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Lasting norovirus immunity may depend on T cells
Protection against norovirus gastroenteritis is supported in part by norovirus-specific CD8+ T cells that reside in peripheral, intestinal, and lymphoid tissues, according to investigators.
These findings, and the molecular tools used to discover them, could guide development of a norovirus vaccine and novel cellular therapies, according to lead author Ajinkya Pattekar, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“Currently, there are no approved pharmacologic therapies against norovirus, and despite several promising clinical trials, an effective vaccine is not available,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, which may stem from an incomplete understanding of norovirus immunity, according to Dr. Pattekar and colleagues.
They noted that most previous research has focused on humoral immunity, which appears variable between individuals, with some people exhibiting a strong humoral response, while others mount only partial humoral protection. The investigators also noted that, depending on which studies were examined, this type of defense could last years or fade within weeks to months and that “immune mechanisms other than antibodies may be important for protection against noroviruses.”
Specifically, cellular immunity may be at work. A 2020 study involving volunteers showed that T cells were cross-reactive to a type of norovirus the participants had never been exposed to.
“These findings suggest that T cells may target conserved epitopes and could offer cross-protection against a broad range of noroviruses,” Dr. Pattekar and colleagues wrote.
To test this hypothesis, they first collected peripheral blood mononuclear cells (PBMCs) from three healthy volunteers with unknown norovirus exposure history. Then serum samples were screened for norovirus functional antibodies via the binding between virus-like particles (VLPs) and histo–blood group antigens (HBGAs). This revealed disparate profiles of blocking antibodies against various norovirus strains. While donor 1 and donor 2 had antibodies against multiple strains, donor 3 lacked norovirus antibodies. Further testing showed that this latter individual was a nonsecretor with limited exposure history.
Next, the investigators tested donor PBMCs for norovirus-specific T-cell responses with use of overlapping libraries of peptides for each of the three norovirus open reading frames (ORF1, ORF2, and ORF3). T-cell responses, predominantly involving CD8+ T cells, were observed in all donors. While donor 1 had the greatest response to ORF1, donors 2 and 3 had responses that focused on ORF2.
“Thus, norovirus-specific T cells targeting ORF1 and ORF2 epitopes are present in peripheral blood from healthy donors regardless of secretor status,” the investigators wrote.
To better characterize T-cell epitopes, the investigators subdivided the overlapping peptide libraries into groups of shorter peptides, then exposed serum to these smaller component pools. This revealed eight HLA class I restricted epitopes that were derived from a genogroup II.4 pandemic norovirus strain; this group of variants has been responsible for all six of the norovirus pandemics since 1996.
Closer examination of the epitopes showed that they were “broadly conserved beyond GII.4.” Only one epitope exhibited variation in the C-terminal aromatic anchor, and it was nondominant. The investigators therefore identified seven immunodominant CD8+ epitopes, which they considered “valuable targets for vaccine and cell-based therapies.
“These data further confirm that epitope-specific CD8+ T cells are a universal feature of the overall norovirus immune response and could be an attractive target for future vaccines,” the investigators wrote.
Additional testing involving samples of spleen, mesenteric lymph nodes, and duodenum from deceased individuals showed presence of norovirus-specific CD8+ T cells, with particular abundance in intestinal tissue, and distinct phenotypes and functional properties in different tissue types.
“Future studies using tetramers and intestinal samples should build on these observations and fully define the location and microenvironment of norovirus-specific T cells,” the investigators wrote. “If carried out in the context of a vaccine trial, such studies could be highly valuable in elucidating tissue-resident memory correlates of norovirus immunity.”
The study was funded by the National Institutes of Health, the Wellcome Trust, and Deutsche Forschungsgemeinschaft. The investigators reported no conflicts of interest.
Understanding the immune correlates of protection for norovirus is important for the development and evaluation of candidate vaccines and to better clarify the variation in host susceptibility to infection. 
Prior research on the human immune response to norovirus infection has largely focused on the antibody response. There is less known about the antinorovirus T cell response, which can target and clear virus-infected cells. Notably, anti-viral CD8+ T cells are critical for control of norovirus infection in mouse models, which suggests a similarly important role in humans. In this study by Dr. Pattekar and colleagues, the authors generated human norovirus-specific peptides covering the entire viral proteome, and then they used these peptides to identify and characterize norovirus-specific CD8+ T cells from the blood, spleen, lymph nodes, and intestinal lamina propria of human donors who were not actively infected by norovirus. The authors identified virus-specific memory T cells in the blood and intestines. Further, they found several HLA class I restricted virus epitopes that are highly conserved amongst the most commonly circulating GII.4 noroviruses. These norovirus-specific T cells represented about 0.5% of all cells and reveal that norovirus induces a durable population of memory T cells.
Further research is needed to determine whether norovirus-specific CD8+ T cells are necessary or sufficient for preventing norovirus infection and disease in people. This important study provides novel tools and increases our understanding of cell-mediated immunity to human norovirus infection that will influence future vaccine design and evaluation for this important human pathogen.
Craig B. Wilen, MD, PhD, is assistant professor of laboratory medicine and immunobiology at Yale University, New Haven, Conn. He does not have any conflicts to disclose.
Understanding the immune correlates of protection for norovirus is important for the development and evaluation of candidate vaccines and to better clarify the variation in host susceptibility to infection.
Prior research on the human immune response to norovirus infection has largely focused on the antibody response. There is less known about the antinorovirus T cell response, which can target and clear virus-infected cells. Notably, anti-viral CD8+ T cells are critical for control of norovirus infection in mouse models, which suggests a similarly important role in humans. In this study by Dr. Pattekar and colleagues, the authors generated human norovirus-specific peptides covering the entire viral proteome, and then they used these peptides to identify and characterize norovirus-specific CD8+ T cells from the blood, spleen, lymph nodes, and intestinal lamina propria of human donors who were not actively infected by norovirus. The authors identified virus-specific memory T cells in the blood and intestines. Further, they found several HLA class I restricted virus epitopes that are highly conserved amongst the most commonly circulating GII.4 noroviruses. These norovirus-specific T cells represented about 0.5% of all cells and reveal that norovirus induces a durable population of memory T cells.
Further research is needed to determine whether norovirus-specific CD8+ T cells are necessary or sufficient for preventing norovirus infection and disease in people. This important study provides novel tools and increases our understanding of cell-mediated immunity to human norovirus infection that will influence future vaccine design and evaluation for this important human pathogen.
Craig B. Wilen, MD, PhD, is assistant professor of laboratory medicine and immunobiology at Yale University, New Haven, Conn. He does not have any conflicts to disclose.
Understanding the immune correlates of protection for norovirus is important for the development and evaluation of candidate vaccines and to better clarify the variation in host susceptibility to infection.
Prior research on the human immune response to norovirus infection has largely focused on the antibody response. There is less known about the antinorovirus T cell response, which can target and clear virus-infected cells. Notably, anti-viral CD8+ T cells are critical for control of norovirus infection in mouse models, which suggests a similarly important role in humans. In this study by Dr. Pattekar and colleagues, the authors generated human norovirus-specific peptides covering the entire viral proteome, and then they used these peptides to identify and characterize norovirus-specific CD8+ T cells from the blood, spleen, lymph nodes, and intestinal lamina propria of human donors who were not actively infected by norovirus. The authors identified virus-specific memory T cells in the blood and intestines. Further, they found several HLA class I restricted virus epitopes that are highly conserved amongst the most commonly circulating GII.4 noroviruses. These norovirus-specific T cells represented about 0.5% of all cells and reveal that norovirus induces a durable population of memory T cells.
Further research is needed to determine whether norovirus-specific CD8+ T cells are necessary or sufficient for preventing norovirus infection and disease in people. This important study provides novel tools and increases our understanding of cell-mediated immunity to human norovirus infection that will influence future vaccine design and evaluation for this important human pathogen.
Craig B. Wilen, MD, PhD, is assistant professor of laboratory medicine and immunobiology at Yale University, New Haven, Conn. He does not have any conflicts to disclose.
Protection against norovirus gastroenteritis is supported in part by norovirus-specific CD8+ T cells that reside in peripheral, intestinal, and lymphoid tissues, according to investigators.
These findings, and the molecular tools used to discover them, could guide development of a norovirus vaccine and novel cellular therapies, according to lead author Ajinkya Pattekar, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“Currently, there are no approved pharmacologic therapies against norovirus, and despite several promising clinical trials, an effective vaccine is not available,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, which may stem from an incomplete understanding of norovirus immunity, according to Dr. Pattekar and colleagues.
They noted that most previous research has focused on humoral immunity, which appears variable between individuals, with some people exhibiting a strong humoral response, while others mount only partial humoral protection. The investigators also noted that, depending on which studies were examined, this type of defense could last years or fade within weeks to months and that “immune mechanisms other than antibodies may be important for protection against noroviruses.”
Specifically, cellular immunity may be at work. A 2020 study involving volunteers showed that T cells were cross-reactive to a type of norovirus the participants had never been exposed to.
“These findings suggest that T cells may target conserved epitopes and could offer cross-protection against a broad range of noroviruses,” Dr. Pattekar and colleagues wrote.
To test this hypothesis, they first collected peripheral blood mononuclear cells (PBMCs) from three healthy volunteers with unknown norovirus exposure history. Then serum samples were screened for norovirus functional antibodies via the binding between virus-like particles (VLPs) and histo–blood group antigens (HBGAs). This revealed disparate profiles of blocking antibodies against various norovirus strains. While donor 1 and donor 2 had antibodies against multiple strains, donor 3 lacked norovirus antibodies. Further testing showed that this latter individual was a nonsecretor with limited exposure history.
Next, the investigators tested donor PBMCs for norovirus-specific T-cell responses with use of overlapping libraries of peptides for each of the three norovirus open reading frames (ORF1, ORF2, and ORF3). T-cell responses, predominantly involving CD8+ T cells, were observed in all donors. While donor 1 had the greatest response to ORF1, donors 2 and 3 had responses that focused on ORF2.
“Thus, norovirus-specific T cells targeting ORF1 and ORF2 epitopes are present in peripheral blood from healthy donors regardless of secretor status,” the investigators wrote.
To better characterize T-cell epitopes, the investigators subdivided the overlapping peptide libraries into groups of shorter peptides, then exposed serum to these smaller component pools. This revealed eight HLA class I restricted epitopes that were derived from a genogroup II.4 pandemic norovirus strain; this group of variants has been responsible for all six of the norovirus pandemics since 1996.
Closer examination of the epitopes showed that they were “broadly conserved beyond GII.4.” Only one epitope exhibited variation in the C-terminal aromatic anchor, and it was nondominant. The investigators therefore identified seven immunodominant CD8+ epitopes, which they considered “valuable targets for vaccine and cell-based therapies.
“These data further confirm that epitope-specific CD8+ T cells are a universal feature of the overall norovirus immune response and could be an attractive target for future vaccines,” the investigators wrote.
Additional testing involving samples of spleen, mesenteric lymph nodes, and duodenum from deceased individuals showed presence of norovirus-specific CD8+ T cells, with particular abundance in intestinal tissue, and distinct phenotypes and functional properties in different tissue types.
“Future studies using tetramers and intestinal samples should build on these observations and fully define the location and microenvironment of norovirus-specific T cells,” the investigators wrote. “If carried out in the context of a vaccine trial, such studies could be highly valuable in elucidating tissue-resident memory correlates of norovirus immunity.”
The study was funded by the National Institutes of Health, the Wellcome Trust, and Deutsche Forschungsgemeinschaft. The investigators reported no conflicts of interest.
Protection against norovirus gastroenteritis is supported in part by norovirus-specific CD8+ T cells that reside in peripheral, intestinal, and lymphoid tissues, according to investigators.
These findings, and the molecular tools used to discover them, could guide development of a norovirus vaccine and novel cellular therapies, according to lead author Ajinkya Pattekar, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“Currently, there are no approved pharmacologic therapies against norovirus, and despite several promising clinical trials, an effective vaccine is not available,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology, which may stem from an incomplete understanding of norovirus immunity, according to Dr. Pattekar and colleagues.
They noted that most previous research has focused on humoral immunity, which appears variable between individuals, with some people exhibiting a strong humoral response, while others mount only partial humoral protection. The investigators also noted that, depending on which studies were examined, this type of defense could last years or fade within weeks to months and that “immune mechanisms other than antibodies may be important for protection against noroviruses.”
Specifically, cellular immunity may be at work. A 2020 study involving volunteers showed that T cells were cross-reactive to a type of norovirus the participants had never been exposed to.
“These findings suggest that T cells may target conserved epitopes and could offer cross-protection against a broad range of noroviruses,” Dr. Pattekar and colleagues wrote.
To test this hypothesis, they first collected peripheral blood mononuclear cells (PBMCs) from three healthy volunteers with unknown norovirus exposure history. Then serum samples were screened for norovirus functional antibodies via the binding between virus-like particles (VLPs) and histo–blood group antigens (HBGAs). This revealed disparate profiles of blocking antibodies against various norovirus strains. While donor 1 and donor 2 had antibodies against multiple strains, donor 3 lacked norovirus antibodies. Further testing showed that this latter individual was a nonsecretor with limited exposure history.
Next, the investigators tested donor PBMCs for norovirus-specific T-cell responses with use of overlapping libraries of peptides for each of the three norovirus open reading frames (ORF1, ORF2, and ORF3). T-cell responses, predominantly involving CD8+ T cells, were observed in all donors. While donor 1 had the greatest response to ORF1, donors 2 and 3 had responses that focused on ORF2.
“Thus, norovirus-specific T cells targeting ORF1 and ORF2 epitopes are present in peripheral blood from healthy donors regardless of secretor status,” the investigators wrote.
To better characterize T-cell epitopes, the investigators subdivided the overlapping peptide libraries into groups of shorter peptides, then exposed serum to these smaller component pools. This revealed eight HLA class I restricted epitopes that were derived from a genogroup II.4 pandemic norovirus strain; this group of variants has been responsible for all six of the norovirus pandemics since 1996.
Closer examination of the epitopes showed that they were “broadly conserved beyond GII.4.” Only one epitope exhibited variation in the C-terminal aromatic anchor, and it was nondominant. The investigators therefore identified seven immunodominant CD8+ epitopes, which they considered “valuable targets for vaccine and cell-based therapies.
“These data further confirm that epitope-specific CD8+ T cells are a universal feature of the overall norovirus immune response and could be an attractive target for future vaccines,” the investigators wrote.
Additional testing involving samples of spleen, mesenteric lymph nodes, and duodenum from deceased individuals showed presence of norovirus-specific CD8+ T cells, with particular abundance in intestinal tissue, and distinct phenotypes and functional properties in different tissue types.
“Future studies using tetramers and intestinal samples should build on these observations and fully define the location and microenvironment of norovirus-specific T cells,” the investigators wrote. “If carried out in the context of a vaccine trial, such studies could be highly valuable in elucidating tissue-resident memory correlates of norovirus immunity.”
The study was funded by the National Institutes of Health, the Wellcome Trust, and Deutsche Forschungsgemeinschaft. The investigators reported no conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Infliximab weakens COVID-19 antibody response for IBD patients
Patients treated with infliximab for inflammatory bowel disease (IBD) showed significantly reduced response to COVID-19 antibodies, compared with those treated with vedolizumab, according to data from nearly 7,000 patients.
Although anti–tumor necrosis factor (anti-TNF) drugs are routinely used for patients with IBD, the impact of their immune-suppressing properties on protective immunity to COVID-19 is unknown, wrote Nicholas A. Kennedy, MD, of the University of Exeter (England) and colleagues. These drugs have been reported to impair protective immunity following vaccines for other diseases, such as those for influenza and viral hepatitis.
“By suppressing immune responses, biological and immunosuppression therapies may lead to chronic SARS-CoV-2 infection and have recently been implicated in the evolution and emergence of novel variants,” they noted, citing a study published in Cell.
In the current study, published in Gut, the researchers used data from the CLARITY IBD study to identify 6,935 patients with IBD aged 5 years and older seen at 92 hospitals in the United Kingdom between Sept. 22, 2020, and Dec. 23, 2020. Of these, 4,685 were treated with infliximab, and 2,250 received vedolizumab. The proportion of study participants with a positive anti–SARS-CoV-2 antibody test was the primary outcome, with secondary outcomes including proportion with positive antibodies following positive polymerase chain reaction test for SARS-CoV-2 and the magnitude of antibody reactivity.
Substantial seroprevalence differences seen
Overall, rates of symptomatic and proven SARS-CoV-2 infection and hospitalization were similar between infliximab-treated and vedolizumab-treated patients with IBD. However, seroprevalence was significantly lower in the infliximab group, compared with the vedolizumab group (3.4% vs. 6.0%; P < .0001). In addition, infliximab and immunomodulator use were each independently associated with lower seropositivity, compared with vedolizumab (odds ratio, 0.66 for infliximab and OR, 0.70 for immunomodulators) in a multivariate analysis.
In a sensitivity analysis, 39 of 81 infliximab-treated patients with polymerase chain reaction–confirmed COVID-19 infection seroconverted (48%), compared with 30 of 36 vedolizumab-treated patients (83%) (P < .00044). Infliximab-treated patients with confirmed infections also showed a lower magnitude of anti–SARS-CoV-2 reactivity, compared with vedolizumab-treated patients (P < .0001).
From a clinical perspective, the lower seroconversion rates and reduced levels of anti–SARS-CoV-2 antibody reactivity might increase susceptibility to recurrent COVID-19 infections in infliximab-treated IBD patients, the researchers noted. In addition, the impaired serological responses might promote chronic nasopharyngeal colonization and consequently promote the development of COVID-19 variants and drive persistent transmission, the researchers said.
The study findings were limited by several factors including lack of knowledge on the impact of attenuated immune response on infection risk, the potential for recall bias associated with patient reports, and the focus on infliximab only, the researchers pointed out. However, the key findings are likely apply to other anti-TNF monoclonal antibodies including adalimumab, certolizumab and golimumab, they suggested.
The study was strengthened by the recruitment of a large number of patients in a narrow time frame and comprehensive collection of data on patient-reported outcomes, COVID-19 testing, and serological assay results, the researchers said. Overall, the findings support the public health value of serological testing and virus surveillance to identify suboptimal vaccine response and to consider implications for practice, they added. “If attenuated serological responses following vaccination are also observed, then modified immunization strategies will need to be designed for millions of patients worldwide,” they emphasized.
Findings inform clinical practice and public health
The study is very important for many reasons, said Kim L. Isaacs, MD, PhD, AGAF, of the University of North Carolina at Chapel Hill in an interview. “It is known that there is decreased responsiveness to a number of routine vaccinations in IBD patients on immune active therapy. In terms of SARS-CoV-2, development of an immune response with infection is important in terms of severity of infection, reinfection, and possibly limiting spread of infection in this patient population,” she said. “Looking at both serum seroconversion and reactivity of immune response in patients with known SARS-CoV-2 infection will help to define clinical and public health guidance, and also may be predictive as to what might happen with SARS-CoV-2 immunization based on background biologic or immunosuppressant therapy,” she noted.
Dr. Isaacs said that she was not surprised by the study findings. “Anti-TNF, thiopurine, and methotrexate therapy are all thought to be systemically active and likely to suppress the immune response to infection and vaccination,” she said. Vedolizumab, on the other hand, is thought to be less systemically active and clinically is associated with fewer serious infections.
Data will drive patient counseling
“These results affect counseling of IBD patients on immune active therapy who have had a SARS-CoV-2 infection,” said Dr. Isaacs. “They should be made aware that infection does not indicate protection for further infection. Although the issues that are raised in this study are of concern, patients should not have clinically beneficial therapy discontinued or switched based on these results,” she said.
“Additional research is needed to determine what the seroconversion rate is with the currently available immunizations for SARS-CoV-2,” said Dr. Isaacs. More questions to address include whether there are differences in the different products available, whether immunization after SARS-CoV-2 infection improves both seroconversion and immune reactivity, and whether there is any benefit to transiently stopping dual immune active therapy during the time of immunization, she said.
Further studies can fill knowledge gaps
“There is a knowledge gap in our understanding of susceptibility to SARS-CoV-2 infections among patients with IBD who have previously been infected,” Shirley Cohen-Mekelburg, MD, MS, staff physician and research scientist in the inflammatory bowel disease program at the Veterans Affairs Ann Arbor (Mich.) Healthcare System, said in an interview. ”This is a first step in beginning to narrow this gap – to provide patients and providers with data to drive recommendations during this COVID-19 pandemic.”
She added that, while further work needs to be done, the study findings do support potential benefit for ongoing vigilance among patients receiving infliximab for IBD. “The study findings also drive us to seek answers to more questions: For example, should we consider serological testing for patients on infliximab? How does the presence or absence of anti–SARS-CoV-2 antibodies associate with susceptibility to infection for patients with infliximab?
“Further studies examining anti–SARS-CoV-2 reactivity are necessary to better understand antibody responses between patients with IBD to the general population, or between patients on immunosuppressive therapy and the general population,” she said. “Observational studies are also not designed to examine the causal relationship between infections, medications, and antibody responses. There may be some inherent differences to patients who receive infliximab as compared to vedolizumab for IBD.”
The study was supported by Biogen (Switzerland), Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, Hull University Teaching Hospital NHS Trust, and the Royal Devon and Exeter NHS Foundation Trust. The study authors disclosed financial and nonfinancial relationships with numerous companies, including AbbVie, Biogen, Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, and Immundiagnostik, as well as Janssen, who markets infliximab, and Takeda, who markets vedolizumab. Dr. Isaacs and Dr. Cohen-Mekelburg had no relevant financial conflicts to disclose.
This article was updated 3/31/21.
Patients treated with infliximab for inflammatory bowel disease (IBD) showed significantly reduced response to COVID-19 antibodies, compared with those treated with vedolizumab, according to data from nearly 7,000 patients.
Although anti–tumor necrosis factor (anti-TNF) drugs are routinely used for patients with IBD, the impact of their immune-suppressing properties on protective immunity to COVID-19 is unknown, wrote Nicholas A. Kennedy, MD, of the University of Exeter (England) and colleagues. These drugs have been reported to impair protective immunity following vaccines for other diseases, such as those for influenza and viral hepatitis.
“By suppressing immune responses, biological and immunosuppression therapies may lead to chronic SARS-CoV-2 infection and have recently been implicated in the evolution and emergence of novel variants,” they noted, citing a study published in Cell.
In the current study, published in Gut, the researchers used data from the CLARITY IBD study to identify 6,935 patients with IBD aged 5 years and older seen at 92 hospitals in the United Kingdom between Sept. 22, 2020, and Dec. 23, 2020. Of these, 4,685 were treated with infliximab, and 2,250 received vedolizumab. The proportion of study participants with a positive anti–SARS-CoV-2 antibody test was the primary outcome, with secondary outcomes including proportion with positive antibodies following positive polymerase chain reaction test for SARS-CoV-2 and the magnitude of antibody reactivity.
Substantial seroprevalence differences seen
Overall, rates of symptomatic and proven SARS-CoV-2 infection and hospitalization were similar between infliximab-treated and vedolizumab-treated patients with IBD. However, seroprevalence was significantly lower in the infliximab group, compared with the vedolizumab group (3.4% vs. 6.0%; P < .0001). In addition, infliximab and immunomodulator use were each independently associated with lower seropositivity, compared with vedolizumab (odds ratio, 0.66 for infliximab and OR, 0.70 for immunomodulators) in a multivariate analysis.
In a sensitivity analysis, 39 of 81 infliximab-treated patients with polymerase chain reaction–confirmed COVID-19 infection seroconverted (48%), compared with 30 of 36 vedolizumab-treated patients (83%) (P < .00044). Infliximab-treated patients with confirmed infections also showed a lower magnitude of anti–SARS-CoV-2 reactivity, compared with vedolizumab-treated patients (P < .0001).
From a clinical perspective, the lower seroconversion rates and reduced levels of anti–SARS-CoV-2 antibody reactivity might increase susceptibility to recurrent COVID-19 infections in infliximab-treated IBD patients, the researchers noted. In addition, the impaired serological responses might promote chronic nasopharyngeal colonization and consequently promote the development of COVID-19 variants and drive persistent transmission, the researchers said.
The study findings were limited by several factors including lack of knowledge on the impact of attenuated immune response on infection risk, the potential for recall bias associated with patient reports, and the focus on infliximab only, the researchers pointed out. However, the key findings are likely apply to other anti-TNF monoclonal antibodies including adalimumab, certolizumab and golimumab, they suggested.
The study was strengthened by the recruitment of a large number of patients in a narrow time frame and comprehensive collection of data on patient-reported outcomes, COVID-19 testing, and serological assay results, the researchers said. Overall, the findings support the public health value of serological testing and virus surveillance to identify suboptimal vaccine response and to consider implications for practice, they added. “If attenuated serological responses following vaccination are also observed, then modified immunization strategies will need to be designed for millions of patients worldwide,” they emphasized.
Findings inform clinical practice and public health
The study is very important for many reasons, said Kim L. Isaacs, MD, PhD, AGAF, of the University of North Carolina at Chapel Hill in an interview. “It is known that there is decreased responsiveness to a number of routine vaccinations in IBD patients on immune active therapy. In terms of SARS-CoV-2, development of an immune response with infection is important in terms of severity of infection, reinfection, and possibly limiting spread of infection in this patient population,” she said. “Looking at both serum seroconversion and reactivity of immune response in patients with known SARS-CoV-2 infection will help to define clinical and public health guidance, and also may be predictive as to what might happen with SARS-CoV-2 immunization based on background biologic or immunosuppressant therapy,” she noted.
Dr. Isaacs said that she was not surprised by the study findings. “Anti-TNF, thiopurine, and methotrexate therapy are all thought to be systemically active and likely to suppress the immune response to infection and vaccination,” she said. Vedolizumab, on the other hand, is thought to be less systemically active and clinically is associated with fewer serious infections.
Data will drive patient counseling
“These results affect counseling of IBD patients on immune active therapy who have had a SARS-CoV-2 infection,” said Dr. Isaacs. “They should be made aware that infection does not indicate protection for further infection. Although the issues that are raised in this study are of concern, patients should not have clinically beneficial therapy discontinued or switched based on these results,” she said.
“Additional research is needed to determine what the seroconversion rate is with the currently available immunizations for SARS-CoV-2,” said Dr. Isaacs. More questions to address include whether there are differences in the different products available, whether immunization after SARS-CoV-2 infection improves both seroconversion and immune reactivity, and whether there is any benefit to transiently stopping dual immune active therapy during the time of immunization, she said.
Further studies can fill knowledge gaps
“There is a knowledge gap in our understanding of susceptibility to SARS-CoV-2 infections among patients with IBD who have previously been infected,” Shirley Cohen-Mekelburg, MD, MS, staff physician and research scientist in the inflammatory bowel disease program at the Veterans Affairs Ann Arbor (Mich.) Healthcare System, said in an interview. ”This is a first step in beginning to narrow this gap – to provide patients and providers with data to drive recommendations during this COVID-19 pandemic.”
She added that, while further work needs to be done, the study findings do support potential benefit for ongoing vigilance among patients receiving infliximab for IBD. “The study findings also drive us to seek answers to more questions: For example, should we consider serological testing for patients on infliximab? How does the presence or absence of anti–SARS-CoV-2 antibodies associate with susceptibility to infection for patients with infliximab?
“Further studies examining anti–SARS-CoV-2 reactivity are necessary to better understand antibody responses between patients with IBD to the general population, or between patients on immunosuppressive therapy and the general population,” she said. “Observational studies are also not designed to examine the causal relationship between infections, medications, and antibody responses. There may be some inherent differences to patients who receive infliximab as compared to vedolizumab for IBD.”
The study was supported by Biogen (Switzerland), Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, Hull University Teaching Hospital NHS Trust, and the Royal Devon and Exeter NHS Foundation Trust. The study authors disclosed financial and nonfinancial relationships with numerous companies, including AbbVie, Biogen, Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, and Immundiagnostik, as well as Janssen, who markets infliximab, and Takeda, who markets vedolizumab. Dr. Isaacs and Dr. Cohen-Mekelburg had no relevant financial conflicts to disclose.
This article was updated 3/31/21.
Patients treated with infliximab for inflammatory bowel disease (IBD) showed significantly reduced response to COVID-19 antibodies, compared with those treated with vedolizumab, according to data from nearly 7,000 patients.
Although anti–tumor necrosis factor (anti-TNF) drugs are routinely used for patients with IBD, the impact of their immune-suppressing properties on protective immunity to COVID-19 is unknown, wrote Nicholas A. Kennedy, MD, of the University of Exeter (England) and colleagues. These drugs have been reported to impair protective immunity following vaccines for other diseases, such as those for influenza and viral hepatitis.
“By suppressing immune responses, biological and immunosuppression therapies may lead to chronic SARS-CoV-2 infection and have recently been implicated in the evolution and emergence of novel variants,” they noted, citing a study published in Cell.
In the current study, published in Gut, the researchers used data from the CLARITY IBD study to identify 6,935 patients with IBD aged 5 years and older seen at 92 hospitals in the United Kingdom between Sept. 22, 2020, and Dec. 23, 2020. Of these, 4,685 were treated with infliximab, and 2,250 received vedolizumab. The proportion of study participants with a positive anti–SARS-CoV-2 antibody test was the primary outcome, with secondary outcomes including proportion with positive antibodies following positive polymerase chain reaction test for SARS-CoV-2 and the magnitude of antibody reactivity.
Substantial seroprevalence differences seen
Overall, rates of symptomatic and proven SARS-CoV-2 infection and hospitalization were similar between infliximab-treated and vedolizumab-treated patients with IBD. However, seroprevalence was significantly lower in the infliximab group, compared with the vedolizumab group (3.4% vs. 6.0%; P < .0001). In addition, infliximab and immunomodulator use were each independently associated with lower seropositivity, compared with vedolizumab (odds ratio, 0.66 for infliximab and OR, 0.70 for immunomodulators) in a multivariate analysis.
In a sensitivity analysis, 39 of 81 infliximab-treated patients with polymerase chain reaction–confirmed COVID-19 infection seroconverted (48%), compared with 30 of 36 vedolizumab-treated patients (83%) (P < .00044). Infliximab-treated patients with confirmed infections also showed a lower magnitude of anti–SARS-CoV-2 reactivity, compared with vedolizumab-treated patients (P < .0001).
From a clinical perspective, the lower seroconversion rates and reduced levels of anti–SARS-CoV-2 antibody reactivity might increase susceptibility to recurrent COVID-19 infections in infliximab-treated IBD patients, the researchers noted. In addition, the impaired serological responses might promote chronic nasopharyngeal colonization and consequently promote the development of COVID-19 variants and drive persistent transmission, the researchers said.
The study findings were limited by several factors including lack of knowledge on the impact of attenuated immune response on infection risk, the potential for recall bias associated with patient reports, and the focus on infliximab only, the researchers pointed out. However, the key findings are likely apply to other anti-TNF monoclonal antibodies including adalimumab, certolizumab and golimumab, they suggested.
The study was strengthened by the recruitment of a large number of patients in a narrow time frame and comprehensive collection of data on patient-reported outcomes, COVID-19 testing, and serological assay results, the researchers said. Overall, the findings support the public health value of serological testing and virus surveillance to identify suboptimal vaccine response and to consider implications for practice, they added. “If attenuated serological responses following vaccination are also observed, then modified immunization strategies will need to be designed for millions of patients worldwide,” they emphasized.
Findings inform clinical practice and public health
The study is very important for many reasons, said Kim L. Isaacs, MD, PhD, AGAF, of the University of North Carolina at Chapel Hill in an interview. “It is known that there is decreased responsiveness to a number of routine vaccinations in IBD patients on immune active therapy. In terms of SARS-CoV-2, development of an immune response with infection is important in terms of severity of infection, reinfection, and possibly limiting spread of infection in this patient population,” she said. “Looking at both serum seroconversion and reactivity of immune response in patients with known SARS-CoV-2 infection will help to define clinical and public health guidance, and also may be predictive as to what might happen with SARS-CoV-2 immunization based on background biologic or immunosuppressant therapy,” she noted.
Dr. Isaacs said that she was not surprised by the study findings. “Anti-TNF, thiopurine, and methotrexate therapy are all thought to be systemically active and likely to suppress the immune response to infection and vaccination,” she said. Vedolizumab, on the other hand, is thought to be less systemically active and clinically is associated with fewer serious infections.
Data will drive patient counseling
“These results affect counseling of IBD patients on immune active therapy who have had a SARS-CoV-2 infection,” said Dr. Isaacs. “They should be made aware that infection does not indicate protection for further infection. Although the issues that are raised in this study are of concern, patients should not have clinically beneficial therapy discontinued or switched based on these results,” she said.
“Additional research is needed to determine what the seroconversion rate is with the currently available immunizations for SARS-CoV-2,” said Dr. Isaacs. More questions to address include whether there are differences in the different products available, whether immunization after SARS-CoV-2 infection improves both seroconversion and immune reactivity, and whether there is any benefit to transiently stopping dual immune active therapy during the time of immunization, she said.
Further studies can fill knowledge gaps
“There is a knowledge gap in our understanding of susceptibility to SARS-CoV-2 infections among patients with IBD who have previously been infected,” Shirley Cohen-Mekelburg, MD, MS, staff physician and research scientist in the inflammatory bowel disease program at the Veterans Affairs Ann Arbor (Mich.) Healthcare System, said in an interview. ”This is a first step in beginning to narrow this gap – to provide patients and providers with data to drive recommendations during this COVID-19 pandemic.”
She added that, while further work needs to be done, the study findings do support potential benefit for ongoing vigilance among patients receiving infliximab for IBD. “The study findings also drive us to seek answers to more questions: For example, should we consider serological testing for patients on infliximab? How does the presence or absence of anti–SARS-CoV-2 antibodies associate with susceptibility to infection for patients with infliximab?
“Further studies examining anti–SARS-CoV-2 reactivity are necessary to better understand antibody responses between patients with IBD to the general population, or between patients on immunosuppressive therapy and the general population,” she said. “Observational studies are also not designed to examine the causal relationship between infections, medications, and antibody responses. There may be some inherent differences to patients who receive infliximab as compared to vedolizumab for IBD.”
The study was supported by Biogen (Switzerland), Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, Hull University Teaching Hospital NHS Trust, and the Royal Devon and Exeter NHS Foundation Trust. The study authors disclosed financial and nonfinancial relationships with numerous companies, including AbbVie, Biogen, Celltrion Healthcare, Galapagos, F. Hoffmann-La Roche, and Immundiagnostik, as well as Janssen, who markets infliximab, and Takeda, who markets vedolizumab. Dr. Isaacs and Dr. Cohen-Mekelburg had no relevant financial conflicts to disclose.
This article was updated 3/31/21.
FROM GUT
Cumulative inflammatory burden predicts cancer risk in ulcerative colitis
The cumulative burden of histologic inflammation is a strong predictor of colorectal neoplasia risk in ulcerative colitis, according to a recent case-control study.
David T. Rubin, MD, was the senior author of the study, which provided independent validation of a metric for cumulative burden of inflammation as a risk stratification tool in ulcerative colitis and presented these findings at the Gastroenterology Updates, IBD, Liver Disease Conference. The metric was developed at St. Mark’s Hospital, London, which he called “a leader in the field.”
“The implication of demonstrating this is that, if you control inflammation and keep it controlled over time, it would imply that you can reduce the overall risk for cancer and dysplasia,” explained Dr. Rubin, professor of medicine and chief of the section of gastroenterology, hepatology, and nutrition at the University of Chicago.
The original retrospective St. Mark’s study included 987 patients with extensive ulcerative colitis followed with colonoscopic surveillance for a median of 13 years. Each colonoscopy was scored for severity of microscopic inflammation on a 0-3 scale. The investigators calculated a patient’s cumulative inflammatory burden by adding each histologic inflammatory activity score and multiplying that figure by the surveillance interval in years.
In a multivariate analysis, the London investigators demonstrated that the risk of colorectal neoplasia jumped by 2.1-fold for each 10-unit increase in cumulative inflammatory burden, defined as the equivalent of either 10 years of continuous mild active histologic inflammation, 5 years of continuous moderate inflammation, or 3.3 years of continuous severe inflammation.
The University of Chicago retrospective external validation study included 26 ulcerative colitis patients with colorectal neoplasia and 36 others without cancer. The mean cumulative histologic inflammatory activity score in the group with colorectal neoplasia was 12.63, compared with 7.98 in controls. For each 1-unit increase in cumulative inflammatory burden the risk of developing colorectal neoplasia increased by 8%, consistent with the magnitude of the hazard previously reported at St. Mark’s.
“The way you could take this back to your practice is by thinking carefully about what is the degree of inflammation each time you’ve done a colonoscopy and considering whether the patient who is in deep remission and doing well might deserve a longer interval between their next exam and the one you just completed,” according to the gastroenterologist.
“The most interval I give a patient is 3 years – for somebody in deep remission with no inflammation on the last exam. And when they’ve had prior inflammation but are now doing well, I keep in mind what that prior inflammation was. We’re now working on using that cumulative histologic inflammation score to guide intervals, but we don’t have prospective data to validate this approach. So when you’re not sure, the conservative approach is surveillance colonoscopy every 1-2 years after you’ve had 10 years of disease. That’s probably overutilization of our resources, but we don’t have a better way to do it yet,” Dr. Rubin said.
The novel metric for calculating cumulative histologic inflammation burden as a means of predicting colorectal cancer in ulcerative colitis dovetails with the current emphasis upon individualized risk assessment as recommended in the latest American College of Gastroenterology practice guidelines, for which Dr. Rubin was first author.
“Like we individualize our treatments, we should individualize our colorectal cancer screening and prevention strategies,” he emphasized.
Risk factors for colorectal cancer and dysplasia in patients with ulcerative colitis can be grouped as either potentially modifiable or immutable. Potentially modifiable risk factors include backwash ileitis, pseudopolyps, prior dysplasia, and mass or stricture, as well as the degree of histologic inflammation. Immutable risk factors include younger age at diagnosis, male gender, duration and extent of disease, family history of colorectal cancer, and primary sclerosing cholangitis, Dr. Rubin noted.
He reported receiving grant support from and/or serving as a consultant to more than two dozen medical companies.
The cumulative burden of histologic inflammation is a strong predictor of colorectal neoplasia risk in ulcerative colitis, according to a recent case-control study.
David T. Rubin, MD, was the senior author of the study, which provided independent validation of a metric for cumulative burden of inflammation as a risk stratification tool in ulcerative colitis and presented these findings at the Gastroenterology Updates, IBD, Liver Disease Conference. The metric was developed at St. Mark’s Hospital, London, which he called “a leader in the field.”
“The implication of demonstrating this is that, if you control inflammation and keep it controlled over time, it would imply that you can reduce the overall risk for cancer and dysplasia,” explained Dr. Rubin, professor of medicine and chief of the section of gastroenterology, hepatology, and nutrition at the University of Chicago.
The original retrospective St. Mark’s study included 987 patients with extensive ulcerative colitis followed with colonoscopic surveillance for a median of 13 years. Each colonoscopy was scored for severity of microscopic inflammation on a 0-3 scale. The investigators calculated a patient’s cumulative inflammatory burden by adding each histologic inflammatory activity score and multiplying that figure by the surveillance interval in years.
In a multivariate analysis, the London investigators demonstrated that the risk of colorectal neoplasia jumped by 2.1-fold for each 10-unit increase in cumulative inflammatory burden, defined as the equivalent of either 10 years of continuous mild active histologic inflammation, 5 years of continuous moderate inflammation, or 3.3 years of continuous severe inflammation.
The University of Chicago retrospective external validation study included 26 ulcerative colitis patients with colorectal neoplasia and 36 others without cancer. The mean cumulative histologic inflammatory activity score in the group with colorectal neoplasia was 12.63, compared with 7.98 in controls. For each 1-unit increase in cumulative inflammatory burden the risk of developing colorectal neoplasia increased by 8%, consistent with the magnitude of the hazard previously reported at St. Mark’s.
“The way you could take this back to your practice is by thinking carefully about what is the degree of inflammation each time you’ve done a colonoscopy and considering whether the patient who is in deep remission and doing well might deserve a longer interval between their next exam and the one you just completed,” according to the gastroenterologist.
“The most interval I give a patient is 3 years – for somebody in deep remission with no inflammation on the last exam. And when they’ve had prior inflammation but are now doing well, I keep in mind what that prior inflammation was. We’re now working on using that cumulative histologic inflammation score to guide intervals, but we don’t have prospective data to validate this approach. So when you’re not sure, the conservative approach is surveillance colonoscopy every 1-2 years after you’ve had 10 years of disease. That’s probably overutilization of our resources, but we don’t have a better way to do it yet,” Dr. Rubin said.
The novel metric for calculating cumulative histologic inflammation burden as a means of predicting colorectal cancer in ulcerative colitis dovetails with the current emphasis upon individualized risk assessment as recommended in the latest American College of Gastroenterology practice guidelines, for which Dr. Rubin was first author.
“Like we individualize our treatments, we should individualize our colorectal cancer screening and prevention strategies,” he emphasized.
Risk factors for colorectal cancer and dysplasia in patients with ulcerative colitis can be grouped as either potentially modifiable or immutable. Potentially modifiable risk factors include backwash ileitis, pseudopolyps, prior dysplasia, and mass or stricture, as well as the degree of histologic inflammation. Immutable risk factors include younger age at diagnosis, male gender, duration and extent of disease, family history of colorectal cancer, and primary sclerosing cholangitis, Dr. Rubin noted.
He reported receiving grant support from and/or serving as a consultant to more than two dozen medical companies.
The cumulative burden of histologic inflammation is a strong predictor of colorectal neoplasia risk in ulcerative colitis, according to a recent case-control study.
David T. Rubin, MD, was the senior author of the study, which provided independent validation of a metric for cumulative burden of inflammation as a risk stratification tool in ulcerative colitis and presented these findings at the Gastroenterology Updates, IBD, Liver Disease Conference. The metric was developed at St. Mark’s Hospital, London, which he called “a leader in the field.”
“The implication of demonstrating this is that, if you control inflammation and keep it controlled over time, it would imply that you can reduce the overall risk for cancer and dysplasia,” explained Dr. Rubin, professor of medicine and chief of the section of gastroenterology, hepatology, and nutrition at the University of Chicago.
The original retrospective St. Mark’s study included 987 patients with extensive ulcerative colitis followed with colonoscopic surveillance for a median of 13 years. Each colonoscopy was scored for severity of microscopic inflammation on a 0-3 scale. The investigators calculated a patient’s cumulative inflammatory burden by adding each histologic inflammatory activity score and multiplying that figure by the surveillance interval in years.
In a multivariate analysis, the London investigators demonstrated that the risk of colorectal neoplasia jumped by 2.1-fold for each 10-unit increase in cumulative inflammatory burden, defined as the equivalent of either 10 years of continuous mild active histologic inflammation, 5 years of continuous moderate inflammation, or 3.3 years of continuous severe inflammation.
The University of Chicago retrospective external validation study included 26 ulcerative colitis patients with colorectal neoplasia and 36 others without cancer. The mean cumulative histologic inflammatory activity score in the group with colorectal neoplasia was 12.63, compared with 7.98 in controls. For each 1-unit increase in cumulative inflammatory burden the risk of developing colorectal neoplasia increased by 8%, consistent with the magnitude of the hazard previously reported at St. Mark’s.
“The way you could take this back to your practice is by thinking carefully about what is the degree of inflammation each time you’ve done a colonoscopy and considering whether the patient who is in deep remission and doing well might deserve a longer interval between their next exam and the one you just completed,” according to the gastroenterologist.
“The most interval I give a patient is 3 years – for somebody in deep remission with no inflammation on the last exam. And when they’ve had prior inflammation but are now doing well, I keep in mind what that prior inflammation was. We’re now working on using that cumulative histologic inflammation score to guide intervals, but we don’t have prospective data to validate this approach. So when you’re not sure, the conservative approach is surveillance colonoscopy every 1-2 years after you’ve had 10 years of disease. That’s probably overutilization of our resources, but we don’t have a better way to do it yet,” Dr. Rubin said.
The novel metric for calculating cumulative histologic inflammation burden as a means of predicting colorectal cancer in ulcerative colitis dovetails with the current emphasis upon individualized risk assessment as recommended in the latest American College of Gastroenterology practice guidelines, for which Dr. Rubin was first author.
“Like we individualize our treatments, we should individualize our colorectal cancer screening and prevention strategies,” he emphasized.
Risk factors for colorectal cancer and dysplasia in patients with ulcerative colitis can be grouped as either potentially modifiable or immutable. Potentially modifiable risk factors include backwash ileitis, pseudopolyps, prior dysplasia, and mass or stricture, as well as the degree of histologic inflammation. Immutable risk factors include younger age at diagnosis, male gender, duration and extent of disease, family history of colorectal cancer, and primary sclerosing cholangitis, Dr. Rubin noted.
He reported receiving grant support from and/or serving as a consultant to more than two dozen medical companies.
FROM GUILD 2021
Psychological difficulties persist among patients with IBD
Psychological issues in patients with inflammatory bowel disease should be addressed at both personal and systemic levels, according to a review of current literature.
In a review published in the Journal of Clinical Gastroenterology, researchers highlighted data on the burden of mental disorders in inflammatory bowel disease (IBD) patients and presented several strategies for addressing them.
“From a systems perspective, underrecognized and/or suboptimally treated mental health problems in patients with IBD are associated with increased disability, poorer adherence, and more admissions and surgeries, driving increased health care utilization and costs,” Maia S. Kredentser, PhD, of the University of Manitoba, Winnipeg, and colleagues wrote, citing a 2018 study’s findings.
“There is ample evidence for a higher prevalence of mental disorders in IBD, in particular depression and anxiety, compared with the general population,” the authors wrote.
They cited a recent population-based study in which the incident rate ratios were significantly higher for IBD patients, compared with matched controls for depression (IRR, 1.58), anxiety disorder (IRR, 1.39), bipolar disorder (IRR, 1.82), and schizophrenia (IRR, 1.64).
Mental disorders associated with IBD also include issues of body image and sexuality. Although research on the impact of disease activity on sexual function is inconsistent, one study suggested that body image “may be an important target of treatment in women reporting poor quality of life and psychological distress,” the researchers noted. A French study from 2017 published in the Journal of Crohn’s and Colitis showed that approximately half of men and women reported problems with erectile or sexual dysfunction.
Issues related to environmental stressors may contribute to IBD by promoting chronic inflammation, the researchers wrote. For example, data from longitudinal, population-based research suggest that adverse childhood experiences can promote proinflammatory states across inflammatory illnesses. Research has also suggested that people with IBD have higher rates of these adverse childhood experiences than the general population. However, data also show that many are able to cope and adapt: “Many patients with IBD are resilient, experience growth, and in fact, thrive,” the researchers added. One longitudinal study suggested that patients with IBD who identified with “thriving” had “stronger coping efficacy (the perceived ability to meet illness demands), illness acceptance, and social support and lower depression” and that this was associated with life satisfaction 6 months later.
Fatigue also has been shown to be a factor for patients with IBD. The researchers cited one population-based study showing fatigue in 57%-72% of IBD patients with active disease. IBD patients with quiescent disease also report fatigue. The psychological and behavioral factors driving fatigue could be related to mental disorders or other factors such as suboptimal sleep, stress, and use of caffeine and alcohol, they noted. Management strategies include improving sleep hygiene and evaluation of mental health concerns.
Seek complete picture before treatment
“Addressing psychological comorbidity in IBD requires individual and systemic approaches focused on both the prevention and treatment of mental health concerns,” the researchers wrote. “Because of the pervasiveness of psychological comorbidities in IBD, and recent evidence that they may be part of the disease process itself, assessment of psychological functioning in IBD is considered an essential aspect of disease management.”
Evidence-based psychological interventions include cognitive-behavioral therapy, which includes training in relaxation; treatment with clinical hypnosis; and encouraging mindfulness through acceptance and commitment therapy, which focuses on developing psychological flexibility to cope with suffering. In addition, a small but evolving body of research shows some benefit to motivational interviewing (a strategy focused on behavior change) for IBD patients. Notably, one review of four studies showed benefits of motivational interviewing for improving medication adherence and advice seeking, the researchers reported.
Although several psychological treatment options exist for addressing mental health issues in IBD, randomized trials are needed. “To facilitate this important research and optimize patient care, the integration of psychologists and other mental health providers into IBD care is considered best practice and provides exciting opportunities for improving patient care and outcomes,” the researchers concluded.
Address mental health to ease disease burden
“There is a large burden of mental health issues in patients with inflammatory bowel disease, with depression and anxiety leading the way,” Kim L. Isaacs, MD, of the University of North Carolina at Chapel Hill, said in an interview.
“There are multiple reasons for this, including dealing with chronic pain, social concerns around using the bathroom, body-image issues due to surgery, and drug side effects. There is increasing evidence that the inflammatory process in IBD may be driving some of the changes in the brain which lead to further mental health dysfunction,” she noted.
“Addressing depression, anxiety, [and] sleep disturbance in patients will not only improve quality of life from a mental health perspective but has been shown to improve control of disease,” Dr. Isaacs emphasized.
“Small things like increased medication compliance have a large impact on disease management and decreased need for hospitalization and hospitalization,” said Dr. Isaacs. “As gastroenterologists we need to expand our focus beyond the gut and address the emotional needs of our patients – identifying those patients who need increased mental health support.”
Barriers to better care
The greatest barriers to treating mental health issues in IBD patients are time and knowledge, said Dr. Isaacs. “Many gastroenterologists have limited time in the office to do more than address the acute issues of the patients such as rectal bleeding and worsening diarrhea. It takes time and trust to explore what is going on in a patient’s life. Is the patient anxious and depressed? How are they coping with their current disease manifestations? Simple screening tools may help with this, but then there need to be resources to support interventions.”
Some IBD practices, especially academic ones, have a psychologist in the IBD center or one that’s readily available for consultation. “This is an investment for the practice that may reduce significantly disease burden. The IBD specialty home model includes resources for management of psychiatric issues and nutritional concerns as well as disease management,” she added.
More research in several areas can help reduce the mental health burden of IBD. “On the immunology/biology side, understanding how the microbiome affects the brain/gut may allow for more directed mental health treatment. On the disease management side, larger trials directed at psychiatric interventions may help to determine which therapy is best for each patient,” Dr. Isaacs said. “Further work developing health care systems, such as the medical home, that allow for maximum disease management and decreased system costs will go far in implementation of models of care that address the needs of the entire patient with inflammatory bowel disease.”
The review received no outside funding. The researchers had no financial conflicts to disclose. Dr. Isaacs disclosed consulting on the data safety monitoring board for Janssen.
Psychological issues in patients with inflammatory bowel disease should be addressed at both personal and systemic levels, according to a review of current literature.
In a review published in the Journal of Clinical Gastroenterology, researchers highlighted data on the burden of mental disorders in inflammatory bowel disease (IBD) patients and presented several strategies for addressing them.
“From a systems perspective, underrecognized and/or suboptimally treated mental health problems in patients with IBD are associated with increased disability, poorer adherence, and more admissions and surgeries, driving increased health care utilization and costs,” Maia S. Kredentser, PhD, of the University of Manitoba, Winnipeg, and colleagues wrote, citing a 2018 study’s findings.
“There is ample evidence for a higher prevalence of mental disorders in IBD, in particular depression and anxiety, compared with the general population,” the authors wrote.
They cited a recent population-based study in which the incident rate ratios were significantly higher for IBD patients, compared with matched controls for depression (IRR, 1.58), anxiety disorder (IRR, 1.39), bipolar disorder (IRR, 1.82), and schizophrenia (IRR, 1.64).
Mental disorders associated with IBD also include issues of body image and sexuality. Although research on the impact of disease activity on sexual function is inconsistent, one study suggested that body image “may be an important target of treatment in women reporting poor quality of life and psychological distress,” the researchers noted. A French study from 2017 published in the Journal of Crohn’s and Colitis showed that approximately half of men and women reported problems with erectile or sexual dysfunction.
Issues related to environmental stressors may contribute to IBD by promoting chronic inflammation, the researchers wrote. For example, data from longitudinal, population-based research suggest that adverse childhood experiences can promote proinflammatory states across inflammatory illnesses. Research has also suggested that people with IBD have higher rates of these adverse childhood experiences than the general population. However, data also show that many are able to cope and adapt: “Many patients with IBD are resilient, experience growth, and in fact, thrive,” the researchers added. One longitudinal study suggested that patients with IBD who identified with “thriving” had “stronger coping efficacy (the perceived ability to meet illness demands), illness acceptance, and social support and lower depression” and that this was associated with life satisfaction 6 months later.
Fatigue also has been shown to be a factor for patients with IBD. The researchers cited one population-based study showing fatigue in 57%-72% of IBD patients with active disease. IBD patients with quiescent disease also report fatigue. The psychological and behavioral factors driving fatigue could be related to mental disorders or other factors such as suboptimal sleep, stress, and use of caffeine and alcohol, they noted. Management strategies include improving sleep hygiene and evaluation of mental health concerns.
Seek complete picture before treatment
“Addressing psychological comorbidity in IBD requires individual and systemic approaches focused on both the prevention and treatment of mental health concerns,” the researchers wrote. “Because of the pervasiveness of psychological comorbidities in IBD, and recent evidence that they may be part of the disease process itself, assessment of psychological functioning in IBD is considered an essential aspect of disease management.”
Evidence-based psychological interventions include cognitive-behavioral therapy, which includes training in relaxation; treatment with clinical hypnosis; and encouraging mindfulness through acceptance and commitment therapy, which focuses on developing psychological flexibility to cope with suffering. In addition, a small but evolving body of research shows some benefit to motivational interviewing (a strategy focused on behavior change) for IBD patients. Notably, one review of four studies showed benefits of motivational interviewing for improving medication adherence and advice seeking, the researchers reported.
Although several psychological treatment options exist for addressing mental health issues in IBD, randomized trials are needed. “To facilitate this important research and optimize patient care, the integration of psychologists and other mental health providers into IBD care is considered best practice and provides exciting opportunities for improving patient care and outcomes,” the researchers concluded.
Address mental health to ease disease burden
“There is a large burden of mental health issues in patients with inflammatory bowel disease, with depression and anxiety leading the way,” Kim L. Isaacs, MD, of the University of North Carolina at Chapel Hill, said in an interview.
“There are multiple reasons for this, including dealing with chronic pain, social concerns around using the bathroom, body-image issues due to surgery, and drug side effects. There is increasing evidence that the inflammatory process in IBD may be driving some of the changes in the brain which lead to further mental health dysfunction,” she noted.
“Addressing depression, anxiety, [and] sleep disturbance in patients will not only improve quality of life from a mental health perspective but has been shown to improve control of disease,” Dr. Isaacs emphasized.
“Small things like increased medication compliance have a large impact on disease management and decreased need for hospitalization and hospitalization,” said Dr. Isaacs. “As gastroenterologists we need to expand our focus beyond the gut and address the emotional needs of our patients – identifying those patients who need increased mental health support.”
Barriers to better care
The greatest barriers to treating mental health issues in IBD patients are time and knowledge, said Dr. Isaacs. “Many gastroenterologists have limited time in the office to do more than address the acute issues of the patients such as rectal bleeding and worsening diarrhea. It takes time and trust to explore what is going on in a patient’s life. Is the patient anxious and depressed? How are they coping with their current disease manifestations? Simple screening tools may help with this, but then there need to be resources to support interventions.”
Some IBD practices, especially academic ones, have a psychologist in the IBD center or one that’s readily available for consultation. “This is an investment for the practice that may reduce significantly disease burden. The IBD specialty home model includes resources for management of psychiatric issues and nutritional concerns as well as disease management,” she added.
More research in several areas can help reduce the mental health burden of IBD. “On the immunology/biology side, understanding how the microbiome affects the brain/gut may allow for more directed mental health treatment. On the disease management side, larger trials directed at psychiatric interventions may help to determine which therapy is best for each patient,” Dr. Isaacs said. “Further work developing health care systems, such as the medical home, that allow for maximum disease management and decreased system costs will go far in implementation of models of care that address the needs of the entire patient with inflammatory bowel disease.”
The review received no outside funding. The researchers had no financial conflicts to disclose. Dr. Isaacs disclosed consulting on the data safety monitoring board for Janssen.
Psychological issues in patients with inflammatory bowel disease should be addressed at both personal and systemic levels, according to a review of current literature.
In a review published in the Journal of Clinical Gastroenterology, researchers highlighted data on the burden of mental disorders in inflammatory bowel disease (IBD) patients and presented several strategies for addressing them.
“From a systems perspective, underrecognized and/or suboptimally treated mental health problems in patients with IBD are associated with increased disability, poorer adherence, and more admissions and surgeries, driving increased health care utilization and costs,” Maia S. Kredentser, PhD, of the University of Manitoba, Winnipeg, and colleagues wrote, citing a 2018 study’s findings.
“There is ample evidence for a higher prevalence of mental disorders in IBD, in particular depression and anxiety, compared with the general population,” the authors wrote.
They cited a recent population-based study in which the incident rate ratios were significantly higher for IBD patients, compared with matched controls for depression (IRR, 1.58), anxiety disorder (IRR, 1.39), bipolar disorder (IRR, 1.82), and schizophrenia (IRR, 1.64).
Mental disorders associated with IBD also include issues of body image and sexuality. Although research on the impact of disease activity on sexual function is inconsistent, one study suggested that body image “may be an important target of treatment in women reporting poor quality of life and psychological distress,” the researchers noted. A French study from 2017 published in the Journal of Crohn’s and Colitis showed that approximately half of men and women reported problems with erectile or sexual dysfunction.
Issues related to environmental stressors may contribute to IBD by promoting chronic inflammation, the researchers wrote. For example, data from longitudinal, population-based research suggest that adverse childhood experiences can promote proinflammatory states across inflammatory illnesses. Research has also suggested that people with IBD have higher rates of these adverse childhood experiences than the general population. However, data also show that many are able to cope and adapt: “Many patients with IBD are resilient, experience growth, and in fact, thrive,” the researchers added. One longitudinal study suggested that patients with IBD who identified with “thriving” had “stronger coping efficacy (the perceived ability to meet illness demands), illness acceptance, and social support and lower depression” and that this was associated with life satisfaction 6 months later.
Fatigue also has been shown to be a factor for patients with IBD. The researchers cited one population-based study showing fatigue in 57%-72% of IBD patients with active disease. IBD patients with quiescent disease also report fatigue. The psychological and behavioral factors driving fatigue could be related to mental disorders or other factors such as suboptimal sleep, stress, and use of caffeine and alcohol, they noted. Management strategies include improving sleep hygiene and evaluation of mental health concerns.
Seek complete picture before treatment
“Addressing psychological comorbidity in IBD requires individual and systemic approaches focused on both the prevention and treatment of mental health concerns,” the researchers wrote. “Because of the pervasiveness of psychological comorbidities in IBD, and recent evidence that they may be part of the disease process itself, assessment of psychological functioning in IBD is considered an essential aspect of disease management.”
Evidence-based psychological interventions include cognitive-behavioral therapy, which includes training in relaxation; treatment with clinical hypnosis; and encouraging mindfulness through acceptance and commitment therapy, which focuses on developing psychological flexibility to cope with suffering. In addition, a small but evolving body of research shows some benefit to motivational interviewing (a strategy focused on behavior change) for IBD patients. Notably, one review of four studies showed benefits of motivational interviewing for improving medication adherence and advice seeking, the researchers reported.
Although several psychological treatment options exist for addressing mental health issues in IBD, randomized trials are needed. “To facilitate this important research and optimize patient care, the integration of psychologists and other mental health providers into IBD care is considered best practice and provides exciting opportunities for improving patient care and outcomes,” the researchers concluded.
Address mental health to ease disease burden
“There is a large burden of mental health issues in patients with inflammatory bowel disease, with depression and anxiety leading the way,” Kim L. Isaacs, MD, of the University of North Carolina at Chapel Hill, said in an interview.
“There are multiple reasons for this, including dealing with chronic pain, social concerns around using the bathroom, body-image issues due to surgery, and drug side effects. There is increasing evidence that the inflammatory process in IBD may be driving some of the changes in the brain which lead to further mental health dysfunction,” she noted.
“Addressing depression, anxiety, [and] sleep disturbance in patients will not only improve quality of life from a mental health perspective but has been shown to improve control of disease,” Dr. Isaacs emphasized.
“Small things like increased medication compliance have a large impact on disease management and decreased need for hospitalization and hospitalization,” said Dr. Isaacs. “As gastroenterologists we need to expand our focus beyond the gut and address the emotional needs of our patients – identifying those patients who need increased mental health support.”
Barriers to better care
The greatest barriers to treating mental health issues in IBD patients are time and knowledge, said Dr. Isaacs. “Many gastroenterologists have limited time in the office to do more than address the acute issues of the patients such as rectal bleeding and worsening diarrhea. It takes time and trust to explore what is going on in a patient’s life. Is the patient anxious and depressed? How are they coping with their current disease manifestations? Simple screening tools may help with this, but then there need to be resources to support interventions.”
Some IBD practices, especially academic ones, have a psychologist in the IBD center or one that’s readily available for consultation. “This is an investment for the practice that may reduce significantly disease burden. The IBD specialty home model includes resources for management of psychiatric issues and nutritional concerns as well as disease management,” she added.
More research in several areas can help reduce the mental health burden of IBD. “On the immunology/biology side, understanding how the microbiome affects the brain/gut may allow for more directed mental health treatment. On the disease management side, larger trials directed at psychiatric interventions may help to determine which therapy is best for each patient,” Dr. Isaacs said. “Further work developing health care systems, such as the medical home, that allow for maximum disease management and decreased system costs will go far in implementation of models of care that address the needs of the entire patient with inflammatory bowel disease.”
The review received no outside funding. The researchers had no financial conflicts to disclose. Dr. Isaacs disclosed consulting on the data safety monitoring board for Janssen.
FROM THE JOURNAL OF CLINICAL GASTROENTEROLOGY
Can smoke exposure inform CRC surveillance in IBD?
Cigarette smoking may be associated with a higher probability of developing colorectal neoplasia (CRN) among patients with inflammatory bowel disease (IBD), a finding that if confirmed could help to refine colorectal cancer surveillance guidelines. IBD patients undergo surveillance at specific time points of their disease with the aim to detect and potentially treat early CRN.
But these procedures are costly and burdensome to patients, and some previous studies have revealed a relatively low utility for patients, according to Kimberley van der Sloot, MD, a PhD candidate at the University Medical Center Groningen (the Netherlands). She presented the research at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. The study was also published in Clinical Gastroenterology and Hepatology.
“We aimed to explore the role of cigarette exposure in colorectal neoplasia risk in patients with IBD, and we aimed to improve the CRN risk stratification model that we are currently using for these surveillance guidelines,” Dr. van der Sloot said during her talk.
Commenters during the Q&A period noted that the population database used in the study did not include measures of inflammation, which is a known risk for CRN. One review found that smoking worsens inflammation in Crohn’s disease but improves it in ulcerative colitis.
“It certainly raises the issue that we’ve always said, which is that people should quit smoking for other health reasons, but it doesn’t necessarily answer the question definitively,” said David Rubin, MD, who moderated the session and is professor of medicine at the University of Chicago and chair of the congress’s organizing committee. He added that the association between smoking and CRN risk may nevertheless inform future management surveillance guidelines if it is confirmed.
The researchers analyzed data from the 1000IBD cohort, which is prospectively following IBD patients in the Netherlands. The study included 1,386 patients who had at least one colorectal biopsy. Compared to a general population CRN incidence of 2.4%, Crohn’s disease patients who were never smokers had an incidence of 4.7% versus 10.3% among former or current smokers. In ulcerative colitis, the incidence was 12.5% among never smokers and 17.9% among former or current smokers.
In Crohn’s disease, previous or current smokers had about a twofold increased risk (hazard ratio, 2.04; P = .044). Compared to never smokers, former smokers trended toward an increased risk (HR, 2.16; P = .051), and active smokers had a significantly increased risk (HR, 2.20; P = .044). Passive smoke exposure was also associated with greater risk, both in childhood (HR, 4.79; P = .003) and current (HR, 1.87; P = .024).
In ulcerative colitis, the only statistically significant association between smoke exposure and CRN risk was among former smokers (HR, 1.73; P = .032).
The researchers also looked at patients with a disease duration longer than 8 years and stratified patients according to low risk (left-side ulcerative colitis, <50% of colon affected in Crohn’s disease; n = 425), medium risk (postinflammatory polyposis present or extensive colitis; n = 467), and high risk (concordant primary sclerosing cholangitis or having a first-degree relative with colorectal cancer; n = 143). In Crohn’s disease, current smoking was associated with greater CRN incidence (P = .046), and former smoking trended in that direction but was nonsignificant (P = .068). Former smoking also trended toward a risk in ulcerative colitis (P = .068), but there was no sign of an association for current smoking (P = .883).
In Crohn’s disease, after adjustment for risk stratification, greater CRN risk was associated with passive smoke exposure both during childhood (P = .001) and at present (P = .003).
