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Ulcerative Colitis: The Modern Therapy Ladder from First-Line to RescueIntroduction: A Practical Framework for UC ManagementWelcome to our deep dive into the management of Ulcerative Colitis. In today's episode, we're going to build a clear, step-by-step, and evidence-based guide for managing UC across the full spectrum of disease, from mild proctitis that you might see in clinic to an acute severe flare requiring hospital admission. We know that guidelines can be dense and trial data complex, so our objective is to translate all of that information into an actionable "zero-to-go" plan that you can use at the bedside or in your next clinic. This is for the busy clinician who needs a practical framework for what to start, how to monitor, and exactly what to do when a therapy fails. So, let's get started at the logical beginning: optimizing therapy for mild disease. -------------------------------------------------------------------------------- 1.0 Managing Mild Ulcerative Colitis: Building the FoundationThe strategic importance of getting management right in mild Ulcerative Colitis cannot be overstated. Optimizing first-line therapy here is the foundation of long-term success. Proper initial treatment can prevent disease progression, minimize the need for steroids, and delay or even avoid the escalation to more aggressive and costly advanced therapies. This is where we set the patient up for a stable future.The first-line approach is stratified by the extent of the disease, with the core principle being to deliver the drug directly to the disease.Ulcerative Proctitis: For disease confined to the rectum, the preferred agent is a topical mesalamine (5-ASA) suppository at a dose of 1 gram nightly. This approach is superior to topical steroids for inducing remission and should be continued for maintenance.Left-Sided Colitis: When inflammation extends up to the splenic flexure, combination therapy with both oral and rectal mesalamine is the standard of care. A typical induction regimen includes oral mesalamine (2–2.4 g/day) plus a rectal mesalamine enema (≥1 g/day). This dual approach is more effective than using oral therapy alone. For maintenance, therapy can often be stepped down to oral mesalamine at 1.5 g/day.Extensive Colitis: For mild disease extending beyond the splenic flexure, the primary treatment is oral mesalamine, starting at a dose of 2–2.4 g/day for induction. Once in remission, the maintenance dose is typically 1.5 g/day.For patients with an inadequate response to an optimized 5-ASA regimen, the next step is often to add Budesonide MMX (9 mg once daily). It is critical to remember that this is an induction-only therapy used as a bridge to remission; it has no role in maintenance.Our management is guided by a "Treat-to-Target" strategy with clear goals. The short-term goal is clinical response. Intermediate goals, checked around the 3-month mark, include normalizing C-reactive protein (CRP) and reducing fecal calprotectin to a target range of approximately 100–250 µg/g. The long-term, definitive goal, assessed at 6-12 months, is achieving endoscopic healing.Failure of first-line therapy is not an ambiguous endpoint. The triggers for escalating care are clear and should prompt a move up the treatment ladder:Lack of clinical response after 8-12 weeks of optimized 5-ASA therapy.Failure to meet intermediate biomarker targets (persistently elevated CRP or fecal calprotectin).Inability to taper off budesonide without a clinical relapse, which defines steroid dependency.Once a patient meets these criteria, we are no longer managing mild disease; it's time to transition to the advanced therapy playbook for moderate-to-severe UC. -------------------------------------------------------------------------------- 2.0 Navigating Moderate-to-Severe UC: The Advanced Therapy PlaybookManaging moderate-to-severe Ulcerative Colitis represents the central challenge in modern IBD care. The explosion of new biologics and small molecules has provided an incredible toolkit, but it also creates complexity. This section will demystify the selection and sequencing of these advanced therapies by focusing on two core principles: 1) Selecting the right first-line agent based on a balance of efficacy and safety, and 2) The inviolable rule of switching mechanisms of action upon treatment failure.2.1 Choosing the First-Line Advanced Therapy: An Evidence-Based ApproachFor a biologic-naïve patient, guidelines and head-to-head data point toward two primary first-line anchors: Vedolizumab and Infliximab. The choice between them is nuanced and depends on the specific clinical scenario.Vedolizumab (VDZ) is an excellent default first-line agent for most outpatients. Its gut-selective mechanism of action provides an outstanding long-term safety profile with a lower risk of systemic infections. The landmark VARSITY trial demonstrated its superiority over adalimumab for achieving clinical remission and endoscopic improvement at 52 weeks, cementing its status as a top-tier choice with a favorable net benefit.Infliximab (IFX) is the preferred first choice in specific clinical contexts. Patients with a very high inflammatory burden—evidenced by deep ulcers on endoscopy or a markedly elevated CRP—often benefit from the rapid and potent "torque" of Infliximab. Furthermore, its utility is enhanced by the ability to use Therapeutic Drug Monitoring (TDM) to guide dose optimization from the start.While VDZ and IFX are the primary anchors, other classes of advanced therapies, including JAK inhibitors (e.g., upadacitinib), IL-12/23 inhibitors (Ustekinumab), IL-23 inhibitors (e.g., mirikizumab, risankizumab, guselkumab), and S1P modulators (e.g., etrasimod), are also acceptable first-line options. The selection among these agents is driven by patient factors, such as a strong preference for oral therapy (favoring a JAK or S1P modulator), the need for very rapid symptom control (favoring a JAK inhibitor), or a desire to balance strong efficacy with an excellent safety profile (favoring an IL-23 inhibitor).2.2 The "If This, Then That" Guide to Treatment FailureWhen a first-line advanced therapy fails, the single most important rule is to switch the mechanism of action. Cycling between drugs within the same class is generally not effective. Here is a practical, scenario-based guide to sequencing.If you started Vedolizumab and it fails: The next step is to pivot to a therapy with a different mechanism. The primary options are a JAK inhibitor, which offers the benefit of rapid symptom control and strong efficacy in biologic-experienced patients; an IL-23 inhibitor, which provides robust efficacy and a highly favorable safety profile; or Infliximab, which is a strong choice if you desire the ability to use therapeutic drug monitoring or need to cover extraintestinal manifestations.If you started Infliximab and it fails: The critical first step is to perform Therapeutic Drug Monitoring (TDM). The results will guide your next move. If drug levels are low and there are no anti-drug antibodies, you should dose-escalate to recapture response. However, if anti-drug antibod...