Tag Archives: Ulcerative colitis

Effects of Thiopurine Withdrawal in Randomized Trial of Vedolizumab-Treated Patients with Ulcerative Colitis

Posted on by

A Pudipeddi et al. Clin Gastroenterol Hepatol 2024; 22: 2299-2308. Open Access! Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial

Methods: This was a multicenter randomized controlled trial recruited UC patients (n=62) on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine.

Key findings:

  •  At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 μg/mL versus 15.9 μg/mL, respectively, P = 0.36).
  • The continue group had significantly higher fecal calprotectin remission (calprotectin <150) (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Clinical and endoscopic remission favored the continue group though this did not reach statistical significance.
  • Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6–146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3–33.8; P = .03) predicted clinical relapse after thiopurine withdrawal.

Discussion: “In Australia, requirements are for UC patients to have failed at least 3 months of an immunomodulator before vedolizumab initiation. Consequently, UC patients are typically on combination therapy initially, and hence this study was designed as a withdrawal trial.” The authors note that previous studies have not shown superior outcomes with combination therapy (See blog post: No Benefit of Combination Therapy with Ustekinumab or Vedolizumab). “However, methodological flaws, heterogenous outcomes, and shorter durations of treatment limit these findings.”

My take (borrowed from authors): “Thiopurines might provide an incremental benefit to patients with UC using vedolizumab, … independent of vedolizumab pharmacokinetics.”

Related study: C Yzet et al. Clin Gastroenerol Hepatol 2021; 19: 668-679. Full Text: No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That Are Not Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: A Meta-analysis

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.

AGA Living Guideline for Moderate-to-Severe Ulcerative Colitis –The Good and The Bad

Posted on by

S Singh et al. Gastroenterol 2024; 167: 1307-1343. Open Access! AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis

This is a recent clinical guideline intended to serve as the starting point of a “living guideline” for adults with moderate-to severe ulcerative colitis.

  • The good news is that the AGA plans to update these guidelines semi-annually. The bad news is that this guideline does not provide the best advice.
  • It lumps recommended treatments into broad categories rather than indicating which therapies have the most effectiveness.
  • It is useful that the guidelines specifically recommend against step up therapy.
FDA labelling recommends upadacitinib only in patients who have not responded to anti-TNF therapy

For a recent study that provided more direction into which medications are most effective for both UC and Crohn’s disease: PS Dulai et al. Gastroenterol 2024; 166: 396-408. Open Access! Integrating Evidence to Guide Use of Biologics and Small Molecules for Inflammatory Bowel Diseases (Summarized in blog post: Comparative Evidence and Positioning Advance Therapies for Inflammatory Bowel Disease)

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.

Frequency of Erythema Nodosum and Pyoderma Gangrenosum in 32,497 Pediatric Patients with Inflammatory Bowel Disease

Posted on by

MY Yousif et al. JPGN 2024; 79:1009–1016. Open Access! The association between erythema nodosum and pyoderma gangrenosum and pediatric inflammatory bowel disease

Using the ImproveCareNow prospective registry, the authors analyzed a total of 285,913 visits from 32,497 patients aged ≤ 21 years.

Key findings:

  • The occurrence of erythema nodousm (EN) was 1.57% and the occurrence of pyoderma gangrenosum (PG) was 0.90%. Co-occurrence of EN and PG was reported in 0.30% patients.
  • Both EN and PG were associated (p < 0.0001) with worse intestinal disease, lower remission, higher inflammatory markers, and extraintestinal manifestations (EIMs) arthritis and uveitis. 
  • Limitations: “imperfect and incomplete data entry that may introduce bias. However, due to the extensive longitudinal data, we expect any bias to be minimal.”

My take: This study clarifies how common these dermatologic findings occur in pediatric patients with IBD. Prompt recognition of these disorders is important. Recently, our group cared for a 20 yo patient with inadequately-treated PG by multiple internal medicine physicians; this led to prolonged hospitalization.

Related blog posts:

The Dancer by Auguste Renoir, National Gallery of Art

Phase 2 Trial of Tulisokibart for Ulcerative Colitis

Posted on by

Yesterday’s pumpkin -please no snide remarks about how I can now retire and become a sculptor:

BE Sands et al. N Engl J Med 2024;391:1119-1129. Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis

Background: “Several studies have implicated human tumor necrosis factor–like cytokine 1A (TL1A) in the pathogenesis of inflammatory bowel disease…Tulisokibart (formerly PRA023) is a humanized IgG1 kappa monoclonal antibody that binds to the membrane-bound and soluble forms of TL1A with high affinity and specificity. Tulisokibart prevents the interaction of TL1A and DR3, thereby suppressing type 1 and type 17 helper T-cell responses, increasing regulatory T-cell activity, and decreasing profibrotic pathways.”

Methods: (ARTEMIS-UC trial) The authors “randomly assigned patients with glucocorticoid dependence or failure of conventional or advanced therapies for ulcerative colitis to receive intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10) or placebo. Cohort 1 included patients regardless of status with respect to the test for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response.”

“The inclusion of an integrated assessment of a panel of genetic markers as a diagnostic assay was based on the notion that patients with a propensity to overexpress TL1A might be more likely to have a response to tulisokibart than an unselected population.”

Key findings:

  • In the first cohort, a significantly higher percentage of patients who received tulisokibart had clinical remission than those who received placebo (26% vs. 1%), endoscopic healing (31% vs. 4%), endoscopic improvement (37% vs 6%) and clinical response (66% vs 22%)
  • “Among patients with a positive test for likelihood of response (cohorts 1 and 2 combined), clinical remission occurred in a higher percentage of patients who received tulisokibart than in those who received placebo (32% vs. 11%).”
  • Improvement in CRP and Calprotectin were noted as early as 2 weeks and 6 weeks respectively
  • The incidence of adverse events was similar in the tulisokibart and placebo groups

My take: Tulisokibart was effective in a group of patients with moderately to severely active ulcerative colitis who were refractory to advanced therapies.

Related blog posts:

When and How to Pursue Ileal Diversion in Crohn’s Disease

Posted on by

A Simard et al. J Pediatr Gastroenterol Nutr. 2024;79:800–806. Role of ileal diversion in pediatric inflammatory bowel disease

Indications:

  • Severe, medically refractory colitis
  • Complex and medically refractory perianal disease
  • In combination with bowel resection for irreversible bowel damage (e.g., fistulae, abscesses, or strictures)

Diversion “provides the opportunity to reduce steroid use, improve growth and observe the natural history of the disease in a more controlled manner. It may also enhance quality of life”

My take: This is a handy article when considering ileal diversion in a patient with medically-refractory inflammatory bowel disease.

Related blog posts:

Risankizumab for Ulcerative Colitis

Posted on by

E Louis et al. JAMA 2024; doi:10.1001/jama.2024.12414. Risankizumab for Ulcerative ColitisTwo Randomized Clinical Trials

In June, risankizumab (Skyrizi) received FDA approval as a treatment for moderate to severe ulcerative colitis in adults. FDA approval relied on the data from these two randomized trials.

Methods:  For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks.

Key findings:

  • In the 12-week induction INSPIRE study with 975 patients, the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (P < .001)
  • In the induction trial, a greater proportion of treated patients achieved endoscopic improvement (36.5% vs. 12.1%; P < 0.00001) and endoscopic histologic mucosal improvement (24.5% vs. 7.7%; P < 0.00001) after 12 weeks
  • In the induction trial, a clinical response at 12 weeks was noted in 418/650 (64.3%) of risankizumab-treated patients and 116/325 (35.7%) of the placebo-treated patients
  • In the COMMAND maintenance trial with 548 patients, the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo. Both doses were statistically-significant compared to placebo, P < .001 and P = .002, respectively
  • After 1 year of treatment with either maintenance dose of risankizumab, more than 40% of patients had histologic and endoscopic improvement
  • More than 75% of patients in the maintenance trial had a history of inadequate response to advanced therapies

My take: The published results of risankizumab for Crohn’s disease are much more impressive than the results in this study.

Related blog posts:

Matterhorn (shared by MH) in September 2024

Does Accelerated Dosing of Infliximab Work for Acute Severe Ulcerative Colitis?

Posted on by

MC Choy et al. The Lancet Gastroenterology 2024; Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial

Methods: In this open-label, multicenter, randomized controlled trial, patients aged 18 years or older from 13 Australian tertiary hospitals with intravenous steroid-refractory ASUC were randomly assigned (1:2) to receive a first dose of 10 mg/kg infliximab or 5 mg/kg infliximab (randomization 1). Block randomization was used and stratified by history of thiopurine exposure and study site, with allocation concealment maintained via computer-generated randomization. Patients in the 10 mg/kg group (intensified induction strategy [IIS]) received a second dose at day 7 or earlier at the time of non-response; all patients in the 5 mg/kg group were re-randomized between day 3 and day 7 (1:1; randomization 2) to a standard induction strategy (SIS) or accelerated induction strategy (AIS), resulting in three induction groups. Patients in the SIS group received 5 mg/kg infliximab at weeks 0, 2, and 6, with an extra 5 mg/kg dose between day 3 and day 7 if no response. Patients in the AIS group received
5 mg/kg infliximab at weeks 0, 1, and 3, with the week 1 dose increased to 10 mg/kg and given between day 3 and day 7 if no response.

Thus, this was the first RCT comparing an intensified induction strategy (IIS; 10 mg/kg infliximab at weeks 0 and 1, with the second dose given earlier if no clinical response), an accelerated induction strategy (AIS; 5 mg/kg infliximab at weeks 0, 1, and 3, with the second dose increased to 10 mg/kg and given earlier if no response), and a standard induction strategy (SIS; 5 mg/kg at weeks 0, 2 and 6; with an extra 5 mg/kg dose before day 7 if no
response) in steroid-refractory patients with ASUC.

Key findings:

  • There was no significant difference in the proportion of patients who had a clinical response by day 7 between the 10 mg/kg and 5 mg/kg groups: 65% vs 61%
  • In patients with a baseline albumin of less than 25 g/L, a day 7 response occurred in nine (64%) of 14 patients in the 10 mg/kg group versus 14 (45%) of 31 in the 5 mg/kg group (RR 1·43, p=0·17)
  • In patients with a baseline CRP of 50 mg/L or higher, a day 7 response occurred in six (60%) of ten patients in the 10 mg/kg group versus eight (42%) of 19 in the 5 mg/kg group (RR 1·39, p=0·34)
  • The proportions of patients with clinical response at day 14: 74% in the IIS group, 73% in the AIS group, and 68% of 44 in the SIS group.
  • The clinical remission at month 3: 50% in the IIS group, 52% in the AIS group, and 48% in the SIS group
  • The steroid-free remission at month 3: 41% in the IIS group, 42% in the AIS group, and 41% in the SIS group
  • The endoscopic remission at month 3: 46% in the IIS group, 46% in the AIS group, and 48% in the SIS group
  • The colectomy rate at month 3: 7% in the IIS group, 19% in the AIS group, and 12% in the SIS group colectomy at month 3 were not significantly different between group (P=0.20)
  • The colectomy rate at month 12: 7% in the IIS group, 22% in the AIS group, and 15% in the SIS group colectomy at month 3 were not significantly different between group (p=0.13)
  • In post-hoc analysis of second-dose salvage strategies (among the group who had not responded at day7), a clinical response was observed in 19 (59%) of 32 patients who received a 10 mg/kg salvage dose versus nine (64%) of 14 who received a 5 mg/kg salvage dose (RR 0·92). Endoscopic remission at month 3 was observed in 11 (34%) who received 10 mg/kg salvage versus six (43%) who received 5 mg/kg salvage (RR 0·80). Colectomy by 3 months occurred in ten (31%) who received 10 mg/kg salvage compared with three (21%) who received 5 mg/kg salvage (HR 1·46)
  • Higher proportions of patients with clinical and biochemical remission between weeks 2 and 6 were apparent in the IIS and AIS groups versus the SIS group, but by 3 months, these differences were lost

My take: Intensified, accelerated, and standard induction regimens in the PREDICT-UC study did not result in a statistically-significant difference in clinical response by day 14 or in remission or colectomy rates by month 3. However, there are some important caveats:

  1. There appeared to be a trend towards a lower colectomy rate in the IIS group.
  2. There appeared to be a favorable trend towards an improved response to IIS group in those with low albumin (<25 g/L) and high CRP (>5 mg/L). The smaller numbers in these subgroups could have precluded statistical significance
  3. Also, even the SIS group were able to receive a 4th induction 5 mg/kg dose between days 3-7 if they had not responded to treatment
  4. In patients who had not responded to either 10 mg/kg or 5 mg/kg, a salvage dose at day 7 resulted in a >60% response rate
  5. It is possible that a sustained strategy of more aggressive dosing (not done in this study) aided with therapeutic drug monitoring could result in better outcomes following IIS

Blog Case Report: A Persistent Elevated AST in Teen with IBD and ADHD

Posted on by

A recent case reminded me of the quote by Helena Ravenclaw in Harry Potter: “”If you have to ask, you’ll never know. If you know, you need only ask.”

One of my colleagues recently diagnosed a teenage boy with ulcerative colitis. His past medical history was notable for ADHD. At the time of his evaluation, he was noted to have an elevated AST.

Labs:

  • June: AST 143, ALT 8, Hepatitis B immune
  • August: AST 190, ALT 10, Albumin 4.7, T protein 7.3, T bili 0.4, D bili 0.1, Alk phos 168; GGT 10, CPK 93

The concern at the time was whether his elevated AST should preclude using his ADHD medicine and whether there was an underlying liver disease. Based on the pattern of liver enzyme abnormalities, it was suspected that the patient had macro AST. A blood test was sent to the Mayo clinic and confirmed this diagnosis:

“”The sample was investigated for the presence of macro AST by polyethylene glycol (PEG) precipitation. Serum AST activity = 316 U/L. The AST result post-PEG precipitation = 22 U/L. The results obtained are positive for the presence of macro AST (93% of activity precipitated with PEG). Based on validation studies performed at the Mayo Clinic, a cut-off of >80% AST activity precipitated by PEG indicates the presence of macro AST.” This test is rarely ordered at the Mayo Clinic and is ordered as a miscellaneous test; it is not on the Mayo Clinic’s regular test menu.

Internet description of macro AST: Macro-aspartate aminotransferase (macro AST) is a rare, benign condition that causes a persistent elevation of aspartate aminotransferase (AST) levels in the blood. It’s caused by the binding of AST to immunoglobulins, which results in a high molecular weight macroenzyme that’s excreted from the serum more slowly than normal.

My take: Macro AST diagnosis is useful –it helps eliminate the concern for other conditions. Since it is quite uncommon, it is easier to think of this problem once you have seen it before.

Related blog posts:

Grand Point View Overlook at Canyonlands National Park

How Quickly Does Upadacitinib Work for Crohn’s Disease Symptoms?

Posted on by

JF Colombel. et al. Clin Gastroenterol Hepatol 2024; 22: 1668-1677. Open Access! Upadacitinib Reduces Crohn’s Disease Symptoms Within the First Week of Induction Therapy

This study was a post hoc analysis included pooled data from 2 phase 3, multicenter, double-blind, 12-week induction trials (U-EXCEL and U-EXCEED) and 1 maintenance trial (U-ENDURE). The study included 1021 patients with Crohn’s disease (CD) (n = 674 UPA45; n = 347 PBO).

