Diagnostics and disease monitoring in IBD: State of the art 2011

Transcription

1 Diagnostics and disease monitoring in IBD: State of the art 2011 David T. Rubin, MD Associate Professor of Medicine Co-Director, Inflammatory Bowel Disease Center University of Chicago Medical Center The First Goal of Management in IBD: Obtain a Clear and Accurate Diagnosis A clear diagnosis should provide information that: Explains the patient s current symptoms and problems Is accurate now and withstands the test of time Provides prognostic information Makes a distinction in the management decisions such that therapy chosen now impacts both short- and longterm outcomes. May have implications for the care of others (ie family members). In 2011, should include disease extent and current severity and some element of longitudinal prognosis. David T. Rubin, MD

2 What is Disease Monitoring in IBD? Assessment of the status of disease activity over time. Performed in order to control disease and prevent symptomatic relapses or disability. Monitoring requires: Understanding of the disease process Acceptable methods of assessment Interventions that are effective and tolerable (by the patient and by the MD) Examples: Clinical follow-up Routine laboratory testing for drug efficacy or safety Measures of mucosal integrity or immune activity Clinical Features of UC and CD Ulcerative Colitis Continuous inflammation Colon only Superficial inflammation Variable extent Risk of cancer Extraintestinal manifestations Crohn s Disease Patchy inflammation Mouth to anus involvement Full-thickness inflammation Fistulas and strictures Risk of cancer Extraintestinal manifestations Frequency of Involvement Greatest Least David T. Rubin, MD

3 Montreal Classification Crohn s disease Location (L) L1 L2 L3 L4 Behavior (B) B1 B2 B3 (p) modifier Terminal ileum Colon Ileocolon Upper GI Non-stricturing, nonpenetrating Stricturing Penetrating Perianal Montreal Classification ulcerative colitis Classification by Extent Ulcerative proctitis (E1) Left-sided ulcerative colitis (E2) Extensive ulcerative colitis (E3) David T. Rubin, MD

4 The Challenges to Diagnosis in IBD Lack of knowledge about the disease and its various manifestations (primary care?) Lag time of pre-symptomatic disease before presentation Inaccurate classification system Overlap of phenotypes between UC and Crohn s disease Variations of existing disease presentations The Spectrum of Utility in IBD Predicting Behavior Rx Response Need for Surgery & Outcome Monitoring activity, response David T. Rubin, MD

5 Diagnosis in IBD Primary Dx of IBD Rule out imposters Obvious GI symptoms/signs and classic presentation Extra-intestinal symptoms/signs and findings Re-evaluation over time Clarification of IBD Dx Ileocolonoscopy with biopsy Distinction between IBS and active inflammation Reliable expert pathology Evaluation of small bowel WCE CTE/MRE Exam under anesthesia, exploratory lap Use of other clues family history serologies Non-GI specialists Historical Features that Help to Confirm a Diagnosis of IBD Appendectomy protects against UC Ex-smokers may develop UC Smokers have CD Family history usually concordant Early Appendectomy Protects Against UC Andersson RE, et al. N Engl J Med. 2001;344: David T. Rubin, MD

6 What about these phenotypes? Is this IBD? Oral facial granulomatous disease Isolated perianal disease Hydradenitis supporativa Isolated pyoderma gangrenosum Peri-appendiceal red patch? Gastric inflammation in kids with UC? Rectal sparing in UC? Incidental ileitis Wireless capsule findings? Serologic markers? Most Common Imposters in the Differential Diagnosis of IBD Infectious colitis (including Clostridium difficile) Ischemic colitis Drug-induced (NSAID) enterocolitis Solitary rectal ulcer syndrome Radiation enterocolitis Diversion colitis Endometriosis Malignancy Functional (IBS) Diverticular disease Adapted from Forcione DG, Sands BE. In: Sartor RB, Sandborn WJ. Kirsner s Inflammatory Bowel Diseases. 6th ed. New York: Saunders; 2004: David T. Rubin, MD

7 Imaging in IBD Macroscopic vs Microscopic Diagnosis explanation of symptoms or lab abnormalities clarification of disease extent and severity Cancer screening and surveillance Prognosis, adjunctive to additional testing Choice of therapy (class or delivery system) Prevention of disease expression or complications? Small Intestinal Crohn s Disease as Seen by Wireless Capsule Endoscopy David T. Rubin, MD

8 Promise and Problems of CE in IBD PROMISE Exquisite imaging of small bowel mucosa Less invasive diagnostics (?) Emerging information about significance of findings, etc Recent FDA indication for monitoring of CD PROBLEMS Observer-dependent interpretation training required inter/intra observer variability Uncertain significance of many findings- what s normal? Short-term Long-term Need blinded comparator studies Heterogeneous data quality of studies Capsule retention Are All Small Bowel Lesions CD? David T. Rubin, MD

