증례로 풀어보는 염증성 장질환 크론병 : 진단에서 치료까지 예측은 제가 극복은 여러분 각자가…. 인제의대 해운대백병원 김 태 오

A patient case 24 yrs, Male Cramping abdominal pain, diarrhea for 3 months (5 bowel movements a day) and weight loss(5852kg) for 3 months 172cm / 52kg Smoker laboratory investigations -WBC: 8900/mm3 -Hb: 12.8 g/dL -Albumin:3 g/dL -CRP: 6.82 Stool studies: (-), C. difficile: (-)

Case : Colonoscopic findings Ileocolonoscopy Esophagogastroduodenoscopy: normal CT entero: terminal ileal and AC, TC wall thickening and enhancement Inflamed mucosa with superficial ulcers in TI Deep and superficial ulcers in the AC and TC Deep longitudinal ulcers in the DC and SC Aphtoid and small ulcers in the rectum Inflamed mucosa with superficial ulcers in terminal ileum Deep and superficial ulcers in the ascending colon and transeverse colon Deep longitudinal ulcers in the descending and sigmoid colon Aphtoid and small Superficial ulcers in the rectum

Crohn’s Disease : Endoscopic Features Discontinuous involvement Asymmetric involvement Aphthous ulcers Various shaped ulcers Discrete, deep ulcers Fistula opening and stricture in complicated patients Longitudinal ulcers Cobblestone appearance Longitudinal arrangement of aphthous ulcers

Endoscopic findings: CD vs ITB Colonoscopic finding Intestinal tuberculosis (n = 44) Crohn’s disease (n = 44) P value Fewer than four segments involved 36 (81.8 %) 8 (18.2 %) < 0.001 Anorectal lesions 4 (9.1 %) 37 (84.1 %) Ileocecal lesions* 40 (100 %) 39 (90.7 %) 0.117 Patulous ileocecal valve* 16 (40 %) 4 (9.3 %) < 0.01 Transverse ulcers 29 (65.9 %) 11 (25.0 %) Longitudinal ulcers 1 (2.3 %) 18 (40.9 %) <0.001 Aphthous ulcers 9 (20.5 %) Cobblestone appearance 3 (6.8 %) 15 (34.1 %) <0.01 Scars or pseudopolyps 23 (52.3 %) 12 (27.3 %) < 0.05 Lee YJ, Yang SK Endoscopy 2006;38(6):592-7

Montreal classification of CD Satsangi J, et al. Gut 2006;55(6):749-53

Diagnosis : Crohn disease ileocolonic, non-stricturing, non-penetrating Crohn’s disease (A2, L3, B1)

Biomarkers of Inflammation

Current measures of disease activity

Crohn disease activity index - CDAI Best WR, et al. Gastroenterology 1976;70:439-444

Diagnosis : Moderately to severely active CD CDAI: 284 Diagnosis : Moderately to severely active CD ileocolonic, non-stricturing, non-penetrating Crohn’s disease (A2, L3, B1)

Predictors of CD prognosis Course and outcome Reference Extensive(>100 cm), gastroduodenal or jejunal disease Mortality Munkholm PL. Gastroenterology 1993 Smoking, colitis, non-fibrostenotic Type, young age at diagnosis Corticodependency Franchimont D. Eur J Gastroenterol Hepatol 1998 Disease severity, ileal disease, Corticosteroid use Stenosis or obstruction Lichenstein G. Am J Gastroenterol 2006 Need for steroids, perianal Disease, age at diagnosis <40 y Disabling disease (>2 steroids, IMs, hospitalisation, surgery Within 5 y) Beaugerie L. Gastroenterology 2006 Age <40 y, stricturing disease or Intra-abdominal fistulae, perianal Disease, fever, weight loss >5 kg, High platelet count Severe disease (>2 resections or >50 cm, stoma, complex Perianal disease 5 y) Loly C. Scand J Gastrolenterol 2008

A patient case Prognosis? Treatment goal? Poor: young age, wt loss, deep ulcerations, inflammatory load (CRP), disease extent (based on colonscopy) Uncomplicated state opportunity for to achieve control of inflammation

Crohn’s disease can be a chronic progressive disease

One in four patients will have colectomy within 10 years 100 90 Colectomy 80 70 Disease activity 60 Percentage of patients 50 40 30 Remission 20 10 25 Years after diagnosis n=1161 Risk of colectomy: 24% after 10 years ~ 30% after 20 years Adapted from Langholz E, et al. Gastroenterol 1994;107:3–11. 15 15

IBD treatment goals are evolving

전통적인 약제의 관해유도 효과 약제 용량 반응률 (%) 5-ASA 1.5 ~ 4.0 g/d 43 ~ 64 Prednisolone 0.25 ~ 0.75 mg/kg/d 60 ~ 78 Azathiprine 6-MP 2.5 mg/kg 1.5 mg/kg 36 ~ 91 MTX 15 mg/wk PO 25 mg/wk IM/SQ 36 ~ 54 Placebo 8 ~ 50 Hanauer SB. Gastroenterol Clin North Am 28:297, 1999

Treatment efficacy (-) No or limited healing; (+) Important but slow healing; (++) Important and rapid healing (?) Unknown

Treatment strategies in CD IS + Biologics Surgery Biologics IS + Biologics Disease severity IS Systemic Steroids ?? IS + Steroids Budesonide antibiotics 5-ASA „conventional” „accelerated” „early top-down” Tailored therapy! Smoking cessation Appropriate timing of elective surgery Ordas I Gut 2011

Newly diagnosed CD (N=133) SUTD SUTD: Study Design Newly diagnosed CD (N=133) Episodic strategy D’Haens et al. Lancet 2008;371:660-67.

Patients in Steroid-free Remission SUTD Patients in Steroid-free Remission D’Haens et al. Lancet 2008;371:660-67.

Patients Who Did Not Relapse SUTD Patients Who Did Not Relapse D’Haens et al. Lancet 2008;371:660-67.

Complete Ulcer Disappearance at 2 Years SUTD Complete Ulcer Disappearance at 2 Years 30.4 73.1 20 40 60 80 100 Early combined immunosuppression Conventional management Percentage of Patients (%) 19/26 7/23 p=0.0028 Adapted from D’Haens et al. Lancet 2008;371:660-67.

크론병 치료 국내 가이드라인

A patient case Informed about the diagnosis of Crohn’s disease Treatment options discussed with the patient; informed about possible short- and long-term complications Education booklet given & stop smoking Prednisone (Pd) 40 mg a day initiated (plan: tapered 5 mg/week, 8 week course) + 5-ASA 4g Together with Pd, azathioprine (AZA) 50 mg a day started

스테로이드는 유도요법에 효과적, 유지요법에는 부적합 16 38 26 58 32 28 0% 20% 40% 60% 80% 100% 1 month 1 year Percentage of patients (%) “positive” outcome “negative” remission partial no response prolonged steroid dependent surgery N=74 N=73 Different outcome measures 스테로이드 부작용 : Osteoporosis/osteonecrosis Infections Odema Cushing‘s syndrome (moon face) Cataracts/glaucoma Growth retardation Mood changes Diabetes Cardiovascular complications 스테로이는 유도요법에는 효과적이지만 장기치료에는 부적합합니다. 오직 32%의 환자만이 장기치료시 효과를 보였고, 다른 환자들은 스테로이드에 의존하게 되거나, 수술을 해야하는 등 부정적인 결과가 나타났습니다. 스테로이드는 잘알려진 다음과 같은 부작용들이 있기 때문에 장기간 사용은 피해야합니다. Key takeaways: Traditionally Steroids have been used for the induction of remission => effective for this in most pts only 32% of pts have a long-term benefit other have a negative outcome (steroid dependence or surgery) steroids come with side effects (listed in the bubble) and the use for long-term should be avoided Faubion WA et al. Gastroenterology 2001; 121:255.

첫 진단 후 10년 동안 임상경과 (노르웨이 IBSEN 코호트) 크론병의 자연경과 첫 진단 후 10년 동안 임상경과 (노르웨이 IBSEN 코호트)

A patient case After 1 month Abdominal pain much relieved and 2 bowel movements a day CDAI: 150, WBC: 8300/mm3, CRP 1.4 mg/dL No adverse events to AZA  increased to 75mg/day CDAI: 110, WBC 6200/mm3 , CRP 0.54mg/dL Pd now 15 mg/day, but some abdominal pain and loose stool: relapsing ? AZA increased to 100mg/day (2mg/kg/day) Slow tapering of Pd (5mg/2 weeks) for allowing AZA more time to act Discussed possibility of anti-TNF therapy (if no AZA response) After 1 month After 2 weeks

A patient case Pd tapered off On AZA 100mg/day (2mg/kg/day) for 8 weeks Relapsed with abdominal pain and diarrhea CDAI: 280, WBC 4400/mm3, CRP: 2.4 mg/dL Identified as corticosteroid-dependent After 2 months

Time-bound Crohn’s disease treatment algorithm Aliment PharmacolTher 2008;28:674–88 Planned to initiate anti-TNF Latent TB screeing done : chest PA, TST, IGRA Pd 30 mg re-started

많은 환자들이 AZA 유지요법 기간에 Loss of response 경험 Remission induced by prednisolone; tapered over 12 weeks AZA/6-MP side effects: Gastrointestinal Hepatotoxicity Secondary infections (1%) Lymphoma (including HSTL) Hematologic side effects 100 80 60 40 20 Placebo (PBO) (n=30) AZA 2.5 mg/kg/day (n=33) 80 60 Percentage patients not failing trial (%) 40 AZA는 유지요법에 대표적인 치료제입니다. 하지만 표에서 보시다시피 15개월 동안 반응이 소실되는 환자군이 많이 보입니다. 또한 간독성, 췌장염등이 AZA 치료군에서 흔하게 발견되는 부작용이며 흔하진 않지만 HSTL을 포함한 임파선암도 종종 발견됩니다. Key takeaways: AZA is the hallmark treatment in CD and UC for maintenance of remission AZA better than plo but still a great proportion will lose response on AZA Few data to show efficacy Although AZA is considered a safe treatment it has also been associated with side effects Hepatotoxicity, pancreatitis are typical for AZA users Rare but very severe is HSTL Steroid + AZA/PBO 20 AZA/PBO 15 Duration of trial (months) Candy et al. Gut 1995; 37:674-678.

Prednisone 30 mg/day for 3weeks Symptoms slightly improved with Pd CDAI 260, WBC 4600/mm3, CRP: 2.6 mg/dL anti-TNF therapy start : Remicade initiated After 3 weeks

Comparison of Anti-TNF Agents Etchevers et al. Drugs 2010;70:109

A patient case CRP (mg/dL) CDAI score Prednisolone Azathioprine Anti-TNF

Rapid biochemical response to remicade No abdominal pain and diarrhea CDAI 80, CRP: 0.4 mg/dL Patient in clinical remission Continue remicade Sustained clinical and biochemical remission CDAI 24, CRP: 0.2 mg/dL After 1 month After 3 months

A patient case CRP (mg/dL) CDAI score Prednisolone Azathioprine Anti-TNF

A patient case Still in clinical biochemical remission CDAI 15, CRP: 0.2 mg/dL colonoscopy follow up :1 year after initiating anti-TNF After 5 months

Mucosal Healing as A Surrogate for Longer-Term Outcomes Mucosal healing is associated with: Lower relapse rates Lower hospitalizations rates Less bowel damage (fistulas) Reduced need for surgery Zallot et al. Curr Gastroenterol Rep. 2013;15:315.

CRP (mg/dL) CDAI score Prednisolone Azathioprine Anti-TNF Endoscopic F/U

IBD cases

M/36 2001.12. Kidney transplantation 2009. 10. Abd pain with diarrhea

M/36 Crohn’s disease ? Tuberculous colitis ? He was taking Tacrolimus Mycophenolate Delfazacort Therapeutic trial with anti-TB medication for 2 months

M/36

M/36 Mesalazine Budesonide Anti-TB Infliximab

M/40 1996. 결핵성 장염 의심되어 항결핵제 복용 후 증상 호전 1997.7. 복통 및 설사로 크론병 진단되어 이후 5-ASA 및 간헐적인 스테로이드 용법 2003.4. Azathioprine 시작하였으나 골수 억제로 25mg/d 만 복용 2008.4. 치루로 infliximab#1 시행

M/40 Infliximab #8 (2008.4.- 2009.2.) 2006.10. Abd pain Diarrhea Anal fistula 2009.4. No symptom Infliximab

F/28 2008.5. Remicade 2009.3.

M/43 1998. Ulcerative proctitis 진단 2004. Ankylosing spondylitis (AS) 진단 2010.4. Etanercept for AS 2010.6. Infliximab for AS 2011.11. Abd distension

F/64 2007. 9. 크론병 진단 후 스테로이드, 면역억제제, 레미케이드 사용하였으나 2008.8. 지속되는 출혈로 소장절제술 시행 2009.12. 복통 및 설사로 다시 레미케이드 시작하였으나 증상이 잘 조절되지 않고 간헐적인 출혈 2010.3. 휴미라 시작 2010.9. 전신부종, 복통, 혈변 등으로 입원

F/64 Emphysematous cystitis로 인한 Sepsis로 사망

Monitoring Tools for Decision Making in the Treatment of CD Symptom-based (CDAI, HBI, IBDQ) Biomarkers (CRP, FeCa, Lactoferrin) Endoscopic assessment (CDEIS, SES-CD) Cross-sectional imaging (MRI, CT) CDAI: Crohn’s Disease Activity Index; HBI: Harvey-Bradshaw Index; IBDQ: Inflammatory Bowel Disease Questionnaire; CRP: C-Reactive Protein; FeCa: Fecal Calprotectin; CDEIS: Crohn's Disease Endoscopic Index of Severity; SES: Simple Endoscopic Score; MRI: Magnetic Resonance Imaging; CT: Computed Tomography Papay et al. J Crohns Colitis 2013;7:653-69.

Key steps in Crohn’s disease diagnosis and treatment Assess prognosis early Establish the treatent goal and the managment plan Initiate appropriate therapy Monitor disease activity regularly Based on objective parameters of inflammation

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