Secondhand smoke exposure in both childhood and adulthood is associated with an increased risk of rheumatoid arthritis in women, according to a study presented at the annual European Congress of Rheumatology.

“These results suggest that smoking by-products, whether actively or passively inhaled or absorbed, could generate autoimmunity, at least towards antigens involved in rheumatoid arthritis pathogenesis,” said Yann Nguyen, MD, MPH, of the center for research in epidemiology and population health at the University of Paris-Saclay in Villejuif and of Beaujon Hospital at the University of Paris in Clichy, France.

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

Secondhand smoke exposure in both childhood and adulthood is associated with an increased risk of rheumatoid arthritis in women, according to a study presented at the annual European Congress of Rheumatology.

“These results suggest that smoking by-products, whether actively or passively inhaled or absorbed, could generate autoimmunity, at least towards antigens involved in rheumatoid arthritis pathogenesis,” said Yann Nguyen, MD, MPH, of the center for research in epidemiology and population health at the University of Paris-Saclay in Villejuif and of Beaujon Hospital at the University of Paris in Clichy, France.

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

Secondhand smoke exposure in both childhood and adulthood is associated with an increased risk of rheumatoid arthritis in women, according to a study presented at the annual European Congress of Rheumatology.

“These results suggest that smoking by-products, whether actively or passively inhaled or absorbed, could generate autoimmunity, at least towards antigens involved in rheumatoid arthritis pathogenesis,” said Yann Nguyen, MD, MPH, of the center for research in epidemiology and population health at the University of Paris-Saclay in Villejuif and of Beaujon Hospital at the University of Paris in Clichy, France.

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

As researchers learn more about the genetic etiology of immunopathology, they have been able to more clearly understand rare but debilitating autoinflammatory conditions in ways that have improved identification and management of these diseases. At this year’s European Congress of Rheumatology, two researchers outlined new recommendations from the European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) for the management of two groups of such autoinflammatory diseases: interleukin-1-mediated and Type-I interferonopathies, and suspected macrophage activation syndrome and hemophagocytic lymphohistiocytosis.

These are the first recommendations from EULAR for these diseases, according to Loreto Carmona, MD, PhD, chair of the EULAR scientific program committee and scientific director of the Institute for Musculoskeletal Health in Madrid.

“They are rare diseases and there is a great need to standardize diagnosis and care for the safety and outcome of the patients,” Dr. Carmona said in an interview. “These diseases need deep expertise and so the experts are trying, they are still preliminary, to add clarity to their management.” Dr. Carmona was not involved with the development of the guidelines and moderated the session during which they were presented.

“The rapidly emerging knowledge of the genetic causes of novel systemic autoinflammatory diseases, which present typically in early childhood with severe and chronic systemic and organ-specific inflammation, linked the disease pathogenesis to the pathologic production of major proinflammatory cytokines,” presenter Raphaela Goldbach-Mansky, MD, a senior investigator and chief of the translational autoinflammatory disease studies unit of the U.S. National Institute of Allergy and Infectious Diseases, told congress attendees. This greater understanding led to the “targeted and anticytokine treatments that have changed patients’ lives,” she said.

The guidelines relied on the products of three working groups for each disease type. After meeting to come up with clinical questions, the groups each conducted systematic literature reviews through EMBASE, PubMed, and the Cochrane Library for publications dated from 1970 to August 2020 that excluded non-English-language studies, case reports, and animal model or basic science studies. They then met again to develop final consensus statements.

The interferonopathy and interleukin (IL)-1-mediated systemic autoinflammatory diseases (SAIDs) working groups met throughout 2020, and the hemophagocytic lymphohistiocytosis (HLH)/ macrophage activation syndrome (MAS) working group met in March and April of 2021.

“One needs a lot of experience with these diseases to even think about them,” Dr. Carmona said. “We haven’t been presented yet with all the details of the recommendations, but we hope they are clear because they are much needed.”

She noted that these preliminary recommendations are based on the best available evidence to date along with expertise from multidisciplinary panels.

“We need to be acquainted with these recommendations, as the majority of us, either if we are pediatric or adult rheumatologists, will face some problem with these diseases at some point,” Dr. Carmona said.

IL-1-mediated SAIDs

Recommendations for IL-1-mediated SAIDs focused on mevalonate kinase deficiency (MKD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cryopyrinopathies (CAPS), and deficiency of the IL-1 receptor antagonist (DIRA). Presentation of these conditions involves chronic or intermittent flares of systemic and organ inflammation that can cause progressive organ damage, morbidity, and increased mortality if not treated. Diagnosis requires a multidisciplinary team whose evaluation should include disease-related complications and long-term care plans.

Diagnostic workup should include genetic testing using next-generation sequencing as this “facilitates initiation of targeted treatments, genetic counseling, and informs prognosis” for patients with CAPS, TRAPS, MKD, and DIRA, Erkan Demirkaya, MD, a scientist at the Children’s Health Research Institute and professor of pediatric rheumatology at the University of Western Ontario in London, Canada, told attendees. Evaluation should also include clinical workup that focuses on the extent of inflammatory organ involvement, and screening for disease- and treatment-related comorbidities.

“The goal of therapy is to control clinical signs and symptoms and normalize laboratory biomarkers of systemic inflammation,” Dr. Demirkaya said. Long-term monitoring goals should focus on the following:

• “Adequate treatment adjusted to the needs of the growing child and prevention of systemic and organ-specific inflammatory manifestations;
• Fostering of self-management skills and medical decision-making;
• Initiating a transition program to adult specialist care in adolescent patients.”

Type-1 interferonopathies

The recommendations for this disease group focused on chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE)/proteasome-associated autoinflammatory syndromes (PRAAS), STING-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS).

These patients similarly present with chronic and organ-specific inflammation that leads to progressive organ damage, morbidity, and higher mortality risk when not managed. Each of these diseases requires a confirmed genetic diagnosis so that treatments can be targeted and the patient receives appropriate genetic counseling, screening for complications, and information on prognosis, Dr. Goldbach-Mansky said.

Treatment goals for type-1 interferonopathies are to “reduce systematic and organ inflammation to prevent or limit the development of progression of organ injury or damage and to improve quality of life,” Dr. Goldbach-Mansky told attendees.

Each patient requires a multidisciplinary care provider team that conducts long-term monitoring of disease activity, damage to specific organs, and any treatment-related complications.
 

Management of HLH/MAS

Early recognition and management of HLH and MAS can be challenging because systemic hyperinflammation exists along an immunopathologic continuum with typically nonspecific clinical and laboratory findings, Dr. Goldbach-Mansky said, but holistic, longitudinal consideration of these findings “are recognizable and warrant prompt diagnostic evaluation.” Even if the patient does not meet all specific diagnostic criteria for HLH/MAS, it may be necessary to begin therapies, she said.

One important point to consider is that “systemic hyperinflammation can be associated with hyperferritinemia and can progress to life-threatening HLH/MAS,” Dr. Goldbach-Mansky said. Further, although “systemic hyperinflammation and HLH/MAS can occur in nearly any inflammatory state,” certain common triggers and predisposing conditions can indicate the need to consider these conditions and begin appropriate treatment if needed. Part of effective management of systemic hyperinflammation and HLH/MAS is determining any modifiable factors contributing to the disease and mitigating or treating those.

HLH/MAS requires urgent intervention based on the patient’s degree of inflammation and extent of organ dysfunction, the recommendations state. Treatment goals include preventing or limiting immunopathology, preserving the integrity of the diagnostic workup, and minimizing therapy-related toxicity.

Dr. Carmona, Dr. Goldbach-Mansky, and Dr. Demirkaya have reported no relevant financial relationships.


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

As researchers learn more about the genetic etiology of immunopathology, they have been able to more clearly understand rare but debilitating autoinflammatory conditions in ways that have improved identification and management of these diseases. At this year’s European Congress of Rheumatology, two researchers outlined new recommendations from the European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) for the management of two groups of such autoinflammatory diseases: interleukin-1-mediated and Type-I interferonopathies, and suspected macrophage activation syndrome and hemophagocytic lymphohistiocytosis.

These are the first recommendations from EULAR for these diseases, according to Loreto Carmona, MD, PhD, chair of the EULAR scientific program committee and scientific director of the Institute for Musculoskeletal Health in Madrid.

“They are rare diseases and there is a great need to standardize diagnosis and care for the safety and outcome of the patients,” Dr. Carmona said in an interview. “These diseases need deep expertise and so the experts are trying, they are still preliminary, to add clarity to their management.” Dr. Carmona was not involved with the development of the guidelines and moderated the session during which they were presented.

“The rapidly emerging knowledge of the genetic causes of novel systemic autoinflammatory diseases, which present typically in early childhood with severe and chronic systemic and organ-specific inflammation, linked the disease pathogenesis to the pathologic production of major proinflammatory cytokines,” presenter Raphaela Goldbach-Mansky, MD, a senior investigator and chief of the translational autoinflammatory disease studies unit of the U.S. National Institute of Allergy and Infectious Diseases, told congress attendees. This greater understanding led to the “targeted and anticytokine treatments that have changed patients’ lives,” she said.

The guidelines relied on the products of three working groups for each disease type. After meeting to come up with clinical questions, the groups each conducted systematic literature reviews through EMBASE, PubMed, and the Cochrane Library for publications dated from 1970 to August 2020 that excluded non-English-language studies, case reports, and animal model or basic science studies. They then met again to develop final consensus statements.

The interferonopathy and interleukin (IL)-1-mediated systemic autoinflammatory diseases (SAIDs) working groups met throughout 2020, and the hemophagocytic lymphohistiocytosis (HLH)/ macrophage activation syndrome (MAS) working group met in March and April of 2021.

“One needs a lot of experience with these diseases to even think about them,” Dr. Carmona said. “We haven’t been presented yet with all the details of the recommendations, but we hope they are clear because they are much needed.”

She noted that these preliminary recommendations are based on the best available evidence to date along with expertise from multidisciplinary panels.

“We need to be acquainted with these recommendations, as the majority of us, either if we are pediatric or adult rheumatologists, will face some problem with these diseases at some point,” Dr. Carmona said.

IL-1-mediated SAIDs

Recommendations for IL-1-mediated SAIDs focused on mevalonate kinase deficiency (MKD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cryopyrinopathies (CAPS), and deficiency of the IL-1 receptor antagonist (DIRA). Presentation of these conditions involves chronic or intermittent flares of systemic and organ inflammation that can cause progressive organ damage, morbidity, and increased mortality if not treated. Diagnosis requires a multidisciplinary team whose evaluation should include disease-related complications and long-term care plans.

Diagnostic workup should include genetic testing using next-generation sequencing as this “facilitates initiation of targeted treatments, genetic counseling, and informs prognosis” for patients with CAPS, TRAPS, MKD, and DIRA, Erkan Demirkaya, MD, a scientist at the Children’s Health Research Institute and professor of pediatric rheumatology at the University of Western Ontario in London, Canada, told attendees. Evaluation should also include clinical workup that focuses on the extent of inflammatory organ involvement, and screening for disease- and treatment-related comorbidities.

“The goal of therapy is to control clinical signs and symptoms and normalize laboratory biomarkers of systemic inflammation,” Dr. Demirkaya said. Long-term monitoring goals should focus on the following:

• “Adequate treatment adjusted to the needs of the growing child and prevention of systemic and organ-specific inflammatory manifestations;
• Fostering of self-management skills and medical decision-making;
• Initiating a transition program to adult specialist care in adolescent patients.”

Type-1 interferonopathies

The recommendations for this disease group focused on chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE)/proteasome-associated autoinflammatory syndromes (PRAAS), STING-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS).

These patients similarly present with chronic and organ-specific inflammation that leads to progressive organ damage, morbidity, and higher mortality risk when not managed. Each of these diseases requires a confirmed genetic diagnosis so that treatments can be targeted and the patient receives appropriate genetic counseling, screening for complications, and information on prognosis, Dr. Goldbach-Mansky said.

Treatment goals for type-1 interferonopathies are to “reduce systematic and organ inflammation to prevent or limit the development of progression of organ injury or damage and to improve quality of life,” Dr. Goldbach-Mansky told attendees.

Each patient requires a multidisciplinary care provider team that conducts long-term monitoring of disease activity, damage to specific organs, and any treatment-related complications.
 

Management of HLH/MAS

Early recognition and management of HLH and MAS can be challenging because systemic hyperinflammation exists along an immunopathologic continuum with typically nonspecific clinical and laboratory findings, Dr. Goldbach-Mansky said, but holistic, longitudinal consideration of these findings “are recognizable and warrant prompt diagnostic evaluation.” Even if the patient does not meet all specific diagnostic criteria for HLH/MAS, it may be necessary to begin therapies, she said.

One important point to consider is that “systemic hyperinflammation can be associated with hyperferritinemia and can progress to life-threatening HLH/MAS,” Dr. Goldbach-Mansky said. Further, although “systemic hyperinflammation and HLH/MAS can occur in nearly any inflammatory state,” certain common triggers and predisposing conditions can indicate the need to consider these conditions and begin appropriate treatment if needed. Part of effective management of systemic hyperinflammation and HLH/MAS is determining any modifiable factors contributing to the disease and mitigating or treating those.

HLH/MAS requires urgent intervention based on the patient’s degree of inflammation and extent of organ dysfunction, the recommendations state. Treatment goals include preventing or limiting immunopathology, preserving the integrity of the diagnostic workup, and minimizing therapy-related toxicity.

Dr. Carmona, Dr. Goldbach-Mansky, and Dr. Demirkaya have reported no relevant financial relationships.


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

As researchers learn more about the genetic etiology of immunopathology, they have been able to more clearly understand rare but debilitating autoinflammatory conditions in ways that have improved identification and management of these diseases. At this year’s European Congress of Rheumatology, two researchers outlined new recommendations from the European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) for the management of two groups of such autoinflammatory diseases: interleukin-1-mediated and Type-I interferonopathies, and suspected macrophage activation syndrome and hemophagocytic lymphohistiocytosis.

These are the first recommendations from EULAR for these diseases, according to Loreto Carmona, MD, PhD, chair of the EULAR scientific program committee and scientific director of the Institute for Musculoskeletal Health in Madrid.

“They are rare diseases and there is a great need to standardize diagnosis and care for the safety and outcome of the patients,” Dr. Carmona said in an interview. “These diseases need deep expertise and so the experts are trying, they are still preliminary, to add clarity to their management.” Dr. Carmona was not involved with the development of the guidelines and moderated the session during which they were presented.

“The rapidly emerging knowledge of the genetic causes of novel systemic autoinflammatory diseases, which present typically in early childhood with severe and chronic systemic and organ-specific inflammation, linked the disease pathogenesis to the pathologic production of major proinflammatory cytokines,” presenter Raphaela Goldbach-Mansky, MD, a senior investigator and chief of the translational autoinflammatory disease studies unit of the U.S. National Institute of Allergy and Infectious Diseases, told congress attendees. This greater understanding led to the “targeted and anticytokine treatments that have changed patients’ lives,” she said.

The guidelines relied on the products of three working groups for each disease type. After meeting to come up with clinical questions, the groups each conducted systematic literature reviews through EMBASE, PubMed, and the Cochrane Library for publications dated from 1970 to August 2020 that excluded non-English-language studies, case reports, and animal model or basic science studies. They then met again to develop final consensus statements.

The interferonopathy and interleukin (IL)-1-mediated systemic autoinflammatory diseases (SAIDs) working groups met throughout 2020, and the hemophagocytic lymphohistiocytosis (HLH)/ macrophage activation syndrome (MAS) working group met in March and April of 2021.

“One needs a lot of experience with these diseases to even think about them,” Dr. Carmona said. “We haven’t been presented yet with all the details of the recommendations, but we hope they are clear because they are much needed.”

She noted that these preliminary recommendations are based on the best available evidence to date along with expertise from multidisciplinary panels.

“We need to be acquainted with these recommendations, as the majority of us, either if we are pediatric or adult rheumatologists, will face some problem with these diseases at some point,” Dr. Carmona said.

IL-1-mediated SAIDs

Recommendations for IL-1-mediated SAIDs focused on mevalonate kinase deficiency (MKD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cryopyrinopathies (CAPS), and deficiency of the IL-1 receptor antagonist (DIRA). Presentation of these conditions involves chronic or intermittent flares of systemic and organ inflammation that can cause progressive organ damage, morbidity, and increased mortality if not treated. Diagnosis requires a multidisciplinary team whose evaluation should include disease-related complications and long-term care plans.

Diagnostic workup should include genetic testing using next-generation sequencing as this “facilitates initiation of targeted treatments, genetic counseling, and informs prognosis” for patients with CAPS, TRAPS, MKD, and DIRA, Erkan Demirkaya, MD, a scientist at the Children’s Health Research Institute and professor of pediatric rheumatology at the University of Western Ontario in London, Canada, told attendees. Evaluation should also include clinical workup that focuses on the extent of inflammatory organ involvement, and screening for disease- and treatment-related comorbidities.

“The goal of therapy is to control clinical signs and symptoms and normalize laboratory biomarkers of systemic inflammation,” Dr. Demirkaya said. Long-term monitoring goals should focus on the following:

• “Adequate treatment adjusted to the needs of the growing child and prevention of systemic and organ-specific inflammatory manifestations;
• Fostering of self-management skills and medical decision-making;
• Initiating a transition program to adult specialist care in adolescent patients.”

Type-1 interferonopathies

The recommendations for this disease group focused on chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE)/proteasome-associated autoinflammatory syndromes (PRAAS), STING-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS).

These patients similarly present with chronic and organ-specific inflammation that leads to progressive organ damage, morbidity, and higher mortality risk when not managed. Each of these diseases requires a confirmed genetic diagnosis so that treatments can be targeted and the patient receives appropriate genetic counseling, screening for complications, and information on prognosis, Dr. Goldbach-Mansky said.

Treatment goals for type-1 interferonopathies are to “reduce systematic and organ inflammation to prevent or limit the development of progression of organ injury or damage and to improve quality of life,” Dr. Goldbach-Mansky told attendees.

Each patient requires a multidisciplinary care provider team that conducts long-term monitoring of disease activity, damage to specific organs, and any treatment-related complications.
 

Management of HLH/MAS

Early recognition and management of HLH and MAS can be challenging because systemic hyperinflammation exists along an immunopathologic continuum with typically nonspecific clinical and laboratory findings, Dr. Goldbach-Mansky said, but holistic, longitudinal consideration of these findings “are recognizable and warrant prompt diagnostic evaluation.” Even if the patient does not meet all specific diagnostic criteria for HLH/MAS, it may be necessary to begin therapies, she said.

One important point to consider is that “systemic hyperinflammation can be associated with hyperferritinemia and can progress to life-threatening HLH/MAS,” Dr. Goldbach-Mansky said. Further, although “systemic hyperinflammation and HLH/MAS can occur in nearly any inflammatory state,” certain common triggers and predisposing conditions can indicate the need to consider these conditions and begin appropriate treatment if needed. Part of effective management of systemic hyperinflammation and HLH/MAS is determining any modifiable factors contributing to the disease and mitigating or treating those.

HLH/MAS requires urgent intervention based on the patient’s degree of inflammation and extent of organ dysfunction, the recommendations state. Treatment goals include preventing or limiting immunopathology, preserving the integrity of the diagnostic workup, and minimizing therapy-related toxicity.

Dr. Carmona, Dr. Goldbach-Mansky, and Dr. Demirkaya have reported no relevant financial relationships.


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

The higher the HER2 expression, the more benefit patients get from the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) for HER2-positive metastatic colorectal cancer in the salvage setting, according to a phase 2 report.

Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.

With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.

Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Dr. Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.

HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.

“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Dr. Raghav said.

“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.

Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.

The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.

The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.

They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.

The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.

Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.

Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.

Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Dr. Beg noted.

The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.

The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.

The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Dr. Raghav is an advisor and researcher for the company; Dr. Beg had no relationships with it.

[email protected]

The higher the HER2 expression, the more benefit patients get from the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) for HER2-positive metastatic colorectal cancer in the salvage setting, according to a phase 2 report.

Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.

With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.

Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Dr. Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.

HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.

“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Dr. Raghav said.

“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.

Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.

The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.

The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.

They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.

The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.

Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.

Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.

Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Dr. Beg noted.

The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.

The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.

The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Dr. Raghav is an advisor and researcher for the company; Dr. Beg had no relationships with it.

[email protected]

The higher the HER2 expression, the more benefit patients get from the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) for HER2-positive metastatic colorectal cancer in the salvage setting, according to a phase 2 report.

Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.

With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.

Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Dr. Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.

HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.

“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Dr. Raghav said.

“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.

Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.

The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.

The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.

They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.

The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.

Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.

Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.

Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Dr. Beg noted.

The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.

The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.

The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Dr. Raghav is an advisor and researcher for the company; Dr. Beg had no relationships with it.

[email protected]

Patients with rheumatoid arthritis who carry a specific allele of the gene MUC5B have about double the risk of developing interstitial lung disease when compared with noncarriers, according to a large Finnish biobank study presented at the annual European Congress of Rheumatology.

“The risk difference [or carriers relative to noncarriers] started at about age 65, with a bigger difference [for] men than women,” reported Antti Palomäki, MD, PhD, of the center for rheumatology and clinical immunology at Turku (Finland) University.

The gain-of-function MUC5B variant, which encodes mucin 5B, was first linked to RA-associated interstitial lung disease (ILD) more than 3 years ago. At that time, it was already a known genetic risk factor for idiopathic pulmonary fibrosis in the general population. The new data confirm the association in a longitudinal analysis of a large biobank and suggest the association might have clinical utility.

“This is not ready for clinical practice at the moment. We do not yet know whether we can change therapy to reduce risk,” Dr. Palomäki said, adding “in the future we can look.”

One question that might be asked in clinical studies using MUC5B as a tool to assess and modify risk of ILD in patients with RA is whether one therapy is better than another in avoiding or delaying development of lung fibrosis. Dr. Palomäki noted that biologics, for example, might be a more favorable choice in patients with RA who are at high risk of developing ILD.


The association of the MUC5B variant with increased ILD incidence in patients with RA was drawn from a data set known as FinnGen, a biobank collection of epidemiologic cohorts and hospital samples with genotypes of about 10% of the Finnish population. Follow-up extends to 46 years in some of these individuals.

When 248,4000 individuals in this data set were evaluated, 5,534 had a diagnosis of RA. Of these, 178 (3.2%) developed ILD. About 20% of both those with and without RA were MUC5B variant carriers, meaning the remainder were not.

Sex and age factor into lifetime risk

In patients with RA, the lifetime rate of ILD among MUC5B variant carriers was 16.8% versus only 6.1% among noncarriers. This finding translated into a hazard ratio for ILD of 2.27 (95% confidence interval, 1.75–2.96) for variant carriers versus noncarriers.

The lifetime rate of ILD in patients with RA was greater in men versus women regardless of carrier status (18.5% vs. 8.5%). For women, the lifetime rate was lower for carriers, although the difference relative to female noncarriers was greater (14.5% vs. 4.7%).

ILD, whether in the general population or in patients with RA, is a disease of advancing age. When Dr. Palomäki showed a graph, the rise in ILD incidence did not start in any population, whether those with or without RA and regardless of carrier status, until about age 55. In those without RA and in noncarriers of the variant, ILD incidence remained low and began a discernible climb at around age 70.

In those who did not have RA but were positive for the variant, the rates rose more than twice as fast, particularly after age 70. In people who had RA but not the variant, the rate of ILD was greater than in patients who carried the variant without RA, starting the climb earlier and rising more steeply with age. In those with RA and the variant, the climb in ILD incidence rose rapidly after age 65 years even though the incidence remained fairly similar between all of these groups at age 60.
 

Putting the findings into context

The need to develop ways to prevent ILD in RA is urgent. ILD is one of the most common extraarticular manifestations of RA, developing in up to 60% of patients with RA in older age groups when evaluated with imaging, according to Dr. Palomäki. Although it develops into a clinically significant complication in only about 10% of these patients, ILD still is a significant cause of illness and death in elderly patients with RA.

In the 2018 study that first linked the MUC5B variant to RA-ILD, the investigators also found that the variant was associated with an increased likelihood of developing the usual interstitial pneumonia type of ILD on imaging. David Schwartz, MD, professor of medicine, pulmonary sciences, and critical care and chair of the department of medicine at the University of Colorado at Denver, Aurora, was a senior author of that study. He said these findings build on the 2018 study.

“While the gain-of-function MUC5B promoter variant is important in predicting who will develop RA-ILD, these findings also suggest that MUC5B may be involved in the etiology of RA-ILD, at least for those with the MUC5B variant,” he said.

“The study also raises the possibility that there are several subtypes of RA-ILD, and the subtype that is driven by MUC5B may respond differently to RA biologics or therapeutic agents to treat ILD,” he added.

In the discussion following the presentation by Dr. Palomäki, others agreed, with that statement including Dr. Palomäki. He expressed interest in clinical studies comparing different classes of RA therapies for their relative impact on the risk of developing ILD.Dr. Palomäki reported financial relationships with AbbVie, Merck, Pfizer, and Sanofi. Dr. Schwartz is the founder of Eleven P15, which is developing methods for early diagnosis and treatment of pulmonary fibrosis.

Patients with rheumatoid arthritis who carry a specific allele of the gene MUC5B have about double the risk of developing interstitial lung disease when compared with noncarriers, according to a large Finnish biobank study presented at the annual European Congress of Rheumatology.

“The risk difference [or carriers relative to noncarriers] started at about age 65, with a bigger difference [for] men than women,” reported Antti Palomäki, MD, PhD, of the center for rheumatology and clinical immunology at Turku (Finland) University.

The gain-of-function MUC5B variant, which encodes mucin 5B, was first linked to RA-associated interstitial lung disease (ILD) more than 3 years ago. At that time, it was already a known genetic risk factor for idiopathic pulmonary fibrosis in the general population. The new data confirm the association in a longitudinal analysis of a large biobank and suggest the association might have clinical utility.

“This is not ready for clinical practice at the moment. We do not yet know whether we can change therapy to reduce risk,” Dr. Palomäki said, adding “in the future we can look.”

One question that might be asked in clinical studies using MUC5B as a tool to assess and modify risk of ILD in patients with RA is whether one therapy is better than another in avoiding or delaying development of lung fibrosis. Dr. Palomäki noted that biologics, for example, might be a more favorable choice in patients with RA who are at high risk of developing ILD.


The association of the MUC5B variant with increased ILD incidence in patients with RA was drawn from a data set known as FinnGen, a biobank collection of epidemiologic cohorts and hospital samples with genotypes of about 10% of the Finnish population. Follow-up extends to 46 years in some of these individuals.

When 248,4000 individuals in this data set were evaluated, 5,534 had a diagnosis of RA. Of these, 178 (3.2%) developed ILD. About 20% of both those with and without RA were MUC5B variant carriers, meaning the remainder were not.

Sex and age factor into lifetime risk

In patients with RA, the lifetime rate of ILD among MUC5B variant carriers was 16.8% versus only 6.1% among noncarriers. This finding translated into a hazard ratio for ILD of 2.27 (95% confidence interval, 1.75–2.96) for variant carriers versus noncarriers.

The lifetime rate of ILD in patients with RA was greater in men versus women regardless of carrier status (18.5% vs. 8.5%). For women, the lifetime rate was lower for carriers, although the difference relative to female noncarriers was greater (14.5% vs. 4.7%).

ILD, whether in the general population or in patients with RA, is a disease of advancing age. When Dr. Palomäki showed a graph, the rise in ILD incidence did not start in any population, whether those with or without RA and regardless of carrier status, until about age 55. In those without RA and in noncarriers of the variant, ILD incidence remained low and began a discernible climb at around age 70.

In those who did not have RA but were positive for the variant, the rates rose more than twice as fast, particularly after age 70. In people who had RA but not the variant, the rate of ILD was greater than in patients who carried the variant without RA, starting the climb earlier and rising more steeply with age. In those with RA and the variant, the climb in ILD incidence rose rapidly after age 65 years even though the incidence remained fairly similar between all of these groups at age 60.
 

Putting the findings into context

The need to develop ways to prevent ILD in RA is urgent. ILD is one of the most common extraarticular manifestations of RA, developing in up to 60% of patients with RA in older age groups when evaluated with imaging, according to Dr. Palomäki. Although it develops into a clinically significant complication in only about 10% of these patients, ILD still is a significant cause of illness and death in elderly patients with RA.

In the 2018 study that first linked the MUC5B variant to RA-ILD, the investigators also found that the variant was associated with an increased likelihood of developing the usual interstitial pneumonia type of ILD on imaging. David Schwartz, MD, professor of medicine, pulmonary sciences, and critical care and chair of the department of medicine at the University of Colorado at Denver, Aurora, was a senior author of that study. He said these findings build on the 2018 study.

“While the gain-of-function MUC5B promoter variant is important in predicting who will develop RA-ILD, these findings also suggest that MUC5B may be involved in the etiology of RA-ILD, at least for those with the MUC5B variant,” he said.

“The study also raises the possibility that there are several subtypes of RA-ILD, and the subtype that is driven by MUC5B may respond differently to RA biologics or therapeutic agents to treat ILD,” he added.

In the discussion following the presentation by Dr. Palomäki, others agreed, with that statement including Dr. Palomäki. He expressed interest in clinical studies comparing different classes of RA therapies for their relative impact on the risk of developing ILD.Dr. Palomäki reported financial relationships with AbbVie, Merck, Pfizer, and Sanofi. Dr. Schwartz is the founder of Eleven P15, which is developing methods for early diagnosis and treatment of pulmonary fibrosis.

Patients with rheumatoid arthritis who carry a specific allele of the gene MUC5B have about double the risk of developing interstitial lung disease when compared with noncarriers, according to a large Finnish biobank study presented at the annual European Congress of Rheumatology.

“The risk difference [or carriers relative to noncarriers] started at about age 65, with a bigger difference [for] men than women,” reported Antti Palomäki, MD, PhD, of the center for rheumatology and clinical immunology at Turku (Finland) University.

