Optimizing Management using CRP, Fecal Calprotectin and Ferritin. Peter Laszlo Lakatos 1st Department of Medicine Semmelweis University Budapest

Size: px

Start display at page:

Download "Optimizing Management using CRP, Fecal Calprotectin and Ferritin. Peter Laszlo Lakatos 1st Department of Medicine Semmelweis University Budapest"

Bridget Hope Walsh
5 years ago
Views:

1 Optimizing Management using CRP, Fecal Calprotectin and Ferritin Peter Laszlo Lakatos 1st Department of Medicine Semmelweis University Budapest

2 Objectives Overview of disease progression Old and new treatment goals Patient monitoring: the value of biomarkers Which and how often?

3 Digestive damage Inflammation is ongoing and results in cumulative tissue damage Stricture Fistula / abscess Surgery Stricture Inflammatory activity (CDAI, CDEIS, CRP) Disease onset Diagnosis Early disease Window of opportunity? CDAI: Crohn s disease activity index; CDEIS: Crohn s disease endoscopic index of severity; CRP: C-reactive protein Pariente B, et al. Inflamm Bowel Dis 2011

4 Percent of Patients Natural History of Ulcerative Colitis* 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Status at any given timepoint Years After Diagnosis Colectomy Disease activity Remission Langholz E et al. Gastroenterology. 1994;107:3.

5 IBD a complex phenotype

6 Disease progression prediction Fact(s) or prophecy: one size for all? Prediction is very difficult, especially if it's about the future Niels Bohr

7 PREDICTORS: Possible factors associated with severe course of Crohn s disease have been proposed Young age (Beaugerie L et al Gastro 2006; Loly et al Scand J Gastro 2008) Smoking (Franchimont D EJGH 1998, Lakatos IBD 2013) Extensive small bowel disease (Munkholm Gastro 1993) Peri-anal disease (Beaugerie L et al Gastro 2006; Loly et al Scand J Gastro 2008) Steroids at diagnosis (Beaugerie L et al Gastro 2006) Weight loss (Loly et al Scand J Gastro 2008) Deep ulcerations at endoscopy (Allez M Am J Gastro 2002)

8 The Matrix: Risk of complicated disease IBSEN Definition of advanced disease: at least one of the following criteria: (1) intestinal resection, (2) progression in disease behavior, or (3) need for thiopurines 8 Solberg IC, et al. Inlfamm Bowel Dis 2014;20:60-68.

9 Before starting or modifying any therapy: it is time to set treatment GOALS! The problem with communication... is the illusion that it has been accomplished George Bernard Shaw

10 What is our treatment goal? Clinical remission QoL remission CRP remission Endoscopic remission Faecal marker remission Imaging remission Histologic remission Cytokine remission NORMAL LIFE! CHANGE THE NAUTRAL HISTORY!

AND: goals may be different in different stages of the disease Disease stage Biological remission (Inflammation control) Clinical remission (Symptom control) Outcomes Early disease Mucosal healing;

calprotectin: <250 μg/g Clinical practice: complete absence of symptoms; 1 2 formed stools per day without abdominal pain/cramping Clinical trials: CDAI <150 points Complete absence of symptoms; no

11 AND: goals may be different in different stages of the disease Disease stage Biological remission (Inflammation control) Clinical remission (Symptom control) Outcomes Early disease Mucosal healing; colonoscopy: no ulcers (with the exception of a certain number of aphthous ulcers <5 mm in diameter) Improvements in serum and faecal biomarkers of active inflammation: CRP: <5 mg/l; faecal calprotectin: <250 μg/g Clinical practice: complete absence of symptoms; 1 2 formed stools per day without abdominal pain/cramping Clinical trials: CDAI <150 points Complete absence of symptoms; no disease progression; no complications; no disability; normal quality of life Late disease Mucosal healing; colonoscopy: no ulcers (with the exception of a certain number of aphthous ulcers <5 mm in diameter) Improvements in serum and faecal biomarkers of active inflammation: CRP: <5 mg/l; faecal calprotectin: <250 μg/g Clinical practice: inflammatory symptom improvement (may experience residual symptoms of pain or diarrhoea because of previous surgical treatment or intestinal damage) Clinical trials: CDAI points Stabilisation of noninflammatory symptoms; no progression of structural damage; no progression of disability; improved quality of life Panaccione R, et al. Inflamm Bowel Dis 2013;19:

12 Crohn s disease: What is the consensus target? The target for Crohn s disease is a combination of: and Clinical/PRO remission defined as resolution of abdominal pain and diarrhea/altered bowel habit which should be assessed at a minimum of 3 months during the active disease Endoscopic remission defined as resolution of ulceration at ileocolonoscopy (or resolution of findings of inflammation on cross sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy) which should be assessed at 6-9 month intervals during the active phase Adjunctive measures of disease activity that may be useful in the management of selected patients but are not a target include: CRP Fecal calprotectin Measures of disease activity that are not a target: Histology

13 Ulcerative colitis: What is the consensus target? The target for ulcerative colitis is a combination of: and Clinical/PRO remission defined as resolution of rectal bleeding and diarrhea/altered bowel habit which should be assessed at a minimum of 3 months during the active disease Endoscopic remission defined as resolution of friability and ulceration at flexible sigmoidoscopy or colonoscopy which should be assessed at 3-6 month intervals during the active phase Adjunctive measures of disease activity that may be useful in the management of selected patients but are not a target include: CRP Fecal calprotectin Histology Measures of disease activity that are not a target: Cross sectional imaging

14 Where during the course of IBD are markers needed? Diagnosis and differential diagnosis? Short term prediction: Assessement of disease activity? Long term prediction: Prognosis and risk for complications? Optimazing drug therapy and side effects? Risk for post-operative recurrence?

15 Lessons learned in clinical practice SYMPTOMS ACTIVE INFLAMMATION Functional, stenosis, abscess, bile acid diarrhea, motilityd NO SYMPTOMS NO MUCOSAL LESIONS NORMAL MUCOSA? NO ACTIVE DISEASE Transmural and extramural complications

16 Patient monitoring: which and how often? Clinical markers Genetic markers Serology markers Biomarkers No amount of experimentation can ever prove me right; a single experiment can prove me wrong. Albert Einstein

17 Gastroenterologists (%) Evolving treatment goals: is biomarker a INDICATOR or TARGET? Clinical criteria are used by gastroenterologists to guide therapeutic decisions Main criterion for therapeutic decisions Biomarkers used for IBD activity monitoring Gastroenterologists (%) CRP 94 FBC + differential 78 Calprotectin Iron status 63 0 Clinical Endoscopy Biomarkers ESR 3 Schoepfer AM, et al. JCC 2012;6:

18 Facts: Observed Average Annual Rate for Hospital Visits, Endoscopies, Surgeries, Laboratory Investigations, and Imaging in US health care utilization in 964,633 patients with IBD Van Deen WK et al Inflamm Bowel Dis 2014

19 Serum Markers of Inflammation in IBD N=91 children; Mean age 11 years (3 months 18 years) Referred for endoscopy with symptoms of abdominal pain, diahorrhea, rectal bleeding, weight loss or mouth ulceration for minimum of 3 months All underwent endoscopy, blood tests and small bowel follow-through Investigation Crohn s disease (n=26) Ulcerative colitis (n=13) Polyps (n=8) Normal (n=37) Others* (n=7) Haemoglobin <10 g/dl ESR >25 mm/hour Albumin <36 g/dl Platelet >400 x 10 9 /l C-reactive protein >5mg/L All normal ESR=erythrocyte sedimentation rate *TBC (2), IC (3), lymphoid nodular hyperplasia (3) Beattie RM, Walker-Smith JA, Murch SH. Arch Dis Childhood 1995;73:

20 Median CRP mg/l Serum markers: markers of activity/relapse? Prospective CD (n=64) UC (n=50) Mild Moderate Severe Fagan EA et al. Eur J Clin Invest 1982; 12:

21 Correlation of CRP with Clinical, Endoscopic, Histologic, and Radiographic Activity Logistic regression: OR (95% CI) CRP: CD (n=104) UC (n=43) Clinical activity Endoscopic activity Histologic activity Radiologic changes 4.5 (1.1-18) 4.1 (1.6-11) 10 (1.0-97) NS NS NS p=0.029 NS Ileocolonoscopy shows active CD (n=72) Ileocolonoscopy does not show active CD (n=32) CRP normal 46% 75% CRP elevated 54% 25% Solem CA et al; Inflamm Bowel Dis 2005; 11:8:

CRP as a predictor of active endoscopic disease in CD Sensitivity Assessment of hscrp in Crohn s disease patients undergoing colonoscopy (n=164) 1.0 0.8 0.6 0.4 0.

22 CRP as a predictor of active endoscopic disease in CD Sensitivity Assessment of hscrp in Crohn s disease patients undergoing colonoscopy (n=164) AUC = Specificity Active endoscopic disease was defined as SES-CD score >7 points Jones J, et. al. Clin Gastro Hepatol. 2008;6:

23 How often? EVERY 6 weeks? CRP predicts short-term relapse in IBD 71 CD patients in medical remission CRP >20 mg/l and ESR >15 mm/h were selected as markers predictive of relapse A binary biological predictive score was derived: "negative" when both were lower than their limits, "positive" when otherwise Sensitivity was 89% Specificity was 43% RR of relapse (95% CI) CRP >20 mg/l only 10.5 ( ) ESR >15 mm only 6.1 ( ) Combined 9.9 ( ) Consigny T et al. IBD 2006; 12:551-7

24 Every 12 weeks? Predictors of clinical remission during adalimumab at one year: early deep clinical remission Kiss LS APT 2011;34:911

25 Predictive power of clinical and laboratory parameters to identify patients in clinical remission (CDAI < 150) (A) and endoscopic response (B) at week 52 Kiss LS APT 2011;34:911

26 CRP: every 14 weeks? predicted maintenance of response or remission in ACCENT I Elevated baseline CRP dropped to < 0.5 mg/dl (fixed line) or remained elevated (> 0.5 mg/dl, dotted line) by week 14 Analysis restricted to patients with CRP > 0.5 mg/dl at baseline who were in response (n = 158) or remission (n = 107) at week 14! Reinisch W et al. ATP 2012; 35:568-76

27 Percent CRP a Marker of Long-term Disease Outcome? Percent CRP>23 mg/l at diagnosis in extensive UC and risk for colectomy In 5 years (n=129) CRP>53 mg/l at diagnosis in L1 CD and risk for surgery In 5 years (n=46) Quartile Quartile Henriksen M, et al. Gut 2008;57:

28 Cumulative rate of colectomy (%) Cumulative Risk of Colectomy IBSEN ESR 30 mm/h (HR 2.94) Extensive colitis (HR 2.98) Age 50 (HR 0.28) N at risk: 0 0 ESR = Erythrocyte sedimentation rate; HR = hazard ratio Solberg 28 IC, et al. Scan J Gastroenterol 2009;44(4): Years since diagnosis

Cumulative Risk of Colectomy IBSEN ESR Accuracy 90.3% < 30 > 30 Age @ dg < 40 yrs > 40 yrs 8.0% 95% CI 5.

5 Yes No Need for steroids @ dg Proctitis or leftsided Extensive colitis Location @ dg ESR = Erythrocyte

29 Cumulative Risk of Colectomy IBSEN ESR Accuracy 90.3% < 30 > 30 dg < 40 yrs > 40 yrs 8.0% 95% CI % 95% CI % 95% CI % 95% CI Yes No Need for dg Proctitis or leftsided Extensive colitis dg ESR = Erythrocyte sedimentation rate; HR = hazard ratio Solberg 29 IC, et al. Scan J Gastroenterol 2009;44(4): Cvancarova M et al. Gut 2010;59 Suppl III:A36

30 Predicting the Outcome of Severe UC 85% of patients with : Stool frequency >8/day or C-reactive protein (CRP) >45mg/L and stool frequency 3 8/day on day 3 of intensive treatment required colectomy 1 Validated in 68 patients from 4 Scandinavian centres 2 : Day 3 frequency >4 and CRP >25mg/L: 75% colectomy Sweden index = stool frequency (0.14 x CRP) When index >8, 72% came to colectomy 1. Travis SP, et al. Gut 1996;38: Lindgren SC, et al. Eur J Gastroenterol Hepatol 1998;10:

31 Are we using CRP properly? Things should be made as simple as possible, but not any simpler. Albert Einstein

32 Accuracy of hs-crp for identifying active disease during prospective follow-up app % of CD patients are CRP negative at diagnosis CRP AUC: 0.92 CRP AUC: 0.61 Sensitivity (%) Specificity (%) PPV (%) All CD patients CD patients with a positive NPV (%) CD patients with a negative dg * Cut-off for hs-crp 10mg/l Kiss LS IBD 2012

33 CRP in Crohn s disease; are we using it properly? app % of CD patients are CRP negative at diagnosis CRP CRP Kiss LS IBD 2012

34 Faecal calprotectin (mg/l) Faecal calprotectin in different organic and functional GI disorders 10,000 Differntial dg 1, IBD Cancer Enteropathy Coeliac IBS Crohn s disease UC Infective diarrhoea Diverticular disease Diabetic diarrhoea Organic disease: sensitivity 89% and specificity 79% at 50 µg/g threshold; OR 27.8 ( ) Tibble JA, et al. Gastroenterology 2002;123:

35 Calprotectin mg/l Log scale Calprotectin mg/l Log scale Calprotectin is associated with active disease Faecal Calprotectin, normalizes in 3-4 weeks * P < ,000 10,000 Active disease Remission * * 20,000 10,000 Prednisolone 80 mg + 5-ASA 3 g/daily 5-ASA 3 g/daily 1,000 1,000 Clinical remission Crohn s disease Ulcerative colitis 1 Weeks Roseth A, et al. Digestion 1997;58: Roseth A, et al. Scand J Gastroenterol 2004;39:

Fecal Calprotectin Predicts Endoscopically Active Disease in CD 140 CD, 43 controls CD vs controls: Calpro: 334 vs.18, CRP: 26 vs. 3, Leukocytes: 9.1 vs. 5.

36 Fecal Calprotectin Predicts Endoscopically Active Disease in CD 140 CD, 43 controls CD vs controls: Calpro: 334 vs.18, CRP: 26 vs. 3, Leukocytes: 9.1 vs. 5.4 Calpro correlated strongest with SES-CD Spearman s correlation: RCalpro: 0.73, RCRP: 0.53, Rleukocyta: 0.42, RCDAI: 0.38 Schoepfer AM. Am J Gastroenterol 2010;105: DꞌHaens et al Inflamm Bowel Dis 2012

37 SES-CD Calprotectin as a surrogate marker of endoscopic activity in CD Sensitivity Correlation between SES-CD and calprotectin in Crohn s disease patients requiring colonoscopy (n=87) SES-CD large ulcers (n=48) vs other (n=39) n=87 r=0.490 p< Faecal calprotectin >250 µg/g Sens: 60.4% Spec: 79.5% PPV: 78.4% NPV: 62.0% AUC (95% CI): ( ) Faecal calprotectin (µg/g) Specificity D Haens G, et al. Inflamm Bowel Dis 2012;18:

38 Fecal Calprotectin Predicts Endoscopically Active Disease in UC Faecal Calprotectin (µg/g) 1,500 1, Inactive Mild Moderate High Rachmilewitz Endoscopic Activity Index The values outside the whiskers represent individual outliers Schoepfer, AM. Inlfamm Bowel Dis 2009;15: Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) Calprotectin 50 µg/g Calprotectin 100 µg/g Clinical Activity Index CRP 5 mg/l Blood Leukocytes 7.9 g/l PPV = Positive Predictive Value NPV = Negative Predictive Value

39 Calprotectin as a surrogate marker of endoscopic activity in UC Correlation between MAYO score and calprotectin in ulcerative colitis patients (n=39) D Haens G, et al. Inflamm Bowel Dis 2012;18:

40 USE COMBO: faecal calprotectin and hscrp to predict mucosal healing * Subanalysis of the STORI trial hscrp <5 mg/l Calpro 250 µg/g hscrp <5 mg/l and Calpro 250 µg/g Sensitivity 78% 82% 74% Specificity 39% 53% 72% * Defined as CDEIS 3 Lémann M and the GETAID. Gut 2010;59(Suppl. III):A80:OP370 at UEGW 2010

41 Cumulative survival Sensitivity Predicting the Outcome of severe UC? Calprotectin < μg/g Calprotectin> μg/g Days to colectomy Specificity 1.0 AUC=0.65; P=0.04 Ho GT, et al. Am J Gastroenterol 2009;104:

42 Probability of remaining free of relapses How often to measure:every 12 weeks? Calprotectin predicts risk of relapses 43 CD 25 (58%) 12 month clinical relapse 37 UC 19 (51%) 12 month clinical relapse After 1-4 months of clinical remission UC Calprotectin <50mg/L CD Calprotectin <50 mg/l UC Calprotectin >50 mg/l CD Calprotectin >50 mg/l RR 10.6 (CD) RR 13.4 (UC) Time (Months) Tibble Gastroenterology 2000

43 Calpro (microg/g) Every 16 weeks? STORI sub-analysis: calprotectin levels months before relapse Relapsers n=51 p= Non-relapsers n=62 0 De Suray N. ECCO 2012: P Time before relapse (months) STORI enrolled 115 Crohn's disease patients who were treated with infliximab plus an immunomodulator for at least 1 year, and who were in stable remission for at least 6 months. Infliximab was discontinued, and 39% of patients relapsed within 1 year. 44

44 Fecal Calprotectin Predicts disease activity in patients with IBD: meta-analysis AUCUC: 0.93 ( ) AUCCD: 0.88 ( ) Lin JF et al Inflamm Bowel Dis 2014

45 What is the best cut-off value? Lin JF et al Inflamm Bowel Dis 2014

46 Fecal Calprotectin Predicts relapse in patients with IBD: meta-analysis AUC: 0.83 Mao R et al Inflamm Bowel Dis 2012

47 Calprotectin and postoperative endoscopic recurrence (I2) months predicts 1-year endoscopic recurrence Orlando A Eur Rev Med Pharmacol Sci 2006

48 CALPRO light : Homebrew Elkjaer M APT 2010;31:323-30

49 Proportion without relapse Predictive model for the time-to-relapse Results from the STORI cohort: biomarkers have an added value over endoscopy Kaplan Meier time-to-relapse curves according to multivariate models and scores generated through Cox model using multiple imputations method No. of deleterious factors < > Months since infliximab withdrawal Deleterious factors were: no previous surgery, steroid use within 12-6 months before infliximab withdrawal, male gender, haemoglobin 14.5 g/dl, leukocyte count > /l, hscrp 5 mg/l, faecal calprotectin 300 µg/g, CDEIS >0, infliximab trough 2 mg/l Louis E and the GETAID, GE 2011

50 Anemia: an important surrogate target? Definitions Bermejo et al WJG 2009 Oustamanolakis, et al JCC 2011

51 Anemia: How to diagnose and do we test it?? Oustamanolakis, et al JCC 2011 Steing et al EJGH 2013

52 Anemia: an important surrogate target? Results from a population-based cohort between How frequent? CD UC Lakatos et al WJG 2003

53 Anemia: How to monitor? FERGIcor Real life? Europe in 2011 Relevant changes occur in WEEKS! Evstatiev R, et al Gastroenteorlogy 2011 Steing et al EJGH 2013 Kulnigg-Dabsch S et al PlosOne2012

54 Is tight control leading to superior outcomes? If you can't explain it simply, you don't understand it well enough. Albert Einstein

