Tag Archives: Crohn’s disease

According to the study which you would never qualify for… (2023)

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In 2012, this blog highlighted a study which showed that “only 31.1% of 206 patients with IBD would have been eligible to participate in any of the selected RCTs.” (Post: According to the study which you would never qualify for…).

A recent study shows the same phenomenon in pediatric IBD studies: O Atia et al. Aliment Pharmacol Ther 2022; 56 (5): 794-801. Open Access! Children included in randomised controlled trials of biologics in inflammatory bowel diseases do not represent the real-world patient mix

This study utilized data for children initiating biologics from two prospective real‐world cohorts and one retrospective cohort.

Key findings:

  • Only 62 of 164 (38%) children with moderate–to‐severe disease would have been eligible for inclusion in the original RCTs.
  • The steroid-free remission rate was higher in the eligible children (51%) than in the ineligible children (31%; OR 2.3 [95%CI 1.2–4.5]; p = 0.01)
  • The main exclusion criterion was prohibited previous therapies (47%)

My take (borrowed from authors): “Remission rates were higher among eligible children raising the concern that results presented in regulatory RCTs in paediatric IBD do not necessarily reflect the patient‐mix in the real‐world and should be interpreted with caution when applied to clinical practice.”

Pictures from VilleFranche-Sur-Mer:

CCFA 2023 (Atlanta) Part 5

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Another very good review by David Schwartz on The Daunting Duo: Management of Stictures and Fistula. Below are some of my notes and some slides; my notes may contain errors in transcription or omission. Can get access to all 49 slides here: IBD Pro CCFA 2023 Atlanta

  • Fistula healing rates are poor
  • 78% have complex fistulas
  • Long-term healing: 67% with simple fistulas but only 37% with complex fistulas
  • Seton placement prior to biologic therapy increases likelihood of better outcomes
  • Antibiotic therapy recommended until Seton removed (not short-term treatment) –improved healing rates along with medical therapy
  • Anti-TNF therapy effective in ~40% long-term; higher rates of healing with higher anti-TNF levels
  • MRI and/or EUS helpful in improving fistula healing rates
  • Ustekinumab and Vedolizumab both had fistula healing rates ~40%
  • Adipose derived stem cells with ~50% healing rates (study with high placebo healing rate too ~37%); changes local cytokine profile, cells gone in about 2 weeks but goal for changing trajectory

Strictures

  • 5-24% with stricturing phenotype
  • No effective medical treatments
  • Endoscopic balloon dilatation in shorter strictures (<5 cm) without associated abscess or fistula (needs imaging prior)
  • One-third of balloon dilated strictures will still wind up needing surgery despite dilatation. 5-10% risk of complication. Goal is 15 mm or more (Dr. Schwartz typically does not increase by more than 3 sizes from baseline in one session)

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.

CCFA 2023 (Atlanta) Part 3

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This is third day summarizing some of the talks at the regional CCFA conference. Erin Forster presented on Treatment with Oral Advanced Therapy. Below are my notes and some of the slides; my notes may have errors of omission or transcription. Can get access to full slide set: (n=22) here: Treatment with Oral Advanced Therapy

  • JAK inhibitors (Tofacitinib, Upadacitinib) have rapid onset of action and are taken orally
  • Tofacitinib (Xeljanz) -concern about cardiovascular events was derived from elderly rheumatologic patients.  Cardiovascular events are rare. Higher dose (TID) (in the hospital) associated with lower colectomy rates in acute severe ulcerative colitis.
  • Upadacitinib (Rinvoq) -now approved for CD and UC. Higher dosing could affect liver function (especially if underlying liver disease).  Also, JAK inhibitors as a class have similar safety concerns: increased herpes zoster and concerns for cardiovascular concerns (esp if >50 years)..
  • S!P receptor modulators: Oznaimod, Etrasimod & Amiselimod. Can cause bradycardia -have to check EKG prior.
  • None of the oral agents are safe in pregnancy

CCFA 2023 (Atlanta) Part 2

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There were a bunch useful lectures at CCFA 2023 regional conference in Atlanta. Here are some of my notes and slides from Doug Wolf‘s lecture; my notes may have errors of omission or transcription. Can get access to full slide set (n=37) here: Dose Escalation of Biologic Therapy and Dual Biologic Therapy

  • If loss of response to anti-TNF, consider dose escalation by either re-induction or increasing (doubling) dose. Re-induction is less costly
  • Dose escalation generally not effective for vedolizumab
  • Dose escalation (increased frequency) with ustekinumab can be effective.  Therapeutic drug monitoring can provide guidance.  Re-induction can also be effective in half of patients (especially in patients with either no prior biologics or one prior biologic)
  • Risankizumab can still work in patients who had not responded by 12 weeks (delayed responders)
  • Discussed several combination treatments -no large studies thus far

CCFA 2023 (Atlanta) -Part 1

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I recently attended a regional CCFA conference. David Rubin gave several terrific lectures. Here are some of my notes and some slides from this lecture. My notes may contain transcription errors as well as important omissions. Can get access to full set of slides here: Biologics and Their Biosimilars

“Biologics and Their Biosimilars“

What is a Biologic Therapy?

Dr. Rubin makes a point of explaining the term to patients.  It is a protein made in a living cell that targets another protein.  Term “biologic” can sound scary to patients.  Usually given IV because they cannot be absorbed through the small bowel.

IBD Treatment Revolutions

  • Steroids -overnight changed mortality in IBD
  • Anti-TNF Therapy in IBD -taught many lessons. Treat earlier –>better outcomes. 

Anti-TNF Therapy

  • Frequent loss of response.
  • Earlier treatment with biologics result in better outcomes.
  • Immunogenicity is mainly an issue with anti-TNF agents and not much of an issue with other biologics. Episodic therapy is a big risk factor for anti-drug antibodies. 
  • If staying with in-class medication, after anti-drug antibodies, need to take additional measures to prevent anti-drug antibodies (eg. Immunomodulators).
  • Combination therapy is more effective (SONIC, UC SUCCESS trials).  This is due to using multiple mechanisms of disease control, reduction in anti-drug antibodies, and elevated serum drug levels.
  • Good therapeutic levels appears to deliver similar results as combination therapy
  • Pre-week 6 level of 17 or greater, associated with good response in maintenance.  If level is low, presumption is that higher dosing will be beneficial.
  • Higher levels of infliximab trough levels needed for perianal fistula healing (improved with ciprofloxacin).  Higher levels could be causally-related to healing or could be a marker that there is less inflammation and a patient is responding.
  • Anti-TNFs do not appear to increase risk of infections (see PUCCINI study)

Anti-23 and Anti-IL-12/IL-23

  • Tissue selective targeted therapy –>excellent safety profile
  • IV loading and SC maintenance
  • Excellent for bowel and skin
  • IL-23 is not expressed in joints
  • Ustekinumab is effective for perianal disease and ulcerative colitis
  • Risankizumab is superior to ustekinumab in plaque psoriasis.  If loss of response to ustekinumab, can still respond to Risankizumab

Anti-Integrins:

  • Natalizumab (not used frequently in IBD)
  • Vedolizumab.  Affects mucosa (can explain frequent nasopharyngitis)
  • Vedolizumab -terrific safety profile.  No PML, no malignancy risk

Biosimilars:

  • If biosimilar found effective for one approved condition, extrapolation given to all indications
  • IBD switching studies have NOT shown increased loss of response.  Consider reassess prior to switch to help determine if patient truly in remission prior to switch. Switching often blamed for loss of response when many times the disease was not under good control prior to switch
  • Interchangeable indicates that the drug can be switched by pharmacists
  • Biosimilars are saving insurers money but no proof that this is saving patients money
  • Anti-drug antibodies will cross-react to biosimilars

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.

REMSWITCH: Infliximab IV to SC Study

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A Buisson et al. Clin Gastroenterol Hepatol 2023; 21: 2338-2346. Open Access! Effectiveness of Switching From Intravenous to Subcutaneous Infliximab in Patients With Inflammatory Bowel Diseases: the REMSWITCH Study

In this study, 133 ot 184 patients in clinical remission agreed to switch to subcutaneous infliximab. Key findings:

  •  At visit 3, a relapse occurred in 10.2% (n = 6 of 59), 7.3% (n = 3 of 38), 16.7% (n = 3 of 18), and 66.7% (n = 10 of 15) (P < .001) of patients receiving 5 mg/kg every 8 weeks (5Q8W), 10Q8W, 10Q6W, and 10Q4W, respectively. 
  • Dose escalation to 240 mg every other week led to recapture clinical remission in 93.3% (n = 14 of 15).
  • Infliximab serum levels increased after the switch (P < .0001) except for patients receiving 10 mg/kg every 4 weeks.
  • Conclusion (borrowed from authors): Switching from intravenous to subcutaneous infliximab 120 mg every other week is safe and well accepted, leading to a low risk of relapse in IBD patients except for those receiving 10Q4W; these patients likely require 240 mg every other week

EV Loftus et al. Clin Gastroenterol Hepatol 2023; 21: 2193. Open Access! Therapeutic Drug Monitoring for Subcutaneous Infliximab? Too Early to Conclude (Editorial) This editorial provides a terrific analysis of the above-mentioned study. A few of the points:

  • Reduced (41.7%) or stable (36.8%) serum levels of IFX after the switch (difference: V1-V0) were associated with higher risk of relapse than increased serum levels (>1 μg/mL; 12.7%; P = .020 and P = .019, respectively)
  • Patients receiving IV infusion of IFX 10Q4W had a higher risk of relapse (odds ratio, 12.4; P = .017). In addition to having significantly higher serum levels than in other IFX IV regimens, this group of patients did not see a rise in IFX concentrations at V1, in contrast to other IFX regimens. 
  • Being overweight increases the clearance of CT-P13 SC, with an increase in clearance of 43.2% for a weight increase from 70 to 120 kg. The presence of antibodies to IFX also increases clearance by 39%. Finally, a decrease in serum albumin level (42 g/L vs 3.2 g/L) increases the clearance by 30.1%. 

My take:

  1. Monitoring IFX levels would be helpful in patients switching from IV to SC administration, especially in higher risk groups (eg. high baseline dosing, positive anti-drug antibodies, low serum albumin, overweight individuals)
  2. My experience with SC biologics has been that there is a much higher rate of non-adherence than with IV infusions. If/when SC biologics are used more often, I will need to implement more intensive followup to assure patients receive both the needed medication and the needed monitoring.

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Festive Street in Antibes, France

Comparative Efficacy of Biologics for Crohn’s Disease

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S Singh et al. Clin Gastroenterol Hepatol 2023; 21: 2359-2369. Open Access! Comparative Safety and Effectiveness of Biologic Therapy for Crohn’s Disease: A CA-IBD Cohort Study

There is limited head-to-head data comparing the effectiveness of the biologics used for inflammatory bowel disease. In this study, the authors used a “series of propensity score (PS)-matched cohort studies comparing TNF-α antagonists vs vedolizumab vs ustekinumab in a large, diverse, multicenter, electronic health record (EHR)-based cohort.”

This graphical abstract summarizes the findings, though the first cohort (ustekinumab vs TNFalpha population is actually 1545 not 1030):

Key findings:

  • Ustekinumab-treated patients with CD (n = 515) experienced a lower risk of serious infections (hazard ratio [HR], 0.36), without any difference in the risk of hospitalization (HR, 0.99) or surgery (HR, 1.08) -compared to patients receiving TNF alpha antagonists (n=1030)
  • Ustekinumab-treated patients with CD (n = 221) experienced a lower risk of serious infections (HR, 0.20), without significant differences in risk of hospitalization (HR, 0.76) or surgery (HR, 1.42) -compared to vedolizumab-treated patients (n=221)
  • Compared with TNF-α antagonists (n = 442), vedolizumab-treated patients with CD (n = 221) had a similar risk of serious infections (HR, 1.53), hospitalization (HR, 1.32), and surgery (HR, 0.63).

The increase rate of infections with vedolizumab compared to ustekinumab could be an indication of lower efficacy with vedolizumab as the medication itself has a high safety profile.

In the discussion, the authors comment further on head-to-head studies and lack of these as well. “Biemans et al23 observed that ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (69 patients in each arm, vs vedolizumab; 46.4% vs 29.0%; P = .04) and biochemical remission (42.1% vs 13.2%; P = .01) at 12 months, although these rates were not significant at earlier time points.”

My take: This study provides further evidence that ustekinumab is a good option for Crohn’s disease with regard to both safety and efficacy.

Related blog posts:

Does a Liver Transplantation Improve the Course of Inflammatory Bowel Disease?

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AR Safarpour et al. Inflamm Bowel Dis 2023; 29: 973-985. Alterations in the Course of Inflammatory Bowel Disease Following Liver Transplantation: A Systematic Review and Meta-analysis

The authors identifed 25 studies which met inclusion criteria. Key findings:

  • In the analysis of studies with 3-category outcomes (n = 13), the pooled frequencies of patients (n=646) with improved, unchanged, or aggravated IBD course after LT were 29.4%, 51.4% (, and 25.2%.
  • Subgroup analyses revealed that patients with ulcerative colitis (UC), younger age at LT, or shorter duration of follow-up were more likely to have an improved disease course.
  • In the analysis of studies with 2-category outcomes (n = 12), the pooled frequencies of patients (n=672) with improved/unchanged or aggravated IBD course were 73.6% and 24.1%, respectively

My take: Despite the intensification of immunosuppression, most often the course of IBD is unchanged in patients following a liver transplantation.

Related blog posts:

View from L’Jaardin Exotique in Eze, France

Only 30% Ready for Transition from Pediatric IBD to Adult Practice

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A Foster et al. J Pediatr 2023; 258: 113403. Transition Readiness in Youth with Inflammatory Bowel Disease

In this cross-sectional multicenter study evaluating transition readiness in individuals (n=186, prospectively recruited ) with IBD 16-19 years old, the authors used the validated ON Taking Responsibility for Adolescent to Adult Care (ON TRAC) questionnaire. 

Key findings:

  • ON TRAC scores determined that 26.6% of AYAs at pediatric and 40.4% at adult centers reached the threshold of readiness. The findings are limited by potential nonresponse & sampling bias.
  • Disease remission negatively (P = .03) associated with ON TRAC scores.
  • A significant percentage of AYAs reported moderate-to-severe depression (21.7%) and generalized anxiety (36%); however, neither were significantly associated with ON TRAC scores

The authors suggest that a joint clinic with adult/pediatric providers may be helpful to improve transition.

MB Cohen. J Pediatr 2023; 258. DOI:https://doi.org/10.1016/j.jpeds.2023.113556 Are You Ready to Transition? In commentary on this article, Dr. Cohen writes the following: “a novel finding was that transition readiness was inversely related to disease remission; this confirms what had been previously suggested.1 Patients who are doing well may not be as engaged in developing skills for transition readiness and knowledge about their chronic illness, unlike those with more significant disease or symptoms.”

My take: Many studies show that adolescents and young adults with IBD are not fully prepared to transition to adult medical practices. In my view, it would be better to encourage the young adult to continue engaging with his/her parents until readiness is achieved rather than try to change to a multispecialty clinic.

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Castle Hill Park, Nice France

Infliximab Injections Coming Soon

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  1. L Gianolio et al JPGN 2023; 77(2):p 235-239, August 2023. Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy

Key findings: After switching from IV infliximab to SC 120 mg every other week, 6 of 7 patients remained in clinical remission with no significant changes in laboratory markers and median infliximab trough levels (12.3 µg/mL at baseline; 13.9 and 14.0 µg/mL at 6 and 40 weeks respectively). 

2. Gastroenterology & Endoscopy News (7/31/23) Safety, Efficacy of Subcutaneous Infliximab Supported by Trial

Excerpt:

In this multinational trial, called LIBERTY-CD, the median trough level was 16 mcg/mL, which is higher than that typically associated with IV dosing, according to Dr. Hanauer, who presented the results at Digestive Disease Week 2023 (abstract 1028)… “most professional societies to recommend a trough of 10 mcg/mL,” Dr. Hanauer said….

All patients received induction doses of infliximab by IV at weeks 0, 2 and 6. Those who achieved at least a 100-point reduction in the Crohn’s Disease Activity Index (CDAI), which accounted for 86% of the 396 patients initially enrolled, were randomized in a 2:1 ratio to receive 120 mg of subcutaneous infliximab (CT-P13) or placebo every two weeks.

The proportion of patients meeting the end point of clinical remission, defined on the basis of CDAI, was 62.3% for active therapy and 32.1% for placebo (P<0.0001). The proportion of patients in the active treatment arm achieving an endoscopic response was nearly three times higher than the proportion in the placebo arm (51.1% vs. 17.9%; P<0.0001).

My take: This study shows that SC infliximab (after IV induction) should be effective. A study showing that the SC product is not inferior to the IV dosing would be helpful. It is likely that vedolizumab will receive approval in U.S. for a similar IV induction followed by maintenance subcutaneous therapy in the next year.

Eze, France