MICHIGAN IBD ASUC: Current Best Practice and Future Directions Peter D.R. Higgins, MD, PhD, MSc (CRDSA) Timothy T. Nostrant Endowed Professor of Gastroenterology University of Michigan 

MICHIGAN IBD MICHIGAN IBD Today's Agenda • Traditional Standard of Care (since 1955) • Definitions & Decision Points • Best Practices post-1955 • Stratifying by Risk of Colectomy • Improving Your Practice with Outcome Data • A Pilot Trial • Where Can We Improve? • Future State 

MICHIGAN IBD MICHIGAN IBD Post-1955 Standard of Care • Intravenous Corticosteroids (IVCS) x 72h • Evaluate with criteria: Oxford/Lindgren/Ho • Most (70-100%) go into remission • Transition to maintenance • Many maintenance choices IVCS Monotherapy, N= 663 

MICHIGAN IBD MICHIGAN IBD Re-defining ASUC for 2024 • T&W Criteria for ASUC in 1955 (no one admitted on steroids) • >= 6 BM/day with visible blood AND 1 or more of • Anemia <= 10.5 g/L of Hgb • Fever > 100F/37.8C • Tachycardia > 90 BPM • ESR > 30 mm/hr • Alternate (lab) definition - classify by FCP • FCP > 782 ~ T&W severe UC • How many outpatients have Calpro >782? • Walking around (or running to toilet) with 1955 ASUC… 2024: My patient does not meet T&W criteria for ASUC - Unless I stop the 60 mg of daily prednisone Kedia, S, et al Dig Dis Sci 2018;63:2747-53 

MICHIGAN IBD MICHIGAN IBD ASUC Is A Growing Cytokine Storm: Increasing Momentum Over Time 

MICHIGAN IBD MICHIGAN IBD A Typical Case in 2024 • Abby is a 29 y/o F with pancolonic UC, never smoker • Initially on 5-ASA in Jan after prednisone taper, then urgency returned • April started on Aza 2.5 mg/kg, but HA and N/V – stopped after 4 weeks • Started IFX in July b/c flare – worked somewhat for first 3 doses • Admitted with 18 BM/day, blood in ~90%, temp 38.1, very thirsty • C diff negative by toxin, other infections ruled out by PCR • Has not eaten in 2d, because “it goes right through me” • Urgency time ~ 20 seconds • Hgb 7.9, ESR 46, CRP 124 mg/L, Alb 31 → 26 with fluids Risk Factors: CRP, ESR up Alb down Hgb down, fever, Prior Adv Rx 

MICHIGAN IBD MICHIGAN IBD Alternatives to 1955 Therapy • Are IVCS really still the best first line ASUC therapy? • They are fast & effective in ~ 70%+ • But have lots of side effects, and possibly cause long-term Rx resistance • And we have usually selected AGAINST some fast responders because we have already tried outpatient CS (prednisone) • Other options • Cyclosporine is pretty fast, lots of side effects, not maintenance • IFX is not that fast, leaks a lot, antibodies – kicks can down the road • JAKi are very fast, no leak, no antibodies – relatively few AEs vs CS, can be maintenance or can be a bridge 

MICHIGAN IBD Did We Learn the Wrong Lessons from Biologic RCTs? Incentives for Pharma • Recruit the Sickest Patients • Get the Biggest, Fastest Change • Smaller Sample Size • Save Money • Reasonable Conclusion: • Use biologics in the very sick But what do the data say? • The patients who do the best (highest week 52 CS-free remission) are those who enter with LOW (not zero) inflammation • Vedo for UC – FCP <236 mg/g stool • Uste for CD – CRP < 14.6 mg/L APT. 2018 Mar; 47(6): 763–772. JAMA Netw Open. 2019;2(5):e193721. Small molecules Blazing Smoldering 

MICHIGAN IBD Best Practices ASUC post-1955 

MICHIGAN IBD MICHIGAN IBD Best Practices • Beware of mimics, infections, perforation • Do early flexible sigmoidoscopy < 24h • Give lots of fluids early, be slow to feed, be very slow to TPN • Track CRP daily, FCP at discharge • Figure out noninvasive tracking – can’t scope daily, heal too slowly • Mucosal healing and FCP are relatively slow to normalize • Clinical improvement ≠ Out of the woods 

MICHIGAN IBD MICHIGAN IBD Mimics and Red Herrings 

MICHIGAN IBD MICHIGAN IBD Best Practices • Measure and treat urgency (rectal Rx) • Use 3 criteria (Oxford, Lindgren, Ho) and make decision at 72h • Prevent VTE with enoxaparin daily • Give shingrix vaccine if considering JAKi • Measures to reduce PTSD (quiet hours, no CS>4 PM) • Use prognostic criteria to decide who gets First line IVCS • And who needs stronger 1st line therapy Gut 1996; 38: 905-910 EJGH 1998; 10: 831-835 APT 2004; 19: 1079-87 

MICHIGAN IBD MICHIGAN IBD Phases of Therapy in ASUC First Line Therapy Intravenous steroids (Hydrocortisone or methylprednisolone) Up to 5 mg/kg/day of HC, 1 mg/kg/d of MP Often 100 mg q6h HC, 40q12 of MP JAKi +/- IVCS ? Rescue Therapy Steroids Failing at 72h by 3 criteria Infliximab? Cyclosporine Salvage Therapy Rescue has failed CRP rising Higher risk of infection and death Washout time matters Colectomy is ALWAYS a good option, at any phase Maser, EA CGH. 2008 Oct;6(10):1112. 

MICHIGAN IBD Prognosis of ASUC upon Admission Number of T & W criteria (HR, T, Hgb, ESR) Colectomy Rate (n =294) +1 9% (11/129) +2 31% (29/94) +3 or 4 48% (34/71) Dinesen, L, et al JCC 2010; 4: 431-37 ADMIT-ASC Criteria Corte et al. J Crohns Colitis 2015;9:376-81 Adams, A., et al. Gut. 2023 Mar;72(3):433-442. doi: 10.1136/gutjnl-2022-327533 • 1 point each for: • CRP > 100 mg/Liter • Albumin < 25 g/Liter • UCEIS >= 4 (1 point) (Mayo 2+) • UCEIS >= 7 (add 1 point) (Mayo3+) • 0 points – 100% steroid responsive • 1 point – 30.4% steroid NR • 2 points – 59.3% steroid NR • 3 points – 82.5% steroid NR • 4 points – 100% steroid NR Truelove and Witts Criteria Dinesen, L, et al JCC 2010; 4: 431-37 

MICHIGAN IBD MICHIGAN IBD Why is Our SOC (IVCS) Stuck in 1955? • RCTs in ASUC are hard • Not a lot of patients • ASUC T&W Criteria quite strict for 2024 • Patients anxious, not familiar with trials • Slow to recruit, patients reluctant to enroll • Physicians often reluctant to randomize • 2014: Evolve Therapies through QI approach • When we are confident, run RCTs to prove Rx works Uphill Climb to ASUC RCTs 

MICHIGAN IBD Author Study Year N Years Centers Participants/site /year Active Comparator Initial Rx Lichtiger Cyclosporine Rescue (alternative = colectomy) 1994 20 1 2 10 No No D'Haens Cyclo vs IVCS (initial Rx) 2001 30 1 1 30 Yes Yes Van Assche Cyclo 2 vs Cyclo 4 Rescue (no placebo) 2003 73 5.75 1 12.7 Yes No Jarnerot IFX Rescue 2005 45 2.1 10 2.14 No No Laharie Cyclo vs IFX Rescue (CYSIF) 2012 115 3.25 27 1.3 Yes No Choy IFX vs Accelerated IFX, with 2nd rand 2024 138 5.25 13 2.02 Yes No RCTs in ASUC are long and hard RCTs of ASUC Therapies 

MICHIGAN IBD Who Should Receive Which First Line Therapy? • Low Risk = 1955 Therapy • Only 1 T&W bonus criterion (T, HR, Hgb, ESR) • CRP <100 mg/L, Alb >25 g/L, (CRP/Alb < 2) & Scope ≠ Hamburger • Use • Small Molecule – IVCS • MP 1 mg/kg/d, HC 5 mg/kg/d • Decide if rescue needed at 72h • High Risk = Stronger First Line Therapy • Small Molecules that don’t leak • No risk of antibodies • Short half-life, rapid washout • Options • Cyclosporine + IVCS • JAKi + IVCS • JAKi alone? 

MICHIGAN IBD Who Is At Risk of Colectomy? Modeling with Michigan Data 

MICHIGAN IBD MICHIGAN IBD Modeling Risk of 90-day colectomy • Univariate CRP • JustModels Indep Var Odds Ratio (CI) p value ADMIT_CRP 1.08 (1.05, 1.1) < 0.001 DAY_0_CRP 1.07 (1.05, 1.1) < 0.001 DAY_1_CRP 1.08 (1.05, 1.11) < 0.001 DAY_2_CRP 1.10 (1.06, 1.13) < 0.001 DAY_3_CRP 1.13 (1.09, 1.18) < 0.001 The CRP curve CRP Time University of Michigan ASUC cohort 2014-2024_Q3, N=1106 d0 d1 d2 d3 

MICHIGAN IBD Other Univariate Predictors • Protective vs Colectomy • High Albumin (Admit – d1) NS: • Age, Sex, BMI • High FCP • Favors Colectomy • High Platelets (Admit - d3) • ↑ Bowel movements (d1-d3) • Not Admit, d0 • High ESR (d0, d2) • OSH Transfer = yes • Prior Adv Rx = yes 

MICHIGAN IBD MICHIGAN IBD Modeling Risk of 90-day colectomy • Multivariate Model Independent Variable Odds Ratio (CI) p value Admission CRP (mg/L) 1.07 (1.04-1.09) <0.0001 Admission Alb (g/dL) 0.72 (0.54-0.96) 0.027 OSH Transfer (yes) 1.84 (0.96-3.52) 0.067 University of Michigan ASUC cohort 2014-2024_Q3, N=857 due to missing data 

MICHIGAN IBD Improving Your Practice Can We Change Outcomes in ASUC? Plan Act Measure Change 

MICHIGAN IBD MICHIGAN IBD How to Improve? Start with A Protocol • Standardize Therapy with a protocol • All components of care – control all the other variables • Get EVERYONE to compromise, agree to it • Require data, not vibes • Vibes = new questions to test • Make it public • Hold yourselves accountable – make it public • https://www.med.umich.edu/ibd/docs/severeucprotocol.pdf • Collect data on your outcomes • Try to improve, measure outcomes • If outcomes are not improving, try something else Plan Act Measure Change 

MICHIGAN IBD MICHIGAN IBD Accelerated IFX Era • We started by testing ‘accelerated’ infliximab • To overcome colonic leak • Rescue after 72h IVCS • Dosed at 10 mg/kg, repeat q72h (up to 3 doses) • Could get some patients out of the hospital • Many returned within 90 days for colectomy • Lots of failure between week 6 and week 14 • None of the patients with 3 doses avoided colectomy • Data were not superior to historical 1 dose IFX rescue • Slightly worse (30.3% vs 24.2%) Govani, SM, Higgins, Dig Dis Sci 2020;65:1800-1805. 

MICHIGAN IBD MICHIGAN IBD 2019: First line Tofacitinib + IVCS Tofa + IVCS IVCS Adjusted for number of prior advanced Rx, colonic dilation, endoscopic Mayo score, and albumin nadir value Berinstein, Higgins, et al. CGH. 2021;19:2112. Randy Regal 

MICHIGAN IBD MICHIGAN IBD First line Tofacitinib + IVCS (by Dose) Tofacitinib 10mg TID N=24 IVCS alone Tofacitinib 10mg BID N=16 Adjusted for number of prior advanced Rx, colonic dilation, endoscopic Mayo score, and albumin nadir value 

MICHIGAN IBD MICHIGAN IBD Validated by TACOS Trial • First Line Therapy • IVCS + Tofacitinib tid vs IVCS • IVCS = hydrocortisone 100 mg q 6h • Response = decline in the Lichtiger index by >3 points and an absolute score <10 for 2 consecutive days without the need for rescue therapy by Day 7 83% 59% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% Response at Day 7 Tofa TID + IVCS IVCS Singh, Goyal, AJG, 119: 1365-1372, 2024. 

MICHIGAN IBD MICHIGAN IBD 2023: Upadacitinib 30mg BID + IVCS with d5 Transition to 45 mg qd Upa x 8 weeks Berinstein, J., Higgins, PDR, et al Am J Gastro 2024;119:1421–1425 Upa + IVCS First Line IVCS First Line, IFX Rescue IVCS First Line, Monotherapy Adjusted for prior TNF use, CRP peak value, and albumin nadir value among patients at 5 centers since 2013 

MICHIGAN IBD Tracking Outcomes: Risk of 90-day Colectomy University of Michigan ASUC cohort 2014-2024 May, N=1106 (891 first admission) 

MICHIGAN IBD MICHIGAN IBD Michigan ASUC Cohort 90-Day Colectomy Rate Data through May 2024 

MICHIGAN IBD MICHIGAN IBD Michigan ASUC Cohort 90-Day Colectomy Rate Data through May 2024 

MICHIGAN IBD MICHIGAN IBD Michigan ASUC Cohort 90-Day Colectomy Rate Data through May 2024 

MICHIGAN IBD Piloting a Clinical Trial First Steps Jeff Berinstein 

MICHIGAN IBD MICHIGAN IBD SMART Design ASUC w/prior biologic R IVCS IVCS + Upa 45 Upa 30 bid Maintenance per treating MD Maintenance per treating MD Maintenance per treating MD Response Response Response Fail Fail Fail R R R Add Cyclo Add Upa 30 bid Incr to Upa 30 bid Swap Upa to Cyclo Add IVCS Switch to IVCS + Cyclo 

MICHIGAN IBD MICHIGAN IBD The SMART Dashboard • https://phiggins.quarto.pub/smart-dashboard/ 

MICHIGAN IBD After Discharge: Risk Tolerance Will Change • Imminent Danger of Colectomy • I am in great danger, I can tolerate risk • In sustained remission • I feel fine, and now I want to minimize risk 

MICHIGAN IBD MICHIGAN IBD What is Best Practice for ASUC Today? • A moving target, as QI and trials are underway • Potent First Line therapy appears to be important • Data on short-term, high-dose JAKi are encouraging • Data on biologics in leaky colons are discouraging • We may be able to bridge from small molecules to biologics • We may be able to drop steroids (early, or entirely) Small molecules Start biologic 

MICHIGAN IBD Future Directions Where Can We Improve? 

MICHIGAN IBD Initiation of inflammation (infection, NSAID) Gut epithelial barrier becomes leaky Gut immune cells exposed to luminal microbiome JAK/STAT activated • Cardioversion • Catheter RF ablation • We don't have Cardioverision for the colon • But can we (temporarily) ablate one part of the cycle? 

MICHIGAN IBD MICHIGAN IBD A Proteolysis-Targeting Chimera (PROTAC) Binds to STAT3 linker Activates Ubiquitination • A molecule with 3 functional domains: • Binds target protein • Links to proteolysis activator • Protein ubiquinated • Specific degradation of the target protein by the proteasome • One molecule of PROTAC can transiently bind and flag multiple molecules of the target protein • STAT3 is rapidly degraded, gone for 3+ days • STAT3 is regenerated, but not immediately activated by phosphorylation • Temporary ablation of STAT3 that provides time for the immune system to reset • Now testing SD-2301 SD-36-Me Nature Biotechnology; 40,:12–16 (2022) J Med Chem; 62: 11280-11300 (2019) Shaomeng Wang 

MICHIGAN IBD Is Time (Early) the Wonder Drug? 

MICHIGAN IBD The Reality of the US Emergency Department for a Chronic Disease Emergency Department ED South ED West ED East ED Extension 1 ED Extension 2 (Short Stay Unit) "Currently we have 57 patients in the ED awaiting beds. Please prioritize timely discharges." • You aren't going to die in the next 10 minutes • Your history is long and complicated • Your medication names are really long Adrenaline Junkie = ED Doc 

MICHIGAN IBD MICHIGAN IBD The ADTU (Ambulatory and Diagnostic Treatment Unit) Avoiding the Emergency Department 

MICHIGAN IBD MICHIGAN IBD Patients: ADTU > Emergency Department • Staffed by Nurse Practitioners for flares of chronic diseases • Protocols for CHF, migraine, IBD, other diseases since 2017 • Patient calls with flare symptoms, appointment made for AM • Patient brings in stool, gets blood tests • Rapid FCP, CRP, GI PCR, CBC, Chem, (slower) drug levels • IV fluids, IVCS (possibly JAKi) per protocol • Consult with outpatient GI on next steps / change in maintenance • Option for CTE if needed • In and out within 5 hours 

MICHIGAN IBD MICHIGAN IBD Hospital Care At Home (HCAH) • Started for ASUC in June 2024 at UMichigan • ASUC patients who have ‘turned the corner’ per criteria & physician • Typically 48-72h in hospital • Monitoring recovery curve • Go home with daily home nursing care • IV corticosteroids as needed • Daily Lab testing, Vitals • Daily PROs on mobile phone into EMR • Daily Zoom visits with physician • Can get outpt flex sig, X-ray, or return to GI service if a turn for the worse • Early experience: 40 km radius, 4/4 did well, big patient satisfaction 

MICHIGAN IBD MICHIGAN IBD The Risks of Pushing the Envelope • Rebooting the immune system • Durable immunosuppression, infection, cancer? • To the ADTU instead of the Emergency Department • Will we miss emergencies? • Hospital Care at Home? • Will we be slow to bring patients back to the hospital when needed? 

MICHIGAN IBD MICHIGAN IBD Open questions In whom should we maximize first line Rx? Do we still need steroid tapers?/ Steroids at all? Do all ASUC patients need to be hospitalized? Can patients go home after day 2 with home nursing? Should we delay biologics until smoldering? 

MICHIGAN IBD MICHIGAN IBD One Possible Future State IVCS 5d? Generic JAKi 8-16 weeks Start Biologic: Vedo, Biosim Uste, Biosim IFX? FCP <300 Shingrix Shingrix #2 ASUC FCP >800 Ulcers on Flex R/O infection Stratify by Risk Factors For 90-day Colectomy: HR, T, Hgb, CRP, Alb, Scope, prior Advanced Rx Generic JAKi 8-16 weeks Start Biologic: Vedo, Biosim Uste, Biosim IFX? FCP <300 Shingrix Shingrix #2 Outpatient Inpatient Those doing well – Hospital at Home by Day 3 (or STAT ablation) (or STAT ablation) 

MICHIGAN IBD MICHIGAN IBD Thank You Ann Arbor 

MICHIGAN IBD MICHIGAN IBD 

MICHIGAN IBD MICHIGAN IBD 

MICHIGAN IBD Transparency • Don Poldermans, Cardiologist at Erasmus MC • Hypothesis: perioperative BB for noncardiac surgery • Lots of rapid publications • Led guidelines group, implemented BB in Europe • Other sites data ~ 27% increased mortality • Estimated 800K additional deaths in Europe • Many incentives and paths to research misconduct • External validation is critical • Believe in science, not your beloved hypothesis