The gender gap in gastroenterology persists – currently, women constitute 39% of fellows, but only 22% of senior AGA members and less than 18% of all practicing gastroenterologists – and it has gained even greater significance within the “current historical moment” of the COVID pandemic and growing cognizance of systemic sexism and racism, according to experts.

During the pandemic, women have been more likely to stay home to care for ill family members and children affected by school closures, which increases their already disproportionate share of unpaid work, wrote Jessica Bernica, MD, of Baylor College of Medicine in Houston with her associates in Techniques and Innovations in Gastrointestinal Endoscopy. They noted that, according to one study, this “holds true for female physicians, who despite their more privileged positions, also experience higher demands at home, impacting their ability to contribute to teaching, service, and research.”

At the same time, the pandemic has brought into focus which jobs are “truly essential” – and that they are “overwhelmingly [held] by women and people of color, who are often underpaid and undervalued,” the experts wrote. The growing focus on systemic racism has also increased awareness of the chronic gender discrimination faced by female minorities, as well as by women in general, they added. In the field of gastroenterology, inherent gender bias – both systemic and self-directed – can bar women from advancing beginning as early as medical school.

To help address these issues, the experts outlined key opportunities for change as women navigate professional “forks in the road” throughout their careers.
 

Throughout their careers

During medical school and residency, women can specifically request gastroenterology rotations (“ideally with both inpatient and outpatient exposure”), attend society conferences, participate in research themselves, and join a research track or serve as chief medical resident. When applying for gastroenterology fellowships, they can prioritize programs with female faculty, which were recently found to be more likely to hire female fellows.

During fellowship, women can avail themselves of female mentors, who can help them strategize about ways to address gender bias, connect with GI groups and societies, and learn endoscopy techniques, including “unique approaches ... [that] overcome the challenges of standard scope sizes and accessibility.” At the institutional level, opportunities to affect positive changes for women trainees include “formal education on the benefits of hands-on learning and encouraging explicit and open communication between parties regarding invitation to, comfort with, and type of physical contact prior to a case.”

After fellowship, early-career gastroenterologists should scrutinize contracts for details on pay and research support, and they should ideally join a practice that either already has many women physicians on staff, or that ensures salary transparency and has “parental leave policies that are compatible with [applicants’] personal and professional goals.” But the experts advocated caution about part-time positions, which may purport to offer more flexibility but turn into full-time work for part-time pay and can preclude participation in practice management.

The experts recommended midcareer female gastroenterologists call out their own achievements rather than waiting for recognition, “actively seek promotion and tenure,” negotiate their salaries (as men tend to do routinely), and think twice before accepting professional roles that are uncompensated or do not clearly promote career advancement.

Senior gastroenterologists have unique opportunities to spearhead changes in institutional policies and practices, according to the experts. Specific examples include “explicitly stating [in job listings] that salary is negotiable, creating transparent written compensation plans, and conducting audits of job offers” to help mitigate any inequities in pay or hiring practices. In addition, senior women gastroenterologists can mentor individual women in the field, implement formal trainings on implicit bias, ensure that their practice or department tracks the gender of gastroenterologists who join, leave, or are promoted.

The experts did not report receiving funding for the work. They reported having no conflicts of interest.

The gender gap in gastroenterology persists – currently, women constitute 39% of fellows, but only 22% of senior AGA members and less than 18% of all practicing gastroenterologists – and it has gained even greater significance within the “current historical moment” of the COVID pandemic and growing cognizance of systemic sexism and racism, according to experts.

During the pandemic, women have been more likely to stay home to care for ill family members and children affected by school closures, which increases their already disproportionate share of unpaid work, wrote Jessica Bernica, MD, of Baylor College of Medicine in Houston with her associates in Techniques and Innovations in Gastrointestinal Endoscopy. They noted that, according to one study, this “holds true for female physicians, who despite their more privileged positions, also experience higher demands at home, impacting their ability to contribute to teaching, service, and research.”

At the same time, the pandemic has brought into focus which jobs are “truly essential” – and that they are “overwhelmingly [held] by women and people of color, who are often underpaid and undervalued,” the experts wrote. The growing focus on systemic racism has also increased awareness of the chronic gender discrimination faced by female minorities, as well as by women in general, they added. In the field of gastroenterology, inherent gender bias – both systemic and self-directed – can bar women from advancing beginning as early as medical school.

To help address these issues, the experts outlined key opportunities for change as women navigate professional “forks in the road” throughout their careers.
 

Throughout their careers

During medical school and residency, women can specifically request gastroenterology rotations (“ideally with both inpatient and outpatient exposure”), attend society conferences, participate in research themselves, and join a research track or serve as chief medical resident. When applying for gastroenterology fellowships, they can prioritize programs with female faculty, which were recently found to be more likely to hire female fellows.

During fellowship, women can avail themselves of female mentors, who can help them strategize about ways to address gender bias, connect with GI groups and societies, and learn endoscopy techniques, including “unique approaches ... [that] overcome the challenges of standard scope sizes and accessibility.” At the institutional level, opportunities to affect positive changes for women trainees include “formal education on the benefits of hands-on learning and encouraging explicit and open communication between parties regarding invitation to, comfort with, and type of physical contact prior to a case.”

After fellowship, early-career gastroenterologists should scrutinize contracts for details on pay and research support, and they should ideally join a practice that either already has many women physicians on staff, or that ensures salary transparency and has “parental leave policies that are compatible with [applicants’] personal and professional goals.” But the experts advocated caution about part-time positions, which may purport to offer more flexibility but turn into full-time work for part-time pay and can preclude participation in practice management.

The experts recommended midcareer female gastroenterologists call out their own achievements rather than waiting for recognition, “actively seek promotion and tenure,” negotiate their salaries (as men tend to do routinely), and think twice before accepting professional roles that are uncompensated or do not clearly promote career advancement.

Senior gastroenterologists have unique opportunities to spearhead changes in institutional policies and practices, according to the experts. Specific examples include “explicitly stating [in job listings] that salary is negotiable, creating transparent written compensation plans, and conducting audits of job offers” to help mitigate any inequities in pay or hiring practices. In addition, senior women gastroenterologists can mentor individual women in the field, implement formal trainings on implicit bias, ensure that their practice or department tracks the gender of gastroenterologists who join, leave, or are promoted.

The experts did not report receiving funding for the work. They reported having no conflicts of interest.

The gender gap in gastroenterology persists – currently, women constitute 39% of fellows, but only 22% of senior AGA members and less than 18% of all practicing gastroenterologists – and it has gained even greater significance within the “current historical moment” of the COVID pandemic and growing cognizance of systemic sexism and racism, according to experts.

During the pandemic, women have been more likely to stay home to care for ill family members and children affected by school closures, which increases their already disproportionate share of unpaid work, wrote Jessica Bernica, MD, of Baylor College of Medicine in Houston with her associates in Techniques and Innovations in Gastrointestinal Endoscopy. They noted that, according to one study, this “holds true for female physicians, who despite their more privileged positions, also experience higher demands at home, impacting their ability to contribute to teaching, service, and research.”

At the same time, the pandemic has brought into focus which jobs are “truly essential” – and that they are “overwhelmingly [held] by women and people of color, who are often underpaid and undervalued,” the experts wrote. The growing focus on systemic racism has also increased awareness of the chronic gender discrimination faced by female minorities, as well as by women in general, they added. In the field of gastroenterology, inherent gender bias – both systemic and self-directed – can bar women from advancing beginning as early as medical school.

To help address these issues, the experts outlined key opportunities for change as women navigate professional “forks in the road” throughout their careers.
 

Throughout their careers

During medical school and residency, women can specifically request gastroenterology rotations (“ideally with both inpatient and outpatient exposure”), attend society conferences, participate in research themselves, and join a research track or serve as chief medical resident. When applying for gastroenterology fellowships, they can prioritize programs with female faculty, which were recently found to be more likely to hire female fellows.

During fellowship, women can avail themselves of female mentors, who can help them strategize about ways to address gender bias, connect with GI groups and societies, and learn endoscopy techniques, including “unique approaches ... [that] overcome the challenges of standard scope sizes and accessibility.” At the institutional level, opportunities to affect positive changes for women trainees include “formal education on the benefits of hands-on learning and encouraging explicit and open communication between parties regarding invitation to, comfort with, and type of physical contact prior to a case.”

After fellowship, early-career gastroenterologists should scrutinize contracts for details on pay and research support, and they should ideally join a practice that either already has many women physicians on staff, or that ensures salary transparency and has “parental leave policies that are compatible with [applicants’] personal and professional goals.” But the experts advocated caution about part-time positions, which may purport to offer more flexibility but turn into full-time work for part-time pay and can preclude participation in practice management.

The experts recommended midcareer female gastroenterologists call out their own achievements rather than waiting for recognition, “actively seek promotion and tenure,” negotiate their salaries (as men tend to do routinely), and think twice before accepting professional roles that are uncompensated or do not clearly promote career advancement.

Senior gastroenterologists have unique opportunities to spearhead changes in institutional policies and practices, according to the experts. Specific examples include “explicitly stating [in job listings] that salary is negotiable, creating transparent written compensation plans, and conducting audits of job offers” to help mitigate any inequities in pay or hiring practices. In addition, senior women gastroenterologists can mentor individual women in the field, implement formal trainings on implicit bias, ensure that their practice or department tracks the gender of gastroenterologists who join, leave, or are promoted.

The experts did not report receiving funding for the work. They reported having no conflicts of interest.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

Using low-dose computed tomography (LDCT) to screen for aortic valve calcification during a lung cancer screening could identify those at risk for aortic stenosis, says new research published in Annals of Internal Medicine.

Aortic stenosis is one of the most common valve disease problems and is characterized by the narrowing of the aortic valve opening, according to the American Heart Association. The condition impedes the delivery of blood from the heart to the body.

Researchers found that LDCT, which according to the Centers for Disease Control and Prevention is the only recommended screening test for lung cancer, also can be used to identify aortic valve calcification – a condition in which calcium deposits form on the aortic valve, narrowing it.

Since cardiovascular events and lung cancer are known to have the same modifiable risk factors, people screened for lung cancer could also be diagnosed with cardiovascular diseases, the authors noted in their paper.

Furthermore, a 2019 study published in the Journal of Thoracic Imaging found that LDCT can be useful for identifying not just lung cancer, but the early stages of chronic obstructive pulmonary disease and coronary artery disease.

“LDCT has been described as useful for identifying the early stages of chronic obstructive pulmonary disease and coronary artery disease, but it can also [screen for] calcified aortic valve [which corresponds] with the risk of severe aortic stenosis,” study author Marcin Fijalkowski, MD, PhD, of the Medical University of Gdansk, said in an interview. “This additional evaluation is not time-consuming and is easy to perform.”
 

Methods and results

For the study, Dr. Fijalkowski and his colleagues examined data from 6,631 people between the ages of 50 and 80 years of age with a smoking history of 30 or more pack-years. The group was enrolled in the MOLTEST BIS lung cancer screening program between 2016 and 2018, which assessed the usefulness of LDCT performed during lung cancer screening in determining the degree of aortic valve calcification as an additional finding. The researchers arbitrarily determined a calcium score of 900 as a cutoff point indicating a positive test result. Positive patients were sent for an echocardiogram for confirmation of diagnosis.

Aortic valve calcification was identified in 869 patients, 13.1% of the group. Sixty-eight participants, which is about 8% of this group, were identified as having a calcium score of 900 at least and were referred for echocardiography to confirm these results. Of this group, 0.5% were diagnosed with at least moderate aortic stenosis after receiving an echocardiogram. About 55% of the participants with this condition were unaware of their valvular heart disease, including 23% with a severe form of the disease.
 

Study identified patients who had not been aware of disease

Dr. Fijalkowski said while he was not surprised by the findings, he was surprised that the study may have saved some of the participants’ lives.

“We were expecting the same degree of calcification of aortic valve and correlation with aortic stenosis severity, but what surprised us was that half of diagnosed patients were not aware of disease,” he said. “This additional finding was lifesaving.”

In the paper, the authors noted that cardiology societies do not yet recognize LDCT as a diagnostic tool for aortic stenosis. Based on their findings, they propose that aortic valve calcification become a routine assessment procedure in the LDCT protocol for lung cancer screening.
 

Findings are ‘important’ but not practice changing

Salim S. Virani, MD, FACC, who was not involved in the study, said this new research is important.

The analyses were done well and push the needle further in a direction that suggests “when we are doing imaging for one reason, we should use the totality of information that we have available,” he noted.

“I mean, if you are looking at a lung nodule, if you see an aortic valve that’s very calcified, then it should prompt you to at least ask the patient about some symptoms related to that,” Dr. Virani explained.

However, he said more research is needed on a larger population before LDCT can be considered a diagnostic tool for aortic stenosis.

“I think we have to understand that this study was done in a very specific group of patients,” said Dr. Virani, professor in the sections of cardiology and cardiovascular research at Baylor College of Medicine, Houston. “If you were to do it in a population that was much younger, with much lower risk of even lung cancer, then the yield of a CT to pick up aortic stenosis would be lower.”

Before any practice changes are made regarding LDCT and the diagnosis of aortic stenosis, there needs to be more research on how many people in the general population are getting non–cardiology-related chest imaging and then come up with a population-based metric as to what calcium score cutoff could be used, he said.

Dr. Fijalkowski said he believes the results of his study will encourage physicians to focus not only on pulmonary nodules but also to look for additional things such as aortic valve calcification.

The experts did not disclose any relevant financial relationships.

Using low-dose computed tomography (LDCT) to screen for aortic valve calcification during a lung cancer screening could identify those at risk for aortic stenosis, says new research published in Annals of Internal Medicine.

Aortic stenosis is one of the most common valve disease problems and is characterized by the narrowing of the aortic valve opening, according to the American Heart Association. The condition impedes the delivery of blood from the heart to the body.

Researchers found that LDCT, which according to the Centers for Disease Control and Prevention is the only recommended screening test for lung cancer, also can be used to identify aortic valve calcification – a condition in which calcium deposits form on the aortic valve, narrowing it.

Since cardiovascular events and lung cancer are known to have the same modifiable risk factors, people screened for lung cancer could also be diagnosed with cardiovascular diseases, the authors noted in their paper.

Furthermore, a 2019 study published in the Journal of Thoracic Imaging found that LDCT can be useful for identifying not just lung cancer, but the early stages of chronic obstructive pulmonary disease and coronary artery disease.

“LDCT has been described as useful for identifying the early stages of chronic obstructive pulmonary disease and coronary artery disease, but it can also [screen for] calcified aortic valve [which corresponds] with the risk of severe aortic stenosis,” study author Marcin Fijalkowski, MD, PhD, of the Medical University of Gdansk, said in an interview. “This additional evaluation is not time-consuming and is easy to perform.”
 

Methods and results

For the study, Dr. Fijalkowski and his colleagues examined data from 6,631 people between the ages of 50 and 80 years of age with a smoking history of 30 or more pack-years. The group was enrolled in the MOLTEST BIS lung cancer screening program between 2016 and 2018, which assessed the usefulness of LDCT performed during lung cancer screening in determining the degree of aortic valve calcification as an additional finding. The researchers arbitrarily determined a calcium score of 900 as a cutoff point indicating a positive test result. Positive patients were sent for an echocardiogram for confirmation of diagnosis.

Aortic valve calcification was identified in 869 patients, 13.1% of the group. Sixty-eight participants, which is about 8% of this group, were identified as having a calcium score of 900 at least and were referred for echocardiography to confirm these results. Of this group, 0.5% were diagnosed with at least moderate aortic stenosis after receiving an echocardiogram. About 55% of the participants with this condition were unaware of their valvular heart disease, including 23% with a severe form of the disease.
 

Study identified patients who had not been aware of disease

Dr. Fijalkowski said while he was not surprised by the findings, he was surprised that the study may have saved some of the participants’ lives.

“We were expecting the same degree of calcification of aortic valve and correlation with aortic stenosis severity, but what surprised us was that half of diagnosed patients were not aware of disease,” he said. “This additional finding was lifesaving.”

In the paper, the authors noted that cardiology societies do not yet recognize LDCT as a diagnostic tool for aortic stenosis. Based on their findings, they propose that aortic valve calcification become a routine assessment procedure in the LDCT protocol for lung cancer screening.
 

Findings are ‘important’ but not practice changing

Salim S. Virani, MD, FACC, who was not involved in the study, said this new research is important.

The analyses were done well and push the needle further in a direction that suggests “when we are doing imaging for one reason, we should use the totality of information that we have available,” he noted.

“I mean, if you are looking at a lung nodule, if you see an aortic valve that’s very calcified, then it should prompt you to at least ask the patient about some symptoms related to that,” Dr. Virani explained.

However, he said more research is needed on a larger population before LDCT can be considered a diagnostic tool for aortic stenosis.

“I think we have to understand that this study was done in a very specific group of patients,” said Dr. Virani, professor in the sections of cardiology and cardiovascular research at Baylor College of Medicine, Houston. “If you were to do it in a population that was much younger, with much lower risk of even lung cancer, then the yield of a CT to pick up aortic stenosis would be lower.”

Before any practice changes are made regarding LDCT and the diagnosis of aortic stenosis, there needs to be more research on how many people in the general population are getting non–cardiology-related chest imaging and then come up with a population-based metric as to what calcium score cutoff could be used, he said.

Dr. Fijalkowski said he believes the results of his study will encourage physicians to focus not only on pulmonary nodules but also to look for additional things such as aortic valve calcification.

The experts did not disclose any relevant financial relationships.

Using low-dose computed tomography (LDCT) to screen for aortic valve calcification during a lung cancer screening could identify those at risk for aortic stenosis, says new research published in Annals of Internal Medicine.

Aortic stenosis is one of the most common valve disease problems and is characterized by the narrowing of the aortic valve opening, according to the American Heart Association. The condition impedes the delivery of blood from the heart to the body.

Researchers found that LDCT, which according to the Centers for Disease Control and Prevention is the only recommended screening test for lung cancer, also can be used to identify aortic valve calcification – a condition in which calcium deposits form on the aortic valve, narrowing it.

Since cardiovascular events and lung cancer are known to have the same modifiable risk factors, people screened for lung cancer could also be diagnosed with cardiovascular diseases, the authors noted in their paper.

Furthermore, a 2019 study published in the Journal of Thoracic Imaging found that LDCT can be useful for identifying not just lung cancer, but the early stages of chronic obstructive pulmonary disease and coronary artery disease.

“LDCT has been described as useful for identifying the early stages of chronic obstructive pulmonary disease and coronary artery disease, but it can also [screen for] calcified aortic valve [which corresponds] with the risk of severe aortic stenosis,” study author Marcin Fijalkowski, MD, PhD, of the Medical University of Gdansk, said in an interview. “This additional evaluation is not time-consuming and is easy to perform.”
 

Methods and results

For the study, Dr. Fijalkowski and his colleagues examined data from 6,631 people between the ages of 50 and 80 years of age with a smoking history of 30 or more pack-years. The group was enrolled in the MOLTEST BIS lung cancer screening program between 2016 and 2018, which assessed the usefulness of LDCT performed during lung cancer screening in determining the degree of aortic valve calcification as an additional finding. The researchers arbitrarily determined a calcium score of 900 as a cutoff point indicating a positive test result. Positive patients were sent for an echocardiogram for confirmation of diagnosis.

Aortic valve calcification was identified in 869 patients, 13.1% of the group. Sixty-eight participants, which is about 8% of this group, were identified as having a calcium score of 900 at least and were referred for echocardiography to confirm these results. Of this group, 0.5% were diagnosed with at least moderate aortic stenosis after receiving an echocardiogram. About 55% of the participants with this condition were unaware of their valvular heart disease, including 23% with a severe form of the disease.
 

Study identified patients who had not been aware of disease

Dr. Fijalkowski said while he was not surprised by the findings, he was surprised that the study may have saved some of the participants’ lives.

“We were expecting the same degree of calcification of aortic valve and correlation with aortic stenosis severity, but what surprised us was that half of diagnosed patients were not aware of disease,” he said. “This additional finding was lifesaving.”

In the paper, the authors noted that cardiology societies do not yet recognize LDCT as a diagnostic tool for aortic stenosis. Based on their findings, they propose that aortic valve calcification become a routine assessment procedure in the LDCT protocol for lung cancer screening.
 

Findings are ‘important’ but not practice changing

Salim S. Virani, MD, FACC, who was not involved in the study, said this new research is important.

The analyses were done well and push the needle further in a direction that suggests “when we are doing imaging for one reason, we should use the totality of information that we have available,” he noted.

“I mean, if you are looking at a lung nodule, if you see an aortic valve that’s very calcified, then it should prompt you to at least ask the patient about some symptoms related to that,” Dr. Virani explained.

However, he said more research is needed on a larger population before LDCT can be considered a diagnostic tool for aortic stenosis.

“I think we have to understand that this study was done in a very specific group of patients,” said Dr. Virani, professor in the sections of cardiology and cardiovascular research at Baylor College of Medicine, Houston. “If you were to do it in a population that was much younger, with much lower risk of even lung cancer, then the yield of a CT to pick up aortic stenosis would be lower.”

Before any practice changes are made regarding LDCT and the diagnosis of aortic stenosis, there needs to be more research on how many people in the general population are getting non–cardiology-related chest imaging and then come up with a population-based metric as to what calcium score cutoff could be used, he said.

Dr. Fijalkowski said he believes the results of his study will encourage physicians to focus not only on pulmonary nodules but also to look for additional things such as aortic valve calcification.

The experts did not disclose any relevant financial relationships.

For adult outpatients with moderate to severe Crohn’s disease, new guidelines from the American Gastroenterological Association strongly recommend induction and maintenance therapy with anti–tumor necrosis factor–alpha agents or ustekinumab over no treatment.

“Although [related] evidence supporting infliximab and adalimumab was moderate certainty, the evidence for certolizumab pegol was low certainty,” wrote Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center in Boston and his associates, on behalf of the AGA Clinical Guidelines Committee in Gastroenterology. Vedolizumab received a conditional recommendation based on less robust evidence for induction in this setting.

Outcomes in Crohn’s disease have improved, likely “because of earlier diagnosis, increasing use of biologics, escalation or alteration of therapy based on disease severity, and endoscopic management of colorectal cancer,” Dr. Feuerstein and his associates wrote.

This update reflects these changes, strongly recommending biologic monotherapy over thiopurine monotherapy for induction. It also suggests “early induction with a biologic, with or without an immunomodulator, rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids.” For the latter assessment, the guidelines noted that some studies were open label (which increases risk of bias) and that upfront combination therapy with a biologic and an immunomodulator could sometimes lead to overtreatment. Nonetheless, studies shown associations between the step-up approach and “a potential risk of harm from disease progression related to inadequate disease therapy.”

The guidelines also recommend that patients who have never received biologic drugs receive induction therapy with infliximab, adalimumab, or ustekinumab, rather than certolizumab pegol. This strong recommendation reflects the findings of a network meta-analysis conducted by the AGA in which certolizumab pegol was least effective, with no evidence for clear differences in efficacy among infliximab, adalimumab, and ustekinumab. A network meta-analysis is a type of study that enables experts to compare therapies indirectly when head-to-head trials are lacking.

For patients who are naive to both biologics and immunomodulators, the guidelines suggest combination treatment with infliximab or adalimumab plus a thiopurine rather than monotherapy with either biologic. Because of a lack of randomized controlled trials, no recommendation is made regarding combination therapy with ustekinumab or vedolizumab.

For patients who have received but never responded to anti-TNF-alpha therapy (so-called primary nonresponders), ustekinumab is strongly recommended, and vedolizumab is conditionally recommended. For patients who initially responded to infliximab and then lost their response (secondary nonresponders), adalimumab and ustekinumab are strongly recommended, while vedolizumab receives another conditional recommendation.

For patients with moderate to severe luminal disease, induction and maintenance with infliximab, adalimumab, certolizumab pegol, vedolizumab, or ustekinumab are recommended over no treatment. Thiopurine monotherapy is suggested over no treatment for maintenance of remission, but not for induction. For methotrexate, subcutaneous or intramuscular monotherapy is suggested over no treatment. The sole available trial on oral methotrexate (12.5 mg/week) was negative, and “it is not clear if a higher dose would have been more effective,” according to the guidelines. They strongly recommend against using 5-aminosalicytes or sulfasalazine because of lack of efficacy for maintaining remission and suggest not using natalizumab because of the risk of progressive multifocal leukoencephalopathy (PML). Corticosteroids are considered preferable to no treatment for induction but not for maintenance.

For patients with fistulizing disease, infliximab has “the most robust evidence” and receives a strong recommendation for induction and maintenance, while adalimumab, ustekinumab, and vedolizumab receive conditional recommendations. “In contrast, evidence suggests certolizumab pegol may not be effective for induction of fistula remission,” the guidelines state. For patients with perianal disease with an active fistula but no abscess, combining biologics with antibiotics is strongly recommended over biologic monotherapy.

The guidelines define moderate to severe Crohn’s disease as a Crohn’s Disease Activity Index (CDAI) score of 220 or higher, the typical cutoff used in clinical trials. The recommendations apply to outpatient management, but in most cases would also apply to inpatients.

An expert commentary accompanying the guidelines praises their “rigorous methods” based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Edith Y. Ho, MD, of Stanford (Calif.) University and her associates also laud the “innovative methods” that were used to compare treatments and assess data quality. In addition to the network meta-analysis, the guidelines set an a priori minimal clinically important difference (MCID) score of 10% for risk of treatment failure versus placebo. This led to more clinically relevant guidance, such as the conditional recommendation for vedolizumab in luminal disease since this drug did not meet the MCID threshold. Finally, the commentators emphasized that the guidelines are meant to facilitate, not dictate, treatment decisions: “Choice of therapies and treatment strategies will continue to rely on clinical judgment as well, and will continue to be informed by patient-specific values and preferences.”

The AGA Institute was the sole source of funding. Four coauthors disclosed ties to Celgene, Takeda, Pendopharm, Merck Canada, Guardant Health, Ferring, and AbbVie. Dr. Feurstein and the other guidelines coauthors reported having no conflicts of interest. Some authors on the editorial disclosed relationships with AbbVie, Pfizer, and Janssen, but the remaining had no conflicts to disclose.

For adult outpatients with moderate to severe Crohn’s disease, new guidelines from the American Gastroenterological Association strongly recommend induction and maintenance therapy with anti–tumor necrosis factor–alpha agents or ustekinumab over no treatment.

“Although [related] evidence supporting infliximab and adalimumab was moderate certainty, the evidence for certolizumab pegol was low certainty,” wrote Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center in Boston and his associates, on behalf of the AGA Clinical Guidelines Committee in Gastroenterology. Vedolizumab received a conditional recommendation based on less robust evidence for induction in this setting.

Outcomes in Crohn’s disease have improved, likely “because of earlier diagnosis, increasing use of biologics, escalation or alteration of therapy based on disease severity, and endoscopic management of colorectal cancer,” Dr. Feuerstein and his associates wrote.

This update reflects these changes, strongly recommending biologic monotherapy over thiopurine monotherapy for induction. It also suggests “early induction with a biologic, with or without an immunomodulator, rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids.” For the latter assessment, the guidelines noted that some studies were open label (which increases risk of bias) and that upfront combination therapy with a biologic and an immunomodulator could sometimes lead to overtreatment. Nonetheless, studies shown associations between the step-up approach and “a potential risk of harm from disease progression related to inadequate disease therapy.”

The guidelines also recommend that patients who have never received biologic drugs receive induction therapy with infliximab, adalimumab, or ustekinumab, rather than certolizumab pegol. This strong recommendation reflects the findings of a network meta-analysis conducted by the AGA in which certolizumab pegol was least effective, with no evidence for clear differences in efficacy among infliximab, adalimumab, and ustekinumab. A network meta-analysis is a type of study that enables experts to compare therapies indirectly when head-to-head trials are lacking.

For patients who are naive to both biologics and immunomodulators, the guidelines suggest combination treatment with infliximab or adalimumab plus a thiopurine rather than monotherapy with either biologic. Because of a lack of randomized controlled trials, no recommendation is made regarding combination therapy with ustekinumab or vedolizumab.

For patients who have received but never responded to anti-TNF-alpha therapy (so-called primary nonresponders), ustekinumab is strongly recommended, and vedolizumab is conditionally recommended. For patients who initially responded to infliximab and then lost their response (secondary nonresponders), adalimumab and ustekinumab are strongly recommended, while vedolizumab receives another conditional recommendation.

For patients with moderate to severe luminal disease, induction and maintenance with infliximab, adalimumab, certolizumab pegol, vedolizumab, or ustekinumab are recommended over no treatment. Thiopurine monotherapy is suggested over no treatment for maintenance of remission, but not for induction. For methotrexate, subcutaneous or intramuscular monotherapy is suggested over no treatment. The sole available trial on oral methotrexate (12.5 mg/week) was negative, and “it is not clear if a higher dose would have been more effective,” according to the guidelines. They strongly recommend against using 5-aminosalicytes or sulfasalazine because of lack of efficacy for maintaining remission and suggest not using natalizumab because of the risk of progressive multifocal leukoencephalopathy (PML). Corticosteroids are considered preferable to no treatment for induction but not for maintenance.

For patients with fistulizing disease, infliximab has “the most robust evidence” and receives a strong recommendation for induction and maintenance, while adalimumab, ustekinumab, and vedolizumab receive conditional recommendations. “In contrast, evidence suggests certolizumab pegol may not be effective for induction of fistula remission,” the guidelines state. For patients with perianal disease with an active fistula but no abscess, combining biologics with antibiotics is strongly recommended over biologic monotherapy.

The guidelines define moderate to severe Crohn’s disease as a Crohn’s Disease Activity Index (CDAI) score of 220 or higher, the typical cutoff used in clinical trials. The recommendations apply to outpatient management, but in most cases would also apply to inpatients.

An expert commentary accompanying the guidelines praises their “rigorous methods” based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Edith Y. Ho, MD, of Stanford (Calif.) University and her associates also laud the “innovative methods” that were used to compare treatments and assess data quality. In addition to the network meta-analysis, the guidelines set an a priori minimal clinically important difference (MCID) score of 10% for risk of treatment failure versus placebo. This led to more clinically relevant guidance, such as the conditional recommendation for vedolizumab in luminal disease since this drug did not meet the MCID threshold. Finally, the commentators emphasized that the guidelines are meant to facilitate, not dictate, treatment decisions: “Choice of therapies and treatment strategies will continue to rely on clinical judgment as well, and will continue to be informed by patient-specific values and preferences.”

The AGA Institute was the sole source of funding. Four coauthors disclosed ties to Celgene, Takeda, Pendopharm, Merck Canada, Guardant Health, Ferring, and AbbVie. Dr. Feurstein and the other guidelines coauthors reported having no conflicts of interest. Some authors on the editorial disclosed relationships with AbbVie, Pfizer, and Janssen, but the remaining had no conflicts to disclose.

For adult outpatients with moderate to severe Crohn’s disease, new guidelines from the American Gastroenterological Association strongly recommend induction and maintenance therapy with anti–tumor necrosis factor–alpha agents or ustekinumab over no treatment.

“Although [related] evidence supporting infliximab and adalimumab was moderate certainty, the evidence for certolizumab pegol was low certainty,” wrote Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center in Boston and his associates, on behalf of the AGA Clinical Guidelines Committee in Gastroenterology. Vedolizumab received a conditional recommendation based on less robust evidence for induction in this setting.

Outcomes in Crohn’s disease have improved, likely “because of earlier diagnosis, increasing use of biologics, escalation or alteration of therapy based on disease severity, and endoscopic management of colorectal cancer,” Dr. Feuerstein and his associates wrote.

This update reflects these changes, strongly recommending biologic monotherapy over thiopurine monotherapy for induction. It also suggests “early induction with a biologic, with or without an immunomodulator, rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids.” For the latter assessment, the guidelines noted that some studies were open label (which increases risk of bias) and that upfront combination therapy with a biologic and an immunomodulator could sometimes lead to overtreatment. Nonetheless, studies shown associations between the step-up approach and “a potential risk of harm from disease progression related to inadequate disease therapy.”

The guidelines also recommend that patients who have never received biologic drugs receive induction therapy with infliximab, adalimumab, or ustekinumab, rather than certolizumab pegol. This strong recommendation reflects the findings of a network meta-analysis conducted by the AGA in which certolizumab pegol was least effective, with no evidence for clear differences in efficacy among infliximab, adalimumab, and ustekinumab. A network meta-analysis is a type of study that enables experts to compare therapies indirectly when head-to-head trials are lacking.

For patients who are naive to both biologics and immunomodulators, the guidelines suggest combination treatment with infliximab or adalimumab plus a thiopurine rather than monotherapy with either biologic. Because of a lack of randomized controlled trials, no recommendation is made regarding combination therapy with ustekinumab or vedolizumab.

For patients who have received but never responded to anti-TNF-alpha therapy (so-called primary nonresponders), ustekinumab is strongly recommended, and vedolizumab is conditionally recommended. For patients who initially responded to infliximab and then lost their response (secondary nonresponders), adalimumab and ustekinumab are strongly recommended, while vedolizumab receives another conditional recommendation.

For patients with moderate to severe luminal disease, induction and maintenance with infliximab, adalimumab, certolizumab pegol, vedolizumab, or ustekinumab are recommended over no treatment. Thiopurine monotherapy is suggested over no treatment for maintenance of remission, but not for induction. For methotrexate, subcutaneous or intramuscular monotherapy is suggested over no treatment. The sole available trial on oral methotrexate (12.5 mg/week) was negative, and “it is not clear if a higher dose would have been more effective,” according to the guidelines. They strongly recommend against using 5-aminosalicytes or sulfasalazine because of lack of efficacy for maintaining remission and suggest not using natalizumab because of the risk of progressive multifocal leukoencephalopathy (PML). Corticosteroids are considered preferable to no treatment for induction but not for maintenance.

For patients with fistulizing disease, infliximab has “the most robust evidence” and receives a strong recommendation for induction and maintenance, while adalimumab, ustekinumab, and vedolizumab receive conditional recommendations. “In contrast, evidence suggests certolizumab pegol may not be effective for induction of fistula remission,” the guidelines state. For patients with perianal disease with an active fistula but no abscess, combining biologics with antibiotics is strongly recommended over biologic monotherapy.

The guidelines define moderate to severe Crohn’s disease as a Crohn’s Disease Activity Index (CDAI) score of 220 or higher, the typical cutoff used in clinical trials. The recommendations apply to outpatient management, but in most cases would also apply to inpatients.

An expert commentary accompanying the guidelines praises their “rigorous methods” based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Edith Y. Ho, MD, of Stanford (Calif.) University and her associates also laud the “innovative methods” that were used to compare treatments and assess data quality. In addition to the network meta-analysis, the guidelines set an a priori minimal clinically important difference (MCID) score of 10% for risk of treatment failure versus placebo. This led to more clinically relevant guidance, such as the conditional recommendation for vedolizumab in luminal disease since this drug did not meet the MCID threshold. Finally, the commentators emphasized that the guidelines are meant to facilitate, not dictate, treatment decisions: “Choice of therapies and treatment strategies will continue to rely on clinical judgment as well, and will continue to be informed by patient-specific values and preferences.”

The AGA Institute was the sole source of funding. Four coauthors disclosed ties to Celgene, Takeda, Pendopharm, Merck Canada, Guardant Health, Ferring, and AbbVie. Dr. Feurstein and the other guidelines coauthors reported having no conflicts of interest. Some authors on the editorial disclosed relationships with AbbVie, Pfizer, and Janssen, but the remaining had no conflicts to disclose.

People with migraines appeared to have a higher likelihood of COVID-19 infection and subsequent symptoms of the disease, but they were less likely to receive health care, according to a study presented at the American Headache Society’s 2021 annual meeting.

“These data suggest that people with migraine are either more susceptible to contracting COVID-19, or that they may be more sensitive to the development of symptoms once COVID-19 has been contracted, or both,” Robert Shapiro, MD, PhD, professor of neurological science at the University of Vermont, Burlington. “Further, once COVID-19 has been contracted, people with migraine may be less likely to develop serious COVID-19 outcomes, or they may be less likely to seek health care for COVID-19, or both.”

In providing background information, Dr. Shapiro noted previous research showing that headache is associated with a positive prognosis in COVID-19 inpatients, including lower IL-6 levels throughout the disease course, a 1-week shorter disease course, and a 2.2 times greater relative risk of survival.

Yet in a study across 171 countries, a higher population prevalence of migraine is associated with higher COVID-19 mortality rates. It’s unclear what conclusions can be drawn from that association, however, said Deborah I. Friedman, MD, MPH, professor of neurology and ophthalmology at University of Texas, Dallas, who was not involved in the research.

Dr. Shapiro suggested a theoretical possibility, noting that two genes linked to migraine susceptibility – SCN1A and IFNAR2 – are among 15 host loci also associated with COVID-19 outcomes. Further, Dr. Shapiro noted in his background information, COVID-19 is linked to lower serum calcitonin gene-related peptide levels.

For the study, Dr. Shapiro and colleagues analyzed data from U.S. adults who responded to the National Health and Wellness Survey from April to July 2020. The researchers limited their analysis to the 41,155 participants who had not received the flu vaccine in 2020 since previous research has suggested reduced morbidity among those with COVID-19 who had been vaccinated against the flu. In this group, 4,550 participants had ever been diagnosed by a doctor with migraine (11%) and 36,605 participants had not (89%).

The majority of those with a history of migraine were female (78%), compared with the overall sample (50% female), and tended to be younger, with an average age of 39 compared with 45 for those without migraine (P < .001).

Among those with a previous migraine diagnosis, 3.8% self-reported having had a COVID-19 infection, compared with infection in 2.4% of those without a history of migraine (P < .001). That translated to a 58% increased risk of COVID-19 infection in those with migraine history, with a similar rate of test positivity in both groups (33.7% with migraine history vs. 34.5% without). Test negativity was also similar in both groups (15.9% vs. 17.8%).

Of 360 respondents who had tested positive for COVID-19, the 60 with a history of migraine reported more frequent symptoms than those without migraine. The increased frequency was statistically significant (P < .001 unless otherwise indicated) for the following symptoms:

• Difficulty breathing or shortness of breath (P = .005).
• Fever.
• Headache, sore throat, and/or congestion.
• Fatigue.
• Loss of smell and taste.
• Chills and body aches.
• Persistent pain or pressure in the chest.
• Confusion or inability to arouse.
• Digestive issues (P = .005).
• Bluish lips or face.

For several of these symptoms – such as headache/sore throat/congestion, persistent pain or pressure in the chest, confusion/inability to arouse, and digestive issues – more than twice as many respondents with migraine reported the symptom, vs. those without migraine.
 

Changes in health care utilization

“I think that people with migraine are aware of their bodies and aware of their symptoms more than the average person,” Dr. Friedman said. Yet those with migraine were less likely to use health care while diagnosed with COVID-19 than were those without migraine. Migraine sufferers with a COVID-19 infection were 1.2 times more likely to visit a health care provider than were those without an infection, but the similar relative risk was 1.35 greater for those with COVID-19 infections and no migraines.

Similarly, those with a migraine history were more than twice as likely to visit the emergency department when they had a COVID-19 vaccine infection than were those without an infection (RR = 2.6), but among those without a history of migraine, respondents were nearly five times more likely to visit the emergency department when they had a COVID-19 infection than when they didn’t (RR = 4.9).

Dr. Friedman suggested that the lower utilization rate may have to do with the nature of migraine itself. “There are people with migraine who go to the emergency room all the time, but then there’s most of the people with migraine, who would rather die than go to the emergency room because with the light and the noise, it’s just a horrible place to be if you have migraine,” Dr. Friedman said. “I think the majority of people would prefer not to go to the emergency room if given the choice.”

Increased likelihood of hospitalization among those with migraine and a COVID-19 infection was 4.6 compared with those with a migraine and no infection; the corresponding hospitalization risk for COVID-19 among those without migraine was 7.6 times greater than for those with no infection. All these risk ratios were statistically significant.

Dr. Shapiro then speculated on what it might mean that headache is a positive prognostic indicator for COVID-19 inpatients and that migraine population prevalence is linked to higher COVID-19 mortality.

“A hypothesis emerges that headache as a symptom, and migraine as a disease, may reflect adaptive processes associated with host defenses against viruses,” Dr. Shapiro said. “For example, migraine-driven behaviors, such as social distancing due to photophobia, in the setting of viral illness may play adaptive roles in reducing viral spread.”

The researchers did not receive external funding. Dr. Shapiro has consulted for Eli Lilly and Lundbeck. Dr. Friedman reports grant support and/or advisory board participation for Allergan, Biohaven Pharmaceuticals, Eli Lilly, Impel NeuroPharma, Invex, Lundbeck, Merck, Revance Therapeutics, Satsuma Pharmaceuticals, Teva Pharmaceuticals, Theranica, and Zosano Pharma.

People with migraines appeared to have a higher likelihood of COVID-19 infection and subsequent symptoms of the disease, but they were less likely to receive health care, according to a study presented at the American Headache Society’s 2021 annual meeting.

“These data suggest that people with migraine are either more susceptible to contracting COVID-19, or that they may be more sensitive to the development of symptoms once COVID-19 has been contracted, or both,” Robert Shapiro, MD, PhD, professor of neurological science at the University of Vermont, Burlington. “Further, once COVID-19 has been contracted, people with migraine may be less likely to develop serious COVID-19 outcomes, or they may be less likely to seek health care for COVID-19, or both.”

In providing background information, Dr. Shapiro noted previous research showing that headache is associated with a positive prognosis in COVID-19 inpatients, including lower IL-6 levels throughout the disease course, a 1-week shorter disease course, and a 2.2 times greater relative risk of survival.

Yet in a study across 171 countries, a higher population prevalence of migraine is associated with higher COVID-19 mortality rates. It’s unclear what conclusions can be drawn from that association, however, said Deborah I. Friedman, MD, MPH, professor of neurology and ophthalmology at University of Texas, Dallas, who was not involved in the research.

Dr. Shapiro suggested a theoretical possibility, noting that two genes linked to migraine susceptibility – SCN1A and IFNAR2 – are among 15 host loci also associated with COVID-19 outcomes. Further, Dr. Shapiro noted in his background information, COVID-19 is linked to lower serum calcitonin gene-related peptide levels.

For the study, Dr. Shapiro and colleagues analyzed data from U.S. adults who responded to the National Health and Wellness Survey from April to July 2020. The researchers limited their analysis to the 41,155 participants who had not received the flu vaccine in 2020 since previous research has suggested reduced morbidity among those with COVID-19 who had been vaccinated against the flu. In this group, 4,550 participants had ever been diagnosed by a doctor with migraine (11%) and 36,605 participants had not (89%).

The majority of those with a history of migraine were female (78%), compared with the overall sample (50% female), and tended to be younger, with an average age of 39 compared with 45 for those without migraine (P < .001).

Among those with a previous migraine diagnosis, 3.8% self-reported having had a COVID-19 infection, compared with infection in 2.4% of those without a history of migraine (P < .001). That translated to a 58% increased risk of COVID-19 infection in those with migraine history, with a similar rate of test positivity in both groups (33.7% with migraine history vs. 34.5% without). Test negativity was also similar in both groups (15.9% vs. 17.8%).