9 Diagnostic Yield of Wireless Capsule Endoscopy in Suspected or Known Crohn s Study N Indication Diagnostic Yield Costamagna 3 Suspected CD or 67% CD recurrence Scapa 13 Suspected CD 46% CD Eliakim 20 Suspected CD 60% CD Fireman 17 Suspected CD 71% CD Liangpunsakul 3 Abdominal pain, Fe anemia 100% CD Herrerias 21 Suspected CD 43% CD Mow 50 Known or suspected CD 60% CD Adapted from Loftus EV. Clin Gastroenterol Hepatol. 2004;2:14-16 with permission from American Gastroenterological Association. Suspected CD subgroup Study IY (random) [95% CI] IY (random) [95% CI] Costamagna [-0.85, 0.85] Dubcenco [-0.04, 0.79] Eliakim [0.35, 0.74] Toth [-0.02, 0.37] Chong [-0.11, 0.11] Hara [-0.16, 0.66] Total (95% CI) Total yield (fixed): 43% (CE), 13% (bariumradiography) Test for heterogeneity: P < 0.001, 001 I² = 85.6% Test for overall effect: P = [-0.03, 0.51] Yield higher in barium radiography Yield higher in capsule endoscopy Triester, Leighton, et al. AJG Established CD subgroup Study IY (random) [95% CI] IY (random) [95% CI] Costamagna [-0.21, 1.21] Buchman [-0.20, 0.27] Dubcenco [0.49, 0.90] Marmo [0.23, 0.67] Toth [0.35, 0.87] Chong [0.38, 0.86] Hara [0.34, 0.99] Total (95% CI) Total yield (fixed): 78% (CE), 32% (barium radiography) 0.51 [0.31, 0.70] Test for heterogeneity: P = 0.001, I² = 72.9% Test for overall effect: P < Yield higher in barium radiography Yield higher in capsule endoscopy David T. Rubin, MD

10 How Often do Lesions Occur in Normal Volunteers? Findings from a study of COX-2 selective NSAIDs, and SB injury in normal volunteers 14% on no NSAIDS had mucosal breaks at baseline CE studies in osteoarthritis patients without GI symptoms and on no NSAIDS 17% on acetaminophen and no NSAIDS, had SB lesions at baseline Goldstein et al. CGH 2005 Graham, et al CGH 2005 The Problem of Strictures David T. Rubin, MD

11 Capsule Retention Capsule Retention Rate in CD Depends on Clinical Scenario Author Patients Capsule CD? (n) retention (%) Herrerias 21 0 Suspected Fireman 17 0 Suspected Eliakim 20 0 Suspected Sant Anna 20 5 Susp (hi prob) Mow 50 4 Known Buchman 30 6 Known Cheifetz Known Cheifetz Suspected strictures David T. Rubin, MD

12 Small bowel radiographs: is it time to retire? CT Enterography Combines high-resolution CT scanning with some of the concepts of barium radiography Ingestion of large volume of a negative contrast agent (either PO or via NJT) to distend loops Water or diluted PEG Intravenous contrast, scan after 70 seconds (venous phase) Thin slices on helical CT Signs of inflammation David T. Rubin, MD

13 Segmental Distribution of Small Bowel Mural Thickening Small Bowel Mural Thickening (1-2 cm) David T. Rubin, MD

14 Homogeneous Mural Enhancement of Small Bowel Perienteric Fat Stranding David T. Rubin, MD

15 Fistulas Tracts Usually enhancing (unless perianal) +/- fluid/air Effective Doses of Radiation CXR: 0.1 msv Round trip airflight, NYC-London, 0.1 msv Mammogram: 0.7 msv SBFT: 2-6 msv Average annual background radiation, 2.4 msv Standard CTE (single phase): 8-12 msv Radiation worker exposure annual al limit: 20 msv Bleed protocol CTE (triple phase): msv International Space Station, annual: 170 msv David T. Rubin, MD

16 MR Enterography Ileal Inflammation A. Enteroclysis B. MRI Enterography Schreyer AG, et al. Clin Gastroenterol Hepatol. 2004;2:491. David T. Rubin, MD

17 Accuracy of MRE versus Ileocolonoscopy (IC) 98 subjects with established Crohn s disease underwent tmre and IC 22 pediatric subjects underwent MRE and IC for newly diagnosed Crohn s disease Sensitivity (95% CI) Specificity (95% CI) TI/Anastomosis 72% (53% - 86%) 85% (74 92%) Colorectum 59% (42% - 74%) 90% (80% - 96%) 4/10 false negative MRE s were due to radiologic interpretation errors MRE has modest sensitivity for terminal ileal Crohn s disease, utility in the colon is lower Radiologists interpreting MRE should be well-trained MRE had good sensitivity for ileal lesions, but sensitivity for colonic lesions was limited Bruining et al. DDW 2011; abstract no. Su1189 Veereman et al. DDW 2011; abstract no. Su 1921 Ability of MRI to Evaluate Therapeutic Response in Crohn s Disease Magnetic resonance enterography (MRE) to evaluate response to Crohn s therapy 27 subjects received adalimumab or corticosteroids for induction of remission Novel index (MaRIA) quantified severity of MR findings MaRIA correlated with CDEIS (r=0.70 at week 12) MaRIA score <40 predicted endoscopic remission (sensitivity 0.82, specificity 0.85) MRE can accurately evaluate response to Crohn s therapy MR enteroclysis to evaluate effects of infliximab on transmural Crohn s MR enteroclysis score of severity in ileal Crohn s disease (MICD) calculated Primary endpoint: proportion of subjects with >2 points and >50% decrease in MICD at 26 weeks 15 subjects in final analyses 32% met primary endpoint Results were not compared with endoscopic or histological findings MR enteroclysis can monitor effects of infliximab in Crohn s disease What should be done for patients who have evidence of active disease on MRI but are in clinical remission? Ordás et al. DDW 2011; abstract no. 343 Van Assche et al. DDW 2011; abstract no. 344 David T. Rubin, MD

18 US to predict Crohn s Disease Course Clinical recurrence-free survival by US recurrence Clinical recurrence-free survival by endoscopic recurrence No US recurrence No endoscopic recurrence US recurrence Endoscopic recurrence Small bowel US (SB-US) to predict repeat resection after ileocolectomy among 107 Crohn s patients Median follow-up 3.3 years >i2 recurrence in 86% SB-US predicted need for surgery as well as IC SB-US could be an alternative to IC to assess course after ileocolonic resection for Crohn s Daperno et al. DDW 2011; abstract no. Su1187. Microbial Marker Antibodies in Crohn s Disease (n = 303) Anti- OmpC 5.6% Anti- I2 10.6% 11.2% 24.8% 12.9% 4.6% ASCA 10.2% All Negative 20.1% 79.9% of Patients Reprinted from Mow WS, et al. Gastroenterology. 2004;126: with permission from American Gastroenterological Association. David T. Rubin, MD

19 Serology as Initial Test? No prospectively p supported data Diagnostic algorithms not published prevalence: false positives in autoimmune disorders ASCA: celiac, Behcet's, PBC, hepatitis ANCA: eosinophilic & collagenous colitis OMP-C & I2: infection, diverticulitis Cost Austin et al. Clin Gastr Hep 2007;5: Damoiseaux et al. J Clin Immunol 2002; 2(5):281-8 Serologies in IBD: What is State of the Art in 2011? Diagnosis vs. Prognosis The accurate integration of serology testing is a function of the pre-test probability of IBD i.e. If pre-test probability is low, positive serologies are likely to be false positives i.e. If pre-test probability is high, negative serologies are likely to be false negatives Serologies therefore are of diagnostic value in patients with intermediate likelihood of IBD David T. Rubin, MD

20 Predictors of Disabling Disease: 5-year clinical course after diagnosis Age at onset <40 years vs 40 years; p= Location of disease small bowel + colon vs small bowel only; p=0.002 Smoking status smoker vs ex- or non-smoker; p=0.09 Perianal lesion at diagnosis yes vs no; p=0.01 Required steroids for first flare yes vs no; p= Beaugerie et al, Gastroenterology 2006; 130: 650 Serum Immune Responses Predict Rapid Disease Progression in Children with CD n=70 p=0.03 n=97 Serologic markers: ASCA, anti-ompc, anti-i2, anti- CBir1 Dubinsky M et al. Am J Gastroenterol 101:2006. David T. Rubin, MD

21 The Risk of Chronic Pouchitis is Significantly Increased With Pre-Op High Level panca f ative Incidence of ic Pouchitis (%) Cumula Chroni High level P = 0.03 Medium levell Low level panca-neg Months After IPAA Fleshner, P et al. Gut 2001 Should we be treating to achieve mucosal healing? YES!! The inflamed and injured bowel is the hallmark of active disease A healed bowel is the sign of disease control or resolution Many of our therapies can achieve it. Existing strategies are not effective at longer term management control. WAIT- NOT YET! We can t get there in most patients with existing therapies. How is this defined??? Partial? Complete? Histology? Endoscopy? Radiographic?? Cost Convenience David T. Rubin, MD

22 Fecal Calprotectin Levels in IBD Patients with Active Disease and Mucosal Healing p< * * * lprotectin mg/l Log scale Ca Mucosal healing Roseth Scand J Gastro Crohn s disease active / remission Ulcerative colitis active / remission IBD Diagnosis and Management: The Near Future First Visit: Phenotype: Location, EIM, Behavior IBD Panel Serology Genetics Proteomics IBD Subtype Disease Prognosis Patient-specific treatment plan Disease Monitoring for Efficacy and Safety Targeted-specific therapy David T. Rubin, MD