Biologic Treatment Effectiveness for Esophageal Crohn’s Disease

J Lui et al. Inflamm Bowel Dis 2021; 27: 1544-1547. The Use of Biologics for the Treatment of Esophageal Crohn Disease

In this retrospective review (1998-2018), the authors identified 39 patients with esophageal Crohn disease (ECD) who met inclusion criteria.

Key findings:

  • 35 (92%) had a clinical response to treatment and 21 (55%) went into clinical remission
  • ECD seems to be associated with more disabling intestinal CD phenotypes. Of the 39 patients, 10 (26%) had stricturing phenotype and 21 (54%) had penetrating phenotype; 19 (49%) had perianal disease
  • “Initial treatment after diagnosis with anti-TNFalpha agents compared to other biologics was associated with greater improvement in clinical (97% vs 71%; P=0.02) and endoscopic response (95% vs. 40%; P<0.01) and in clinical remission (64.5% vs. 14.2%; P=0.01).”
  • Initial treatment with an anti-TNFalpha agent was initial treatment in 18 patients with ECD; 14 had an inflammatory, 3 had a stricturing, and 1 had a fistulizing phenotype.

While this study showed better response to anti-TNFalpha agents compared to other biologics (eg. anti-IL-12/IL-23 agents), this may be due to a selection bias as other biologics are often used as a second-line treatment and are selected more often in refractory disease.

My take: Esophageal Crohn’s disease is a rare diagnosis and appears associated with more severe disease.

Chesapeake and Ohio Canal National Historic Park (near Washington D.C.)

Vedolizumab vs Adalimumab: Histology Outcomes from Varsity Trial

L Peyrin-Biroulet et al. Gastroenterol 2021; Open Access DOI:https://doi.org/10.1053/j.gastro.2021.06.015. Histologic Outcomes With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With Ulcerative Colitis (VARSITY)

In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52.

Key findings:

Vedolizumab induced greater histologic remission than adalimumab:

  • week 14: Geboes: 16.7% vs 7.3%, RHI: 25.6% vs 16.1%
  • week 52: Geboes: 29.2% vs 8.3%, RHI: 37.6% vs 19.9%
  • Histologic outcomes were generally better in anti–TNF-naïve vs -failure patients

My take: This study shows that histologic outcomes with vedolizumab, similar to clinical outcomes, were better than with adalimumab. Some of this difference could be due to the trail design which did not allow optimization of adalimumab dosing.

Related posts:

ImproveCareNow Work in Progress

P Kandavel et al. JPGN 2021; 73: 345-351. Reduced Systemic Corticosteroid Use among Pediatric Patients With Inflammatory Bowel Disease in a Large Learning Health System

In this study of 27,321 patients enrolled in the ImproveCareNow (ICN) learning health system, key findings:

  • Corticosteroid use decreased from 28% (2007) to 12% (2018)
  • Black patients received corticosteroids more commonly than white patients. This disparity improved as corticosteroid use decreased in both groups
  • Anti-tumor necrosis factor-alpha medication use <120 days after diagnosis was associated with a reduction in corticosteroid use
  • As corticosteroid use decreased, steroid-sparing therapy use increased and height and weight z scores improved, particularly among children with Crohn disease
  • 27 centers (31%) had a significant reduction in steroid use, 5 (6%) had a significant increase, and 45 (52%) had variability in steroid use. 9 centers (11%) had <2 years of data.

My take: These findings are expected but nice to see. Patients in the ICN are using less steroids and growing better. Given the variation in care among centers, there is more work needed.

From JPGN twitter feed

Related blog posts:

Expert Consensus: New Recommendations for Therapeutic Drug Monitoring

AS Cheifetz et al. Am J Gastroenterol 2021;00:1–12. A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease (published online August 13, 2021)

Key recommendations:

  • The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response
  • It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10–15 mg/mL was achieved
  • Consensus was also achieved regarding the utility of proactive TDM for anti–tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance.
  • More data are needed with regard to proactive TDM for biologics other than anti-TNF agents
  • There are no differences in interpreting TDM between originator biologics and biosimilars
  • When considering switching within drug class in case of secondary loss of response to a first anti-TNF drug because of the development of antidrug antibodies, an immunomodulator should be added to a subsequent anti-TNF therapy
  • Low-titer antidrug antibodies can be overcome by treatment optimization (dose escalation, dose interval shortening, and/or addition of an immunomodulator)

My take: This article should help support the practice of proactive TDM and discourage stopping anti-TNF agents until an adequate therapeutic level is achieved.

Related blog posts:

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‘Dual Immunotherapy’ for IBD

A recent study (MT Dolinger et al. Inflamm Bowel Dis 2021; 27: 1210-1214) and the associated editorial (D Geem, S Kugathasan. Inflamm Bowel Dis 2021; 27: 1361-1362) describe the use of multiple therapies (biologics and small molecule therapy) to target refractory pediatric inflammatory bowel disease. Since the term “combination therapy” is already in broad use for those receiving a biologic agent and an immunomodulator, I plan to refer to these new combinations as ‘dual immunotherapy’ for IBD.

Dolinger et al (Dual Biologic and Small Molecule Therapy for the Treatment of Refractory Pediatric Inflammatory Bowel Disease) described 16 children with dual immunotherapy. Nine (56%) were treated with vedolizumab/tofacitinib, 4 (25%) with ustekinumab/vedolizumab, and 3 (19%) with ustekinumab/tofacitinib. Twelve (75%; 7 ulcerative colitis/IBD-unspecified, 5 Crohn’s disease ) achieved steroid-free remission at 6 months. One patient on 30 mg of vedolizumab/tofacitinib and prednisone daily developed septic arthritis and a deep vein thrombosis.

In the editorial (It Takes Two to Make It Right: Dual Biologic and Small Molecule Therapy for Treatment-Refractory Pediatric Inflammatory Bowel Disease), Geem et al make a number of key points:

  • Except for “anti-TNF medications (infliximab and adalimumab), no other biologic therapies are FDA-approved for children with IBD”
  • “Clinical disease remission is achieved in only 40-60% of patients on anti-TNF medications”
  • With ustekinumab, “limited pediatric data reveal that in patients who have failed at least 1 biologic therapy, 38.6-58% achieve clinical remission by week 52…[And] vedolizumab …demonstrated steroid-free remission in 20% by week 22 in a single-center prospective observational cohort study.”
  • The response to dual immunotherapy is most likely due to the synergistic effects of two medications rather than the start of a new medication. The authors note a prior study which showed a positive experience of adding ustekinumab in 5 children who developed severe paradoxical psoriasis with infliximab and in another subset of pediatric patients, there was improvement with combination vedolizumab/infliximab (Paediatr Drugs 2020; 22: 409-416)

My take (borrowed from editorial): “Given the phenotypic heterogeneity of pediatric IBD and the multiple inflammatory immune pathways implicated in its pathogenesis, the approach of biologic monotherapy–may not be suitable for all patients…patients may require specific combinations…to quell multiple arms of their dysregulated immune response.” More trials are needed to determine the safety of these regimens (especially with regard to malignancy and infections).

Burlington VT (Lake Champlain)

Predicting IBD Outcomes –New Tools

In an observational prospective longitudinal study of with newly diagnosed Crohn’s disease in 156 adults followed for nearly 1.5 years, Yanai et al found that 52 patients (33.3%) had an indolent course of CD, 29 (18.5%) required hospitalizations, and 75 (48%) were recommended to start steroid, immunomodulator, or biologic therapies. An “indolent course” indicated a lack of needing steroids, immunomodulators, anti-TNF agents, hospitalization or surgery.  Key findings:

  • There were 4 factors associated with complicated course in treatment-naïve patients: body mass index <25 kg/m2 (hazard ratio [HR], 2.45; 95% CI, 1.07–5.43; P = .033), serum level of vitamin B12 <350 pg/mL (HR, 2.78; 95% CI, 1.21–6.41; P = .016), white blood cells ≥7 × 103/μL (HR, 2.419; 95% CI, 1.026–5.703; P = .044), and serum level of ALT ≥25 IU/L (HR, 2.680; 95% CI, 1.186–6.058; P = .018).
  • This model discriminated between patients with vs without a complicated course of disease with 90% and 89% accuracy at 6 and 12 months after diagnosis, respectively. A validation cohort demonstrated a discriminatory ability of 79% at 3 months after diagnosis, and a nomogram was constructed (see below)
Points on the nomogram are based on: BMI <25 kg/m2 = 87 or ≥25 kg/m2 = 0, WBC <7 × 103/μL = 0 or ≥7 × 103/μL = 83, vitamin B12 <350 pg/mL = 100 or ≥350 pg/mL = 0, and ALT <25 IU/L = 0 or ≥25 IU/L = 76. The sum score for all variables corresponds with the probability of having an indolent course of disease at different time points after diagnosis.

My take: In this study, low BMI, low Vit B12, high wbc, and high ALT were associated with a more complicated course. These particularly risk factors do not seem intuitive to me. These findings need to be looked at in the pediatric age group, which likely has a lower rate of an indolent course.

G Le Baut et al. Clin Gastroenterol Hepatol 2021; 19: 1602-1610. A Scoring System to Determine Patients’ Risk of Colectomy Within 1 Year After Hospital Admission for Acute Severe Ulcerative Colitis

In this retrospective study of 270 consecutive adult patients with acute severe ulcerative colitis (ASUC) (2002-2017), the cumulative risk of colectomy was 12.3% (95% CI, 8.6–16.8). Key findings:

  • Based on multivariate analysis, previous treatment with TNF antagonists or thiopurines (hazard ratio [HR], 3.86), Clostridioides difficile infection (HR, 3.73), serum level of C-reactive protein above 3.0 mg/dL (HR, 3.06), and serum level of albumin below 3.0 g/dL (HR, 2.67) were associated with increased risk of colectomy
  • The cumulative risks of colectomy within 1 y in patients with scores of 0, 1, 2, 3, or 4 were 0.0%, 9.4% (95% CI, 4.3%–16.7%), 10.6% (95% CI, 5.6%–17.4%), 51.2% (95% CI, 26.6%–71.3%), and 100%. Negative predictive values ranged from 87% (95% CI, 82%–91%) to 92% (95% CI, 88%–95.0%). Findings from the validation cohort were consistent with findings from the derivation cohort.

My take: These findings confirm other studies in patients with ulcerative colitis which have shown that each of these criteria were predictors of severe disease.

Related blog posts:

Calprotectin Less Accurate for Isolated Ileal Crohn’s Disease

G D’Arcangelo et al. JPGN 2021; 73: 242-246. Is Fecal Calprotectin a Useful Marker for Small Bowel Crohn Disease?

In this retrospective study with 98 patients, the authors examined the sensitivity and specificity of fecal calprotectin (FC) at a cutoff of 150 mcg/g in comparison to findings of ileocolonoscopy and MRE in those with isolated ileal CD (L1, n=14), colonic CD (L2, n=10) and ilecolonic CD (L3, n=74) . Note: the abstract erroneously states the cutoff as 50 mcg/g.

Key findings:

  • The sensitivity and specificity of FC for L1 CD were 36% and 91%, respectively, compared to 93% and 75% for L2 and 70% and 95% for L3.
  • An FC of 95 mg/kg was identified as the best cut off for identification of active isolated ileal disease, with a sensitivity of 77% and a specificity of 56%

My take: Though this study had only 14 patients with isolated ileal disease, it is likely that a calprotectin level is less reliable as a biomarker in these patients.

Related article: Jukic A, Bakiri L, Wagner EF, et al Calprotectin: from biomarker to biological functionGut Published Online First: 18 June 2021. doi: 10.1136/gutjnl-2021-324855. Thanks to KT Park for this reference. Open Access- Full text: Calprotectin: from biomarker to biological function

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Paternal Exposure to IBD Medications and Neonatal Outcomes

COVID-19 Vaccine Effectiveness (8/10/21):

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J Meserve et al. Gastroenterol 2021; 161: 107-115. Full text: Paternal Exposure to Immunosuppressive and/or Biologic Agents and Birth Outcomes in Patients With Immune-Mediated Inflammatory Diseases

Methods: The investigators used a deidentified administrative claims database (OptumLabs Data Warehouse) with a total of 7453 expectant fathers with immune-mediated diseases.

Key findings:

  • As compared to unexposed fathers (3.4% prevalence of major congenital malformations), exposure to immunosuppressives/biologics were not associated with increased risk of major congenital malformations: thiopurines (relative risk [RR], 1.12; 95% confidence interval [CI], 0.66–1.76), methotrexate (RR, 0.67; 95% CI, 0.21–1.55), TNF-α antagonists (RR, 1.14; 95% CI, 0.81-1.57), and non–TNF-targeting biologic agents (RR, 1.75; 95% CI, 0.80–3.24).
  • No association was observed between paternal medication exposure and risk of preterm birth or low birth weight.

Editorial, pg 24-27: S Friedman et al. Full text: Does Fatherhood Matter? Preconception Use of Biologics and Immunomodulators by Fathers With Immune-Mediated Diseases and Birth Outcomes of Their Offspring

“Regarding major congenital malformations, we believe that the results should be interpreted with caution. The numbers of these outcomes are relatively low and the statistical precision of the risk estimates should be taken into consideration.”

My take: Overall, this study is reassuring. Though it is difficult to prove these medications do not have impacts on newborns, if these effects were frequent, it would likely be evident in this type of study.

Anti-TNF Therapy and Lower Rates of Colon Cancer & Financial Hardship Due to IBD

M Aklkhayyat et al. Inflamm Bowel Dis 2021; 27: 1052-1060. Lower Rates of Colorectal Cancer in Patients With Inflammatory Bowel Disease Using Anti-TNF Therapy

Using a selected sample from a database with >62 million patients, this retrospective cohort study determined the rates of colorectal cancer among patients with IBD. Key finding:

Among the IBD cohort, patients treated with anti-TNF agents were less likely to develop CRC; patients with Crohn’s disease: odds ratio, 0.69; 95% confidence interval, 0.66-0.73; P < 0.0001 vs patients with ulcerative colitis: odds ratio, 0.78; 95% confidence interval, 0.73-0.83; P < 0.0001.

My take: This study found an association between anti-TNF therapy and a reduced risk of CRC in patients with IBD.

Related blog posts:

NH Nguyen et al. Inflamm Bowel Dis 1068-1078. National Estimates of Financial Hardship From Medical Bills and Cost-related Medication Nonadherence in Patients With Inflammatory Bowel Diseases in the United States

Using the National Health Interview survey (2015), the authors identified individuals with self-reported IBD and assessed national estimates of financial toxicity. Key findings:

  • 23% reported financial hardships due to medical bills, 16% of patients reported cost-related medication nonadherence, and 31% reported cost-reducing behaviors
  • Approximately 62% of patients reported personal and/or health-related financial distress, and 10% of patients deemed health care unaffordable
  • Inflammatory bowel disease was associated with 1.6 to 2.6 times higher odds of financial toxicity across domains compared with patients without IBD

My take: In addition to the physical and emotional toll of having IBD, there is also significant financial hardships for many.

2021 AGA Guidelines For Crohn’s Disease

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:

From Spotlight: