IBD & Intestinal Disorders

Irritable bowel syndrome symptoms were improved in about one-third of patients who took an inactivated bacterial treatment, pointing the way to a therapeutic path that could avoid some risks of live probiotic use.

Of 443 patients taking part in a randomized, double-blind, placebo-controlled trial of a heat-inactivated nonviable Bifidobacterium probiotic, 221 received the probiotic while 222 received placebo capsules. The study’s primary endpoint was a composite of at least 30% improvement in abdominal pain and “adequate relief” of overall irritable bowel syndrome (IBS) symptoms in at least 4 of the 8 weeks of the study.

Within the B. bifidum group, 74 patients (34%) reached this endpoint, compared with 43 (19%) of those in the placebo group, for a risk ratio of 1.7 (P = .0007). Patients had no serious adverse events from the oral therapy, which they took in the form of two capsules daily for 8 weeks, and participants found both the inactivated Bifidobacterium treatment and placebo tolerable overall.

Bowel movements became more frequent in those who received B. bifidum capsules who had constipation-predominant IBS and less frequent in those with diarrhea-predominant IBS; the changes were statistically significant in both subgroups.

“Some probiotic strains can adhere well to epithelial cells and strengthen intestinal barrier function, providing an explanation for the efficacy of at least some probiotics in the treatment of IBS,” wrote Viola Andresen, MD, MSc, the study‘s lead author.

“Accordingly, enhancing the gut barrier is a useful treatment approach for patients with IBS,” added Dr. Andresen, of the department of internal medicine at the University of Hamburg (Germany) Teaching Hospital, and collaborators. The adherent properties of some strains of Bifidobacteria are mainly dependent on properties of the cell surface that are not changed by heat inactivation, which makes the bacteria nonviable – and removes the risk of infection.

Additional benefits of using nonviable bacteria for IBS therapy might include more stability and enhanced standardization, although previous studies have shown a reduction in efficacy when bacteria are made nonviable. Inactivated B. bifidum MIMBb75 was used in this study because it had previously been shown effective against IBS symptoms, noted Dr. Andresen and coauthors.

Adult patients were included if they met criteria for IBS according to Rome III and had abdominal pain rated at least 4 on an 11-point scale for at least 2 days of a 2-week run-in phase. Among the many criteria for exclusion from the study were history of inflammatory gastrointestinal disease, cancer, other serious stomach diseases, diabetes, many abdominal surgeries, and recent antipsychotic or steroid use.

During the study, participants recorded their abdominal pain over the last 24 hours daily; weekly averages were tallied for each patient. Patients were also asked to rate their relief of IBS symptoms, including abdominal pain, bowel habits, and other symptoms over the past week at weekly time points on a 7-point Likert scale, where scores of 3 or less indicated some measure of relief; IBS symptoms were considered to be adequately relieved with a score of 3 or less.

Secondary outcome measures for the study included changes in the Subjects’ Global Assessment of symptoms, and changes in individual symptoms. Number of bowel movements, stool form, sensation of incomplete evacuation, and medication use were also recorded daily.

Participants were aged a mean of 41 years, and about 70% were female. The mean body mass index was just under 25 kg/m². About half of each study arm had diarrhea-predominant IBS. About a quarter had constipation-predominant IBS, and most of the rest were not subtyped.

Looking at the primary endpoint, the number needed to treat for benefit was 7.1 in favor of the inactivated bacterium, using an intention-to-treat analysis. Results were similar when a per-protocol analysis was applied. The investigators saw response to treatment climb through the duration of the study for both the probiotic and the placebo arms, with the gap in improvement between the groups widening over the 8-week study period.

“It might be assumed that the use of nonviable bacteria for the treatment of IBS could be a safe alternative, even in patients who are potentially susceptible to infection,” concluded Dr. Andresen and colleagues. A further advantage, noted the researchers, is greater product stability in fluctuating temperatures compared with viable bacteria, ensuring better standardization even in regions with warm or changing climates.

Perspective was offered in an accompanying commentary whose lead author was Nicholas Talley, MD, PhD, a gastroenterologist, adjunct professor, and pro vice-chancellor for global research at the University of Newcastle (Australia).

“By heat inactivating the bacteria the researchers did not administer a probiotic but a bacterial therapy,” wrote Dr. Talley and coauthors. In any event, they added, the exact mechanism by which probiotics benefit individuals with IBS is unknown.

“The concept that a probiotic might be efficacious in IBS even if nonviable organisms are administered is an important observation,” they wrote. Fewer benefits have been seen with oral probiotic therapy than with fecal microbial transfer, and oral therapy does not produce durable results unless administered on a chronic basis, Dr. Talley and coauthors added.

“The absence of fundamental knowledge in terms of how bacterial therapy alters mechanisms in IBS continues to hamper improvements in treatment, limiting any success to short-term symptom control rather than the true goal, reversal of disease,” they concluded.

The study was funded by Synformulas. Dr. Andresen reported financial relationships with several pharmaceutical companies. Dr. Talley reported financial relationships with several pharmaceutical and nutritional companies.

[email protected]

SOURCE: Andresen V et al. Lancet Gastroenterol Hepatol. 2020 Apr 8. doi: 10.1016/S2468-1253(20)30079-0

Irritable bowel syndrome symptoms were improved in about one-third of patients who took an inactivated bacterial treatment, pointing the way to a therapeutic path that could avoid some risks of live probiotic use.

Of 443 patients taking part in a randomized, double-blind, placebo-controlled trial of a heat-inactivated nonviable Bifidobacterium probiotic, 221 received the probiotic while 222 received placebo capsules. The study’s primary endpoint was a composite of at least 30% improvement in abdominal pain and “adequate relief” of overall irritable bowel syndrome (IBS) symptoms in at least 4 of the 8 weeks of the study.

Within the B. bifidum group, 74 patients (34%) reached this endpoint, compared with 43 (19%) of those in the placebo group, for a risk ratio of 1.7 (P = .0007). Patients had no serious adverse events from the oral therapy, which they took in the form of two capsules daily for 8 weeks, and participants found both the inactivated Bifidobacterium treatment and placebo tolerable overall.

Bowel movements became more frequent in those who received B. bifidum capsules who had constipation-predominant IBS and less frequent in those with diarrhea-predominant IBS; the changes were statistically significant in both subgroups.

“Some probiotic strains can adhere well to epithelial cells and strengthen intestinal barrier function, providing an explanation for the efficacy of at least some probiotics in the treatment of IBS,” wrote Viola Andresen, MD, MSc, the study‘s lead author.

“Accordingly, enhancing the gut barrier is a useful treatment approach for patients with IBS,” added Dr. Andresen, of the department of internal medicine at the University of Hamburg (Germany) Teaching Hospital, and collaborators. The adherent properties of some strains of Bifidobacteria are mainly dependent on properties of the cell surface that are not changed by heat inactivation, which makes the bacteria nonviable – and removes the risk of infection.

Additional benefits of using nonviable bacteria for IBS therapy might include more stability and enhanced standardization, although previous studies have shown a reduction in efficacy when bacteria are made nonviable. Inactivated B. bifidum MIMBb75 was used in this study because it had previously been shown effective against IBS symptoms, noted Dr. Andresen and coauthors.

Adult patients were included if they met criteria for IBS according to Rome III and had abdominal pain rated at least 4 on an 11-point scale for at least 2 days of a 2-week run-in phase. Among the many criteria for exclusion from the study were history of inflammatory gastrointestinal disease, cancer, other serious stomach diseases, diabetes, many abdominal surgeries, and recent antipsychotic or steroid use.

During the study, participants recorded their abdominal pain over the last 24 hours daily; weekly averages were tallied for each patient. Patients were also asked to rate their relief of IBS symptoms, including abdominal pain, bowel habits, and other symptoms over the past week at weekly time points on a 7-point Likert scale, where scores of 3 or less indicated some measure of relief; IBS symptoms were considered to be adequately relieved with a score of 3 or less.

Secondary outcome measures for the study included changes in the Subjects’ Global Assessment of symptoms, and changes in individual symptoms. Number of bowel movements, stool form, sensation of incomplete evacuation, and medication use were also recorded daily.

Participants were aged a mean of 41 years, and about 70% were female. The mean body mass index was just under 25 kg/m². About half of each study arm had diarrhea-predominant IBS. About a quarter had constipation-predominant IBS, and most of the rest were not subtyped.

Looking at the primary endpoint, the number needed to treat for benefit was 7.1 in favor of the inactivated bacterium, using an intention-to-treat analysis. Results were similar when a per-protocol analysis was applied. The investigators saw response to treatment climb through the duration of the study for both the probiotic and the placebo arms, with the gap in improvement between the groups widening over the 8-week study period.

“It might be assumed that the use of nonviable bacteria for the treatment of IBS could be a safe alternative, even in patients who are potentially susceptible to infection,” concluded Dr. Andresen and colleagues. A further advantage, noted the researchers, is greater product stability in fluctuating temperatures compared with viable bacteria, ensuring better standardization even in regions with warm or changing climates.

Perspective was offered in an accompanying commentary whose lead author was Nicholas Talley, MD, PhD, a gastroenterologist, adjunct professor, and pro vice-chancellor for global research at the University of Newcastle (Australia).

“By heat inactivating the bacteria the researchers did not administer a probiotic but a bacterial therapy,” wrote Dr. Talley and coauthors. In any event, they added, the exact mechanism by which probiotics benefit individuals with IBS is unknown.

“The concept that a probiotic might be efficacious in IBS even if nonviable organisms are administered is an important observation,” they wrote. Fewer benefits have been seen with oral probiotic therapy than with fecal microbial transfer, and oral therapy does not produce durable results unless administered on a chronic basis, Dr. Talley and coauthors added.

“The absence of fundamental knowledge in terms of how bacterial therapy alters mechanisms in IBS continues to hamper improvements in treatment, limiting any success to short-term symptom control rather than the true goal, reversal of disease,” they concluded.

The study was funded by Synformulas. Dr. Andresen reported financial relationships with several pharmaceutical companies. Dr. Talley reported financial relationships with several pharmaceutical and nutritional companies.

[email protected]

SOURCE: Andresen V et al. Lancet Gastroenterol Hepatol. 2020 Apr 8. doi: 10.1016/S2468-1253(20)30079-0

Irritable bowel syndrome symptoms were improved in about one-third of patients who took an inactivated bacterial treatment, pointing the way to a therapeutic path that could avoid some risks of live probiotic use.

Of 443 patients taking part in a randomized, double-blind, placebo-controlled trial of a heat-inactivated nonviable Bifidobacterium probiotic, 221 received the probiotic while 222 received placebo capsules. The study’s primary endpoint was a composite of at least 30% improvement in abdominal pain and “adequate relief” of overall irritable bowel syndrome (IBS) symptoms in at least 4 of the 8 weeks of the study.

Within the B. bifidum group, 74 patients (34%) reached this endpoint, compared with 43 (19%) of those in the placebo group, for a risk ratio of 1.7 (P = .0007). Patients had no serious adverse events from the oral therapy, which they took in the form of two capsules daily for 8 weeks, and participants found both the inactivated Bifidobacterium treatment and placebo tolerable overall.

Bowel movements became more frequent in those who received B. bifidum capsules who had constipation-predominant IBS and less frequent in those with diarrhea-predominant IBS; the changes were statistically significant in both subgroups.

“Some probiotic strains can adhere well to epithelial cells and strengthen intestinal barrier function, providing an explanation for the efficacy of at least some probiotics in the treatment of IBS,” wrote Viola Andresen, MD, MSc, the study‘s lead author.

“Accordingly, enhancing the gut barrier is a useful treatment approach for patients with IBS,” added Dr. Andresen, of the department of internal medicine at the University of Hamburg (Germany) Teaching Hospital, and collaborators. The adherent properties of some strains of Bifidobacteria are mainly dependent on properties of the cell surface that are not changed by heat inactivation, which makes the bacteria nonviable – and removes the risk of infection.

Additional benefits of using nonviable bacteria for IBS therapy might include more stability and enhanced standardization, although previous studies have shown a reduction in efficacy when bacteria are made nonviable. Inactivated B. bifidum MIMBb75 was used in this study because it had previously been shown effective against IBS symptoms, noted Dr. Andresen and coauthors.

Adult patients were included if they met criteria for IBS according to Rome III and had abdominal pain rated at least 4 on an 11-point scale for at least 2 days of a 2-week run-in phase. Among the many criteria for exclusion from the study were history of inflammatory gastrointestinal disease, cancer, other serious stomach diseases, diabetes, many abdominal surgeries, and recent antipsychotic or steroid use.

During the study, participants recorded their abdominal pain over the last 24 hours daily; weekly averages were tallied for each patient. Patients were also asked to rate their relief of IBS symptoms, including abdominal pain, bowel habits, and other symptoms over the past week at weekly time points on a 7-point Likert scale, where scores of 3 or less indicated some measure of relief; IBS symptoms were considered to be adequately relieved with a score of 3 or less.

Secondary outcome measures for the study included changes in the Subjects’ Global Assessment of symptoms, and changes in individual symptoms. Number of bowel movements, stool form, sensation of incomplete evacuation, and medication use were also recorded daily.

Participants were aged a mean of 41 years, and about 70% were female. The mean body mass index was just under 25 kg/m². About half of each study arm had diarrhea-predominant IBS. About a quarter had constipation-predominant IBS, and most of the rest were not subtyped.

