Category Archives: inflammatory bowel disease

Expert Guidance on Current Management of IBD (Part 1)

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A recent issue of Clinical Gastroenterology and Hepatology focused solely on the clinical features and management of inflammatory bowel disease. Even for those with expertise in IBD, there is a lot of useful information and concise reviews of what is known.

Here are some of my notes from this issue:

AN Ananthakrishnan et al. Clin Gastroenterol Hepatol 2020; 18: 1252-60. Changing Global Epidemiology of Inflammatory Bowel Diseases: Sustaining Health Care Delivery Into the 21st Century

Reviews risk factors and recommends the following as ways to lower risk of developing IBD for at-risk individuals:

  • Breastfeeding in infancy
  • Do not start smoking
  • Avoid vitamin D deficiency
  • Minimize non-steroidal anti-inflammatory drug use
  • Minimize antibiotic use especially for young children and during pregnancy
  • Encourage moderate physical activity, healthy weight, low stress and regular sleep
  • Diet high in fruit, vegetables, fiber, and fish

Reviews the epidemiology and notes that there has been a evidence of a decline in incidence in IBD in (at least) the Western world; however, because of compounding prevalence, it is expected that the number of individuals with IBD will continue to rise.  In Canada, for example, it is expected that the prevalence will rise from 0.7% in 2018 to 1% by 2030.

In newly industrialized countries, it is expected that rising incidence is going to substantially increase the global disease burden. The authors note the following as areas needed in research and clinical care to meet global IBD care burden:

  • tools for early diagnosis
  • early effective intervention to prevent irreversible bowel damage
  • precision medicine to select the right treatment for the right patient
  • need for less costly and more safe therapies
  • simple tools to monitor disease activity
  • primary disease prevention strategies, especially for those at high risk

CA Siegel, CN Bernstein. Clin Gastroenterol Hepatol 2020; 18: 1261-7. Identifying Patients With Inflammatory Bowel Diseases at High vs Low Risk of Complications

This article’s disease-stratification information overlaps with subsequent articles which detail the positioning of therapies for Crohn’s disease (CD) and ulcerative colitis (UC) respectively.

NH Nguyen, S Singh, WJ Sandborn. Clin Gastroenterol Hepatol 2020; 18: 1267-79. Positioning Therapies in the Management of Crohn’s Disease.

Some of the information summarized in this article:

Table 2 -Comparative Efficacy of Biologics for Moderate to Severe Active Crohn’s Disease (CD):

  • Infliximab: For induction: OR compared to placebo for remission: 5.90 (2.78-12.51); probability of remission 60%. For maintenance in those with clinical response: probability of remission SUCRA ranking: 48%; 0.68
  • Adalimumab: For induction: OR compared to placebo for remission: 3.80 (1.76-8.18); probability of remission 49%. For maintenance in those with clinical response: probability of remission SUCRA ranking: 58%; 0.97
  • Ustekinumab: For induction: OR compared to placebo for remission: 2.75 (1.76-4.32); probability of remission 41%.  For maintenance in those with clinical response: probability of remission SUCRA ranking: 39%; 0.36
  • Vedolizumab: For induction: OR compared to placebo for remission: 2.69 (1.36-5.32); probability of remission 40%.  For maintenance in those with clinical response: probability of remission SUCRA ranking: 42%; 0.52
  • Certolizumab pegol: For induction:  OR compared to placebo for remission: 1.36 (0.89-2.08); probability of remission 25%.  For maintenance in those with clinical response: probability of remission SUCRA ranking: 42%; 0.48

In deciding therapy, the authors specify factors that help classify as high-risk CD Table1):

  • Structural damage: large or deep mucosal lesions, fistula or perianal abscess, prior resections (especially if >40 cm)
  • Inflammatory burden: extensive disease involvement (ileal disease >40 cm or pancolitis), increased C-reactive protein, low albumin
  • Impact on quality of life: presence of stoma, >10 loose stools/week, lack of symptomatic improvement with prior biologics and/or immunomodulators, presence of anorectal symptoms, anemia, daily abdominal pain
  • Emerging predictors: antimicrobial antibody pattern, antimicrobial genetic peptide signature

Though the authors note a lack of adequate head-to-head comparative studies, they make some recommendations for treatment:

  • For severe disease, they suggest first-line therapy for CD would be infliximab or adalimumab in combination therapy regimen (with infliximab favored for higher disease severity)
  • For second-line therapy, they suggest ustekinumab for most patients in combination therapy or 2nd anti-TNF in those with loss or response due to immunogenicity or intolerance
  • For those with higher risk factors for adverse events (or preference) and moderate disease severity, the authors recommend vedolizumab as 1st line and ustekinumab as 2nd line.  For this same group with higher disease severity, they suggest ustekinumab as 1st line treatment.

Other key points:

  • In terms of risk of malignancy, the authors note that in a comprehensive systematic review of 23 RCTs of TNF-alpha antagonists in IBD, there was NO significant increase in the risk of malignancy with TNF-alpha antagonists.
  • In terms of combination therapy, the authors note that their has been an observed benefit which is “at least partly attributed to achieving a higher biologic trough concentration….no differences in efficacy of combination therapy vs infliximab were observed when evaluating patients by quartiles of infliximab trough concentration; however, currently this represents association rather than causation, and it is possible that superior remission rates drove higher trough concentrations, rather than vice versa.”

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 to Get Rid of the Placebo Effect in Inflammatory Bowel Disease Trials

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A recent study (M Duijvestein et al. Clin Gastroenterol Hepatol 2020; 18: 1121-32, editorial 1030-32) analyzed data from recent randomized, double-blind, placebo-controlled trials for Crohn’s disease (CD).  In these induction trials fro eldelumab, filgotinib, risankizumab, and ustekinumab, the authors found very low rates of placebo response (n=188 in placebo arms).

Key findings:

  • Based on endoscopic assessment of CD activity, response rate to placebo was 16.2%; response indicated >50% reduction in the simple endoscopic score for CD.
  • The rate of remission was 5.2%
  • Even lower rates of response were noted in those with elevated CRP at baseline (OR 0.93) and those with history of anti-TNF therapy (OR 0.31)

Commentary:

  • The key to lowering the placebo response are to use objective biologic markers rather than relying exclusively on clinical symptoms.
  • Central reading of endoscopic endpoints also is thought to minimize placebo effect
  • The editorial notes that the use of placebo in clinical trials “must be justified by the importance of the additional scientific value gained, and placebo should be used in trials only if there is genuine equipoise between the active treatment and placebo.”
  • “Because of ethical questions concerning placebo and the emergence of head-to-head trials, placebo arms may disappear from future IBD trials.”

My take: In reality, very few individuals with CD improve without adequate treatment.  Use of objective criteria is crucial to finding out what really works, both in clinical trials and in clinical practice.

Related blog posts:

Early Treatment with Anti-TNF Agents and Development of Perianal Fistulas

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AAM Singer, DA Bloom, J Adler. Clin Gastroenterol Hepatol 2020; In Press: Factors Associated With Development of Perianal Fistulas in Pediatric Patients With Crohn’s Disease

Also, related article:

Full Text: 2019 Jan 1;25(1):1-13. doi: 10.1093/ibd/izy247. Clinical Practice Guideline for the Medical Management of Perianal Fistulizing Crohn’s Disease: The Toronto Consensus.

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.

Economic Burden of Inflammatory Bowel Disease, Fewer Operations and Emerging Treatments

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Pouillon, L., Travis, S., Bossuyt, P. et al. Head-to-head trials in inflammatory bowel disease: past, present and future. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-0293-9 (Thanks to KT Park for this reference)

An excerpt:

This Perspective provides an overview of the past, current and future concepts in IBD trial design, with a detailed focus on the role of comparative research and the challenges and pitfalls in undertaking and interpreting the results from such studies.

Related blog posts:

GR Lichenstein et al. Clin Gastroenterol Hepatol 2020; 18: 889-97.  Using Truven MarketScan Insurance Claims data (2008-2015) from more than 160,000 patients with inflammatory bowel disease (IBD), the authors estimated economic burdens from Crohn’s disease (CD) and ulcerative colitis (UC).

  • For CD, lifetime incremental cost was $416,352 on average, but was $707,711 if diagnosis was established between 0-11 years of age. The lifetime costs, $622,056, consisted of $273,056 for outpatient care, $164,298 for inpatient care, $163,722 for pharmacy costs, and $20,979 for emergency room care.
  • For UC, lifetime incremental cost averaged $230,102, but was $369,955 if diagnosis was established between 0-11 years of age. The lifetime costs, $405,496, consisted of $153,670 for outpatient care, $123,190 for inpatient care, $105,142 for pharmacy costs, and $13,493 for emergency room care.
  • The lifetime costs for UC and CD were both greater than that for rheumatoid arthritis ($100,273) and for type 2 diabetes ($89,064).
  • Related blog post: IBD Shorts 2020  Cost of IBD Care is Increasing. From Healio Gastro: Chronic inflammatory disease expenditures nearly double over last 2 decades