The gain-of-function MUC5B variant, which encodes mucin 5B, was first linked to RA-associated interstitial lung disease (ILD) more than 3 years ago. At that time, it was already a known genetic risk factor for idiopathic pulmonary fibrosis in the general population. The new data confirm the association in a longitudinal analysis of a large biobank and suggest the association might have clinical utility.

“This is not ready for clinical practice at the moment. We do not yet know whether we can change therapy to reduce risk,” Dr. Palomäki said, adding “in the future we can look.”

One question that might be asked in clinical studies using MUC5B as a tool to assess and modify risk of ILD in patients with RA is whether one therapy is better than another in avoiding or delaying development of lung fibrosis. Dr. Palomäki noted that biologics, for example, might be a more favorable choice in patients with RA who are at high risk of developing ILD.


The association of the MUC5B variant with increased ILD incidence in patients with RA was drawn from a data set known as FinnGen, a biobank collection of epidemiologic cohorts and hospital samples with genotypes of about 10% of the Finnish population. Follow-up extends to 46 years in some of these individuals.

When 248,4000 individuals in this data set were evaluated, 5,534 had a diagnosis of RA. Of these, 178 (3.2%) developed ILD. About 20% of both those with and without RA were MUC5B variant carriers, meaning the remainder were not.

Sex and age factor into lifetime risk

In patients with RA, the lifetime rate of ILD among MUC5B variant carriers was 16.8% versus only 6.1% among noncarriers. This finding translated into a hazard ratio for ILD of 2.27 (95% confidence interval, 1.75–2.96) for variant carriers versus noncarriers.

The lifetime rate of ILD in patients with RA was greater in men versus women regardless of carrier status (18.5% vs. 8.5%). For women, the lifetime rate was lower for carriers, although the difference relative to female noncarriers was greater (14.5% vs. 4.7%).

ILD, whether in the general population or in patients with RA, is a disease of advancing age. When Dr. Palomäki showed a graph, the rise in ILD incidence did not start in any population, whether those with or without RA and regardless of carrier status, until about age 55. In those without RA and in noncarriers of the variant, ILD incidence remained low and began a discernible climb at around age 70.

In those who did not have RA but were positive for the variant, the rates rose more than twice as fast, particularly after age 70. In people who had RA but not the variant, the rate of ILD was greater than in patients who carried the variant without RA, starting the climb earlier and rising more steeply with age. In those with RA and the variant, the climb in ILD incidence rose rapidly after age 65 years even though the incidence remained fairly similar between all of these groups at age 60.
 

Putting the findings into context

The need to develop ways to prevent ILD in RA is urgent. ILD is one of the most common extraarticular manifestations of RA, developing in up to 60% of patients with RA in older age groups when evaluated with imaging, according to Dr. Palomäki. Although it develops into a clinically significant complication in only about 10% of these patients, ILD still is a significant cause of illness and death in elderly patients with RA.

In the 2018 study that first linked the MUC5B variant to RA-ILD, the investigators also found that the variant was associated with an increased likelihood of developing the usual interstitial pneumonia type of ILD on imaging. David Schwartz, MD, professor of medicine, pulmonary sciences, and critical care and chair of the department of medicine at the University of Colorado at Denver, Aurora, was a senior author of that study. He said these findings build on the 2018 study.

“While the gain-of-function MUC5B promoter variant is important in predicting who will develop RA-ILD, these findings also suggest that MUC5B may be involved in the etiology of RA-ILD, at least for those with the MUC5B variant,” he said.

“The study also raises the possibility that there are several subtypes of RA-ILD, and the subtype that is driven by MUC5B may respond differently to RA biologics or therapeutic agents to treat ILD,” he added.

In the discussion following the presentation by Dr. Palomäki, others agreed, with that statement including Dr. Palomäki. He expressed interest in clinical studies comparing different classes of RA therapies for their relative impact on the risk of developing ILD.Dr. Palomäki reported financial relationships with AbbVie, Merck, Pfizer, and Sanofi. Dr. Schwartz is the founder of Eleven P15, which is developing methods for early diagnosis and treatment of pulmonary fibrosis.

The U.S. Food and Drug Administration has approved a 2.4 mg/week subcutaneous dose of the glucagonlike peptide–1 (GLP-1) receptor agonist semaglutide (Wegovy, Novo Nordisk) for weight loss.

Specifically, this drug format and dosage are approved as an adjunct to a reduced-calorie diet and increased physical activity to treat adults who have obesity (body mass index [BMI] ≥ 30 kg/m²) or are overweight (BMI ≥ 27 kg/m²) with at least one weight-related comorbidity.

Semaglutide “induces weight loss by reducing hunger, increasing feelings of fullness, and thereby helping people eat less and reduce their calorie intake,” according to a company statement.

Novo Nordisk plans to launch Wegovy later this month in the United States. The prescribing information can be found here.

This weight-loss drug is currently under review by the European Medicines Agency.

Several experts told Medscape that they believe the approval of this drug – as long as it is reimbursed – has the potential to change the paradigm of care when it comes to weight loss.


 

‘Game changer’ drug tested in STEP clinical trial program

The favorable FDA ruling is based on results from the Semaglutide Treatment Effect in People With Obesity (STEP) program of four phase 3 clinical trials that tested the drug’s safety and efficacy in more than 4,500 adults with overweight or obesity obesity who were randomized to receive a reduced a calorie meal plan and increased physical activity (placebo) or this lifestyle intervention plus semaglutide.

The four 68-week trials of subcutaneous semaglutide 2.4 mg/week versus placebo were published in February and March 2021.

As previously reported by this news organization, all trials were in adults with overweight or obesity:

•  was in 1,961 adults (N Engl J Med. 2021 March 18;384:989-1002).
•  was in 1,210 adults who also had diabetes (Lancet. 2021 Mar 13;397;971-84).
•  was in 611 adults, where those in the treatment group also underwent an intensive lifestyle intervention (JAMA. 2021 Feb 24;325:1403-13.
•  was in 803 adults who had reached a target dose of 2.4 mg semaglutide after a 20-week run-in (and the trial examined further weight loss in the subsequent 48 weeks) (JAMA 2021 Mar 23;325:1414-25).

In the STEP 1, 2, and 4 trials of individuals with overweight and obesity, those in the semaglutide groups attained a 15%-18% weight loss over 68 weeks.

The dosage was well-tolerated. The most common side effects were gastrointestinal, and they were transient and mild or moderate in severity.

The side effects, contraindications, and a black box warning about thyroid C-cell tumors are spelled out in the prescribing information.

A coauthor of the STEP 1 trial, Rachel Batterham, MBBS, PhD, of the Centre for Obesity Research at University College London, said at the time of publication: “The findings of this study represent a major breakthrough for improving the health of people with obesity.”

“No other drug has come close to producing this level of weight loss – this really is a gamechanger. For the first time, people can achieve through drugs what was only possible through weight-loss surgery,” she added.
 

Welcome Addition, But Will Insurance Coverage, Price Thwart Access?

Thomas A. Wadden, PhD, from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and lead author of STEP 3, commented in an email to this news organization that “semaglutide 2.4 mg appears to be the breakthrough in weight management that healthcare providers and their patients with obesity have been waiting for.”

The mean 15% weight loss at 68 weeks is nearly twice what is seen with other FDA-approved anti-obesity medications, he noted, and moreover, 70% of patients taking semaglutide lost at least 10% of their initial weight, which is associated with clinically meaningful improvements in obesity-related type 2 diabetes, hypertension, obstructive sleep apnea, and impaired quality of life.

And “nearly one-third of users are likely to lose 20% or more of their starting weight, an outcome which eludes traditional diet and exercise interventions and which approaches weight losses produced by the most widely performed bariatric surgery, sleeve gastrectomy (with mean losses of 25% of initial weight at 1 year).” Dr. Wadden stressed.

Thus “the efficacy of semaglutide 2.4 mg, combined with its favorable safety profile, makes this medication a potential game changer,” he summarized, echoing Dr. Batterham.

However, insurance coverage and price could block uptake.

“I hope that the millions of people – in the U.S. and worldwide – who could benefit from this medication eventually will have access to it,” said Dr. Wadden. “In the U.S., the coverage of anti-obesity medications by insurers and employers will need to improve to ensure this happens, and the medication must be reasonably priced. These changes are critical to making this medication the game changer it could be.”

“This approval is an important development,” Scott Kahan, MD, director of the National Center for Weight and Wellness, Washington, who was not involved in the clinical trials of this drug, similarly wrote in an email.

“In a field with relatively few medication options, the availability of additional obesity pharmacotherapy agents is welcome,” he said. “In particular, semaglutide has shown impressive efficacy and safety data; as such it should be a valuable clinical option for many patients.”

However, it is concerning that “access to obesity treatments has traditionally been a challenge,” Dr. Kahan warned. “Novo Nordisk’s other obesity medication, Saxenda, has been a valuable tool, but one that exceedingly few patients are able to utilize due to minimal insurance reimbursement and very high cost.”

“It remains to be seen how accessible semaglutide will be for patients,” according to Dr. Kahan, “Still, if the challenge of limited coverage and high cost can be mitigated, this medication has a chance to significantly change the current paradigm of care, which until till now has included minimal use of pharmacotherapy outside specialty clinics,” he maintains.

Subcutaneous semaglutide at doses up to 1 mg/week (Ozempic, Novo Nordisk), which comes as prefilled pens at doses of 0.5 mg or 1.0 mg, is already approved for the treatment of type 2 diabetes.

The company is also applying for approval for a higher dose of semaglutide, 2 mg/week, for use in type 2 diabetes, and has just resubmitted its label expansion application to the FDA, after the agency issued a refusal to file letter in March.

And in September 2019, the FDA approved oral semaglutide (Rybelsus, Novo Nordisk), in doses of 7 and 14 mg/day, to improve glycemic control in type 2 diabetes, making it the first GLP-1 receptor agonist available in tablet form.
 

CVOT and oral format trials for obesity on the horizon

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial will shed light on cardiovascular outcomes after 2.5-5 years in patients with cardiovascular disease and overweight or obesity but without type 2 diabetes. Participants will receive semaglutide in doses up to a maximum of 2.4 mg/week, or placebo, as an adjunct to lifestyle recommendations focused on cardiovascular risk reduction. The study is expected to complete in 2023.

And Novo Nordisk plans to initiate a global 68-week phase 3 trial in the second half of 2021 on the efficacy and safety of oral semaglutide 50 mg compared with placebo in 1000 people with obesity or overweight and comorbidities.

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

This article was updated 6/7/21.

The U.S. Food and Drug Administration has approved a 2.4 mg/week subcutaneous dose of the glucagonlike peptide–1 (GLP-1) receptor agonist semaglutide (Wegovy, Novo Nordisk) for weight loss.

Specifically, this drug format and dosage are approved as an adjunct to a reduced-calorie diet and increased physical activity to treat adults who have obesity (body mass index [BMI] ≥ 30 kg/m²) or are overweight (BMI ≥ 27 kg/m²) with at least one weight-related comorbidity.

Semaglutide “induces weight loss by reducing hunger, increasing feelings of fullness, and thereby helping people eat less and reduce their calorie intake,” according to a company statement.

Novo Nordisk plans to launch Wegovy later this month in the United States. The prescribing information can be found here.

This weight-loss drug is currently under review by the European Medicines Agency.

Several experts told Medscape that they believe the approval of this drug – as long as it is reimbursed – has the potential to change the paradigm of care when it comes to weight loss.


 

‘Game changer’ drug tested in STEP clinical trial program

The favorable FDA ruling is based on results from the Semaglutide Treatment Effect in People With Obesity (STEP) program of four phase 3 clinical trials that tested the drug’s safety and efficacy in more than 4,500 adults with overweight or obesity obesity who were randomized to receive a reduced a calorie meal plan and increased physical activity (placebo) or this lifestyle intervention plus semaglutide.

The four 68-week trials of subcutaneous semaglutide 2.4 mg/week versus placebo were published in February and March 2021.

As previously reported by this news organization, all trials were in adults with overweight or obesity:

•  was in 1,961 adults (N Engl J Med. 2021 March 18;384:989-1002).
•  was in 1,210 adults who also had diabetes (Lancet. 2021 Mar 13;397;971-84).
•  was in 611 adults, where those in the treatment group also underwent an intensive lifestyle intervention (JAMA. 2021 Feb 24;325:1403-13.
•  was in 803 adults who had reached a target dose of 2.4 mg semaglutide after a 20-week run-in (and the trial examined further weight loss in the subsequent 48 weeks) (JAMA 2021 Mar 23;325:1414-25).

In the STEP 1, 2, and 4 trials of individuals with overweight and obesity, those in the semaglutide groups attained a 15%-18% weight loss over 68 weeks.

The dosage was well-tolerated. The most common side effects were gastrointestinal, and they were transient and mild or moderate in severity.

The side effects, contraindications, and a black box warning about thyroid C-cell tumors are spelled out in the prescribing information.

A coauthor of the STEP 1 trial, Rachel Batterham, MBBS, PhD, of the Centre for Obesity Research at University College London, said at the time of publication: “The findings of this study represent a major breakthrough for improving the health of people with obesity.”

“No other drug has come close to producing this level of weight loss – this really is a gamechanger. For the first time, people can achieve through drugs what was only possible through weight-loss surgery,” she added.
 

Welcome Addition, But Will Insurance Coverage, Price Thwart Access?

Thomas A. Wadden, PhD, from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and lead author of STEP 3, commented in an email to this news organization that “semaglutide 2.4 mg appears to be the breakthrough in weight management that healthcare providers and their patients with obesity have been waiting for.”

The mean 15% weight loss at 68 weeks is nearly twice what is seen with other FDA-approved anti-obesity medications, he noted, and moreover, 70% of patients taking semaglutide lost at least 10% of their initial weight, which is associated with clinically meaningful improvements in obesity-related type 2 diabetes, hypertension, obstructive sleep apnea, and impaired quality of life.

And “nearly one-third of users are likely to lose 20% or more of their starting weight, an outcome which eludes traditional diet and exercise interventions and which approaches weight losses produced by the most widely performed bariatric surgery, sleeve gastrectomy (with mean losses of 25% of initial weight at 1 year).” Dr. Wadden stressed.

Thus “the efficacy of semaglutide 2.4 mg, combined with its favorable safety profile, makes this medication a potential game changer,” he summarized, echoing Dr. Batterham.

However, insurance coverage and price could block uptake.

“I hope that the millions of people – in the U.S. and worldwide – who could benefit from this medication eventually will have access to it,” said Dr. Wadden. “In the U.S., the coverage of anti-obesity medications by insurers and employers will need to improve to ensure this happens, and the medication must be reasonably priced. These changes are critical to making this medication the game changer it could be.”

“This approval is an important development,” Scott Kahan, MD, director of the National Center for Weight and Wellness, Washington, who was not involved in the clinical trials of this drug, similarly wrote in an email.

“In a field with relatively few medication options, the availability of additional obesity pharmacotherapy agents is welcome,” he said. “In particular, semaglutide has shown impressive efficacy and safety data; as such it should be a valuable clinical option for many patients.”

However, it is concerning that “access to obesity treatments has traditionally been a challenge,” Dr. Kahan warned. “Novo Nordisk’s other obesity medication, Saxenda, has been a valuable tool, but one that exceedingly few patients are able to utilize due to minimal insurance reimbursement and very high cost.”

“It remains to be seen how accessible semaglutide will be for patients,” according to Dr. Kahan, “Still, if the challenge of limited coverage and high cost can be mitigated, this medication has a chance to significantly change the current paradigm of care, which until till now has included minimal use of pharmacotherapy outside specialty clinics,” he maintains.

Subcutaneous semaglutide at doses up to 1 mg/week (Ozempic, Novo Nordisk), which comes as prefilled pens at doses of 0.5 mg or 1.0 mg, is already approved for the treatment of type 2 diabetes.

The company is also applying for approval for a higher dose of semaglutide, 2 mg/week, for use in type 2 diabetes, and has just resubmitted its label expansion application to the FDA, after the agency issued a refusal to file letter in March.

And in September 2019, the FDA approved oral semaglutide (Rybelsus, Novo Nordisk), in doses of 7 and 14 mg/day, to improve glycemic control in type 2 diabetes, making it the first GLP-1 receptor agonist available in tablet form.
 

CVOT and oral format trials for obesity on the horizon

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial will shed light on cardiovascular outcomes after 2.5-5 years in patients with cardiovascular disease and overweight or obesity but without type 2 diabetes. Participants will receive semaglutide in doses up to a maximum of 2.4 mg/week, or placebo, as an adjunct to lifestyle recommendations focused on cardiovascular risk reduction. The study is expected to complete in 2023.

And Novo Nordisk plans to initiate a global 68-week phase 3 trial in the second half of 2021 on the efficacy and safety of oral semaglutide 50 mg compared with placebo in 1000 people with obesity or overweight and comorbidities.

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

This article was updated 6/7/21.

The U.S. Food and Drug Administration has approved a 2.4 mg/week subcutaneous dose of the glucagonlike peptide–1 (GLP-1) receptor agonist semaglutide (Wegovy, Novo Nordisk) for weight loss.

Specifically, this drug format and dosage are approved as an adjunct to a reduced-calorie diet and increased physical activity to treat adults who have obesity (body mass index [BMI] ≥ 30 kg/m²) or are overweight (BMI ≥ 27 kg/m²) with at least one weight-related comorbidity.

Semaglutide “induces weight loss by reducing hunger, increasing feelings of fullness, and thereby helping people eat less and reduce their calorie intake,” according to a company statement.

Novo Nordisk plans to launch Wegovy later this month in the United States. The prescribing information can be found here.

This weight-loss drug is currently under review by the European Medicines Agency.

Several experts told Medscape that they believe the approval of this drug – as long as it is reimbursed – has the potential to change the paradigm of care when it comes to weight loss.


 

‘Game changer’ drug tested in STEP clinical trial program

The favorable FDA ruling is based on results from the Semaglutide Treatment Effect in People With Obesity (STEP) program of four phase 3 clinical trials that tested the drug’s safety and efficacy in more than 4,500 adults with overweight or obesity obesity who were randomized to receive a reduced a calorie meal plan and increased physical activity (placebo) or this lifestyle intervention plus semaglutide.

The four 68-week trials of subcutaneous semaglutide 2.4 mg/week versus placebo were published in February and March 2021.

As previously reported by this news organization, all trials were in adults with overweight or obesity:

•  was in 1,961 adults (N Engl J Med. 2021 March 18;384:989-1002).
•  was in 1,210 adults who also had diabetes (Lancet. 2021 Mar 13;397;971-84).
•  was in 611 adults, where those in the treatment group also underwent an intensive lifestyle intervention (JAMA. 2021 Feb 24;325:1403-13.
•  was in 803 adults who had reached a target dose of 2.4 mg semaglutide after a 20-week run-in (and the trial examined further weight loss in the subsequent 48 weeks) (JAMA 2021 Mar 23;325:1414-25).

In the STEP 1, 2, and 4 trials of individuals with overweight and obesity, those in the semaglutide groups attained a 15%-18% weight loss over 68 weeks.

The dosage was well-tolerated. The most common side effects were gastrointestinal, and they were transient and mild or moderate in severity.

The side effects, contraindications, and a black box warning about thyroid C-cell tumors are spelled out in the prescribing information.

A coauthor of the STEP 1 trial, Rachel Batterham, MBBS, PhD, of the Centre for Obesity Research at University College London, said at the time of publication: “The findings of this study represent a major breakthrough for improving the health of people with obesity.”

“No other drug has come close to producing this level of weight loss – this really is a gamechanger. For the first time, people can achieve through drugs what was only possible through weight-loss surgery,” she added.
 

Welcome Addition, But Will Insurance Coverage, Price Thwart Access?

Thomas A. Wadden, PhD, from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and lead author of STEP 3, commented in an email to this news organization that “semaglutide 2.4 mg appears to be the breakthrough in weight management that healthcare providers and their patients with obesity have been waiting for.”

The mean 15% weight loss at 68 weeks is nearly twice what is seen with other FDA-approved anti-obesity medications, he noted, and moreover, 70% of patients taking semaglutide lost at least 10% of their initial weight, which is associated with clinically meaningful improvements in obesity-related type 2 diabetes, hypertension, obstructive sleep apnea, and impaired quality of life.

And “nearly one-third of users are likely to lose 20% or more of their starting weight, an outcome which eludes traditional diet and exercise interventions and which approaches weight losses produced by the most widely performed bariatric surgery, sleeve gastrectomy (with mean losses of 25% of initial weight at 1 year).” Dr. Wadden stressed.

Thus “the efficacy of semaglutide 2.4 mg, combined with its favorable safety profile, makes this medication a potential game changer,” he summarized, echoing Dr. Batterham.

However, insurance coverage and price could block uptake.

“I hope that the millions of people – in the U.S. and worldwide – who could benefit from this medication eventually will have access to it,” said Dr. Wadden. “In the U.S., the coverage of anti-obesity medications by insurers and employers will need to improve to ensure this happens, and the medication must be reasonably priced. These changes are critical to making this medication the game changer it could be.”

“This approval is an important development,” Scott Kahan, MD, director of the National Center for Weight and Wellness, Washington, who was not involved in the clinical trials of this drug, similarly wrote in an email.

“In a field with relatively few medication options, the availability of additional obesity pharmacotherapy agents is welcome,” he said. “In particular, semaglutide has shown impressive efficacy and safety data; as such it should be a valuable clinical option for many patients.”

However, it is concerning that “access to obesity treatments has traditionally been a challenge,” Dr. Kahan warned. “Novo Nordisk’s other obesity medication, Saxenda, has been a valuable tool, but one that exceedingly few patients are able to utilize due to minimal insurance reimbursement and very high cost.”

“It remains to be seen how accessible semaglutide will be for patients,” according to Dr. Kahan, “Still, if the challenge of limited coverage and high cost can be mitigated, this medication has a chance to significantly change the current paradigm of care, which until till now has included minimal use of pharmacotherapy outside specialty clinics,” he maintains.

Subcutaneous semaglutide at doses up to 1 mg/week (Ozempic, Novo Nordisk), which comes as prefilled pens at doses of 0.5 mg or 1.0 mg, is already approved for the treatment of type 2 diabetes.

The company is also applying for approval for a higher dose of semaglutide, 2 mg/week, for use in type 2 diabetes, and has just resubmitted its label expansion application to the FDA, after the agency issued a refusal to file letter in March.

And in September 2019, the FDA approved oral semaglutide (Rybelsus, Novo Nordisk), in doses of 7 and 14 mg/day, to improve glycemic control in type 2 diabetes, making it the first GLP-1 receptor agonist available in tablet form.
 

CVOT and oral format trials for obesity on the horizon

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial will shed light on cardiovascular outcomes after 2.5-5 years in patients with cardiovascular disease and overweight or obesity but without type 2 diabetes. Participants will receive semaglutide in doses up to a maximum of 2.4 mg/week, or placebo, as an adjunct to lifestyle recommendations focused on cardiovascular risk reduction. The study is expected to complete in 2023.

And Novo Nordisk plans to initiate a global 68-week phase 3 trial in the second half of 2021 on the efficacy and safety of oral semaglutide 50 mg compared with placebo in 1000 people with obesity or overweight and comorbidities.

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

This article was updated 6/7/21.

New guidelines from the American College of Gastroenterology on idiosyncratic drug-induced liver injury (DILI) emphasize that idiosyncratic DILI is increasingly driven by the burgeoning popularity of herbal and dietary supplements, as well as tyrosine kinase inhibitors and immune checkpoint inhibitors used to treat cancer.

Sebastian Kaulitzki/Science Photo Library

The guidelines, which represent an update from 2014, are published in The American Journal of Gastroenterology.

DILI is commonly seen by gastroenterologists and hepatologists, but it is challenging to diagnose because there are many potential causes, and no objective diagnostic tests. Its incidence in the general population is low, but it must be considered when facing unexplained liver injury. Its potential presence should also be considered when prescribing gastrointestinal medications like azathioprine, anti–tumor necrosis factor agents, and sulfonamides.

DILI can be characterized as intrinsic or idiosyncratic. Intrinsic DILI is somewhat predictable, based on human or animal studies that have revealed the potential for liver toxicity at higher doses. The best-known example is acetaminophen. Idiosyncratic DILI is rarer and shows up in individuals with a preexisting susceptibility. Clinical signs of idiosyncratic DILI are more diverse than intrinsic DILI. The ACG guideline focuses on idiosyncratic DILI, since guidelines are already available for intrinsic DILI.

Idiosyncratic DILI diagnosis can have a wide range of presentations, including asymptomatic liver biochemistry, jaundice, liver failure, and chronic hepatitis. Diagnosis is made by eliminating other potential causes.

In the presence of hepatocellular jaundice, mortality can reach 10%. DILI patients who develop progressive jaundice, regardless of concomitant coagulopathy, should be sent to a tertiary center and may be a candidate for liver transplantation.

Corticosteroids may be considered when there is uncertainty if a liver injury is from DILI or autoimmune hepatitis, but this remains controversial because some studies have shown benefit, while others have not, according to Bubu Banini, MD, PhD, assistant professor of medicine and research director of the metabolic health and weight management program at Yale University, New Haven, Conn. “Large-scale randomized controlled trials are needed for further elucidation of the role of steroids in DILI. For now, the guideline recommends consideration of steroid therapy, particularly in patients with features of autoimmune hepatitis,” she added.

An important factor driving DILI is the increasing popularity of herbal supplements, as well as increased use of some cancer therapies. “With the advent of immune checkpoint inhibitors as effective therapies for a variety of malignancies, physicians need to be aware of the potential side effects of these agents and the possibility of immune checkpoint inhibitor–related drug induced liver injury,” Dr. Banini said. The updated ACG guideline summarizes current FDA-approved immune checkpoint inhibitors and their potential to cause DILI. The drugs can also lead to reactivation of hepatitis B infection. Studies have shown liver enzyme elevation occurs in about 30% of patients treated with immune checkpoint inhibitors.

The guidelines recommend assessing DILI patients for hepatitis B and C, and treating patients prior to, or in combination with, immune checkpoint inhibitors or other chemotherapy drugs. The recommendations are in line with preliminary data from the ICI field, according to Dr. Banini.

Dr. Banini also noted there has been an increase in the use of herbal and dietary supplements in the United States over the past decade, and these now account for about one-fifth of DILI cases. The guidelines recommend that severe cholestatic disease from these agents should be managed similarly to cases caused by prescription drugs, and patients should be considered for liver transplant if necessary.

A web-based 6-month mortality calculator for suspected DILI is available. It uses Model for End-Stage Liver Disease, Charlson comorbidity Index, and serum albumin data. Those variables predict mortality in liver disease, and an independent analysis showed they predict 6-month mortality in DILI.

DILI is difficult to diagnose, but physicians should keep it in mind when faced with a case of liver enzyme abnormality, where other possibilities have been excluded. “With over a thousand medications potentially causing DILI, physicians should be familiar with LiverTox as a very useful and practical resource. The DILI mortality calculator can serve as a clinical tool to predict 6-month mortality in patients with suspected DILI,” Dr. Banini said.

Some authors disclosed relationships with several pharmaceutical companies. Dr. Banini reports having nothing to disclose.

New guidelines from the American College of Gastroenterology on idiosyncratic drug-induced liver injury (DILI) emphasize that idiosyncratic DILI is increasingly driven by the burgeoning popularity of herbal and dietary supplements, as well as tyrosine kinase inhibitors and immune checkpoint inhibitors used to treat cancer.

Sebastian Kaulitzki/Science Photo Library

The guidelines, which represent an update from 2014, are published in The American Journal of Gastroenterology.

DILI is commonly seen by gastroenterologists and hepatologists, but it is challenging to diagnose because there are many potential causes, and no objective diagnostic tests. Its incidence in the general population is low, but it must be considered when facing unexplained liver injury. Its potential presence should also be considered when prescribing gastrointestinal medications like azathioprine, anti–tumor necrosis factor agents, and sulfonamides.

DILI can be characterized as intrinsic or idiosyncratic. Intrinsic DILI is somewhat predictable, based on human or animal studies that have revealed the potential for liver toxicity at higher doses. The best-known example is acetaminophen. Idiosyncratic DILI is rarer and shows up in individuals with a preexisting susceptibility. Clinical signs of idiosyncratic DILI are more diverse than intrinsic DILI. The ACG guideline focuses on idiosyncratic DILI, since guidelines are already available for intrinsic DILI.

Idiosyncratic DILI diagnosis can have a wide range of presentations, including asymptomatic liver biochemistry, jaundice, liver failure, and chronic hepatitis. Diagnosis is made by eliminating other potential causes.

In the presence of hepatocellular jaundice, mortality can reach 10%. DILI patients who develop progressive jaundice, regardless of concomitant coagulopathy, should be sent to a tertiary center and may be a candidate for liver transplantation.

Corticosteroids may be considered when there is uncertainty if a liver injury is from DILI or autoimmune hepatitis, but this remains controversial because some studies have shown benefit, while others have not, according to Bubu Banini, MD, PhD, assistant professor of medicine and research director of the metabolic health and weight management program at Yale University, New Haven, Conn. “Large-scale randomized controlled trials are needed for further elucidation of the role of steroids in DILI. For now, the guideline recommends consideration of steroid therapy, particularly in patients with features of autoimmune hepatitis,” she added.

An important factor driving DILI is the increasing popularity of herbal supplements, as well as increased use of some cancer therapies. “With the advent of immune checkpoint inhibitors as effective therapies for a variety of malignancies, physicians need to be aware of the potential side effects of these agents and the possibility of immune checkpoint inhibitor–related drug induced liver injury,” Dr. Banini said. The updated ACG guideline summarizes current FDA-approved immune checkpoint inhibitors and their potential to cause DILI. The drugs can also lead to reactivation of hepatitis B infection. Studies have shown liver enzyme elevation occurs in about 30% of patients treated with immune checkpoint inhibitors.

The guidelines recommend assessing DILI patients for hepatitis B and C, and treating patients prior to, or in combination with, immune checkpoint inhibitors or other chemotherapy drugs. The recommendations are in line with preliminary data from the ICI field, according to Dr. Banini.

Dr. Banini also noted there has been an increase in the use of herbal and dietary supplements in the United States over the past decade, and these now account for about one-fifth of DILI cases. The guidelines recommend that severe cholestatic disease from these agents should be managed similarly to cases caused by prescription drugs, and patients should be considered for liver transplant if necessary.

A web-based 6-month mortality calculator for suspected DILI is available. It uses Model for End-Stage Liver Disease, Charlson comorbidity Index, and serum albumin data. Those variables predict mortality in liver disease, and an independent analysis showed they predict 6-month mortality in DILI.

DILI is difficult to diagnose, but physicians should keep it in mind when faced with a case of liver enzyme abnormality, where other possibilities have been excluded. “With over a thousand medications potentially causing DILI, physicians should be familiar with LiverTox as a very useful and practical resource. The DILI mortality calculator can serve as a clinical tool to predict 6-month mortality in patients with suspected DILI,” Dr. Banini said.

Some authors disclosed relationships with several pharmaceutical companies. Dr. Banini reports having nothing to disclose.

New guidelines from the American College of Gastroenterology on idiosyncratic drug-induced liver injury (DILI) emphasize that idiosyncratic DILI is increasingly driven by the burgeoning popularity of herbal and dietary supplements, as well as tyrosine kinase inhibitors and immune checkpoint inhibitors used to treat cancer.

Sebastian Kaulitzki/Science Photo Library

The guidelines, which represent an update from 2014, are published in The American Journal of Gastroenterology.

DILI is commonly seen by gastroenterologists and hepatologists, but it is challenging to diagnose because there are many potential causes, and no objective diagnostic tests. Its incidence in the general population is low, but it must be considered when facing unexplained liver injury. Its potential presence should also be considered when prescribing gastrointestinal medications like azathioprine, anti–tumor necrosis factor agents, and sulfonamides.

DILI can be characterized as intrinsic or idiosyncratic. Intrinsic DILI is somewhat predictable, based on human or animal studies that have revealed the potential for liver toxicity at higher doses. The best-known example is acetaminophen. Idiosyncratic DILI is rarer and shows up in individuals with a preexisting susceptibility. Clinical signs of idiosyncratic DILI are more diverse than intrinsic DILI. The ACG guideline focuses on idiosyncratic DILI, since guidelines are already available for intrinsic DILI.

Idiosyncratic DILI diagnosis can have a wide range of presentations, including asymptomatic liver biochemistry, jaundice, liver failure, and chronic hepatitis. Diagnosis is made by eliminating other potential causes.

In the presence of hepatocellular jaundice, mortality can reach 10%. DILI patients who develop progressive jaundice, regardless of concomitant coagulopathy, should be sent to a tertiary center and may be a candidate for liver transplantation.

Corticosteroids may be considered when there is uncertainty if a liver injury is from DILI or autoimmune hepatitis, but this remains controversial because some studies have shown benefit, while others have not, according to Bubu Banini, MD, PhD, assistant professor of medicine and research director of the metabolic health and weight management program at Yale University, New Haven, Conn. “Large-scale randomized controlled trials are needed for further elucidation of the role of steroids in DILI. For now, the guideline recommends consideration of steroid therapy, particularly in patients with features of autoimmune hepatitis,” she added.

An important factor driving DILI is the increasing popularity of herbal supplements, as well as increased use of some cancer therapies. “With the advent of immune checkpoint inhibitors as effective therapies for a variety of malignancies, physicians need to be aware of the potential side effects of these agents and the possibility of immune checkpoint inhibitor–related drug induced liver injury,” Dr. Banini said. The updated ACG guideline summarizes current FDA-approved immune checkpoint inhibitors and their potential to cause DILI. The drugs can also lead to reactivation of hepatitis B infection. Studies have shown liver enzyme elevation occurs in about 30% of patients treated with immune checkpoint inhibitors.

The guidelines recommend assessing DILI patients for hepatitis B and C, and treating patients prior to, or in combination with, immune checkpoint inhibitors or other chemotherapy drugs. The recommendations are in line with preliminary data from the ICI field, according to Dr. Banini.

Dr. Banini also noted there has been an increase in the use of herbal and dietary supplements in the United States over the past decade, and these now account for about one-fifth of DILI cases. The guidelines recommend that severe cholestatic disease from these agents should be managed similarly to cases caused by prescription drugs, and patients should be considered for liver transplant if necessary.

A web-based 6-month mortality calculator for suspected DILI is available. It uses Model for End-Stage Liver Disease, Charlson comorbidity Index, and serum albumin data. Those variables predict mortality in liver disease, and an independent analysis showed they predict 6-month mortality in DILI.

DILI is difficult to diagnose, but physicians should keep it in mind when faced with a case of liver enzyme abnormality, where other possibilities have been excluded. “With over a thousand medications potentially causing DILI, physicians should be familiar with LiverTox as a very useful and practical resource. The DILI mortality calculator can serve as a clinical tool to predict 6-month mortality in patients with suspected DILI,” Dr. Banini said.

Some authors disclosed relationships with several pharmaceutical companies. Dr. Banini reports having nothing to disclose.

On the medication front, there are now “four pillars of survival” in the setting of heart failure with reduced ejection fraction (EF), a cardiologist told hospitalists recently at SHM Converge, the annual conference of the Society of Hospital Medicine.

The quartet of drugs are beta blockers, angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists, and the newest addition – sodium-glucose cotransporter 2 inhibitors.

“If we use all four of these medications, the absolute risk reduction [in mortality] is 25% over a 2-year period,” said cardiologist Celeste T. Williams, MD, of Henry Ford Hospital, Detroit. “So it is very important that we use these medications,” she said.

But managing the medications, she said, can be challenging. Dr. Williams offered these tips about the use of medication in heart failure.
 

Beta blockers are crucial players

“Beta blockers save lives,” Dr. Williams said, “but there’s always a debate about how much we should titrate beta blockers.”

How can you determine the proper titration? Focus on heart rates, she recommended. “We know that higher heart rates in heart failure patients are associated with worse outcomes. There was subgroup analysis in the BEAUTIFUL study that looked at 5,300 patients with EF less than 40% who had CAD [coronary artery disease]. They found that patients with heart rates greater than 70 had a 34% increased risk of cardiovascular death and a 53% increased risk of heart failure hospitalization compared to heart rates less than 70.”

Focus on getting your patient’s heart rate lower than 70 while maintaining their blood pressure, she said.

“Another question we have is, ‘When these patients come into hospitals, what should we do with the beta blocker? Should we continue it? Should we stop it?’ If you can, you always want to continue the beta blocker or the ACE [angiotensin-converting enzyme] inhibitor, because studies have shown us that the likelihood for patients to be on these medications 90 days later is dismal,” she said. “But you also need to look at the patient. If the patient is in cardiogenic shock, their beta blocker should be stopped.”
 

Consider multiple factors when titrating various medications

“In the hospital, we always will look at hemodynamic compromise in the patient. Is the patient in cardiogenic shock?” Dr. Williams said. “We also must think about compliance concerns. Are the patients even taking their medication? And if they are taking their medications, are they tolerating standard medical therapy? Are they hypotensive? Are they only able to tolerate minimal meds? Have you seen that their creatine continues to rise? Or are they having poor diuresis with the rise in diuretics?”

All these questions are useful, she said, as you determine whether you should titrate medication yourself or refer the patient to an advanced heart failure specialist.
 

Understand when to stick with guideline-directed medical therapy

Dr. Williams said another question often arises: “If your patient’s EF recovers, should you stop guideline-directed medical therapy [GDMT]?” She highlighted a TRED-HF study that evaluated patients who had recovered from dilated, nonischemic cardiomyopathy and were receiving GDMT. “They withdrew GDMT for half of the patients and looked at their echoes 6 months later. They found that 40% of the patients relapsed. Their EFs went below 40% again. Stopping medications is not the best idea for most of these patients.”

However, she said, there are scenarios in which GDMT may be withdrawn, such as for patients with tachycardia-induced cardiomyopathies whose EF recovers after ablation, those whose EF recovers after alcoholic cardiomyopathy, and those who receive valve replacements. “We need to remember that a lot of the patients who develop stage C heart failure have risk factors. Even though their heart failure has recovered, they have risks that need to be treated, and you can use the same medications that you use for heart failure to control their risk. Therefore, you would not get into trouble by withdrawing their medications.”

She added: “If you’re unable to titrate GDMT because the blood pressure is too soft, the creatine continues to rise, or the patient just has a lot of heart failure symptoms, this is indicative that the patient is sicker than they may appear.” At this point, defer to a heart failure specialist, she said.
 

Consider ivabradine as an add-on when appropriate

In some cases, a heart rate of less than 70 bpm will not be achieved even with GDMT and maximum tolerated doses, Dr. Williams said. “If they’re in sinus, you can add on a medication called ivabradine, which was studied in the SHIFT study. This looked at patients with EF of less than 35% who had class 2-3 heart failure in sinus rhythm. They had to have a hospitalization within the last 12 months. The patients were randomized to either ivabradine or placebo. The primary outcome was [cardiovascular] death or heart failure hospitalization. They found that patients who had ivabradine had a decrease in heart failure hospitalization.”

The lesson, she said, is that “ivabradine is a great medication to add on to patients who are still tachycardic in sinus when you cannot titrate up the beta blocker.”

Dr. Williams reports no relevant financial relationships.

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

On the medication front, there are now “four pillars of survival” in the setting of heart failure with reduced ejection fraction (EF), a cardiologist told hospitalists recently at SHM Converge, the annual conference of the Society of Hospital Medicine.

The quartet of drugs are beta blockers, angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists, and the newest addition – sodium-glucose cotransporter 2 inhibitors.

“If we use all four of these medications, the absolute risk reduction [in mortality] is 25% over a 2-year period,” said cardiologist Celeste T. Williams, MD, of Henry Ford Hospital, Detroit. “So it is very important that we use these medications,” she said.

But managing the medications, she said, can be challenging. Dr. Williams offered these tips about the use of medication in heart failure.
 

Beta blockers are crucial players

“Beta blockers save lives,” Dr. Williams said, “but there’s always a debate about how much we should titrate beta blockers.”

How can you determine the proper titration? Focus on heart rates, she recommended. “We know that higher heart rates in heart failure patients are associated with worse outcomes. There was subgroup analysis in the BEAUTIFUL study that looked at 5,300 patients with EF less than 40% who had CAD [coronary artery disease]. They found that patients with heart rates greater than 70 had a 34% increased risk of cardiovascular death and a 53% increased risk of heart failure hospitalization compared to heart rates less than 70.”

Focus on getting your patient’s heart rate lower than 70 while maintaining their blood pressure, she said.

“Another question we have is, ‘When these patients come into hospitals, what should we do with the beta blocker? Should we continue it? Should we stop it?’ If you can, you always want to continue the beta blocker or the ACE [angiotensin-converting enzyme] inhibitor, because studies have shown us that the likelihood for patients to be on these medications 90 days later is dismal,” she said. “But you also need to look at the patient. If the patient is in cardiogenic shock, their beta blocker should be stopped.”
 

Consider multiple factors when titrating various medications

“In the hospital, we always will look at hemodynamic compromise in the patient. Is the patient in cardiogenic shock?” Dr. Williams said. “We also must think about compliance concerns. Are the patients even taking their medication? And if they are taking their medications, are they tolerating standard medical therapy? Are they hypotensive? Are they only able to tolerate minimal meds? Have you seen that their creatine continues to rise? Or are they having poor diuresis with the rise in diuretics?”

All these questions are useful, she said, as you determine whether you should titrate medication yourself or refer the patient to an advanced heart failure specialist.
 

Understand when to stick with guideline-directed medical therapy

Dr. Williams said another question often arises: “If your patient’s EF recovers, should you stop guideline-directed medical therapy [GDMT]?” She highlighted a TRED-HF study that evaluated patients who had recovered from dilated, nonischemic cardiomyopathy and were receiving GDMT. “They withdrew GDMT for half of the patients and looked at their echoes 6 months later. They found that 40% of the patients relapsed. Their EFs went below 40% again. Stopping medications is not the best idea for most of these patients.”

However, she said, there are scenarios in which GDMT may be withdrawn, such as for patients with tachycardia-induced cardiomyopathies whose EF recovers after ablation, those whose EF recovers after alcoholic cardiomyopathy, and those who receive valve replacements. “We need to remember that a lot of the patients who develop stage C heart failure have risk factors. Even though their heart failure has recovered, they have risks that need to be treated, and you can use the same medications that you use for heart failure to control their risk. Therefore, you would not get into trouble by withdrawing their medications.”

She added: “If you’re unable to titrate GDMT because the blood pressure is too soft, the creatine continues to rise, or the patient just has a lot of heart failure symptoms, this is indicative that the patient is sicker than they may appear.” At this point, defer to a heart failure specialist, she said.
 

Consider ivabradine as an add-on when appropriate

In some cases, a heart rate of less than 70 bpm will not be achieved even with GDMT and maximum tolerated doses, Dr. Williams said. “If they’re in sinus, you can add on a medication called ivabradine, which was studied in the SHIFT study. This looked at patients with EF of less than 35% who had class 2-3 heart failure in sinus rhythm. They had to have a hospitalization within the last 12 months. The patients were randomized to either ivabradine or placebo. The primary outcome was [cardiovascular] death or heart failure hospitalization. They found that patients who had ivabradine had a decrease in heart failure hospitalization.”

The lesson, she said, is that “ivabradine is a great medication to add on to patients who are still tachycardic in sinus when you cannot titrate up the beta blocker.”

Dr. Williams reports no relevant financial relationships.

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

On the medication front, there are now “four pillars of survival” in the setting of heart failure with reduced ejection fraction (EF), a cardiologist told hospitalists recently at SHM Converge, the annual conference of the Society of Hospital Medicine.

The quartet of drugs are beta blockers, angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists, and the newest addition – sodium-glucose cotransporter 2 inhibitors.

“If we use all four of these medications, the absolute risk reduction [in mortality] is 25% over a 2-year period,” said cardiologist Celeste T. Williams, MD, of Henry Ford Hospital, Detroit. “So it is very important that we use these medications,” she said.

But managing the medications, she said, can be challenging. Dr. Williams offered these tips about the use of medication in heart failure.
 

Beta blockers are crucial players

“Beta blockers save lives,” Dr. Williams said, “but there’s always a debate about how much we should titrate beta blockers.”

How can you determine the proper titration? Focus on heart rates, she recommended. “We know that higher heart rates in heart failure patients are associated with worse outcomes. There was subgroup analysis in the BEAUTIFUL study that looked at 5,300 patients with EF less than 40% who had CAD [coronary artery disease]. They found that patients with heart rates greater than 70 had a 34% increased risk of cardiovascular death and a 53% increased risk of heart failure hospitalization compared to heart rates less than 70.”

Focus on getting your patient’s heart rate lower than 70 while maintaining their blood pressure, she said.

“Another question we have is, ‘When these patients come into hospitals, what should we do with the beta blocker? Should we continue it? Should we stop it?’ If you can, you always want to continue the beta blocker or the ACE [angiotensin-converting enzyme] inhibitor, because studies have shown us that the likelihood for patients to be on these medications 90 days later is dismal,” she said. “But you also need to look at the patient. If the patient is in cardiogenic shock, their beta blocker should be stopped.”
 

Consider multiple factors when titrating various medications

“In the hospital, we always will look at hemodynamic compromise in the patient. Is the patient in cardiogenic shock?” Dr. Williams said. “We also must think about compliance concerns. Are the patients even taking their medication? And if they are taking their medications, are they tolerating standard medical therapy? Are they hypotensive? Are they only able to tolerate minimal meds? Have you seen that their creatine continues to rise? Or are they having poor diuresis with the rise in diuretics?”

All these questions are useful, she said, as you determine whether you should titrate medication yourself or refer the patient to an advanced heart failure specialist.
 

Understand when to stick with guideline-directed medical therapy

Dr. Williams said another question often arises: “If your patient’s EF recovers, should you stop guideline-directed medical therapy [GDMT]?” She highlighted a TRED-HF study that evaluated patients who had recovered from dilated, nonischemic cardiomyopathy and were receiving GDMT. “They withdrew GDMT for half of the patients and looked at their echoes 6 months later. They found that 40% of the patients relapsed. Their EFs went below 40% again. Stopping medications is not the best idea for most of these patients.”

However, she said, there are scenarios in which GDMT may be withdrawn, such as for patients with tachycardia-induced cardiomyopathies whose EF recovers after ablation, those whose EF recovers after alcoholic cardiomyopathy, and those who receive valve replacements. “We need to remember that a lot of the patients who develop stage C heart failure have risk factors. Even though their heart failure has recovered, they have risks that need to be treated, and you can use the same medications that you use for heart failure to control their risk. Therefore, you would not get into trouble by withdrawing their medications.”

She added: “If you’re unable to titrate GDMT because the blood pressure is too soft, the creatine continues to rise, or the patient just has a lot of heart failure symptoms, this is indicative that the patient is sicker than they may appear.” At this point, defer to a heart failure specialist, she said.
 

Consider ivabradine as an add-on when appropriate

In some cases, a heart rate of less than 70 bpm will not be achieved even with GDMT and maximum tolerated doses, Dr. Williams said. “If they’re in sinus, you can add on a medication called ivabradine, which was studied in the SHIFT study. This looked at patients with EF of less than 35% who had class 2-3 heart failure in sinus rhythm. They had to have a hospitalization within the last 12 months. The patients were randomized to either ivabradine or placebo. The primary outcome was [cardiovascular] death or heart failure hospitalization. They found that patients who had ivabradine had a decrease in heart failure hospitalization.”

The lesson, she said, is that “ivabradine is a great medication to add on to patients who are still tachycardic in sinus when you cannot titrate up the beta blocker.”

Dr. Williams reports no relevant financial relationships.

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

On May 25, Jena Hausmann, CEO of Children’s Hospital Colorado, Aurora, declared a state of emergency in youth mental health in response to an astronomical increase in pediatric mental health cases, including suicide, which has overwhelmed the institution.

From April 2019 to April 2021, the demand for pediatric behavioral health treatment at the hospital system increased by 90%. In Colorado, suicide is now the number one cause of death among youth and occurs in children as young as 10 years of age.

“Now we are seeing our pediatric emergency departments and our inpatient units overrun with kids attempting suicide and suffering from other forms of major mental health illness,” Dr. Hausmann said in a press release.

“We had to draw attention to what we’re seeing in our hospital and our community on an everyday basis – an unprecedented number of suicidal children who need acute treatment for behavioral health problems – and when I say ‘unprecedented,’ I’m serious – I’ve been in pediatrics for two decades and have never seen anything like this before,” David Brumbaugh, MD, a pediatric gastroenterologist and chief medical officer for Children’s Colorado, told this news organization.

Christine Crawford, MD, associate medical director of the National Alliance on Mental Illness, stated in an interview that she “commends the CEO of the hospital for making this announcement, because it is outrageous to see what is happening with more and more children with significant psychiatric symptoms who are not getting adequate care.”

Jenna Glover, PhD, child psychologist and director of psychology training at Children’s Hospital, said that during the past decade, there has been a steady increase in depression, anxiety, and suicide among youth in Colorado. Suicide, she added, is now the number one cause of death in youth, “so we were already in a state of crisis.” She added that COVID-19 was “the straw that broke the camel’s back.”

“In January to April of this year, behavioral health ED visits to Children’s Hospital were 72% higher than they were 2 years ago at this time,” she said. “Colorado Springs had a 145% increase for ED behavioral health visits during the first 4 months of 2021, compared to the first 4 months of 2020.”
 

COVID’s impact

Other problems that have been “skyrocketing” in youth are self-harm, substance use, and eating disorders. Younger children are experiencing an increase in behavioral problems, including developmental regression, such as tantrums, and problems with sleeping, toileting, and eating, Dr. Glover noted.

The youth mental health crisis has mushroomed, although social distancing requirements are now beginning to ease and we are in the “home stretch of the pandemic,” Dr. Brumbaugh said.

One possible reason “is that we took kids out of their normal routines, social circles, friendships, etc., for 12 months, and that was the limit of their physiological or mental resistance, and they got to the end of their rope,” he speculated.

Dr. Glover said, “Kids are burned out, and although they’re asking to return to their life, they don’t feel they have the resources. They feel so behind; they don’t know how to catch up.”

Dr. Brumbaugh said that there are not enough child psychiatrists to provide outpatient services or enough inpatient beds for children in crisis.

“This is an unacceptable situation. We would never allow a child with leukemia or appendicitis to go several weeks without treatment,” he said.

Community donors have come forward, enabling an anticipated 50% increase in Children’s Hospital’s mental health outpatient, inpatient, and day services by March 2022.

“On a hospital level, we are continuing to do things to expand access to care, like opening units that provide different levels of care for patients with psychiatric problems, as well as expanding into areas that are more rural,” Dr. Glover said.

However, the “blueprint is not in action yet, and a lot of money still needs to be allocated. A workforce has to be created, because there are not enough clinicians to fill these roles,” she added.
 

Chronic underfunding

Dr. Brumbaugh said Colorado has always had a “relatively underfunded behavioral health system for kids.” A 2021 report by Mental Health America ranks Colorado among the lowest states in the country in terms of overall pediatric behavioral health funding.

However, Dr. Glover noted that Colorado is “not exceptional.” The increased vulnerability to youth mental illness and suicide is characteristic of other mountain states, which have larger rural areas, less access to care, and increased access to guns, she said.

Mass shootings may have amped up stress levels. “For some kids, this is happening in their schools or towns, and they feel traumatized and unsafe,” Dr. Glover added.

Dr. Crawford, who is an assistant professor of psychiatry at Boston University, also pointed out that the mental health crisis in youth is not unique to Colorado.

“Throughout the country, we’ve seen these colliding pandemics – inadequate mental health resources for children and COVID-19, which exacerbated the existing mental health crisis,” she said.

“The pandemic led to an increase in telehealth services, making individual and group psychotherapy available to kids in areas that never had access to these before, which is a ‘silver lining’ of the pandemic,” Dr. Glover said.

Dr. Crawford is “encouraged that we are having more conversations about pediatric mental health, because the pandemic amplified what was already going on and made it impossible to ignore.”
 

Screening is essential

Screening for mental health problems should be at the top of the mind of pediatricians and other clinicians who work with children, Dr. Glover said.

“Pediatricians are in the best place to catch potentially suicidal kids, because they are more likely to see these kids than therapists,” she noted.

She suggested using a rapid screen for depression, such as the Patient Health Questionnaire-9 (PHQ-9) modified for adolescents. Parents can also fill out a PHQ-9 for younger children and even for themselves.

“Depression, anxiety, and suicidality affect the whole family, so screening for these conditions in adults will benefit the children too,” she said. Teachers should also “be aware of what depression and anxiety symptoms look like in kids, because sometimes they can manifest more as irritability,” Dr. Glover added.

Policymakers and insurers need to prioritize pediatric mental health when determining allocation of health care, said Dr. Crawford.

“Financial incentives should be provided for hospitals to want to reserve beds for psychiatric patients, and in the outpatient setting, we also need to look at the payment structure of psychiatric visits,” she added.

Many psychiatrists do not want to accept insurance because of the increased bureaucracy and low reimbursement rates of insurance companies, and families cannot afford to pay out of pocket, “so we really need to look at the insurance issue at a policy level,” Dr. Crawford said.

Dr. Brumbaugh, Dr. Glover, and Dr. Crawford have disclosed no relevant financial relationships.

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

On May 25, Jena Hausmann, CEO of Children’s Hospital Colorado, Aurora, declared a state of emergency in youth mental health in response to an astronomical increase in pediatric mental health cases, including suicide, which has overwhelmed the institution.

From April 2019 to April 2021, the demand for pediatric behavioral health treatment at the hospital system increased by 90%. In Colorado, suicide is now the number one cause of death among youth and occurs in children as young as 10 years of age.

“Now we are seeing our pediatric emergency departments and our inpatient units overrun with kids attempting suicide and suffering from other forms of major mental health illness,” Dr. Hausmann said in a press release.

“We had to draw attention to what we’re seeing in our hospital and our community on an everyday basis – an unprecedented number of suicidal children who need acute treatment for behavioral health problems – and when I say ‘unprecedented,’ I’m serious – I’ve been in pediatrics for two decades and have never seen anything like this before,” David Brumbaugh, MD, a pediatric gastroenterologist and chief medical officer for Children’s Colorado, told this news organization.

Christine Crawford, MD, associate medical director of the National Alliance on Mental Illness, stated in an interview that she “commends the CEO of the hospital for making this announcement, because it is outrageous to see what is happening with more and more children with significant psychiatric symptoms who are not getting adequate care.”

Jenna Glover, PhD, child psychologist and director of psychology training at Children’s Hospital, said that during the past decade, there has been a steady increase in depression, anxiety, and suicide among youth in Colorado. Suicide, she added, is now the number one cause of death in youth, “so we were already in a state of crisis.” She added that COVID-19 was “the straw that broke the camel’s back.”

“In January to April of this year, behavioral health ED visits to Children’s Hospital were 72% higher than they were 2 years ago at this time,” she said. “Colorado Springs had a 145% increase for ED behavioral health visits during the first 4 months of 2021, compared to the first 4 months of 2020.”
 

COVID’s impact

Other problems that have been “skyrocketing” in youth are self-harm, substance use, and eating disorders. Younger children are experiencing an increase in behavioral problems, including developmental regression, such as tantrums, and problems with sleeping, toileting, and eating, Dr. Glover noted.

The youth mental health crisis has mushroomed, although social distancing requirements are now beginning to ease and we are in the “home stretch of the pandemic,” Dr. Brumbaugh said.

One possible reason “is that we took kids out of their normal routines, social circles, friendships, etc., for 12 months, and that was the limit of their physiological or mental resistance, and they got to the end of their rope,” he speculated.

Dr. Glover said, “Kids are burned out, and although they’re asking to return to their life, they don’t feel they have the resources. They feel so behind; they don’t know how to catch up.”

Dr. Brumbaugh said that there are not enough child psychiatrists to provide outpatient services or enough inpatient beds for children in crisis.

“This is an unacceptable situation. We would never allow a child with leukemia or appendicitis to go several weeks without treatment,” he said.

Community donors have come forward, enabling an anticipated 50% increase in Children’s Hospital’s mental health outpatient, inpatient, and day services by March 2022.

“On a hospital level, we are continuing to do things to expand access to care, like opening units that provide different levels of care for patients with psychiatric problems, as well as expanding into areas that are more rural,” Dr. Glover said.

However, the “blueprint is not in action yet, and a lot of money still needs to be allocated. A workforce has to be created, because there are not enough clinicians to fill these roles,” she added.
 

Chronic underfunding

Dr. Brumbaugh said Colorado has always had a “relatively underfunded behavioral health system for kids.” A 2021 report by Mental Health America ranks Colorado among the lowest states in the country in terms of overall pediatric behavioral health funding.

However, Dr. Glover noted that Colorado is “not exceptional.” The increased vulnerability to youth mental illness and suicide is characteristic of other mountain states, which have larger rural areas, less access to care, and increased access to guns, she said.

Mass shootings may have amped up stress levels. “For some kids, this is happening in their schools or towns, and they feel traumatized and unsafe,” Dr. Glover added.

Dr. Crawford, who is an assistant professor of psychiatry at Boston University, also pointed out that the mental health crisis in youth is not unique to Colorado.

“Throughout the country, we’ve seen these colliding pandemics – inadequate mental health resources for children and COVID-19, which exacerbated the existing mental health crisis,” she said.

“The pandemic led to an increase in telehealth services, making individual and group psychotherapy available to kids in areas that never had access to these before, which is a ‘silver lining’ of the pandemic,” Dr. Glover said.

Dr. Crawford is “encouraged that we are having more conversations about pediatric mental health, because the pandemic amplified what was already going on and made it impossible to ignore.”
 

Screening is essential

Screening for mental health problems should be at the top of the mind of pediatricians and other clinicians who work with children, Dr. Glover said.

“Pediatricians are in the best place to catch potentially suicidal kids, because they are more likely to see these kids than therapists,” she noted.

She suggested using a rapid screen for depression, such as the Patient Health Questionnaire-9 (PHQ-9) modified for adolescents. Parents can also fill out a PHQ-9 for younger children and even for themselves.

“Depression, anxiety, and suicidality affect the whole family, so screening for these conditions in adults will benefit the children too,” she said. Teachers should also “be aware of what depression and anxiety symptoms look like in kids, because sometimes they can manifest more as irritability,” Dr. Glover added.

Policymakers and insurers need to prioritize pediatric mental health when determining allocation of health care, said Dr. Crawford.

“Financial incentives should be provided for hospitals to want to reserve beds for psychiatric patients, and in the outpatient setting, we also need to look at the payment structure of psychiatric visits,” she added.

Many psychiatrists do not want to accept insurance because of the increased bureaucracy and low reimbursement rates of insurance companies, and families cannot afford to pay out of pocket, “so we really need to look at the insurance issue at a policy level,” Dr. Crawford said.

Dr. Brumbaugh, Dr. Glover, and Dr. Crawford have disclosed no relevant financial relationships.

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

On May 25, Jena Hausmann, CEO of Children’s Hospital Colorado, Aurora, declared a state of emergency in youth mental health in response to an astronomical increase in pediatric mental health cases, including suicide, which has overwhelmed the institution.

From April 2019 to April 2021, the demand for pediatric behavioral health treatment at the hospital system increased by 90%. In Colorado, suicide is now the number one cause of death among youth and occurs in children as young as 10 years of age.

“Now we are seeing our pediatric emergency departments and our inpatient units overrun with kids attempting suicide and suffering from other forms of major mental health illness,” Dr. Hausmann said in a press release.

“We had to draw attention to what we’re seeing in our hospital and our community on an everyday basis – an unprecedented number of suicidal children who need acute treatment for behavioral health problems – and when I say ‘unprecedented,’ I’m serious – I’ve been in pediatrics for two decades and have never seen anything like this before,” David Brumbaugh, MD, a pediatric gastroenterologist and chief medical officer for Children’s Colorado, told this news organization.

