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Primary sclerosing cholangitis (PSC) is a rare liver disease that often strikes people in the “rush hour” of life, with no approved medical cure. Italian hepatologist Dr Laura Cristoferi, PhD, shares an HCP’s perspective on the unmet needs in PSC—from unreliable biomarkers and poorly controlled symptoms, to transplant relapse and psychological burden, and explains how AI-driven imaging, international collaboration and patient-powered research are slowly reshaping the future

Written by Nicola Miller, RARE Revolution
Interview with Dr Laura Cristoferi, PhD, Italian consultant hepatologist with a special interest in
immune-mediated cholestatic disease – PSC

Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease in which the bile ducts inside and outside the liver become inflamed and scarred. Over time, this can lead to cirrhosis, liver failure and cholangiocarcinoma (a rare but aggressive bile duct cancer). For individuals, it can mean living with an uncertain future; for clinicians, it is a race against a disease with no approved medical cure and only one definitive, but not curative option—liver transplantation.

At the Fondazione IRCCS San Gerardo dei Tintori in Monza, northern Italy, Dr Laura Cristoferi is at the frontline of PSC care. A hepatologist and researcher with a background in gastroenterology, she works in a national reference centre for immune-mediated cholestatic diseases. Her work spans day-to-day clinical care, radiology-based biomarker research and leadership of the new Italian national PSC registry, collaborating with around 80 centres.

Laura’s work connects her to the PSC community and scientific endeavours, and her clinical work keeps her grounded in the patient experience, as she explains:

“The fire and the fuel of the clinical research are the patients and their clinical stories.”

From a clinical perspective, PSC is complex to diagnose, manage and treat, as Laura explains. “PSC is a disease that clinicians’ approach with concern and a degree of frustration because of the potential complications it carries.”

Several features make PSC particularly difficult to manage:

• heterogeneous presentation – symptoms and progression vary dramatically
• lack of timely diagnosis
  

“Diagnosis is often made at an already advanced stage with the biliary tract already severely compromised.”

• Lack of approved medical therapy 
  

“The lack of approved therapy makes the management particularly difficult—currently there is no curative option, and liver transplantation remains the primary surgical intervention.”

• critical transplant timing and relapse risks – clinicians must pick the transplant window carefully
  

“The timing of liver transplantation is critical because the disease can recur, so you need to transplant at exactly the right time—without anticipating too much but also without arriving too late.”

Additionally, PSC is also tightly linked to inflammatory bowel disease (IBD), often forcing clinicians to manage two interrelated conditions together, as Laura outlines.

“The prevalence of concomitant inflammatory bowel disease poses the challenge of dealing with two related diseases together. Management needs to be synergic and consider the other disease. They cannot be seen separately.”

For optimum care, PSC should be built around multidisciplinary collaboration Laura explains: “We have the fortune to have an IBD specialist—both in IBD and IBD related to PSC. For us it is simpler, because, when we have to decide on the best treatment for the patient, we deal with gastroenterologists with knowledge of PSC and the potential implications of any intervention.” Laura adds, “You cannot forget that there is the bowel involvement, which is correlated with the biliary tract, so we make a good team.”

The limits of traditional biomarkers and imaging

In many liver diseases, clinicians rely on blood tests and standard radiology reports. In PSC, these can be misleading as Laura explains: “The biochemical biomarkers are often not reliable because they fluctuate and sometimes what we see is that even in patients with normal or near to normal cholestasis, there is a radiology worsening over time.”

This mismatch is confusing for patients. “We face this problem in the clinics, responding to a patient who says, ‘Oh my God, the exams are good’—with ‘yes, but the MRCP (magnetic resonance cholangiopancreatography), is actually not going well’.”

Radiology is central in PSC—for diagnosis, monitoring and cancer surveillance—but it is also subjective: “Radiology is usually affected by interobserver variability between radiologists. Meaning reports are not always reliable, and we spend a lot of time reviewing the images and showing the images to our expert radiologists. It’s time consuming but helpful in standardising the reading and interpretation.”

Building quantitative, AI-derived biomarkers

To address this, Laura and colleagues are using radiomics and AI-assisted analysis to turn visual impressions into measurable numbers.

“We wanted to develop a biomarker which was quantitative and not subjective to the interpretation of the human eye, and that can be monitored over time and derived from the images in an automatic way. A number which helps in the prognosis.”

In multidisciplinary meetings, they noticed that certain heterogeneous patterns on T2-weighted MRI images were linked to more inflamed disease—heterogeneity in T2 phase is also described in literature but is difficult to quantify. They segmented the liver semi-automatically and extracted radiomic features; one stood out: “Among the 50 features that we tested in more than five sequences, what came out was that the heterogeneity of the pixels in this specific sequence was the feature that consistently emerged as prognostic in PSC.” For Laura, it was a confirmation of clinical feeling: It was exciting to quantify with a number a feature which comes out frequently both in meetings and in literature as a prognostic feature and to confirm this in our cohort.”

Ongoing collaborations with centres internationally aim to validate such features and combine them with other quantitative tools. Laura adds, “Sometimes it is not just one feature. Brick-after-brick, hopefully, all the prognostic biomarkers discovered by the entire community will be merged in a unique model with greater performance, putting together biochemical markers, radiology-based markers and liver fibrosis markers with the aim of being as precise as possible with the risk stratification in the disease.”

Symptoms in the “rush hour of life”

While long-term outcomes matter, the daily reality of PSC is often dominated by pruritus (chronic itch), fatigue and profound uncertainty. “The patients are young, and they are working, or they are students, or they are dads and mums—they are in the rush hour of life.” As a result, symptom reporting can be complicated and often under-reported: “Some patients underestimate the symptoms because they try to avoid mentally the disease.” Others struggle to describe symptoms burden because the impact is felt in so many areas of their lives. 

Laura is clear, numerical scales alone might not be enough:

“What I try to do in my practice is to assess what is the impact of the symptoms in patients’ lives?’—Do they need to change the programme of their busy lives, their social interactions, their career or family goals?”

Despite this high burden, effective interventions are limited, especially for fatigue: “The symptoms are another source of frustration for the clinicians, because we want to alleviate the individuals’ symptoms, but often we lack effective tools to do so. In fatigue, there is nothing to offer meaningful relief.”

There are more options for pruritus, but they are still imperfect. One of Laura’s strongest hopes is: “To aid quality of life, I would like to see us finally removing—not improving but removing—itching from our list of problems.”

Psychological impact and the weight of uncertainty

A diagnosis with no curative medical therapy and a possible transplant ahead, carries a heavy emotional load. The inability to precisely predict each individual’s trajectory compounds this: “Not being able to communicate accurately to patients their likelihood of experiencing a clinical outcome often generates anxiety. Patients want answers that we unfortunately struggle to provide.”

Laura’s approach is to narrow the focus: “What I typically recommend at our centre is to address one problem at a time and one stage of the disease at a time, without looking so far ahead, and to place trust in ongoing research.” Involving patients in studies is both scientifically and emotionally important, she adds: “By involving patients in research projects we try to transmit an optimistic idea of research—that we are here now, but we can do much more with your help.”

The goal, Laura says, is not false reassurance but grounded understanding: “What we try to do is to help the patient to be rational and to stay in their condition that moment.”

Liver transplantation remains the primary intervention, but it is far from a perfect solution. PSC can recur in the graft: “We have patients who underwent three transplants. In almost 20 to 30%¹ of individuals the disease relapses, and usually the relapse is faster compared to the primary disease.”

Post-transplant patients cannot access clinical trials and off-label therapies may be risky, meaning, “They are completely without any therapeutic perspective—that’s another reason why we need to go fast in the therapeutical research line.”

To address the unmet needs the wish list includes:

• earlier and more accurate diagnosis
• robust biomarkers to stratify risk and monitor treatment
• better management of symptoms and psychological burden
• clearer regulatory endpoints to support drug approval

On biomarkers and trial endpoints, Laura sees the greatest opportunity: “What I would love to have in the years ahead is a good model of biomarkers that merge together biochemical, radiological, fibrosis, elastography—many aspects of the disease put together—aiding assessment of treatment response and the prognosis of the patient.” She is encouraged by advances in elastography, radiology and large prospective studies such as the WIND project, but Laura stresses: “There are many things ongoing, and I’m very optimistic but we need more strong data.”

Without reliable endpoints, she adds, industry investment is hard to secure and sustain:

“If you don’t have a way to measure the outcomes, then of course a company might not be keen to invest. And we need investment and that the interest remains high.”

Laura is clear that international collaboration is essential, “In rare diseases, you need to collaborate and to stay together with the willingness to take an active role if you want to discover something.” Underpinning this ethos Laura sees the following as positive steps: 

• the Italian national PSC registry, expected to identify up to 800 patients
• participation in the International PSC Study Group
• imaging and biomarker collaborations worldwide
• patient-driven initiatives that shape research priorities

“Sometimes it’s hard because there is a lot of bureaucracy, but the results pay the efforts—the larger the cohorts, the stronger the results.”

Despite the complexities, Laura is passionate about PSC as a field: “From a research perspective, it’s a very interesting disease with many things yet to be discovered, which have the potential for meaningful impact on the lives of families. “If I could, I would choose to do my PhD on this disease all over again. Therefore, I encourage ambitious young researchers to try join the mission, to uncover something new about this complex condition.” 

Looking five years ahead, Laura’s says, “I hope that we would have an interview together asking ourselves, not do we have a therapy, but instead: Which is the best therapy? Based on solid and quantitative biomarkers. But a single therapy would still be very great news with a confirmation with a real-world study that it is effective. That’s the less ambitious but more realistic hope.”

Until then, Laura’s work—and that of many colleagues and patients worldwide—continues, towards a future where PSC care is defined not by frustration and unmet need, but by effective treatments, robust biomarkers and lives lived in more comfort with far less fear.

References

[1] Visseren T et al., Transplant International 2021 PMID: 34028110 — DOI: 10.1111/tri.13925

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