Improving Outcomes with Proactive Therapeutic Drug Monitoring + Swiss COVID1- Data

Another recent study showing the benefits of proactive therapeutic drug monitoring (pTDM):

SW Syverson et al. JAMA. 2021;326(23):2375-2384. Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases (The article is only 10 pages; however, the supplementary material (which I did not read) is an additional 258 pages.) Thanks to Ben Gold for sharing article reference. Also, this study was reviewed in Healio Gastro: Link: Therapeutic drug monitoring sustains disease control during infliximab maintenance

Methods: Randomized, parallel-group, open-label clinical trial including 458 adults (mean age, 44.8 years; 49.8% women) with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis (n=81), Crohn disease (n=66), or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospital

Key finding:

  • Sustained disease control without worsening was evident in 73.9% of pTDM group compared with 55.9% in standard infliximab group

Some limitations of this study:

  1. The open-label study was not powered to detect the difference of pTDM in each of the six diseases
  2. The therapeutic goal for maintenance infliximab was 3 to 8 mg/L, which is a little lower than current goals (ACG expert panel suggests a level of at least 5-10)

My take: This study supports recent expert guidance (see blog post below) on the benefit of pTDM as part of evidence-based care. It is likely that pTDM is even more important in children/teens due to growth.

Time to Disease Worsening

Related blog posts:

Also data from Switzerland:

2-Fold Risk of Urolithiasis in Patients with Inflammatory Bowel Disease

H Dimke et al. Clin Gastroenterol Hepatol 2021; 19: 2532-2540. Risk of Urolithiasis in Patients With Inflammatory Bowel Disease: A Nationwide Danish Cohort Study 1977–2018

Using national registries, the authors identified all patients with IBD (>15 years of age) and all cases of urolithiasis in Denmark during 1977-2018. Key findings:

  • 2,549 (3%) of 75,236 IBD patients and 11,258 (2%) of 767,403 non-IBD individuals developed urolithiasis, resulting in a 2-fold increased risk of urolithiasis (HR, 2.27; 95% CI, 2.17-2.38) in patients with IBD
  • The authors note that a small risk of urolithiasis preceded the diagnosis of IBD: with OR, 1.42; 95% CI: 1.34-1.50 prior to diagnosis
  • After IBD diagnosis, risk of urolithiasis was associated with anti-TNF therapy and surgery (increased disease severity appears to be associated with increased risk). Anti-TNF therapy had a RR of 2.68 in patients with ulcerative colitis and a RR of 3.56 in patients with Crohn’s disease; for surgery, the RR were 3.14 and 2.74 respectively
  • One limitation is detection bias as patients with IBD may have more asymptomatic stones identified due to more frequent imaging

My take: This confirms an increased risk of urolithiaiss in patients with IBD and is a good reminder to consider this when patients present with severe abdominal pain/possible flare-up.

Siesta Key, FL

IBD Shorts: Fecal Calprotectin in UC & Medication Withdrawal, Outcome of Biosimilar Reverse Switches, Vedolizumab after Anti-TNF Therapy

TW Stevens et al. Inflamm Bowel Dis 2021; 19: 2333-2342. Open Access. Diagnostic Accuracy of Fecal Calprotectin Concentration in Evaluating Therapeutic Outcomes of Patients With Ulcerative Colitis

Key finding: A post hoc analysis of data from a phase 4 trial (the MOMENTUM trial) found that, even in patients (n=593 at week 8, n=305 at week 52) with complete endoscopic healing of UC, FC concentration can be used to discriminate patients with ongoing microscopic inflammation from patients with histologic remission.  The optimal FC cut-off concentrations for identification of patients with histologic remission were 75 μg/g at week 8 and 99 μg/g at week 52.

A Cassinotti et al. Clin Gastroenterol Hepatol 2021; 19: 2293-2301. Noninvasive Monitoring After Azathioprine Withdrawal in Patients With Inflammatory Bowel Disease in Deep Remission

Key finding: In this prospective study, 57 patients in deep remission stopped azathioprine after a median of 7 years. 26 (46%) relapsed within a median of 15 months. Fecal calprotectin (FC) levels were >50 mcg/g in all patients with relapse (FC specificity 100%) but the sensitivity was only 50%. Thus, having a normal FC does not preclude relapse but elevated FC is associated with relapse.

S Mahmmod et al. Inflamm Bowel Dis 2021; 27: 1954-1962. Outcome of Reverse Switching From CT-P13 to Originator Infliximab in Patients With Inflammatory Bowel Disease

In this retrospective study, 75 patients, 9.9% of all patients, who had been changed from originator infliximab to a biosimilar had clinical worsening. Key finding: Improvement of reported symptoms was seen in 73.3% of patients after reverse switching back to originator infliximab; alsor 7 out of 9 patients (77.8%) with loss of response regained response

J Kim et al. Inflamm Bowel Dis 2021; 27: 1931-1941. Clinical Outcomes and Response Predictors of Vedolizumab Induction Treatment for Korean Patients With Inflammatory Bowel Diseases Who Failed Anti-TNF Therapy: A KASID Prospective Multicenter Cohort Study

Key finding: Clinical remission rates with vedolizumab among patients with CD (n=80) and patients with UC (n=78) were 44.1% and 44.0%. Among patients with UC, the endoscopic remission rate was 32.4%

Emerging Data on Risankizumab for Crohn’s Disease

From Gastroenterology and Endoscopy News: New Anti–IL-23 Therapy Shows Benefit in Crohn’s Disease

An excerpt:

Two phase 3 placebo-controlled trials with the immune modulator risankizumab demonstrated control of Crohn’s disease whether or not patients had previously received a biologic agent.

Rates of clinical remission at 12 weeks with the interleukin (IL)-23 inhibitor risankizumab (Skyrizi, AbbVie), were about 48% in patients without prior exposure to biologic therapy and more than 40% in those with prior exposure…

The two trials, ADVANCE and MOTIVATE were presented together at the 2021 Digestive Disease Week (abstract 775a)…

Only 12% of patients in the placebo group achieved endoscopic remission versus 40.3% of those on the 600-mg dose of risankizumab (P<0.001). [Rates of endoscopic remission were higher in the biologic-naive (50.5%)]

My take: In addition to ustekinumab (already approved), a number of other therapeutic agents that target IL-23 are likely to be available soon to help manage Crohn’s disease. This includes risankizumab but others with phase 3 studies include brazikumab, mirikizumab, and guselkumab..

Slide from David Rubin Twitter Feed (March 2021). Ozanimod now approved.

Ustekinumab vs Adalimumab: Head-to-Head Study

From Gastroenterology & Endoscopy News: Head-to-Head Trial Shows Similar Efficacy and Safety With Ustekinumab and Adalimumab

An excerpt:

The first head-to-head trial comparing ustekinumab and adalimumab has found the two drugs are similarly safe and effective in patients with moderate to severe Crohn’s disease

Dr. Scherl and her co-investigators in the SEAVUE trial randomly assigned 386 biologic-naive patients with Crohn’s disease to receive one year of treatment with either ustekinumab or adalimumab at standard on-label doses, with no dose escalation throughout the study period and no concomitant immunomodulators...

The findings, which were presented at the 2021 annual meeting of the European Crohn’s and Colitis Organisation (oral presentation OP02), showed that after one year of treatment, 65% of patients who received ustekinumab and 61% of those who received adalimumab achieved clinical remission, defined as a CDAI below 150...[And] similar additional outcomes, including clinical response at one year (72.3% for ustekinumab vs. 66.2% for adalimumab), corticosteroid-free remission at one year (60.7% vs. 57.4%, respectively), endoscopic remission at one year (28.5% vs. 30.7%) 

My take: This study indicates that ustekinumab likely has similar safety and efficacy as adalimumab (though the study did not allow dose escalation or immunomodulators); thus, it could be positioned as a first-line treatment. It is administered less frequently as well.

Related blog posts:

Preclinical Disease Detection of Inflammatory Bowel Disease

Recent articles indicate the possibility of preclinical disease detection of inflammatory bowel disease; perhaps this is analagous to the “precrime’ detection in The Minority Report which allowed the police to arrest people before they committed their crime.

D Bergemalm et al. Gastroenterol 2021; 161: 1526-1539. Open Access: Systemic Inflammation in Preclinical Ulcerative Colitis

In this study from Sweden, the authors used biobanked plasma samples from 72 individuals with ulcerative colitis (UC) and matched healthy controls (n=140). Then the findings were validated in an inception cohort (n=101 with UC and 50 healthy controls. In addition, a cohort of heathy twin siblings of patients with UC (n=41) were matched with healthy controls (n=37).

Key findings:

  • Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls
  • MMP10, CXCL9, CXCL11, and MCP1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings. This up-regulation is triggered by exposure to genetic and early environmental factors.

The discussion elaborates on the role of these proteins.

  • MMP10 is classified as a stromelysin. Upregulated levels of stromelysin have been detected in inflamed segments of the colon from patients with ulcerative colitis….The observed preclinical upregulation of MMP10 [thought to promote wound healing] in plasma might indicate that endogenous pathways for wound healing are up-regulated several years before clinically overt ulcerative colitis to counteract disease progression and maintain mucosal homeostasis”
  • “Eotaxin (CCL11) is a potent chemoattractant of monocytes…eosinophilic-driven inflammation represents an early element in the pathogenesis of ulcerative colitis”
  • CXCL9 and CXCL11 has been observed previously in inflamed colonic tissue specimens and blood from patients with ulcerative colitis… Both chemokines are regulated by IFN-gamma and attract CXCR3-positive CD4þ T cells and natural killer cells to the inflammatory site”

My take: This study shows up-regulation of 6 plasma proteins indicating activation of both pro-inflammatory and tissue-repairing pathways several years before clinically overt UC. It offers hope of intervention to prevent the development of UC.

Related study: S-H Lee et al. Gastroenterol 2021; 161: 1540-1551. Open Access: Anti-Microbial Antibody Response is Associated With Future Onset of Crohn’s Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk

In this study, the authors measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS).

Key finding:

“High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4–12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.

The Really Simplified Endoscopy Scoring

A recent article on simplifying the “simple” endoscopic assessment for Crohn’s disease reminded me of a scene from “There’s Something About Mary” (see below) where one of the characters plans to market a 7 minute abs video to replace the 8 minute abs video craze.

The article describes replacing the current “SES-CD” (or Simple Endoscopic Score for Crohn’s disease) with SEMA-CD (or Simplified Endoscopic Mucosal Assessment for Crohn’s disease).

YouTube: 7-minute abs Scene (from There’s Something About Mary)

J Adler et al. Inflamm Bowel Dis 2021; 27: 1585-1592. Development and Testing of a New Simplified Endoscopic Mucosal Assessment for Crohn’s Disease: The SEMA-CD

The SEMA-CD was scored by assigning a numerical value ranging from 0 (remission) to 4 (severe disease) for each bowel region (ileum and colon). The colon score was multiplied by the number of involved colonic segments and then added to the ileum score. “For example, if overall the colon was felt to have moderate involvement, and only the ascending and transverse colon had mucosal abnormalities, then a score of 3 for moderate disease would be multiplied by a total of 2 segments for a total [colon] score of 6.”

Key finding:

  • While there was excellent correlation between SES-CD and SEMA-CD, SEMA-CD was much easier as it required one scoring for the entire colon rather than evaluation of each segment

The authors note that clinical assessment is inadequate to monitor CD. CDAI (PCDAI) are poor surrogates for mucosal improvement…”30-68% of patients in clinical remission have evidence of mucosal inflammation on colonoscopy….Patients whose disease is managed based on clinical information alone are more likely to have disease complications, need more surgeries, or lose response to medications.”

My take: The SEMA-CD appears to be much easier than the SES-CD and thus more likely to be useful in clinical practice (& research), especially as it becomes incorporated into routine endoscopy software. If the SEMA-CD is widely adopted, we will need to be on the lookout for the ‘6 minute ab’ version.

Related blog post: Pediatric Adoption of ‘Treat to Target’ & Difficulty ‘Unlearning’

Thanks to Jeremy Adler for sharing this figure

Infection or Flareup in IBD: GI PCR Panel Helps

S Hong et al. Inflamm Bowel Dis 2021; 27: 1634-1640. Comparative Evaluation of Conventional Stool Testing and Multiplex Molecular Panel in Outpatients With Relapse of Inflammatory Bowel Disease

In this retrospective cohort study with 268 adult patients with inflammatory bowel disease, the authors compared the use of a GI PCR panel with 22 analytes (BioFire) and C diff testing to ‘conventional’ stool testing (culture, O&P and C diff). Key findings:

  • Pathogens were more frequently identified on GI PCR (26 vs 5%; P < 0.01)
  • GI PCR was associated with less escalation in IBD therapy (16 vs 29%; P < 0.01) and fewer posttest endoscopies (10% vs 18%; P = 0.04), with no differences in IBD outcomes
  • Those with recent travel had a higher pathogen detection rate: 38% vs 14%; P<0.01
  • In the GI PCR group, the most common pathogens were E coli species 22 (including 12 Enteropathogenic E coli), Campylobacter 10, Multiple pathogens 7, Norovirus 6, Yersinia 3, C diff 3,

The authors note that the group who underwent GI PCR panel testing were more likely to present with severe symptoms (eg. fever, rectal bleeding) as well as a history of recent travel. Even when controlling for symptoms and biomarkers of inflammation, GI PCR testing was still associated with lower likelihood of escalating IBD therapies.

My take: This study indicates that identification of an infectious pathogen which is more likely with a GI PCR panel helps avoid escalation of IBD therapy and need for endoscopy in the outpatient setting.

Related blog post: Molecular Panels for Identifying Etiology with Acute GI Symptoms

Ustekinumab in Pediatric Patients and More on VTE Prophylaxis

FS Kim et al. JPGN 2021; 73: 610-614. Open Access (PDF): Experience Using Ustekinumab in Pediatric Patients With Medically Refractory Crohn Disease

In this retrospective study with 38 pediatric patients with Crohn’s disease, 34% had stricturing or penetrating disease. Key findings:

  • At time of last follow-up, 84.2% of patients remained on UST for a median duration on UST of 62.1 weeks, and 60.5% achieved clinical remission
  • 89.5% of patients had no significant adverse events
  • Sixteen (of 38, 42.1%) patients required dose escalation, to every 4 weeks (n= 15 of these 16, 93.8%) or every 6 weeks (Nn=1 of 16, 6.3%)

My take: Ustekinumab had good efficacy in this group of refractory pediatric patients.

Related blog posts:

E Story et al. JPGN 2021; 73: 604-609. Safety of Venous Thromboprophylaxis With Low-molecular-weight Heparin in Children With Ulcerative Colitis

In this retrospective study with 218 inpatient pediatric patients with active ulcerative colitis, the key findings:

  • Use of enoxaparin did not result in a greater fall in hemoglobin among those with acute severe colitis (initial PUCAI ≥65) during the week following admission and there was not an increased risk of needing a transfusion
  • VTE occurred in 2 of 130 in control group and 1 of 88 in enoxaparin group (enoxaparin group was sicker)

My take: The absolute risk of VTE is low in the pediatric population. This study shows that enoxaparin prophylaxis is NOT associated with increased issues with blood loss. In those with active disease, the presence of CVC and use of steroids are known risk factors and require consideration of, at minimum, nonpharmacologic interventions.

Related blog posts:

Billy Goat Trail, Chesapeake and Ohio Canal National Park

Dietary Therapy for Adults with Crohn’s Disease

H Yanai et al. The Lancet 2021; The Crohn’s disease exclusion diet for induction and maintenance of remission in adults with mild-to-moderate Crohn’s disease (CDED-AD): an open-label, pilot, randomised trial

In this open-label trial of adults with mild-to-moderate biologic naive Crohn’s disease, key findings:

  • At week 6, 13 (68%) of 19 patients in the CDED plus partial enteral nutrition group and 12 (57%) of 21 patients in the CDED group had achieved clinical remission (p=0·4618)
  • Among the 25 patients in remission at week 6, 20 (80%) were in sustained remission at week 24 (12 patients in the CDED plus partial enteral nutrition group and eight in the CDED alone group)
  • 14 (35%) of 40 patients were in endoscopic remission at week 24 (eight patients in the CDED plus partial enteral nutrition group and six in the CDED alone group)

My take: Dietary therapy may be effective option for motivated adult patients with Crohn’s disease.

Related blog posts: