Why Do Immunosuppression and Colectomy Do Not Alter Primary Sclerosing Cholangitis Progression?

Primary sclerosing cholangitis (PSC) is one of hepatology’s most complex and heterogenous diseases. Patients with PSC have chronic cholestasis, inflammation, and progressive fibrosis of intra and extrahepatic bile ducts, often leading to cirrhosis and cholangiocarcinoma. The etiology of PSC is not fully understood. Majority of the patients with PSC (60-80%) have concurrent inflammatory bowel disease (IBD) mostly in the form of ulcerative colitis (UC), suggesting a significant interplay between the gut and liver. Currently, there are no effective therapies for PSC.   In this series, we explore why immunosuppression and colectomy have failed to alter disease progression or improve long-term outcomes. 

What causes PSC? 

The etiology of PSC is remains poorly understood. Although PSC is frequently considered an autoimmune-mediated disease, this classification is controversial. Unlike primary biliary cholangitis or autoimmune hepatitis (AIH), PSC lacks several defining features of classic autoimmune disorders, including a clearly defined pathogenic autoantigen. In addition, the marked male predominance and the proposed role of innate immune system, potentially driven by bacterial components delivered to the liver via the portal circulation, suggest immune dysregulation rather than a classic autoimmune process. Genetic susceptibility further supports a multifactorial pathogenesis, as first-degree relatives have over 80-fold increased risk of PSC developing PSC. Overall, the consensus suggests that PSC arises from a complex interplay of genetic predisposition, immune dysfunction, and unidentified environmental triggers.

How do we treat PSC?

The incomplete understanding of PSC pathogenesis has translated into a lack of effective disease-modifying therapies, leaving management largely supportive. Ursodeoxycholic acid may improve liver biochemistries at low doses but has not demonstrated survival benefit. Immunosuppressive agents have consistently failed to alter PSC progression and are reserved only for overlap syndromes or concomitant IBD. Antibiotics such as      oral vancomycin have shown biochemical improvements in small studies, particularly in patients with concurrent IBS and in pediatric populations, but lack robust evidence for durable clinical benefit and raise concerns regarding long-term safety.      Colectomy, despite the strong association between PSC and IBD, does not prevent PSC development or progression. Current care focuses on symptom management, endoscopic treatment of dominant strictures, surveillance for malignancy and      cirrhosis-related complications, and timely referral for liver transplantation or clinical trials, which remains the only definitive therapy for advanced disease.

Why immunosuppression often fails?

For decades, immunosuppressive agents including steroids, azathioprine, methotrexate, calcineurin inhibitors, biologics targeting TNF or interleukins have been trialed in PSC. The expectation was that if PSC were primarily immune-mediated, these medications would suppress the immune system, which would slow the inflammation and fibrosis. However, clinical trials were not successful and these drugs did not convincingly impact the inflammation, liver biochemistries, or convincingly slow fibrosis and delay the need for transplantation. One explanation is that PSC’s inflammation may be driven more by innate immune mechanisms than classic adaptive autoimmunity.

PSC does not behave like AIH. Unlike AIH, PSC lacks a specific pathogenic autoantibody and does not show a consistent and robust response to corticosteroid or other immunosuppressive agents. Histologically, PSC is characterized by fibro obliterative injury of the bile ducts rather than predominant immune-cell mediated hepatocellular inflammation, making it less amenable to immune suppression alone.

In addition, growing evidence suggests that PSC pathogenesis involves immune dysregulation rather than autoimmunity, with complex interactions between genetic susceptibility, aberrant gut-liver axis signaling, microbiota-derived antigens, and cholangiocyte injury. In this context, immune activation may be secondary or perpetuating rather than the primary driver of disease, and the progressive bile duct fibrosis and cholestasis that define PSC may become self-sustaining, such that suppressing inflammation does not reverse established structural damage. Once fibrosis and bile duct loss occur, immunosuppression cannot restore bile duct architecture.

Recurrent PSC after Liver Transplantation 

Even after liver transplantation (LT) when patients are maintained on systemic immunosuppression, PSC recurrence still occurs in approximately 15–30% of patients over time. This observation further supports the concept that immunosuppression does not adequately target the key pathogenic mechanisms of PSC and suggests that factors beyond classic adaptive immune activation as disease recurrence is often seen after LT.

Why colectomy often does not help?

PSC is strongly associated with IBD, particularly UC. This association prompted the logical hypothesis: if the inflamed colon is a source of gut-derived triggers (lymphocytes, interleukins, or microbial metabolites) injuring the bile ducts, removing it might slow PSC. While some patients see a modest, short-term improvement in liver enzymes after colectomy, long-term progression to cirrhosis or cholangiocarcinoma is largely unchanged. 

Importantly, PSC frequently progresses independent of IBD activity. Many patients continue to experience bile duct injury and fibrosis despite well-controlled colitis, and PSC can progress even after colectomy, indicating that colectomy does not eliminate the primary drivers of liver disease. One explanation is that, while the gut–liver axis is central to PSC pathogenesis, the pathogenic immune imprinting may already be established before colectomy. Aberrant homing of gut-primed lymphocytes to the liver and long-lived immune memory cells may persist after colon removal, allowing immune-mediated cholangiocyte injury to continue.

Moreover, extra-colonic factors likely contribute to ongoing disease, including genetic susceptibility, altered bile acid metabolism, persistent dysbiosis of the small intestine, and innate immune activation within the biliary epithelium. Colectomy does not address these mechanisms. Observational data remain mixed. An analysis from International PSC Registry involving 3,110 patients, including 470 who underwent colectomy, suggested that proctocolectomy with permanent ileostomy was associated with decreased rates of LT and PSC-related death compared to patients with intact colon, but the study susceptible for confounding and immortal time bias. Clinical studies have not shown consistent improvements in liver biochemistries, fibrosis progression, or transplant-free survival following colectomy in PSC patients. A meta-analysis of limited available literatures failed to demonstrate colectomy to have an effect on LT. Existing evidence is limited because of small sample sizes and potential confounders by unobserved risk factors, or time dependency in the effect of colectomy.  As a result, colectomy is recommended strictly for standard IBD-related indications, and not a therapeutic intervention for PSC.

Table 1. Therapeutic Strategies in PSC

Table 2. Studies Evaluating IBD Therapy After LT in Patients With PSC

Clinical implications

Immunosuppressive therapy in PSC should be reserved for clearly defined indications such as coexisting AIH or active IBD, rather than for PSC itself. Similarly, colectomy decisions should be guided by standard IBD-related indications and not by the presence or progression of PSC. Immunosuppression and colectomy, though logical in theory, do not alter the natural history. Understanding why these strategies fail sheds light on the complex, multi-factorial pathogenesis of PSC and highlights the need for mechanism-based therapies.

Key Points:

• PSC remains without effective disease-modifying medical therapy.
• Immunosuppressive agents have consistently failed to improve fibrosis progression, transplant-free survival, or long-term outcomes in PSC.
• PSC behaves differently from classic autoimmune liver diseases and appears driven by immune dysregulation rather than adaptive autoimmunity alone.
• Although PSC is strongly associated with IBD, colectomy does not reliably prevent or slow PSC progression.
• Disease mechanisms likely involve a multifactorial interplay of genetic susceptibility, gut–liver axis signaling, cholangiocyte vulnerability, microbiome alterations, and environmental triggers.