Category Archives: Gastroenterology

Genetic Test to Help Determine Need for Combination Therapy with Anti-TNF

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V Solitano et al. Clin Gastroenterol Hepatol 2023; 21: 3019-3029. HLA-DQA1∗05 Genotype and Immunogenicity to Tumor Necrosis Factor-α Antagonists: A Systematic Review and Meta-analysis

Key findings:

  • On meta-analysis of 13 studies (3756 patients; median follow-up, 12 months; 41% with variants), HLA-DQA1∗05 variants were associated with 75% higher risk of immunogenicity compared with non-carriers (relative risk, 1.75) with considerable heterogeneity (I2 = 62%) (low certainty evidence).
  • In addition, patients with HLA-QQA1*05 variants had clinical loss of response (LOR) in 67% compared to 30% in those without this variant (wild-type); thus, a 124% higher risk of LOR.
  • Positive and negative predictive values of HLA-DQA1∗05 variants for predicting immunogenicity were 30% and 80%, respectively
  • Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs, and TNF-α antagonist-type, modified this association.

My take:

  • The ~40% of individuals with HLA-DQA1*05 variants are at higher risk of LOR and are more likely to benefit from both therapeutic drug monitoring and probably from use of combination (with immunomodulator) therapy.
  • The positive predictive value (30%) is low indicating that the majority of patients with these variants will not develop anti-drug antibodies within 12 months.
  • In those with negative testing for HLA-DQA1*05 (~60%), the higher negative predictive value indicates a patient is more likely to do well with monotherapy.
  • HLA-DQA1*05 testing is available commercially (usually part of Celiac HLA typing).

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This is the Initiation Well at Quinta da Regaleira in Sintra, Portugal.
It is pretty cool because it seems to start at ground level and then goes down many floors.
There is an exit to a number of tunnels at the lower level.

IBD Brief Updates: Anti-TNF Loss of Response, Upadacitinib for ASUC, Risk Factors for Developing IBD

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EHJ Savelkoul et al. Inflamm Bowel Dis 2023; 29: 1633-1647. Open Access! Systematic Review and Meta-analysis: Loss of Response and Need for Dose Escalation of Infliximab and Adalimumab in Ulcerative Colitis

Methods: A systematic search was conducted from August 1999 to July 2021 for studies (50 studies identified) reporting loss of response and dose escalation during infliximab and/or adalimumab use in ulcerative colitis patients with primary response

Key findings:

  • Annual loss of response was 10% for infliximab and 13% for adalimumab, with higher rates during the first year.
  • The annual LOR incidences were higher during the first 65 weeks of treatment for both IFX (14%) and ADA (23%).
  • Annual dose escalation rates were 14% (infliximab) and 21% (adalimumab), with clinical benefit in 72% and 52%, respectively

CH Zinger et al. Inflamm Bowel Dis 2023; 29: 1667-1669. Upadacitinib for Acute Severe Ulcerative Colitis

Key finding: 4 patients (age 18-25 yrs) received upadacitinib for acute severe ulcerative colitis (ASUC) after failing to respond to infliximab and IV steroids. 3 of 4 responded to treatment (45 mg/day) between 4 to 8 days. Three months later, two of these patients were in steroid-free clinical-endoscopic remission and one had maintained a clinical response.

In their discussion, the authors note a similar response rate to tofacitinib, another JAK inhibitor, for ASUC; though, the authors speculate that upadacitinib may be efficacious.

N Narula et al. Clin Gastroenterol Hepatol 2023; 21: 2649-2659. Associations of Antibiotics, Hormonal Therapies, Oral Contraceptives, and Long-Term NSAIDS With Inflammatory Bowel Disease: Results From the Prospective Urban Rural Epidemiology (PURE) Study

In a a prospective cohort study of 133,137 individuals between the ages of 20 and 80 from 24 countries, the authors examined the relationship between exposures to antibiotics, NSAIDs and hormonal therapies with the development of IBD over a median 11 year period.

Key findings:

  • Incident IBD was associated significantly with baseline antibiotic (aOR, 2.81; P = .0001) and hormonal medication use (aOR, 4.43; P = .001).
  • Nonsteroidal anti-inflammatory drug users also were observed to have increased odds of IBD (aOR, 1.80 P = .002), which was driven by long-term use (aOR, 5.58; P < .001)
Near Cassis, France

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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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.

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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.

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).

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.

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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What’s Going on With Refractory Heartburn?

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L Guadagnoli, A Geeraerts et al. Gastroenterol 2023; 165: 848-860. Open Access! Psychological Processes, Not Physiological Parameters, Are Most Important Contributors to Symptom Severity in Patients With Refractory Heartburn/Regurgitation Symptoms

Methods: Consecutive adult patients (n=393) with refractory heartburn/regurgitation symptoms underwent standard 24-hour pH-impedance monitoring and completed questionnaires assessing past and current gastrointestinal and psychological health. Refractory reflux meant that they continued to have symptoms after completing at least 12 weeks of PPI (twice per day) treatment.

Key findings: Psychological symptoms were significantly associated with reflux symptom severity, and physiological reflux variables (eg, number of reflux episodes) were not.

In the discussion, the authors note that ” prior research demonstrates psychological symptoms, including depression, anxiety, and post-traumatic stress, are associated with reflux symptom severity.25, 26, 27 Indeed, psychological processes are believed to impact the brain–gut axis, particularly its central components,28 leading to enhanced esophageal symptom perception and reporting.6,29,30“

My take: Psychological factors (depression, anxiety, post-traumatic stress, and poor sleep) are important factors in refractory reflux and they need to be considered early in the evaluation.

A related article: NY Times Magazine 10/4/23, M Velasques-Manoff. The Mystery of My Burning Esophagus. In this article, the writer describes burning pain associated with his diagnosis of eosinophilic esophagitis. This article has some useful information about eosinophilic esophagitis and about lingering symptoms after responding to treatment.

“My new gastroenterologist had a theory to explain the all-consuming pain under my sternum. Sometimes patients develop a hypersensitivity syndrome, she told me. The original insult — in my case, inflammation of some kind — might be long gone, but the nerves that convey pain can become overactive and begin firing at the slightest provocation…Scientists don’t completely understand how antidepressants help pain syndromes, but certain ones seem to impede pain signals in the nervous system…

Doctors are increasingly aware of these kinds of pain syndromes in many disorders, including GERD. The condition, whose primary symptom is known colloquially as heartburn, is pervasive, afflicting an estimated one in five Americans. Some of these patients continue to feel intense pain even after their stomach acid has been reduced with antacids, a malady most likely caused by a hypersensitivity syndrome similar to mine.”

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Greenville County (SC) Museum of Art

Do We Need to Reimmunize Patients (with IBD or Celiac) with Low Hepatitis B Surface Antibody Levels?

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JA Ulrich et al. Clin Gastroenterol Hepatol 2023; 21: 2901-2907. Open Access! Effectiveness of Hepatitis B Vaccination for Patients With Inflammatory Bowel and Celiac Disease

In 2022, a study in JPGN showed that the rate of Hepatitis B virus (HBV) vaccination and immunity was similar in individuals with and without celiac disease (CD). In addition, there was no increased risk of HBV infection detected in CD patients. Thus, routinely checking hepatitis B status in all patients with CD was no longer justified. (See: Celiac Disease, Hepatitis B and Paul Harvey).

The same researchers in this study expand their findings to inflammatory bowel disease (IBD) and CD. In this retrospective cohort (2000-2019), using the Rochester Epidemiology Project which includes data from 162,847 residents. Key findings:

  • 1264 incident cases of IBD/CD, only 6 HBV infections were diagnosed before the index date; 5 of the 6 had risk factors including IV drug use or living in endemic region.
  • No new HBV infection developed in any of 1258 patients with IBD/CD during a median follow-up of 9.4 years
  • The proportion of patients with HBV-protective titers (≥10 mIU/mL) decreased with time before plateauing, with protective titer rates of 45% at 5 up to 10 years and 41% at 15 up to 20 years after the last HBV vaccination. The control population with protective titers also decreased similarly with time though was consistently higher than the levels of patients with IBD/CD within 15 years after the last HBV vaccination

Context/Discussion:

  • Only 16% of vaccine recipients have measurable protective titers by age 18 years, according to the CDC.32
  • “Time-related waning of Ab levels to HBV after vaccination has unclear clinical significance. Although screening persons for HBV immunity by using anti-HBs titers is widely accepted, prior study results have shown that cellular immunity can also provide long-term HBV protection, even in the setting of nonprotective titers.”
  • Reactivation of HBV is a well-documented complication of immunosuppression in patients with IBD, and screening for dormant infection is of paramount importance at diagnosis
  • Limitations: the study population had a low rate of HBV acquisition; thus, the study findings may not apply to areas with higher risk for HBV.

My take: This study shows that treating low hepatitis B surface antibody levels with reimmunization is likely NOT needed in either the IBD or the celiac disease population, except perhaps in those at high risk. Checking HBV status prior to immunosuppressive therapy, though, is still needed to prevent reactivation of HBV in those at risk.

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Chalk Art in Sandy Springs:

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.

How Much Ustekinumab (Stelara) Is Needed to Get a Good Response

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K Chen et al. Inflamm Bowel Dis 2023; 29: 1499-1503. Serum Ustekinumab Concentrations Are Associated With Improved Outcomes With the Magnetic Resonance Index of Activity for Crohn’s Disease

This retrospective trial included thirty three patients with Crohn’s disease (CD) receiving maintenance ustekinumab (UST). The simplified Magnetic Resonance Index of Activity (sMARIA) and biomarkers were correlated with UST levels. The authors utilized a homologous mobility shift assay (HMSA) (Prometheus) for their UST levels.

Key findings:

With UST level greater or equal to 8.4, radiologic remission was seen in 63% compared to 21% in those with levels <8.4. Similarly, the absence of severe inflammation was seen in 78.9% of those with higher levels compared with only 36.8% in those with levels below 8.4.
Both findings were clinically-significant P=.01
With UST levels greater or equal to 6.1, FCP less than 50 was seen in 72.2% compared to only 12.5% in those with a level less than 6.1. P<.01

My take: This study show the need for higher levels of UST to achieve optimal outcomes. Levels of at least 8.4 appear to be a good target.

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.