Looking at the primary endpoint, the number needed to treat for benefit was 7.1 in favor of the inactivated bacterium, using an intention-to-treat analysis. Results were similar when a per-protocol analysis was applied. The investigators saw response to treatment climb through the duration of the study for both the probiotic and the placebo arms, with the gap in improvement between the groups widening over the 8-week study period.

“It might be assumed that the use of nonviable bacteria for the treatment of IBS could be a safe alternative, even in patients who are potentially susceptible to infection,” concluded Dr. Andresen and colleagues. A further advantage, noted the researchers, is greater product stability in fluctuating temperatures compared with viable bacteria, ensuring better standardization even in regions with warm or changing climates.

Perspective was offered in an accompanying commentary whose lead author was Nicholas Talley, MD, PhD, a gastroenterologist, adjunct professor, and pro vice-chancellor for global research at the University of Newcastle (Australia).

“By heat inactivating the bacteria the researchers did not administer a probiotic but a bacterial therapy,” wrote Dr. Talley and coauthors. In any event, they added, the exact mechanism by which probiotics benefit individuals with IBS is unknown.

“The concept that a probiotic might be efficacious in IBS even if nonviable organisms are administered is an important observation,” they wrote. Fewer benefits have been seen with oral probiotic therapy than with fecal microbial transfer, and oral therapy does not produce durable results unless administered on a chronic basis, Dr. Talley and coauthors added.

“The absence of fundamental knowledge in terms of how bacterial therapy alters mechanisms in IBS continues to hamper improvements in treatment, limiting any success to short-term symptom control rather than the true goal, reversal of disease,” they concluded.

The study was funded by Synformulas. Dr. Andresen reported financial relationships with several pharmaceutical companies. Dr. Talley reported financial relationships with several pharmaceutical and nutritional companies.

[email protected]

SOURCE: Andresen V et al. Lancet Gastroenterol Hepatol. 2020 Apr 8. doi: 10.1016/S2468-1253(20)30079-0

The adoption of the infused biosimilar infliximab therapies Inflectra and Renflexis was slower at an academic medical center than at a neighboring Veterans Affairs Medical Center (VAMC) during the same time period in 2015-2019, according to an analysis published in Arthritis and Rheumatology.

The use of the biosimilars also was associated with cost savings at the VAMC, but not at the academic medical center, which illustrates that insufficient financial incentives can delay the adoption of biosimilars and the health care system’s realization of cost savings, according to the authors.

Medicare, which is not allowed to negotiate drug prices, is one of the largest payers for infused therapies. Medicare reimbursement for infused therapies is based on the latter’s average selling price (ASP) during the previous quarter. Institutions may negotiate purchase prices with drug manufacturers and receive Medicare reimbursement. Biosimilars generally have lower ASPs than their corresponding reference therapies, and biosimilar manufacturers may have less room to negotiate prices than reference therapy manufacturers. Consequently, a given institution might have a greater incentive to use reference products than to use biosimilars.
 

An examination of pharmacy data

The VA negotiates drug prices for all of its medical centers and has mandated that clinicians prefer biosimilars to their corresponding reference therapies, so Joshua F. Baker, MD, of the University of Pennsylvania and the Corporal Michael J. Crescenz VAMC, both in Philadelphia, and his colleagues hypothesized that the adoption of biosimilars had proceeded more quickly at a VAMC than at a nearby academic medical center.

The investigators examined pharmacy data from the University of Pennsylvania Health System (UPHS) electronic medical record and the Corporal Michael J. Crescenz VAMC to compare the frequency of prescribing biosimilars at these sites between Jan. 1, 2015, and May 31, 2019. Dr. Baker and his associates focused specifically on reference infliximab (Remicade) and the reference noninfusion therapies filgrastim (Neupogen) and pegfilgrastim (Neulasta) and on biosimilars of these therapies (infliximab-dyyb [Inflectra], infliximab-abda [Renflexis], filgrastim-sndz [Zarxio], and pegfilgrastim-jmdb [Fulphila]).

Because Medicare was the predominant payer, the researchers estimated reimbursement for reference and biosimilar infliximabs according to the Medicare Part B reimbursement policy. They defined an institution’s incentive to use a given therapy as the difference between the reimbursement and acquisition cost for that therapy. Dr. Baker and colleagues compared the incentives for UPHS with those for the VAMC.
 

VAMC saved 81% of reference product cost

The researchers identified 15,761 infusions of infliximab at UPHS and 446 at the VAMC during the study period. The proportion of infusions that used the reference product was 99% at UPHS and 62% at the VAMC. ASPs for biosimilar infliximab have been consistently lower than those for the reference product since July 2017. In December 2017, the VAMC switched to the biosimilar infliximab.

Institutional incentives based on Medicare Part B reimbursement and acquisitions costs for reference and biosimilar infliximab have been similar since 2018. In 2019, the institutional incentive favored the reference product by $49-$64 per 100-mg vial. But at the VAMC, the cost per 100-mg vial was $623.48 for the reference product and $115.58 for the biosimilar Renflexis. Purchasing the biosimilar thus yielded a savings of 81%. The current costs for the therapies are $546 and $116, respectively.

In addition, Dr. Baker and colleagues identified 46,683 orders for filgrastim or pegfilgrastim at UPHS. Approximately 90% of the orders were for either of the two reference products despite the ASP of biosimilar filgrastim being approximately 40% lower than that of its reference product. At the VAMC, about 88% of orders were for the reference products. Biosimilars became available in 2016. UPHS began using them at a modest rate, but their adoption was greater at the VAMC, which designated them as preferred products.

Tendering and a nationwide policy mandating use of biosimilars have resulted in financial savings for the VAMC, wrote Dr. Baker and colleagues. “These data suggest that, with current Medicare Part B reimbursement policy, the absence of financial incentives to encourage use of infliximab biosimilars has resulted in slower uptake of biosimilar use at institutions outside of the VA system. The implications of this are a slower reduction in costs to the health care system, since decreases in ASP over time are predicated on negotiations at the institutional level, which have been gradual and stepwise. ...

“Although some of our results may not be applicable to other geographical regions of the U.S., the comparison of two affiliated institutions in geographical proximity and with shared health care providers is a strength,” they continued. “Our findings should be replicated using national VAMC data or data from other health care systems.”

The researchers said that their findings may not apply to noninfused therapies, which are not covered under Medicare Part B, and they did not directly study the impact of pharmacy benefit managers. However, they noted that their data on filgrastim and pegfilgrastim support the hypothesis that pharmacy benefit managers receive “incentives that continue to promote the use of reference products that have higher manufacturer’s list prices, which likely will limit the uptake of both infused and injectable biosimilar therapies over time.” They said that “this finding has important implications for when noninfused biosimilars (e.g. etanercept and adalimumab) are eventually introduced to the U.S. market.”

European governments incentivize use of biosimilars

Government and institutional incentives have increased the adoption of biosimilars in Europe, wrote Guro Lovik Goll, MD, and Tore Kristian Kvien, MD, of the department of rheumatology at Diakonhjemmet Hospital in Oslo, in an accompanying editorial. Norway and Denmark have annual national tender systems in which biosimilars and reference products compete. The price of infliximab biosimilar was 39% lower than the reference product in 2014 and 69% lower in 2015. “Competition has caused dramatically lower prices both for biosimilars and also for the originator drugs competing with them,” wrote the authors.

In 2015, the government of Denmark mandated that patients on infliximab be switched to a biosimilar, and patients in Norway also have been switched to biosimilars. The use of etanercept in Norway increased by 40% from 2016 to 2019, and the use of infliximab has increased by more than threefold since 2015. “In Norway, the consequence of competition, national tenders, and availability of biosimilars have led to better access to therapy for more people in need of biologic drugs, while at the same time showing a total cost reduction of biologics for use in rheumatology, gastroenterology, and dermatology,” wrote the authors.

Health care costs $10,000 per capita in the United States, compared with $5,300 for other wealthy countries in the Organization for Economic Cooperation and Development. Low life expectancy and high infant mortality in the U.S. indicate that high costs are not associated with better outcomes. “As Americans seem to lose out on the cost-cutting potential of biosimilars, this missed opportunity is set to get even more expensive,” the authors concluded.

The U.S. Department of Veterans Affairs, the National Institutes of Health, and the American Diabetes Association contributed funding for the study. Dr. Baker reported receiving consulting fees from Bristol-Myers Squibb and Gilead, and another author reported receiving research support paid to his institution by Pfizer and UCB, as well as receiving consulting fees from nine pharmaceutical companies. Dr. Goll and Dr. Kvien both reported receiving fees for speaking and/or consulting from numerous pharmaceutical companies, including Pfizer.

AGA is taking the lead in educating health care providers and patients about biosimilars and how they can be used for IBD patient care. Learn more at www.gastro.org/biosimilars.

[email protected]

SOURCES: Baker JF et al. Arthritis Rheumatol. 2020 Apr 6. doi: 10.1002/art.41277.

The adoption of the infused biosimilar infliximab therapies Inflectra and Renflexis was slower at an academic medical center than at a neighboring Veterans Affairs Medical Center (VAMC) during the same time period in 2015-2019, according to an analysis published in Arthritis and Rheumatology.

The use of the biosimilars also was associated with cost savings at the VAMC, but not at the academic medical center, which illustrates that insufficient financial incentives can delay the adoption of biosimilars and the health care system’s realization of cost savings, according to the authors.

Medicare, which is not allowed to negotiate drug prices, is one of the largest payers for infused therapies. Medicare reimbursement for infused therapies is based on the latter’s average selling price (ASP) during the previous quarter. Institutions may negotiate purchase prices with drug manufacturers and receive Medicare reimbursement. Biosimilars generally have lower ASPs than their corresponding reference therapies, and biosimilar manufacturers may have less room to negotiate prices than reference therapy manufacturers. Consequently, a given institution might have a greater incentive to use reference products than to use biosimilars.
 

An examination of pharmacy data

The VA negotiates drug prices for all of its medical centers and has mandated that clinicians prefer biosimilars to their corresponding reference therapies, so Joshua F. Baker, MD, of the University of Pennsylvania and the Corporal Michael J. Crescenz VAMC, both in Philadelphia, and his colleagues hypothesized that the adoption of biosimilars had proceeded more quickly at a VAMC than at a nearby academic medical center.

The investigators examined pharmacy data from the University of Pennsylvania Health System (UPHS) electronic medical record and the Corporal Michael J. Crescenz VAMC to compare the frequency of prescribing biosimilars at these sites between Jan. 1, 2015, and May 31, 2019. Dr. Baker and his associates focused specifically on reference infliximab (Remicade) and the reference noninfusion therapies filgrastim (Neupogen) and pegfilgrastim (Neulasta) and on biosimilars of these therapies (infliximab-dyyb [Inflectra], infliximab-abda [Renflexis], filgrastim-sndz [Zarxio], and pegfilgrastim-jmdb [Fulphila]).

Because Medicare was the predominant payer, the researchers estimated reimbursement for reference and biosimilar infliximabs according to the Medicare Part B reimbursement policy. They defined an institution’s incentive to use a given therapy as the difference between the reimbursement and acquisition cost for that therapy. Dr. Baker and colleagues compared the incentives for UPHS with those for the VAMC.
 

VAMC saved 81% of reference product cost

The researchers identified 15,761 infusions of infliximab at UPHS and 446 at the VAMC during the study period. The proportion of infusions that used the reference product was 99% at UPHS and 62% at the VAMC. ASPs for biosimilar infliximab have been consistently lower than those for the reference product since July 2017. In December 2017, the VAMC switched to the biosimilar infliximab.

Institutional incentives based on Medicare Part B reimbursement and acquisitions costs for reference and biosimilar infliximab have been similar since 2018. In 2019, the institutional incentive favored the reference product by $49-$64 per 100-mg vial. But at the VAMC, the cost per 100-mg vial was $623.48 for the reference product and $115.58 for the biosimilar Renflexis. Purchasing the biosimilar thus yielded a savings of 81%. The current costs for the therapies are $546 and $116, respectively.

In addition, Dr. Baker and colleagues identified 46,683 orders for filgrastim or pegfilgrastim at UPHS. Approximately 90% of the orders were for either of the two reference products despite the ASP of biosimilar filgrastim being approximately 40% lower than that of its reference product. At the VAMC, about 88% of orders were for the reference products. Biosimilars became available in 2016. UPHS began using them at a modest rate, but their adoption was greater at the VAMC, which designated them as preferred products.

Tendering and a nationwide policy mandating use of biosimilars have resulted in financial savings for the VAMC, wrote Dr. Baker and colleagues. “These data suggest that, with current Medicare Part B reimbursement policy, the absence of financial incentives to encourage use of infliximab biosimilars has resulted in slower uptake of biosimilar use at institutions outside of the VA system. The implications of this are a slower reduction in costs to the health care system, since decreases in ASP over time are predicated on negotiations at the institutional level, which have been gradual and stepwise. ...

“Although some of our results may not be applicable to other geographical regions of the U.S., the comparison of two affiliated institutions in geographical proximity and with shared health care providers is a strength,” they continued. “Our findings should be replicated using national VAMC data or data from other health care systems.”

The researchers said that their findings may not apply to noninfused therapies, which are not covered under Medicare Part B, and they did not directly study the impact of pharmacy benefit managers. However, they noted that their data on filgrastim and pegfilgrastim support the hypothesis that pharmacy benefit managers receive “incentives that continue to promote the use of reference products that have higher manufacturer’s list prices, which likely will limit the uptake of both infused and injectable biosimilar therapies over time.” They said that “this finding has important implications for when noninfused biosimilars (e.g. etanercept and adalimumab) are eventually introduced to the U.S. market.”

European governments incentivize use of biosimilars

Government and institutional incentives have increased the adoption of biosimilars in Europe, wrote Guro Lovik Goll, MD, and Tore Kristian Kvien, MD, of the department of rheumatology at Diakonhjemmet Hospital in Oslo, in an accompanying editorial. Norway and Denmark have annual national tender systems in which biosimilars and reference products compete. The price of infliximab biosimilar was 39% lower than the reference product in 2014 and 69% lower in 2015. “Competition has caused dramatically lower prices both for biosimilars and also for the originator drugs competing with them,” wrote the authors.

In 2015, the government of Denmark mandated that patients on infliximab be switched to a biosimilar, and patients in Norway also have been switched to biosimilars. The use of etanercept in Norway increased by 40% from 2016 to 2019, and the use of infliximab has increased by more than threefold since 2015. “In Norway, the consequence of competition, national tenders, and availability of biosimilars have led to better access to therapy for more people in need of biologic drugs, while at the same time showing a total cost reduction of biologics for use in rheumatology, gastroenterology, and dermatology,” wrote the authors.

Health care costs $10,000 per capita in the United States, compared with $5,300 for other wealthy countries in the Organization for Economic Cooperation and Development. Low life expectancy and high infant mortality in the U.S. indicate that high costs are not associated with better outcomes. “As Americans seem to lose out on the cost-cutting potential of biosimilars, this missed opportunity is set to get even more expensive,” the authors concluded.

The U.S. Department of Veterans Affairs, the National Institutes of Health, and the American Diabetes Association contributed funding for the study. Dr. Baker reported receiving consulting fees from Bristol-Myers Squibb and Gilead, and another author reported receiving research support paid to his institution by Pfizer and UCB, as well as receiving consulting fees from nine pharmaceutical companies. Dr. Goll and Dr. Kvien both reported receiving fees for speaking and/or consulting from numerous pharmaceutical companies, including Pfizer.

AGA is taking the lead in educating health care providers and patients about biosimilars and how they can be used for IBD patient care. Learn more at www.gastro.org/biosimilars.

[email protected]

SOURCES: Baker JF et al. Arthritis Rheumatol. 2020 Apr 6. doi: 10.1002/art.41277.

The adoption of the infused biosimilar infliximab therapies Inflectra and Renflexis was slower at an academic medical center than at a neighboring Veterans Affairs Medical Center (VAMC) during the same time period in 2015-2019, according to an analysis published in Arthritis and Rheumatology.

The use of the biosimilars also was associated with cost savings at the VAMC, but not at the academic medical center, which illustrates that insufficient financial incentives can delay the adoption of biosimilars and the health care system’s realization of cost savings, according to the authors.

Medicare, which is not allowed to negotiate drug prices, is one of the largest payers for infused therapies. Medicare reimbursement for infused therapies is based on the latter’s average selling price (ASP) during the previous quarter. Institutions may negotiate purchase prices with drug manufacturers and receive Medicare reimbursement. Biosimilars generally have lower ASPs than their corresponding reference therapies, and biosimilar manufacturers may have less room to negotiate prices than reference therapy manufacturers. Consequently, a given institution might have a greater incentive to use reference products than to use biosimilars.
 

An examination of pharmacy data

The VA negotiates drug prices for all of its medical centers and has mandated that clinicians prefer biosimilars to their corresponding reference therapies, so Joshua F. Baker, MD, of the University of Pennsylvania and the Corporal Michael J. Crescenz VAMC, both in Philadelphia, and his colleagues hypothesized that the adoption of biosimilars had proceeded more quickly at a VAMC than at a nearby academic medical center.

The investigators examined pharmacy data from the University of Pennsylvania Health System (UPHS) electronic medical record and the Corporal Michael J. Crescenz VAMC to compare the frequency of prescribing biosimilars at these sites between Jan. 1, 2015, and May 31, 2019. Dr. Baker and his associates focused specifically on reference infliximab (Remicade) and the reference noninfusion therapies filgrastim (Neupogen) and pegfilgrastim (Neulasta) and on biosimilars of these therapies (infliximab-dyyb [Inflectra], infliximab-abda [Renflexis], filgrastim-sndz [Zarxio], and pegfilgrastim-jmdb [Fulphila]).

Because Medicare was the predominant payer, the researchers estimated reimbursement for reference and biosimilar infliximabs according to the Medicare Part B reimbursement policy. They defined an institution’s incentive to use a given therapy as the difference between the reimbursement and acquisition cost for that therapy. Dr. Baker and colleagues compared the incentives for UPHS with those for the VAMC.
 

VAMC saved 81% of reference product cost

The researchers identified 15,761 infusions of infliximab at UPHS and 446 at the VAMC during the study period. The proportion of infusions that used the reference product was 99% at UPHS and 62% at the VAMC. ASPs for biosimilar infliximab have been consistently lower than those for the reference product since July 2017. In December 2017, the VAMC switched to the biosimilar infliximab.

Institutional incentives based on Medicare Part B reimbursement and acquisitions costs for reference and biosimilar infliximab have been similar since 2018. In 2019, the institutional incentive favored the reference product by $49-$64 per 100-mg vial. But at the VAMC, the cost per 100-mg vial was $623.48 for the reference product and $115.58 for the biosimilar Renflexis. Purchasing the biosimilar thus yielded a savings of 81%. The current costs for the therapies are $546 and $116, respectively.

In addition, Dr. Baker and colleagues identified 46,683 orders for filgrastim or pegfilgrastim at UPHS. Approximately 90% of the orders were for either of the two reference products despite the ASP of biosimilar filgrastim being approximately 40% lower than that of its reference product. At the VAMC, about 88% of orders were for the reference products. Biosimilars became available in 2016. UPHS began using them at a modest rate, but their adoption was greater at the VAMC, which designated them as preferred products.

Tendering and a nationwide policy mandating use of biosimilars have resulted in financial savings for the VAMC, wrote Dr. Baker and colleagues. “These data suggest that, with current Medicare Part B reimbursement policy, the absence of financial incentives to encourage use of infliximab biosimilars has resulted in slower uptake of biosimilar use at institutions outside of the VA system. The implications of this are a slower reduction in costs to the health care system, since decreases in ASP over time are predicated on negotiations at the institutional level, which have been gradual and stepwise. ...

“Although some of our results may not be applicable to other geographical regions of the U.S., the comparison of two affiliated institutions in geographical proximity and with shared health care providers is a strength,” they continued. “Our findings should be replicated using national VAMC data or data from other health care systems.”

The researchers said that their findings may not apply to noninfused therapies, which are not covered under Medicare Part B, and they did not directly study the impact of pharmacy benefit managers. However, they noted that their data on filgrastim and pegfilgrastim support the hypothesis that pharmacy benefit managers receive “incentives that continue to promote the use of reference products that have higher manufacturer’s list prices, which likely will limit the uptake of both infused and injectable biosimilar therapies over time.” They said that “this finding has important implications for when noninfused biosimilars (e.g. etanercept and adalimumab) are eventually introduced to the U.S. market.”

European governments incentivize use of biosimilars

Government and institutional incentives have increased the adoption of biosimilars in Europe, wrote Guro Lovik Goll, MD, and Tore Kristian Kvien, MD, of the department of rheumatology at Diakonhjemmet Hospital in Oslo, in an accompanying editorial. Norway and Denmark have annual national tender systems in which biosimilars and reference products compete. The price of infliximab biosimilar was 39% lower than the reference product in 2014 and 69% lower in 2015. “Competition has caused dramatically lower prices both for biosimilars and also for the originator drugs competing with them,” wrote the authors.

In 2015, the government of Denmark mandated that patients on infliximab be switched to a biosimilar, and patients in Norway also have been switched to biosimilars. The use of etanercept in Norway increased by 40% from 2016 to 2019, and the use of infliximab has increased by more than threefold since 2015. “In Norway, the consequence of competition, national tenders, and availability of biosimilars have led to better access to therapy for more people in need of biologic drugs, while at the same time showing a total cost reduction of biologics for use in rheumatology, gastroenterology, and dermatology,” wrote the authors.

Health care costs $10,000 per capita in the United States, compared with $5,300 for other wealthy countries in the Organization for Economic Cooperation and Development. Low life expectancy and high infant mortality in the U.S. indicate that high costs are not associated with better outcomes. “As Americans seem to lose out on the cost-cutting potential of biosimilars, this missed opportunity is set to get even more expensive,” the authors concluded.

The U.S. Department of Veterans Affairs, the National Institutes of Health, and the American Diabetes Association contributed funding for the study. Dr. Baker reported receiving consulting fees from Bristol-Myers Squibb and Gilead, and another author reported receiving research support paid to his institution by Pfizer and UCB, as well as receiving consulting fees from nine pharmaceutical companies. Dr. Goll and Dr. Kvien both reported receiving fees for speaking and/or consulting from numerous pharmaceutical companies, including Pfizer.

AGA is taking the lead in educating health care providers and patients about biosimilars and how they can be used for IBD patient care. Learn more at www.gastro.org/biosimilars.

[email protected]

SOURCES: Baker JF et al. Arthritis Rheumatol. 2020 Apr 6. doi: 10.1002/art.41277.

Patients with inflammatory bowel disease (IBD) may benefit from biotin supplementation, according to a preclinical study.

In mice, biotin supplementation delayed onset of colitis, minimized pathology, and accelerated healing, reported lead author Jonathan Skupsky, MD, of the University of California, Irvine, and colleagues.

“Biotin deficiency often is overlooked in the setting of IBD and there have been several reports of biotin deficiency in patients with IBD,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.

In addition to these clinical reports, Dr. Skupsky and colleagues were motivated by their previous research, which showed that, in mice, knockout of the sodium-dependent multivitamin transporter (SMVT) for intestinal biotin uptake led to intestinal inflammation and dysplasia, thereby adding evidence that IBD and biotin could be linked.

In the present study, the investigators first compared mice fed a biotin-deficient diet with those fed a biotin-rich diet. Mice lacking biotin developed alopecia and weight loss within 7 weeks, and over time, stool that was soft and bloody. At week 14, mice fed the biotin-deficient diet had intestinal inflammation, based on elevated fecal calprotectin levels. In contrast, mice fed a biotin-rich diet had no gastrointestinal pathology.

“Although no mouse model entirely recapitulates patients with IBD, this model reproduces many of the findings including weight loss, bloody diarrhea, increased fecal calprotectin, altered crypt architecture, and infiltration of neutrophils and lymphocytes to the mucosa and submucosa,” the investigators wrote.

After this experiment, another group of mice were given drinking water with 3% dextran sodium sulfate (DSS), which induced severe colitis within 7 days. The distal colons of these mice had reduced expression of SMVT, the biotin transporter. This finding was also observed in biopsy samples from patients with ulcerative colitis, suggesting a shared pathway.

“This raises the possibility that [the biotin transport pathway] could be a target for therapy,” the investigators wrote.

Next the investigators tested the effect of prophylactic biotin supplementation in mice receiving 1.5% DSS in drinking water. Compared with mice that went without biotin, those that received a week of supplementation before DSS challenge had delayed, milder colitis, with histologic findings and fecal calprotectin levels that approximated those of healthy controls.

In a similar experiment, two groups of mice were given DSS for 7 days, then water or water plus biotin. Those in the biotin group recovered faster and more completely, again with clinical and histologic findings that was close to controls.

According to the investigators, these findings suggest that biotin may be able to protect against development of colitis and speed healing during early remission.

Further experiments dove deeper into cellular processes and molecular mechanisms, ultimately revealing that biotin supplementation reduced activation of NF-kappaB, which led to decreased intestinal permeability and inflammatory cytokines.

“The specific mechanism(s) linking biotin and NF-kappaB is unclear but could be mediated via the different cellular pathways that are affected by biotin availability,” the investigators wrote.

They noted that IBD is a complex condition, which can make it difficult to accurately model the disease; however, they also suggested that the findings are compelling enough to prompt further investigation in human patients because biotin could be a convenient therapeutic add-on.

“We are optimistic that the data presented here will serve as the foundation for future clinical studies to determine if biotin supplementation should be used as adjunct therapy in IBD,” the investigators wrote. “Biotin is available over the counter, is affordable, and it has minimal side effects, making it an ideal therapeutic if clinical trials can show similar efficacy to what we have seen in this preclinical model.

The study was funded by the Veteran’s Administration and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Skupsky J et al. Cell Mol Gastroenterol Hepatol. 2019 Nov 28. doi: 10.1016/j.jcmgh.2019.11.011.

Patients with inflammatory bowel disease (IBD) may benefit from biotin supplementation, according to a preclinical study.

In mice, biotin supplementation delayed onset of colitis, minimized pathology, and accelerated healing, reported lead author Jonathan Skupsky, MD, of the University of California, Irvine, and colleagues.

“Biotin deficiency often is overlooked in the setting of IBD and there have been several reports of biotin deficiency in patients with IBD,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.

In addition to these clinical reports, Dr. Skupsky and colleagues were motivated by their previous research, which showed that, in mice, knockout of the sodium-dependent multivitamin transporter (SMVT) for intestinal biotin uptake led to intestinal inflammation and dysplasia, thereby adding evidence that IBD and biotin could be linked.

In the present study, the investigators first compared mice fed a biotin-deficient diet with those fed a biotin-rich diet. Mice lacking biotin developed alopecia and weight loss within 7 weeks, and over time, stool that was soft and bloody. At week 14, mice fed the biotin-deficient diet had intestinal inflammation, based on elevated fecal calprotectin levels. In contrast, mice fed a biotin-rich diet had no gastrointestinal pathology.

“Although no mouse model entirely recapitulates patients with IBD, this model reproduces many of the findings including weight loss, bloody diarrhea, increased fecal calprotectin, altered crypt architecture, and infiltration of neutrophils and lymphocytes to the mucosa and submucosa,” the investigators wrote.

After this experiment, another group of mice were given drinking water with 3% dextran sodium sulfate (DSS), which induced severe colitis within 7 days. The distal colons of these mice had reduced expression of SMVT, the biotin transporter. This finding was also observed in biopsy samples from patients with ulcerative colitis, suggesting a shared pathway.

“This raises the possibility that [the biotin transport pathway] could be a target for therapy,” the investigators wrote.

Next the investigators tested the effect of prophylactic biotin supplementation in mice receiving 1.5% DSS in drinking water. Compared with mice that went without biotin, those that received a week of supplementation before DSS challenge had delayed, milder colitis, with histologic findings and fecal calprotectin levels that approximated those of healthy controls.

In a similar experiment, two groups of mice were given DSS for 7 days, then water or water plus biotin. Those in the biotin group recovered faster and more completely, again with clinical and histologic findings that was close to controls.

According to the investigators, these findings suggest that biotin may be able to protect against development of colitis and speed healing during early remission.

Further experiments dove deeper into cellular processes and molecular mechanisms, ultimately revealing that biotin supplementation reduced activation of NF-kappaB, which led to decreased intestinal permeability and inflammatory cytokines.

“The specific mechanism(s) linking biotin and NF-kappaB is unclear but could be mediated via the different cellular pathways that are affected by biotin availability,” the investigators wrote.

They noted that IBD is a complex condition, which can make it difficult to accurately model the disease; however, they also suggested that the findings are compelling enough to prompt further investigation in human patients because biotin could be a convenient therapeutic add-on.

“We are optimistic that the data presented here will serve as the foundation for future clinical studies to determine if biotin supplementation should be used as adjunct therapy in IBD,” the investigators wrote. “Biotin is available over the counter, is affordable, and it has minimal side effects, making it an ideal therapeutic if clinical trials can show similar efficacy to what we have seen in this preclinical model.

The study was funded by the Veteran’s Administration and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Skupsky J et al. Cell Mol Gastroenterol Hepatol. 2019 Nov 28. doi: 10.1016/j.jcmgh.2019.11.011.

Patients with inflammatory bowel disease (IBD) may benefit from biotin supplementation, according to a preclinical study.

In mice, biotin supplementation delayed onset of colitis, minimized pathology, and accelerated healing, reported lead author Jonathan Skupsky, MD, of the University of California, Irvine, and colleagues.

“Biotin deficiency often is overlooked in the setting of IBD and there have been several reports of biotin deficiency in patients with IBD,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.

In addition to these clinical reports, Dr. Skupsky and colleagues were motivated by their previous research, which showed that, in mice, knockout of the sodium-dependent multivitamin transporter (SMVT) for intestinal biotin uptake led to intestinal inflammation and dysplasia, thereby adding evidence that IBD and biotin could be linked.

In the present study, the investigators first compared mice fed a biotin-deficient diet with those fed a biotin-rich diet. Mice lacking biotin developed alopecia and weight loss within 7 weeks, and over time, stool that was soft and bloody. At week 14, mice fed the biotin-deficient diet had intestinal inflammation, based on elevated fecal calprotectin levels. In contrast, mice fed a biotin-rich diet had no gastrointestinal pathology.

“Although no mouse model entirely recapitulates patients with IBD, this model reproduces many of the findings including weight loss, bloody diarrhea, increased fecal calprotectin, altered crypt architecture, and infiltration of neutrophils and lymphocytes to the mucosa and submucosa,” the investigators wrote.

After this experiment, another group of mice were given drinking water with 3% dextran sodium sulfate (DSS), which induced severe colitis within 7 days. The distal colons of these mice had reduced expression of SMVT, the biotin transporter. This finding was also observed in biopsy samples from patients with ulcerative colitis, suggesting a shared pathway.

“This raises the possibility that [the biotin transport pathway] could be a target for therapy,” the investigators wrote.

Next the investigators tested the effect of prophylactic biotin supplementation in mice receiving 1.5% DSS in drinking water. Compared with mice that went without biotin, those that received a week of supplementation before DSS challenge had delayed, milder colitis, with histologic findings and fecal calprotectin levels that approximated those of healthy controls.

In a similar experiment, two groups of mice were given DSS for 7 days, then water or water plus biotin. Those in the biotin group recovered faster and more completely, again with clinical and histologic findings that was close to controls.

According to the investigators, these findings suggest that biotin may be able to protect against development of colitis and speed healing during early remission.

Further experiments dove deeper into cellular processes and molecular mechanisms, ultimately revealing that biotin supplementation reduced activation of NF-kappaB, which led to decreased intestinal permeability and inflammatory cytokines.

“The specific mechanism(s) linking biotin and NF-kappaB is unclear but could be mediated via the different cellular pathways that are affected by biotin availability,” the investigators wrote.

They noted that IBD is a complex condition, which can make it difficult to accurately model the disease; however, they also suggested that the findings are compelling enough to prompt further investigation in human patients because biotin could be a convenient therapeutic add-on.

“We are optimistic that the data presented here will serve as the foundation for future clinical studies to determine if biotin supplementation should be used as adjunct therapy in IBD,” the investigators wrote. “Biotin is available over the counter, is affordable, and it has minimal side effects, making it an ideal therapeutic if clinical trials can show similar efficacy to what we have seen in this preclinical model.

The study was funded by the Veteran’s Administration and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Skupsky J et al. Cell Mol Gastroenterol Hepatol. 2019 Nov 28. doi: 10.1016/j.jcmgh.2019.11.011.

For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.

Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.

“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.

The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).

Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.

Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.

“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.

Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).

“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.

Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.

“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”

The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.

“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.

The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.

SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.

For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.

Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.

“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.

The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).

Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.

Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.

“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.

Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).

“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.

Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.

“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”

The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.

“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.

The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.

SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.

For patients with inflammatory bowel disease or other immune-mediated inflammatory diseases, Janus kinase (JAK) inhibitors appear generally safe, though they may increase the risk of herpes zoster infection, according to a large-scale systematic review and meta-analysis.

Data from more than 66,000 patients revealed no significant links between JAK inhibitors and risks of serious infections, malignancy, or major adverse cardiovascular events, reported lead author Pablo Olivera, MD, of Centro de Educación Médica e Investigación Clínica (CEMIC) in Buenos Aires and colleagues.

“To the best of our knowledge, this is the first systematic review evaluating the risk profile of JAK inhibitors in a wide spectrum of immune-mediated inflammatory diseases,” they wrote in Gastroenterology.

The investigators drew studies from the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from 1990 to 2019 and from conference databases from 2012 to 2018. Out of 973 studies identified, 82 were included in the final analysis, of which two-thirds were randomized clinical trials. In total, 101,925 subjects were included, of whom a majority had rheumatoid arthritis (n = 86,308), followed by psoriasis (n = 9,311), inflammatory bowel disease (n = 5,987), and ankylosing spondylitis (n = 319).

Meta-analysis of JAK inhibitor usage involved 66,159 patients. Four JAK inhibitors were included: tofacitinib, filgotinib, baricitinib, and upadacitinib. The primary outcomes were the incidence rates of adverse events and serious adverse events. The investigators also estimated incidence rates of herpes zoster infection, serious infections, mortality, malignancy, and major adverse cardiovascular events. These rates were compared with those of patients who received placebo or an active comparator in clinical trials.

Analysis showed that almost 9 out of 10 patients (87.16%) who were exposed to a JAK inhibitor received tofacitinib. The investigators described high variability in treatment duration and baseline characteristics of participants. Rates of adverse events and serious adverse events also fell across a broad spectrum, from 10% to 82% and from 0% to 29%, respectively.

“Most [adverse events] were mild, and included worsening of the underlying condition, probably showing lack of efficacy,” the investigators wrote.

Rates of mortality and most adverse events were not significantly associated with JAK inhibitor exposure. In contrast, relative risk of herpes zoster infection was 57% higher in patients who received a JAK inhibitor than in those who received a placebo or comparator (RR, 1.57; 95% confidence interval, 1.01-2.37).

“Regarding the risk of herpes zoster with JAK inhibitors, the largest evidence comes from the use of tofacitinib, but it appears to be a class effect, with a clear dose-dependent effect,” the investigators wrote.

Although risks of herpes zoster may be carried across the drug class, they may not be evenly distributed given that a subgroup analysis revealed that some JAK inhibitors may bring higher risks than others; specifically, tofacitinib and baricitinib were associated with higher relative risks of herpes zoster than were upadacitinib and filgotinib.

“Although this is merely a qualitative comparison, this difference could be related to the fact that both filgotinib and upadacitinib are selective JAK1 inhibitors, whereas tofacitinib is a JAK1/JAK3 inhibitor and baricitinib a JAK1/JAK2 inhibitor,” the investigators wrote. “Further studies are needed to determine if JAK isoform selectivity affects the risk of herpes zoster.”

The investigators emphasized this need for more research. While the present findings help illuminate the safety profile of JAK inhibitors, they are clouded by various other factors, such as disease-specific considerations, a lack of real-world data, and studies that are likely too short to accurately determine risk of malignancy, the investigators wrote.

“More studies with long follow-up and in the real world setting, in different conditions, will be needed to fully elucidate the safety profile of the different JAK inhibitors,” the investigators concluded.

The investigators disclosed relationships with AbbVie, Takeda, Pfizer, and others.

SOURCE: Olivera P et al. Gastroenterology. 2020 Jan 8. doi: 10.1053/j.gastro.2020.01.001.

Adalimumab biosimilars are years away from entering the marketplace in the United States because of patent disputes, but they already have led to substantial discounts in Denmark, researchers wrote in JAMA Internal Medicine.

The Danish health care system switched almost entirely to adalimumab biosimilars after the patent on the original adalimumab product, Humira, expired there in October 2018. The switch to biosimilars led to an 82% decrease in costs for the medication, wrote Thomas Bo Jensen, MD, and colleagues in a research letter.

Denmark did not automatically substitute biosimilars, but the Danish Medicines Council recommended adalimumab biosimilars for all indications following Humira’s patent expiration. The recommendations “included switching patients to a biosimilar who were already well treated with the originator,” the researchers wrote.

To study the shift to adalimumab biosimilars across all indications in Denmark and calculate cost reductions, Dr. Jensen, of the department of clinical pharmacology at Copenhagen University Hospital Bispebjerg, and coinvestigators examined monthly data on drug sales from Amgros, which purchases all hospital drugs in the country.

“The proportion of adalimumab biosimilars increased from 71.6% (7,040 of 9,829 pens) in November 2018 to 95.1% (8,974 of 9,438 pens) in December 2018,” the researchers wrote. “Costs of adalimumab decreased by 82.8% from September 2018 to December 2018 (September: 8,197 pens at $5.13 million; December: 9,438 pens at $1.01 million).” The results were similar in rheumatology, dermatology, and gastroenterology.

The Food and Drug Administration has approved five adalimumab biosimilars in the United States, but “they will not enter the market until 2023 owing to patent disputes with AbbVie, the manufacturer of Humira,” wrote Jennifer D. Claytor, MD, of the department of internal medicine at University of California, San Francisco, and Walid Gellad, MD, of the division of general internal medicine at University of Pittsburgh, in an accompanying editorial.

The annual postrebate price of Humira doubled between 2013 and 2018, from $19,000 to $38,000, and these price increases may influence the price of biosimilars, “which will be priced using Humira’s price as an anchor,” Dr. Claytor and Dr. Gellad wrote.

A rapid shift to adalimumab biosimilars across the United States when they become available is “unlikely,” they wrote. Nonetheless, “some health care systems of comparable size to Denmark (e.g., the Veterans Affairs system) and others that are larger (e.g., Kaiser Permanente) ... have the ability to switch products quickly through use of formularies and a prescriber workforce. For example, Kaiser Permanente has successfully replaced Remicade (infliximab) with biosimilars in 80% of patients.”

Given the many biologics in development and increasing health care spending, “we need to take seriously the substantial savings offered by biosimilars and the feasibility, as evidenced by Denmark, of switching to biosimilars quickly once they are available on the market,” Dr. Claytor and Dr. Gellad concluded.

The research was supported by an unrestricted grant from Helsefonden. One author disclosed receiving grants from Pfizer, AbbVie, Roche, and Bristol-Myers Squibb outside the current study. The editorial authors had no disclosures.

Help your patients better understand their treatment options by sharing AGA’s patient education on biologics and biosimilars at https://www.gastro.org/practice-guidance/gi-patient-center/topic/biosimilars. 

[email protected]

SOURCE: Jensen TB et al. JAMA Intern Med. 2020 Mar 30. doi: 10.1001/jamainternmed.2020.0338.

Adalimumab biosimilars are years away from entering the marketplace in the United States because of patent disputes, but they already have led to substantial discounts in Denmark, researchers wrote in JAMA Internal Medicine.

The Danish health care system switched almost entirely to adalimumab biosimilars after the patent on the original adalimumab product, Humira, expired there in October 2018. The switch to biosimilars led to an 82% decrease in costs for the medication, wrote Thomas Bo Jensen, MD, and colleagues in a research letter.

Denmark did not automatically substitute biosimilars, but the Danish Medicines Council recommended adalimumab biosimilars for all indications following Humira’s patent expiration. The recommendations “included switching patients to a biosimilar who were already well treated with the originator,” the researchers wrote.

To study the shift to adalimumab biosimilars across all indications in Denmark and calculate cost reductions, Dr. Jensen, of the department of clinical pharmacology at Copenhagen University Hospital Bispebjerg, and coinvestigators examined monthly data on drug sales from Amgros, which purchases all hospital drugs in the country.

“The proportion of adalimumab biosimilars increased from 71.6% (7,040 of 9,829 pens) in November 2018 to 95.1% (8,974 of 9,438 pens) in December 2018,” the researchers wrote. “Costs of adalimumab decreased by 82.8% from September 2018 to December 2018 (September: 8,197 pens at $5.13 million; December: 9,438 pens at $1.01 million).” The results were similar in rheumatology, dermatology, and gastroenterology.

The Food and Drug Administration has approved five adalimumab biosimilars in the United States, but “they will not enter the market until 2023 owing to patent disputes with AbbVie, the manufacturer of Humira,” wrote Jennifer D. Claytor, MD, of the department of internal medicine at University of California, San Francisco, and Walid Gellad, MD, of the division of general internal medicine at University of Pittsburgh, in an accompanying editorial.

The annual postrebate price of Humira doubled between 2013 and 2018, from $19,000 to $38,000, and these price increases may influence the price of biosimilars, “which will be priced using Humira’s price as an anchor,” Dr. Claytor and Dr. Gellad wrote.

A rapid shift to adalimumab biosimilars across the United States when they become available is “unlikely,” they wrote. Nonetheless, “some health care systems of comparable size to Denmark (e.g., the Veterans Affairs system) and others that are larger (e.g., Kaiser Permanente) ... have the ability to switch products quickly through use of formularies and a prescriber workforce. For example, Kaiser Permanente has successfully replaced Remicade (infliximab) with biosimilars in 80% of patients.”

Given the many biologics in development and increasing health care spending, “we need to take seriously the substantial savings offered by biosimilars and the feasibility, as evidenced by Denmark, of switching to biosimilars quickly once they are available on the market,” Dr. Claytor and Dr. Gellad concluded.

The research was supported by an unrestricted grant from Helsefonden. One author disclosed receiving grants from Pfizer, AbbVie, Roche, and Bristol-Myers Squibb outside the current study. The editorial authors had no disclosures.

Help your patients better understand their treatment options by sharing AGA’s patient education on biologics and biosimilars at https://www.gastro.org/practice-guidance/gi-patient-center/topic/biosimilars. 

[email protected]

SOURCE: Jensen TB et al. JAMA Intern Med. 2020 Mar 30. doi: 10.1001/jamainternmed.2020.0338.

Adalimumab biosimilars are years away from entering the marketplace in the United States because of patent disputes, but they already have led to substantial discounts in Denmark, researchers wrote in JAMA Internal Medicine.

The Danish health care system switched almost entirely to adalimumab biosimilars after the patent on the original adalimumab product, Humira, expired there in October 2018. The switch to biosimilars led to an 82% decrease in costs for the medication, wrote Thomas Bo Jensen, MD, and colleagues in a research letter.

Denmark did not automatically substitute biosimilars, but the Danish Medicines Council recommended adalimumab biosimilars for all indications following Humira’s patent expiration. The recommendations “included switching patients to a biosimilar who were already well treated with the originator,” the researchers wrote.

To study the shift to adalimumab biosimilars across all indications in Denmark and calculate cost reductions, Dr. Jensen, of the department of clinical pharmacology at Copenhagen University Hospital Bispebjerg, and coinvestigators examined monthly data on drug sales from Amgros, which purchases all hospital drugs in the country.

“The proportion of adalimumab biosimilars increased from 71.6% (7,040 of 9,829 pens) in November 2018 to 95.1% (8,974 of 9,438 pens) in December 2018,” the researchers wrote. “Costs of adalimumab decreased by 82.8% from September 2018 to December 2018 (September: 8,197 pens at $5.13 million; December: 9,438 pens at $1.01 million).” The results were similar in rheumatology, dermatology, and gastroenterology.

The Food and Drug Administration has approved five adalimumab biosimilars in the United States, but “they will not enter the market until 2023 owing to patent disputes with AbbVie, the manufacturer of Humira,” wrote Jennifer D. Claytor, MD, of the department of internal medicine at University of California, San Francisco, and Walid Gellad, MD, of the division of general internal medicine at University of Pittsburgh, in an accompanying editorial.

The annual postrebate price of Humira doubled between 2013 and 2018, from $19,000 to $38,000, and these price increases may influence the price of biosimilars, “which will be priced using Humira’s price as an anchor,” Dr. Claytor and Dr. Gellad wrote.

A rapid shift to adalimumab biosimilars across the United States when they become available is “unlikely,” they wrote. Nonetheless, “some health care systems of comparable size to Denmark (e.g., the Veterans Affairs system) and others that are larger (e.g., Kaiser Permanente) ... have the ability to switch products quickly through use of formularies and a prescriber workforce. For example, Kaiser Permanente has successfully replaced Remicade (infliximab) with biosimilars in 80% of patients.”

Given the many biologics in development and increasing health care spending, “we need to take seriously the substantial savings offered by biosimilars and the feasibility, as evidenced by Denmark, of switching to biosimilars quickly once they are available on the market,” Dr. Claytor and Dr. Gellad concluded.

The research was supported by an unrestricted grant from Helsefonden. One author disclosed receiving grants from Pfizer, AbbVie, Roche, and Bristol-Myers Squibb outside the current study. The editorial authors had no disclosures.

Help your patients better understand their treatment options by sharing AGA’s patient education on biologics and biosimilars at https://www.gastro.org/practice-guidance/gi-patient-center/topic/biosimilars. 

[email protected]

SOURCE: Jensen TB et al. JAMA Intern Med. 2020 Mar 30. doi: 10.1001/jamainternmed.2020.0338.

Fecal microbiota transplantation (FMT) appears safe and effective for treating recurrent Clostridioides difficile infection in patients with inflammatory bowel disease (IBD), according to an ongoing prospective trial.

Most patients were cured of C. difficile after one fecal transplant, reported Jessica Allegretti, MD, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.

“[For patients without IBD], fecal microbiota transplantation has been shown to be very effective for the treatment of recurrent C. diff,” Dr. Allegretti said at the annual Gut Microbiota for Health World Summit.

But similar data for patients with IBD are scarce, and this knowledge gap has high clinical relevance, Dr. Allegretti said. She noted that C. difficile infections are eight times more common among patients with IBD, and risk of recurrence is increased 4.5-fold.

According to Dr. Allegretti, three small clinical trials have tested FMT for treating recurrent C. difficile infections in patients with IBD.

“[These studies were] somewhat prospective, but [data] mainly retrospectively collected, as they relied heavily on chart review for the assessment of IBD disease activity,” she said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility..

Across the trials, C. difficile infection cure rates were comparable with non-IBD cohorts; but disease flare rates ranged from 17.9% to 54%, which raised concern that FMT may trigger inflammation.

To investigate further, Dr. Allegretti and her colleagues designed a prospective trial that is set to enroll 50 patients with IBD. Among 37 patients treated to date, a slight majority were women (56.8%), about one-third had Crohn’s disease (37.8%), and two-thirds had ulcerative colitis (62.2%). The average baseline calprotectin level, which measures inflammation in the intestines, was 1,804.8 microg/g of feces, which is far above the upper limit of 50 microg/g.

“This is a very inflamed patient population,” Dr. Allegretti said.

Out of these 37 patients, 34 (92%) were cured of C. difficile infection after only one fecal transplant, and the remaining three patients were cured after a second FMT.

“They all did very well,” Dr. Allegretti said.

Concerning IBD clinical scores, all patients with Crohn’s disease either had unchanged or improved disease. Among those with ulcerative colitis, almost all had unchanged or improved disease, except for one patient who had a de novo flare.

Early microbiome analyses showed patients had increased alpha diversity and richness after FMT that was sustained through week 12. Because only three patients had recurrence, numbers were too small to generate predictive data based on relative abundance.

Dr. Allegretti continued her presentation with a review of FMT for IBD in general.

“For Crohn’s disease, the role [of microbiome manipulation] seems a bit more clear,” Dr. Allegretti said, considering multiple effective treatments that alter gut flora, such as antibiotics.

In contrast, the role for microbiome manipulation in treating ulcerative colitis “has remained a bit unclear,” she said. Although some probiotics appear effective for treating mild disease, other microbiome-altering treatments, such as diversion of fecal stream, antibiotics, and bowel rest, have fallen short.

Still, pooled data from four randomized clinical trials showed that FMT led to remission in 28% of patients with ulcerative colitis, compared with 9% who receive placebo.

“You may be thinking that seems a bit underwhelming compared to the 90% or so cure rate we get for C. diff trials,” Dr. Allegretti said. “However, if you look at our other biologic trials in IBD, 28% puts FMT on par with our other IBD therapies.”

According to Dr. Allegretti, at least three stool-based, FMT-like therapeutics are poised to become commercially available in the next few years for the treatment of C. difficile infection, including broad- and narrow-spectrum enema bags and oral capsules.

“I certainly think we will start to see off-label usage in our IBD patients, and we will start to have an easier and more systemic way of utilizing these microbiome-based therapies,” Dr. Allegretti said. “They will be coming to market, and when they do, whether or not we are allowed to still do traditional FMT in its current form remains unseen. The FDA may not allow us to do that in the future when we have an FDA-approved product.”Dr. Allegretti disclosed relationships with Merck, Openbiome, Finch Therapeutics, and others.

[email protected]

Fecal microbiota transplantation (FMT) appears safe and effective for treating recurrent Clostridioides difficile infection in patients with inflammatory bowel disease (IBD), according to an ongoing prospective trial.

Most patients were cured of C. difficile after one fecal transplant, reported Jessica Allegretti, MD, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.

“[For patients without IBD], fecal microbiota transplantation has been shown to be very effective for the treatment of recurrent C. diff,” Dr. Allegretti said at the annual Gut Microbiota for Health World Summit.

But similar data for patients with IBD are scarce, and this knowledge gap has high clinical relevance, Dr. Allegretti said. She noted that C. difficile infections are eight times more common among patients with IBD, and risk of recurrence is increased 4.5-fold.

According to Dr. Allegretti, three small clinical trials have tested FMT for treating recurrent C. difficile infections in patients with IBD.

“[These studies were] somewhat prospective, but [data] mainly retrospectively collected, as they relied heavily on chart review for the assessment of IBD disease activity,” she said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility..

Across the trials, C. difficile infection cure rates were comparable with non-IBD cohorts; but disease flare rates ranged from 17.9% to 54%, which raised concern that FMT may trigger inflammation.

To investigate further, Dr. Allegretti and her colleagues designed a prospective trial that is set to enroll 50 patients with IBD. Among 37 patients treated to date, a slight majority were women (56.8%), about one-third had Crohn’s disease (37.8%), and two-thirds had ulcerative colitis (62.2%). The average baseline calprotectin level, which measures inflammation in the intestines, was 1,804.8 microg/g of feces, which is far above the upper limit of 50 microg/g.

“This is a very inflamed patient population,” Dr. Allegretti said.

Out of these 37 patients, 34 (92%) were cured of C. difficile infection after only one fecal transplant, and the remaining three patients were cured after a second FMT.

“They all did very well,” Dr. Allegretti said.

Concerning IBD clinical scores, all patients with Crohn’s disease either had unchanged or improved disease. Among those with ulcerative colitis, almost all had unchanged or improved disease, except for one patient who had a de novo flare.

Early microbiome analyses showed patients had increased alpha diversity and richness after FMT that was sustained through week 12. Because only three patients had recurrence, numbers were too small to generate predictive data based on relative abundance.

Dr. Allegretti continued her presentation with a review of FMT for IBD in general.

“For Crohn’s disease, the role [of microbiome manipulation] seems a bit more clear,” Dr. Allegretti said, considering multiple effective treatments that alter gut flora, such as antibiotics.

In contrast, the role for microbiome manipulation in treating ulcerative colitis “has remained a bit unclear,” she said. Although some probiotics appear effective for treating mild disease, other microbiome-altering treatments, such as diversion of fecal stream, antibiotics, and bowel rest, have fallen short.

Still, pooled data from four randomized clinical trials showed that FMT led to remission in 28% of patients with ulcerative colitis, compared with 9% who receive placebo.

“You may be thinking that seems a bit underwhelming compared to the 90% or so cure rate we get for C. diff trials,” Dr. Allegretti said. “However, if you look at our other biologic trials in IBD, 28% puts FMT on par with our other IBD therapies.”

According to Dr. Allegretti, at least three stool-based, FMT-like therapeutics are poised to become commercially available in the next few years for the treatment of C. difficile infection, including broad- and narrow-spectrum enema bags and oral capsules.

“I certainly think we will start to see off-label usage in our IBD patients, and we will start to have an easier and more systemic way of utilizing these microbiome-based therapies,” Dr. Allegretti said. “They will be coming to market, and when they do, whether or not we are allowed to still do traditional FMT in its current form remains unseen. The FDA may not allow us to do that in the future when we have an FDA-approved product.”Dr. Allegretti disclosed relationships with Merck, Openbiome, Finch Therapeutics, and others.

[email protected]

Fecal microbiota transplantation (FMT) appears safe and effective for treating recurrent Clostridioides difficile infection in patients with inflammatory bowel disease (IBD), according to an ongoing prospective trial.

Most patients were cured of C. difficile after one fecal transplant, reported Jessica Allegretti, MD, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.

“[For patients without IBD], fecal microbiota transplantation has been shown to be very effective for the treatment of recurrent C. diff,” Dr. Allegretti said at the annual Gut Microbiota for Health World Summit.

But similar data for patients with IBD are scarce, and this knowledge gap has high clinical relevance, Dr. Allegretti said. She noted that C. difficile infections are eight times more common among patients with IBD, and risk of recurrence is increased 4.5-fold.

According to Dr. Allegretti, three small clinical trials have tested FMT for treating recurrent C. difficile infections in patients with IBD.

“[These studies were] somewhat prospective, but [data] mainly retrospectively collected, as they relied heavily on chart review for the assessment of IBD disease activity,” she said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility..

Across the trials, C. difficile infection cure rates were comparable with non-IBD cohorts; but disease flare rates ranged from 17.9% to 54%, which raised concern that FMT may trigger inflammation.

To investigate further, Dr. Allegretti and her colleagues designed a prospective trial that is set to enroll 50 patients with IBD. Among 37 patients treated to date, a slight majority were women (56.8%), about one-third had Crohn’s disease (37.8%), and two-thirds had ulcerative colitis (62.2%). The average baseline calprotectin level, which measures inflammation in the intestines, was 1,804.8 microg/g of feces, which is far above the upper limit of 50 microg/g.

“This is a very inflamed patient population,” Dr. Allegretti said.

Out of these 37 patients, 34 (92%) were cured of C. difficile infection after only one fecal transplant, and the remaining three patients were cured after a second FMT.

“They all did very well,” Dr. Allegretti said.

Concerning IBD clinical scores, all patients with Crohn’s disease either had unchanged or improved disease. Among those with ulcerative colitis, almost all had unchanged or improved disease, except for one patient who had a de novo flare.

Early microbiome analyses showed patients had increased alpha diversity and richness after FMT that was sustained through week 12. Because only three patients had recurrence, numbers were too small to generate predictive data based on relative abundance.

Dr. Allegretti continued her presentation with a review of FMT for IBD in general.

“For Crohn’s disease, the role [of microbiome manipulation] seems a bit more clear,” Dr. Allegretti said, considering multiple effective treatments that alter gut flora, such as antibiotics.

In contrast, the role for microbiome manipulation in treating ulcerative colitis “has remained a bit unclear,” she said. Although some probiotics appear effective for treating mild disease, other microbiome-altering treatments, such as diversion of fecal stream, antibiotics, and bowel rest, have fallen short.

Still, pooled data from four randomized clinical trials showed that FMT led to remission in 28% of patients with ulcerative colitis, compared with 9% who receive placebo.

“You may be thinking that seems a bit underwhelming compared to the 90% or so cure rate we get for C. diff trials,” Dr. Allegretti said. “However, if you look at our other biologic trials in IBD, 28% puts FMT on par with our other IBD therapies.”

According to Dr. Allegretti, at least three stool-based, FMT-like therapeutics are poised to become commercially available in the next few years for the treatment of C. difficile infection, including broad- and narrow-spectrum enema bags and oral capsules.

“I certainly think we will start to see off-label usage in our IBD patients, and we will start to have an easier and more systemic way of utilizing these microbiome-based therapies,” Dr. Allegretti said. “They will be coming to market, and when they do, whether or not we are allowed to still do traditional FMT in its current form remains unseen. The FDA may not allow us to do that in the future when we have an FDA-approved product.”Dr. Allegretti disclosed relationships with Merck, Openbiome, Finch Therapeutics, and others.

[email protected]

The Food and Drug Administration has issued a Safety Alert warning of the potential for SARS-CoV-2 transmission through fecal microbiota transplantation and that additional safety procedures may be required.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The risk of SARS-CoV-2 transmission through fecal microbiota transplant is unknown, but “several recent studies have documented the presence of SARS-CoV-2 ribonucleic acid (RNA) and/or SARS-CoV-2 virus in stool of infected individuals,” the FDA said in the press release. The testing of nasopharyngeal specimens from stool donors may not be available, and the availability and sensitivity of direct testing of stool for SARS-CoV-2 is currently unknown.

Because of the risk of serious adverse events, the FDA has issued several recommendations for any medically necessary usage of fecal microbiota transplantation involving stool samples donated after Dec. 1, 2019.

• Donor screening with questions directed at identifying those currently or recently infected with SARS-CoV-2.
• Testing donors and/or donor stool for SARS-CoV-2, as feasible.
• Development of criteria for exclusion of donors and donor stool based on screening and testing.
• Informed consent that includes information about the potential for transmission of SARS-CoV-2 via fecal microbiota transplantation, including transplantation prepared from stool from donors who are asymptomatic for COVID-19.

“As the scientific community learns more about SARS-CoV-2 and COVID-19, FDA will provide further information as warranted,” the agency said.

[email protected]

The Food and Drug Administration has issued a Safety Alert warning of the potential for SARS-CoV-2 transmission through fecal microbiota transplantation and that additional safety procedures may be required.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The risk of SARS-CoV-2 transmission through fecal microbiota transplant is unknown, but “several recent studies have documented the presence of SARS-CoV-2 ribonucleic acid (RNA) and/or SARS-CoV-2 virus in stool of infected individuals,” the FDA said in the press release. The testing of nasopharyngeal specimens from stool donors may not be available, and the availability and sensitivity of direct testing of stool for SARS-CoV-2 is currently unknown.

Because of the risk of serious adverse events, the FDA has issued several recommendations for any medically necessary usage of fecal microbiota transplantation involving stool samples donated after Dec. 1, 2019.

• Donor screening with questions directed at identifying those currently or recently infected with SARS-CoV-2.
• Testing donors and/or donor stool for SARS-CoV-2, as feasible.
• Development of criteria for exclusion of donors and donor stool based on screening and testing.
• Informed consent that includes information about the potential for transmission of SARS-CoV-2 via fecal microbiota transplantation, including transplantation prepared from stool from donors who are asymptomatic for COVID-19.

“As the scientific community learns more about SARS-CoV-2 and COVID-19, FDA will provide further information as warranted,” the agency said.

[email protected]

The Food and Drug Administration has issued a Safety Alert warning of the potential for SARS-CoV-2 transmission through fecal microbiota transplantation and that additional safety procedures may be required.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The risk of SARS-CoV-2 transmission through fecal microbiota transplant is unknown, but “several recent studies have documented the presence of SARS-CoV-2 ribonucleic acid (RNA) and/or SARS-CoV-2 virus in stool of infected individuals,” the FDA said in the press release. The testing of nasopharyngeal specimens from stool donors may not be available, and the availability and sensitivity of direct testing of stool for SARS-CoV-2 is currently unknown.

Because of the risk of serious adverse events, the FDA has issued several recommendations for any medically necessary usage of fecal microbiota transplantation involving stool samples donated after Dec. 1, 2019.

• Donor screening with questions directed at identifying those currently or recently infected with SARS-CoV-2.
• Testing donors and/or donor stool for SARS-CoV-2, as feasible.
• Development of criteria for exclusion of donors and donor stool based on screening and testing.
• Informed consent that includes information about the potential for transmission of SARS-CoV-2 via fecal microbiota transplantation, including transplantation prepared from stool from donors who are asymptomatic for COVID-19.

“As the scientific community learns more about SARS-CoV-2 and COVID-19, FDA will provide further information as warranted,” the agency said.

[email protected]

Gastroenterologists and other clinicians caring for patients with inflammatory bowel disease are being encouraged to report outcomes for pediatric and adult patients with IBD and COVID-19 infections to a new international registry.

The Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry is a repository for data on all cases of COVID-19 in patients with IBD, including those who are asymptomatic and detected only through public health screening.

The idea for the registry came from gastroenterologists at the University of North Carolina at Chapel Hill and at the Icahn School of Medicine at Mount Sinai, New York.

It was developed out of the recognition that, “with the emergence of this international health crisis, it would make sense to develop a registry to allow clinicians taking care of patients with inflammatory bowel disease to report on the specifics of their cases, so that we could then quickly define what the impact is of this disease on our patients, and determine how disease severity, medication, and specific demographics impact COVID-related outcomes in our population,” said registry cofounder Erica Brenner, MD, a pediatric gastroenterology fellow at UNC.

As of March 19, 2020, 14 cases of COVID-19 infections in patients with IBD had been reported to the registry: 6 from the United States, 3 from Spain, and 1 each from the United Kingdom, Switzerland, Ireland, Italy and the Netherlands. There were no patient deaths, and only two required hospitalization. Neither of the hospitalized patients required intensive care or ventilator support.

Dr. Brenner noted that it’s still early days, and that a clearer picture of the pandemic will begin to emerge as more cases are reported.

“We are planning at least weekly to update our ‘Updates and Data’ tab on the registry with summary data and aggregate information,” she said in an interview.

All data in the registry are deidentified in accordance with HIPAA Safe Harbor standards. The UNC–Chapel Hill Office for Human Research Ethics has determined that storage and analysis of deidentified data is exempt from institutional review board requirement because it does not constitute human subjects research as defined under federal regulations.

SECURE-IBD was the inspiration for a similarly designed COVID-19 registry for clinicians who treat patients with rheumatologic disorders, who often are treated with immunosuppressive agents familiar to the rheumatology community, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and methotrexate.

“We’re in the process of talking to different leaders across specialties to leverage our blueprint to implement registries in all sorts of disease states, including cirrhosis, psoriasis, lupus, and sickle cell disease,” Dr. Brenner said.

The data entry process is estimated to take 5 minutes. Participating clinicians are requested to reported on confirmed COVID-19 cases only “after sufficient time has passed to observe the disease course through resolution of acute illness and/or death.”

“The success of this registry depends on international collaboration and buy-in from clinicians around the world, so we really encourage all clinicians who take care of patients with inflammatory bowel disease to go to our website and report a case,” Dr. Brenner said.

Gastroenterologists and other clinicians caring for patients with inflammatory bowel disease are being encouraged to report outcomes for pediatric and adult patients with IBD and COVID-19 infections to a new international registry.

The Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry is a repository for data on all cases of COVID-19 in patients with IBD, including those who are asymptomatic and detected only through public health screening.

The idea for the registry came from gastroenterologists at the University of North Carolina at Chapel Hill and at the Icahn School of Medicine at Mount Sinai, New York.

It was developed out of the recognition that, “with the emergence of this international health crisis, it would make sense to develop a registry to allow clinicians taking care of patients with inflammatory bowel disease to report on the specifics of their cases, so that we could then quickly define what the impact is of this disease on our patients, and determine how disease severity, medication, and specific demographics impact COVID-related outcomes in our population,” said registry cofounder Erica Brenner, MD, a pediatric gastroenterology fellow at UNC.

As of March 19, 2020, 14 cases of COVID-19 infections in patients with IBD had been reported to the registry: 6 from the United States, 3 from Spain, and 1 each from the United Kingdom, Switzerland, Ireland, Italy and the Netherlands. There were no patient deaths, and only two required hospitalization. Neither of the hospitalized patients required intensive care or ventilator support.

Dr. Brenner noted that it’s still early days, and that a clearer picture of the pandemic will begin to emerge as more cases are reported.

“We are planning at least weekly to update our ‘Updates and Data’ tab on the registry with summary data and aggregate information,” she said in an interview.

All data in the registry are deidentified in accordance with HIPAA Safe Harbor standards. The UNC–Chapel Hill Office for Human Research Ethics has determined that storage and analysis of deidentified data is exempt from institutional review board requirement because it does not constitute human subjects research as defined under federal regulations.

SECURE-IBD was the inspiration for a similarly designed COVID-19 registry for clinicians who treat patients with rheumatologic disorders, who often are treated with immunosuppressive agents familiar to the rheumatology community, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and methotrexate.

“We’re in the process of talking to different leaders across specialties to leverage our blueprint to implement registries in all sorts of disease states, including cirrhosis, psoriasis, lupus, and sickle cell disease,” Dr. Brenner said.

The data entry process is estimated to take 5 minutes. Participating clinicians are requested to reported on confirmed COVID-19 cases only “after sufficient time has passed to observe the disease course through resolution of acute illness and/or death.”

“The success of this registry depends on international collaboration and buy-in from clinicians around the world, so we really encourage all clinicians who take care of patients with inflammatory bowel disease to go to our website and report a case,” Dr. Brenner said.

Gastroenterologists and other clinicians caring for patients with inflammatory bowel disease are being encouraged to report outcomes for pediatric and adult patients with IBD and COVID-19 infections to a new international registry.

The Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD) registry is a repository for data on all cases of COVID-19 in patients with IBD, including those who are asymptomatic and detected only through public health screening.

The idea for the registry came from gastroenterologists at the University of North Carolina at Chapel Hill and at the Icahn School of Medicine at Mount Sinai, New York.

It was developed out of the recognition that, “with the emergence of this international health crisis, it would make sense to develop a registry to allow clinicians taking care of patients with inflammatory bowel disease to report on the specifics of their cases, so that we could then quickly define what the impact is of this disease on our patients, and determine how disease severity, medication, and specific demographics impact COVID-related outcomes in our population,” said registry cofounder Erica Brenner, MD, a pediatric gastroenterology fellow at UNC.

As of March 19, 2020, 14 cases of COVID-19 infections in patients with IBD had been reported to the registry: 6 from the United States, 3 from Spain, and 1 each from the United Kingdom, Switzerland, Ireland, Italy and the Netherlands. There were no patient deaths, and only two required hospitalization. Neither of the hospitalized patients required intensive care or ventilator support.

Dr. Brenner noted that it’s still early days, and that a clearer picture of the pandemic will begin to emerge as more cases are reported.

“We are planning at least weekly to update our ‘Updates and Data’ tab on the registry with summary data and aggregate information,” she said in an interview.

All data in the registry are deidentified in accordance with HIPAA Safe Harbor standards. The UNC–Chapel Hill Office for Human Research Ethics has determined that storage and analysis of deidentified data is exempt from institutional review board requirement because it does not constitute human subjects research as defined under federal regulations.

SECURE-IBD was the inspiration for a similarly designed COVID-19 registry for clinicians who treat patients with rheumatologic disorders, who often are treated with immunosuppressive agents familiar to the rheumatology community, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and methotrexate.

“We’re in the process of talking to different leaders across specialties to leverage our blueprint to implement registries in all sorts of disease states, including cirrhosis, psoriasis, lupus, and sickle cell disease,” Dr. Brenner said.

The data entry process is estimated to take 5 minutes. Participating clinicians are requested to reported on confirmed COVID-19 cases only “after sufficient time has passed to observe the disease course through resolution of acute illness and/or death.”

“The success of this registry depends on international collaboration and buy-in from clinicians around the world, so we really encourage all clinicians who take care of patients with inflammatory bowel disease to go to our website and report a case,” Dr. Brenner said.

The novel coronavirus (2019-nCoV) shows evidence of causing gastrointestinal symptoms and has the potential to be transmitted by the fecal-oral route, according to a new report from physicians at Shanghai Jiao Tong University, published online (Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054).

The virus’s respiratory symptoms are well documented and suggest primary transmission by droplet or contact, while other symptoms such as diarrhea, nausea, vomiting, and abdominal discomfort are less common and appear to vary between populations. The SARS coronavirus showed up in stool, even sometimes in patients discharged from the hospital. In a study of hospitalized patients in Wuhan, China, 10.1% of coronavirus patients had diarrhea and nausea in the 1-2 days before onset of fever and dyspnea. The first U.S. patient to be diagnosed had a 2-day history of nausea and vomiting, and had a loose bowel movement on the second day in the hospital. Clinicians later confirmed the presence of viral RNA in both the patient’s stool and airway.

The authors say that researchers in China have isolated viral RNA from the stool of two patients (unpublished), and it has been found in saliva, suggesting the possibility of the salivary gland as an infection or transmission route.

The authors maintain that previous studies likely overlooked or neglected patients who had mild intestinal symptoms. “Many efforts should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation and early intervention,” the authors wrote.

Like other coronaviruses, it appears that 2019-nCoV infects cells through an interaction between viral transmembrane spike glycoprotein (S-protein) receptor-binding domain, and the cell receptors angiotensin-converting enzyme 2 (ACE-2) and host cellular transmembrane serine protease (TMPRSS). Transcriptome analysis has shown that human lung AT2 cells express ACE-2 and TMPRSS, but esophagus upper and stratified epithelial cells also express both factors, as do stratified epithelial cells and absorptive enterocytes in the ileum and colon.

The researchers call for investigation into ACE-2 fusion proteins and TMPRSS inhibitors for diagnosis, prophylaxis, or treatment of COVID-19.

The authors also noted that COVID-19 has been linked to mild to moderate liver injury as revealed by elevated aminotransferases, hypoproteinemia and prothrombin time prolongation. This also has precedent in that the SARS coronavirus can infect the liver, and biopsies revealed mitoses and apoptosis, along with other abnormalities. SARS-associated hepatitis may be the result of viral hepatitis, immune overreaction, or a secondary effect of antiviral medications or other drugs. Little is known to date about the ability of 2019-nCoV to infect the liver, but single-cell RNA sequencing data from two distinct cohorts showed more ACE-2 expression in cholangiocytes (59.7%) than hepatocytes (2.6%), which indicates that the virus might directly affect intrahepatic bile ducts.

The authors had no sources of funding or financial conflicts.

SOURCE: GU J et al. Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054.

*This story was updated on 4/10.2020.

The novel coronavirus (2019-nCoV) shows evidence of causing gastrointestinal symptoms and has the potential to be transmitted by the fecal-oral route, according to a new report from physicians at Shanghai Jiao Tong University, published online (Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054).

The virus’s respiratory symptoms are well documented and suggest primary transmission by droplet or contact, while other symptoms such as diarrhea, nausea, vomiting, and abdominal discomfort are less common and appear to vary between populations. The SARS coronavirus showed up in stool, even sometimes in patients discharged from the hospital. In a study of hospitalized patients in Wuhan, China, 10.1% of coronavirus patients had diarrhea and nausea in the 1-2 days before onset of fever and dyspnea. The first U.S. patient to be diagnosed had a 2-day history of nausea and vomiting, and had a loose bowel movement on the second day in the hospital. Clinicians later confirmed the presence of viral RNA in both the patient’s stool and airway.

The authors say that researchers in China have isolated viral RNA from the stool of two patients (unpublished), and it has been found in saliva, suggesting the possibility of the salivary gland as an infection or transmission route.

The authors maintain that previous studies likely overlooked or neglected patients who had mild intestinal symptoms. “Many efforts should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation and early intervention,” the authors wrote.

Like other coronaviruses, it appears that 2019-nCoV infects cells through an interaction between viral transmembrane spike glycoprotein (S-protein) receptor-binding domain, and the cell receptors angiotensin-converting enzyme 2 (ACE-2) and host cellular transmembrane serine protease (TMPRSS). Transcriptome analysis has shown that human lung AT2 cells express ACE-2 and TMPRSS, but esophagus upper and stratified epithelial cells also express both factors, as do stratified epithelial cells and absorptive enterocytes in the ileum and colon.

The researchers call for investigation into ACE-2 fusion proteins and TMPRSS inhibitors for diagnosis, prophylaxis, or treatment of COVID-19.

The authors also noted that COVID-19 has been linked to mild to moderate liver injury as revealed by elevated aminotransferases, hypoproteinemia and prothrombin time prolongation. This also has precedent in that the SARS coronavirus can infect the liver, and biopsies revealed mitoses and apoptosis, along with other abnormalities. SARS-associated hepatitis may be the result of viral hepatitis, immune overreaction, or a secondary effect of antiviral medications or other drugs. Little is known to date about the ability of 2019-nCoV to infect the liver, but single-cell RNA sequencing data from two distinct cohorts showed more ACE-2 expression in cholangiocytes (59.7%) than hepatocytes (2.6%), which indicates that the virus might directly affect intrahepatic bile ducts.

The authors had no sources of funding or financial conflicts.

SOURCE: GU J et al. Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054.

*This story was updated on 4/10.2020.

The novel coronavirus (2019-nCoV) shows evidence of causing gastrointestinal symptoms and has the potential to be transmitted by the fecal-oral route, according to a new report from physicians at Shanghai Jiao Tong University, published online (Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054).

The virus’s respiratory symptoms are well documented and suggest primary transmission by droplet or contact, while other symptoms such as diarrhea, nausea, vomiting, and abdominal discomfort are less common and appear to vary between populations. The SARS coronavirus showed up in stool, even sometimes in patients discharged from the hospital. In a study of hospitalized patients in Wuhan, China, 10.1% of coronavirus patients had diarrhea and nausea in the 1-2 days before onset of fever and dyspnea. The first U.S. patient to be diagnosed had a 2-day history of nausea and vomiting, and had a loose bowel movement on the second day in the hospital. Clinicians later confirmed the presence of viral RNA in both the patient’s stool and airway.

The authors say that researchers in China have isolated viral RNA from the stool of two patients (unpublished), and it has been found in saliva, suggesting the possibility of the salivary gland as an infection or transmission route.

The authors maintain that previous studies likely overlooked or neglected patients who had mild intestinal symptoms. “Many efforts should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation and early intervention,” the authors wrote.

Like other coronaviruses, it appears that 2019-nCoV infects cells through an interaction between viral transmembrane spike glycoprotein (S-protein) receptor-binding domain, and the cell receptors angiotensin-converting enzyme 2 (ACE-2) and host cellular transmembrane serine protease (TMPRSS). Transcriptome analysis has shown that human lung AT2 cells express ACE-2 and TMPRSS, but esophagus upper and stratified epithelial cells also express both factors, as do stratified epithelial cells and absorptive enterocytes in the ileum and colon.

The researchers call for investigation into ACE-2 fusion proteins and TMPRSS inhibitors for diagnosis, prophylaxis, or treatment of COVID-19.

The authors also noted that COVID-19 has been linked to mild to moderate liver injury as revealed by elevated aminotransferases, hypoproteinemia and prothrombin time prolongation. This also has precedent in that the SARS coronavirus can infect the liver, and biopsies revealed mitoses and apoptosis, along with other abnormalities. SARS-associated hepatitis may be the result of viral hepatitis, immune overreaction, or a secondary effect of antiviral medications or other drugs. Little is known to date about the ability of 2019-nCoV to infect the liver, but single-cell RNA sequencing data from two distinct cohorts showed more ACE-2 expression in cholangiocytes (59.7%) than hepatocytes (2.6%), which indicates that the virus might directly affect intrahepatic bile ducts.

The authors had no sources of funding or financial conflicts.

SOURCE: GU J et al. Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054.

*This story was updated on 4/10.2020.

For moderate to severe ulcerative colitis, treatment with any one of the leading biologic agents is superior to no treatment at all. And in treatment-naive patients, infliximab or vedolizumab should be used rather than adalimumab for inducing remission. These are key recommendations from the American Gastroenterological Association guideline for patients with moderate to severe ulcerative colitis (UC), published in Gastroenterology (doi: 10.1053/j.gastro.2020.01.006).

In all, the guideline comprises 11 recommendations for using immunomodulators, biologics, and small-molecule agents to induce and maintain remission in outpatients with moderate to severe UC and to decrease the need for colectomy in hospitalized patients with acute severe UC. The latest guideline follows a guideline for mild to moderate UC published last year (Gastroenterology. 2019;156[3]:748-64). A technical review accompanied the most recent publication (Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.007).

An updated guideline was long overdue, lead author Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center, Boston, said in an interview. “The care of patients with inflammatory bowel disease – both ulcerative colitis and Crohn’s – has become increasingly complicated with many newer drugs becoming available,” he said. “The paradigm of how we are treating the disease is evolving, but we haven’t had updated, evidence-based guidelines.” Dr. Feuerstein is the lead author of this guideline.

The guideline can also aid in influencing payers’ policies that now require step-up therapy – that is, failing with the least costly drug before moving onto newer and more effective but costlier agents – Dr. Feuerstein said. “These guidelines show now that we should be treating people based on the evidence and not based on just an insurance company’s preferred policy,” he said.

The strongest recommendation is to use the tumor necrosis factor–alpha (TNF-alpha) antagonists infliximab, adalimumab, and golimumab, the anti-integrin agent vedolizumab, or the anti-interleukin 12/23 agent ustekinumab — all biologics — or the synthetic JAK inhibitor tofacitinib rather than not treating the UC. This is the only recommendation labeled as “strong,” based on “moderate quality evidence.” The relative risk profiles the committee analyzed all favored the biologics over the JAK inhibitor.

Also based on moderate evidence is the recommendation to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who had taken biologic agents before. The other recommendations are based on evidence listed at “low” or “very low” quality, or citing a “knowledge gap.”

“The quality of the evidence available is variable, and we can only make our recommendations based on the quality of the evidence there, but it doesn’t negate the effects of the guideline itself,” Dr. Feuerstein said. The strong recommendation is based on randomized clinical trials that led to the Food and Drug Administration approvals, said Aline Charabaty-Pishvaian, MD, AGAF, associate professor at Johns Hopkins University, Baltimore, and director of the Inflammatory Bowel Disease Center at Sibley Memorial Hospital, Washington. “For everything else, we do not have randomized controlled trials to help make a decision, and the recommendations are made based on the interpretation of different RCTs [randomized controlled trials], knowing that these trials have different designs, patient populations, and endpoints, as well as on experts’ opinions,” she said in an interview.

The only other recommendation based on moderate quality evidence is to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who haven’t previously used biologic agents. The guideline also recommends using tofacitinib in these patients in the confines of a clinical trial; and using ustekinumab or tofacitinib rather than vedolizumab or adalimumab in patients who’ve already been on infliximab, particularly if they haven’t responded to treatment.

The guideline also recommends against thiopurine monotherapy to induce remission, but, for maintenance of remission, recommends such treatment vs. none. However, the guideline suggests against methotrexate monotherapy to induce or maintain remission. And biologic monotherapy is preferred to thiopurine to induce remission, but the guideline makes no recommendation for biologic vs. thiopurine monotherapy to maintain remission. Likewise, combining vedolizumab or ustekinumab with thiopurines or methotrexate is preferred to monotherapy with either a biologic or thiopurine.

The guideline also addresses step-up therapy. It suggests biologics as a first treatment, either as monotherapy or in combination with an immunomodulator, rather than a step-up after failure with 5-aminosalicylates. Also, it recommends against continuing 5-aminosalicylates to induce or maintain remission after a patient has achieved remission with biologics as monotherapy or in combination with immunomodulators or tofacitinib.

The guideline also offers four recommendations for hospitalized patients with acute severe ulcerative colitis: use of intravenous 40-60 mg/d methylprednisolone rather than higher dose IV corticosteroids, no adjunctive antibiotics in the absence of infection; use of infliximab or cyclosporine when IV corticosteroids fail, and no recommendation on the use of intensive vs. standard infliximab dosing when IV corticosteroids fail and the patient is already on infliximab.

The guideline will be meaningful in closing the evidence gap going forward because it can help direct the design of clinical trials, Dr. Charabaty-Pishvaian said. “The guideline highlights areas of need in terms of randomized clinical trials,” she said. “We need these trials to answer the questions we ask ourselves in our daily practice when managing patients with UC: Which drug to choose as the first-line agent? Which drug is the second-line therapy when the disease doesn’t respond or loses response to the first-line agent? Do we need to use combination therapy with all biologics, or only with anti-TNF-alpha agents? For how long? Can we use vedolizumab or ustekinumab as monotherapy when used as a first-line agent? And is there any advantage in adding an immunomodulator when these agents are used as third- or fourth-line therapy?”

Dr. Feuerstein has no relevant financial relationships to disclose. Guideline author Kim Isaacs, MD, disclosed relationships with AbbVie, Takeda, UCB, Janssen and Hoffmann-Laroche. All other committee members have no relevant disclosures.

*This story was updated on 5/7/2020.

SOURCE: Feuerstein JD et al. on behalf of the AGA Institute Clinical Guidelines Committee. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.006.

For moderate to severe ulcerative colitis, treatment with any one of the leading biologic agents is superior to no treatment at all. And in treatment-naive patients, infliximab or vedolizumab should be used rather than adalimumab for inducing remission. These are key recommendations from the American Gastroenterological Association guideline for patients with moderate to severe ulcerative colitis (UC), published in Gastroenterology (doi: 10.1053/j.gastro.2020.01.006).

In all, the guideline comprises 11 recommendations for using immunomodulators, biologics, and small-molecule agents to induce and maintain remission in outpatients with moderate to severe UC and to decrease the need for colectomy in hospitalized patients with acute severe UC. The latest guideline follows a guideline for mild to moderate UC published last year (Gastroenterology. 2019;156[3]:748-64). A technical review accompanied the most recent publication (Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.007).

An updated guideline was long overdue, lead author Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center, Boston, said in an interview. “The care of patients with inflammatory bowel disease – both ulcerative colitis and Crohn’s – has become increasingly complicated with many newer drugs becoming available,” he said. “The paradigm of how we are treating the disease is evolving, but we haven’t had updated, evidence-based guidelines.” Dr. Feuerstein is the lead author of this guideline.

The guideline can also aid in influencing payers’ policies that now require step-up therapy – that is, failing with the least costly drug before moving onto newer and more effective but costlier agents – Dr. Feuerstein said. “These guidelines show now that we should be treating people based on the evidence and not based on just an insurance company’s preferred policy,” he said.

The strongest recommendation is to use the tumor necrosis factor–alpha (TNF-alpha) antagonists infliximab, adalimumab, and golimumab, the anti-integrin agent vedolizumab, or the anti-interleukin 12/23 agent ustekinumab — all biologics — or the synthetic JAK inhibitor tofacitinib rather than not treating the UC. This is the only recommendation labeled as “strong,” based on “moderate quality evidence.” The relative risk profiles the committee analyzed all favored the biologics over the JAK inhibitor.

Also based on moderate evidence is the recommendation to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who had taken biologic agents before. The other recommendations are based on evidence listed at “low” or “very low” quality, or citing a “knowledge gap.”

“The quality of the evidence available is variable, and we can only make our recommendations based on the quality of the evidence there, but it doesn’t negate the effects of the guideline itself,” Dr. Feuerstein said. The strong recommendation is based on randomized clinical trials that led to the Food and Drug Administration approvals, said Aline Charabaty-Pishvaian, MD, AGAF, associate professor at Johns Hopkins University, Baltimore, and director of the Inflammatory Bowel Disease Center at Sibley Memorial Hospital, Washington. “For everything else, we do not have randomized controlled trials to help make a decision, and the recommendations are made based on the interpretation of different RCTs [randomized controlled trials], knowing that these trials have different designs, patient populations, and endpoints, as well as on experts’ opinions,” she said in an interview.

The only other recommendation based on moderate quality evidence is to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who haven’t previously used biologic agents. The guideline also recommends using tofacitinib in these patients in the confines of a clinical trial; and using ustekinumab or tofacitinib rather than vedolizumab or adalimumab in patients who’ve already been on infliximab, particularly if they haven’t responded to treatment.

The guideline also recommends against thiopurine monotherapy to induce remission, but, for maintenance of remission, recommends such treatment vs. none. However, the guideline suggests against methotrexate monotherapy to induce or maintain remission. And biologic monotherapy is preferred to thiopurine to induce remission, but the guideline makes no recommendation for biologic vs. thiopurine monotherapy to maintain remission. Likewise, combining vedolizumab or ustekinumab with thiopurines or methotrexate is preferred to monotherapy with either a biologic or thiopurine.

The guideline also addresses step-up therapy. It suggests biologics as a first treatment, either as monotherapy or in combination with an immunomodulator, rather than a step-up after failure with 5-aminosalicylates. Also, it recommends against continuing 5-aminosalicylates to induce or maintain remission after a patient has achieved remission with biologics as monotherapy or in combination with immunomodulators or tofacitinib.

The guideline also offers four recommendations for hospitalized patients with acute severe ulcerative colitis: use of intravenous 40-60 mg/d methylprednisolone rather than higher dose IV corticosteroids, no adjunctive antibiotics in the absence of infection; use of infliximab or cyclosporine when IV corticosteroids fail, and no recommendation on the use of intensive vs. standard infliximab dosing when IV corticosteroids fail and the patient is already on infliximab.

The guideline will be meaningful in closing the evidence gap going forward because it can help direct the design of clinical trials, Dr. Charabaty-Pishvaian said. “The guideline highlights areas of need in terms of randomized clinical trials,” she said. “We need these trials to answer the questions we ask ourselves in our daily practice when managing patients with UC: Which drug to choose as the first-line agent? Which drug is the second-line therapy when the disease doesn’t respond or loses response to the first-line agent? Do we need to use combination therapy with all biologics, or only with anti-TNF-alpha agents? For how long? Can we use vedolizumab or ustekinumab as monotherapy when used as a first-line agent? And is there any advantage in adding an immunomodulator when these agents are used as third- or fourth-line therapy?”

Dr. Feuerstein has no relevant financial relationships to disclose. Guideline author Kim Isaacs, MD, disclosed relationships with AbbVie, Takeda, UCB, Janssen and Hoffmann-Laroche. All other committee members have no relevant disclosures.

*This story was updated on 5/7/2020.

SOURCE: Feuerstein JD et al. on behalf of the AGA Institute Clinical Guidelines Committee. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.006.

For moderate to severe ulcerative colitis, treatment with any one of the leading biologic agents is superior to no treatment at all. And in treatment-naive patients, infliximab or vedolizumab should be used rather than adalimumab for inducing remission. These are key recommendations from the American Gastroenterological Association guideline for patients with moderate to severe ulcerative colitis (UC), published in Gastroenterology (doi: 10.1053/j.gastro.2020.01.006).

In all, the guideline comprises 11 recommendations for using immunomodulators, biologics, and small-molecule agents to induce and maintain remission in outpatients with moderate to severe UC and to decrease the need for colectomy in hospitalized patients with acute severe UC. The latest guideline follows a guideline for mild to moderate UC published last year (Gastroenterology. 2019;156[3]:748-64). A technical review accompanied the most recent publication (Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.007).

An updated guideline was long overdue, lead author Joseph D. Feuerstein, MD, of Beth Israel Deaconess Medical Center, Boston, said in an interview. “The care of patients with inflammatory bowel disease – both ulcerative colitis and Crohn’s – has become increasingly complicated with many newer drugs becoming available,” he said. “The paradigm of how we are treating the disease is evolving, but we haven’t had updated, evidence-based guidelines.” Dr. Feuerstein is the lead author of this guideline.

The guideline can also aid in influencing payers’ policies that now require step-up therapy – that is, failing with the least costly drug before moving onto newer and more effective but costlier agents – Dr. Feuerstein said. “These guidelines show now that we should be treating people based on the evidence and not based on just an insurance company’s preferred policy,” he said.

The strongest recommendation is to use the tumor necrosis factor–alpha (TNF-alpha) antagonists infliximab, adalimumab, and golimumab, the anti-integrin agent vedolizumab, or the anti-interleukin 12/23 agent ustekinumab — all biologics — or the synthetic JAK inhibitor tofacitinib rather than not treating the UC. This is the only recommendation labeled as “strong,” based on “moderate quality evidence.” The relative risk profiles the committee analyzed all favored the biologics over the JAK inhibitor.

Also based on moderate evidence is the recommendation to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who had taken biologic agents before. The other recommendations are based on evidence listed at “low” or “very low” quality, or citing a “knowledge gap.”

“The quality of the evidence available is variable, and we can only make our recommendations based on the quality of the evidence there, but it doesn’t negate the effects of the guideline itself,” Dr. Feuerstein said. The strong recommendation is based on randomized clinical trials that led to the Food and Drug Administration approvals, said Aline Charabaty-Pishvaian, MD, AGAF, associate professor at Johns Hopkins University, Baltimore, and director of the Inflammatory Bowel Disease Center at Sibley Memorial Hospital, Washington. “For everything else, we do not have randomized controlled trials to help make a decision, and the recommendations are made based on the interpretation of different RCTs [randomized controlled trials], knowing that these trials have different designs, patient populations, and endpoints, as well as on experts’ opinions,” she said in an interview.

The only other recommendation based on moderate quality evidence is to use infliximab or vedolizumab rather than adalimumab to induce remission in patients who haven’t previously used biologic agents. The guideline also recommends using tofacitinib in these patients in the confines of a clinical trial; and using ustekinumab or tofacitinib rather than vedolizumab or adalimumab in patients who’ve already been on infliximab, particularly if they haven’t responded to treatment.

The guideline also recommends against thiopurine monotherapy to induce remission, but, for maintenance of remission, recommends such treatment vs. none. However, the guideline suggests against methotrexate monotherapy to induce or maintain remission. And biologic monotherapy is preferred to thiopurine to induce remission, but the guideline makes no recommendation for biologic vs. thiopurine monotherapy to maintain remission. Likewise, combining vedolizumab or ustekinumab with thiopurines or methotrexate is preferred to monotherapy with either a biologic or thiopurine.

The guideline also addresses step-up therapy. It suggests biologics as a first treatment, either as monotherapy or in combination with an immunomodulator, rather than a step-up after failure with 5-aminosalicylates. Also, it recommends against continuing 5-aminosalicylates to induce or maintain remission after a patient has achieved remission with biologics as monotherapy or in combination with immunomodulators or tofacitinib.

The guideline also offers four recommendations for hospitalized patients with acute severe ulcerative colitis: use of intravenous 40-60 mg/d methylprednisolone rather than higher dose IV corticosteroids, no adjunctive antibiotics in the absence of infection; use of infliximab or cyclosporine when IV corticosteroids fail, and no recommendation on the use of intensive vs. standard infliximab dosing when IV corticosteroids fail and the patient is already on infliximab.

The guideline will be meaningful in closing the evidence gap going forward because it can help direct the design of clinical trials, Dr. Charabaty-Pishvaian said. “The guideline highlights areas of need in terms of randomized clinical trials,” she said. “We need these trials to answer the questions we ask ourselves in our daily practice when managing patients with UC: Which drug to choose as the first-line agent? Which drug is the second-line therapy when the disease doesn’t respond or loses response to the first-line agent? Do we need to use combination therapy with all biologics, or only with anti-TNF-alpha agents? For how long? Can we use vedolizumab or ustekinumab as monotherapy when used as a first-line agent? And is there any advantage in adding an immunomodulator when these agents are used as third- or fourth-line therapy?”

Dr. Feuerstein has no relevant financial relationships to disclose. Guideline author Kim Isaacs, MD, disclosed relationships with AbbVie, Takeda, UCB, Janssen and Hoffmann-Laroche. All other committee members have no relevant disclosures.

*This story was updated on 5/7/2020.

SOURCE: Feuerstein JD et al. on behalf of the AGA Institute Clinical Guidelines Committee. Gastroenterology. 2020. doi: 10.1053/j.gastro.2020.01.006.