Implementation of disease and safety predictors during disease management in UC DR ARIELLA SHITRIT DIGESTIVE DISEASES INSTITUTE SHAARE ZEDEK MEDICAL CENTER JERUSALEM
Case presentation A 52 year old male patient, Ashkenazi origin was diagnosed with UC A non-smoker, with only occasional alcohol consumption The patient`s father had CRC (diagnosed at 61 years of age), no history of IBD in family He has had to stop his work for the last 3 weeks due to a high number of stools and tenesmus
Prognosis items Gender The patient is a male Poor outcome Colectomy rates higher for men vs women, both for early colectomy ( < 90 days from diagnosis date) (males vs females: 2.6% vs 1.1%; HR = 2.37, 95%; CI = 1.43-3.93; P = 0.0009) and for late colectomy (> 90 days from diagnosis) (males vs females: HR=1.28, 1.08-1.6, P= 0.036) Targownik LE et al. The epidemiology of colectomy in UC: results from a population-based cohort. Am J Gastroenterol 2012
AGE He is 52 years old at diagnosis Not prognostic Older age at diagnosis of UC ( 60y <) Increases the risk of CRC (P=0.033), may also reduce the risk a shorter disease duration ( SIR=8.6;95% CI=3.8-19.5) Reduces the risk of disease extension Reduces the risk of acute-severe colitis and colectomy ( p=0.0003, HR=0.28;95% CI=0.12-0.65) Shi HY et al. Natural history of elderly-onset UC. JCC 2016; Jess T et al. Risk of CRC in patients with UC. Clin Gastroenterol Hepatol 2012; Charpenter C et al. Natural history of elderly-onset IBD. GUT 2014; Solberg IC et al. Clinical course during the first 10 years of UC. Scand J Gastroenterol 2009.
LIFESTYLE He is an ex-smoker and an occasional drinker Poor outcome Active smoking in UC has been associated with a lower risk of: Hospitalization (p=0.01) Flares (HR=0.8;95% CI=0.6-0.9) Colectomy (OR=0.57;95% CI= 0.38-0.85) Insufficient evidence that alcohol consumption has a definite prognostic value in UC Odes HS et al. Effects of cigarette smoking on clinical course of CD and UC. Dig Dis Sci 2001; Hoie O et al. UC: patient chracteristics may predict 10-year disease recurrence. Am J Gastroenterol 2007.
Family history The patient`s father had CRC Poor outcome CRC in a first-degree relative increases the risk of CRC The prognosis of CRC is poorer for patients with UC than for patients without UC A family history of IBD can help predict UC diagnosis, but no definite prognostic value in UC Askling J et al. Gastroenterology 2001; Jensen AB et al. Survival after CRC in patients with UC. Am J Gastroenterol 2006.
CASE PRESENTATION- CONT The patient has experienced back pain for the last 2-3 years with morning stiffness He was prescribed NSAID`S > 1 year ago by his primary physician, were effective against the pain, were stopped due to a severe allergic reaction At consultation, his joints are not swollen, and there is no limitation in movement of the axial or peripheral joints There are no skin lesions present. No EIM was diagnosed
EIM manifestations No EIM was diagnosed Favorable outcome EIM in pediatric UC populations higher risk of colectomy (HR=3.5;1.2-10.5) and UC-related surgery In adult UC patients higher risk of UC-related surgery (p< 0.001, OR = 0.2341;95% CI=1.483-3.695) As EIMs were not diagnosed at presentation, a favorable outcome is likely Whilst not prognostic, ongoing NSAID`S use is associated with an increased risk of flares in UC In this case, the patient stopped taking NSAID`S more than 1 year ago Safroneeva E et al. Prevalence and risk factors for therapy escalation in UC. Inflamm Bowel Dis 2015; Kvasnovsky CL et al. NSAID`S ese and excacerbations of IBD. Scand J Gastroenterol 2015.
Clinical examination 7-8 stools /day ( of which ~ 50% are bloody) Tenesmus- debilitating for employment Mild abdominal pain No fever Pulse rate = 17 beats/min Blood pressure = 135/85 mmhg No evidence of acute-severe colitis Partial Mayo Score of 5 was calculated (5/9) Not prognostic No predictors of outcome were found on examination
Laboratory tests HB 12.8 g/dl WBC- 5960 cells/mm3 CRP 1.4 mg/l (normal < 5) Albumin 4.2 mg/dl Fecal Calprotectin was not measured Favorable outcome Travis SP et al. Predicting outcome in severe UC. GUT 2008.; Kumar S et al. Severe UC: prospective study of parameters determining outcome. J Gastroenterol Hepatol 2004.
Endoscopy Active inflammation up to 45 cm Complete loss of vascular pattern, moderate friability with bleeding upon contact Small erosions, but no large or deep ulcers A series of inflammatory pseudopolyps in sigmoid Normal mucosa beyond 45 cm upon cecum UC endoscopic index of severity (UCEIS) = 6 Endoscopic Mayo score = 2 Favorable outcome No sign of severe colitis (deep ulcers, mucosal abrasion etc.) or extensive disease Presence of multiple pseudopolyps an increased risk of CRC Beaugerie L et al. Clinical, serological and genetic predictors of IBD course. World J Gastroenterol 2012; Velayos FS et al. Predictive and protective factors associated with CRC in UC. Gastroenterol 2006.
