IBD Updates: Probability of Needing a Stoma with Crohn’s Disease, “CEASE” anti-TNF study, Extending Tofacitinib Response Time

AH Everhov et al. Inflamm Bowel Dis 2022; 28: 1160-1168. Open Access! Probability of Stoma in Incident Patients With Crohn’s Disease in Sweden 2003-2019: A Population-based Study

In a nationwide Swedish cohort of 18,815 incident patients with a minimum 5 years of follow-up, 652 (3.5%) underwent formation of a stoma. The 5-year cumulative incidence of stoma formation was 2.5%, with no differences between calendar periods  (2003–2006, 2007–2010, and 2011–2014).

RWM Pauweis et al. Clin Gastroentol Hepatol 2022; 20: 1671-1686. Open Access! Prediction of Relapse After Anti-Tumor Necrosis Factor Cessation in Crohn’s Disease: Individual Participant Data Meta-analysis of 1317 Patients From 14 Studies

C Ma. Clin Gastroentol Hepatol 2022; 20: 1668-1670. Associated editorial. Open Access! To Stop or Not to Stop? Predicting Relapse After Anti-TNF Cessation in Patients With Crohn’s Disease

This study captured data from 1317 patients (including 927 patients stopping infliximab and 390 patients stopping adalimumab) to develop risk prediction models.  “The authors confirm many of the high risk, albeit rather intuitive, factors that are associated with the risk of relapse, including younger age, younger age at diagnosis, smoking, upper gastrointestinal tract involvement, longer disease duration, absence of concomitant immunosuppressant use, previous anti-TNF failure, and absence of clinical remission.”

The editorial notes that even in the lowest risk group, more than 20% had risk of relapse within 1 year; in addition, stopping therapy increases risk of not recapturing remission with restart of treatment. “Stopping anti-TNF therapy is a highly personalized treatment decision and is one that carries considerable risks…therapeutic discontinuation of TNF antagonists should be reserved for the very small minority of patients who are in deep remission, have a strong desire to stop treatment, have no (or very few) characteristics of high-risk CD, can tolerate a substantial disease flare, and are fully informed of the risks of therapeutic withdrawal.”

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WJ Sandborn et al. Clin Gastroenterol Hepatol 2022; 20: 1821-1830. Open Access! Efficacy and Safety of Extended Induction With Tofacitinib for the Treatment of Ulcerative Colitis

Graphical abstract below shows that 52.2% of patients who did not achieve clinical response to 8 weeks’ treatment with tofacitinib 10 mg BID in the induction studies achieved a clinical response following extended induction (delayed responders). At Month 12 of OCTAVE Open, 70.3%, 56.8%, and 44.6% of delayed responders maintained clinical response and achieved endoscopic improvement and remission, respectively. Corresponding values at Month 36 were 56.1%, 52.0%, and 44.6%.

My take: By extending the treatment induction to 16 weeks to determine response (rather than 8 weeks), the authors showed that 75% of patients with ulcerative colitis in the initial cohort respond to tofacitinib.

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IBD Updates: SC Vedolizumab, PRODUCE study: Specific Carbohydrate Diet, Racial Epidemiology of IBD, and Microbiome in UC

Briefly noted –all of these articles are open access:

A Volkers et al. AP&T 2022; https://doi.org/10.1111/apt.17153 Open access: Real-world experience of switching from intravenous to subcutaneous vedolizumab maintenance treatment for inflammatory bowel disease. In this prospective cohort study, patients (n=135) with IBD who had ≥4 months IV vedolizumab were switched to SC vedolizumab. 

Key findings:

  • 4 patients with Crohn’s disease had loss of response.
  • 9% of patients were switched back to IV vedolizumab due to adverse events or fear of needles.
  • Median clinical and biochemical disease activity remained stable after the switch. Median vedolizumab serum concentrations increased from 19 μg/ml at the time of the switch to 31 μg/ml 12 weeks after the switch (p < 0.005).

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HC Kaplan et al. Am J Gastroenterol 2022 Jun 1;117(6):902-917. Open access: Personalized Research on Diet in Ulcerative Colitis and Crohn’s Disease: A Series of N-of-1 Diet Trials. In this study, 21 patients (completed trial) were randomized to 1 of 2 sequences of 4 alternating 8-week SCD (specific carbohydrate diet) and MSCD (modified specific carbohydrate diet) periods.

Key findings: “SCD and MSCD did not consistently improve symptoms or inflammation.” “Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not.” The authors note that it took 18 months to recruit 54 patients for this study across 19 research sites.

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EL Barnes et al. Inflamm Bowel Dis 2022; 28: 983-987. Open access: Racial and Ethnic Distribution of Inflammatory Bowel Disease in the United States The authors electronic health records from 337 centers from January 2013 to December 2018 with nearly 40 million patients in U.S.

Key findings:

  • Black adult patients were significantly less likely than White patients to have a diagnosis of CD (odds ratio [OR], 0.53) or UC (OR, 0.41). Pediatric Black patients were also less likely to have a diagnosis of CD (OR, 0.41) or UC (OR, 0.38)
  • Adult Hispanic patients were less likely to have a diagnosis of CD (OR, 0.33) or UC (OR, 0.45) compared with non-Hispanic patients. Similarly, pediatric Hispanic patients were less likely to have a diagnosis of CD (OR, 0.34) or UC (OR, 0.50).
  • Thus, these data suggest that CD and UC are modestly less prevalent among patients of non-White races and Hispanic ethnicity

M Frioirksmork et al. Inflamm Bowel Dis 2022; 28: 1081-1089. Open access: Similar Gut Bacterial Composition Between Patients With Ulcerative Colitis and Healthy Controls in a High Incidence Population: A Cross-sectional Study of the Faroe Islands IBD Cohort. This cross-sectional study from the Faroe Islands (which has very high incidence of IBD) consisted of 41 patients with established ulcerative colitis and 144 age- and sex-matched healthy controls.

Key findings: There was a similarity in bacterial community composition and absence of the beneficial Akkermansia genus in both groups.

Head-to-Head (Sort of): Infliximab vs Ustekinumab for Crohn’s Disease

N Narula et al. Clin Gastroenterol Hepatol 2022; 20: 1579-1587. Comparative Efficacy and Rapidity of Action for Infliximab vs Ustekinumab in Biologic Naïve Crohn’s Disease

Using a post hoc analysis of 2 large Crohn’s disease (CD) trial with 420 biologic-naive adult patients, the authors found the following Key Findings:

  • At week 6, a comparable number of patients achieved clinical remission with infliximab compared with patients treated with ustekinumab (44.9% vs 37.9%; adjusted odds ratio [aOR], 1.22)
  • At week 6 the clinical response rates were not significantly different (58.4% infliximab vs 54.9% ustekinumab; aOR, 1.25)
  • At week 6, 42.3% infliximab vs 34.7% ustekinumab had fecal calprotectin level less than 250 mcg/L in those with increased values at baseline

My take: A true head-to-head trial, rather than a post-hoc analysis, would more definitively determine relative efficacy and relative time to response. This study indicates that both agents have similar efficacy by week 6.

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Fountain at Forsyth Park in Savannah

AGA Guidelines for Pharmacologic Therapy of IBS-D and IBS-C

A Lembo, S Sultan et al. Gastroenterol 2022; 162: 137-151. Open access PDF: AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Diarrhea

LChang, S Sultan et al. Gastroenterol 2022; 162: 118-136. Open access: AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation

The associated 1-page summary (“Spotlight: IBS Treatment“) on pg 153 reviews society guidelines on testing in IBS. This includes for IBS-D celiac serology, calprotectin/lactoferrin, CRP, possilby Giardia antigen (if in endemic area) and possibly bile acid diarrhea testing. Not recommended include food allergy/sensitivity testing, colonoscopy if <45 years and lactulose or glucose hydrogen breath testing. This 1-page summary details therapeutic dosing and costs. Monthly costs of selected medications according to this report:

  • Lubiprostone (Amitiza): $374
  • Linaclotide (Linzess): $523
  • Pleacnatide (Trulance): $528
  • Tegaserod (Zelnorm): $480
  • Tenapanor (IBSRELA): $1680
  • Rifaximin (Xifaxan) $1544 (for 14 day course)
  • Eluxadoline (Viberzi): $1550
  • Alosetron (Lotronex): $1457-1929 (starting dose), $2915-3859 (max dose)

My take: These guideline publications provide comprehensive information regarding potential pharmacological therapies.

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Implications of Serene Studies

In a previous post, this blog highlighted SERENE-CD which showed that higher induction doses of adalimumab did not improve outcomes compared to standard dosing (SERENE Study: Does a Higher Induction Dose of Adalimumab Help for Crohn’s Disease?)

However, there was a 2nd SERENE study: SERENE-UC: J Panes et al. Gastroenterol 2022; 162: 1891-1910. Open Access: Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results The online version includes supplementary material (link: supplement) which is needed to understand the response rate more fully.

The main component of this double-blind, randomized (no placebo) study allocated 512 patients with ulcerative colitis to a higher induction regimen (HIR) of adalimumab and 340 patients to a standard induction regimen (SIR). A maintenance phase continued with 374 main patients who were clinical responders at week 8 (n=757 who completed induction). The study results are presented in a confusing manner, in part because of a subgroup from Japan as well as a great deal of data from both the induction phase and the maintenance phase.

Key findings:

  • In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen (HIR) vs standard induction regimen (SIR) achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265)
  • Among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069).
  • Figure S2 below shows that approximately 50% of patients treated with adalimumab had a clinical response at week 8

My takes on this study:

  1. Fairly low response to adalimumab: the clinical remission rate for adalimumab is low at week 8 (10-13%) and the 8-week response rate is less than 50%
  2. Higher doses during induction were not helpful & did not result in significantly better responses at week 8
  3. Therapeutic drug monitoring was not beneficial in this study
  4. Higher doses during maintenance were associated with improved responses: patients receiving weekly adalimumab during maintenance treatment had improved week 52 remission. The editorial (pages 1831-1832) note that this effect was demonstrated in those with “elevated C-reactive protein, low albumin, extensive UC or long disease burden”
Figure S2: Clinical response was defined as Partial Mayo Score decrease from baseline ≥ 2 and ≥ 30% plus ≥ 1-point
decrease from baseline in rectal bleeding subscore or absolute rectal bleeding subscore of 0 or 1.
Clinical remission was defined as Partial Mayo Score ≤ 2 with no subscore > 1.
ADA, adalimumab; HIR, higher induction regimen; SD, standard deviation; SIR, standard induction regimen

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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.

Ustekinumab Efficacy in Crohn’s Disease With Concurrent Autoimmune Skin Disease

E Fradkov et al. Inflamm Bowel Dis 2022; 28: 895-904. Efficacy of Ustekinumab in Crohn’s Disease With and Without Concurrent Autoimmune Skin Disease

This retrospective study reviewed 395 CD patients received ustekinumab therapy (79 CD-ASD (autoimmune skin disease), 316 CD-none). ASD included atopic dermatitis, eczema, psoriasis/psoriaform dermatitis and alopecia. The skin disease group also included those with cutaneous manifestations of Crohn’s disease: erythema nodosum, pyoderma gangrenosum, pyostomatitis vegetans, Sweet’s syndrome, granulomatous vasculitis, and leukocytoclastic vasculitis. 55 of the 79 with CD-ASD had psoriatic disease, 20 had eczema, 11 had erythema nodosum, 8 had pyoderma gangrenosum.

Key findings:

  • Ustekinumab had greater efficacy in CD-ASD when evaluated by fecal calprotectin (P = .0337) and CRP (P = .078). For calprotectin, the values decreased by 61% after at least 5 months of therapy (394 to 164) in the CD-ASD group compared to 11% in the group without skin disease (365 to 265)
  • The CD-ASD group also showed better outcomes in Likert scores of endoscopy (P = .016), histopathology (P = .074), and imaging (P = .094). 

My take: Ustekinumab appears to be particularly effective in patients with concurrent skin disease.

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Chattahoochee River near Morgan Falls

Safety of Preoperative Tumor Necrosis Factor  Inhibitor Exposure in Patients With Inflammatory Bowel Disease Undergoing Intra-abdominal Surgery

BL Cohen et al. Gastroenterol; 2022; 163: 204-221. Prospective Cohort Study to Investigate the Safety of Preoperative Tumor Necrosis Factor Inhibitor Exposure in Patients With Inflammatory Bowel Disease Undergoing Intra-abdominal Surgery

Key finding:

  • Preoperative TNFi exposure was not associated with postoperative infectious complications in a large prospective multicenter cohort. Any infection (18.1% vs 20.2%, P = .469) and SSI (12.0% vs 12.6%, P = .889) rates were similar in patients currently exposed to TNFis and those unexposed.

Updated Microscopic Colitis Epidemiology (2011-2019)

J Tome et al. Clin Gastroenterol Hepatol 2022; 20: 1085-1094. Open Access: The Epidemiology of Microscopic Colitis in Olmsted County, Minnesota: Population-Based Study From 2011 to 2019

Key points:

  • “The overall incidence of MC in Olmsted County, MN, increased from 1985 to 2001, stabilized between 2002 and 2010, and continues to show a plateau between 2011 and 2019.”
  • Medications associated with a risk of microscopic colitis (MC) include statins, SSRIs, PPIs, aspirin, other NSAIDs, and histamine H2-receptor antagonists within 3 months of diagnosis. “A recent US multicenter cohort study found an inverse association with PPIs and histamine H2-receptor antagonists when compared with controls with chronic diarrhea; only NSAID use was associated with MC. 31 It is plausible these medications do not cause MC, but instead aggravate diarrhea and bring the diagnosis to clinical attention.”

Related blog post/related article:

Increased Risk, Increased Reward (possibly) with Tofacitinib

T Straatmijer et al. Clin Gastroenterol Hepatol 2022; Full text Pre-Proof PDF: Superior effectiveness of tofacitinib compared to vedolizumab in anti-TNF experienced ulcerative colitis patients: a nationwide Dutch Registry study. DOI:https://doi.org/10.1016/j.cgh.2022.04.038

Methods: Ulcerative colitis patients who failed anti-TNF treatment and initiated vedolizumab (n=83) or tofacitinib (n=65) treatment, were identified in the ICC Registry in the Netherlands.

Key findings:

  • Tofacitinib treated patients were more likely to achieve corticosteroid-free clinical remission and biochemical remission at week 12, 24 and 52 compared to vedolizumab treated patients (OR: 6.33, OR: 3.02, and OR 1.86 and OR: 3.27, OR: 1.87, and OR:1.81, respectively).
  • There was no difference in infection rate or severe adverse events.

My take: The response rates with tofacitinib were significantly better than vedolizumab at all time points; however, by 52 weeks, the differences were less pronounced. Nevertheless, the safety profile of vedolizumab is much more favorable than tofacitinib and this is a very important consideration.

Related blog posts -Tofacitinib:

GI Bleeding -Forrest Classification

My take: Good images on twitter for classification of ulcers/bleeding risk

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