Key findings:

  • Upadacitinib 45 mg taken once daily resulted in rapid relief from CD symptoms within 5 to 6 days of treatment initiation and improved clinical outcomes starting at week 2.
  • The present analysis demonstrates symptomatic relief as early as day 5 to 6 for patients receiving UPA, with 16.7% of patients experiencing daily SF/APS clinical remission by day 5. 
  • The first achievement of daily stool frequency/abdominal pain score (SF/APS) clinical remission occurred earlier with UPA45 (median, 13 d) vs PBO (median, 32 d)
  • Patients treated with UPA45 showed improved rates of SF/APS clinical remission (21.1% UPA45 vs 8.9% PBO) and clinical response (58.8% UPA45 vs 37.9% PBO) starting at week 2 (both P ≤ .01).

In their discussion, the authors note that time to response to treatment with upadacitinib compares favorably to other advanced therapies:

“Vedolizumab resulted in symptomatic improvement within 2 to 4 weeks of treatment initiation16; ustekinumab led to clinical response and remission at week 3 or 6, depending on the dose.17 Similarly, of the time points analyzed, clinical response and/or clinical remission was observed as early as week 2 for risankizumab, 5 infliximab,18 and certolizumab pegol,19 and as early as week 1 for adalimumab.20,21“

My take: The rapid response seen in many patients indicate that upadacitinib can be a steroid-sparing therapy in patients with Crohn’s disease.

Unrelated article: E Louis et al. JAMA 2024; doi:10.1001/jama.2024.12414. Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials

Key findings:  Among the 975 patients with moderate to severe ulcerative colitis, analyzed in the induction trial, 1200 mg of risankizumab significantly increased the rates of clinical remission at 12-week follow-up compared with placebo (20.3% vs 6.2%, respectively). Among 548 patients included in the primary efficacy analysis for the maintenance trial, 180 mg of risankizumab and 360 mg of risankizumab significantly increased the rates of clinical remission (40.2% and 37.6%, respectively) compared with placebo (25.1%).

Related blog posts:

IBD Updates: SMART IBD App, SC Vedolizumab Durability, Risk Factors in Acute Severe Ulcerative Colitis

Posted on by

KA Hommel et al. JPGN 2024; 78:1273–1278. Pilot and feasibility of the SMART IBD mobile app to improve self-management in pediatric inflammatory bowel disease

The Self‐Management Assistance with Recommended Treatment (SMART) IBD app –Key findings:

  • Patients rated the app quality as good and accessed the app adequately overall, with some pages being used often.
  • Medication adherence increased over the course of the study and was associated with sleep duration, mood, and stool consistency and blood content.

My take: IBD Management apps could be quite helpful, especially for teens and young adults.

S Hsiang et al. Inflammatory Bowel Diseases, Volume 30, Issue 8, August 2024, Pages 1284–1294, https://doi.org/10.1093/ibd/izad166. Safety, Effectiveness, and Treatment Persistence of Subcutaneous Vedolizumab in IBD: A Multicenter Study From the United Kingdom

Methods: IBD patients (n=563) on IV vedolizumab across 11 UK sites agreed to transition to SC injections or otherwise continued IV treatment

Key findings:

  • Data from 563 patients, demonstrated no differences in disease activity, remission rates, and quality of life between the SC and IV groups at all time points
  • Drug persistence at week 52 was similar (81.1% vs 81.2%; P = .98)

Related blog posts:

CFD Li Wai Suen, et al. Inflammatory Bowel Diseases, Volume 30, Issue 8, August 2024, Pages 1389–1405, https://doi.org/10.1093/ibd/izad183. Factors Associated With Response to Rescue Therapy in Acute Severe Ulcerative Colitis 

This systematic review identified 101 completed studies were eligible for inclusion.

Related blog posts: