IBD Shorts -September 2018

S Sridhar et al. Inflamm Bowel Dis 2018; 24: 2086-92.  This retrospective pediatric study with 409 patients examined dermatologic manifestations on anti-TNF therapy.  47 (11.4%) had dermatologic findings recorded including 33 with psoriasis, 28 with infections, and 10 with eczema (some had multiple skin findings). The majority were able to continue with current anti-TNF regmimen, including 60% of those with psoriasis.

Related blog posts:

NA Rozette et al. Inflamm Bowel Dis 2018; 24: 2007-14. This study with 50 subjects showed good safety of rapid versus standard infliximab infusions. One interesting aspect of their study which included a retrospective arm (standard infusion) and a prospective arm (rapid infusion) was a declining use of premedication, though even in their prospective group 60% received premedication including the combination of acetaminophen, benadryl, and methylprednisolone in 30%.  There were two patients in the rapid infusion with mild reactions who reverted to standard infusion rates.

CJ Moran, JL Kaplan, HS Winter. Inflamm Bowel Dis 2018; 24: 2048-52. This study with 199 subjects with active Crohn’s disease (CD) (21-86 years) –had their BioBank blood tested for 5 common CRP genetic variants.  Some specific variants,  rs2794520TT & rs1800947, were associated with lower CRP levels. This study helps explain why CRP is not a useful marker in some patients with CD.

Sunshine Meadows, Banff

CALM Study: Tight Control Improves Outcomes in Crohn’s Disease

A recent study (JF Colombel et al. Lancet 2017; http://dx.doi.org/10.1016/S0140-6736(17)32641-7 ) shows that “tight control” improves outcomes in Crohn’s disease.  This study was alluded to in a previous post: CCFA 2017 Updates (part 2)

Background: The CALM study was an open-label, randomized study.  122 adult patients were randomized to typical clinical management and 122 patients received “tight control” in which treatment was modified by fecal calprotectin (≥250 mcg/g) and CRP (≥ 0.5 mg/dL) values in addition to clinical symptoms.

Treatment was escalated in both groups in a stepwise manner.  Initial treatment was with adalimumab induction and then every other week. If patient did not meet treatment objectives, which differed in the groups, then adalimumab would be given every week, and then, if still needed, azathioprine would be added. Interestingly, both groups had ~25% of participants who were smokers which is known to worsen outcomes.

Key Findings:

  • Mucosal healing (CDEIS <4) was significantly improved in tight control group at week 48: 46% vs. 30%.
  • Similarly, steroid-free remission based on CDAI <150 was better in tight control group compared with standard treatment at week 48: 59.8% vs. 39.3%.  Endoscopic response was 50.8% compared with 40.2% respectively.

My take (1st part borrowed from authors): “Tight control of inflammation in patients with Crohn’s disease, with objective markers of disease activity  and clinical symptoms to drive treatment decisions, achieved better endoscopic and clinical outcomes than conventional care based on symptoms alone.” Yet, there are a large number who do not respond adequately and better treatments in these patients are needed.

As an aside, these response rates based on objective markers are far lower than the remission rates claimed by ImproveCareNow; thus, while ImproveCareNow is forward-thinking and helping improve outcomes with inflammatory bowel disease, we need to be careful about citing remission rate trends that are not directly linked to objective markers.

Briefly Noted: Celiac Serology Normalization, Inflammatory Markers in Crohn’s Disease, Nutrition in Neurologically-Impaired

  • DM Isaac et al. JPGN 2017; 65: 195-99.

This retrospective study of 487 pediatric patients shows that it takes a long time to normalize celiac serology/anti-tissue transglutaminase antibody (TTG). The median time was 407 days for the 80.5% of patients that normalized their serology in the study time frame.  The time was 364 days for those who were considered adherent to a gluten-free diet.  Patients with type 1 diabetes were less likely to normalize their TTG levels. Faster normalization occurred in those with lower titers at baseline.

Related blog posts:

  • A Alper et al. JPGN 2017; 65: e25-e27

In this chart review, among 135 children, normal ESR and CRP were observed in 28% of children with Crohn disease and 42% of children with ulcerative colitis.

Related blog post: Do you really need both a ESR and CRP?

  • C Romano et al. JPGN 2017; 65: 242-64

This guideline paper details 31 recommendations (some with multiple parts) for the evaluation and management of children with neurologic impairment.  The recommendations include detailed evaluations including knee heights, skinfold thickness measures, DXA scan, routine micronutrient bloodwork, along with a low threshold for oropharyngeal dysphagia assessment.  The paper has recommendations for evaluations of reflux, constipation, and dental problems.  The authors suggest “considering use of enteral feeding if total oral feeding time exceeds 3 hours per day.”

Related blog post: Surgery for reflux works best for those who need it the least

Identifying IBD Years Before Symptoms

A while back there was a movie called “Minority Report.”  The movie’s premise was that crimes could be predicted and stopped before they occurred.  A recent study (P Lochhead et al. Clin Gastroenterol Hepatol 2016; 14: 818-24) presents intriguing data suggesting a similar scenario for inflammatory bowel disease (IBD).

The authors used a prospective, nested case control study of participants in the Nurses’ Health Study I and II. Median age of patients with Crohn’s disease (CD) (n=83) and ulcerative colitis (UC) (n=90) was 52.7 years and 50.4 years respectively. Key findings:

  • Median prediagnostic hsCRP levels (mg/L) were 2.3 in CD, 2.2 in UC and 1.5 in controls (n=344).
  • Median prediagnostic IL6 levels (pg/mL) were 1.7 in CD, 1.2 in UC, and 1.0 in controls.
  • Median time interval between blood collection and diagnosis was 6.6 years for CD and 6.8 years for UC.
  • There was increased odds for developing disease even after adjustment for potentially confounding variables like smoking.  This analysis held up even when excluding disease that developed within 2 years of sampling.

Overall, this study suggests that there is a significant population of patients with subclinical IBD which precedes the diagnosis by several years.  This report adds to a number of other studies showing potential “preclinical phase” of many diseases including rheumatoid arthritis and type 1 diabetes.

My take: It is fascinating that bloodwork can be abnormal years before clinical symptoms. However, as in “Minority Report” the problem will be with identifying a crime/disease that might never occur.

Unrelated –Chart Depicting Car Temps:

car temp

Biomarkers identify patients who benefit and how

Fecal calprotectin and serum CRP levels are helping to identify which patients benefit most from biologic therapies, how frequently to dose individuals and how well inflammation correlates with changes in CDAI.  Several abstracts from ACG highlight these issues:

Abstract #1175: Fecal calprotectin concentration and clinical remission in patients with active Crohn’s disease treated with certolizumab pegol: results from PRECiSE 1 (Sandborn W et al).

Abstract #1164: Baseline C-reactive protein is associated with disease progression in  patients with Crohn’s disease (Colmbel J-F et al).

Abstract #1165: Association of baseline C-reactive protein with maintenance of remission in patients with moderate to severe Crohn’s disease treated with adalimumab (Sandborn W et al)

Abstract 1175 uses a post hoc analysis of patients with active Crohn’s disease (CD) who were treated with certolizumab or placebo for 26 weeks.  Baseline calprotectin concentrations were higher in patients who achieved remission.  Another interesting finding of this study was that placebo patients did not have improvement in calprotectin levels.  So, even though some patients  had improvement in CDAI scores, indicating subjective improvement, inflammatory activity did not decline.  This is another indicator of how flawed a CDAI is for indicating the effectiveness of an IBD therapy.

Abstract 1164 looked at 238 patients with moderate to severe CD who were randomized to placebo arm in the CHARM study.  These patients were given open-label adalimumab for induction (80 mg week 0, 40 mg week 2) followed by blinded weekly placebo treatment from weeks 4-56 with a switch to open-label adalimumab after week 12 for a disease flare.  Higher baseline CRP levels in patients with moderate or severe CD were associated with higher disease scores after four weeks and after one year.  This suggests that a patient with higher CRP is more likely to have disease progression without adequate treatment.

Abstract 1165 examined the relationship between CRP and remission in CHARM patients. In the high baseline CRP group, 39 patients received adalimumab every other week, 28 weekly, and 34 received placebo.  In the low baseline CRP group, there were 42 every other week patients, 33 weekly, and 39 placebo patients.  In the high baseline CRP group, remission rates were 50% higher in the weekly treatment group compared to the every other week group.  Patients with low baseline CRP had similar results when treated weekly versus every other week.  Thus, patients with high baseline CRP are more likely to benefit from dose escalation and low CRP patients are more likely to have coexistent issues contributing to their symptoms (eg. IBS).

One other caveat: CRP production is geneticallly-determined and some patients do not make CRP in spite of active inflammation.

Related blog entries:

Food as medicine

Speed matters

Additional calprotectin references:

  • -IBD 2010; 16: 482. Calprotectin correlated with inflammation of ileum after pouch creation in children.
  • -IBD 2009; 12: 1851. Calprotectin was the only marker to correlate with endoscopic activity; n=134.
  • -JPGN 2009; 48: 48. Good sensitivity/specificity of calprotectin & lactoferrin. Up to 96% sensitivity & specificity.
  • -Clin Gastro & Hep 2008; 6: 1218. Lack of correlation between clinical symptoms and fecal biomarkers. However, biomarkers do correlate with mucosal/endoscopic disease. n=164.
  • -IBD 2008; 14: 1392. Monitoring IBD activity level c calprotectin & lactoferrin; n=15.
  • -IBD 2008; 14: 1229. Clinical utility in assessing histological relapse in kids. n=73 over 8yrs…may allow avoidance of invasive tests; cut off of 275mcg/gm had 97% sensitivity/neg pred value 85% pos pred value/specificity at predicting relapse.
  • -IBD 2008; 14: 669. Fecal calprotectin good at predicting relapse in pediatric IBD w cutoff of 400.

C-reactive protein references:

  • -J Pediatr 2011; 159: 340. CRP helps identify IBD.
  • -Clin Gastro & Hepatology 2011; 9: 421. CRP predicts response to IFX. n=718. those with high CRP had 91% response vs 83% in pts with NL CRP.
  • -Gastro 2004; 126: 1574-81. Crohn’s review. High CRP suggests likely response to anti-TNFα treatment.
  • -JPGN 2004; 38: 509-12. CRP more reliable than ESR for IBD.
  • -NEJM 1999; 340: 448. Review on acute phase reactants. CRP better than ESR as ESR is an indirect measure (resistance of plasma, due to fibrinogen, to the falling of RBCs) & broader range for CRP.