Tag Archives: Ulcerative colitis

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.

Giving Tacrolimus Another Look for Severe Colitis

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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.

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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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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.

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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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More Data: Upadacitinib “is Effective and Safe” Plus 2 in Kids

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S Friedberg et al. Clin Gastroenterol Hepatol 2023; 21: 1913-1923. Open Access! Upadacitinib Is Effective and Safe in Both Ulcerative Colitis and Crohn’s Disease: Prospective Real-World Experience

Methods: “We performed a prospective analysis of clinical outcomes on upadacitinib in patients with UC and CD using predetermined intervals at weeks 0, 2, 4, and 8 as part of a formalized treatment protocol.” 84 met inclusion criteria  (44 UC patients, 40 CD patients) -though complete data was available for only a fraction of these. All of the patients had received prior anti-TNF therapy and 89% had received 2 or more advanced therapies. 

Key findings:

  • Ulcerative colitis: At 4 and 8 weeks of treatment, 19 of 25 (76.0%) and 23 of 27 (85.2%) achieved clinical response and 18 of 26 (69.2%) and 22 of 27 (81.5%) achieved clinical remission, respectively. Of those who previously were tofacitinib-exposed, 7 of 9 (77.8%) achieved clinical remission by 8 weeks.
  • Crohn’s disease: In CD, 13 of 17 (76.5.%) achieved clinical response and 12 of 17 (70.6%) achieved clinical remission by 8 weeks. Of those with increased fecal calprotectin and C-reactive protein levels, 62% and 64% normalized by week 8, respectively. 
  • Results were seen as early as week 2 in both UC and CD, with clinical remission rates of 36% and 56.3.%,
  • Acne was the most commonly reported adverse event, occurring in 24 of 105 patients (22.9%) (Table 4). Six patients stopped upadacitinib due to adverse effects.

My take: “In this large real-world experience in medically resistant patients with UC or CD, we report that upadacitinib is rapidly effective and safe, including in those who had prior tofacitinib exposure.” In pediatrics, the effectiveness of this upadacitinib is a logical target for ImproveCareNow. More pediatric data will be needed to garner FDA approval.

Related articles:

LV Collen. Inflamm Bowel Dis 2023; 29: 1175-1176. Rapid Clinical Remission With Upadacitinib in a Pediatric Patient With Refractory Crohn’s Disease A pediatric patient with Crohn’s disease refractory to anti-tumor necrosis factor therapy, vedolizumab, ustekinumab, and 6-mercaptopurine achieved rapid clinical remission with upadacitinib.

A Bousvaros, BAR Schmidt, M Kurtz. Gastroenterology & Hepatology 2023; 19: 401-403. Open Access! “Treatment of Genital Crohn’s Disease with Upadacitinib in a Male Child: A Case Report”. This report describes the rapid response to upadacitinib in a 12 yo with refractory Crohn’s ileocolitis (x 5 yrs) with associated “granulomatous lymphangitis” affecting the penis and scrotum. It notes that “anti-TNF therapy was described as the most effective treatment, with either improvement or resolution of scrotal swelling in most patients. However, intermittent penile swelling persisted in a subset of the patients.18“…”Although data on the use of JAK inhibitors to treat pediatric IBD are limited, the fact that these are small molecules with wide systemic effects suggests that JAK inhibitors may be useful in the treatment of extraintestinal manifestations of IBD….[and]  that JAK inhibitors such as upadacitinib may play an important role in the treatment of such refractory patients.”

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The Expanding Adalimumab Options

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S White, R Morrow, I Pan, EF de Zoeten. JPGN 2023; 76: 701-703.
Riding the Wave of Adalimumab Biosimilars: Considerations for Pediatric Gastroenterologists

This article is a very handy update on approved adalimumab biosimilars, though even more biosimilars are expected to become available soon. The table below which is similar to a table in the article outlines the similarities and differences in these products compared to the reference product.

These biosimilars are FDA-approved for the treatment of adult and pediatric patients aged 6 and older with Crohn disease. “However, the biosimilar products are only approved for treatment of adult patients” (18 and older) with ulcerative colitis. “This may be due to the recent change in pediatric ulcerative colitis Humira FDA-approved dosing.”

My take (borrowed in part from authors): Insurance coverage decisions are likely to overlook some of these factors which are very important for pediatric patients. “The adalimumab biosimilars will likely provide a clinically effective, cost saving option for our patients, but consideration of a number of factors will be key when selecting between” them.

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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.