“We believe this is the first study to describe the important role of cigarette smoking in development of colorectal neoplasia in IBD patients in a large, prospective, cohort, and I think [it] has shown the importance of lifestyle and smoking particularly in IBD. This is one more example. Alongside that, we’ve shown that adding this risk factor can improve the current risk stratification that is used for surveillance guidelines, and might be of benefit in the development of future guidelines,” said Dr. van der Sloot.
Dr. van der Sloot and Dr. Rubin had no relevant financial disclosures.
This article was updated Mar. 11, 2021.
Cigarette smoking may be associated with a higher probability of developing colorectal neoplasia (CRN) among patients with inflammatory bowel disease (IBD), a finding that if confirmed could help to refine colorectal cancer surveillance guidelines. IBD patients undergo surveillance at specific time points of their disease with the aim to detect and potentially treat early CRN.
But these procedures are costly and burdensome to patients, and some previous studies have revealed a relatively low utility for patients, according to Kimberley van der Sloot, MD, a PhD candidate at the University Medical Center Groningen (the Netherlands). She presented the research at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. The study was also published in Clinical Gastroenterology and Hepatology.
“We aimed to explore the role of cigarette exposure in colorectal neoplasia risk in patients with IBD, and we aimed to improve the CRN risk stratification model that we are currently using for these surveillance guidelines,” Dr. van der Sloot said during her talk.
Commenters during the Q&A period noted that the population database used in the study did not include measures of inflammation, which is a known risk for CRN. One review found that smoking worsens inflammation in Crohn’s disease but improves it in ulcerative colitis.
“It certainly raises the issue that we’ve always said, which is that people should quit smoking for other health reasons, but it doesn’t necessarily answer the question definitively,” said David Rubin, MD, who moderated the session and is professor of medicine at the University of Chicago and chair of the congress’s organizing committee. He added that the association between smoking and CRN risk may nevertheless inform future management surveillance guidelines if it is confirmed.
The researchers analyzed data from the 1000IBD cohort, which is prospectively following IBD patients in the Netherlands. The study included 1,386 patients who had at least one colorectal biopsy. Compared to a general population CRN incidence of 2.4%, Crohn’s disease patients who were never smokers had an incidence of 4.7% versus 10.3% among former or current smokers. In ulcerative colitis, the incidence was 12.5% among never smokers and 17.9% among former or current smokers.
In Crohn’s disease, previous or current smokers had about a twofold increased risk (hazard ratio, 2.04; P = .044). Compared to never smokers, former smokers trended toward an increased risk (HR, 2.16; P = .051), and active smokers had a significantly increased risk (HR, 2.20; P = .044). Passive smoke exposure was also associated with greater risk, both in childhood (HR, 4.79; P = .003) and current (HR, 1.87; P = .024).
In ulcerative colitis, the only statistically significant association between smoke exposure and CRN risk was among former smokers (HR, 1.73; P = .032).
The researchers also looked at patients with a disease duration longer than 8 years and stratified patients according to low risk (left-side ulcerative colitis, <50% of colon affected in Crohn’s disease; n = 425), medium risk (postinflammatory polyposis present or extensive colitis; n = 467), and high risk (concordant primary sclerosing cholangitis or having a first-degree relative with colorectal cancer; n = 143). In Crohn’s disease, current smoking was associated with greater CRN incidence (P = .046), and former smoking trended in that direction but was nonsignificant (P = .068). Former smoking also trended toward a risk in ulcerative colitis (P = .068), but there was no sign of an association for current smoking (P = .883).
In Crohn’s disease, after adjustment for risk stratification, greater CRN risk was associated with passive smoke exposure both during childhood (P = .001) and at present (P = .003).
“We believe this is the first study to describe the important role of cigarette smoking in development of colorectal neoplasia in IBD patients in a large, prospective, cohort, and I think [it] has shown the importance of lifestyle and smoking particularly in IBD. This is one more example. Alongside that, we’ve shown that adding this risk factor can improve the current risk stratification that is used for surveillance guidelines, and might be of benefit in the development of future guidelines,” said Dr. van der Sloot.
Dr. van der Sloot and Dr. Rubin had no relevant financial disclosures.
This article was updated Mar. 11, 2021.
Cigarette smoking may be associated with a higher probability of developing colorectal neoplasia (CRN) among patients with inflammatory bowel disease (IBD), a finding that if confirmed could help to refine colorectal cancer surveillance guidelines. IBD patients undergo surveillance at specific time points of their disease with the aim to detect and potentially treat early CRN.
But these procedures are costly and burdensome to patients, and some previous studies have revealed a relatively low utility for patients, according to Kimberley van der Sloot, MD, a PhD candidate at the University Medical Center Groningen (the Netherlands). She presented the research at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. The study was also published in Clinical Gastroenterology and Hepatology.
“We aimed to explore the role of cigarette exposure in colorectal neoplasia risk in patients with IBD, and we aimed to improve the CRN risk stratification model that we are currently using for these surveillance guidelines,” Dr. van der Sloot said during her talk.
Commenters during the Q&A period noted that the population database used in the study did not include measures of inflammation, which is a known risk for CRN. One review found that smoking worsens inflammation in Crohn’s disease but improves it in ulcerative colitis.
“It certainly raises the issue that we’ve always said, which is that people should quit smoking for other health reasons, but it doesn’t necessarily answer the question definitively,” said David Rubin, MD, who moderated the session and is professor of medicine at the University of Chicago and chair of the congress’s organizing committee. He added that the association between smoking and CRN risk may nevertheless inform future management surveillance guidelines if it is confirmed.
The researchers analyzed data from the 1000IBD cohort, which is prospectively following IBD patients in the Netherlands. The study included 1,386 patients who had at least one colorectal biopsy. Compared to a general population CRN incidence of 2.4%, Crohn’s disease patients who were never smokers had an incidence of 4.7% versus 10.3% among former or current smokers. In ulcerative colitis, the incidence was 12.5% among never smokers and 17.9% among former or current smokers.
In Crohn’s disease, previous or current smokers had about a twofold increased risk (hazard ratio, 2.04; P = .044). Compared to never smokers, former smokers trended toward an increased risk (HR, 2.16; P = .051), and active smokers had a significantly increased risk (HR, 2.20; P = .044). Passive smoke exposure was also associated with greater risk, both in childhood (HR, 4.79; P = .003) and current (HR, 1.87; P = .024).
In ulcerative colitis, the only statistically significant association between smoke exposure and CRN risk was among former smokers (HR, 1.73; P = .032).
The researchers also looked at patients with a disease duration longer than 8 years and stratified patients according to low risk (left-side ulcerative colitis, <50% of colon affected in Crohn’s disease; n = 425), medium risk (postinflammatory polyposis present or extensive colitis; n = 467), and high risk (concordant primary sclerosing cholangitis or having a first-degree relative with colorectal cancer; n = 143). In Crohn’s disease, current smoking was associated with greater CRN incidence (P = .046), and former smoking trended in that direction but was nonsignificant (P = .068). Former smoking also trended toward a risk in ulcerative colitis (P = .068), but there was no sign of an association for current smoking (P = .883).
In Crohn’s disease, after adjustment for risk stratification, greater CRN risk was associated with passive smoke exposure both during childhood (P = .001) and at present (P = .003).
“We believe this is the first study to describe the important role of cigarette smoking in development of colorectal neoplasia in IBD patients in a large, prospective, cohort, and I think [it] has shown the importance of lifestyle and smoking particularly in IBD. This is one more example. Alongside that, we’ve shown that adding this risk factor can improve the current risk stratification that is used for surveillance guidelines, and might be of benefit in the development of future guidelines,” said Dr. van der Sloot.
Dr. van der Sloot and Dr. Rubin had no relevant financial disclosures.
This article was updated Mar. 11, 2021.
FROM THE CROHN’S AND COLITIS CONGRESS
Adalimumab earns FDA approval for ulcerative colitis in children
Adalimumab has received approval from the Food and Drug Administration for use in pediatric patients aged 5 years and older with moderately to severely active ulcerative colitis (UC), according to a press release from manufacturer AbbVie.
Approval was based on data from the phase 3 ENVISION 1 randomized, double-blind study (NCT02065557) in which 60% of patients receiving the higher induction dose showed clinical remission according to Partial May Score (PMS) at 8 weeks, 45% of whom were in remission according to Full Mayo Score (FMS) at 1 year. The approval means that children with UC and their families have the option of a subcutaneous biologic that can be administered at home.
In the ENVISION 1 study, clinical remission was defined as a PMS (based on stool frequency, rectal bleeding, and physician’s global assessment) ranging from 0 to 3 at the end of the 8-week induction period or FMS (which adds endoscopy) at the end of 52 weeks as less than or equal to 2 points total, with no individual subscore greater than 1. The study included children aged 4-17 years with active UC who were randomized to a low-dose or high-dose group.
“Through week 8, patients in both dosage groups received 2.4 mg/kg (maximum of 160 mg) at week 0, 1.2 mg/kg (maximum of 80 mg) at week 2, and 0.6 mg/kg (maximum of 40 mg) at weeks 4 and 6. The higher-dosage group also received an additional dosage of 2.4 mg/kg (maximum of 160 mg) at week 1,” according to the company press release. Between weeks 8 and 52, patients received double-blind placebo or 0.6 mg/kg adalimumab (maximum of 40 mg) every other week (maintenance standard dose) or every week (maintenance high dose).
No new adalimumab safety signals were noted in the study; headache and worsening UC were the most frequently reported treatment-emergent adverse events, and 22.6% of patients experienced a serious adverse event. “No deaths, malignancies, active tuberculosis or demyelinating disease were observed in this study,” according to the company. Full prescribing information can be found on the FDA website.
Approval expands options
“The number of FDA-approved biologics to treat pediatric UC has been limited,” said Atsushi Sakuraba, MD, PhD, an inflammatory bowel disease specialist at the University of Chicago, in an interview. “Infliximab is approved for pediatric UC and CD [Crohn’s disease], but adalimumab was only approved for CD in pediatric patients, and vedolizumab and ustekinumab are approved for neither UC nor CD in pediatric patients,” he said. “Thus, the addition of adalimumab as a treatment option for pediatric UC is of great benefit for pediatricians and patients.”
The approval will impact clinical practice in several ways, Dr. Sakuraba said. “Adalimumab may be used for those who lose response to infliximab, but may also be used as a first-line biologic because it is self-injectable,” he emphasized. Given that adalimumab is already in use for pediatric patients with Crohn’s disease, Dr. Sakuraba said he does not see any barriers to implementation of its use for children with UC. In addition, “the potential for better disease control, reduction of disease-related complications, and improved quality of life outweighs the risk of adverse reactions,” Dr. Sakuraba said. “The news of no new safety concern in the 52-week study period further supports the safety of biologic treatment in pediatric patients,” he added.
As for additional research: “It remains to be determined whether combination therapy with an immunomodulator would be more effective than monotherapy, and also whether there are any additional risks of adverse events with the addition of immunomodulators such as long-term risk of malignancy, especially lymphoproliferative disorders,” Dr. Sakuraba noted. “Therapeutic options for pediatric [inflammatory bowel disease] are limited and lagging, compared to adult patients, so studies of non-TNF [tumor necrosis factor] biologics such vedolizumab and ustekinumab are also awaited,” he said.
Dr. Sakuraba had no financial conflicts to disclose.
This article was updated March 3, 2021.
Adalimumab has received approval from the Food and Drug Administration for use in pediatric patients aged 5 years and older with moderately to severely active ulcerative colitis (UC), according to a press release from manufacturer AbbVie.
Approval was based on data from the phase 3 ENVISION 1 randomized, double-blind study (NCT02065557) in which 60% of patients receiving the higher induction dose showed clinical remission according to Partial May Score (PMS) at 8 weeks, 45% of whom were in remission according to Full Mayo Score (FMS) at 1 year. The approval means that children with UC and their families have the option of a subcutaneous biologic that can be administered at home.
In the ENVISION 1 study, clinical remission was defined as a PMS (based on stool frequency, rectal bleeding, and physician’s global assessment) ranging from 0 to 3 at the end of the 8-week induction period or FMS (which adds endoscopy) at the end of 52 weeks as less than or equal to 2 points total, with no individual subscore greater than 1. The study included children aged 4-17 years with active UC who were randomized to a low-dose or high-dose group.
“Through week 8, patients in both dosage groups received 2.4 mg/kg (maximum of 160 mg) at week 0, 1.2 mg/kg (maximum of 80 mg) at week 2, and 0.6 mg/kg (maximum of 40 mg) at weeks 4 and 6. The higher-dosage group also received an additional dosage of 2.4 mg/kg (maximum of 160 mg) at week 1,” according to the company press release. Between weeks 8 and 52, patients received double-blind placebo or 0.6 mg/kg adalimumab (maximum of 40 mg) every other week (maintenance standard dose) or every week (maintenance high dose).
No new adalimumab safety signals were noted in the study; headache and worsening UC were the most frequently reported treatment-emergent adverse events, and 22.6% of patients experienced a serious adverse event. “No deaths, malignancies, active tuberculosis or demyelinating disease were observed in this study,” according to the company. Full prescribing information can be found on the FDA website.
Approval expands options
“The number of FDA-approved biologics to treat pediatric UC has been limited,” said Atsushi Sakuraba, MD, PhD, an inflammatory bowel disease specialist at the University of Chicago, in an interview. “Infliximab is approved for pediatric UC and CD [Crohn’s disease], but adalimumab was only approved for CD in pediatric patients, and vedolizumab and ustekinumab are approved for neither UC nor CD in pediatric patients,” he said. “Thus, the addition of adalimumab as a treatment option for pediatric UC is of great benefit for pediatricians and patients.”
The approval will impact clinical practice in several ways, Dr. Sakuraba said. “Adalimumab may be used for those who lose response to infliximab, but may also be used as a first-line biologic because it is self-injectable,” he emphasized. Given that adalimumab is already in use for pediatric patients with Crohn’s disease, Dr. Sakuraba said he does not see any barriers to implementation of its use for children with UC. In addition, “the potential for better disease control, reduction of disease-related complications, and improved quality of life outweighs the risk of adverse reactions,” Dr. Sakuraba said. “The news of no new safety concern in the 52-week study period further supports the safety of biologic treatment in pediatric patients,” he added.
As for additional research: “It remains to be determined whether combination therapy with an immunomodulator would be more effective than monotherapy, and also whether there are any additional risks of adverse events with the addition of immunomodulators such as long-term risk of malignancy, especially lymphoproliferative disorders,” Dr. Sakuraba noted. “Therapeutic options for pediatric [inflammatory bowel disease] are limited and lagging, compared to adult patients, so studies of non-TNF [tumor necrosis factor] biologics such vedolizumab and ustekinumab are also awaited,” he said.
Dr. Sakuraba had no financial conflicts to disclose.
This article was updated March 3, 2021.
Adalimumab has received approval from the Food and Drug Administration for use in pediatric patients aged 5 years and older with moderately to severely active ulcerative colitis (UC), according to a press release from manufacturer AbbVie.
Approval was based on data from the phase 3 ENVISION 1 randomized, double-blind study (NCT02065557) in which 60% of patients receiving the higher induction dose showed clinical remission according to Partial May Score (PMS) at 8 weeks, 45% of whom were in remission according to Full Mayo Score (FMS) at 1 year. The approval means that children with UC and their families have the option of a subcutaneous biologic that can be administered at home.
In the ENVISION 1 study, clinical remission was defined as a PMS (based on stool frequency, rectal bleeding, and physician’s global assessment) ranging from 0 to 3 at the end of the 8-week induction period or FMS (which adds endoscopy) at the end of 52 weeks as less than or equal to 2 points total, with no individual subscore greater than 1. The study included children aged 4-17 years with active UC who were randomized to a low-dose or high-dose group.
“Through week 8, patients in both dosage groups received 2.4 mg/kg (maximum of 160 mg) at week 0, 1.2 mg/kg (maximum of 80 mg) at week 2, and 0.6 mg/kg (maximum of 40 mg) at weeks 4 and 6. The higher-dosage group also received an additional dosage of 2.4 mg/kg (maximum of 160 mg) at week 1,” according to the company press release. Between weeks 8 and 52, patients received double-blind placebo or 0.6 mg/kg adalimumab (maximum of 40 mg) every other week (maintenance standard dose) or every week (maintenance high dose).
No new adalimumab safety signals were noted in the study; headache and worsening UC were the most frequently reported treatment-emergent adverse events, and 22.6% of patients experienced a serious adverse event. “No deaths, malignancies, active tuberculosis or demyelinating disease were observed in this study,” according to the company. Full prescribing information can be found on the FDA website.
Approval expands options
“The number of FDA-approved biologics to treat pediatric UC has been limited,” said Atsushi Sakuraba, MD, PhD, an inflammatory bowel disease specialist at the University of Chicago, in an interview. “Infliximab is approved for pediatric UC and CD [Crohn’s disease], but adalimumab was only approved for CD in pediatric patients, and vedolizumab and ustekinumab are approved for neither UC nor CD in pediatric patients,” he said. “Thus, the addition of adalimumab as a treatment option for pediatric UC is of great benefit for pediatricians and patients.”
The approval will impact clinical practice in several ways, Dr. Sakuraba said. “Adalimumab may be used for those who lose response to infliximab, but may also be used as a first-line biologic because it is self-injectable,” he emphasized. Given that adalimumab is already in use for pediatric patients with Crohn’s disease, Dr. Sakuraba said he does not see any barriers to implementation of its use for children with UC. In addition, “the potential for better disease control, reduction of disease-related complications, and improved quality of life outweighs the risk of adverse reactions,” Dr. Sakuraba said. “The news of no new safety concern in the 52-week study period further supports the safety of biologic treatment in pediatric patients,” he added.
As for additional research: “It remains to be determined whether combination therapy with an immunomodulator would be more effective than monotherapy, and also whether there are any additional risks of adverse events with the addition of immunomodulators such as long-term risk of malignancy, especially lymphoproliferative disorders,” Dr. Sakuraba noted. “Therapeutic options for pediatric [inflammatory bowel disease] are limited and lagging, compared to adult patients, so studies of non-TNF [tumor necrosis factor] biologics such vedolizumab and ustekinumab are also awaited,” he said.
Dr. Sakuraba had no financial conflicts to disclose.
This article was updated March 3, 2021.
Vedolizumab looks safer than anti-TNF drugs in older adults with IBD
A large analysis of Medicare data from all 50 states suggests that vedolizumab may be just as effective as anti–tumor necrosis factor (anti-TNF) agents in controlling inflammatory bowel disease (IBD) in patients aged over 65 years, with fewer infectious disease hospitalizations.
The study was prompted by the fact that older adults are greatly underrepresented in clinical trials of approved IBD medications. There is a second peak in IBD diagnosis among people in their 50s and 60s, and IBD patients are living longer with more effective medications. So although a significant number of IBD patients are aged 65 years or older, that group encompasses less than 1% of adults in clinical trials, Bharati Kochar, MD, reported at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
“Therefore, we don’t know how well these medications work and how safe they are specifically in older adults,” said Dr. Kochar, a gastroenterologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston.
The data largely support what had been known mechanistically about vedolizumab. “It suggests that both drugs work well enough to prevent [IBD-related] hospitalizations, but clearly there was a benefit toward the safer medication, Entyvio [vedolizumab], in the infection-related hospitalizations. That’s not the only readout in infections, but it is an important readout because infections that get hospitalized are the ones that predict mortality and disability,” said Matthew Ciorba, MD, who attended the session. Dr. Ciorba is director of the IBD Center at Washington University in St. Louis and was not involved in the study.
“I think this study is reassuring to clinicians. It provides important clinical data that support what we know about the mechanisms of vedolizumab. The safety data we predicted is borne out in this large and well-done study,” said Dr. Ciorba.
The researchers collected a 20% random sample from a 50-state Medicare claims database, including patients who were aged 65 years or older, who had two or more codes for Crohn’s disease or ulcerative colitis, and had 18 months of continuous enrollment. It excluded Medicare Part C patients; those who used ustekinumab, natalizumab, cyclosporine, or tacrolimus during the look back and study period; and those with two or more codes for rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis during the study period.
Among those included, 480 patients were on vedolizumab, while 1,152 were on anti-TNF medications. The two groups were broadly similar in their characteristics: Twenty-nine percent of both groups took budesonide, although the anti-TNF group had a higher frequency use of systemic corticosteroids (68% vs. 57%), 5-ASA drugs (62% vs. 42%), and immunomodulators (32% vs. 28%).
There were no significant differences between the two groups with respect to frequency of IBD-related hospitalizations, IBD-related surgery, steroid prescription rate after induction, or all-cause hospitalization. However, infection-related hospitalizations were less frequent in the vedolizumab group (crude incidence, 0.03 vs. 0.05 per person-year; adjusted hazard ratio, 0.47; 95% confidence interval, 0.25-0.86).
“I think it’s important to use your clinical judgment to treat the patient in front of you, and these data should simply help contextualize risk for older IBD patients newly initiating vedolizumab and anti-TNF agents,” said Dr. Kochar. However, recognizing the limitations of any retrospective study based on administrative data, she called for additional research. “There is a vast need for additional large and robust comparative effectiveness and safety studies in older adults of the rapidly proliferating arsenal of IBD medications,” Dr. Kochar concluded.
Dr. Kochar and Dr. Ciorba have no relevant financial disclosures.
A large analysis of Medicare data from all 50 states suggests that vedolizumab may be just as effective as anti–tumor necrosis factor (anti-TNF) agents in controlling inflammatory bowel disease (IBD) in patients aged over 65 years, with fewer infectious disease hospitalizations.
The study was prompted by the fact that older adults are greatly underrepresented in clinical trials of approved IBD medications. There is a second peak in IBD diagnosis among people in their 50s and 60s, and IBD patients are living longer with more effective medications. So although a significant number of IBD patients are aged 65 years or older, that group encompasses less than 1% of adults in clinical trials, Bharati Kochar, MD, reported at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
“Therefore, we don’t know how well these medications work and how safe they are specifically in older adults,” said Dr. Kochar, a gastroenterologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston.
The data largely support what had been known mechanistically about vedolizumab. “It suggests that both drugs work well enough to prevent [IBD-related] hospitalizations, but clearly there was a benefit toward the safer medication, Entyvio [vedolizumab], in the infection-related hospitalizations. That’s not the only readout in infections, but it is an important readout because infections that get hospitalized are the ones that predict mortality and disability,” said Matthew Ciorba, MD, who attended the session. Dr. Ciorba is director of the IBD Center at Washington University in St. Louis and was not involved in the study.
“I think this study is reassuring to clinicians. It provides important clinical data that support what we know about the mechanisms of vedolizumab. The safety data we predicted is borne out in this large and well-done study,” said Dr. Ciorba.
The researchers collected a 20% random sample from a 50-state Medicare claims database, including patients who were aged 65 years or older, who had two or more codes for Crohn’s disease or ulcerative colitis, and had 18 months of continuous enrollment. It excluded Medicare Part C patients; those who used ustekinumab, natalizumab, cyclosporine, or tacrolimus during the look back and study period; and those with two or more codes for rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis during the study period.
Among those included, 480 patients were on vedolizumab, while 1,152 were on anti-TNF medications. The two groups were broadly similar in their characteristics: Twenty-nine percent of both groups took budesonide, although the anti-TNF group had a higher frequency use of systemic corticosteroids (68% vs. 57%), 5-ASA drugs (62% vs. 42%), and immunomodulators (32% vs. 28%).
There were no significant differences between the two groups with respect to frequency of IBD-related hospitalizations, IBD-related surgery, steroid prescription rate after induction, or all-cause hospitalization. However, infection-related hospitalizations were less frequent in the vedolizumab group (crude incidence, 0.03 vs. 0.05 per person-year; adjusted hazard ratio, 0.47; 95% confidence interval, 0.25-0.86).
“I think it’s important to use your clinical judgment to treat the patient in front of you, and these data should simply help contextualize risk for older IBD patients newly initiating vedolizumab and anti-TNF agents,” said Dr. Kochar. However, recognizing the limitations of any retrospective study based on administrative data, she called for additional research. “There is a vast need for additional large and robust comparative effectiveness and safety studies in older adults of the rapidly proliferating arsenal of IBD medications,” Dr. Kochar concluded.
Dr. Kochar and Dr. Ciorba have no relevant financial disclosures.
A large analysis of Medicare data from all 50 states suggests that vedolizumab may be just as effective as anti–tumor necrosis factor (anti-TNF) agents in controlling inflammatory bowel disease (IBD) in patients aged over 65 years, with fewer infectious disease hospitalizations.
The study was prompted by the fact that older adults are greatly underrepresented in clinical trials of approved IBD medications. There is a second peak in IBD diagnosis among people in their 50s and 60s, and IBD patients are living longer with more effective medications. So although a significant number of IBD patients are aged 65 years or older, that group encompasses less than 1% of adults in clinical trials, Bharati Kochar, MD, reported at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
“Therefore, we don’t know how well these medications work and how safe they are specifically in older adults,” said Dr. Kochar, a gastroenterologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston.
The data largely support what had been known mechanistically about vedolizumab. “It suggests that both drugs work well enough to prevent [IBD-related] hospitalizations, but clearly there was a benefit toward the safer medication, Entyvio [vedolizumab], in the infection-related hospitalizations. That’s not the only readout in infections, but it is an important readout because infections that get hospitalized are the ones that predict mortality and disability,” said Matthew Ciorba, MD, who attended the session. Dr. Ciorba is director of the IBD Center at Washington University in St. Louis and was not involved in the study.
“I think this study is reassuring to clinicians. It provides important clinical data that support what we know about the mechanisms of vedolizumab. The safety data we predicted is borne out in this large and well-done study,” said Dr. Ciorba.
The researchers collected a 20% random sample from a 50-state Medicare claims database, including patients who were aged 65 years or older, who had two or more codes for Crohn’s disease or ulcerative colitis, and had 18 months of continuous enrollment. It excluded Medicare Part C patients; those who used ustekinumab, natalizumab, cyclosporine, or tacrolimus during the look back and study period; and those with two or more codes for rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis during the study period.
Among those included, 480 patients were on vedolizumab, while 1,152 were on anti-TNF medications. The two groups were broadly similar in their characteristics: Twenty-nine percent of both groups took budesonide, although the anti-TNF group had a higher frequency use of systemic corticosteroids (68% vs. 57%), 5-ASA drugs (62% vs. 42%), and immunomodulators (32% vs. 28%).
There were no significant differences between the two groups with respect to frequency of IBD-related hospitalizations, IBD-related surgery, steroid prescription rate after induction, or all-cause hospitalization. However, infection-related hospitalizations were less frequent in the vedolizumab group (crude incidence, 0.03 vs. 0.05 per person-year; adjusted hazard ratio, 0.47; 95% confidence interval, 0.25-0.86).
“I think it’s important to use your clinical judgment to treat the patient in front of you, and these data should simply help contextualize risk for older IBD patients newly initiating vedolizumab and anti-TNF agents,” said Dr. Kochar. However, recognizing the limitations of any retrospective study based on administrative data, she called for additional research. “There is a vast need for additional large and robust comparative effectiveness and safety studies in older adults of the rapidly proliferating arsenal of IBD medications,” Dr. Kochar concluded.
Dr. Kochar and Dr. Ciorba have no relevant financial disclosures.
FROM THE CROHN’S & COLITIS CONGRESS
FDA alert confirms heart and cancer risks with tofacitinib (Xeljanz)
The Food and Drug Administration has alerted the public to an increased risk of serious heart-related problems and cancer risk associated with the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR), based on early results from a safety clinical trial comparing tofacitinib and tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA).
The FDA is awaiting further results from the trial, but in a safety communication issued on Feb. 4, the agency advised patients not to discontinue tofacitinib without consulting their health care providers and advised health care professionals to weigh the risks and benefits when prescribing the drug and continue to follow the current prescribing information.
Tofacitinib was approved for treatment of RA in 2012 at a 5-mg dose. After this approval, the FDA required drug manufacturer Pfizer to conduct a safety clinical trial that included the 5-mg twice-daily dose and a 10-mg twice-daily dose that is currently approved only for ulcerative colitis. In addition to RA and ulcerative colitis, tofacitinib is approved for adults with active psoriatic arthritis and patients aged 2 years or older with active polyarticular course juvenile idiopathic arthritis.
Pfizer announced partial results of the study, known as the ORAL Surveillance trial, in a press release on Jan. 27. The randomized trial included 4,362 RA patients aged 50 years and older who received either 5-mg or 10-mg doses of tofacitinib or a TNF inhibitor (adalimumab or etanercept).
The full results have yet to be released, but based on data from approximately 10,000 person-years for the combined tofacitinib groups and approximately 5,000 person-years for the TNF inhibitor group, the rate of major cardiovascular adverse events was significantly higher in the combined tofacitinib group, compared with the TNF inhibitor group (0.98 vs. 0.73 per 100 person-years; hazard ratio, 1.33). In addition, the rate of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNF inhibitor group (1.13 vs. 0.77 per 100 person-years; HR, 1.48).
In February 2019, the FDA issued a warning stating an increased risk of pulmonary embolism and death associated with the 10-mg twice-daily dose of tofacitinib, following interims results from the safety study.
In July 2019, the FDA added a boxed warning to tofacitinib advising of the increased risk for pulmonary embolism and death associated with the 10-mg twice-daily dose.
The FDA encouraged health care professionals and patients to report any side effects from tofacitinib or other medications through the FDA MedWatch program online or by phone at 1-800-332-1088.
Until nuances revealed, no change in practice
The preliminary study findings contain some nuances that are a bit complicated from a statistical standpoint, according to Daniel Furst, MD, professor emeritus of medicine at the University of California, Los Angeles; adjunct professor at the University of Washington, Seattle; and research professor at the University of Florence (Italy).
This is supposed to be a noninferiority study, so something might not be noninferior, “but that doesn’t mean it is inferior,” explained Dr. Furst, who is also a member of the MDedge Rheumatology Editorial Advisory Board.
Dr. Furst said he was surprised by the study findings, because “I didn’t expect there to be any differences, and in fact it is not clear how great the differences are” among the groups in the study, he said.
When the complete findings are released, in one of the instances, “the statistics may show a very small statistical difference that indicates we may have to be more careful in this particularly high-risk group,” Dr. Furst noted.
“When we understand the data more closely, we may find that there are some nuances we need to be careful about,” he said. However, “until those data are out, I would not make any changes in my practice.”
Whether the current study findings represent a class effect is “impossible to say,” since tofacitinib affects three enzymes, while other JAK inhibitors affect only one or two, he noted.
Dr. Furst disclosed receiving grant/research support from and/or consulting for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech.
The Food and Drug Administration has alerted the public to an increased risk of serious heart-related problems and cancer risk associated with the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR), based on early results from a safety clinical trial comparing tofacitinib and tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA).
The FDA is awaiting further results from the trial, but in a safety communication issued on Feb. 4, the agency advised patients not to discontinue tofacitinib without consulting their health care providers and advised health care professionals to weigh the risks and benefits when prescribing the drug and continue to follow the current prescribing information.
Tofacitinib was approved for treatment of RA in 2012 at a 5-mg dose. After this approval, the FDA required drug manufacturer Pfizer to conduct a safety clinical trial that included the 5-mg twice-daily dose and a 10-mg twice-daily dose that is currently approved only for ulcerative colitis. In addition to RA and ulcerative colitis, tofacitinib is approved for adults with active psoriatic arthritis and patients aged 2 years or older with active polyarticular course juvenile idiopathic arthritis.
Pfizer announced partial results of the study, known as the ORAL Surveillance trial, in a press release on Jan. 27. The randomized trial included 4,362 RA patients aged 50 years and older who received either 5-mg or 10-mg doses of tofacitinib or a TNF inhibitor (adalimumab or etanercept).
The full results have yet to be released, but based on data from approximately 10,000 person-years for the combined tofacitinib groups and approximately 5,000 person-years for the TNF inhibitor group, the rate of major cardiovascular adverse events was significantly higher in the combined tofacitinib group, compared with the TNF inhibitor group (0.98 vs. 0.73 per 100 person-years; hazard ratio, 1.33). In addition, the rate of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNF inhibitor group (1.13 vs. 0.77 per 100 person-years; HR, 1.48).
In February 2019, the FDA issued a warning stating an increased risk of pulmonary embolism and death associated with the 10-mg twice-daily dose of tofacitinib, following interims results from the safety study.
In July 2019, the FDA added a boxed warning to tofacitinib advising of the increased risk for pulmonary embolism and death associated with the 10-mg twice-daily dose.
The FDA encouraged health care professionals and patients to report any side effects from tofacitinib or other medications through the FDA MedWatch program online or by phone at 1-800-332-1088.
Until nuances revealed, no change in practice
The preliminary study findings contain some nuances that are a bit complicated from a statistical standpoint, according to Daniel Furst, MD, professor emeritus of medicine at the University of California, Los Angeles; adjunct professor at the University of Washington, Seattle; and research professor at the University of Florence (Italy).
This is supposed to be a noninferiority study, so something might not be noninferior, “but that doesn’t mean it is inferior,” explained Dr. Furst, who is also a member of the MDedge Rheumatology Editorial Advisory Board.
Dr. Furst said he was surprised by the study findings, because “I didn’t expect there to be any differences, and in fact it is not clear how great the differences are” among the groups in the study, he said.
When the complete findings are released, in one of the instances, “the statistics may show a very small statistical difference that indicates we may have to be more careful in this particularly high-risk group,” Dr. Furst noted.
“When we understand the data more closely, we may find that there are some nuances we need to be careful about,” he said. However, “until those data are out, I would not make any changes in my practice.”
Whether the current study findings represent a class effect is “impossible to say,” since tofacitinib affects three enzymes, while other JAK inhibitors affect only one or two, he noted.
Dr. Furst disclosed receiving grant/research support from and/or consulting for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech.
The Food and Drug Administration has alerted the public to an increased risk of serious heart-related problems and cancer risk associated with the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR), based on early results from a safety clinical trial comparing tofacitinib and tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA).
The FDA is awaiting further results from the trial, but in a safety communication issued on Feb. 4, the agency advised patients not to discontinue tofacitinib without consulting their health care providers and advised health care professionals to weigh the risks and benefits when prescribing the drug and continue to follow the current prescribing information.
Tofacitinib was approved for treatment of RA in 2012 at a 5-mg dose. After this approval, the FDA required drug manufacturer Pfizer to conduct a safety clinical trial that included the 5-mg twice-daily dose and a 10-mg twice-daily dose that is currently approved only for ulcerative colitis. In addition to RA and ulcerative colitis, tofacitinib is approved for adults with active psoriatic arthritis and patients aged 2 years or older with active polyarticular course juvenile idiopathic arthritis.
Pfizer announced partial results of the study, known as the ORAL Surveillance trial, in a press release on Jan. 27. The randomized trial included 4,362 RA patients aged 50 years and older who received either 5-mg or 10-mg doses of tofacitinib or a TNF inhibitor (adalimumab or etanercept).
The full results have yet to be released, but based on data from approximately 10,000 person-years for the combined tofacitinib groups and approximately 5,000 person-years for the TNF inhibitor group, the rate of major cardiovascular adverse events was significantly higher in the combined tofacitinib group, compared with the TNF inhibitor group (0.98 vs. 0.73 per 100 person-years; hazard ratio, 1.33). In addition, the rate of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNF inhibitor group (1.13 vs. 0.77 per 100 person-years; HR, 1.48).
In February 2019, the FDA issued a warning stating an increased risk of pulmonary embolism and death associated with the 10-mg twice-daily dose of tofacitinib, following interims results from the safety study.
In July 2019, the FDA added a boxed warning to tofacitinib advising of the increased risk for pulmonary embolism and death associated with the 10-mg twice-daily dose.
The FDA encouraged health care professionals and patients to report any side effects from tofacitinib or other medications through the FDA MedWatch program online or by phone at 1-800-332-1088.
Until nuances revealed, no change in practice
The preliminary study findings contain some nuances that are a bit complicated from a statistical standpoint, according to Daniel Furst, MD, professor emeritus of medicine at the University of California, Los Angeles; adjunct professor at the University of Washington, Seattle; and research professor at the University of Florence (Italy).
This is supposed to be a noninferiority study, so something might not be noninferior, “but that doesn’t mean it is inferior,” explained Dr. Furst, who is also a member of the MDedge Rheumatology Editorial Advisory Board.
Dr. Furst said he was surprised by the study findings, because “I didn’t expect there to be any differences, and in fact it is not clear how great the differences are” among the groups in the study, he said.
When the complete findings are released, in one of the instances, “the statistics may show a very small statistical difference that indicates we may have to be more careful in this particularly high-risk group,” Dr. Furst noted.
“When we understand the data more closely, we may find that there are some nuances we need to be careful about,” he said. However, “until those data are out, I would not make any changes in my practice.”
Whether the current study findings represent a class effect is “impossible to say,” since tofacitinib affects three enzymes, while other JAK inhibitors affect only one or two, he noted.
Dr. Furst disclosed receiving grant/research support from and/or consulting for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech.
AGA Clinical Practice Update: Diagnosis and management of immune checkpoint inhibitor enterocolitis and hepatitis
Endoscopy with biopsies is best for diagnosing immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs), but another option is to first test the stool for lactoferrin or calprotectin to identify patients with mild diarrhea who could benefit from endoscopy, according to a clinical practice update from the American Gastroenterological Association.
Writing in Gastroenterology, Michael Dougan, MD, PhD, of Harvard Medical School, Boston, and colleagues noted that stool lactoferrin had been found in one study to be 90% sensitive for detecting histologic inflammation, while another study found that mucosal inflammation is absent in 20%-30% of patients with suspected ICI enterocolitis. Nonetheless, clinicians should consider diagnostic endoscopy before starting high-dose corticosteroids for ICI enterocolitis, especially because “colonic ulceration identified by endoscopy is the only established factor that predicts how ICI enterocolitis will respond to treatment,” Dr. Dougan and colleagues wrote. If performed, endoscopy must be prompt because ICI colitis can progress within days, especially if patients are receiving ipilimumab.
ICIs can induce autoimmune inflammation in almost any organ system because they target pathways that play “key roles in regulating autoimmunity,” the experts wrote. The gastrointestinal tract is one of the most common sites of toxicity: One study from 2006 and another from 2019 suggested that colitis, with or without enteritis, affects up to 40% of patients depending on the pathway targeted by the treatment. Oncologists manage most gastrointestinal ICI toxicities, but gastroenterologists and hepatologists often help with diagnosis, risk assessment, and managing complex, atypical, or treatment-refractory cases; to help guide this process, the experts reviewed the literature and made 15 relevant recommendations.
The authors noted that the differential diagnosis is broad, but suggested that Clostridioides difficile testing and stool culture (or stool pathogen testing, where available) should be performed in all patients to rule out infectious causes prior to any immunosuppressive treatments, such as corticosteroids. Abdominal imaging is not recommended if a patient only has diarrhea but can help rule out complications if fever, bleeding, or abdominal pain are also present. Laboratory blood tests are rarely informative.
High-dose glucocorticoids are usually effective, often being started at 0.5-2.0 mg/kg prednisone or equivalent daily and tapered over 4-6 weeks after clinical improvement, but these doses and schedules have not been rigorously examined. For glucocorticoid-refractory ICI enterocolitis, infliximab and vedolizumab “are reasonable options” for second line immunosuppression and should be individualized based on the underlying cancer and other risk factors; patients usually respond to these immunomodulators in less than a week, “an important contrast with IBD,” the experts wrote. Most cases of ICI enterocolitis do not recur unless the ICI is restarted, but “many patients require the full loading dose for infliximab or vedolizumab, and maintenance therapy may still be required for certain cases.”
ICI-induced hepatitis is less common, affecting less than 5% of patients in clinical trials according to the authors, but incidence rises if patients are on ICI combinations or an ICI plus chemotherapy. Before starting any ICI, patients’ total bilirubin, alkaline phosphatase, AST, and ALT levels should be checked, as should testing for hepatitis B. Liver chemistries should be repeated before each ICI cycle, and rising chemistries should trigger an assessment for other causes of liver injury.
Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hepatitis – defined as AST or ALT 1-3 times the upper limit of normal or total bilirubin 1-1.5 times upper limit of normal – should receive liver function tests once or twice weekly. For CTCAE grade 2 hepatitis, (AST/ALT more than 3-5 times upper limit of normal or total bilirubin more than 1.5-3 times upper limit of normal), ICI should be held until resolution to grade 1, and corticosteroids (prednisone or its equivalent dosed at 0.5-1.0 mg/kg daily) should be considered if there are clinical symptoms of liver toxicity. For grade 3 hepatitis (AST/ALT greater than 5-20 times upper limit of normal or total bilirubin more than 3-10 times upper limit of normal), ICI therapy should be halted, “and urgent consultation with a gastroenterologist/hepatologist is appropriate.” In this context, methylprednisone (1-2 mg/kg) is suggested, and azathioprine or mycophenolate mofetil can be considered if clinical hepatitis does not improve in 3-5 days. For CTCAE grade 4 hepatitis, hospitalization is recommended, and patients should permanently stop the ICI and receive 2 mg/kg per day of methylprednisolone or its equivalent.
The authors received no funding support. Dr. Dougan reported consulting or advisory relationships with Neoleukin Therapeutics, Genentech, Tillotts Pharma, and Partner Therapeutics and grant support from Novartis and Genentech. Two coauthors also reported ties to several pharmaceutical companies.
Endoscopy with biopsies is best for diagnosing immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs), but another option is to first test the stool for lactoferrin or calprotectin to identify patients with mild diarrhea who could benefit from endoscopy, according to a clinical practice update from the American Gastroenterological Association.
Writing in Gastroenterology, Michael Dougan, MD, PhD, of Harvard Medical School, Boston, and colleagues noted that stool lactoferrin had been found in one study to be 90% sensitive for detecting histologic inflammation, while another study found that mucosal inflammation is absent in 20%-30% of patients with suspected ICI enterocolitis. Nonetheless, clinicians should consider diagnostic endoscopy before starting high-dose corticosteroids for ICI enterocolitis, especially because “colonic ulceration identified by endoscopy is the only established factor that predicts how ICI enterocolitis will respond to treatment,” Dr. Dougan and colleagues wrote. If performed, endoscopy must be prompt because ICI colitis can progress within days, especially if patients are receiving ipilimumab.
ICIs can induce autoimmune inflammation in almost any organ system because they target pathways that play “key roles in regulating autoimmunity,” the experts wrote. The gastrointestinal tract is one of the most common sites of toxicity: One study from 2006 and another from 2019 suggested that colitis, with or without enteritis, affects up to 40% of patients depending on the pathway targeted by the treatment. Oncologists manage most gastrointestinal ICI toxicities, but gastroenterologists and hepatologists often help with diagnosis, risk assessment, and managing complex, atypical, or treatment-refractory cases; to help guide this process, the experts reviewed the literature and made 15 relevant recommendations.
The authors noted that the differential diagnosis is broad, but suggested that Clostridioides difficile testing and stool culture (or stool pathogen testing, where available) should be performed in all patients to rule out infectious causes prior to any immunosuppressive treatments, such as corticosteroids. Abdominal imaging is not recommended if a patient only has diarrhea but can help rule out complications if fever, bleeding, or abdominal pain are also present. Laboratory blood tests are rarely informative.
High-dose glucocorticoids are usually effective, often being started at 0.5-2.0 mg/kg prednisone or equivalent daily and tapered over 4-6 weeks after clinical improvement, but these doses and schedules have not been rigorously examined. For glucocorticoid-refractory ICI enterocolitis, infliximab and vedolizumab “are reasonable options” for second line immunosuppression and should be individualized based on the underlying cancer and other risk factors; patients usually respond to these immunomodulators in less than a week, “an important contrast with IBD,” the experts wrote. Most cases of ICI enterocolitis do not recur unless the ICI is restarted, but “many patients require the full loading dose for infliximab or vedolizumab, and maintenance therapy may still be required for certain cases.”
ICI-induced hepatitis is less common, affecting less than 5% of patients in clinical trials according to the authors, but incidence rises if patients are on ICI combinations or an ICI plus chemotherapy. Before starting any ICI, patients’ total bilirubin, alkaline phosphatase, AST, and ALT levels should be checked, as should testing for hepatitis B. Liver chemistries should be repeated before each ICI cycle, and rising chemistries should trigger an assessment for other causes of liver injury.
Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hepatitis – defined as AST or ALT 1-3 times the upper limit of normal or total bilirubin 1-1.5 times upper limit of normal – should receive liver function tests once or twice weekly. For CTCAE grade 2 hepatitis, (AST/ALT more than 3-5 times upper limit of normal or total bilirubin more than 1.5-3 times upper limit of normal), ICI should be held until resolution to grade 1, and corticosteroids (prednisone or its equivalent dosed at 0.5-1.0 mg/kg daily) should be considered if there are clinical symptoms of liver toxicity. For grade 3 hepatitis (AST/ALT greater than 5-20 times upper limit of normal or total bilirubin more than 3-10 times upper limit of normal), ICI therapy should be halted, “and urgent consultation with a gastroenterologist/hepatologist is appropriate.” In this context, methylprednisone (1-2 mg/kg) is suggested, and azathioprine or mycophenolate mofetil can be considered if clinical hepatitis does not improve in 3-5 days. For CTCAE grade 4 hepatitis, hospitalization is recommended, and patients should permanently stop the ICI and receive 2 mg/kg per day of methylprednisolone or its equivalent.
The authors received no funding support. Dr. Dougan reported consulting or advisory relationships with Neoleukin Therapeutics, Genentech, Tillotts Pharma, and Partner Therapeutics and grant support from Novartis and Genentech. Two coauthors also reported ties to several pharmaceutical companies.
Endoscopy with biopsies is best for diagnosing immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs), but another option is to first test the stool for lactoferrin or calprotectin to identify patients with mild diarrhea who could benefit from endoscopy, according to a clinical practice update from the American Gastroenterological Association.
Writing in Gastroenterology, Michael Dougan, MD, PhD, of Harvard Medical School, Boston, and colleagues noted that stool lactoferrin had been found in one study to be 90% sensitive for detecting histologic inflammation, while another study found that mucosal inflammation is absent in 20%-30% of patients with suspected ICI enterocolitis. Nonetheless, clinicians should consider diagnostic endoscopy before starting high-dose corticosteroids for ICI enterocolitis, especially because “colonic ulceration identified by endoscopy is the only established factor that predicts how ICI enterocolitis will respond to treatment,” Dr. Dougan and colleagues wrote. If performed, endoscopy must be prompt because ICI colitis can progress within days, especially if patients are receiving ipilimumab.
ICIs can induce autoimmune inflammation in almost any organ system because they target pathways that play “key roles in regulating autoimmunity,” the experts wrote. The gastrointestinal tract is one of the most common sites of toxicity: One study from 2006 and another from 2019 suggested that colitis, with or without enteritis, affects up to 40% of patients depending on the pathway targeted by the treatment. Oncologists manage most gastrointestinal ICI toxicities, but gastroenterologists and hepatologists often help with diagnosis, risk assessment, and managing complex, atypical, or treatment-refractory cases; to help guide this process, the experts reviewed the literature and made 15 relevant recommendations.
The authors noted that the differential diagnosis is broad, but suggested that Clostridioides difficile testing and stool culture (or stool pathogen testing, where available) should be performed in all patients to rule out infectious causes prior to any immunosuppressive treatments, such as corticosteroids. Abdominal imaging is not recommended if a patient only has diarrhea but can help rule out complications if fever, bleeding, or abdominal pain are also present. Laboratory blood tests are rarely informative.
High-dose glucocorticoids are usually effective, often being started at 0.5-2.0 mg/kg prednisone or equivalent daily and tapered over 4-6 weeks after clinical improvement, but these doses and schedules have not been rigorously examined. For glucocorticoid-refractory ICI enterocolitis, infliximab and vedolizumab “are reasonable options” for second line immunosuppression and should be individualized based on the underlying cancer and other risk factors; patients usually respond to these immunomodulators in less than a week, “an important contrast with IBD,” the experts wrote. Most cases of ICI enterocolitis do not recur unless the ICI is restarted, but “many patients require the full loading dose for infliximab or vedolizumab, and maintenance therapy may still be required for certain cases.”
ICI-induced hepatitis is less common, affecting less than 5% of patients in clinical trials according to the authors, but incidence rises if patients are on ICI combinations or an ICI plus chemotherapy. Before starting any ICI, patients’ total bilirubin, alkaline phosphatase, AST, and ALT levels should be checked, as should testing for hepatitis B. Liver chemistries should be repeated before each ICI cycle, and rising chemistries should trigger an assessment for other causes of liver injury.
Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 1 hepatitis – defined as AST or ALT 1-3 times the upper limit of normal or total bilirubin 1-1.5 times upper limit of normal – should receive liver function tests once or twice weekly. For CTCAE grade 2 hepatitis, (AST/ALT more than 3-5 times upper limit of normal or total bilirubin more than 1.5-3 times upper limit of normal), ICI should be held until resolution to grade 1, and corticosteroids (prednisone or its equivalent dosed at 0.5-1.0 mg/kg daily) should be considered if there are clinical symptoms of liver toxicity. For grade 3 hepatitis (AST/ALT greater than 5-20 times upper limit of normal or total bilirubin more than 3-10 times upper limit of normal), ICI therapy should be halted, “and urgent consultation with a gastroenterologist/hepatologist is appropriate.” In this context, methylprednisone (1-2 mg/kg) is suggested, and azathioprine or mycophenolate mofetil can be considered if clinical hepatitis does not improve in 3-5 days. For CTCAE grade 4 hepatitis, hospitalization is recommended, and patients should permanently stop the ICI and receive 2 mg/kg per day of methylprednisolone or its equivalent.
The authors received no funding support. Dr. Dougan reported consulting or advisory relationships with Neoleukin Therapeutics, Genentech, Tillotts Pharma, and Partner Therapeutics and grant support from Novartis and Genentech. Two coauthors also reported ties to several pharmaceutical companies.
FROM GASTROENTEROLOGY
Defining wellness in IBD
Physicians treating patients with IBD typically focus on disease and symptom management along with quality of life measures, but the latter are not the final word on patient well-being. Social well-being is another outcome that can more accurately portray a patient’s satisfaction with their treatment.
That was the message delivered by Laurie Keefer, PhD, at a session on diet, stress, health literacy, and disparities in IBD treatment at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. “When we talk about disease management, we’re talking about these outcomes of mucosal healing, remission, and lack of hospitalizations, but we don’t always talk about wellness,” said Dr. Keefer, director of psychobehavioral research in the department of gastroenterology at Icahn School of Medicine at Mount Sinai, New York.
Dr. Keefer advocated for incorporating measures that focus on the patient’s ability to feel fulfilled, pursue happiness, and contribute to the community. “Wellness is defined as a state of complete physical, mental, and social well-being. It’s a holistic definition, not merely the absence of those things,” she said during her talk.
Social determinants of health, such as income, inequality, health literacy, numeracy, financial stress, social connections, community, place of resonance, and housing coresidents, play important roles.
“Subjective well-being is a state in which an individual feels they are able to do work productively and creatively, have relationships, and contribute to their community. We want them to thrive. We want them to live well. We want them to reach their potential. There’s no reason you cannot reach your potential even though you’re living with IBD,” said Dr. Keefer.
Subjective well-being doesn’t replace quality of life assessment. “Absolutely, quality of life is an important metric, [but I want to] make a plug that maybe we should start to add subjective well-being into these outcome measures,” said Dr. Keefer.
The approach does away with specific measures of health, employment, financial security, or even living situation. “It takes away all of those things we just assume are part of being well. It measures it differently. It measures what makes us happy, divided by the degree of happiness we obtain,” said Dr. Keefer. She presented examples from a study her group is conducting that showed patients’ responses to what made them want to be well. “Some people want to be well to take care of their children or families or a parent, some people want to be well so they can go adventure skydiving, other people just want to be able to exercise and take care of their health. That’s what the target needs to be for wellness. In that sense, wellness is an achievement of best health possible in all domains, not just one. It’s a lifelong pursuit. It forces us to ask not just ‘Are my patient’s symptoms gone? Are they in clinical remission? Are they in histological remission? Are they in deep remission?’ but ‘Is my patient thriving? Are they meeting their potential? Are they getting what they want out of treatment? Are they happy?’ ”
Quality of life measures can provide some insight, but they are limited because they are anchored in physical symptoms, and they focus on a narrow, recent window, usually the past week. “You can imagine that as symptoms improve, those metrics kind of improve, and it looks like quality of life is great. But that’s not always the case, and we’re really missing an opportunity to go deeper. It’s also less sensitive when somebody is in remission, so it’s also very difficult to continue that proactive [approach] of thriving and living well when you’re already coming up positive on quality of life indices,” said Dr. Keefer.
Subjective well-being measures ignore physical symptoms, and focus instead on questions like the patient’s ability to work, socialize, and maintain relationships with family, and whether the patient feels able to contribute meaningfully to society. The measure is insensitive to factors such as inflammation, trauma, or changes to medication. As a result, measures can be used much less frequently – every 6 months, or even once a year.
Subjective well-being can also rely on the patient to define well-being, and that makes it more culturally sensitive. “It can allow for people to be well in whatever way they think they want to be well,” said Dr. Keefer.
There are various resources for measuring subjective well-being. The Organization for Economic Cooperation and Development has guidelines for measuring subjective well-being. The National Institutes of Health PROMIS includes useful measures of psychological well-being, positive affect, and general life satisfaction; they are available for free and include 6-8 items. Other useful measures include the Satisfaction with Life scale, the Positive and Negative Affect scale, and the Harmony in Life scale. “All of those have been well validated and used internationally as measures of well-being,” said Dr. Keefer.
Physicians can also address patients directly, asking them about how satisfied they are with their life. “You’re opening up that discussion to ask them not just, ‘How is your IBD and how is your IBD affecting your work?’ but ‘How is your life going?’ You’re proactively trying to help your patients thrive,” said Dr. Keefer.
Session moderators praised Dr. Keefer’s presentation as an appropriate wrap-up to talks that looked at stress, diet, economic disparities, health literacy, and numeracy.
“We capped it all with a discussion around what is well-being. We often talk about biologics or medicines or surgery when it comes to Crohn’s disease and ulcerative colitis, but what about holistic wellness? It’s all of this. It’s the medication piece, but it’s all of these other pillars involved in the process as well. I think looking at this from many different angles is very important so that patients can achieve the best quality of life possible,” said comoderator Tina Aswani Omprakash, a patient advocate who is pursuing a master’s degree in public health at Mount Sinai’s Icahn School of Medicine.
The other comoderator, Kelly Issokson, MS, RD, CNSC, agreed. “You can’t adequately treat patients with diet alone or stress management alone. You really need a holistic approach for best outcomes,” said Ms. Issokson, clinical nutritional coordinator at the digestive disease clinic at Cedars-Sinai Medical Center in Los Angeles.
Dr. Keefer has received research funding from AbbVie and is a cofounder and equity holder in Trellus Health. Ms. Aswani Omprakash has consulted for Genentech, AbbVie, Janssen, and Arena Pharmaceuticals. Ms. Issokson has no relevant financial disclosures.
Physicians treating patients with IBD typically focus on disease and symptom management along with quality of life measures, but the latter are not the final word on patient well-being. Social well-being is another outcome that can more accurately portray a patient’s satisfaction with their treatment.
That was the message delivered by Laurie Keefer, PhD, at a session on diet, stress, health literacy, and disparities in IBD treatment at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. “When we talk about disease management, we’re talking about these outcomes of mucosal healing, remission, and lack of hospitalizations, but we don’t always talk about wellness,” said Dr. Keefer, director of psychobehavioral research in the department of gastroenterology at Icahn School of Medicine at Mount Sinai, New York.
Dr. Keefer advocated for incorporating measures that focus on the patient’s ability to feel fulfilled, pursue happiness, and contribute to the community. “Wellness is defined as a state of complete physical, mental, and social well-being. It’s a holistic definition, not merely the absence of those things,” she said during her talk.
Social determinants of health, such as income, inequality, health literacy, numeracy, financial stress, social connections, community, place of resonance, and housing coresidents, play important roles.
“Subjective well-being is a state in which an individual feels they are able to do work productively and creatively, have relationships, and contribute to their community. We want them to thrive. We want them to live well. We want them to reach their potential. There’s no reason you cannot reach your potential even though you’re living with IBD,” said Dr. Keefer.
Subjective well-being doesn’t replace quality of life assessment. “Absolutely, quality of life is an important metric, [but I want to] make a plug that maybe we should start to add subjective well-being into these outcome measures,” said Dr. Keefer.
The approach does away with specific measures of health, employment, financial security, or even living situation. “It takes away all of those things we just assume are part of being well. It measures it differently. It measures what makes us happy, divided by the degree of happiness we obtain,” said Dr. Keefer. She presented examples from a study her group is conducting that showed patients’ responses to what made them want to be well. “Some people want to be well to take care of their children or families or a parent, some people want to be well so they can go adventure skydiving, other people just want to be able to exercise and take care of their health. That’s what the target needs to be for wellness. In that sense, wellness is an achievement of best health possible in all domains, not just one. It’s a lifelong pursuit. It forces us to ask not just ‘Are my patient’s symptoms gone? Are they in clinical remission? Are they in histological remission? Are they in deep remission?’ but ‘Is my patient thriving? Are they meeting their potential? Are they getting what they want out of treatment? Are they happy?’ ”
Quality of life measures can provide some insight, but they are limited because they are anchored in physical symptoms, and they focus on a narrow, recent window, usually the past week. “You can imagine that as symptoms improve, those metrics kind of improve, and it looks like quality of life is great. But that’s not always the case, and we’re really missing an opportunity to go deeper. It’s also less sensitive when somebody is in remission, so it’s also very difficult to continue that proactive [approach] of thriving and living well when you’re already coming up positive on quality of life indices,” said Dr. Keefer.
Subjective well-being measures ignore physical symptoms, and focus instead on questions like the patient’s ability to work, socialize, and maintain relationships with family, and whether the patient feels able to contribute meaningfully to society. The measure is insensitive to factors such as inflammation, trauma, or changes to medication. As a result, measures can be used much less frequently – every 6 months, or even once a year.
Subjective well-being can also rely on the patient to define well-being, and that makes it more culturally sensitive. “It can allow for people to be well in whatever way they think they want to be well,” said Dr. Keefer.
There are various resources for measuring subjective well-being. The Organization for Economic Cooperation and Development has guidelines for measuring subjective well-being. The National Institutes of Health PROMIS includes useful measures of psychological well-being, positive affect, and general life satisfaction; they are available for free and include 6-8 items. Other useful measures include the Satisfaction with Life scale, the Positive and Negative Affect scale, and the Harmony in Life scale. “All of those have been well validated and used internationally as measures of well-being,” said Dr. Keefer.
Physicians can also address patients directly, asking them about how satisfied they are with their life. “You’re opening up that discussion to ask them not just, ‘How is your IBD and how is your IBD affecting your work?’ but ‘How is your life going?’ You’re proactively trying to help your patients thrive,” said Dr. Keefer.
Session moderators praised Dr. Keefer’s presentation as an appropriate wrap-up to talks that looked at stress, diet, economic disparities, health literacy, and numeracy.
“We capped it all with a discussion around what is well-being. We often talk about biologics or medicines or surgery when it comes to Crohn’s disease and ulcerative colitis, but what about holistic wellness? It’s all of this. It’s the medication piece, but it’s all of these other pillars involved in the process as well. I think looking at this from many different angles is very important so that patients can achieve the best quality of life possible,” said comoderator Tina Aswani Omprakash, a patient advocate who is pursuing a master’s degree in public health at Mount Sinai’s Icahn School of Medicine.
The other comoderator, Kelly Issokson, MS, RD, CNSC, agreed. “You can’t adequately treat patients with diet alone or stress management alone. You really need a holistic approach for best outcomes,” said Ms. Issokson, clinical nutritional coordinator at the digestive disease clinic at Cedars-Sinai Medical Center in Los Angeles.
Dr. Keefer has received research funding from AbbVie and is a cofounder and equity holder in Trellus Health. Ms. Aswani Omprakash has consulted for Genentech, AbbVie, Janssen, and Arena Pharmaceuticals. Ms. Issokson has no relevant financial disclosures.
Physicians treating patients with IBD typically focus on disease and symptom management along with quality of life measures, but the latter are not the final word on patient well-being. Social well-being is another outcome that can more accurately portray a patient’s satisfaction with their treatment.
That was the message delivered by Laurie Keefer, PhD, at a session on diet, stress, health literacy, and disparities in IBD treatment at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. “When we talk about disease management, we’re talking about these outcomes of mucosal healing, remission, and lack of hospitalizations, but we don’t always talk about wellness,” said Dr. Keefer, director of psychobehavioral research in the department of gastroenterology at Icahn School of Medicine at Mount Sinai, New York.
Dr. Keefer advocated for incorporating measures that focus on the patient’s ability to feel fulfilled, pursue happiness, and contribute to the community. “Wellness is defined as a state of complete physical, mental, and social well-being. It’s a holistic definition, not merely the absence of those things,” she said during her talk.
Social determinants of health, such as income, inequality, health literacy, numeracy, financial stress, social connections, community, place of resonance, and housing coresidents, play important roles.
“Subjective well-being is a state in which an individual feels they are able to do work productively and creatively, have relationships, and contribute to their community. We want them to thrive. We want them to live well. We want them to reach their potential. There’s no reason you cannot reach your potential even though you’re living with IBD,” said Dr. Keefer.
Subjective well-being doesn’t replace quality of life assessment. “Absolutely, quality of life is an important metric, [but I want to] make a plug that maybe we should start to add subjective well-being into these outcome measures,” said Dr. Keefer.
The approach does away with specific measures of health, employment, financial security, or even living situation. “It takes away all of those things we just assume are part of being well. It measures it differently. It measures what makes us happy, divided by the degree of happiness we obtain,” said Dr. Keefer. She presented examples from a study her group is conducting that showed patients’ responses to what made them want to be well. “Some people want to be well to take care of their children or families or a parent, some people want to be well so they can go adventure skydiving, other people just want to be able to exercise and take care of their health. That’s what the target needs to be for wellness. In that sense, wellness is an achievement of best health possible in all domains, not just one. It’s a lifelong pursuit. It forces us to ask not just ‘Are my patient’s symptoms gone? Are they in clinical remission? Are they in histological remission? Are they in deep remission?’ but ‘Is my patient thriving? Are they meeting their potential? Are they getting what they want out of treatment? Are they happy?’ ”
Quality of life measures can provide some insight, but they are limited because they are anchored in physical symptoms, and they focus on a narrow, recent window, usually the past week. “You can imagine that as symptoms improve, those metrics kind of improve, and it looks like quality of life is great. But that’s not always the case, and we’re really missing an opportunity to go deeper. It’s also less sensitive when somebody is in remission, so it’s also very difficult to continue that proactive [approach] of thriving and living well when you’re already coming up positive on quality of life indices,” said Dr. Keefer.
Subjective well-being measures ignore physical symptoms, and focus instead on questions like the patient’s ability to work, socialize, and maintain relationships with family, and whether the patient feels able to contribute meaningfully to society. The measure is insensitive to factors such as inflammation, trauma, or changes to medication. As a result, measures can be used much less frequently – every 6 months, or even once a year.
Subjective well-being can also rely on the patient to define well-being, and that makes it more culturally sensitive. “It can allow for people to be well in whatever way they think they want to be well,” said Dr. Keefer.
There are various resources for measuring subjective well-being. The Organization for Economic Cooperation and Development has guidelines for measuring subjective well-being. The National Institutes of Health PROMIS includes useful measures of psychological well-being, positive affect, and general life satisfaction; they are available for free and include 6-8 items. Other useful measures include the Satisfaction with Life scale, the Positive and Negative Affect scale, and the Harmony in Life scale. “All of those have been well validated and used internationally as measures of well-being,” said Dr. Keefer.
Physicians can also address patients directly, asking them about how satisfied they are with their life. “You’re opening up that discussion to ask them not just, ‘How is your IBD and how is your IBD affecting your work?’ but ‘How is your life going?’ You’re proactively trying to help your patients thrive,” said Dr. Keefer.
Session moderators praised Dr. Keefer’s presentation as an appropriate wrap-up to talks that looked at stress, diet, economic disparities, health literacy, and numeracy.
“We capped it all with a discussion around what is well-being. We often talk about biologics or medicines or surgery when it comes to Crohn’s disease and ulcerative colitis, but what about holistic wellness? It’s all of this. It’s the medication piece, but it’s all of these other pillars involved in the process as well. I think looking at this from many different angles is very important so that patients can achieve the best quality of life possible,” said comoderator Tina Aswani Omprakash, a patient advocate who is pursuing a master’s degree in public health at Mount Sinai’s Icahn School of Medicine.
The other comoderator, Kelly Issokson, MS, RD, CNSC, agreed. “You can’t adequately treat patients with diet alone or stress management alone. You really need a holistic approach for best outcomes,” said Ms. Issokson, clinical nutritional coordinator at the digestive disease clinic at Cedars-Sinai Medical Center in Los Angeles.
Dr. Keefer has received research funding from AbbVie and is a cofounder and equity holder in Trellus Health. Ms. Aswani Omprakash has consulted for Genentech, AbbVie, Janssen, and Arena Pharmaceuticals. Ms. Issokson has no relevant financial disclosures.
FROM THE CROHN’S & COLITIS CONGRESS