Of 360 respondents who had tested positive for COVID-19, the 60 with a history of migraine reported more frequent symptoms than those without migraine. The increased frequency was statistically significant (P < .001 unless otherwise indicated) for the following symptoms:

• Difficulty breathing or shortness of breath (P = .005).
• Fever.
• Headache, sore throat, and/or congestion.
• Fatigue.
• Loss of smell and taste.
• Chills and body aches.
• Persistent pain or pressure in the chest.
• Confusion or inability to arouse.
• Digestive issues (P = .005).
• Bluish lips or face.

For several of these symptoms – such as headache/sore throat/congestion, persistent pain or pressure in the chest, confusion/inability to arouse, and digestive issues – more than twice as many respondents with migraine reported the symptom, vs. those without migraine.
 

Changes in health care utilization

“I think that people with migraine are aware of their bodies and aware of their symptoms more than the average person,” Dr. Friedman said. Yet those with migraine were less likely to use health care while diagnosed with COVID-19 than were those without migraine. Migraine sufferers with a COVID-19 infection were 1.2 times more likely to visit a health care provider than were those without an infection, but the similar relative risk was 1.35 greater for those with COVID-19 infections and no migraines.

Similarly, those with a migraine history were more than twice as likely to visit the emergency department when they had a COVID-19 vaccine infection than were those without an infection (RR = 2.6), but among those without a history of migraine, respondents were nearly five times more likely to visit the emergency department when they had a COVID-19 infection than when they didn’t (RR = 4.9).

Dr. Friedman suggested that the lower utilization rate may have to do with the nature of migraine itself. “There are people with migraine who go to the emergency room all the time, but then there’s most of the people with migraine, who would rather die than go to the emergency room because with the light and the noise, it’s just a horrible place to be if you have migraine,” Dr. Friedman said. “I think the majority of people would prefer not to go to the emergency room if given the choice.”

Increased likelihood of hospitalization among those with migraine and a COVID-19 infection was 4.6 compared with those with a migraine and no infection; the corresponding hospitalization risk for COVID-19 among those without migraine was 7.6 times greater than for those with no infection. All these risk ratios were statistically significant.

Dr. Shapiro then speculated on what it might mean that headache is a positive prognostic indicator for COVID-19 inpatients and that migraine population prevalence is linked to higher COVID-19 mortality.

“A hypothesis emerges that headache as a symptom, and migraine as a disease, may reflect adaptive processes associated with host defenses against viruses,” Dr. Shapiro said. “For example, migraine-driven behaviors, such as social distancing due to photophobia, in the setting of viral illness may play adaptive roles in reducing viral spread.”

The researchers did not receive external funding. Dr. Shapiro has consulted for Eli Lilly and Lundbeck. Dr. Friedman reports grant support and/or advisory board participation for Allergan, Biohaven Pharmaceuticals, Eli Lilly, Impel NeuroPharma, Invex, Lundbeck, Merck, Revance Therapeutics, Satsuma Pharmaceuticals, Teva Pharmaceuticals, Theranica, and Zosano Pharma.

People with migraines appeared to have a higher likelihood of COVID-19 infection and subsequent symptoms of the disease, but they were less likely to receive health care, according to a study presented at the American Headache Society’s 2021 annual meeting.

“These data suggest that people with migraine are either more susceptible to contracting COVID-19, or that they may be more sensitive to the development of symptoms once COVID-19 has been contracted, or both,” Robert Shapiro, MD, PhD, professor of neurological science at the University of Vermont, Burlington. “Further, once COVID-19 has been contracted, people with migraine may be less likely to develop serious COVID-19 outcomes, or they may be less likely to seek health care for COVID-19, or both.”

In providing background information, Dr. Shapiro noted previous research showing that headache is associated with a positive prognosis in COVID-19 inpatients, including lower IL-6 levels throughout the disease course, a 1-week shorter disease course, and a 2.2 times greater relative risk of survival.

Yet in a study across 171 countries, a higher population prevalence of migraine is associated with higher COVID-19 mortality rates. It’s unclear what conclusions can be drawn from that association, however, said Deborah I. Friedman, MD, MPH, professor of neurology and ophthalmology at University of Texas, Dallas, who was not involved in the research.

Dr. Shapiro suggested a theoretical possibility, noting that two genes linked to migraine susceptibility – SCN1A and IFNAR2 – are among 15 host loci also associated with COVID-19 outcomes. Further, Dr. Shapiro noted in his background information, COVID-19 is linked to lower serum calcitonin gene-related peptide levels.

For the study, Dr. Shapiro and colleagues analyzed data from U.S. adults who responded to the National Health and Wellness Survey from April to July 2020. The researchers limited their analysis to the 41,155 participants who had not received the flu vaccine in 2020 since previous research has suggested reduced morbidity among those with COVID-19 who had been vaccinated against the flu. In this group, 4,550 participants had ever been diagnosed by a doctor with migraine (11%) and 36,605 participants had not (89%).

The majority of those with a history of migraine were female (78%), compared with the overall sample (50% female), and tended to be younger, with an average age of 39 compared with 45 for those without migraine (P < .001).

Among those with a previous migraine diagnosis, 3.8% self-reported having had a COVID-19 infection, compared with infection in 2.4% of those without a history of migraine (P < .001). That translated to a 58% increased risk of COVID-19 infection in those with migraine history, with a similar rate of test positivity in both groups (33.7% with migraine history vs. 34.5% without). Test negativity was also similar in both groups (15.9% vs. 17.8%).

Of 360 respondents who had tested positive for COVID-19, the 60 with a history of migraine reported more frequent symptoms than those without migraine. The increased frequency was statistically significant (P < .001 unless otherwise indicated) for the following symptoms:

• Difficulty breathing or shortness of breath (P = .005).
• Fever.
• Headache, sore throat, and/or congestion.
• Fatigue.
• Loss of smell and taste.
• Chills and body aches.
• Persistent pain or pressure in the chest.
• Confusion or inability to arouse.
• Digestive issues (P = .005).
• Bluish lips or face.

For several of these symptoms – such as headache/sore throat/congestion, persistent pain or pressure in the chest, confusion/inability to arouse, and digestive issues – more than twice as many respondents with migraine reported the symptom, vs. those without migraine.
 

Changes in health care utilization

“I think that people with migraine are aware of their bodies and aware of their symptoms more than the average person,” Dr. Friedman said. Yet those with migraine were less likely to use health care while diagnosed with COVID-19 than were those without migraine. Migraine sufferers with a COVID-19 infection were 1.2 times more likely to visit a health care provider than were those without an infection, but the similar relative risk was 1.35 greater for those with COVID-19 infections and no migraines.

Similarly, those with a migraine history were more than twice as likely to visit the emergency department when they had a COVID-19 vaccine infection than were those without an infection (RR = 2.6), but among those without a history of migraine, respondents were nearly five times more likely to visit the emergency department when they had a COVID-19 infection than when they didn’t (RR = 4.9).

Dr. Friedman suggested that the lower utilization rate may have to do with the nature of migraine itself. “There are people with migraine who go to the emergency room all the time, but then there’s most of the people with migraine, who would rather die than go to the emergency room because with the light and the noise, it’s just a horrible place to be if you have migraine,” Dr. Friedman said. “I think the majority of people would prefer not to go to the emergency room if given the choice.”

Increased likelihood of hospitalization among those with migraine and a COVID-19 infection was 4.6 compared with those with a migraine and no infection; the corresponding hospitalization risk for COVID-19 among those without migraine was 7.6 times greater than for those with no infection. All these risk ratios were statistically significant.

Dr. Shapiro then speculated on what it might mean that headache is a positive prognostic indicator for COVID-19 inpatients and that migraine population prevalence is linked to higher COVID-19 mortality.

“A hypothesis emerges that headache as a symptom, and migraine as a disease, may reflect adaptive processes associated with host defenses against viruses,” Dr. Shapiro said. “For example, migraine-driven behaviors, such as social distancing due to photophobia, in the setting of viral illness may play adaptive roles in reducing viral spread.”

The researchers did not receive external funding. Dr. Shapiro has consulted for Eli Lilly and Lundbeck. Dr. Friedman reports grant support and/or advisory board participation for Allergan, Biohaven Pharmaceuticals, Eli Lilly, Impel NeuroPharma, Invex, Lundbeck, Merck, Revance Therapeutics, Satsuma Pharmaceuticals, Teva Pharmaceuticals, Theranica, and Zosano Pharma.

In the approach to treatment of patients with rheumatoid arthritis (RA), methotrexate monotherapy is often followed by addition of a biologic disease modifying anti-rheumatic drugs (bDMARDs) for best disease outcomes. Combination DMARDs therapy with methotrexate, hydroxychloroquine, and sulfasalazine (triple therapy) has been proposed as an alternative to biologic therapy. Combination methotrexate and leflunomide is not as frequently addressed in the literature, perhaps due in part to concerns about hepatotoxicity. Bredemeier et al address safety concerns regarding combination methotrexate and leflunomide in the treatment of patients with RA. In this multicenter Brazilian registry study, they compared adverse events (including infection) among patients receiving bDMARDs or JAK inhibitors. Patients treated with combination methotrexate and leflunomide had comparable rates of adverse effects as patients treated with either medication alone; infectious and serious adverse events were fewer compared to patients treated with bDMARDs or JAK inhibitors. Given this reassuring information, further study of the efficacy and durability of combination methotrexate and leflunomide therapy would be helpful to firmly establish its place in treatment of RA, especially among newer biologic choices.

Tofacitinib and tocilizumab, for example, have been under investigation for safety and efficacy, alone and in combination with conventional synthetic DMARDs (csDMARDs). Prior studies have suggested that tofacitinib is more effective in bDMARD-naïve patients than patients who have had inadequate efficacy with one or more bDMARDs. In this multicenter Japanese cohort study, Mori et al examine RA outcomes in new users of tofacitinib and tocilizumab. Clinical disease activity index (CDAI) responses and remission rates were significantly better among bDMARD-naïve patients receiving tofacitinib compared to those receiving tocilizumab; interestingly, this difference was not seen in patients who had previously received bDMARDs. Interpretation of these results is somewhat hampered by the use of the lower every-other-week tocilizimab injection dose, but they still raise the question as to whether timing and sequence of biologics can affect future response to therapy.

The role of conventional DMARDs has also been questioned in the converse role: tapering of therapy. Lillegraven et al compare tapering of csDMARDs to continuing therapy in this randomized multicenter Norwegian study. The possibility of biologic tapering in RA has previously been addressed with some evidence of success in the form of reduced frequency of administration. Unfortunately, despite being in stable remission, patients assigned to reduce csDMARDs to half-dose had more flares than those continuing therapy, suggesting that reducing csDMARDs to half-dose in RA patients in remission may not be easily accomplished. Whether this changes in patients with prolonged or “deep” remission is as yet unknown.

Finally, with all of these options for tailored therapy, how does our treatment of early RA fare? Combe et al report the 10-year outcomes of a French early RA cohort (ESPOIR), including patients with RA for <6 months recruited from 2003-2005. 521 patients were followed; at year 10, half were in DAS28 remission, and 14% in drug-free remission. Compared to outcomes from an earlier community- based study, patients in the ESPOIR cohort have better outcomes, possibly due to more aggressive treatment for RA, use of bDMARDs, or perhaps even earlier identification of patients for treatment. Due to the sizeable proportion of patients in drug-free remission, the impact of stringency of entry criteria should be considered, and a comparison to a later cohort with patients identified using 2019 ACR/EULAR criteria would be of great interest.

In the approach to treatment of patients with rheumatoid arthritis (RA), methotrexate monotherapy is often followed by addition of a biologic disease modifying anti-rheumatic drugs (bDMARDs) for best disease outcomes. Combination DMARDs therapy with methotrexate, hydroxychloroquine, and sulfasalazine (triple therapy) has been proposed as an alternative to biologic therapy. Combination methotrexate and leflunomide is not as frequently addressed in the literature, perhaps due in part to concerns about hepatotoxicity. Bredemeier et al address safety concerns regarding combination methotrexate and leflunomide in the treatment of patients with RA. In this multicenter Brazilian registry study, they compared adverse events (including infection) among patients receiving bDMARDs or JAK inhibitors. Patients treated with combination methotrexate and leflunomide had comparable rates of adverse effects as patients treated with either medication alone; infectious and serious adverse events were fewer compared to patients treated with bDMARDs or JAK inhibitors. Given this reassuring information, further study of the efficacy and durability of combination methotrexate and leflunomide therapy would be helpful to firmly establish its place in treatment of RA, especially among newer biologic choices.

Tofacitinib and tocilizumab, for example, have been under investigation for safety and efficacy, alone and in combination with conventional synthetic DMARDs (csDMARDs). Prior studies have suggested that tofacitinib is more effective in bDMARD-naïve patients than patients who have had inadequate efficacy with one or more bDMARDs. In this multicenter Japanese cohort study, Mori et al examine RA outcomes in new users of tofacitinib and tocilizumab. Clinical disease activity index (CDAI) responses and remission rates were significantly better among bDMARD-naïve patients receiving tofacitinib compared to those receiving tocilizumab; interestingly, this difference was not seen in patients who had previously received bDMARDs. Interpretation of these results is somewhat hampered by the use of the lower every-other-week tocilizimab injection dose, but they still raise the question as to whether timing and sequence of biologics can affect future response to therapy.

The role of conventional DMARDs has also been questioned in the converse role: tapering of therapy. Lillegraven et al compare tapering of csDMARDs to continuing therapy in this randomized multicenter Norwegian study. The possibility of biologic tapering in RA has previously been addressed with some evidence of success in the form of reduced frequency of administration. Unfortunately, despite being in stable remission, patients assigned to reduce csDMARDs to half-dose had more flares than those continuing therapy, suggesting that reducing csDMARDs to half-dose in RA patients in remission may not be easily accomplished. Whether this changes in patients with prolonged or “deep” remission is as yet unknown.

Finally, with all of these options for tailored therapy, how does our treatment of early RA fare? Combe et al report the 10-year outcomes of a French early RA cohort (ESPOIR), including patients with RA for <6 months recruited from 2003-2005. 521 patients were followed; at year 10, half were in DAS28 remission, and 14% in drug-free remission. Compared to outcomes from an earlier community- based study, patients in the ESPOIR cohort have better outcomes, possibly due to more aggressive treatment for RA, use of bDMARDs, or perhaps even earlier identification of patients for treatment. Due to the sizeable proportion of patients in drug-free remission, the impact of stringency of entry criteria should be considered, and a comparison to a later cohort with patients identified using 2019 ACR/EULAR criteria would be of great interest.

In the approach to treatment of patients with rheumatoid arthritis (RA), methotrexate monotherapy is often followed by addition of a biologic disease modifying anti-rheumatic drugs (bDMARDs) for best disease outcomes. Combination DMARDs therapy with methotrexate, hydroxychloroquine, and sulfasalazine (triple therapy) has been proposed as an alternative to biologic therapy. Combination methotrexate and leflunomide is not as frequently addressed in the literature, perhaps due in part to concerns about hepatotoxicity. Bredemeier et al address safety concerns regarding combination methotrexate and leflunomide in the treatment of patients with RA. In this multicenter Brazilian registry study, they compared adverse events (including infection) among patients receiving bDMARDs or JAK inhibitors. Patients treated with combination methotrexate and leflunomide had comparable rates of adverse effects as patients treated with either medication alone; infectious and serious adverse events were fewer compared to patients treated with bDMARDs or JAK inhibitors. Given this reassuring information, further study of the efficacy and durability of combination methotrexate and leflunomide therapy would be helpful to firmly establish its place in treatment of RA, especially among newer biologic choices.

Tofacitinib and tocilizumab, for example, have been under investigation for safety and efficacy, alone and in combination with conventional synthetic DMARDs (csDMARDs). Prior studies have suggested that tofacitinib is more effective in bDMARD-naïve patients than patients who have had inadequate efficacy with one or more bDMARDs. In this multicenter Japanese cohort study, Mori et al examine RA outcomes in new users of tofacitinib and tocilizumab. Clinical disease activity index (CDAI) responses and remission rates were significantly better among bDMARD-naïve patients receiving tofacitinib compared to those receiving tocilizumab; interestingly, this difference was not seen in patients who had previously received bDMARDs. Interpretation of these results is somewhat hampered by the use of the lower every-other-week tocilizimab injection dose, but they still raise the question as to whether timing and sequence of biologics can affect future response to therapy.

The role of conventional DMARDs has also been questioned in the converse role: tapering of therapy. Lillegraven et al compare tapering of csDMARDs to continuing therapy in this randomized multicenter Norwegian study. The possibility of biologic tapering in RA has previously been addressed with some evidence of success in the form of reduced frequency of administration. Unfortunately, despite being in stable remission, patients assigned to reduce csDMARDs to half-dose had more flares than those continuing therapy, suggesting that reducing csDMARDs to half-dose in RA patients in remission may not be easily accomplished. Whether this changes in patients with prolonged or “deep” remission is as yet unknown.

Finally, with all of these options for tailored therapy, how does our treatment of early RA fare? Combe et al report the 10-year outcomes of a French early RA cohort (ESPOIR), including patients with RA for <6 months recruited from 2003-2005. 521 patients were followed; at year 10, half were in DAS28 remission, and 14% in drug-free remission. Compared to outcomes from an earlier community- based study, patients in the ESPOIR cohort have better outcomes, possibly due to more aggressive treatment for RA, use of bDMARDs, or perhaps even earlier identification of patients for treatment. Due to the sizeable proportion of patients in drug-free remission, the impact of stringency of entry criteria should be considered, and a comparison to a later cohort with patients identified using 2019 ACR/EULAR criteria would be of great interest.

