IBD: A Comorbidity of PSC Laura Raffals, MD, MS

The Spectrum of IBD 1.6 Million Americans ULCERATIVE COLITIS Continuous inflammation Colon only Superficial inflammation Variable involvement Risk of cancer Strictures (cancer) Extraintestinal manifestations CROHN’S DISEASE Patchy inflammation Mouth to anus involvement Full-thickness inflammation Variable involvement Fistulas Strictures Extraintestinal manifestations Indeterminate colitis 10-15%

Temporal Trend in the Incidence of Crohn’s Disease in Olmsted County, 1940-2004 This graph shows the temporal trend in the incidence of Crohn’s disease in Olmsted County for the period 1940-2000 In the 1940s the incidence rate for Crohn’s disease was low. During the 1950s and 60s the incidence rate rose sharply, but since the early 1970s the incidence rate has remained relatively stable. Ingle SB, et al. Gastroenterology 2007 Suppl

Temporal Trend in the Incidence of Ulcerative Colitis in Olmsted County, 1940-2004 A similar trend is seen for ulcerative colitis. Again, in the 1940s the incidence rate is low, climbs sharply in the 1950s and 1960s, and has remained stable since the 1970s. Ingle SB, et al. Gastroenterology 2007 Suppl

Changing Geographic Distribution of IBD 1950 2000 5

Genetic susceptibility Environmental triggers Pathogenesis of IBD Immune Response Genetic susceptibility Environmental triggers IBD CP1169260-9

Disease Extent Crohn’s can involve any part of GI track But colon alone in 20-30% UC involves only the colon But “backwash ileitis” in 7-15% PSC-IBD Is this its own entity?

Anatomic Distribution of CD Upper gut < 10% Small bowel alone 33% Ileocolonic 45% Colon alone 20%

CD: Clinical Patterns Fibrostenotic Inflammatory Fistulizing

CD: Clinical Patterns Fistulae and Abscesses

Anatomic Extent of UC Left-Sided Colitis Pancolitis Procto- sigmoiditis

PSC-IBD

PSC & IBD 70% of PSC patients have IBD 80% UC 10% CD 10% Indeterminate 5% of IBD patients have PSC All IBD patients should have liver enzymes tested annually

PSC-IBD PSC-IBD is a unique entity Relatively quiescent disease Increased risk for colorectal cancer IBD usually precedes PSC diagnosis (median 10 years) PSC can develop after colectomy

PSC-IBD Characteristics UC Pancolitis Rectal sparing and backwash ileitis Right side > left side CD Often ileocolonic Isolated small bowel disease is rare Fibrostenotic and penetrating complications are rare Are these often mischaracterized PSC-IBD patients?

PSC-IBD Relationship between colectomy and PSC Early colectomy is associated with decreased risk for future liver transplantation Colectomy prior to liver transplant associated with lower risk for recurrent PSC IBD disease activity NOT associated with risk of recurrent PSC after liver transplant

What is the link between IBD & PSC We don’t know Bile acids “Leaky gut” Gut dysbiosis Lymphocyte homing Genetics

Risk of colorectal cancer in PSC Risk of CRC is higher in IBD compared to general population Patients with PSC-IBD at greater risk of CRC compared to IBD alone Pancolitis and inflammation are additional risk factors for CRC

CRC screening guidelines Colonoscopy should be done in all patients at time of PSC diagnosis if no history of IBD If no colitis, continue colonoscopies every 3- 5 years In patients with PSC-IBD, annual colonoscopy Chromoendoscopy Colectomy is recommended if CRC or high grade dysplasia

IBD Treatment

Treatment goals in IBD in 2019 are rapidly evolving Cure Mucosal Healing Reduction in Hospitalizations and Surgeries Maintenance of Steroid-Free Remission Induction of Remission Alleviate Symptoms Changing The Natural History of Disease?

Improved Clinical Outcomes Have Coincided With The Expanding IBD Therapeutic Armamentarium Re-format Danese S, Vuitton L, Peyrin-Biroulet L. Nat Rev Gastroenterol Hepatol 2015;12:537-45

Treatment categories Therapy 5-ASA Immunomodulators Anti-TNF Mesalamine (oral & topical) Sulfasalazine Immunomodulators Thiopurines Methotrexate Anti-TNF Infliximab Adalimumab Certolizumab Golimumab Anti-Integrins Vedolizumab Natalizumab Anti-IL23 Ustekinumab Small molecules Tofacitinib

Better Treatment Strategies Are Essential for Improving Clinical Outcomes 1. Early intervention

The Window of Opportunity for Early Intervention in IBD Stricture Surgery Intestinal damage Disability Fistula/abscess Inflammatory activity (CDAI, CDEIS, CRP) Stricture Window of opportunity? Kara showed us this slide outlining the natural history of CD and the risk of developing complications from disease. Disease onset Diagnosis Early disease 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;17:1415–22

Inflammatory activity (CDAI, CDEIS, CRP) New Treatment Goals - Blocking Disease Progression and Preventing Damage and Disability Intestinal damage Disability Inflammatory activity (CDAI, CDEIS, CRP) 10.04 so this er concept…………with arthritis 10.41 Disease onset Diagnosis Early disease 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;17:1415–22 26 26 26 26 26

Better Treatment Strategies Are Essential for Improving Clinical Outcomes 1. Early intervention 2. Individualized treatment

Predicting the course of disease: Treatment goals individualized based on disease activity & severity, patient goals and risks We can’t undo the past We can impact the future Defining the likely course of disease Disease activity: How is the patient now? PROs & objective markers Disease severity: What has been the patient’s disease course? Crohn’s disease and ulcerative colitis are heterogeneous diseases, and each aspect of the T2T strategy may need to be tailored to the individual patient. For example, outcomes in late-stage disease will differ from those achievable in early disease. The choice of treatment target may also vary, given that a stringent target may not be achievable in some patient types. For example, symptomatic remission may not be achievable in late-stage disease, and mucosal healing may also be harder to achieve in longstanding disease where there is considerable accumulated bowel damage. Individual PRO goals should also be considered, and the frequency of PRO outcome assessments tailored to the patient’s symptoms (for example, a minimum every 3 months until symptom resolution and at least every 6-12 months after resolution). Treatment choices will be tailored to the patient’s prognosis and disease type, and to the risk of treatment toxicity. The frequency and choice of monitoring assessments may also vary by patient.

New Paradigm: Treating beyond symptoms Biologic therapy Immunomodulators Corticosteroids Biologic therapy Immunomodulators Corticosteroids, 5-ASA therapies Symptom severity Step-up approach Top-down approach

Better Treatment Strategies Are Essential for Improving Clinical Outcomes 1. Early intervention 2. Individualized treatment 4. Tight control monitoring 3. Treat to target

Evolving goals of therapy for IBD: sustained deep remission Clinical parameters Outcomes Response Improved symptoms Improved QoL No symptoms Decreased hospitalization Remission Normal labs Dr Remo Panaccione presented this theoretical model during an Abbott symposium at the ECCO 2010 meeting. The goals of Crohn’s disease management – together with the corresponding clinical parameters and outcomes – have evolved. Dr Panaccione suggested that we may be able to sustain these outcomes, and proposed sustained deep remission as potential new treatment goal. Normal endoscopy Avoidance of surgery Deep remission Mucosal healing Minimal/no disability SUSTAINED DISEASE CONTROL David T. Rubin, MD 2014 31 31

Therapeutic Decision Making in IBD is Individualized in Every Patient RISKS OF UNDER- TREATMENT RISKS OF OVER- TREATMENT Corticosteroid exposure Complications - Fibrostenosis / Penetrating Hospitalizations and surgeries Colorectal cancer Disability / Absenteeism Reduced QOL Infections Lymphoma Other rare AEs Cost

Balancing Risk of Disease & Risk of Treatment

Putting risk in perspective Over a lifetime, the risk of dying from: Lightning 1 out of 164,968 Bicycling accident 1 out of 4,535 Drowning 1 out of 1,113 Riding in a car 1 out of 470 Cancer 1 out of 7 Heart disease Odds of Dying, National Safety Council. Available at: http://www.nsc.org/lrs/statinfo/odds.htm. Accessed 2015.

Risk of Developing non-Hodgkin’s Lymphoma Patient receiving Immunomodulator +/- anti-TNF Therapy for 1 year Risk without medication Risk of lymphoma with immune suppression Siegel CA, Inflamm Bowel Dis 2010;16:2168.

Preventive Care IBD patients do not receive preventive services at same rate as general medical patients IBD patients on immunomodulators or biologics have unique needs Vaccinations Screening for osteoporosis Cervical cancer Skin cancer Depression/anxiety Smoking cessation Health maintenance issues need to be co-managed by PCP and gastroenterologist Farraye F, et al. American Journal of Gastroenterology. 112(2):241–258, FEB 2017

Inactive vaccine recommendations Infectious agent Target population Dosing Corynebacterium diphtheria, Clostridium tetani, Bordetella pertussis All Booster every 10 years Hepatitis B If low or absent titer, revaccinate at 1, 1-2, and 4-6 months HPV Ages 11-26 Doses at 0, 2, 6 months Influenza Annual, inactivated Neisseria meningitidis High risk adults 2-3 doses depending on vaccine Streptococcus pneumonia PCV13 followed by PPSV23 after 2-12 months Farraye F, et al. American Journal of Gastroenterology. 112(2):241–258, FEB 2017

Multidisciplinary approach – the best care for all Behavioral health Radiology & Pathology Primary care Specialists IBD center Surgeons Hepatologists Quinn et al. “Impact of a Multidisciplinary eBoard for Management of Complex IBD”, presented at Crohn’s Colitis Congress 2019

Questions & Discussion raffals.laura@mayo.edu