Christine Crawford, MD, associate medical director of the National Alliance on Mental Illness, stated in an interview that she “commends the CEO of the hospital for making this announcement, because it is outrageous to see what is happening with more and more children with significant psychiatric symptoms who are not getting adequate care.”

Jenna Glover, PhD, child psychologist and director of psychology training at Children’s Hospital, said that during the past decade, there has been a steady increase in depression, anxiety, and suicide among youth in Colorado. Suicide, she added, is now the number one cause of death in youth, “so we were already in a state of crisis.” She added that COVID-19 was “the straw that broke the camel’s back.”

“In January to April of this year, behavioral health ED visits to Children’s Hospital were 72% higher than they were 2 years ago at this time,” she said. “Colorado Springs had a 145% increase for ED behavioral health visits during the first 4 months of 2021, compared to the first 4 months of 2020.”
 

COVID’s impact

Other problems that have been “skyrocketing” in youth are self-harm, substance use, and eating disorders. Younger children are experiencing an increase in behavioral problems, including developmental regression, such as tantrums, and problems with sleeping, toileting, and eating, Dr. Glover noted.

The youth mental health crisis has mushroomed, although social distancing requirements are now beginning to ease and we are in the “home stretch of the pandemic,” Dr. Brumbaugh said.

One possible reason “is that we took kids out of their normal routines, social circles, friendships, etc., for 12 months, and that was the limit of their physiological or mental resistance, and they got to the end of their rope,” he speculated.

Dr. Glover said, “Kids are burned out, and although they’re asking to return to their life, they don’t feel they have the resources. They feel so behind; they don’t know how to catch up.”

Dr. Brumbaugh said that there are not enough child psychiatrists to provide outpatient services or enough inpatient beds for children in crisis.

“This is an unacceptable situation. We would never allow a child with leukemia or appendicitis to go several weeks without treatment,” he said.

Community donors have come forward, enabling an anticipated 50% increase in Children’s Hospital’s mental health outpatient, inpatient, and day services by March 2022.

“On a hospital level, we are continuing to do things to expand access to care, like opening units that provide different levels of care for patients with psychiatric problems, as well as expanding into areas that are more rural,” Dr. Glover said.

However, the “blueprint is not in action yet, and a lot of money still needs to be allocated. A workforce has to be created, because there are not enough clinicians to fill these roles,” she added.
 

Chronic underfunding

Dr. Brumbaugh said Colorado has always had a “relatively underfunded behavioral health system for kids.” A 2021 report by Mental Health America ranks Colorado among the lowest states in the country in terms of overall pediatric behavioral health funding.

However, Dr. Glover noted that Colorado is “not exceptional.” The increased vulnerability to youth mental illness and suicide is characteristic of other mountain states, which have larger rural areas, less access to care, and increased access to guns, she said.

Mass shootings may have amped up stress levels. “For some kids, this is happening in their schools or towns, and they feel traumatized and unsafe,” Dr. Glover added.

Dr. Crawford, who is an assistant professor of psychiatry at Boston University, also pointed out that the mental health crisis in youth is not unique to Colorado.

“Throughout the country, we’ve seen these colliding pandemics – inadequate mental health resources for children and COVID-19, which exacerbated the existing mental health crisis,” she said.

“The pandemic led to an increase in telehealth services, making individual and group psychotherapy available to kids in areas that never had access to these before, which is a ‘silver lining’ of the pandemic,” Dr. Glover said.

Dr. Crawford is “encouraged that we are having more conversations about pediatric mental health, because the pandemic amplified what was already going on and made it impossible to ignore.”
 

Screening is essential

Screening for mental health problems should be at the top of the mind of pediatricians and other clinicians who work with children, Dr. Glover said.

“Pediatricians are in the best place to catch potentially suicidal kids, because they are more likely to see these kids than therapists,” she noted.

She suggested using a rapid screen for depression, such as the Patient Health Questionnaire-9 (PHQ-9) modified for adolescents. Parents can also fill out a PHQ-9 for younger children and even for themselves.

“Depression, anxiety, and suicidality affect the whole family, so screening for these conditions in adults will benefit the children too,” she said. Teachers should also “be aware of what depression and anxiety symptoms look like in kids, because sometimes they can manifest more as irritability,” Dr. Glover added.

Policymakers and insurers need to prioritize pediatric mental health when determining allocation of health care, said Dr. Crawford.

“Financial incentives should be provided for hospitals to want to reserve beds for psychiatric patients, and in the outpatient setting, we also need to look at the payment structure of psychiatric visits,” she added.

Many psychiatrists do not want to accept insurance because of the increased bureaucracy and low reimbursement rates of insurance companies, and families cannot afford to pay out of pocket, “so we really need to look at the insurance issue at a policy level,” Dr. Crawford said.

Dr. Brumbaugh, Dr. Glover, and Dr. Crawford have disclosed no relevant financial relationships.

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

Communication and relationships cannot be taken for granted, particularly in the physician-patient relationship, where life-altering diagnoses may be given. With one diagnosis, someone’s life may be changed, and both physicians and patients need to be cognizant of the importance of a strong relationship and clear communication.

In the current US health care system, both physicians and patients often are not getting their needs met, and studies that include factors of race, ethnicity, and socioeconomic status suggest that physician-patient relationship barriers contribute to racial disparities in health care.^1,2 Although patient-centered care is a widely recognized and upheld model, relationship-centered care between physician and patient involves focusing on the patient and the physician-patient relationship through recognizing personhood, affect (being empathic), and reciprocal influence.^3,4 Although it is not necessarily intuitive because it can appear to be yet another task for busy physicians, relationship-centered care improves health care delivery for both physicians and patients through decreased physician burnout, reduced medical errors, and better patient outcomes and satisfaction.^5,6

Every physician, patient, and physician-patient relationship is different; unlike the standard questions directed at a routine patient history focused on gathering data, there is no one-size-fits-all relationship-centered conversation.^7-10 As with any successful interaction between 2 people, there is a certain amount of necessary self-awareness (Table 1)¹¹ that allows for improvisation and appropriate responsiveness to what is seen, heard, and felt. Rather than attending solely to disease states, the focus of relationship-centered care is on patients, interpersonal interaction, and promoting health and well-being.¹⁵

This review summarizes the existing literature on relationship-centered care, introduces the use of metacognition (Table 1), and suggests creating simple habits to promote such care. The following databases were searched from inception through November 23, 2020, using the term relationship-centered care: MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), Scopus, Web of Science Core Collection, CINAHL Complete (EBSCO), Academic Search Premier (EBSCOhost), and ERIC (ProQuest). A total of 1772 records were retrieved through searches, and after deduplication of 1116 studies, 350 records were screened through a 2-part process. Articles were first screened by title and abstract for relevance to the relationship between physician and patient, with 185 studies deemed irrelevant (eg, pertaining to the relationship of veterinarian to animal). The remaining 165 studies were assessed for eligibility, with 69 further studies excluded for various reasons. The screening process resulted in 96 articles considered in this review.

Definitions/key terms, as used in this article, are listed in Table 1.

Background of Relationship-Centered Care

Given time constraints, the diagnosis and treatment of medical problems often are the focus of physicians. Although proper medical diagnosis and treatment are important, and their delivery is made possible by the physician having the appropriate knowledge, a physician-patient relationship that focuses solely on disease without acknowledging the patient creates a system that ultimately neglects both patients and physicians.¹⁵ This prevailing physician-patient relationship paradigm is suboptimal, and a proposed remedy is relationship-centered care, which focuses on relationships among the human beings in health care interactions.³ Relationship-centered care has 4 principles: (1) the personhood of each party must be recognized, (2) emotion is part of relationships, (3) relationships are reciprocal and not just one way, and (4) creating these types of relationships is morally valuable³ and beneficial to patient care.¹⁶

Assessment of the Need for Relationship-Centered Care

Relationship-centered care has been studied in physician-patient interactions in various health care settings.^17-23 For at least 2 decades, relationship-centered care has been set forth as a model,^4,24,25 but there are challenges. Physicians tend to overrate or underrate their communication skills in patient interactions.^26,27 A given physician’s preferences often still seem to supersede those of the patient.^3,28,29 The impetus to develop relationship-centered care skills generally needs to be internally driven,^4,30 as, ultimately, physicians and patients have varying needs.^4,31 However, providing physicians with a potential structure is helpful.³²

A Solution: Metacognition in the Physician-Patient Interaction

Metacognition is important to integrating basic science knowledge into medical learning and practice,^33,34 and it is no less important in translating interpersonal knowledge to the physician-patient interaction. Decreased metacognitive effort³⁵ may underpin the decline in empathy seen with increasing medical training.^36,37 Understanding how metacognitive practices foster relationship-centered care is important for teaching, developing, and maintaining that care.

Metacognition is already embedded in the fabric of the physician-patient interaction.^33,34 The complex interplay of the physician-patient interview, patient examination, and integration of physical as well as ancillary data requires higher-order thinking and the ability to parse out that thinking successfully. As a concrete example, coming to a diagnosis requires thinking about what has been presented during the physician-patient interaction and considering what supports and suggests the disease while a list of potential differential diagnosis alternatives is being generated. Physicians are trained to apply this clinical reasoning approach to their patient care.

Conversely, although communication skills are a key component of doctoring,³⁸ both between physician and patient as well as among other colleagues and staff, many physicians have never received formal training in communication skills,^26,32,39 though it is now an integral part of medical school curricula.⁴⁰ When such training is mandatory, less than 1% of physicians continue to believe that there was no benefit, even from a single 8-hour communications skills training session.⁴¹ Communication cannot be taught comprehensively in 8 hours; thus, the benefit of such training may be the end result of metacognition and increased self-awareness (Table 1).^42,43

Building Relationship-Centered Care Through Metacognitive Attention

Metacognition as manifested by such self-awareness can build relationship-centered care.⁴ Self-awareness can be taught through mentorship or role models.⁴⁴ Journaling,⁴⁰ meditation, and appreciation of beauty and the arts⁴⁵ can contribute, as well as more formal training programs,^32,38,42 as offered by the Academy of Communication in Healthcare. Creating opportunities for patient empowerment also supports relationship-centered care, as does applying knowledge of implicit bias.⁴⁶

Even without formal training, relationship-centered care can be built through attention to cues⁹—visual (eg, sitting down, other body language),^47,48 auditory (eg, knocking, language, tone, conversational flow),^48,49 and emotional (eg, clinical empathy, emotional intelligence)(Table 2). Such attention is familiar to everyone, not just physicians or patients, through interactions outside of health care; inattention may be due to the hidden curriculum or culture of medicine⁴⁰ as well as real-time changes, such as the introduction of the electronic health record.⁵¹ Inattention to these cues also may be a result of context-specific knowledge, in which a physician’s real-life communication skills are not applied to the unique context of patient care.

Metacognitive Attention Can Generate Habit

Taking metacognition a step further, these small interventions can become habit^11,14,39 through self-awareness, deliberate practice, and feedback.⁴³ Habit is generated by linking a given intervention to another defined cue. For example, placing a hand on a doorknob to enter an examination room can be the cue to generate a habit of entering with presence.¹⁴ Alternatively, before entering an examination room, taking 3 deep breaths can be the cue to trigger presence.¹⁴ Habits can be created in just 3 weeks,⁵⁷ and other proposed cues to generate habits toward relationship-centered care are listed in Table 2. By creating habit through metacognitive attention, relationship-centered care will become something that happens subconsciously without further burdening physicians with another task. Asking patients for permission to record video of an interaction also can create opportunities for self-awareness and self-evaluation through rewatching the video.⁵⁸

Final Thoughts

Physicians already have the tools to create relationship-centered care in physician-patient interactions. A critical mental shift is to develop habits and apply thinking patterns toward understanding and responding appropriately to patients of all ethnicities and their emotions in the physician-patient interaction. This shift is aided by metacognitive awareness (Table 1) and the development of useful habits (Table 2).

Communication and relationships cannot be taken for granted, particularly in the physician-patient relationship, where life-altering diagnoses may be given. With one diagnosis, someone’s life may be changed, and both physicians and patients need to be cognizant of the importance of a strong relationship and clear communication.

In the current US health care system, both physicians and patients often are not getting their needs met, and studies that include factors of race, ethnicity, and socioeconomic status suggest that physician-patient relationship barriers contribute to racial disparities in health care.^1,2 Although patient-centered care is a widely recognized and upheld model, relationship-centered care between physician and patient involves focusing on the patient and the physician-patient relationship through recognizing personhood, affect (being empathic), and reciprocal influence.^3,4 Although it is not necessarily intuitive because it can appear to be yet another task for busy physicians, relationship-centered care improves health care delivery for both physicians and patients through decreased physician burnout, reduced medical errors, and better patient outcomes and satisfaction.^5,6

Every physician, patient, and physician-patient relationship is different; unlike the standard questions directed at a routine patient history focused on gathering data, there is no one-size-fits-all relationship-centered conversation.^7-10 As with any successful interaction between 2 people, there is a certain amount of necessary self-awareness (Table 1)¹¹ that allows for improvisation and appropriate responsiveness to what is seen, heard, and felt. Rather than attending solely to disease states, the focus of relationship-centered care is on patients, interpersonal interaction, and promoting health and well-being.¹⁵

This review summarizes the existing literature on relationship-centered care, introduces the use of metacognition (Table 1), and suggests creating simple habits to promote such care. The following databases were searched from inception through November 23, 2020, using the term relationship-centered care: MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), Scopus, Web of Science Core Collection, CINAHL Complete (EBSCO), Academic Search Premier (EBSCOhost), and ERIC (ProQuest). A total of 1772 records were retrieved through searches, and after deduplication of 1116 studies, 350 records were screened through a 2-part process. Articles were first screened by title and abstract for relevance to the relationship between physician and patient, with 185 studies deemed irrelevant (eg, pertaining to the relationship of veterinarian to animal). The remaining 165 studies were assessed for eligibility, with 69 further studies excluded for various reasons. The screening process resulted in 96 articles considered in this review.

Definitions/key terms, as used in this article, are listed in Table 1.

Background of Relationship-Centered Care

Given time constraints, the diagnosis and treatment of medical problems often are the focus of physicians. Although proper medical diagnosis and treatment are important, and their delivery is made possible by the physician having the appropriate knowledge, a physician-patient relationship that focuses solely on disease without acknowledging the patient creates a system that ultimately neglects both patients and physicians.¹⁵ This prevailing physician-patient relationship paradigm is suboptimal, and a proposed remedy is relationship-centered care, which focuses on relationships among the human beings in health care interactions.³ Relationship-centered care has 4 principles: (1) the personhood of each party must be recognized, (2) emotion is part of relationships, (3) relationships are reciprocal and not just one way, and (4) creating these types of relationships is morally valuable³ and beneficial to patient care.¹⁶

Assessment of the Need for Relationship-Centered Care

Relationship-centered care has been studied in physician-patient interactions in various health care settings.^17-23 For at least 2 decades, relationship-centered care has been set forth as a model,^4,24,25 but there are challenges. Physicians tend to overrate or underrate their communication skills in patient interactions.^26,27 A given physician’s preferences often still seem to supersede those of the patient.^3,28,29 The impetus to develop relationship-centered care skills generally needs to be internally driven,^4,30 as, ultimately, physicians and patients have varying needs.^4,31 However, providing physicians with a potential structure is helpful.³²

A Solution: Metacognition in the Physician-Patient Interaction

Metacognition is important to integrating basic science knowledge into medical learning and practice,^33,34 and it is no less important in translating interpersonal knowledge to the physician-patient interaction. Decreased metacognitive effort³⁵ may underpin the decline in empathy seen with increasing medical training.^36,37 Understanding how metacognitive practices foster relationship-centered care is important for teaching, developing, and maintaining that care.

