Is Risankizumab More Effective for Crohn’s Disease Than Ustekinumab?

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M Dubinsky et al. Adv Ther. 2023; 40(9): 3896–3911. Open Access! Matching-Adjusted Indirect Comparison Between Risankizumab and Ustekinumab for Induction and Maintenance Treatment of Moderately to Severely Active Crohn’s Disease

Background/Methods: Risankizumab (RZB) and ustekinumab (UST), interleukin (IL)-23 and IL-12/23 inhibitors, respectively, are approved treatments for moderately to severely active Crohn’s disease (CD); direct comparison between the two is ongoing. The authors indirectly compared efficacy of RZB versus UST using data from phase 3 trials (three trials for each medication):

Key findings:

Induction: Higher proportions of patients achieved clinical and endoscopic outcomes with RZB vs. UST, resulting in significantly (p ≤ 0.05) greater percent differences between groups for CDAI remission (15%) and endoscopic response (26%) and remission (9%)

Rates of response and remission following induction therapy with RZB (600 mg) or UST (6 mg/kg). *p ≤ 0.05 for RZB versus UST. Relative effect measures are shown as the percent difference between treatment groups; absolute effect measures are the proportions of patients achieving each outcome in each treatment group. BF biologic failure, CCF conventional care failure, CDAI Crohn’s Disease Activity Index, IV intravenous, PBO placebo, RZB risankizumab, UST ustekinumab

Maintenance: rates of CDAI remission were similar (range − 0.3% to − 5.0%) for RZB vs. UST; however, endoscopic response and remission rates appeared more favorable (see Figure 2 below)

Rates of response and remission following maintenance therapy with RZB (180 mg or 360 mg) or UST (90 mg Q8W). *p ≤ 0.05 for RZB versus UST. Relative effect measures are shown as the percent difference between treatment groups; absolute effect measures are the proportions of patients achieving each outcome in each treatment group. BF biologic failure, CCF conventional care failure, CDAI Crohn’s Disease Activity Index, PBO placebo, Q8W every 8 weeks, Q12W every 12 weeks, RZB risankizumab, SC subcutaneous, UST ustekinumab

My take: Since this was not a direct randomization trial, these results are not definitive. However, in this indirect analysis, risankizumab appears to be superior to utekinumab in effectiveness of for Crohn’s disease.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

What’s Changing in IBD Care: Hospitalization Rates and Authorizations

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The Good News:

MJ Buie et al. Inflamm Bowel Dis 2023; 29: 1536-1545. Open Access! Hospitalization Rates for Inflammatory Bowel Disease Are Decreasing Over Time: A Population-based Cohort Study

This population-based administrative data cohort study provides annual IBD hospitalization rates in Alberta, Canada.

Key findings:

  • From 2002-2003 to 2018-2019, all-cause hospitalization rates decreased from 36.57 to 16.72 per 100 IBD patients (Average Annual Percentage Change (AAPC), −4.18%)
  • Inflammatory bowel disease–related hospitalization rate decreased from 26.44 to 9.24 per 100 IBD patients (AAPC, −5.54%)
  • The absolute number of hospitalizations, however, likely did not improve because this is affected by the increase in IBD prevalence. In Alberta, there was a 3-fold increase from 2002 to 2018 (general population increased 1.4 fold during this period)

“The last 2 decades have seen the introduction of several advanced therapies with novel mechanisms of action.22 The introduction of these therapies has been accompanied by changes in management strategies that include earlier introduction of advanced therapies based on risk stratification, treat-to-target, and monitoring strategies.5,23–26 These advancements include risk stratification, allowing for earlier introduction of advanced therapies; proactive clinical management algorithms to monitor disease activity; and therapeutic drug monitoring allowing for continued concentration-based dosing.23–26The net effect of these medical advances shifted IBD management from the hospital to the outpatient setting.27“

The Bad News:

DK Choi et al. Inflamm Bowel Dis 2023; 29: 1658-1661. Delays in Therapy Associated With Current Prior Authorization Process for the Treatment of Inflammatory Bowel Disease

This retrospective study of 1693 prior authorizations (PAs) from 2020-2021. Key findings:

  • 1397 PA initially approved, 209 first-level PAs approved, 23 second-level PAs approve, and 11 external review requests approved. In total 97% (1640 of 1697) were approved
  • Dose escalations had the lowest approval rate of 67.6%
  • FDA approval had favorable OR for PA approval of 4.45
  • The median time to biologic initiation was 21 days, with appeals causing further delays to initiation

Median Days to Determination by Insurance Level:

  • Prior authorization: 11 days
  • First level appeal: 29 days
  • Second level appeal: 51 days
  • External review request: 73 days

My take: The PA process usually results in few denials (if pursued) but does result in significant delays in therapy. At the same time, these newer therapies have been associated with improvement in hospitalizations rates.

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Aerodigestive Complexity Score

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HM Horita et al. J Pediatr 2023; 261: 113549. Open Access! Development of a Medical Complexity Score for Pediatric Aerodigestive Patients

Methods: The authors in this study developed a 7-point medical complexity score .  One point was assigned for each comorbid diagnosis in the following categories: airway anomaly, neurologic, cardiac, respiratory, gastrointestinal, genetic diagnoses, and prematurity. A retrospective chart review was conducted of patients (n=234) seen in the aerodigestive clinic who had ≥2 visits between 2017 and 2021. 

Improvements were followed in the Functional Oral Intake Scale (FOIS)–assigned by aerodigestive feeding therapists.6 The FOIS scale is as follows:

  • •1 = Nothing by mouth
  • •2 = Tube-dependent with minimal attempts of food or liquids (<10%)
  • •3 = Tube-dependent with consistent oral intake of food or liquids
  • •4 = Total oral diet of a single consistency
  • •5 = Total oral diet with multiple consistencies, but requiring special preparations or compensations
  • •6 = Total oral diet with multiple consistencies without special preparation, but with specific food limitations
  • •7 = Total oral diet with no restriction, or <12 months of age on age-appropriate diet

Key findings:

  • At presentation, 69.5% were not at unrestricted age-appropriate diet; 22.7% of the cohort (n = 53) were completely tube dependent
  • There were 165 patients who were not at unrestricted total age-appropriate oral diet at presentation, and the majority (54% [n = 90]) showed improvement in their FOIS scores after aerodigestive team intervention.
  • “For each 1-unit increase in complexity score, there was a 33% decrease in the odds of improvement in FOIS scores (OR, 0.66; 95% CI, 0.51-0.84; P = .001);” however, only neurological comorbidity (OR, 0.26; 95% CI, 0.13-0.53; P < .001) and airway anomaly (OR, 0.35; 95% CI, 0.15-0.79; P = .01) were significantly associated with decreased likelihood to progress in feeding based on FOIS scores
  • Of the 125 patients who were tube fed at initial presentation, 20% (n = 25) were able to achieve full oral feeding after intervention

My take: While the complexity score did correlate with likelihood of progressing with oral feedings, it appears that this score is unnecessary as likelihood of progressing is mainly related to two factors: neurological comorbidities and airway anomalies.

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Current Approach for FPIES

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Our excellent nutritionist, Bailey Koch, recently gave our group a terrific update on FPIES. Bailey is part of the medical advisory board for THE FPIES Foundation, as is Dr. Benjamin Gold from our group. Here are many of the slides from her lecture.

Link: FPIES foundation action plan sheet:

From International guidelines:

Nowak-Węgrzyn A, Chehade M, Groetch ME, et al. Open Access: International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2017;139:1111-26.

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From FPIES 2017 Guidelines:

  • #4. “Consider specific IgE testing of children with FPIES to their trigger food because comorbid IgE-mediated sensitization to triggers, such as CM [cow’s milk], can infer a greater chance of persistent disease.
  • ”#8. Conduct food challenges “in patients with suspected FPIES in medically supervised settings in which access to rapid fluid resuscitation is available and prolonged observation can be provided, if necessary.”
  • #14. Do not routinely obtain endoscopic evaluation as part of the evaluation of FPIES.
  • #17. Acute FPIES should be considered a medical emergency. “Approximately 15% of patients can have hypovolemic shock.”
  • #19. Consider ondansetron treatment as an adjunct (if >6 months of age)
  • #21. Do not recommend routine maternal dietary elimination of offending triggers while breast-feeding if the infant is asymptomatic.
  • #23. FPIES can occur to multiple foods.  “The majority of children (65% to 80%) have FPIES to a single food, most commonly CM.”  In one study, 5% to 10% of children reacted to more than 3 foods.
  • #26. Use hypoallergenic formula in infants who can no longer breast-feed and are given a diagnosis of FPIES caused by CM. Most will tolerate extensively hydrolyzed formulas; some may require an amino acid based formula
  • #29. Reviews natural history.  “The age of CM tolerance appears to be around 3 years” but there has been variability in reports. For FPIES due to grains, average age of tolerance is 35 months and other solid foods is 42 months.  The average age for soy is 12 months (later in some studies), for rice 4.7 years and 4.0 years for oats. For CM-FPIES with positive SPT response, a much protracted course has been reported, with older age of tolerance (~13.8 years)

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Atlantis Study: Possibly Best Evidence That Tricyclics May Help Irritable Bowel

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Thanks to Ben Gold for this reference.

AC Ford et al. The Lancet 2023; DOI:https://doi.org/10.1016/S0140-6736(23)01523-4. Open Access! Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial

In this randomized, double-blind, placebo-controlled study of 463 adults (median age 48 yrs), the authors compared low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily). The use of the Rome IV criteria resulted in the selection of a group of patients with higher symptom severity,50 borne out by the mean IBS-SSS scores at baseline, which were in the moderate to severe range. The median duration of IBS among participants was 10 years.

Key findings:

  • Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (–27·0, 95% CI –46·9 to –7·10; p=0·0079)
  • 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months.

In their discussion, the authors note that “this is the largest trial of a tricyclic antidepressant in IBS ever undertaken and the first based entirely in a primary care setting…low-dose amitriptyline met the primary outcome, with a mean decrease in IBS-SSS of almost 100 points at both months 3 and 6 compared with baseline, and also met the key secondary outcome for effectiveness, as well as other IBS symptom measures.”

“There was no effect of low-dose amitriptyline on somatoform symptom-reporting scores, or anxiety or depression scores, during 6 month follow-up, nor was there any impact on work and social activities.:

Key secondary outcome of SGA of relief of IBS symptoms at 6 months. SGA=subjective global assessment.

My take (borrowed from authors): Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

COMBO-IBD Study -Combination Immunomodulator Use and Thresholds

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AJ Yarur et al. Clin Gastroenterol Hepatol 2023; 21: 2908-2917. Open Access! Combination Therapy With Immunomodulators Improves the Pharmacokinetics of Infliximab But Not Vedolizumab or Ustekinumab

In this prospective cohort with 369 patients, treatment included the following 113 infliximab, 133 vedolizumab, and 123 ustekinumab. All patients received standard dosing (eg. 5 mg/kg/dose every 8 weeks with infliximab). Per Table 1, dose of thiopurine was 100 mg (range 50-150, “using a 2:1 ratio of azathioprrine and mercaptopurine”); most patients received methotrexate at a dose of 12.5 mg. Key findings:

  • Infliximab levels were much improved in patients receiving combination therapy with either a thiopurine or methotrexate. In those patients receiving a thiopurine, a threshold of 6-TGN ≥146 was considered optimal.
  • Patients receiving combination therapy with methotrexate or a thiopurine and a 6-TGN concentration ≥146 pmol per 8 × 108 RBCs, and those with baseline infliximab level ≥12.3 μg/mL had a lower rate of secondary nonresponse when compared with those on monotherapy, thiopurine with 6-TGN <146 pmol per 8 × 108 RBCs, and baseline infliximab level <12.3 μg/mL (88.2 vs 11.8% [P = .04], 71.2 vs 45.5% [P = .04])
  • Ustekinumab and vedolizumab levels were NOT increased in patients receiving an immunomodulator

My take: This study reinforces the idea that there are pharmacokinetic benefits of combination therapy with infliximab (and extrapolated to other anti-TNF agents); there is a lack of benefit for most patients receiving ustekinumab and vedolizumab. Even with ustekinumab and vedolizumab, it is possible that patients with more severe disease may still benefit independent of pharmacokinetic effects on biologic agent.

Higher doses of infliximab monotherapy with therapeutic drug monitoring may achieve similar results as combination therapy. However, patients switching from one anti-TNF to another due to immunogenicity/antidrug antibodies are particularly likely to benefit from combination therapy. In addition, a recent ImproveCareNow study showed better outcomes for pediatric patients who received methotrexate with adalimumab (see below).

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Why It is Still Not a Good Idea to Test Healthy Children for Enteric Pathogens & Infant Mortality Rates Rising in Georgia (& much of U.S.)

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BR Lee et al. J Pediatr 2023; 261: 113551. A Comparison of Pathogen Detection and Risk Factors among Symptomatic Children with Gastroenteritis Compared with Asymptomatic Children in the Post-rotavirus Vaccine Era

Patients (<11 yrs old) with acute gastroenteritis (AGE, n=2503) and healthy controls (HC, n=537) old enrolled in the New Vaccine Surveillance Network study between December 2011 to June 2016. Key findings:

  • One or more organisms was detected in 1159 of 2503 children (46.3%) with AGE compared with 99 of 537 HC (17.3%).
  • Norovirus was detected most frequently among AGE (n = 568 [22.7%]). The other frequent pathogens detected were rotavirus 7.8% (despite ~75% vaccinated population), adenovirus 4.8%, C difficile 5.3%, Salmonella 6.4%, and Shigella 4.5%. 63.5% of all pathogens detected were viruses.
  • C difficile was detected more frequently in the HC population (7% vs 5.3%). E coli infections, likewise, were very commonly observed in the HC population (2.1% vs 1.1%). The false positive rates for C difficile pathogenicity would have been higher if the authors had not restricted their analysis to >12 months for C diff. The rates of Norovirus and Rotavirus in the HC group was 6.8% and 2.6% respectively.
  • Codetection of multiple pathogens was common. For example, with norovirus, 20.8% had a copathogen detected. Salmonella and C difficile had the highest codection rates of 53.5% and 54.5% respectively.

This study shows substantial improvement in rotavirus infections with a drop from 26% in detection prior to vaccine era to 6% afterwards.

My take: These muliplex molecular assays are quite useful and have improved our ability to determine underlying infections. This is particularly useful in children with underlying diseases (eg. IBD, malignancy). However, this report serves as a cautionary note that many pathogens, including C diff and E coli, are frequently identified with PCR assays in healthy children

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In 2022, 892 infants died in Georgia, an increase of 116 from prior year. About 7 infants dying for every 1000 births. AJC 11/1/23: CDC: Georgia’s infant mortality increase is among the worst in U.S.

Bromelia

Increasing Prevalence of Steatotic Liver Disease in Adolescents

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P Hartmann et al. Hepatology 2023; 78: 1168-1181. Open Access! Global and national prevalence of nonalcoholic fatty liver disease in adolescents: An analysis of the global burden of disease study 2019

The authors  analyzed data from the Global Burden of Disease Study 2019 to compare global, continental, and national prevalence rates of adolescent (15-19 yrs of age) NAFLD.

Key finding:

  • The global NAFLD prevalence in adolescents increased from 3.73% in 1990 to 4.71% in 2019 (a relative increase of 26.27%). NAFLD is now termed metabolic dysfunction-associated steatotic liver disease (MASLD).
  • High body mass index and not type 2 diabetes mellitus correlated with NAFLD prevalence in adolescents globally. 

In the associated editorial (S Xanthakos, Hepatology 78(4):p 1017-1019, October 2023, Rising tide of NAFLD in youth: A warning bell and call to action), some of the key points:

  • “The Global Burden of Disease (GBD) Study is the most comprehensive and long-standing effort to systematically and scientifically collate data on hundreds of diseases and injuries across the globe, including related clinical outcomes. Beginning in 1990, the GBD Study initially collected data on 106 conditions and 10 risk factors, across 5 age groups.1 Over time, the GBD Study has expanded through serial iterations to involve >9000 international researchers collecting data on 369 diseases and injuries across 204 countries and territories in the most recent 2019 report.1“
  • ” From the GBD Study, we learned that NAFLD is the most rapidly rising cause of chronic liver disease in adolescents and adults,2 and the fastest-growing contributor to cirrhosis, liver cancer, and liver-related deaths globally.”
  • “The global prevalence of NAFLD in adolescents shows no sign of abating, rather has continued to increase steadily from 3.7% in 1990 to 4.7% in 2019.”
  • “As with all epidemiological research, the GBD study faces the primary limitation of relying on data sources that employ varying and less accurate measures of NAFLD prevalence (alanine aminotransferase and/or ultrasound primarily). However, the rigorous methodological approach employed by the GBD including frequent assessment of face validity, and the tremendous input of data sources (>80,000 in 2019) nonetheless results in the most comprehensive global data set available.”

My take (borrowed from editorial): Without intervention, “the increase in adolescent NAFLD certainly portends a future increase in NAFLD-related cirrhosis and liver-related deaths in young adults in the coming decades, and a likely escalation in cardiovascular and diabetes-related morbidity.

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Flu Shots & Other Vaccines Linked to Lower Rates of Dementia

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10/26/23 Washington Post: Flu shots may protect against the risk of Alzheimer’s, related dementias

An excerpt:

A number of studies have found that people receiving vaccinations for flu and several other infectious diseases appear less likely than the unvaccinated to develop dementia, although scientists aren’t sure why…

In the flu study, the researchers took participants from a national patient database, two groups of 935,887 each, one group vaccinated, the other not. To avoid the potential influence of various factors that could affect the results, the scientists ensured that each group shared many of the same characteristics… found that an annual flu vaccination for three consecutive years reduced the dementia risk 20 percent over the next four to eight years, while six shots doubled it to a 40-percent reduction…

“All this requires further studies, but vaccination, along with good diet, exercise, intellectual and emotional stimulation are key factors for healthy aging,” Hotez said.

The article notes reductions in dementia with Shingles vaccine, Tdap or Td, and pneumococcal vaccines.

These cliffs of the calanques (near Cassis, France) are about 260 meters in elevation

Upadacitinib Works Quickly and with High Response

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D Ahuja et al. Am J Gastroenterol 2023; Open Access! Comparative Speed of Early Symptomatic Remission With Advanced Therapies for Moderate-to-Severe Ulcerative Colitis: A Systematic Review and Network Meta-Analysis Thanks to Ben Gold for this article.

Key findings:

  • On network meta-analysis of 14 RCTs, upadacitinib was more effective than all agents in achieving symptomatic remission at weeks 2 (range of RR, 2.85–6.27), 4 (range of RR, 1.78–2.37), and 6 (range of RR, 1.84–2.79). 

This study has a number of limitations including the following:

  • Potential differences in patient-level characteristics between these trials
  • Symptoms may not always correlate with endoscopic findings
  • Data from some medications (eg. tofacitinib) were incomplete and not included

My take: This study indicates an impressive early symptomatic response to upadacitinib compared to other agents for ulcerative colitis.

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