Key clinical point: Rheumatologists mostly preferred tumor necrosis factor inhibitors (TNFi) for the management of patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate. Abatacept seemed to be the more preferred option for patients with pulmonary involvement or a high risk for infection.

Major finding: TNFi was the preferred strategy in 80% of vignettes, except in cases with a history of infection and pulmonary comorbidity where abatacept was the first choice (global BW score: TNFi, 0.53 and abatacept, 0.38). Tocilizumab was the third most preferred strategy, chosen in 83% of the cases (global BW score: 0.11).

Study details: This was a noninterventional multicenter study involving 64 hypothetical clinical vignettes of patients with RA with an inadequate response to methotrexate. These case vignettes were presented to 211 French rheumatologists to elicit their therapeutic preferences.

Disclosures: The study was funded by Eli Lilly and Company, Indianapolis, IN, USA. Some of the authors declared receiving research grants, consultancy fees, and/or being employees and/or shareholders of Eli Lilly and Company and FAST4.

Source: Senbel E et al. Rheumatol Ther. 2021 May 3. doi: 10.1007/s40744-021-00311-1.

Key clinical point: Rheumatologists mostly preferred tumor necrosis factor inhibitors (TNFi) for the management of patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate. Abatacept seemed to be the more preferred option for patients with pulmonary involvement or a high risk for infection.

Major finding: TNFi was the preferred strategy in 80% of vignettes, except in cases with a history of infection and pulmonary comorbidity where abatacept was the first choice (global BW score: TNFi, 0.53 and abatacept, 0.38). Tocilizumab was the third most preferred strategy, chosen in 83% of the cases (global BW score: 0.11).

Study details: This was a noninterventional multicenter study involving 64 hypothetical clinical vignettes of patients with RA with an inadequate response to methotrexate. These case vignettes were presented to 211 French rheumatologists to elicit their therapeutic preferences.

Disclosures: The study was funded by Eli Lilly and Company, Indianapolis, IN, USA. Some of the authors declared receiving research grants, consultancy fees, and/or being employees and/or shareholders of Eli Lilly and Company and FAST4.

Source: Senbel E et al. Rheumatol Ther. 2021 May 3. doi: 10.1007/s40744-021-00311-1.

Key clinical point: Rheumatologists mostly preferred tumor necrosis factor inhibitors (TNFi) for the management of patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate. Abatacept seemed to be the more preferred option for patients with pulmonary involvement or a high risk for infection.

Major finding: TNFi was the preferred strategy in 80% of vignettes, except in cases with a history of infection and pulmonary comorbidity where abatacept was the first choice (global BW score: TNFi, 0.53 and abatacept, 0.38). Tocilizumab was the third most preferred strategy, chosen in 83% of the cases (global BW score: 0.11).

Study details: This was a noninterventional multicenter study involving 64 hypothetical clinical vignettes of patients with RA with an inadequate response to methotrexate. These case vignettes were presented to 211 French rheumatologists to elicit their therapeutic preferences.

Disclosures: The study was funded by Eli Lilly and Company, Indianapolis, IN, USA. Some of the authors declared receiving research grants, consultancy fees, and/or being employees and/or shareholders of Eli Lilly and Company and FAST4.

Source: Senbel E et al. Rheumatol Ther. 2021 May 3. doi: 10.1007/s40744-021-00311-1.

Key clinical point: Patients with rheumatoid arthritis (RA) have distinct clinical and biomechanical factors that place them at an increased risk for falls.

Major finding: The fallers vs. nonfallers were older (P = .05), had significantly higher pain scores (P less than .01), experienced dizziness (P less than .01), and were taking psychotropic medications (P = .02). The fallers vs. nonfallers had significantly higher anteroposterior sway (P = .03) and sway range (P = .02) and medial-lateral sway (P = .01) and sway range (P = .02) when standing with eyes open and a greater asymmetry during isometric extension at 90° (P = .05) and 60° (P = .02).

Study details: This was a nested case-control biomechanical analysis of 436 patients (aged 60 years or older) with RA who completed a 1-year prospective survey of falls.

Disclosures: This work was supported by the National Institute for Health Research, Research for Patient Benefit, and NIHR Manchester Biomedical Research Centre. The authors declared no conflicts of interest.

Source: Smith TO et al. Rheumatology (Oxford). 2021 Apr 26. doi:10.1093/rheumatology/keab388.

Key clinical point: Patients with rheumatoid arthritis (RA) have distinct clinical and biomechanical factors that place them at an increased risk for falls.

Major finding: The fallers vs. nonfallers were older (P = .05), had significantly higher pain scores (P less than .01), experienced dizziness (P less than .01), and were taking psychotropic medications (P = .02). The fallers vs. nonfallers had significantly higher anteroposterior sway (P = .03) and sway range (P = .02) and medial-lateral sway (P = .01) and sway range (P = .02) when standing with eyes open and a greater asymmetry during isometric extension at 90° (P = .05) and 60° (P = .02).

Study details: This was a nested case-control biomechanical analysis of 436 patients (aged 60 years or older) with RA who completed a 1-year prospective survey of falls.

Disclosures: This work was supported by the National Institute for Health Research, Research for Patient Benefit, and NIHR Manchester Biomedical Research Centre. The authors declared no conflicts of interest.

Source: Smith TO et al. Rheumatology (Oxford). 2021 Apr 26. doi:10.1093/rheumatology/keab388.

Key clinical point: Patients with rheumatoid arthritis (RA) have distinct clinical and biomechanical factors that place them at an increased risk for falls.

Major finding: The fallers vs. nonfallers were older (P = .05), had significantly higher pain scores (P less than .01), experienced dizziness (P less than .01), and were taking psychotropic medications (P = .02). The fallers vs. nonfallers had significantly higher anteroposterior sway (P = .03) and sway range (P = .02) and medial-lateral sway (P = .01) and sway range (P = .02) when standing with eyes open and a greater asymmetry during isometric extension at 90° (P = .05) and 60° (P = .02).

Study details: This was a nested case-control biomechanical analysis of 436 patients (aged 60 years or older) with RA who completed a 1-year prospective survey of falls.

Disclosures: This work was supported by the National Institute for Health Research, Research for Patient Benefit, and NIHR Manchester Biomedical Research Centre. The authors declared no conflicts of interest.

Source: Smith TO et al. Rheumatology (Oxford). 2021 Apr 26. doi:10.1093/rheumatology/keab388.

Key clinical point: Obese patients with established rheumatoid arthritis (RA) were less likely to achieve remission and more likely to experience intensive exposure to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) than patients with normal body mass index (BMI).

Major finding: At 6 months, obese patients vs. those with normal BMI were less likely to achieve disease activity score 28 remission (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.28-0.69) and more likely to be treated with combination csDMARD therapy than monotherapy (OR, 1.59; 95% CI, 1.03-2.45).

Study details: The findings are from a real-world analysis of 1,313 patients diagnosed with RA collected from the METEOR database.

Disclosures: No funding was received for this study. The authors declared no conflicts of interest.

Source: Dey M et al. Rheumatology (Oxford). 2021 Apr 30. doi: 10.1093/rheumatology/keab389.

Key clinical point: Obese patients with established rheumatoid arthritis (RA) were less likely to achieve remission and more likely to experience intensive exposure to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) than patients with normal body mass index (BMI).

Major finding: At 6 months, obese patients vs. those with normal BMI were less likely to achieve disease activity score 28 remission (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.28-0.69) and more likely to be treated with combination csDMARD therapy than monotherapy (OR, 1.59; 95% CI, 1.03-2.45).

Study details: The findings are from a real-world analysis of 1,313 patients diagnosed with RA collected from the METEOR database.

Disclosures: No funding was received for this study. The authors declared no conflicts of interest.

Source: Dey M et al. Rheumatology (Oxford). 2021 Apr 30. doi: 10.1093/rheumatology/keab389.

Key clinical point: Obese patients with established rheumatoid arthritis (RA) were less likely to achieve remission and more likely to experience intensive exposure to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) than patients with normal body mass index (BMI).

Major finding: At 6 months, obese patients vs. those with normal BMI were less likely to achieve disease activity score 28 remission (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.28-0.69) and more likely to be treated with combination csDMARD therapy than monotherapy (OR, 1.59; 95% CI, 1.03-2.45).

Study details: The findings are from a real-world analysis of 1,313 patients diagnosed with RA collected from the METEOR database.

Disclosures: No funding was received for this study. The authors declared no conflicts of interest.

Source: Dey M et al. Rheumatology (Oxford). 2021 Apr 30. doi: 10.1093/rheumatology/keab389.