irrevocably, epigenetically altered and activated.

“You do not want to have this [COVID],” he added.

The study also highlights the researchers’ novel approach to isolating hematopoietic stem cells, found largely in bone marrow. This type of research has been limited in the past because of how costly and invasive it can be to analyze cells in bone marrow. But, by isolating and enriching hematopoietic stem cells, the team can decipher the full cellular diversity of the cells’ bone marrow counterparts.

“This revelation opened the doors to study, at single-cell resolution, how stem cells are affected upon infection and vaccination with a simple blood draw,” representatives from the Jackson lab said in a press release.

A version of this article appeared on Medscape.com.

Those who run Taylor Swift’s Eras Tour have something in common with those who run ERAS, the Electronic Residency Application Service. They cause agita to the people they purport to serve.

Most medical students won’t see Taylor Swift perform her hit song “Cruel Summer,” but they will spend thousands of dollars on ERAS as they prepare for the 2024 residency match. Medical students applying for residency tend to be as stressed out as Swifties trying to score concert tickets. Aside from the expenses of residency applications, students also face an increasingly complex application process: a match algorithm many of them do not understand and major changes to the application process that most learn about right before the application cycle begins.

I have gone through two matches myself, one for internal medicine and one for neurology, and I have also guided students through the process for almost a decade as a dean of student affairs at a medical school. Every summer, the application process is filled with numerous changes, often with little, if any, warning for the students. One year, for example, a specialty required additional essays tailored to each program. Though this requirement may have helped programs discern which students are most enthusiastic about their programs, it also disadvantaged students working on busier rotations, strapped for time to write as many as 70 additional essays in a matter of weeks.

Other recent changes have included “signaling” programs, selecting preferred regions, and preinterview recordings for some specialties. In 2023, students cannot include more than 10 activities on their ERAS application. I have spoken to students at numerous medical schools concerned about the difficulty of selecting 10 activities out of dozens of meaningful pursuits throughout their journeys; this challenge is particularly acute for students who had other careers before entering medical school.

The stress continues to mount even after residency applications have been submitted. Students often feel tied to their phones because offers for residency interviews roll in day and night by email, and if they wait more than a few hours to respond, they’re often moved to a waiting list for their preferred interview date. One year, while we were rounding on patients, a student stepped away to schedule an interview; while doing so, he missed out on managing a patient who developed a neurologic emergency. Thankfully, many but not all specialties have put rules in place to allow students more time to think through interview offers. Having more time to think, even if it’s just 48 hours, may decrease stress, limit the negative impacts on medical education, and promote informed decisions during interview season.

To be sure, most changes are being made in an effort to improve the experience of the students and programs. But as with anything, the result has been a mix of good and bad. The transition to virtual interviews allowed students to apply more broadly to programs without worrying about travel costs. The move also benefits students with disabilities who face accessibility and other challenges with traveling. However, virtual interviews came with several downsides, including but not limited to an increased number of applications submitted (recall that this was also a benefit), interview hoarding, and challenges of connecting personally via virtual platform. Despite the virtual format, applicants increasingly are doing in-person second looks, which some worry may give those applicants an additional advantage over applicants who do not have the time or financial resources to travel for a second look. Despite these shortcomings, it is important that virtual interviews remain an option for those applicants who need it.

Another change, which has been extensively debated in medical education in recent years, was the switch to pass/fail on the USMLE Step 1 exam. Though this move decreased the stress students experienced in the first 2 years of medical school, it has resulted in a new challenge as many residency programs put more emphasis on USMLE Step 2. Many medical students feel they do not have a good gauge of their competitiveness until a few weeks before they submit their application, particularly those applicants attending medical schools that do not provide them with information regarding their class standing until right before they submit their applications.

By the time Swift’s Eras Tour ends in the summer of 2024, medical students will already have matched and started their residency programs. At the same time, a new batch of students will be entering the next year’s match. Though the number of anticipated changes may not reach the level of seismic activity caused by the Swifties at her Seattle concert, many medical students fear that the changes may be just like tectonic plates shifting the match process away from its original purpose: to provide an orderly and fair mechanism for matching the preferences of applicants for U.S. residency positions with the preferences of residency program directors.

Dr. Etienne is with WMCHealth Good Samaritan Hospital, New York, and New York Medical College. He disclosed no relevant conflicts of interest.

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

Those who run Taylor Swift’s Eras Tour have something in common with those who run ERAS, the Electronic Residency Application Service. They cause agita to the people they purport to serve.

Most medical students won’t see Taylor Swift perform her hit song “Cruel Summer,” but they will spend thousands of dollars on ERAS as they prepare for the 2024 residency match. Medical students applying for residency tend to be as stressed out as Swifties trying to score concert tickets. Aside from the expenses of residency applications, students also face an increasingly complex application process: a match algorithm many of them do not understand and major changes to the application process that most learn about right before the application cycle begins.

I have gone through two matches myself, one for internal medicine and one for neurology, and I have also guided students through the process for almost a decade as a dean of student affairs at a medical school. Every summer, the application process is filled with numerous changes, often with little, if any, warning for the students. One year, for example, a specialty required additional essays tailored to each program. Though this requirement may have helped programs discern which students are most enthusiastic about their programs, it also disadvantaged students working on busier rotations, strapped for time to write as many as 70 additional essays in a matter of weeks.

Other recent changes have included “signaling” programs, selecting preferred regions, and preinterview recordings for some specialties. In 2023, students cannot include more than 10 activities on their ERAS application. I have spoken to students at numerous medical schools concerned about the difficulty of selecting 10 activities out of dozens of meaningful pursuits throughout their journeys; this challenge is particularly acute for students who had other careers before entering medical school.

The stress continues to mount even after residency applications have been submitted. Students often feel tied to their phones because offers for residency interviews roll in day and night by email, and if they wait more than a few hours to respond, they’re often moved to a waiting list for their preferred interview date. One year, while we were rounding on patients, a student stepped away to schedule an interview; while doing so, he missed out on managing a patient who developed a neurologic emergency. Thankfully, many but not all specialties have put rules in place to allow students more time to think through interview offers. Having more time to think, even if it’s just 48 hours, may decrease stress, limit the negative impacts on medical education, and promote informed decisions during interview season.

To be sure, most changes are being made in an effort to improve the experience of the students and programs. But as with anything, the result has been a mix of good and bad. The transition to virtual interviews allowed students to apply more broadly to programs without worrying about travel costs. The move also benefits students with disabilities who face accessibility and other challenges with traveling. However, virtual interviews came with several downsides, including but not limited to an increased number of applications submitted (recall that this was also a benefit), interview hoarding, and challenges of connecting personally via virtual platform. Despite the virtual format, applicants increasingly are doing in-person second looks, which some worry may give those applicants an additional advantage over applicants who do not have the time or financial resources to travel for a second look. Despite these shortcomings, it is important that virtual interviews remain an option for those applicants who need it.

Another change, which has been extensively debated in medical education in recent years, was the switch to pass/fail on the USMLE Step 1 exam. Though this move decreased the stress students experienced in the first 2 years of medical school, it has resulted in a new challenge as many residency programs put more emphasis on USMLE Step 2. Many medical students feel they do not have a good gauge of their competitiveness until a few weeks before they submit their application, particularly those applicants attending medical schools that do not provide them with information regarding their class standing until right before they submit their applications.

By the time Swift’s Eras Tour ends in the summer of 2024, medical students will already have matched and started their residency programs. At the same time, a new batch of students will be entering the next year’s match. Though the number of anticipated changes may not reach the level of seismic activity caused by the Swifties at her Seattle concert, many medical students fear that the changes may be just like tectonic plates shifting the match process away from its original purpose: to provide an orderly and fair mechanism for matching the preferences of applicants for U.S. residency positions with the preferences of residency program directors.

Dr. Etienne is with WMCHealth Good Samaritan Hospital, New York, and New York Medical College. He disclosed no relevant conflicts of interest.

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

Those who run Taylor Swift’s Eras Tour have something in common with those who run ERAS, the Electronic Residency Application Service. They cause agita to the people they purport to serve.

Most medical students won’t see Taylor Swift perform her hit song “Cruel Summer,” but they will spend thousands of dollars on ERAS as they prepare for the 2024 residency match. Medical students applying for residency tend to be as stressed out as Swifties trying to score concert tickets. Aside from the expenses of residency applications, students also face an increasingly complex application process: a match algorithm many of them do not understand and major changes to the application process that most learn about right before the application cycle begins.

I have gone through two matches myself, one for internal medicine and one for neurology, and I have also guided students through the process for almost a decade as a dean of student affairs at a medical school. Every summer, the application process is filled with numerous changes, often with little, if any, warning for the students. One year, for example, a specialty required additional essays tailored to each program. Though this requirement may have helped programs discern which students are most enthusiastic about their programs, it also disadvantaged students working on busier rotations, strapped for time to write as many as 70 additional essays in a matter of weeks.

Other recent changes have included “signaling” programs, selecting preferred regions, and preinterview recordings for some specialties. In 2023, students cannot include more than 10 activities on their ERAS application. I have spoken to students at numerous medical schools concerned about the difficulty of selecting 10 activities out of dozens of meaningful pursuits throughout their journeys; this challenge is particularly acute for students who had other careers before entering medical school.

The stress continues to mount even after residency applications have been submitted. Students often feel tied to their phones because offers for residency interviews roll in day and night by email, and if they wait more than a few hours to respond, they’re often moved to a waiting list for their preferred interview date. One year, while we were rounding on patients, a student stepped away to schedule an interview; while doing so, he missed out on managing a patient who developed a neurologic emergency. Thankfully, many but not all specialties have put rules in place to allow students more time to think through interview offers. Having more time to think, even if it’s just 48 hours, may decrease stress, limit the negative impacts on medical education, and promote informed decisions during interview season.

To be sure, most changes are being made in an effort to improve the experience of the students and programs. But as with anything, the result has been a mix of good and bad. The transition to virtual interviews allowed students to apply more broadly to programs without worrying about travel costs. The move also benefits students with disabilities who face accessibility and other challenges with traveling. However, virtual interviews came with several downsides, including but not limited to an increased number of applications submitted (recall that this was also a benefit), interview hoarding, and challenges of connecting personally via virtual platform. Despite the virtual format, applicants increasingly are doing in-person second looks, which some worry may give those applicants an additional advantage over applicants who do not have the time or financial resources to travel for a second look. Despite these shortcomings, it is important that virtual interviews remain an option for those applicants who need it.

Another change, which has been extensively debated in medical education in recent years, was the switch to pass/fail on the USMLE Step 1 exam. Though this move decreased the stress students experienced in the first 2 years of medical school, it has resulted in a new challenge as many residency programs put more emphasis on USMLE Step 2. Many medical students feel they do not have a good gauge of their competitiveness until a few weeks before they submit their application, particularly those applicants attending medical schools that do not provide them with information regarding their class standing until right before they submit their applications.

By the time Swift’s Eras Tour ends in the summer of 2024, medical students will already have matched and started their residency programs. At the same time, a new batch of students will be entering the next year’s match. Though the number of anticipated changes may not reach the level of seismic activity caused by the Swifties at her Seattle concert, many medical students fear that the changes may be just like tectonic plates shifting the match process away from its original purpose: to provide an orderly and fair mechanism for matching the preferences of applicants for U.S. residency positions with the preferences of residency program directors.

Dr. Etienne is with WMCHealth Good Samaritan Hospital, New York, and New York Medical College. He disclosed no relevant conflicts of interest.

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

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

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

Dr. Bruggemeyer

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

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

A sample of pivotal clinical trials

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

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

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

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

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

Unblinding risk to clinical trial validity

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

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

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

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

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

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

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

Unblinding measure needs validation

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Bruggemeyer

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

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

A sample of pivotal clinical trials

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

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

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

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

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

Unblinding risk to clinical trial validity

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

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

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

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

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

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

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

Unblinding measure needs validation

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Bruggemeyer

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

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

A sample of pivotal clinical trials

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

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

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

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

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

Unblinding risk to clinical trial validity

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

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

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

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

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

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

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

Unblinding measure needs validation

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

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

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

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

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

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

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

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

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

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

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

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

It’s been estimated that up to one-third of people who survive acute SARS-CoV-2 infection will suffer a post-viral syndrome with lingering neurologic and other symptoms – now known as long COVID or neurological postacute sequelae of SARS-CoV-2 infection (Neuro-PASC).

However, new research suggests that may be an underestimate and that far more people may be suffering from long COVID without ever having tested positive for the virus. Researchers found a significant proportion of patients in their small study who had never tested positive for COVID-19 but who were having symptoms of long COVID nevertheless showed evidence of immune responses consistent with previous exposure.

“We estimate that millions of people got COVID in the U.S. during the first year of the pandemic and then developed long COVID, yet they did not get a positive COVID diagnosis because of testing limitations,” Igor J. Koralnik, MD, of Northwestern Medicine Comprehensive COVID-19 Center in Chicago, said in an interview.

He noted that many post-COVID-19 clinics in the United States don’t accept people with long COVID symptoms who do not have a positive test result.

Patients with long COVID symptoms but without laboratory evidence of prior infection, “who have often been rejected and stigmatized, should feel vindicated by the results of our study,” Dr. Koralnik said.

“We think that those patients deserve the same clinical care as those with a positive test, as well as inclusion in research studies. This is what we are doing at Northwestern Medicine’s Comprehensive COVID[-19] Center,” Dr. Koralnik added.

The study was published online in the journal Neurology: Neuroimmunology & Neuroinflammation.

Delayed care

The researchers measured SARS-CoV-2-specific humoral and cell-mediated immune responses against nucleocapsid protein and spike proteins, which indicate a prior COVID-19 infection, in 29 patients with post-viral syndrome after suspected COVID-19, including neurologic symptoms such as cognitive impairment, headache, and fatigue, but who did not have a confirmed positive COVID-19 test.

They did the same in 32 age- and sex-matched COVID long haulers with confirmed Neuro-PASC and 18 healthy controls with none of the symptoms of long COVID and no known exposure to SARS-CoV-2 or positive test result.

They found that 12 of the 29 patients (41%) with post-viral syndrome (but no positive COVID-19 test) had detectable humoral and cellular immune responses consistent with prior exposure to SARS-CoV-2. Three-quarters harbored antinucleocapsid and 50% harbored antispike responses.

“Our data suggest that at least 4 million people with post-viral syndrome similar to long COVID may indeed have detectable immune responses to support a COVID diagnosis,” Dr. Koralnik said in a news release.

The 12 patients with post-viral syndrome but without a confirmed COVID-19 test had neurologic symptoms similar to those of patients with confirmed Neuro-PASC.

However, lack of a confirmed COVID-19 diagnosis likely contributed to the 5-month delay in the median time from symptom onset to clinic visit, the researchers said. They were evaluated at a median of 10.7 months vs. 5.4 months for Neuro-PASC patients.

Dr. Koralnik said in an interview that the “most important take-home message” of the study is that patients with post-viral syndrome often present with clinical manifestations similar to those of confirmed patients with Neuro-PASC, suggesting that a positive result by commercially available SARS-CoV-2 diagnostic test should not be a prerequisite for accessing care.

Patients with post-viral syndrome may benefit from the same clinical care as confirmed patients with Neuro-PASC, and the absence of a positive SARS-CoV-2 test should not preclude or delay treatment, he added.
 

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

This article was updated 8/28/23.

It’s been estimated that up to one-third of people who survive acute SARS-CoV-2 infection will suffer a post-viral syndrome with lingering neurologic and other symptoms – now known as long COVID or neurological postacute sequelae of SARS-CoV-2 infection (Neuro-PASC).

However, new research suggests that may be an underestimate and that far more people may be suffering from long COVID without ever having tested positive for the virus. Researchers found a significant proportion of patients in their small study who had never tested positive for COVID-19 but who were having symptoms of long COVID nevertheless showed evidence of immune responses consistent with previous exposure.

“We estimate that millions of people got COVID in the U.S. during the first year of the pandemic and then developed long COVID, yet they did not get a positive COVID diagnosis because of testing limitations,” Igor J. Koralnik, MD, of Northwestern Medicine Comprehensive COVID-19 Center in Chicago, said in an interview.

He noted that many post-COVID-19 clinics in the United States don’t accept people with long COVID symptoms who do not have a positive test result.

Patients with long COVID symptoms but without laboratory evidence of prior infection, “who have often been rejected and stigmatized, should feel vindicated by the results of our study,” Dr. Koralnik said.

“We think that those patients deserve the same clinical care as those with a positive test, as well as inclusion in research studies. This is what we are doing at Northwestern Medicine’s Comprehensive COVID[-19] Center,” Dr. Koralnik added.

The study was published online in the journal Neurology: Neuroimmunology & Neuroinflammation.

Delayed care

The researchers measured SARS-CoV-2-specific humoral and cell-mediated immune responses against nucleocapsid protein and spike proteins, which indicate a prior COVID-19 infection, in 29 patients with post-viral syndrome after suspected COVID-19, including neurologic symptoms such as cognitive impairment, headache, and fatigue, but who did not have a confirmed positive COVID-19 test.

They did the same in 32 age- and sex-matched COVID long haulers with confirmed Neuro-PASC and 18 healthy controls with none of the symptoms of long COVID and no known exposure to SARS-CoV-2 or positive test result.

They found that 12 of the 29 patients (41%) with post-viral syndrome (but no positive COVID-19 test) had detectable humoral and cellular immune responses consistent with prior exposure to SARS-CoV-2. Three-quarters harbored antinucleocapsid and 50% harbored antispike responses.

“Our data suggest that at least 4 million people with post-viral syndrome similar to long COVID may indeed have detectable immune responses to support a COVID diagnosis,” Dr. Koralnik said in a news release.

The 12 patients with post-viral syndrome but without a confirmed COVID-19 test had neurologic symptoms similar to those of patients with confirmed Neuro-PASC.

However, lack of a confirmed COVID-19 diagnosis likely contributed to the 5-month delay in the median time from symptom onset to clinic visit, the researchers said. They were evaluated at a median of 10.7 months vs. 5.4 months for Neuro-PASC patients.

Dr. Koralnik said in an interview that the “most important take-home message” of the study is that patients with post-viral syndrome often present with clinical manifestations similar to those of confirmed patients with Neuro-PASC, suggesting that a positive result by commercially available SARS-CoV-2 diagnostic test should not be a prerequisite for accessing care.

Patients with post-viral syndrome may benefit from the same clinical care as confirmed patients with Neuro-PASC, and the absence of a positive SARS-CoV-2 test should not preclude or delay treatment, he added.
 

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

This article was updated 8/28/23.

It’s been estimated that up to one-third of people who survive acute SARS-CoV-2 infection will suffer a post-viral syndrome with lingering neurologic and other symptoms – now known as long COVID or neurological postacute sequelae of SARS-CoV-2 infection (Neuro-PASC).

However, new research suggests that may be an underestimate and that far more people may be suffering from long COVID without ever having tested positive for the virus. Researchers found a significant proportion of patients in their small study who had never tested positive for COVID-19 but who were having symptoms of long COVID nevertheless showed evidence of immune responses consistent with previous exposure.

“We estimate that millions of people got COVID in the U.S. during the first year of the pandemic and then developed long COVID, yet they did not get a positive COVID diagnosis because of testing limitations,” Igor J. Koralnik, MD, of Northwestern Medicine Comprehensive COVID-19 Center in Chicago, said in an interview.

He noted that many post-COVID-19 clinics in the United States don’t accept people with long COVID symptoms who do not have a positive test result.

Patients with long COVID symptoms but without laboratory evidence of prior infection, “who have often been rejected and stigmatized, should feel vindicated by the results of our study,” Dr. Koralnik said.

“We think that those patients deserve the same clinical care as those with a positive test, as well as inclusion in research studies. This is what we are doing at Northwestern Medicine’s Comprehensive COVID[-19] Center,” Dr. Koralnik added.

The study was published online in the journal Neurology: Neuroimmunology & Neuroinflammation.

Delayed care

The researchers measured SARS-CoV-2-specific humoral and cell-mediated immune responses against nucleocapsid protein and spike proteins, which indicate a prior COVID-19 infection, in 29 patients with post-viral syndrome after suspected COVID-19, including neurologic symptoms such as cognitive impairment, headache, and fatigue, but who did not have a confirmed positive COVID-19 test.

They did the same in 32 age- and sex-matched COVID long haulers with confirmed Neuro-PASC and 18 healthy controls with none of the symptoms of long COVID and no known exposure to SARS-CoV-2 or positive test result.

They found that 12 of the 29 patients (41%) with post-viral syndrome (but no positive COVID-19 test) had detectable humoral and cellular immune responses consistent with prior exposure to SARS-CoV-2. Three-quarters harbored antinucleocapsid and 50% harbored antispike responses.

“Our data suggest that at least 4 million people with post-viral syndrome similar to long COVID may indeed have detectable immune responses to support a COVID diagnosis,” Dr. Koralnik said in a news release.

The 12 patients with post-viral syndrome but without a confirmed COVID-19 test had neurologic symptoms similar to those of patients with confirmed Neuro-PASC.

However, lack of a confirmed COVID-19 diagnosis likely contributed to the 5-month delay in the median time from symptom onset to clinic visit, the researchers said. They were evaluated at a median of 10.7 months vs. 5.4 months for Neuro-PASC patients.

Dr. Koralnik said in an interview that the “most important take-home message” of the study is that patients with post-viral syndrome often present with clinical manifestations similar to those of confirmed patients with Neuro-PASC, suggesting that a positive result by commercially available SARS-CoV-2 diagnostic test should not be a prerequisite for accessing care.

Patients with post-viral syndrome may benefit from the same clinical care as confirmed patients with Neuro-PASC, and the absence of a positive SARS-CoV-2 test should not preclude or delay treatment, he added.
 

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

This article was updated 8/28/23.

A consumer watchdog group is pressing for broader public access to a confidential federal database that tracks disciplinary records for physicians in a new report, arguing that extra public scrutiny could pressure state medical boards to be more aggressive watchdogs.

Public Citizen’s report includes an analysis of how frequently medical boards sanctioned physicians in 2019, 2020, and 2021. These sanctions include license revocations, suspensions, voluntary surrenders of licenses, and limitations on practice while under investigation.

The report used data from the National Practitioner Data Bank (NPDB), a federal repository of reports about state licensure, discipline, and certification actions as well as medical malpractice payments. The database is closed to the public, but hospitals, malpractice insurers, and investigators can query it.

According to Public Citizen’s calculations, states most likely to take serious disciplinary action against physicians were:

• Michigan: 1.74 serious disciplinary actions per 1,000 physicians per year
• Ohio: 1.61
• North Dakota: 1.60
• Colorado: 1.55
• Arizona: 1.53
• The states least likely to do so were:
• Nevada: 0.24 serious disciplinary actions per 1,000 physicians per year
• New Hampshire: 0.25
• Georgia: 0.27
• Indiana: 0.28
• Nebraska: 0.32
• California, the largest U.S. state by both population and number of physicians, landed near the middle, ranking 27th with a rate of 0.83 serious actions per 1,000 physicians, Public Citizen said.

“There is no evidence that physicians in any state are, overall, more or less likely to be incompetent or miscreant than the physicians in any other state,” said Robert Oshel, PhD, a former NPDB associate director for research and an author of the report.

The differences instead reflect variations in boards’ enforcement of medical practice laws, domination of licensing boards by physicians, and inadequate budgets, he noted.

Public Citizen said Congress should change federal law to let members of the public get information from the NPDB to do a background check on physicians whom they are considering seeing or are already seeing. This would not only help individuals but also would spur state licensing boards to do their own checks with the NPDB, the group said.

“If licensing boards routinely queried the NPDB, they would not be faulted by the public and state legislators for not knowing about malpractice payments or disciplinary actions affecting their licensees and therefore not taking reasonable actions concerning their licensees found to have poor records,” the report said.
 

Questioning NPDB access for consumers

Michelle Mello, JD, PhD, a professor of law and health policy at Stanford (Calif.) University, has studied the current applications of the NPDB. In 2019, she published an article in The New England Journal of Medicine examining changes in practice patterns for clinicians who faced multiple malpractice claims.

Dr. Mello questioned what benefit consumers would get from direct access to the NPDB’s information.

“It provides almost no context for the information it reports, making it even harder for patients to make sense of what they see there,” Dr. Mello said in an interview.

Hospitals are already required to routinely query the NPDB. This legal requirement should be expanded to include licensing boards, which the report called “the last line of defense for the public from incompetent and miscreant physicians,” Public Citizen said.

“Ideally, this amendment should include free continuous query access by medical boards for all their licensees,” the report said. “In the absence of any action by Congress, individual state legislatures should require their licensing boards to query all their licensees or enroll in continuous query, as a few states already do.”

The Federation of State Medical Boards agreed with some of the other suggestions Public Citizen offered in the report. The two concur on the need for increased funding to state medical boards to ensure that they have adequate resources and staffing to fulfill their duties, FSMB said in a statement.

But FSMB disagreed with Public Citizens’ approach to ranking boards, saying it could mislead. The report lacks context about how boards’ funding and authority vary, Humayun Chaudhry, DO, FSMB’s chief executive officer, said. He also questioned the decision to focus only on serious disciplinary actions.

“The Public Citizen report does not take into account the wide range of disciplinary steps boards can take such as letters of reprimand or fines, which are often enough to stop problem behaviors – preempting further problems in the future,” Dr. Chaudhry said.
 

D.C. gets worst rating

The District of Columbia earned the worst mark in the Public Citizen ranking, holding the 51st spot, the same place it held in the group’s similar ranking on actions taken in the 2017-2019 period. There were 0.19 serious disciplinary actions per 1,000 physicians a year in Washington, Public Citizen said.

In an email to this news organization, Dr. Oshel said that the Public Citizen analysis focused on the number of licensed physicians in each state and D.C. that can be obtained and compared reliably. It avoided using the term “practicing physicians” owing in part to doubts about the reliability of these counts, he said.

As many as 20% of physicians nationwide are focused primarily on work outside of clinical care, Dr. Oshel estimated. In D.C., perhaps 40% of physicians may fall into this category. Of the more than 13,700 physicians licensed in D.C., there may be only about 8,126 actively practicing, according to Dr. Oshel.

But even using that lower estimate of practicing physicians would only raise D.C.’s ranking to 46, signaling a need for stepped-up enforcement, Dr. Oshel said.

“[Whether it’s] 46th or 51st, both are bad,” Dr. Oshel said.

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

A consumer watchdog group is pressing for broader public access to a confidential federal database that tracks disciplinary records for physicians in a new report, arguing that extra public scrutiny could pressure state medical boards to be more aggressive watchdogs.

Public Citizen’s report includes an analysis of how frequently medical boards sanctioned physicians in 2019, 2020, and 2021. These sanctions include license revocations, suspensions, voluntary surrenders of licenses, and limitations on practice while under investigation.

The report used data from the National Practitioner Data Bank (NPDB), a federal repository of reports about state licensure, discipline, and certification actions as well as medical malpractice payments. The database is closed to the public, but hospitals, malpractice insurers, and investigators can query it.

According to Public Citizen’s calculations, states most likely to take serious disciplinary action against physicians were:

• Michigan: 1.74 serious disciplinary actions per 1,000 physicians per year
• Ohio: 1.61
• North Dakota: 1.60
• Colorado: 1.55
• Arizona: 1.53
• The states least likely to do so were:
• Nevada: 0.24 serious disciplinary actions per 1,000 physicians per year
• New Hampshire: 0.25
• Georgia: 0.27
• Indiana: 0.28
• Nebraska: 0.32
• California, the largest U.S. state by both population and number of physicians, landed near the middle, ranking 27th with a rate of 0.83 serious actions per 1,000 physicians, Public Citizen said.

“There is no evidence that physicians in any state are, overall, more or less likely to be incompetent or miscreant than the physicians in any other state,” said Robert Oshel, PhD, a former NPDB associate director for research and an author of the report.

The differences instead reflect variations in boards’ enforcement of medical practice laws, domination of licensing boards by physicians, and inadequate budgets, he noted.

Public Citizen said Congress should change federal law to let members of the public get information from the NPDB to do a background check on physicians whom they are considering seeing or are already seeing. This would not only help individuals but also would spur state licensing boards to do their own checks with the NPDB, the group said.

“If licensing boards routinely queried the NPDB, they would not be faulted by the public and state legislators for not knowing about malpractice payments or disciplinary actions affecting their licensees and therefore not taking reasonable actions concerning their licensees found to have poor records,” the report said.
 

Questioning NPDB access for consumers

Michelle Mello, JD, PhD, a professor of law and health policy at Stanford (Calif.) University, has studied the current applications of the NPDB. In 2019, she published an article in The New England Journal of Medicine examining changes in practice patterns for clinicians who faced multiple malpractice claims.

Dr. Mello questioned what benefit consumers would get from direct access to the NPDB’s information.

“It provides almost no context for the information it reports, making it even harder for patients to make sense of what they see there,” Dr. Mello said in an interview.

Hospitals are already required to routinely query the NPDB. This legal requirement should be expanded to include licensing boards, which the report called “the last line of defense for the public from incompetent and miscreant physicians,” Public Citizen said.

“Ideally, this amendment should include free continuous query access by medical boards for all their licensees,” the report said. “In the absence of any action by Congress, individual state legislatures should require their licensing boards to query all their licensees or enroll in continuous query, as a few states already do.”

The Federation of State Medical Boards agreed with some of the other suggestions Public Citizen offered in the report. The two concur on the need for increased funding to state medical boards to ensure that they have adequate resources and staffing to fulfill their duties, FSMB said in a statement.

But FSMB disagreed with Public Citizens’ approach to ranking boards, saying it could mislead. The report lacks context about how boards’ funding and authority vary, Humayun Chaudhry, DO, FSMB’s chief executive officer, said. He also questioned the decision to focus only on serious disciplinary actions.

“The Public Citizen report does not take into account the wide range of disciplinary steps boards can take such as letters of reprimand or fines, which are often enough to stop problem behaviors – preempting further problems in the future,” Dr. Chaudhry said.
 

D.C. gets worst rating

The District of Columbia earned the worst mark in the Public Citizen ranking, holding the 51st spot, the same place it held in the group’s similar ranking on actions taken in the 2017-2019 period. There were 0.19 serious disciplinary actions per 1,000 physicians a year in Washington, Public Citizen said.

In an email to this news organization, Dr. Oshel said that the Public Citizen analysis focused on the number of licensed physicians in each state and D.C. that can be obtained and compared reliably. It avoided using the term “practicing physicians” owing in part to doubts about the reliability of these counts, he said.

As many as 20% of physicians nationwide are focused primarily on work outside of clinical care, Dr. Oshel estimated. In D.C., perhaps 40% of physicians may fall into this category. Of the more than 13,700 physicians licensed in D.C., there may be only about 8,126 actively practicing, according to Dr. Oshel.

But even using that lower estimate of practicing physicians would only raise D.C.’s ranking to 46, signaling a need for stepped-up enforcement, Dr. Oshel said.

“[Whether it’s] 46th or 51st, both are bad,” Dr. Oshel said.

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

A consumer watchdog group is pressing for broader public access to a confidential federal database that tracks disciplinary records for physicians in a new report, arguing that extra public scrutiny could pressure state medical boards to be more aggressive watchdogs.

Public Citizen’s report includes an analysis of how frequently medical boards sanctioned physicians in 2019, 2020, and 2021. These sanctions include license revocations, suspensions, voluntary surrenders of licenses, and limitations on practice while under investigation.

The report used data from the National Practitioner Data Bank (NPDB), a federal repository of reports about state licensure, discipline, and certification actions as well as medical malpractice payments. The database is closed to the public, but hospitals, malpractice insurers, and investigators can query it.

According to Public Citizen’s calculations, states most likely to take serious disciplinary action against physicians were:

• Michigan: 1.74 serious disciplinary actions per 1,000 physicians per year
• Ohio: 1.61
• North Dakota: 1.60
• Colorado: 1.55
• Arizona: 1.53
• The states least likely to do so were:
• Nevada: 0.24 serious disciplinary actions per 1,000 physicians per year
• New Hampshire: 0.25
• Georgia: 0.27
• Indiana: 0.28
• Nebraska: 0.32
• California, the largest U.S. state by both population and number of physicians, landed near the middle, ranking 27th with a rate of 0.83 serious actions per 1,000 physicians, Public Citizen said.

“There is no evidence that physicians in any state are, overall, more or less likely to be incompetent or miscreant than the physicians in any other state,” said Robert Oshel, PhD, a former NPDB associate director for research and an author of the report.

The differences instead reflect variations in boards’ enforcement of medical practice laws, domination of licensing boards by physicians, and inadequate budgets, he noted.

Public Citizen said Congress should change federal law to let members of the public get information from the NPDB to do a background check on physicians whom they are considering seeing or are already seeing. This would not only help individuals but also would spur state licensing boards to do their own checks with the NPDB, the group said.

“If licensing boards routinely queried the NPDB, they would not be faulted by the public and state legislators for not knowing about malpractice payments or disciplinary actions affecting their licensees and therefore not taking reasonable actions concerning their licensees found to have poor records,” the report said.
 

Questioning NPDB access for consumers

Michelle Mello, JD, PhD, a professor of law and health policy at Stanford (Calif.) University, has studied the current applications of the NPDB. In 2019, she published an article in The New England Journal of Medicine examining changes in practice patterns for clinicians who faced multiple malpractice claims.

Dr. Mello questioned what benefit consumers would get from direct access to the NPDB’s information.

“It provides almost no context for the information it reports, making it even harder for patients to make sense of what they see there,” Dr. Mello said in an interview.

Hospitals are already required to routinely query the NPDB. This legal requirement should be expanded to include licensing boards, which the report called “the last line of defense for the public from incompetent and miscreant physicians,” Public Citizen said.

“Ideally, this amendment should include free continuous query access by medical boards for all their licensees,” the report said. “In the absence of any action by Congress, individual state legislatures should require their licensing boards to query all their licensees or enroll in continuous query, as a few states already do.”

The Federation of State Medical Boards agreed with some of the other suggestions Public Citizen offered in the report. The two concur on the need for increased funding to state medical boards to ensure that they have adequate resources and staffing to fulfill their duties, FSMB said in a statement.

But FSMB disagreed with Public Citizens’ approach to ranking boards, saying it could mislead. The report lacks context about how boards’ funding and authority vary, Humayun Chaudhry, DO, FSMB’s chief executive officer, said. He also questioned the decision to focus only on serious disciplinary actions.

“The Public Citizen report does not take into account the wide range of disciplinary steps boards can take such as letters of reprimand or fines, which are often enough to stop problem behaviors – preempting further problems in the future,” Dr. Chaudhry said.
 

D.C. gets worst rating

The District of Columbia earned the worst mark in the Public Citizen ranking, holding the 51st spot, the same place it held in the group’s similar ranking on actions taken in the 2017-2019 period. There were 0.19 serious disciplinary actions per 1,000 physicians a year in Washington, Public Citizen said.

In an email to this news organization, Dr. Oshel said that the Public Citizen analysis focused on the number of licensed physicians in each state and D.C. that can be obtained and compared reliably. It avoided using the term “practicing physicians” owing in part to doubts about the reliability of these counts, he said.

As many as 20% of physicians nationwide are focused primarily on work outside of clinical care, Dr. Oshel estimated. In D.C., perhaps 40% of physicians may fall into this category. Of the more than 13,700 physicians licensed in D.C., there may be only about 8,126 actively practicing, according to Dr. Oshel.

But even using that lower estimate of practicing physicians would only raise D.C.’s ranking to 46, signaling a need for stepped-up enforcement, Dr. Oshel said.

“[Whether it’s] 46th or 51st, both are bad,” Dr. Oshel said.

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

A new strain of COVID-19 that was identified only a week ago in the United States has prompted the Centers for Disease Control and Prevention to take the rare step of issuing a formal message that it could evade vaccines or the protection of natural immunity. 

The strain is called BA.2.86 and is of particular concern because of its more than 30 mutations, which means it may behave very differently than previous versions of the virus. That number of mutations is on par with the difference between variants so serious that they were formally named, such as between Delta and Omicron, the CDC explained in the risk assessment issued Aug. 23.

Worldwide, health agencies are issuing a flurry of updates on BA.2.86. The strain only recently landed on the World Health Organization’s radar when it was named a “variant under monitoring” on Aug. 17. The CDC announced the same day that it had been detected in the United States.

Among the characteristics the CDC monitors for are how contagious a strain is, how well it responds to treatment, and how severely it affects people.

“BA.2.86 may be more capable of causing infection in people who have previously had COVID-19 or who have received COVID-19 vaccines,” the CDC risk assessment stated.

The agency is evaluating how well the forthcoming updated vaccine, due out in September, performs against BA.2.86.

A new forecast also released this week by the CDC predicts hospitalizations due to the virus will continue their upward trend through at least mid-September. Currently, about 1,800 people are hospitalized daily with COVID-19. The new prediction shows that number has a small potential to drop as low as 1,100 daily, but it could also increase by as many as 7,500 per day. The most likely scenario lands somewhere in the middle of that range, with daily hospital admissions of between 2,000 and 4,000 people by Sept. 18.

The CDC said there is “no evidence” that BA.2.86 is causing more severe illness but said that could change as more information becomes available. Health experts typically gauge severity by the rate of COVID hospitalizations.

The journal Nature reported that many scientists see similarities between the emergence of BA.2.86 and that of Omicron, which rapidly spread around the world in late 2021.

“There’s a little bit of déjà vu all over again,” University of Michigan virologist Adam Lauring, MD, PhD, whose lab detected one of the first U.S. cases of BA.2.86, told Nature.

Dr. Lauring, as well as the CDC and the WHO, all caution that more data is needed to truly understand the threat posed by BA.2.86.

“There’s good reason to think it won’t be like the Omicron wave, but it’s early days,” Dr. Lauring said.

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

A new strain of COVID-19 that was identified only a week ago in the United States has prompted the Centers for Disease Control and Prevention to take the rare step of issuing a formal message that it could evade vaccines or the protection of natural immunity. 

The strain is called BA.2.86 and is of particular concern because of its more than 30 mutations, which means it may behave very differently than previous versions of the virus. That number of mutations is on par with the difference between variants so serious that they were formally named, such as between Delta and Omicron, the CDC explained in the risk assessment issued Aug. 23.

Worldwide, health agencies are issuing a flurry of updates on BA.2.86. The strain only recently landed on the World Health Organization’s radar when it was named a “variant under monitoring” on Aug. 17. The CDC announced the same day that it had been detected in the United States.

Among the characteristics the CDC monitors for are how contagious a strain is, how well it responds to treatment, and how severely it affects people.

“BA.2.86 may be more capable of causing infection in people who have previously had COVID-19 or who have received COVID-19 vaccines,” the CDC risk assessment stated.

The agency is evaluating how well the forthcoming updated vaccine, due out in September, performs against BA.2.86.

A new forecast also released this week by the CDC predicts hospitalizations due to the virus will continue their upward trend through at least mid-September. Currently, about 1,800 people are hospitalized daily with COVID-19. The new prediction shows that number has a small potential to drop as low as 1,100 daily, but it could also increase by as many as 7,500 per day. The most likely scenario lands somewhere in the middle of that range, with daily hospital admissions of between 2,000 and 4,000 people by Sept. 18.

The CDC said there is “no evidence” that BA.2.86 is causing more severe illness but said that could change as more information becomes available. Health experts typically gauge severity by the rate of COVID hospitalizations.

The journal Nature reported that many scientists see similarities between the emergence of BA.2.86 and that of Omicron, which rapidly spread around the world in late 2021.

“There’s a little bit of déjà vu all over again,” University of Michigan virologist Adam Lauring, MD, PhD, whose lab detected one of the first U.S. cases of BA.2.86, told Nature.

Dr. Lauring, as well as the CDC and the WHO, all caution that more data is needed to truly understand the threat posed by BA.2.86.

“There’s good reason to think it won’t be like the Omicron wave, but it’s early days,” Dr. Lauring said.

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

A new strain of COVID-19 that was identified only a week ago in the United States has prompted the Centers for Disease Control and Prevention to take the rare step of issuing a formal message that it could evade vaccines or the protection of natural immunity. 

The strain is called BA.2.86 and is of particular concern because of its more than 30 mutations, which means it may behave very differently than previous versions of the virus. That number of mutations is on par with the difference between variants so serious that they were formally named, such as between Delta and Omicron, the CDC explained in the risk assessment issued Aug. 23.

Worldwide, health agencies are issuing a flurry of updates on BA.2.86. The strain only recently landed on the World Health Organization’s radar when it was named a “variant under monitoring” on Aug. 17. The CDC announced the same day that it had been detected in the United States.

Among the characteristics the CDC monitors for are how contagious a strain is, how well it responds to treatment, and how severely it affects people.

“BA.2.86 may be more capable of causing infection in people who have previously had COVID-19 or who have received COVID-19 vaccines,” the CDC risk assessment stated.

The agency is evaluating how well the forthcoming updated vaccine, due out in September, performs against BA.2.86.

A new forecast also released this week by the CDC predicts hospitalizations due to the virus will continue their upward trend through at least mid-September. Currently, about 1,800 people are hospitalized daily with COVID-19. The new prediction shows that number has a small potential to drop as low as 1,100 daily, but it could also increase by as many as 7,500 per day. The most likely scenario lands somewhere in the middle of that range, with daily hospital admissions of between 2,000 and 4,000 people by Sept. 18.

The CDC said there is “no evidence” that BA.2.86 is causing more severe illness but said that could change as more information becomes available. Health experts typically gauge severity by the rate of COVID hospitalizations.

The journal Nature reported that many scientists see similarities between the emergence of BA.2.86 and that of Omicron, which rapidly spread around the world in late 2021.

“There’s a little bit of déjà vu all over again,” University of Michigan virologist Adam Lauring, MD, PhD, whose lab detected one of the first U.S. cases of BA.2.86, told Nature.

Dr. Lauring, as well as the CDC and the WHO, all caution that more data is needed to truly understand the threat posed by BA.2.86.

“There’s good reason to think it won’t be like the Omicron wave, but it’s early days,” Dr. Lauring said.

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

Early in his career as a pain researcher, Daniel Whibley, PhD, was struck by an article that drew parallels between methods of torture and the experiences of patients with insomnia and chronic pain.

The author of that article, Nicole Tang, DPhil, observed that two methods used by torturers – pain infliction and sleep deprivation – harm people in ways that also are experienced by many patients with pain and sleep conditions.

Patients are “essentially living in this perpetually undesirable, at best, situation where both of these features are playing out in their lives,” said Dr. Whibley, a research assistant professor of physical medicine and rehabilitation at the University of Michigan, Ann Arbor.

The problems create a “kind of vicious circle,” he said. Pain disrupts sleep. Insufficient sleep worsens pain.

Studies have established important relationships between the conditions, but investigators are still trying to clarify the mechanisms that connect them and the best ways to intervene to improve patient outcomes.

To that end, Dr. Whibley has developed an intervention known as Move & Snooze to benefit patients with pain associated with osteoarthritis.

The program includes remote exercise coaching and an automated 6-week course of digital cognitive-behavioral therapy for insomnia (CBT-I). Dr. Whibley’s hypothesis is that addressing sleep disturbances will help patients stay engaged with the physical activity component of the program and help with pain management.

He and his colleagues have tested the intervention in a feasibility study and are in the process of securing grant funding to test it in a large, nationwide trial.
 

Losing sleep for science

Michael Smith, PhD, is examining the sleep-pain connection from a different angle.

Dr. Smith, the director of the Behavioral Medicine Research Laboratory at Johns Hopkins University, Baltimore, is recruiting healthy adults to endure restless nights and painful stimuli.

His team is conducting a study known as Sleep-MOR that aims to reveal how different types of sleep disturbances influence pain and a person’s response to opioids.

Nearly three dozen participants have completed the study so far, Dr. Smith said, out of what he hopes will be 200 in all.

Participants are randomly assigned to sleep normally or to undergo an experimental condition that is designed to mimic the sleep disturbances of insomnia or obstructive sleep apnea (OSA).

In a “forced awakening” group, participants are awakened for 20-minute intervals every hour and for a full hour-long window during the night. In this condition, they could sleep for about four hours in all. Forced awakening is intended to represent insomnia

A “sleep fragmentation” group is meant to represent patients with OSA. About 30 times per hour, tones and tactile buzzers rouse sleeping participants without fully waking them up. Although the experiment involves brief arousals such as those experienced by patients with OSA, it does not capture another important feature of sleep apnea – the cessation of breathing, Dr. Smith noted.

The next day, researchers perform pain testing and brain imaging and see how opioid receptors respond to pain medication.

“Some of the forms of sleep loss that we are studying may actually alter the efficacy of the binding of those receptors, and that might then require you to have higher doses of an opioid to get the same effect,” Dr. Smith said. “That’s our hypothesis.”

If that bears out, disturbed sleep may play a role in the development of opioid use disorder and have implications for patients who receive opioids after surgery, he said.

In the lab, researchers examine pain thresholds using techniques such as thermal pain testing, in which a thermode attached to a participant’s arm heats up. The temperature “slowly goes up and the patient just says: ‘Ouch,’ when it first hurts. Then we have their pain threshold,” Dr. Smith said.
 

A bidirectional relationship

Epidemiologic studies have found that, if you follow women who do not have pain, those with complaints about sleep are more than twice as likely to develop fibromyalgia.

Dr. Smith’s group and others have shown that if you deprive a healthy person of sleep, they become more sensitive to pain.

Inflammation could be one possible reason for this effect. In one study, participants who experienced forced awakening experienced less slow-wave sleep, which was tied to more inflammation in the morning. Increased inflammation was linked to greater pain sensitivity.

“We are starting to piece together some of the pathways. That’s just one,” Dr. Smith said.

A recent study by researchers at Harvard University and elsewhere investigated how sleep disturbances affected three pain pathways. In that study, the results varied by sex. The data indicate that optimal treatment approaches might differ for men and women, the researchers said.
 

Waking up to the problem

Sleep problems can be neglected in medical school and in the clinic. “People just have other things to focus on that they clearly know what they can do about it,” Dr. Smith said.

But clinicians should not hesitate to screen for conditions such as insomnia or OSA and refer patients to a specialist. If a patient has had pain for 6 months and treatments are not working, the chance that they have a treatable sleep disorder “is very high, above 50%,” Dr. Smith said. Many could have more than one sleep disorder, he added.

Continuous positive airway pressure for OSA and CBT for insomnia can improve sleep. Dr. Smith said he expects these measures will improve overall pain management as well.

If treating a sleep disorder fails to help with pain, however, it may still help prevent other sleep-related problems, such as depression, poor glucose control, and heart disease. It also could improve patients’ ability to function day to day, he said.

Evidence on whether treating sleep problems reduces pain has so far been mixed.

“We’ve done some studies showing that if you have CBT-I and you have knee arthritis, improvements in the amount of time you spend awake at night translate into improvements in pain at 6 months. There is a signal there, but it’s not as strong as we would like,” he said. “It may be that it takes longer than anyone would like” to have an effect.

A structured intervention such as CBT-I is likely more beneficial than education about sleep hygiene alone in resolving sleep disturbances, Dr. Whibley said. CBT-I includes active components such as sleep restriction therapy and stimulus control therapy and is recommended by the American Academy of Sleep Medicine as the first-line treatment for chronic insomnia (J Clin Sleep Med. 2008 Oct 15;4[5]:487-504).

Patients should consider the role that sleep may play in their chronic pain condition, he said.

“An increasing number of researchers and clinicians are becoming more interested in this as a foundational pillar of health, alongside activity and diet,” Dr. Whibley said. “Sleep is recognized as just as important but doesn’t seem to get the airtime.”

Clinicians, he added, should regularly assess their patients’ sleep and know where to refer those whom they feel would benefit from more advanced management: “They [should] know that they have at least got it on their radar to check as one of the important pillars of health that you should be able to control.”
 

Sleep trials seeking pain patients

Researchers around the United States are conducting dozens of studies related to sleep and pain. The following trials are recruiting participants, according to ClinicalTrials.gov.

Sleep and Pain Interventions in Women With Fibromyalgia (SPIN-II). Investigators at the University of Missouri–Columbia are examining two cognitive-behavioral treatments for women with fibromyalgia and insomnia. “This trial will yield important information about the roles of sleep, arousal, and brain structure and function in the development and maintenance of chronic pain in women with fibromyalgia,” the researchers say.

Prospective Randomized Trial of CPAP for SDB in Patients Who Use Opioids (PRESTO). At the University of California, San Diego, researchers are investigating whether patients with chronic pain who use opioids and have sleep-disordered breathing may benefit from treatment with continuous positive airway pressure. They plan to assess the intervention’s effects on sleep quality, pain, and quality of life. They also will see which patients are least likely to benefit from this treatment approach.

Latent Aging Mechanisms in Pain and Sleep (LAMPS). Researchers at the University of Florida are studying the effects of oral gamma-aminobutyric acid in older adults with chronic pain and sleep difficulties.

Sleep and Pain in Sickle Cell Disease. At Johns Hopkins University, investigators are evaluating how behavioral sleep interventions influence pain and brain function in patients with sickle cell disease.

Pain in Long COVID-19: The Role of Sleep. Researchers at Beth Israel Deaconess Medical Center are conducting an observational study of patients with long COVID who have pain and sleep disturbances. The study aims “to understand the role of sleep in the development and persistence of pain symptoms in long COVID.”

Intervention for Sleep and Pain in Youth: A Randomized Controlled Trial (I-SPY-RCT). Adolescents with migraine are being recruited by a team at Seattle Children’s Hospital for a randomized controlled trial. The study will examine the effects of CBT-I as well as the combined effect of CBT-I and pain interventions on reducing insomnia symptoms and headache-related disability in this population.

A version of this article appeared on Medscape.com.

Early in his career as a pain researcher, Daniel Whibley, PhD, was struck by an article that drew parallels between methods of torture and the experiences of patients with insomnia and chronic pain.

The author of that article, Nicole Tang, DPhil, observed that two methods used by torturers – pain infliction and sleep deprivation – harm people in ways that also are experienced by many patients with pain and sleep conditions.

Patients are “essentially living in this perpetually undesirable, at best, situation where both of these features are playing out in their lives,” said Dr. Whibley, a research assistant professor of physical medicine and rehabilitation at the University of Michigan, Ann Arbor.

The problems create a “kind of vicious circle,” he said. Pain disrupts sleep. Insufficient sleep worsens pain.

Studies have established important relationships between the conditions, but investigators are still trying to clarify the mechanisms that connect them and the best ways to intervene to improve patient outcomes.

To that end, Dr. Whibley has developed an intervention known as Move & Snooze to benefit patients with pain associated with osteoarthritis.

The program includes remote exercise coaching and an automated 6-week course of digital cognitive-behavioral therapy for insomnia (CBT-I). Dr. Whibley’s hypothesis is that addressing sleep disturbances will help patients stay engaged with the physical activity component of the program and help with pain management.

He and his colleagues have tested the intervention in a feasibility study and are in the process of securing grant funding to test it in a large, nationwide trial.
 

Losing sleep for science

Michael Smith, PhD, is examining the sleep-pain connection from a different angle.

Dr. Smith, the director of the Behavioral Medicine Research Laboratory at Johns Hopkins University, Baltimore, is recruiting healthy adults to endure restless nights and painful stimuli.

His team is conducting a study known as Sleep-MOR that aims to reveal how different types of sleep disturbances influence pain and a person’s response to opioids.

Nearly three dozen participants have completed the study so far, Dr. Smith said, out of what he hopes will be 200 in all.

Participants are randomly assigned to sleep normally or to undergo an experimental condition that is designed to mimic the sleep disturbances of insomnia or obstructive sleep apnea (OSA).

In a “forced awakening” group, participants are awakened for 20-minute intervals every hour and for a full hour-long window during the night. In this condition, they could sleep for about four hours in all. Forced awakening is intended to represent insomnia

A “sleep fragmentation” group is meant to represent patients with OSA. About 30 times per hour, tones and tactile buzzers rouse sleeping participants without fully waking them up. Although the experiment involves brief arousals such as those experienced by patients with OSA, it does not capture another important feature of sleep apnea – the cessation of breathing, Dr. Smith noted.

The next day, researchers perform pain testing and brain imaging and see how opioid receptors respond to pain medication.

“Some of the forms of sleep loss that we are studying may actually alter the efficacy of the binding of those receptors, and that might then require you to have higher doses of an opioid to get the same effect,” Dr. Smith said. “That’s our hypothesis.”

If that bears out, disturbed sleep may play a role in the development of opioid use disorder and have implications for patients who receive opioids after surgery, he said.

In the lab, researchers examine pain thresholds using techniques such as thermal pain testing, in which a thermode attached to a participant’s arm heats up. The temperature “slowly goes up and the patient just says: ‘Ouch,’ when it first hurts. Then we have their pain threshold,” Dr. Smith said.
 

A bidirectional relationship

Epidemiologic studies have found that, if you follow women who do not have pain, those with complaints about sleep are more than twice as likely to develop fibromyalgia.

Dr. Smith’s group and others have shown that if you deprive a healthy person of sleep, they become more sensitive to pain.

Inflammation could be one possible reason for this effect. In one study, participants who experienced forced awakening experienced less slow-wave sleep, which was tied to more inflammation in the morning. Increased inflammation was linked to greater pain sensitivity.

“We are starting to piece together some of the pathways. That’s just one,” Dr. Smith said.

A recent study by researchers at Harvard University and elsewhere investigated how sleep disturbances affected three pain pathways. In that study, the results varied by sex. The data indicate that optimal treatment approaches might differ for men and women, the researchers said.
 

Waking up to the problem

Sleep problems can be neglected in medical school and in the clinic. “People just have other things to focus on that they clearly know what they can do about it,” Dr. Smith said.

But clinicians should not hesitate to screen for conditions such as insomnia or OSA and refer patients to a specialist. If a patient has had pain for 6 months and treatments are not working, the chance that they have a treatable sleep disorder “is very high, above 50%,” Dr. Smith said. Many could have more than one sleep disorder, he added.

Continuous positive airway pressure for OSA and CBT for insomnia can improve sleep. Dr. Smith said he expects these measures will improve overall pain management as well.

If treating a sleep disorder fails to help with pain, however, it may still help prevent other sleep-related problems, such as depression, poor glucose control, and heart disease. It also could improve patients’ ability to function day to day, he said.

Evidence on whether treating sleep problems reduces pain has so far been mixed.

“We’ve done some studies showing that if you have CBT-I and you have knee arthritis, improvements in the amount of time you spend awake at night translate into improvements in pain at 6 months. There is a signal there, but it’s not as strong as we would like,” he said. “It may be that it takes longer than anyone would like” to have an effect.

A structured intervention such as CBT-I is likely more beneficial than education about sleep hygiene alone in resolving sleep disturbances, Dr. Whibley said. CBT-I includes active components such as sleep restriction therapy and stimulus control therapy and is recommended by the American Academy of Sleep Medicine as the first-line treatment for chronic insomnia (J Clin Sleep Med. 2008 Oct 15;4[5]:487-504).

Patients should consider the role that sleep may play in their chronic pain condition, he said.

“An increasing number of researchers and clinicians are becoming more interested in this as a foundational pillar of health, alongside activity and diet,” Dr. Whibley said. “Sleep is recognized as just as important but doesn’t seem to get the airtime.”

Clinicians, he added, should regularly assess their patients’ sleep and know where to refer those whom they feel would benefit from more advanced management: “They [should] know that they have at least got it on their radar to check as one of the important pillars of health that you should be able to control.”
 

Sleep trials seeking pain patients

Researchers around the United States are conducting dozens of studies related to sleep and pain. The following trials are recruiting participants, according to ClinicalTrials.gov.

Sleep and Pain Interventions in Women With Fibromyalgia (SPIN-II). Investigators at the University of Missouri–Columbia are examining two cognitive-behavioral treatments for women with fibromyalgia and insomnia. “This trial will yield important information about the roles of sleep, arousal, and brain structure and function in the development and maintenance of chronic pain in women with fibromyalgia,” the researchers say.

Prospective Randomized Trial of CPAP for SDB in Patients Who Use Opioids (PRESTO). At the University of California, San Diego, researchers are investigating whether patients with chronic pain who use opioids and have sleep-disordered breathing may benefit from treatment with continuous positive airway pressure. They plan to assess the intervention’s effects on sleep quality, pain, and quality of life. They also will see which patients are least likely to benefit from this treatment approach.

Latent Aging Mechanisms in Pain and Sleep (LAMPS). Researchers at the University of Florida are studying the effects of oral gamma-aminobutyric acid in older adults with chronic pain and sleep difficulties.

Sleep and Pain in Sickle Cell Disease. At Johns Hopkins University, investigators are evaluating how behavioral sleep interventions influence pain and brain function in patients with sickle cell disease.

Pain in Long COVID-19: The Role of Sleep. Researchers at Beth Israel Deaconess Medical Center are conducting an observational study of patients with long COVID who have pain and sleep disturbances. The study aims “to understand the role of sleep in the development and persistence of pain symptoms in long COVID.”

Intervention for Sleep and Pain in Youth: A Randomized Controlled Trial (I-SPY-RCT). Adolescents with migraine are being recruited by a team at Seattle Children’s Hospital for a randomized controlled trial. The study will examine the effects of CBT-I as well as the combined effect of CBT-I and pain interventions on reducing insomnia symptoms and headache-related disability in this population.

A version of this article appeared on Medscape.com.

Early in his career as a pain researcher, Daniel Whibley, PhD, was struck by an article that drew parallels between methods of torture and the experiences of patients with insomnia and chronic pain.

The author of that article, Nicole Tang, DPhil, observed that two methods used by torturers – pain infliction and sleep deprivation – harm people in ways that also are experienced by many patients with pain and sleep conditions.

Patients are “essentially living in this perpetually undesirable, at best, situation where both of these features are playing out in their lives,” said Dr. Whibley, a research assistant professor of physical medicine and rehabilitation at the University of Michigan, Ann Arbor.

The problems create a “kind of vicious circle,” he said. Pain disrupts sleep. Insufficient sleep worsens pain.

Studies have established important relationships between the conditions, but investigators are still trying to clarify the mechanisms that connect them and the best ways to intervene to improve patient outcomes.

To that end, Dr. Whibley has developed an intervention known as Move & Snooze to benefit patients with pain associated with osteoarthritis.

The program includes remote exercise coaching and an automated 6-week course of digital cognitive-behavioral therapy for insomnia (CBT-I). Dr. Whibley’s hypothesis is that addressing sleep disturbances will help patients stay engaged with the physical activity component of the program and help with pain management.

He and his colleagues have tested the intervention in a feasibility study and are in the process of securing grant funding to test it in a large, nationwide trial.
 

Losing sleep for science

Michael Smith, PhD, is examining the sleep-pain connection from a different angle.

Dr. Smith, the director of the Behavioral Medicine Research Laboratory at Johns Hopkins University, Baltimore, is recruiting healthy adults to endure restless nights and painful stimuli.

His team is conducting a study known as Sleep-MOR that aims to reveal how different types of sleep disturbances influence pain and a person’s response to opioids.

Nearly three dozen participants have completed the study so far, Dr. Smith said, out of what he hopes will be 200 in all.

Participants are randomly assigned to sleep normally or to undergo an experimental condition that is designed to mimic the sleep disturbances of insomnia or obstructive sleep apnea (OSA).

In a “forced awakening” group, participants are awakened for 20-minute intervals every hour and for a full hour-long window during the night. In this condition, they could sleep for about four hours in all. Forced awakening is intended to represent insomnia

A “sleep fragmentation” group is meant to represent patients with OSA. About 30 times per hour, tones and tactile buzzers rouse sleeping participants without fully waking them up. Although the experiment involves brief arousals such as those experienced by patients with OSA, it does not capture another important feature of sleep apnea – the cessation of breathing, Dr. Smith noted.

The next day, researchers perform pain testing and brain imaging and see how opioid receptors respond to pain medication.

“Some of the forms of sleep loss that we are studying may actually alter the efficacy of the binding of those receptors, and that might then require you to have higher doses of an opioid to get the same effect,” Dr. Smith said. “That’s our hypothesis.”

If that bears out, disturbed sleep may play a role in the development of opioid use disorder and have implications for patients who receive opioids after surgery, he said.

In the lab, researchers examine pain thresholds using techniques such as thermal pain testing, in which a thermode attached to a participant’s arm heats up. The temperature “slowly goes up and the patient just says: ‘Ouch,’ when it first hurts. Then we have their pain threshold,” Dr. Smith said.
 

A bidirectional relationship

Epidemiologic studies have found that, if you follow women who do not have pain, those with complaints about sleep are more than twice as likely to develop fibromyalgia.

Dr. Smith’s group and others have shown that if you deprive a healthy person of sleep, they become more sensitive to pain.

Inflammation could be one possible reason for this effect. In one study, participants who experienced forced awakening experienced less slow-wave sleep, which was tied to more inflammation in the morning. Increased inflammation was linked to greater pain sensitivity.

“We are starting to piece together some of the pathways. That’s just one,” Dr. Smith said.

A recent study by researchers at Harvard University and elsewhere investigated how sleep disturbances affected three pain pathways. In that study, the results varied by sex. The data indicate that optimal treatment approaches might differ for men and women, the researchers said.
 

Waking up to the problem

Sleep problems can be neglected in medical school and in the clinic. “People just have other things to focus on that they clearly know what they can do about it,” Dr. Smith said.

But clinicians should not hesitate to screen for conditions such as insomnia or OSA and refer patients to a specialist. If a patient has had pain for 6 months and treatments are not working, the chance that they have a treatable sleep disorder “is very high, above 50%,” Dr. Smith said. Many could have more than one sleep disorder, he added.

Continuous positive airway pressure for OSA and CBT for insomnia can improve sleep. Dr. Smith said he expects these measures will improve overall pain management as well.

If treating a sleep disorder fails to help with pain, however, it may still help prevent other sleep-related problems, such as depression, poor glucose control, and heart disease. It also could improve patients’ ability to function day to day, he said.

Evidence on whether treating sleep problems reduces pain has so far been mixed.

“We’ve done some studies showing that if you have CBT-I and you have knee arthritis, improvements in the amount of time you spend awake at night translate into improvements in pain at 6 months. There is a signal there, but it’s not as strong as we would like,” he said. “It may be that it takes longer than anyone would like” to have an effect.

A structured intervention such as CBT-I is likely more beneficial than education about sleep hygiene alone in resolving sleep disturbances, Dr. Whibley said. CBT-I includes active components such as sleep restriction therapy and stimulus control therapy and is recommended by the American Academy of Sleep Medicine as the first-line treatment for chronic insomnia (J Clin Sleep Med. 2008 Oct 15;4[5]:487-504).

Patients should consider the role that sleep may play in their chronic pain condition, he said.

“An increasing number of researchers and clinicians are becoming more interested in this as a foundational pillar of health, alongside activity and diet,” Dr. Whibley said. “Sleep is recognized as just as important but doesn’t seem to get the airtime.”

Clinicians, he added, should regularly assess their patients’ sleep and know where to refer those whom they feel would benefit from more advanced management: “They [should] know that they have at least got it on their radar to check as one of the important pillars of health that you should be able to control.”
 

Sleep trials seeking pain patients

Researchers around the United States are conducting dozens of studies related to sleep and pain. The following trials are recruiting participants, according to ClinicalTrials.gov.

Sleep and Pain Interventions in Women With Fibromyalgia (SPIN-II). Investigators at the University of Missouri–Columbia are examining two cognitive-behavioral treatments for women with fibromyalgia and insomnia. “This trial will yield important information about the roles of sleep, arousal, and brain structure and function in the development and maintenance of chronic pain in women with fibromyalgia,” the researchers say.

Prospective Randomized Trial of CPAP for SDB in Patients Who Use Opioids (PRESTO). At the University of California, San Diego, researchers are investigating whether patients with chronic pain who use opioids and have sleep-disordered breathing may benefit from treatment with continuous positive airway pressure. They plan to assess the intervention’s effects on sleep quality, pain, and quality of life. They also will see which patients are least likely to benefit from this treatment approach.

Latent Aging Mechanisms in Pain and Sleep (LAMPS). Researchers at the University of Florida are studying the effects of oral gamma-aminobutyric acid in older adults with chronic pain and sleep difficulties.

Sleep and Pain in Sickle Cell Disease. At Johns Hopkins University, investigators are evaluating how behavioral sleep interventions influence pain and brain function in patients with sickle cell disease.

Pain in Long COVID-19: The Role of Sleep. Researchers at Beth Israel Deaconess Medical Center are conducting an observational study of patients with long COVID who have pain and sleep disturbances. The study aims “to understand the role of sleep in the development and persistence of pain symptoms in long COVID.”

Intervention for Sleep and Pain in Youth: A Randomized Controlled Trial (I-SPY-RCT). Adolescents with migraine are being recruited by a team at Seattle Children’s Hospital for a randomized controlled trial. The study will examine the effects of CBT-I as well as the combined effect of CBT-I and pain interventions on reducing insomnia symptoms and headache-related disability in this population.