Tag Archives: Ulcerative colitis

Upadacitinib Works Quickly and with High Response

Posted on by

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.

Related blog posts:

Thiopurines Efficacy in Children with Ulcerative Colitis

Posted on by

FA Hanna et al. JPGN 2023; 77: 505-511. Thiopurines Maintenance Therapy in Children With Ulcerative Colitis: A Multicenter Retrospective Study

In this retrospective study with 133 children (2008-2019), typical dosing of thiopurines: azathioprine 2-2.5 mg/kg/day and 6-mercaptopurine 1.5 mg/kg/day. Patients with previous or concomitant treatment with 5-ASA were allowed in the study. 62% (n=83) of the cohort had pancolitis. Key Findings:

  • Seventy-four patients (56%) had CS-free clinical remission at week 52 without rescue therapy
  • In the cohort in clinical remission, 67 and 51 patients had both CRP and calprotectin measurements at 1 year and end of follow-up. Sufficient biomarker response (CRP <1 mg/dL, calprotectin <250 mcg/g) was achieved by 44 (66%) and 44 (86%) at those two time points.
  • The likelihood of remaining free of rescue therapy among thiopurines-treated patients was 83%, 62%, 45%, and 37% at 1, 2, 3, and 4 years, respectively
  • 8 of 133 (6%) stopped thiopurine therapy due to adverse effects

In their discussion, the authors make several points regarding efficacy and safety of thiopurines.

  • Many experts have advocated use of anti-TNF therapy agents for ulcerative colitis especially when 5-ASA medications are not effective.. This is based on higher efficacy and safety. With regard to safety, the authors note an “extremely low risk of lymphoma” citing a study from Israel in which children were followed until age of 30 years. No cases of hepatosplenic T-cell lymphoma were identified and the lymphoma rate was not statistically significant (O Atia et al. J Crohns Coliitis 2022; 16: 786-795 Open Access! Risk of Cancer in Paediatric onset Inflammatory Bowel Diseases: A Nation-wide Study From the epi-IIRN).
  • The authors note a recent review “rejected the hypothesis that initiation of biologic treatment later in the disease course correlates with lower response and remission rates in UC patients.”
  • Based on the efficacy and safety, the authors advocate for use of thiopurines “either early in the treatment course or as part of a de-escalation therapy…Thiopurines should be considered in the treatment of UC patients before the initiation of biologic drugs in most children.”

My take: In the U.S., it appears that thiopurine monotherapy, and even combination therapy, in pediatrics with IBD is used infrequently. Anti-TNF therapy with therapeutic drug monitoring is used routinely in patients if a 5-ASA is ineffective or not a good option. This article is a reminder that thiopurines are still a reasonable option. This would have been a good opportunity for a commentary in JPGN to add some context to this article regarding the role of these agents.

AGA guidelines for moderate-to-severe ulcerative colitis: “In adult outpatients with moderate to severe UC in remission, AGA makes no recommendation in favor of or against using biologic monotherapy or tofacitinib rather than thiopurine monotherapy for maintenance of remission.”

Related blog posts:

Ospedaletti, Italy
Calanques, France

When Patients Have an IBD Flare, It Might Be Something Else -Case in Point

Posted on by

R Paknikar et al. NEJM 2023; 389: 1321-1326. Digging into the Histology

In this case report, a 33-year-old man (from the midwest) with ulcerative colitis (diagnosis seven years prior) who was receiving treatment with tofacitinib (a Janus kinase inhibitor) presented to the hospital with fatigue (x 8 months) and bloody diarrhea. He also had had fevers (x 4 months), 23 lb weight loss, and drenching night sweats. Before tofacitinib, treatment had included adalimumab and azathioprine. He had undergone a sigmoidoscopy two months prior to presentation.

His workup included a CXR showing diffuse reticulonodular opacities, a CT scan showing thickening in the colon and extensive infection workup. On the third hospital day, he had a perforation and resection which led to the diagnosis of invasive histoplasmosis.

My take: This article is useful for understanding how to workup secondary infections in IBD patients on long-term immunosuppressive agents.

One example: “testing for 1,3-β-d-glucan can serve as an adjunctive test for invasive fungal infections caused by fungi expressing 1,3-β-d-glucan in their cell walls, including candida, aspergillus, Pneumocystis jirovecii, Histoplasma capsulatum, and coccidioides; such testing has a high negative predictive value for infection with these organisms. In contrast, cryptococcus and blastomyces produce very low levels of 1,3-β-d-glucan in their cell walls and are therefore not readily detected by serum testing for the cell-wall antigen.”

CT showed  shows diffuse wall thickening in the rectosigmoid colon and extravasation of extraluminal contrast material (arrow) into the area adjacent to the sigmoid colon, with layering of the contrast material, findings that are thought to indicate a perforation.

Related blog posts:

The Quality of Evidence for Dietary Treatments in Inflammatory Bowel Disease

Posted on by

BN Limketkai et al. Clin Gastroenterol Hepatol 2023; 21: 2508-2525. Open Access! Dietary Interventions for the Treatment of Inflammatory Bowel Diseases: An Updated Systematic Review and Meta-analysis

This was a systematic review of prospective controlled trials (n=27) of solid food diets for the induction or maintenance of remission in IBD.

Key findings:

  • For induction of remission in Crohn’s disease (CD), the Mediterranean diet was similar to the Specific Carbohydrate Diet (low certainty of evidence), and partial enteral nutrition (PEN) was similar to exclusive enteral nutrition (very low certainty of evidence).
  • PEN reduced risk of relapse (very low certainty of evidence), whereas reduction of red meat or refined carbohydrates did not (low certainty of evidence).
  • For ulcerative colitis, diets were similar to controls (very low and low certainty of evidence).

My take: Most of the dietary treatments for IBD have low to very low certainty of evidence regarding their effectiveness. Dietary changes are very likely to be helpful but more studies with rigorous endpoints are still needed.

Related blog posts:

Risk Factors for Inflammatory Bowel Disease: Ultra-Processed Food (Part 1)

Posted on by

N Narula et al. Clin Gastroenterol Hepatol 2023; 21: 2483-2495. Open Access! Food Processing and Risk of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

JA Fitzpatrick et al. Clin Gastroenterol Hepatol 2023; 21: 2478-2480 (editorial). Open Access! Ultra-processed Foods and Risk of Crohn’s Disease: How Much is Too Much?

Figure 1 from editorial: The NOVA classification of food

A total of 1,068,425 participants were included (13,594,422 person-years) among 5 cohort studies published between 2020 and 2022. The average age of participants ranged from 43 to 56 years. Key findings:

  • Crohn’s disease:  During follow-up, 916 participants developed CD, and 1934 developed UC. There was an increased risk for development of CD for participants with higher consumption of ultra-processed foods compared with those with lower consumption (HR, 1.71; 95% CI, 1.37–2.14; I2 = 0%) and a lower risk of CD for participants with higher consumption of unprocessed/minimally processed foods compared with those with lower consumption (HR, 0.71; 95% CI, 0.53–0.94; I2 = 11%). 
  • Ulcerative colitis: There was no significant association between risk of UC and ultra-processed foods (HR, 1.17; 95% CI, 0.86–1.61; I2 = 74%) or unprocessed/minimally processed foods (HR, 0.84; 95% CI, 0.68–1.02; I2 = 0%).

The associated editorial by Fitzpatrick et al, notes that “there are plausible mechanisms that explain the associations of higher UPFs and development of CD, such as: (1) displacing the intake of minimally processed foods and subsequently reducing exposure to beneficial micronutrients, antioxidants, and phytochemicals; (2) driving overconsumption of total calories7; and (3) increasing exposure to non-nutritive food substances that have been implicated in the development of CD in pre-clinical studies…The notion is that a lower UPF intake is better, but a cutoff value remains elusive.”8

My take (borrowed from editorial): “the population studies have indicated that the extremes of UPF intake are related to risk of CD and that such associations are underpinned by plausible biological mechanisms, suggesting causality.”

Related blog posts:

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

Posted on by

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 3

Posted on by

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

Posted on by

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

Posted on by

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.

Giving Tacrolimus Another Look for Severe Colitis

Posted on by

The retrospective study by Zimmerman et al involved 170 pediatric patients (IFX (n = 84) and TAC (n = 86)) with acute severe colitis (ASC) form 2005 to 2017; TAC was generally used prior to 2014 and patients were more likely to be receiving 6MP as a long-term maintenance agent; the mean TAC level was 10.7 ng/mL. The mean dose of infliximab (IFX) initially was 7 mg/kg. Key findings:

  • The rate of colectomy 6 months from rescue therapy was similar whether patients received IFX or TAC (22.6% vs 26.7%, respectively, P = 0.53).
  • The mean decline in Pediatric Ulcerative Colitis Activity Index scores from admission to discharge in those treated with IFX (31.9) or TAC (29.8) was similar (P = 0.63).
  • Similar rates of adverse effects were seen. 4 patients in the TAC group experienced neurologic symptoms.
  • About half of the steroid-refractory ASC patients failing either agent as initial rescue therapy required colectomy, even if they switched to the alternative agent.
  • 17.9% of patients receiving high-dose IFX required colectomy by 6 months compared to 25% in the “typical” IFX dosing group; this was not statistically significant, likely due to limitations of sample size.

In the systematic review/meta-analysis study by Bolia et al., the authors identified 7 studies with 166 children (111 steroid-refractory, 52 steroid-dependent, 3 no steroids). The majority of cases (150/166 [90%]) were naïve to biologics. None of the participants in these studies have been treated recently (only 10 patients since 2014 and none after 2016). The two most recently published studies in 2018 and 2019 had enrollment in 2014-2016 and 2000-2012, respectively. Key findings:

  • An initial response to tacrolimus therapy was seen in 84% 
  • No difference was observed between children with high (>10 ng/mL) or low tacrolimus levels (127/150 [85%] vs 12/16 [75%], P = 0.3).
  • The pooled frequency of 1-year colectomy-free survival in children treated with initial oral tacrolimus was 64% (95% CI: 53%–75%). Twelve (7.2%) patients required cessation of therapy because of side effects.

My take: Both of these studies indicate that tacrolimus could be a useful agent for ASC and may find a role as a bridge therapy for biologic agents with slower onset of action.

Related blog posts:

NRocks Climb in Circleville, WV