T Shinagawa et al. Clin Gastroenterol Hepatol 2020; 18: 898-907.  In this study from Japan with 1871 patients with CD, the 5- and 10-year reoperation rates were 23.4% and 48.0% respectively.  However, reoperation rates were significantly lower after 2002 than prior with HR 0.72.  Postoperative use of immunomodulators (OR 0.60) and anti-TNF therapy (HR 0.71) were associated with a reduced the risk of reoperation.

AGA Guidelines: Moderate to Severe Ulcerative Colitis

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Full Text: JD Feuerstein et al. Gastroenterol 2020; 158: 1450-61. AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis

Full Tex PDF: AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis

 

Associated articles included the following:

  • Clinical decision support tool (1462-63)
  • PDF: Spotlight (summary -images above) (1464)
  • Technical Review (1465-96)

Key recommendations:

  • 2a. In adult outpatients with moderate to severe UC who are naïve to biologic agents, the AGA suggests using infliximab or vedolizumab rather than adalimumab, for induction of remission. Comment: Patients, particularly those with less severe disease, who place higher value on the convenience of self-administered subcutaneous injection, and a lower value on the relative efficacy of medications, may reasonably chose adalimumab as an alternative
  • 2c. In adult outpatients with moderate to severe UC who have previously been exposed to infliximab, particularly those with primary nonresponse, the AGA suggests using ustekinumab or tofacitinib rather than vedolizumab or adalimumab for induction of remission.
  • 6. In adult outpatients with moderate to severe UC, the AGA suggests early use of biologic agents with or without immunomodulator therapy rather than gradual step up after failure of 5-ASA. Comment: Patients, particularly those with less severe disease, who place higher value on the safety of 5-ASA therapy and lower value on the efficacy of biologic agents or tofacitinib may reasonably chose gradual step therapy with 5-ASA therapy.
  • 10. In hospitalized adult patients with ASUC refractory to intravenous corticosteroids, the AGA suggests using infliximab or cyclosporine

Summary of recommendations:

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

IBD Pediatric Costs & Cannabis Still No Data for IBD

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Happy birthday to my favorite follower!!!

A recent single-center study (AW Fondell et al. Inflamm Bowel Dis 2020; 26: 635-40, editorial by Joel Rosh, 641-2) examined the first-year costs of children with inflammatory bowel disease (IBD) in 2016.  There were 67 patients (43 with Crohn’s disease (CD), and 24 with ulcerative colitis (UC)).

Key findings:

  • Mean cost was $45,753; $43,095 for CD, $50,516 for UC
  • Severe CD (n=11) was $71,176 and severe UC (n=5) was $134,178; it is notable that only one patient with CD had surgery and only one patient with UC had surgery.
  • Overall cost distribution: 37% from infusion costs, 25% hospital costs, 18% outpatient procedures, 10% outpatient oral medications, 7% outpatient imaging and 3% outpatient visits.
  • 69% of CD patients and 33% of UC patients received biologics
  • 21% (n=9) of CD patients and 45% (n=11) of UC patients were hospitalized
  • Private payer reimbursement was a mean of $51,269 compared to $24,610 mean for Medicaid.

Limitations: 

  • In any cost analysis, many assumptions are needed.  For medications, for example, the author used pharmaceutical retail prices.  The actual costs are near-impossible to calculate as every insurance policy and every hospital system has a multitude of charges based on proprietary negotiations.
  • While this data comes from a referral center, all of the patients in the study were from Connecticut.

Due to the expense of care, Dr. Rosh points out that many insurers have often mandated the use of “standard dosing” of biologic therapy, “ignoring that robust data” indicate that this dosing is “the exception rather than the rule in pediatric IBD patients.”  These type of short-sighted interventions could affect long-term medical outcomes.

My take: There clearly are areas where costs can be reduced (eg. lower infusion costs, lower endoscopy costs, biosimilars).  However, no amount of cost cutting will change the conclusion that good care for IBD is expensive.

Briefly noted: TS Kafil et al. Inflamm Bowel Dis 2020; 26: 502-9.   This study examined evidence for cannabis effectiveness in IBD.  After performing a literature search, the authors could only identify five randomized controlled trials (n=185).  Each study used different doses, formulations and routes of administration.  No studies evaluated maintenance treatment and relapse in CD or UC.  Findings: “no firm conclusions can be made regarding the safety and effectiveness of cannabis and cannabionoids in adults with CD and UC.”

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Cobb County -Concord Covered Bridge Historic District

 

Bigger Data Needed and Other IBD Updates April 2020

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R Pittayanon et al. Gastroenterol 2020; 158: 930-46.  In this systematic review of the relationship between gut microbiota and inflammatory bowel disease, 48 studies and 45 articles were included from a total of 2631 citations.  Overall, the authors found inconsistent results with differences in the abundances of some bacteria in IBD. My take: These microbiota studies use ‘big data’ to look for abnormal patterns in patients with IBD.  Overall, most of these studies support a reduced diversity among patients with IBD.  Specific variation in microbes varies widely and remains unclear if they are a cause or a consequence of IBD.

J Piercy et al. JPGN 2020; 70: 318-23. Among 90 adolescents with IBD, “perfectionistic concerns (self-critical and socially prescribed perfectionism) were associated with higher rates of adolescent-reported externalizing symptoms” Thus, perfectionism may help with self-management but lead to more stress and psychosocial symptoms.

S Jardine et al. Gastroenterol 2020; 158: 1000-15. This study used both TTC7A-knockout cells and a zebrafish model to screen compounds that have been FDA approved for treatment of inflammatory bowel disease caused by TTC7A deficiency.  The authors identified leflunomide that reduces apotosis and levels of active caspase 3 in TTC-7A-knockout cells and restored gut motility along with improvement of intestinal cell survival in zebrafish. This study has some amazing figures detailing the changes induced by leflunomide. My take: Although some centers have offered hematopoetic stem cell transplant (with dismal results), there is NOT a currently accepted treatment for TTC7A deficiency-induced IBD.  This study suggests an agent which may help.

CLD Prevost et al. AP&T 2020. https://doi.org/10.1111/apt.15681 Key finding:  Among patients exposed to anti‐TNF, the Lémann Index was lower in those who were exposed in the first 2 years of their disease (P = 0.015).  My take: Early treatment with anti-TNF agents can reduce risk of permanent bowel damage. This was seen as well in the RISK study which showed that anti-TNF therapy reduced the development of penetrating disease. (Related post: CCFA Update 2017, Part 3)

Full link: Bowel damage and disability in Crohn’s disease: a prospective study in a tertiary referral centre of the Lémann Index and Inflammatory Bowel Disease Disability Index

What Happens After The First Anti-TNF Agent Doesn’t Work?

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A recent intriguing retrospective study (MJ Casanova et al. Inflamm Bowel Dis 2020; 26: 606-16, editorial 617-18) examines a large cohort (n=1122) who received either a 2nd or 3rd anti-TNF agent.  This relied on the ENEIDA registry which is a prospectively maintained registry from Spain with 11,866 patients. In this study, clinical remission was gauged with a Harvey Bradshaw Index score of ≤4 in Crohn’s disease (CD) or a partial Mayo score of ≤2 in ulcerative colitis (UC).

Key findings:

  • 45% of patients achieved remission with the second anti-TNF at 12 weeks (short-term); loss of response was 19% per patient-year subsequently. Patients with intolerance to the first drug had higher remission rates compared to those who switched due to secondary failure (52% vs 42%) or primary failure (52% vs 39%).
  • Among the 45% who responded to a second anti-TNF agent, 77% maintained remission at 1 year following switch.
  • There was similar initial response to a second anti-TNF among patients with CD and UC: 46% vs 41%, though patients with UC were more likely to lose efficacy.
  • Combination therapy was associated with a higher likelihood of failure, HR 2.4 (possibly as an indicator of more aggressive disease)
  • Among the 71 patients who progressed to a 3rd anti-TNF agent, 55% achieved remission at 12 weeks. 

Discussion:

  • The authors in their discussion not that “primary failure is considered a class effect phenomenon…However, our results indicate that remission may still be achieved with a second anti-TNF in approximately 50% of patients.”
  • The editorial notes that the results need to be interpreted with caution.  Therapeutic drug monitoring (TDM) which is not incorporated in this study is crucial in optimizing response and switching.  “Importantly, nearly two-thirds of patients with therapeutic drug levels in the study form the Mayo Clinic had no active inflammation.  Thus, a change in therapy would be inappropriate in this population.”

My take: This study indicates that a 2nd anti-TNF agent can be effective in those who do not respond to a 1st.  At the same time, careful assessment including TDM is needed when changing agents, especially in view of the limited number of effective therapies.

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From Atlanta Botanical Garden

Ups (mostly) and Downs with IBD Epidemiology

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Two articles describe both increasing and decreasing trends in the prevalence of inflammatory bowel disease (IBD).

  • Y Ye et al. Inflamm Bowel Dis 2020; 26: 619-25, editorial 626-27
  • M Torabi et al. Inflamm Bowel Dis 2020; 26: 581-90, editorial 591-92 

The first study by Ye et al provides the familiar message that IBD prevalence has been increasing in pediatrics and adults.  This study examined 2 large claims databases.  The Optum database covered ~18 million annually during the study period (total ~57 million from 2007-2017) and Truven covered ~44 million annually (total ~240 million since 1995)

Key findings:

  • Pediatric IBD prevalence increased by 133% from 2007 to 2016: from 33 per 100,000 to 77 per 100,000. Crohn’s disease (CD) was twice as prevalent as ulcerative colitis (UC) in the pediatric population (46 vs 22)
  • Adult IBD prevalence increased by 123% from 2007 to 2016: from 215 per 100,000 to 478 per 100,000. The prevalence rates of CD and UC were similar in adults: 198 vs 181)
  • The Northeast region had the highest prevalence of IBD, followed by Midwest, South and then West.
  • Based on these prevalence data, there are an estimated 58,000 children (2-17) and 1.2 million adults with IBD in U.S.   Or, 1 in 1299 children and 1 in 209 adults.

Limitations:

  • Diagnosis and data derived from claims database
  • Cases can vary significantly based on how sensitive the definition for IBD is in a given study.  In this study, the authors indicate in supplementary material, that the prevalence rates could be doubled in adults if they chose a more sensitive/less specific case definitions.

The second study by Torabi et al, which utilized the Manitoba Epidemiology Database (n=1.2 million) showed a decrease in IBD incidence.  The authors examined 296 small geographic areas (SGAs) and found that many had persistently high IBD incidence rates.

Key findings:

  • The incidence of IBD decreased from 1990 when it was 23.6 per 100,000 to 16.2 per 100,000 in 2012.
  • In the study period (1990-2012), there were 3114 cases of CD and 3499 cases of UC diagnosed in Manitoba

In the discussion, the authors speculate on the reasons for the decline in IBD incidence in an area with high rates of IBD.  Some of the change may be related to changes in the population mix –more immigrants from areas with lower rates of IBD.  In the editorial, it is noted that a recent systematic review (Lancet 2018; 390: 2769-78) indicated that the “incidence of IBD is stabilizing in Western countries.”

My take: There are a lot kids and adults with IBD.  The preponderance of epidemiology studies point to increasing incidence and prevalence.

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Dose Escalation of Ustekinumab & Support Tool “Should I Have IBD Surgery?”

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A recent large retrospective study (Effectiveness of Ustekinumab Dose Escalation in Patients with Crohn’s Disease. JE Ollech, et al. Clinical Gastroenterology and Hepatology, EPUB) shows that increasing the frequency of ustekinumab from every 8 weeks to every 4 weeks improves outcomes in those who are not responding optimally. Among 506 patients receiving ustekinumab, 110 had dose escalation.

From abstract:

Results

Following dose interval shortening, the patients’ median HBI [Harvey Bradshaw index] decreased from 4.5 to 3 (P=.002), the median level of CRP decreased from 8 mg/l to 3 mg/l (P=.031), and median level of fecal calprotectin decreased from 378 μg/g to 157 μg/g (P=.57). Among patients who had an HBI >4, a level of CRP ≥5mg/dl, a level of fecal calprotectin >250ug/g, or endoscopic evidence for disease activity before dose interval shortening, after the dose interval was shortened, 28% achieved clinical remission (an HBI score ≤4), 22% had a normal level of CRP (<5 mg/dl), 50% had reduced levels of fecal calprotectin, and 36% achieved endoscopic remission.

My take (borrowed from authors): “Shortening the ustekinumab 90 mg dose interval to 4 weeks for patients with CD who did not respond to doses every 8 weeks improved clinical and biological indices of disease activity. Patients who lose response to the standard dose of ustekinumab might benefit from dose interval shortening, which was effective and safe.”

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From ImproveCareNow: Should I Have Surgery? A Shared Decision Making Tool  –Recommended for families in working through this difficult treatment decision.

Tiny door on the Atlanta Beltline