2021 AGA Guidelines For Crohn’s Disease

Posted on July 13, 2021 by gutsandgrowth

A series of articles details the 2021 AGA Guidelines for Crohn’s disease (CD) including a clinical practice guideline (pg 2496-2508), a clinical decision support tool (2509-2510), a spotlight summary (pg 2511), a technical review (2512-2557), and a review of the recommendations (pg 2557-2262). I will highlight the first article.

JD Feuerstein et al. Gastroenterol 2021; 160: 2496-2508. Full text: AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease

Full text: Spotlight

For me the most important of their recommendations was #7:

In adult outpatients with moderate to severe CD, the AGA suggests early introduction with a biologic with or without an immunomodulator rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids.

Other points:

For moderate to severe CD, the authors support the use of anti-TNF therapy in combination with immunomodulators, support the use of ustekinumab and vedolizumab, and support the use of SC/IM (but not oral) methotrexate.
The authors are AGAINST the use of mesalamine/sulfasalazine products as well as corticosteroids for maintenance of remission for CD
See full text link to Table 3 for summary of all of their recommendations: AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease

From Spotlight:

Combating Anti-Drug Antibodies with Immunomodulators in Pediatric IBD

Posted on May 7, 2021 by gutsandgrowth

RJ Colman et al. Inflamm Bowel Dis 2021; 27: 507-515. Favorable Outcomes and Anti-TNF Durability After Addition of an Immunomodulator for Anti-Drug Antibodies in Pediatric IBD Patients

In this retrospective review with 89 patients who developed antidrug antibodies (ADAs), the authors identified 30 who started an immunomodulator (IM) within 3 months of developing an ADA and compared with 59 who did not start an IM. The main IM used was methotrexate (n= 28, 93%)

Key findings:

61 of the 89 patients (69%) had quiescent disease based on physician global assessment at their previous clinic visit
The initial anti-TNF was stopped shortly after ADA detection in 36% of the No-IM patients vs none of the IM patients. Thus, anti-TNF agents durability was prolonged in the IM group.
Dose intensification was also undertaken at the time of ADA detection: 25 (83%) of IM group and 28 (48%) of non-IM group.
At 12 months, steroid-free clinical and biochemical remission on the same anti-TNF occurred in 53.9% of the IM group vs 26.8% in the No-IM group (P = 0.025).
Drug levels rose higher (P = 0.003) and ADA levels fell farther (P = 0.037) in the IM group than in the No-IM group
Lower ADAs often improved without IM: An ADA level <329 ng/mL had a 76.2% sensitivity and an 83.3% specificity for ADA reversal without IM.

My take: If a patient develops a significantly elevated anti-drug antibody, addition of methotrexate/immunomodulator along with dose intensification increases the likelihood that the anti-TNF agent will continue to be effective.

Related blog posts:

IBD Shorts February 2020

Posted on February 21, 2020 by gutsandgrowth

Cost of IBD Care is Increasing. From Healio Gastro: Chronic inflammatory disease expenditures nearly double over last 2 decades Reference: Click B, et al. Poster 22. Presented at: Crohn’s and Colitis Congress; Jan. 23-25, 2020; Austin, Texas

An excerpt from Healio Gastro summary: [Using] the Medical Expenditure Panel Survey (MEPS), a nationally representative database of health care use and expenditure data collected since 1998…The researchers assessed total annual, outpatient, inpatient, emergency and pharmacy expenditures in both patients with IBD (n = 641) and RA (n = 641). They used three separate time periods – 1998-2001, 2006-2009 and 2012-2015 –to compare expenditures over time…

Median per-patient annual health care expenditure in patients with IBD was $6,570 compared with $4,010 in patients with RA across all years of the study. Total annual spending increased approximately 2.2 times (95% CI, 1.6-3; P < .01) over the study period and was 36% higher in IBD than RA (P = 0.01).

Pharmaceutical spending increased more than fourfold (95% CI, 3.2-6.1; P < .01) and became the largest cost category (44% total). However, inpatient expenses in IBD decreased 40% over the study period.

My take: While the cost has increased, these new treatments are improving outcomes. With the emergence of biosimilars, there may be improvement in pharmaceutical spending.

More on Proactive Therapeutic Drug Monitoring (pTDM) Being Helpful: SR Fernandes et al. Inflamm Bowel Dis 2020; 26: 263-70, editorial 271-2. In this study, a prospective group of patients (n=56) undergoing pTDM were compared with a historical control group (n=149). pTDM had less frequent surgery (9% vs. 21%) and higher rates of mucosal healing (73% vs. 39%). Treatment escalation was 3 times more common with pTDM than in the control group.

Increased risk of VTE in IBD patients: JD McCurdy et al. Inflamm Bowel Dis 2020; https://doi.org/10.1093/ibd/izaa002

Abstract Link: Risk of Venous Thromboembolism After Hospital Discharge in Patients With Inflammatory Bowel Disease: A Population-based Study

In a population-based study from Ontario, the authors analyzed a total of 81,900 IBD discharges (62,848 nonsurgical and 19,052 surgical) which were matched to non-IBD controls… The cumulative incidence of VTE at 12 months after discharge was 2.3% for nonsurgical IBD patients and 1.6% for surgical IBD patients…Nonsurgical IBD patients and surgical patients with ulcerative colitis are 1.7-fold more likely to develop postdischarge VTE than non-IBD patients.

Video for Patients: Benefits and Risks of IBD Treatment & Risks of Untreated IBD

Posted on February 5, 2020 by gutsandgrowth

A recent study (NE Newman, KL Williams, BJ Zikmunde-Fisher, J Adler. JPGN 2020;70: e33-36) highlights work to communicate the benefits and risks of the treatment for inflammatory bowel disease (IBD) along with the risks of untreated IBD. “We developed a simple video aid to illustrate competing risks associated with medications and underling disease in context of inflammatory bowel disease…Those who viewed the video aid had more realistic perceptions than those who did not view it.”

Here is a link to the ~13 minute online video: IBD: Risk of Disease and Treatments

Overall, the presentation is very helpful and thoughtful. I think this would be an excellent overview for families. For practitioners, a few points that could benefit from some nuance are noted below some screenshots. It is worth stating that the authors had started this project a few years ago and some of the points below are related to more information that has emerged.

In the section of treatment benefits (above), the presentation suggests that thiopurines (azathioprine, 6-mercaptopurine) and methotrexate both are effective in about 50%; this is probably an overestimate; in addition, methotrexate as monotherapy is definitely less effective (if effective at all) for ulcerative colitis . Also, it would be worthwhile to indicate that anti-TNF monotherapy with therapeutic drug monitoring may help achieve similar benefits as dual therapy.

In the section of colon cancer, the authors provide useful data that current treatments lower this risk substantially. It is notable that more recent reports suggest that there have been improvements in the rates of colon cancer associated with IBD.

Overall, the section on lymphoma is very good.

In the section on other complications, the presentation suggests that there may be impaired wound-healing with anti-TNFs. I think this risk is overstated in this slide. Also, I think the risk of severe infection with thiopurines is a little bit higher than stated; though, this can be mitigated with careful monitoring.

I think this summary slide could be improved by noting that the overall risk of serious cancers is likely lowered by treating IBD. Since colon cancer is a fairly common cancer and IBD treatment reduces the risk, this likely outweighs the increased risk of other cancers (eg. lymphoma) which are much less common.

Another link to video: https://tinyurl.com/IBDTreatments

Related 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.

Toronto Consensus Guidelines for Luminal Crohn’s Disease

Posted on September 5, 2019 by gutsandgrowth

The recommendations from the Canadian Association of Gastroenterology for luminal Crohn’s Disease in adults were published in two journals. R Panaccione et al. Clin Gastroenterol Hepatol 2019; 17: 1680-1713 and R Panaccione et al J Can Assoc Gastroenterol. 2019 Aug; 2(3): e1–e34.

Full text link : Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Luminal Crohn’s Disease

A few of the 41 statement recommendations:

6. In patients with mild to moderate ileal and/or right colonic Crohn’s disease, we suggest oral budesonide beginning at 9 mg/day as first-line therapy to induce complete remission. GRADE: Conditional recommendation, low-quality evidence
20. In patients with moderate to severe luminal Crohn’s disease with risk factors of poor prognosis, we recommend anti-TNF therapy (infliximab, adalimumab) as first-line therapy to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
23. In patients with active Crohn’s disease, when starting anti-TNF therapy, we suggest it be combined with a thiopurine or methotrexate over monotherapy to improve pharmacokinetic parameters. GRADE: Conditional recommendation, very low-quality evidence for infliximab, very low-quality evidence for adalimumab
29. We suggest against switching between anti-TNF therapies in patients who are doing well on anti-TNF therapy. GRADE: Conditional recommendation, low-quality evidence
30. In patients with moderate to severe Crohn’s disease who fail to achieve complete remission with any of corticosteroids, thiopurines, methotrexate, or anti-TNF therapy, we recommend vedolizumab to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
34. In patients with moderate to severe Crohn’s disease who fail to achieve complete remission with any of corticosteroids, thiopurines, methotrexate, or anti-TNF therapy, we recommend ustekinumab to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
37-41: Authors against the use of probiotics, omega-3 fatty acids, marijuana, naltrexone and enteral nutrition/diet therapies.

Crater Lake and Wizard Island

Is Standard Infliximab Dose Too Low in Pediatrics?

Posted on November 17, 2018 by gutsandgrowth

Briefly noted from Twitter:

Close up of previous image

Also –with regard to Methotrexate:

Methotrexate -Not Effective as Monotherapy for Ulcerative Colitis

Posted on November 12, 2018 by gutsandgrowth

A recent study (H Hansfarth et al. Gastroenterol 2018; 155: 1098-1108) examined the use of methotrexate for ulcerative colitis (UC). The authors performed a 48-week trial (MERIT-UC trial) with 179 patients with a mean age of 42 years in the induction period. In those who improved during induction, methotrexate was continued in 44 patients and compared to 40 patients who received placebo; this was a double-blind, placebo-controlled trial.

Key findings:

During induction which included 16 weeks with methotrexate at 25 mg per week SC and a 12-week steroid taper, 51% had achieved a response.
During maintenance, 60% of patients receiving placebo and 66% of patients receiving methotrexate had a relapse of UC. At 48 weeks, 30% in the placebo group and 27% in the methotrexate group were in steroid-free clinical remission.
No new safety signals were evident with methotrexate.

The associated editorial by Dulai (pg 967-69) which reviewed this study and a prior study (METEOR) comes to the conclusion that: “there is likely no place for methotrexate monotherapy in UC.”

Related blog posts:

IBD Shorts October 2018

Posted on October 12, 2018 by gutsandgrowth

C Ma et al. Clin Gastroenterol Hepaatol 2018; 16: 1407-19. This study examined endpoints in randomized controlled trials (RCTs) of Crohn’s disease. Key finding: Among 116 included RCTs (n=27,263 patients), there were 38 unique definitions of clinical response or remission and 32 definitions of loss of response. The most common endpoint was CD activity index.

RP Hirten et al. Clin Gastroenterol Hepatol 2018; 16: 1374-84. This review examines the topic of combining biologics in inflammatory bowel disease. Currently, there is little data in IBD. From studies completed in rheumatology and dermatology, there are some safety concerns. One current study, the EXPLORER study, which is a phase 4 open label trial evaluating the use of vedolizumab in combination with adalimumab and methotrexate, will provide some useful information. With regard to safety, gut-specific anti-integrin therapies are likely to be safer in combination than other biologic therapies.

RJ Colman et al. Inflamm Bowel Dis 2018; 24: 2135-41. This systematic review and meta-analysis which included 14 eligible studies showed that the pooled clinical remission rate with methotrexate monotherapy for pediatric Crohn’s disease was 57.7% at 3-6 months and 37.1% at 1 year.

AA Wren et al. Inflamm Bowel Dis 2018; 24: 2093-2105. This study with 93,668 patients in a cohort from Truven MarketScan Database (2007-2015) identified a high rate of opioid therapy usage in U.S. adolescents and young adults (15-29 year olds). Annual prevalence of chronic opioid use was 9.3% in 2007 and peaked at 12.2% in 2011. In 2015, the prevalence dropped to 10.8%. Overall, 18.2% had received chronic opioid therapy. Among the 2503 with chronic opioid usage who were followed longitudinally, 30.5% received opioids for 2 years and 5.3% for 4 years. The associated editorial (ME Kuenzig, EI Benchimol, pg 2140-5) note that these prevalence data may underestimate the true rate of opioid use due to the case definition of IBD used when analyzing the administrative data.

Lake Moraine, Banff

CCFA Conference Notes 2016 (part 2) -Pediatric Lecture

Posted on April 27, 2016 by gutsandgrowth

This blog entry has abbreviated/summarized this terrific presentation; most of the material has been covered in this blog in prior entries but still this was a useful review. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

2^nd Lecture: What is Next in Treatments for Pediatric Patients? –Dr. Michael Rosen

I really enjoyed meeting Dr. Rosen. He is super-friendly and knowledgeable.

Combination therapy. Grossi V et al showed improvement in infliximab durability with concomitant therapy.

Now starting COMBINE trial (ImproveCareNow)–randomized to low dose MTX or placebo in combination with anti-TNF agent.

Therapeutic drug monitoring in pediatrics. Is this an alternative to combination therapy? Rationale (see slide): lower antibody formation if trough levels maintained. IFX level >5.5 associated with persistent remission (Singh et al 2014). Children are growing and they may need more adjustments. In Cincy, checking levels at week 14 after initiation and then every 6-12 months.

Acute Severe Ulcerative Colitis. High rates of dose escalation in this population. Some of this is due to more rapid clearance of anti-TNF –leaking in gut and other mechanisms as well. Week 8 level of 40 associated with clinical response. Thus, this population may benefit from 10 mg/kg at start (in those with albumin <3) and may need more frequent dosing, especially early into treatment (?0, 2, 6, 10). ARCH study to look into this further

Vedolizumab. Conrad MA 2015. About 1/3^rd of these refractory patients in this abstract responded.

Ustekinumab . IL-12 & IL-23 blockage. No studies in pediatrics. Case report reviewed of good response in a refractory case.

Enteral therapy. Specific carbohydrate diet experience. These diets have some published data, most retrospective studies. Our group (Cohen SA et al) did perform a small prospective study. Sigall-Boneh R et al showed improvement with partial enteral nutrition.

Very early-onset of IBD. IL-10 receptor deficiency was a key early discovery and can be treated with stem cell transplant. STAT3 mutation case reviewed which was managed with tocilizumab. More targeted therapy expected based on specific mutations.

Should Methotrexate Be Used For Ulcerative Colitis?

Posted on January 7, 2016 by gutsandgrowth

A recent study (F Carbonnel et al. Gastroenterol http://dx.doi.org/10.1053/j.gastro.2015.10.050, article in press; thanks to KT Park twitter feed for reference) with 111 patients provides more questions than answers. It appears that methotrexate improved clinical remission but the overall difference is fairly small; the abstract is below.

My initial impression: Immunomodulators (including methotrexate and thiopurines) have some efficacy as monotherapy agents in patients with inflammatory bowel disease. Their role as part of combination therapy (with anti-TNF agents) has been associated with improved outcomes but how long to use combination therapy and at what dosage is still being worked out.

Here’s the abstract and a link: Methotrexate is not Superior to Placebo in Inducing Steroid-free Remission, but Induces Steroid-free Clinical Remission in a Larger Proportion of Patients with Ulcerative Colitis

Background & Aims

Parenteral methotrexate is an effective treatment for patients with Crohn’s disease but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC.

Methods

We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/week) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe, from 2007 through 2013. Patients were given prednisone (10 to 40 mg/day) when the study began, and randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary endpoint was steroid-free remission (defined as a Mayo score ≤ 2 with no item > 1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤ 2 with no item > 1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24.

Results

Steroid-free remission at week 16 was achieved by 19/60 patients given methotrexate (31.7%) and 10/51 patients given placebo (19.6%)—a difference of 12.1% (95% confidence interval [CI], –4.0% to 28.1%; P=.15). The proportions of patients in steroid-free clinical remission at week 16 were 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI, 1.1%–35.2%; P=.04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group—a difference of 9.5% (95% CI, –7.5% to 26.5%; P=.28). No differences were observed in other secondary endpoints. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P=.03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P=.006).

Conclusions

In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC.