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

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

Pouillon, L., Travis, S., Bossuyt, P. et al. Head-to-head trials in inflammatory bowel disease: past, present and futureNat 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 postIBD 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

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

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

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?

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

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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