55 REACT: therapeutic algorithm for Crohn s disease Without fistula Active Luminal CD (HBS >4) With fistula GCS (bud vs pred depending on disease activity and localisation) Complex fistula * For patients in Belgium, evaluate in 12 wks Re-evaluate in 12 wks remission? Yes No maintenance therapy Yes Evaluate in 4 wks * remission? (HBS 4) No No Re-evaluate in 12 wks remission? Yes No Continue combination maintenance therapy Taper GCS Adalimumab + AZA or MTX (GCS as needed) Yes Continue combination maintenance therapy Yes Yes Add adalimumab + AZA or MTX Taper GCS, re-evaluate in 12 wks remission? Increase adalimumab to weekly dose Continue combination maintenance therapy Re-evaluate in 12 wks remission? No Switch antimetabolite Re-evaluate in 12 wks remission? Yes MRI, US, EUA to rule out abscess Drainage / seton + antibiotics Yes Yes No Follow algorithm for Switch TNF blocker active luminal CD without fistula Re-evaluate in 12 wks remission? Continue combination maintenance therapy Consider resection No No Antibiotics / fistulotomy Abscess present? No Re-evaluate in 4 wks - improved? No Surgical reassessment Khanna R, et al. ECCO 2014, Copenhagen;OP004

56 Patients (%) Patients (%) Patients (%) Patients (%) REACT: time to initiation of treatment 40 Corticosteroids 40 Antimetabolites 30 p= p< Early combined immunosuppression Time (months) TNF antagonists p< Antimetabolites and TNF antagonist p<0.001 Time (months) Conventional management Time (months) Time (months) Khanna R, et al. ECCO 2014, Copenhagen;OP004

Patients (%) REACT: symptomatic remission Harvey Bradshaw Index 4 and no corticosteroids 100 90 80 Conventional management Early combined

57 Patients (%) REACT: symptomatic remission Harvey Bradshaw Index 4 and no corticosteroids Conventional management Early combined immunosuppression p=0.790 p=0.498 p=0.389 p= Baseline Month 6 Month 12 Month 18 Month 24 Khanna R, et al. ECCO 2014, Copenhagen;OP004

58 Hospitalisation, surgery or complications (%) REACT: time to first hospitalisation, surgery or complication 40 HR (95% CI) = 0.73 (0.62, 0.86), p< Conventional management Early combined immunosuppression 34.7% 27.4% Time (months) Khanna R, et al. ECCO 2014, Copenhagen;OP004

59 Conclusions Biomarkers are important both in the short and long term follow-up of IBD patients Identify relevant clinical questions! Use a combination of clinical variables and biomarkers Disease phenotype, Endoscopic results, Medical management, Environmental factors Laboratory markers: e.g. serum/fecal markers (ESR/ (hs)crp/calprotectin) Sequential reassessment! A tailored approach is needed Assess patients heterogeneity and stratify Assess patient s specific markers or group of markers 61

) + imaging (MRI and/or scope) q12 Clinical review + lab (CRP+ FC?

60 Tight monitoring my practice in CD Mild disease Moderate disease Severe disease risk factors + risk factors Clinical review q3m + lab (CRP+ FC?) + imaging (MRI and/or scope) q12 Clinical review + lab (CRP+ FC?) q6m Annual review : Clinical review, bloods (FBC, U&E, LFT, Alb, CRP, Ferritin, Fo, B12), faecal calprotectin (FC?) * * Colonoscopy and MRE in selected individuals at 12m or if increase CRP/FC indicates active disease

5/2/2018 SHOULD DEEP REMISSION BE A TREATMENT GOAL? YES! Disclosures: R. Balfour Sartor, MD

5/2/2018 SHOULD DEEP REMISSION BE A TREATMENT GOAL? YES! Disclosures: R. Balfour Sartor, MD 5/2/218 SHOULD DEEP REMISSION BE A TREATMENT GOAL? YES! Disclosures: R. Balfour Sartor, MD Grant support for preclinical studies: Janssen, Gusto Global, Vedanta, Artizan BALFOUR SARTOR, MD DISTINGUISHED