Metacognition is already embedded in the fabric of the physician-patient interaction.^33,34 The complex interplay of the physician-patient interview, patient examination, and integration of physical as well as ancillary data requires higher-order thinking and the ability to parse out that thinking successfully. As a concrete example, coming to a diagnosis requires thinking about what has been presented during the physician-patient interaction and considering what supports and suggests the disease while a list of potential differential diagnosis alternatives is being generated. Physicians are trained to apply this clinical reasoning approach to their patient care.

Conversely, although communication skills are a key component of doctoring,³⁸ both between physician and patient as well as among other colleagues and staff, many physicians have never received formal training in communication skills,^26,32,39 though it is now an integral part of medical school curricula.⁴⁰ When such training is mandatory, less than 1% of physicians continue to believe that there was no benefit, even from a single 8-hour communications skills training session.⁴¹ Communication cannot be taught comprehensively in 8 hours; thus, the benefit of such training may be the end result of metacognition and increased self-awareness (Table 1).^42,43

Building Relationship-Centered Care Through Metacognitive Attention

Metacognition as manifested by such self-awareness can build relationship-centered care.⁴ Self-awareness can be taught through mentorship or role models.⁴⁴ Journaling,⁴⁰ meditation, and appreciation of beauty and the arts⁴⁵ can contribute, as well as more formal training programs,^32,38,42 as offered by the Academy of Communication in Healthcare. Creating opportunities for patient empowerment also supports relationship-centered care, as does applying knowledge of implicit bias.⁴⁶

Even without formal training, relationship-centered care can be built through attention to cues⁹—visual (eg, sitting down, other body language),^47,48 auditory (eg, knocking, language, tone, conversational flow),^48,49 and emotional (eg, clinical empathy, emotional intelligence)(Table 2). Such attention is familiar to everyone, not just physicians or patients, through interactions outside of health care; inattention may be due to the hidden curriculum or culture of medicine⁴⁰ as well as real-time changes, such as the introduction of the electronic health record.⁵¹ Inattention to these cues also may be a result of context-specific knowledge, in which a physician’s real-life communication skills are not applied to the unique context of patient care.

Metacognitive Attention Can Generate Habit

Taking metacognition a step further, these small interventions can become habit^11,14,39 through self-awareness, deliberate practice, and feedback.⁴³ Habit is generated by linking a given intervention to another defined cue. For example, placing a hand on a doorknob to enter an examination room can be the cue to generate a habit of entering with presence.¹⁴ Alternatively, before entering an examination room, taking 3 deep breaths can be the cue to trigger presence.¹⁴ Habits can be created in just 3 weeks,⁵⁷ and other proposed cues to generate habits toward relationship-centered care are listed in Table 2. By creating habit through metacognitive attention, relationship-centered care will become something that happens subconsciously without further burdening physicians with another task. Asking patients for permission to record video of an interaction also can create opportunities for self-awareness and self-evaluation through rewatching the video.⁵⁸

Final Thoughts

Physicians already have the tools to create relationship-centered care in physician-patient interactions. A critical mental shift is to develop habits and apply thinking patterns toward understanding and responding appropriately to patients of all ethnicities and their emotions in the physician-patient interaction. This shift is aided by metacognitive awareness (Table 1) and the development of useful habits (Table 2).

Communication and relationships cannot be taken for granted, particularly in the physician-patient relationship, where life-altering diagnoses may be given. With one diagnosis, someone’s life may be changed, and both physicians and patients need to be cognizant of the importance of a strong relationship and clear communication.

In the current US health care system, both physicians and patients often are not getting their needs met, and studies that include factors of race, ethnicity, and socioeconomic status suggest that physician-patient relationship barriers contribute to racial disparities in health care.^1,2 Although patient-centered care is a widely recognized and upheld model, relationship-centered care between physician and patient involves focusing on the patient and the physician-patient relationship through recognizing personhood, affect (being empathic), and reciprocal influence.^3,4 Although it is not necessarily intuitive because it can appear to be yet another task for busy physicians, relationship-centered care improves health care delivery for both physicians and patients through decreased physician burnout, reduced medical errors, and better patient outcomes and satisfaction.^5,6

Every physician, patient, and physician-patient relationship is different; unlike the standard questions directed at a routine patient history focused on gathering data, there is no one-size-fits-all relationship-centered conversation.^7-10 As with any successful interaction between 2 people, there is a certain amount of necessary self-awareness (Table 1)¹¹ that allows for improvisation and appropriate responsiveness to what is seen, heard, and felt. Rather than attending solely to disease states, the focus of relationship-centered care is on patients, interpersonal interaction, and promoting health and well-being.¹⁵

This review summarizes the existing literature on relationship-centered care, introduces the use of metacognition (Table 1), and suggests creating simple habits to promote such care. The following databases were searched from inception through November 23, 2020, using the term relationship-centered care: MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), Scopus, Web of Science Core Collection, CINAHL Complete (EBSCO), Academic Search Premier (EBSCOhost), and ERIC (ProQuest). A total of 1772 records were retrieved through searches, and after deduplication of 1116 studies, 350 records were screened through a 2-part process. Articles were first screened by title and abstract for relevance to the relationship between physician and patient, with 185 studies deemed irrelevant (eg, pertaining to the relationship of veterinarian to animal). The remaining 165 studies were assessed for eligibility, with 69 further studies excluded for various reasons. The screening process resulted in 96 articles considered in this review.

Definitions/key terms, as used in this article, are listed in Table 1.

Background of Relationship-Centered Care

Given time constraints, the diagnosis and treatment of medical problems often are the focus of physicians. Although proper medical diagnosis and treatment are important, and their delivery is made possible by the physician having the appropriate knowledge, a physician-patient relationship that focuses solely on disease without acknowledging the patient creates a system that ultimately neglects both patients and physicians.¹⁵ This prevailing physician-patient relationship paradigm is suboptimal, and a proposed remedy is relationship-centered care, which focuses on relationships among the human beings in health care interactions.³ Relationship-centered care has 4 principles: (1) the personhood of each party must be recognized, (2) emotion is part of relationships, (3) relationships are reciprocal and not just one way, and (4) creating these types of relationships is morally valuable³ and beneficial to patient care.¹⁶

Assessment of the Need for Relationship-Centered Care

Relationship-centered care has been studied in physician-patient interactions in various health care settings.^17-23 For at least 2 decades, relationship-centered care has been set forth as a model,^4,24,25 but there are challenges. Physicians tend to overrate or underrate their communication skills in patient interactions.^26,27 A given physician’s preferences often still seem to supersede those of the patient.^3,28,29 The impetus to develop relationship-centered care skills generally needs to be internally driven,^4,30 as, ultimately, physicians and patients have varying needs.^4,31 However, providing physicians with a potential structure is helpful.³²

A Solution: Metacognition in the Physician-Patient Interaction

Metacognition is important to integrating basic science knowledge into medical learning and practice,^33,34 and it is no less important in translating interpersonal knowledge to the physician-patient interaction. Decreased metacognitive effort³⁵ may underpin the decline in empathy seen with increasing medical training.^36,37 Understanding how metacognitive practices foster relationship-centered care is important for teaching, developing, and maintaining that care.

Metacognition is already embedded in the fabric of the physician-patient interaction.^33,34 The complex interplay of the physician-patient interview, patient examination, and integration of physical as well as ancillary data requires higher-order thinking and the ability to parse out that thinking successfully. As a concrete example, coming to a diagnosis requires thinking about what has been presented during the physician-patient interaction and considering what supports and suggests the disease while a list of potential differential diagnosis alternatives is being generated. Physicians are trained to apply this clinical reasoning approach to their patient care.

Conversely, although communication skills are a key component of doctoring,³⁸ both between physician and patient as well as among other colleagues and staff, many physicians have never received formal training in communication skills,^26,32,39 though it is now an integral part of medical school curricula.⁴⁰ When such training is mandatory, less than 1% of physicians continue to believe that there was no benefit, even from a single 8-hour communications skills training session.⁴¹ Communication cannot be taught comprehensively in 8 hours; thus, the benefit of such training may be the end result of metacognition and increased self-awareness (Table 1).^42,43

Building Relationship-Centered Care Through Metacognitive Attention

Metacognition as manifested by such self-awareness can build relationship-centered care.⁴ Self-awareness can be taught through mentorship or role models.⁴⁴ Journaling,⁴⁰ meditation, and appreciation of beauty and the arts⁴⁵ can contribute, as well as more formal training programs,^32,38,42 as offered by the Academy of Communication in Healthcare. Creating opportunities for patient empowerment also supports relationship-centered care, as does applying knowledge of implicit bias.⁴⁶

Even without formal training, relationship-centered care can be built through attention to cues⁹—visual (eg, sitting down, other body language),^47,48 auditory (eg, knocking, language, tone, conversational flow),^48,49 and emotional (eg, clinical empathy, emotional intelligence)(Table 2). Such attention is familiar to everyone, not just physicians or patients, through interactions outside of health care; inattention may be due to the hidden curriculum or culture of medicine⁴⁰ as well as real-time changes, such as the introduction of the electronic health record.⁵¹ Inattention to these cues also may be a result of context-specific knowledge, in which a physician’s real-life communication skills are not applied to the unique context of patient care.

Metacognitive Attention Can Generate Habit

Taking metacognition a step further, these small interventions can become habit^11,14,39 through self-awareness, deliberate practice, and feedback.⁴³ Habit is generated by linking a given intervention to another defined cue. For example, placing a hand on a doorknob to enter an examination room can be the cue to generate a habit of entering with presence.¹⁴ Alternatively, before entering an examination room, taking 3 deep breaths can be the cue to trigger presence.¹⁴ Habits can be created in just 3 weeks,⁵⁷ and other proposed cues to generate habits toward relationship-centered care are listed in Table 2. By creating habit through metacognitive attention, relationship-centered care will become something that happens subconsciously without further burdening physicians with another task. Asking patients for permission to record video of an interaction also can create opportunities for self-awareness and self-evaluation through rewatching the video.⁵⁸

Final Thoughts

Physicians already have the tools to create relationship-centered care in physician-patient interactions. A critical mental shift is to develop habits and apply thinking patterns toward understanding and responding appropriately to patients of all ethnicities and their emotions in the physician-patient interaction. This shift is aided by metacognitive awareness (Table 1) and the development of useful habits (Table 2).

Background: Current U.S. guidelines recommend colonoscopy within 24 hours for patients presenting with high-risk or severe acute lower gastrointestinal bleeding. However, prior meta-analyses of the timing of colonoscopy relied primarily on observational studies, and a recent multicenter randomized, controlled trial suggests no substantial benefit for early colonoscopy.

Synopsis: The authors identified four randomized, controlled trials that compared early colonoscopy (defined as within 24 hours) with elective colonoscopy (defined as beyond 24 hours) and/or other diagnostic tests for patients presenting with acute lower GI bleeding. They performed a meta-analysis, including 463 patients, which showed no significant difference in risk of persistent or recurrent bleeding for early versus elective colonoscopy. The authors also found no significant differences in secondary outcomes of mortality, endoscopic intervention, primary hemostatic intervention, or identification of bleeding source. Limitations of this research include the relatively small number of studies included, and potential for selection bias in the original studies. Notably two of the four studies included were prematurely terminated before their planned sample sizes were reached.

Bottom line: In patients hospitalized with acute lower GI bleeding, colonoscopy within 24 hours may not reduce further bleeding or mortality when compared with elective colonoscopy.

Citation: Tsay C et al. Early colonoscopy does not improve outcomes of patients with lower gastrointestinal bleeding: Systematic review of randomized trials. Clin Gastroenterol Hepatol. 2019 Dec 13. doi: 10.1016/j.cgh.2019.11.061.

Dr. Hu is a hospitalist at Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, both in Boston.

Background: Current U.S. guidelines recommend colonoscopy within 24 hours for patients presenting with high-risk or severe acute lower gastrointestinal bleeding. However, prior meta-analyses of the timing of colonoscopy relied primarily on observational studies, and a recent multicenter randomized, controlled trial suggests no substantial benefit for early colonoscopy.

Synopsis: The authors identified four randomized, controlled trials that compared early colonoscopy (defined as within 24 hours) with elective colonoscopy (defined as beyond 24 hours) and/or other diagnostic tests for patients presenting with acute lower GI bleeding. They performed a meta-analysis, including 463 patients, which showed no significant difference in risk of persistent or recurrent bleeding for early versus elective colonoscopy. The authors also found no significant differences in secondary outcomes of mortality, endoscopic intervention, primary hemostatic intervention, or identification of bleeding source. Limitations of this research include the relatively small number of studies included, and potential for selection bias in the original studies. Notably two of the four studies included were prematurely terminated before their planned sample sizes were reached.

Bottom line: In patients hospitalized with acute lower GI bleeding, colonoscopy within 24 hours may not reduce further bleeding or mortality when compared with elective colonoscopy.

Citation: Tsay C et al. Early colonoscopy does not improve outcomes of patients with lower gastrointestinal bleeding: Systematic review of randomized trials. Clin Gastroenterol Hepatol. 2019 Dec 13. doi: 10.1016/j.cgh.2019.11.061.

Dr. Hu is a hospitalist at Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, both in Boston.

Background: Current U.S. guidelines recommend colonoscopy within 24 hours for patients presenting with high-risk or severe acute lower gastrointestinal bleeding. However, prior meta-analyses of the timing of colonoscopy relied primarily on observational studies, and a recent multicenter randomized, controlled trial suggests no substantial benefit for early colonoscopy.

Synopsis: The authors identified four randomized, controlled trials that compared early colonoscopy (defined as within 24 hours) with elective colonoscopy (defined as beyond 24 hours) and/or other diagnostic tests for patients presenting with acute lower GI bleeding. They performed a meta-analysis, including 463 patients, which showed no significant difference in risk of persistent or recurrent bleeding for early versus elective colonoscopy. The authors also found no significant differences in secondary outcomes of mortality, endoscopic intervention, primary hemostatic intervention, or identification of bleeding source. Limitations of this research include the relatively small number of studies included, and potential for selection bias in the original studies. Notably two of the four studies included were prematurely terminated before their planned sample sizes were reached.

Bottom line: In patients hospitalized with acute lower GI bleeding, colonoscopy within 24 hours may not reduce further bleeding or mortality when compared with elective colonoscopy.

Citation: Tsay C et al. Early colonoscopy does not improve outcomes of patients with lower gastrointestinal bleeding: Systematic review of randomized trials. Clin Gastroenterol Hepatol. 2019 Dec 13. doi: 10.1016/j.cgh.2019.11.061.

Dr. Hu is a hospitalist at Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, both in Boston.