UCEIS: Evolving endoscopic scoring in UC
MAYO UC endoscopic scoring
Initial treatment The patient was initially treated with 5-ASA ( 4 gr orally and 1 gr suppositories) Favorable outcome Use of steroids upon diagnosis associated with proximal disease extension in adults with ulcerative proctitis An absence of response to first-line treatment with mesalazine and a need for early steroid therapy increased risk of disease extension Kim B et al. Proximal disese extension and related predicting factors in UC. Scand J Gastroenterol 2014; Waterman M et al. Predictors of outcome in UC. Inflamm Bowel Dis 2015.
Age > 60 y Prognostic factors for benign disease course Lack of EIM diagnosis on presentation No extensive colitis Presentation with mild/moderate flare only (reflected by initial laboratory tests and endoscopy)
Young age Prognostic factors for poor outcome Presence of pseudopolyps risk for CRC (if inflammation is not controlled) Absence of response to primary therapy of 5-ASA increased risk for disease extension and colectomy
Case presentation - Cont No significant improvement was observed with oral and rectal mesalazine Severe tenesmus,10 bloody stool movements a day Low grade fever and abdominal tenderness PO steroid therapy was initiated No response Severe weakness and worsening of rectal bleeding Hospitalization and administration of IV steroids
What are bad prognostic factors for acute severe colitis? 1. Concomitant PSC 2. Extensive disease 3. Active smoking 4. Family history of IBD 5. Disease duration > 10 y
Prognostic factors for acute severe UC Extensive disease Younger age at diagnosis Shorter duration of disease Concurrent infection-cmv/cdt clinical risk factors PSC Active smoking Protective prognostic factors
Potential UC disease course over first 10 y
Natural history of UC
Features of progressive disease in UC
Laboratory tests HB 9 g/dl bad outcome WBC- 13000 cells/mm3 CRP 25 mg/l (normal < 5) Albumin 2.1 mg/dl Fecal Calprotectin - 850 Increased CRP at diagnosis Increased risk of colectomy (p = 0.02, OR= 4.8;95% CI= 1.5-15.1) Increased CRP Increased risk of refractoriness to medical therapy, particularly in acute severe colitis Severe anemia (< 10 g/dl)- A sign of acute-severe colitis in association with other factors Low albumin levels- A marker of severe colitis and a predictor of refractoriness to medical therapy (p = 0.026) Travis SP et al. Predicting outcome in severe UC. GUT 2008.; Kumar S et al. Severe UC: prospective study of parameters determining outcome. J Gastroenterol Hepatol 2004.
Severe and refractory colitis on endoscopy
Case presentation - cont Steroid pulse therapy without response CT- diffuse sigmoid and des. Colon thickening Repeat Sigmoidoscopy showing very severe UC, CMV neg Still had 12-15 bloody BM/day, 2-3 BM/night, weight loss of 7 kg over 10 days Mantoux test inconclusive under steroids Anti- TNF therapy was initiated
Which anti-tnf to choose? Infliximab? Adalimumab?
ADA and IFX were similarly effective in the treatment of moderate to severe UC in the real world clinical setting
Yet, in acute severe colitis: IFX is recommended!
Acute severe colitis (ASUC) The most aggressive presentation of UC Occurs in 15% of patients Refractoriness to iv steroids in 50% of adults and 33% of children Similar rates of response to calcineurin inhibitors and IFX More favorable adverse effect profile of anti-tnf 30% of adults with ASUC colectomy within 60 days, 20% of children within a year
Higher serum concentrations of anti-tnf biologics = better outcome
ASUC- accelerated clearance of anti-tnf
Alternative dosing regimens may be needed in patients with ASUC
Which of the factors is most associated with rapid anti-tnf clearance? 1. Elevated CRP 2. Weight under 40 kg 3. High levels of fecal calprotectin 4. Low albumin 5. Positive panca
Factors associated with drug PK and/or clinical outcomes after anti TNF therapy for UC Baseline factors Age Sex Race Weight Albumin Association with PK IFX clearance rates faster in men Directly associated with IFX volume of distribution Directly associated with serum IFX levels in children Low albumin associated with low serum IFX concentrations rapid clearance Association with outcomes Inversely associated with clinical response to IFX Increased rates of response of GLM in females White race associated with higher rates of GLM clinical response Inversely associated with frequency of IFX dose escalation in children Low albumin associated with lower IFX response rates, increased colectomy rates and increased frequency of IFX dose escalation in children
Baseline factor CRP ESR Fecal inflammatory markers Association with PK Inversely associated with IFX levels Association with outcomes Inversely associated with GLM response High ESR increased frequency of IFX dose escalation in children Fecal lactoferrin inversely associated with GLM response Fecal calpro inversely related to IFX response in ASUC Mayo score panca TNF Inversely associated with IFX levels Inversely associated with incidence of clinical remission Associated with decreased rates of clinical response to IFX Mucosal TNF gene expression inversely associated with response to IFX
Case presentation - cont Slight improvement. Still 7 bloody diarrhea a day, CRP 18 High dose of anti TNF (10 mg/kg) was administered a week after
Over the course of the next 1-2 weeks, slow improvement After 3 rd induction dose of IFX- complete remission Follow up colonoscopy- complete mucosal healing, some pseudopolyps Continues on Infliximab and 5-ASA
In summary Acute severe colitis is an emergency setting in IBD It is characterized with higher clearance rates of anti TNF However, optimal time points and targets for early anti-tnf levels are unknown Proactive strategy with frequent and higher dosages of anti-tnf with monitoring of drug level is highly recommended
The future development and clinical application of PK modeling will likely result in Sustained exposure to the drug Mucosal healing Fewer colectomies in children and adults with ASUC
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