Infliximab Home Infusions

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SR Gupta et al. JPGN 2023; 76: 776-781. Outcomes for Standardized Home and Hospital-Based Infusions of Infliximab for Children With Inflammatory Bowel Disease

In this retrospective study with 102 children, key findings:

  • There were similar outcomes among carefully-selected children receiving home infusions (HI), “drug durability, AOs [adverse outcomes], and laboratory values were similar between HI and hospital-based infusions.” 30% of eligible patients received HI.
  • Within 2 years, only 19% remained on 5 mg/kg every 8 week dosing and the remainder required increased dosing or decreased interval.  (Further supporting data showing that 5 mg/kg every 8 week dosing is inadequate in ~80%)

The authors note that HI were arranged with a single home health company with pediatric PALS-trained nurses. In addition, there was “direct communication between the home health nurse and IBD nurse after each infusion.”

Prior studies of HI have shown increased AOs in patients receiving HI including stopping therapy, ER visits, and hospitalizations (Clin Gastroenterol Hepatol 2020; 18: 257-258, Am J Gastroenterol 2020; 115: 1698-1706, JAMA New Open 2021; 4: e2110268).

My take: If set up properly, home infusions could be a reasonable alternative to hospital-based or office-based infusions.

In this article, from May 31, 2023: Sick Workers Tied to 40% of Food Poisoning Outbreaks, C.D.C. Says

“Each year, 48 million people become sick from a food-borne illness, according to C.D.C. estimates. Of those, 128,000 are hospitalized and 3,000 die.”

Data on Fecal Microbiota Transplantation for Ulcerative Colitis and Case Report of Vancomycin for Refractory Ulcerative Colitis

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NEH Chehade et al. Inflamm Bowel Dis 2023; 29: 808-817. Efficacy of Fecal Microbiota Transplantation in the Treatment of Active Ulcerative Colitis: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials

HS Almomen, B Al-Bawardy. Inflamm Bowel Dis 2023; 29: 837-838. Oral Vancomycin Induced and Maintained Clinical and Endoscopic Remission in Ulcerative Colitis and Primary Sclerosing Cholangitis Post-liver Transplantation

In the first study by Chehade et al, the authors analyzed six RCTs involving 324 patients. Key findings:

  • Compared with placebo, FMT has significant benefit in inducing combined clinical and endoscopic remission (odds ratio, 4.11; 95% confidence interval, 2.19-7.72; P < .0001)
  • clinical remission with FMT was 46.2% compared 22.5% for placebo
  • clinical response with FMT was 51.6% compared to 30.1% for placebo
  • endoscopic remission with FMT was 18.9% compared to 6.1% for placebo
  • endoscopic response with FMT was 36.7% compared to 22.4% for placebo

Discussion Points:

  • “The studies included in our article indicate that there is a shift in the microbiota composition of responders in the FMT group to resemble the profile of healthy donors”
  • FMT delivery via upper GI tract was equally effective as delivery via lower GI tract in these studies in inducing combined remission
  • “The understanding of FMT effectiveness for IBD is in its infancy.”

In the case report by Alomomen et al, a 34 year old with refractory ulcerative colitis and PSC (post-transplant) had not responded to infliximab, vedolizumab, adalimumab, tofacitinib or 10 months of ustekinumab (every 4 weeks). In addition, he was receiving tacrolimus therapy due to his liver transplant. His colonoscopy demonstrated a continuous Mayo 3 colitis. Subsequently, vancomycin therapy was added to his treatment (500 mg BID); he continued ustekimumab. Six months afterwards, his fecal calprotectin had dropped to 277 from 1600 and his CRP and hemoglobin had normalized. Repeat colonoscopy demonstrated complete endoscopic healing.

My take: There are many patients who do not respond to current IBD therapies. These two studies show that both FMT and vancomycin could be useful in selected patients.

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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.

How Long to Hold Biologics and Small Molecule Drugs Perioperatively

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BL Cohen et al. Clin Gastroenterol Hepatol l2023; 21: 1148-1151. How to Manage Targeted Immune Suppressants (Biologics and Oral Small-molecule Drugs) Perioperatively for Inflammatory Bowel Disease and non-Inflammatory Bowel Disease surgery

This article makes pragmatic recommendations with regard to surgery timing in individuals taking medications that target the immune system.

Key points:

  • Several recent large studies have “observed no association between biologic exposure and postoperative infectious outcomes.”
  • The primary risk factor for infectious complications has been corticosteroid/glucocorticoid use.
  • For IBD Surgery: “If patients are deriving therapeutic benefit, including reducing the need for steroids, we propose continuing treatment until surgery…It may be practical to perform the surgery mid to late dosing interaval in the case of biologics with longer half-lives…Our expert opinion is that therapy may be resumed 14 days postoperatively or when recovered from infectious complications.”
  • For Non-IBD surgery: “Expert opinion suggests medications may be re-dosed by 14 days postoperatively if there have been no complications. Consideration should be given to resuming oral small molecules earlier given their short half-lives.”
  • Emergency or urgent surgeries “should be performed promptly regardless of targeted immune suppressant use.”
David Yetman Trail (Tucson)

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.