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%

Correlating Calprotectin with Disease Severity in Pediatric IBD

E Crawford et al. JPGN Reports 2021; 22 – Issue 4 – p e129. Open Access: Association of Fecal Calprotectin With Endoscopic and Histologic Activity in Pediatric Inflammatory Bowel Disease

This retrospective study used data from 331 patients (n=107 with IBD). Fecal calprotectin (FC) was done between 30 days and 1 day before colonoscopy.

Key findings:

  • Correlation with endoscopy: median FC was lowest for all IBD patients with no active disease (181 μg/g) and highest in severe disease (921 μg/g), with significant difference between no disease and moderate and severe disease (P = 0.019, 0.003), and between mild and severe disease (P = 0.012)
  • Correlation with histology: median FC was lowest with no active disease (328 μg/g) and highest in severe disease (895 μg/g), with significant difference between no disease and moderate and severe disease (P = 0.021, 0.018)
  • The control population had median FC of 35.5 compared to 181 μg/g for the IBD population in endoscopic remission (P = 0.018).

My take: Calprotectin levels are particularly helpful as a screen for IBD (probably using threshold of at least 120) and its use to monitor clinical response. This study shows it has some utility in predicting disease severity.

Figure 1: Fecal calprotectin association with endoscopic disease severity of IBD
(A), Crohn’s disease (B) and ulcerative colitis (C). IBD = inflammatory bowel disease.

Narrowing the Workup for Chronic Abdominal Pain –Carlo DiLorenzo Was Right!

In the good old days when we could have large meetings, Carlo DiLorenzo gave a terrific summary of recurrent abdominal pain (#NASPGHAN19 Postgraduate Course -part 3).  One of the slides, shown below, is supported by a new study (J Zeevenhooven et al. J Pediatr 2020; 219: 76-82)

In this recent reterospective study, the authors examined 853 patients, of whom 102 (12%) had an organic disorder; all had abdominal pain >2 months. The authors compared two diagnostic strategies:

  • Group 1: anti-TTG IgA, fecal calprotectin, Giardia, along with blood tests (hemoglobin, CRP, ESR)
  • Group 2: anti-TTG IgA, fecal calprotectin, and Giardia (if diarrhea)

Calprotectin was considered normal if <50 mcg/g,  “gray zone” if 51-250, mildly elevated if 251-1000, and elevated/active inflammation if >1000.

Key findings:

  • Sensitivity of the strategies was 90% and 88% for Group 1 and Group 2 respectively
  • In the presence of 1 or more alarm symptoms, the sensitivity was 92% for both strategies.
  • The sensitivity/specificity of calprotectin varied based on the cutoff value.
    • For >50, the sensitivity 75%, specificity 87%, PPV 44%, and NPV 96%
    • For >250, the sensitivity 48%, specificity 99%, PPV 82%, and NPV 93%
    • For >1000, the sensitivity 38%, specificity 100%, PPV 98%, and NPV 92%

Alarm symptoms

  • Alarm symptoms that were statistically different in the organic group included the following:
    • Chronic diarrhea (P <.001), occurred in 32% organic compared to 6% functional
    • GI blood loss (P <.001) , occurred in 35% organic compared to 5% functional
    • Recurrent vomiting (P=.029), occurred in 10% organic compared to 5% functional
    • Perianal complications (P=.001), occurred in 6% organic compared to 1% functional
    • Impaired growth (P=.023), occurred in 4% organic compared to 1% functional
  • Interestingly, the study found that having a positive family history of IBD/celiac/FMF did not differentiate functional and organic patients, occuring in 12% and 15% respectively.
  • Pain in RUQ or lower region also did not differentiate functional and organic patients, occuring in 3% and 4% respectively.
  • The authors note that 30 (29%) patients with organic disease did not have an identified alarm symptom -this compares to 479 (64%) patients with functional disease did not have an identified alarm symptom

From my experience with our recent study (Digestive Diseases (Full Text): Diagnostic Yield Variation with Colonoscopy among Pediatric Endoscopists) which focused on diagnostic yield with colonoscopy, it is clear that there are significant limitations with data collection in a retrospective study regarding recurrent abdominal pain.  Even the definition of chronic diarrhea may vary considerably among practitioners.  At the same time, we did find that an abnormal calprotectin had the highest diagnostic yield (See related blog post for summary: Our Study: Provider Level Variability in Colonoscopy Yield)

It is surprising to me that only 10 patients (1%) in their cohort were identified as having impaired growth.

My take: This study shows that anti-TTG testing and calprotectin are the most useful tests in children with persistent abdominal pain.  The addition of hemoglobin, CRP, and ESR “can be left out in the clinical evaluation of chronic abdominal pain in children.”  The authors advocate, as well, for a prospective cohort study to confirm their observations.

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

Calprotectin in Triaging Potential Pediatric IBD Cases

Thanks to KT Park’s Twitter feed for this reference: GA Holtman et al. JAMA Pediatr. Published online August 14, 2017. doi:10.1001/jamapediatrics.2017.1736

An excerpt from abstract:

Results  Of the 16 eligible studies, authors of 8 studies (n = 1120 patients) provided their data sets. All blood markers and fecal calprotectin individually significantly improved the discrimination between pediatric patients with and those without IBD, when added to evaluation of symptoms. The best marker—fecal calprotectin—improved the area under the curve of symptoms by 0.26 (95% CI, 0.21-0.31). The second best marker—erythrocyte sedimentation rate—improved the area under the curve of symptoms by 0.16 (95% CI, 0.11-0.21). When fecal calprotectin was added to the model, the proportion of patients without IBD correctly classified as low risk of IBD increased from 33% to 91%. The proportion of patients with IBD incorrectly classified as low risk of IBD decreased from 16% to 9%. The proportion of the total number of patients assigned to the intermediate-risk category decreased from 55% to 6%.

Conclusions and Relevance  In a hospital setting, fecal calprotectin added the most diagnostic value to symptoms compared with blood markers. Adding fecal calprotectin to the diagnostic workup of pediatric patients with symptoms suggestive of IBD considerably decreased the number of patients in the group in whom challenges in clinical decision making are most prevalent.

From: Inflamm Bowel Dis. 2017 Aug 16. doi: 10.1097/MIB.0000000000001202. [Epub ahead of print]

Value of Calprotectin

A large study (WJ Sandborn et al Gastroenterol 2016; 150: 96-102) focuses on the question of how well calprotectin values correlate with clinical outcomes.  As part of a double-blind, placebo-controlled phase 2 trial of 194 patients who received various doses of tofacitinib or placebo, the authors obtained data on fecal calprotectin (FCP).  Here were the key findings:

  • Week 8 FCP levels were significantly lower in those with a clinical response: 156 vs 725 mg/kg, in clinical remission: 64 vs 617 mg/kg, in endoscopic remission: 44 vs 489 mg/kg and in mucosal healing: 127 vs. 753 mg/kg.
  • On an individual level, FCP showed only moderate agreement for these measures.

For clinical remission, FCP concentration:

  • At 50 mg/kg, the specificity was 0.91, sensitivity was 0.43
  • At 150 mg/kg, the specificity was 0.79, sensitivity was 0.68

For endoscopic remission, FCP concentration:

  • At 50 mg/kg, the specificity was 0.88, sensitivity was 0.52
  • At 150 mg/kg, the specificity was 0.75, sensitivity was 0.79

For mucosal healing, FCP concentration:

  • At 50 mg/kg, the specificity was 0.92, sensitivity was 0.29
  • At 150 mg/kg, the specificity was 0.85, sensitivity was 0.54

The authors speculate that the only fair to good accuracy of FCP in classifying clinical and endoscopic outcomes of individual patients could be related to day-to-day variability in FCP levels and due to residual microscopic inflammation.

My take: While a single normal calprotectin value is not entirely reassuring, I would not be surprised if these values outperform the PGA (physician global assessment).  It is likely that serial calprotectin values will be helpful in tracking clinical progress.

In brief:

Agardh et al. JPGN 2016; 62: 43-46.  Authors show that fecal calprotectin levels were markedly elevated (median 844 mg/kg) in 11 of 12 patients with juvenile polyps and that these levels normalized after polypectomy.  These levels were similar to their cohort (n=129) of children with active IBD (median values of 962 mg/kg).

Heida et al. JPGN 2016; 62: 47-49.  The investigators retrospectively examined 80 children who had endoscopy due to suspected inflammatory bowel disease.  In all 10 of the children with calprotectin levels less than 50 (mcg/g), IBD was excluded.

Related blog posts:

Old Town, San Juan

Old Town, San Juan