1 INTRODUCTION

Primary sclerosing cholangitis (PSC) is a rare progressive liver disease closely associated with inflammatory bowel disease (IBD). Progression is usually slow with mean time to liver failure or need for liver transplantation being around 20 years.^1-3 However, the heterogeneity of PSC is large and varies from more active rapidly progressing disease with multiple severe symptoms such as jaundice, itch, bacterial cholangitis or cirrhosis complications to slowly progressive asymptomatic disease that is stable for decades. There is currently no medication that can slow down disease progression or decrease the risk of cancer. Ursodeoxycholic acid (UDCA) is broadly used despite limited evidence of its efficacy, but many new potential treatments are being investigated.^{4, 5} One of the more feared complications is the development of malignancies in the liver, especially cholangiocarcinoma (CCA), which can occur at any disease stage. The risk for CCA is highest in older people or with recently diagnosed PSC with a lifetime risk of 8% and is a major cause of death in PSC.^{1, 3, 6, 7} Children more often present with concomitant autoinflammatory features with more pronounced elevated IgG, auto-antibodies and degree of inflammation seen at liver histology.⁸

Management and follow-up strategies for PSC vary considerably between centres and countries,^{9, 10} likely due to the lack of evidence-based practice in PSC. Furthermore, they vary according to the age of the patients due to differences in disease course. A recent survey showed substantial difference between specialised European centres in treatment and monitoring.¹⁰ Updated clinical practice guidelines for sclerosing cholangitis have recently been published by the European and American associations (EASL and AALSD),^{11, 12} both including the paediatric perspective. Such guidelines can contribute to improved quality of PSC care and the implementation of best practice globally. Because the rarity of PSC can lead to a lack of clinical experience in general gastroenterological practice, access to up-to-date recommendations is important for improving knowledge despite limited evidence.

Adoption of new guidelines by healthcare providers can be slow and adherence varies. For example, the United Kingdom (UK) audit found IBD screening and colonic cancer surveillance to be suboptimal in a large UK cohort of people with PSC,¹³ and treatment of cholestatic itch is inconsistent and undertreatment is common.¹⁴ A slow implementation may be due to multiple factors, and behaviour changes in populations and in healthcare systems are well known to take a long time. ERN RARE-LIVER is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States and co-funded by the European Commission. A key goal of the ERN RARE-LIVER is to improve rare liver disease care through the education of both patients and caregivers and by facilitating the implementation of best practice care recommendations.

Identifying the most important areas of improvement by asking patients about their experience of care is one way to increase physicians' awareness of the needs of people with PSC and to facilitate the implementation of best practice. ERN RARE-LIVER PSC Working Group is a platform from which such investigation can be undertaken.

The main aim of this study was therefore to assess patient-reported quality of care in people with PSC to identify and increase awareness of the most important areas for improvement.

2 METHOD

3 RESULTS

3.2 Symptom burden

Eighty-seven per cent of respondents reported having had at least one symptom. The most frequently reported symptom was fatigue (75.8%) followed by abdominal pain (63.4%) and itch (59.9%). Multiple symptoms were common, and more than half of all respondents reported three or more symptoms (Figure 1). Detailed information on frequency of symptoms was not collected in the interests of minimising the survey length and focussing on care. Responders with IBD vs. non-IBD had a similar symptom burden except for abdominal pain, which was more common in IBD responders 66.3% (287/432) vs. 57.2% (151/264), p = 0.019.

3.3 Investigations

Data on how PSC was monitored and contacts with healthcare were reported. Frequency of clinical visits, blood sampling and imaging varied between countries, shown in Supplementary Table S3. In our survey, 24.2% (193) had never undergone an elastography and 48.6% (388) had never had or did not have liver elastography regularly; 7.6% (61) had not had an ultrasound scan (US), and 27.2% (217) did not have this regularly. 11.4% (91) did not have regular scanning with either US or MRI. The use of regular liver elastography was more frequent in academic referral centres than in general hospitals, but nearly 40% of patients treated at an academic referral centre did not have a regular liver elastography (Table S3a).

Colonoscopy had never been performed in 8.1% (65). Of responders with PSC-IBD, 14.8% (64) had a colonoscopy less frequently than every 2 years. Investigations per age group are shown in Figure 2.

Half, 50.9% (406) of all respondents had ever undergone a bone density scan. This scan was more commonly performed in patients having concomitant autoimmune hepatitis (AIH) (62.5% vs. 48.8%, p = 0.02), in females ((55.3%) vs. males (43.6%), p = 0.002) and in older patients, the frequencies being: children 31.8%, young adults 18.7%, adults 50.6% and seniors 71.8%, (p < 0.001). No difference in frequency of bone density scans was seen in people with IBD (52.2%) vs. non-IBD (56.1%) responders. Detailed information about monitoring is shown in Tables S3a–c.

4 DISCUSSION

In this ERN-initiated global survey with 798 nontransplanted respondents with PSC, we report views from a patient perspective about symptom burden, routine care and monitoring, treatments and perceived quality of care. Care for PSC varies between countries. In general, overall disease monitoring is suboptimal, with low frequencies of important routine investigations for some individuals, for example colonoscopies, elastographies, bone density scans and imaging, and in some cases, these investigations have not been performed at all. Medical treatments used also vary considerably between countries. Similar findings were reported by healthcare providers in a recent survey of PSC physicians from expert ERN healthcare centres conducted in 2020.¹⁰

One important issue and unmet need for people with PSC is prognostication.¹² In this context, the low use of elastography in PSC needs immediate attention. Despite nearly two-thirds of responders being treated in academic referral centres, only 43% of respondents reported having regular elastography and 24% never having had this scan. This is surprisingly low since elastography has been used in clinical hepatology for more than a decade and has impact on management if cirrhotic stage is diagnosed.¹⁵

The risk of osteopenia in PSC is lower than in primary biliary cholangitis (PBC),²⁰ and bone density has been reported to reduce by 1% per year for people with PSC.²¹ The mechanism for bone loss in PSC is suggested to be associated with Th17-mediated inflammation not associated with disease duration or liver fibrosis, like in PBC.²² The very low frequency of bone density scanning in our survey population is striking where only half have ever undergone a bone density scan, although higher (62%) in people with PSC and AIH. Only 24% take calcium-vitamin D supplements.

The relatively high proportion of respondents of 41% who had been offered participation in research is encouraging. This figure may be overestimated due to the selection of responders being aware of such opportunities through their patient organisation or ERN. People with PSC are in general engaged and interested in research.²⁴ EASL highlights the importance of expert consultation for people with PSC at diagnosis and referral for those with symptomatic and/or progressive PSC to an experienced centre with ready access to PSC clinical trials and a dedicated multidisciplinary team.

Medications, including UDCA, taken by respondents varied, particularly between countries and may be a reflection on local prescribing policies. In contrast to earlier guidelines,¹⁸ the use of medium-dose UDCA (15–20 mg/kg/d) is now stated as a treatment option in PSC, in keeping with current practice in many centres. Despite recommendation against oral vancomycin outside clinical trials in the guideline for adult patients, there seems to some use of oral vancomycin in the paediatric population (22.7%). The heterogeneous treatment regimes in different countries may make recruitment for clinical multicentre clinical trials of new drugs challenging.

In line with previous patient surveys, fatigue, abdominal pain and itch were the three most commonly reported symptoms.²⁵ It is important to consider fatigue as a discrete symptom but also related to itch and consequent sleep disturbance. However, less than half of those who reported itch had been given a treatment for it. The most commonly reported treatment for itch was antihistamines, a medication known to be ineffective in cholestatic itch and consequently not recommended in clinical practice. Bezafibrate or rifampicin is now recommended as first-line treatment of moderate-to-severe pruritus.¹²

This study has limitations. Most importantly is the potentially low representativeness of respondents and selection bias. Most respondents in our survey were female, which does not reflect the well-known male predominance seen in PSC. However, this was expected since more women engage with patient groups than males. We also failed to effectively reach out to patients in some countries, and responders from the UK and France are clearly overrepresented. The UK and France have strong patient organisations, and representatives from these countries were deeply involved in this work, which likely influenced the response rate. However, since PSC is a rare disease, not every country has PSC patient representation, or has a patient organisation with sufficient capacity to engage to this extent (understandably, as some are very small patient organisations, typically a single person, often a PSC patient themselves, volunteering their time). We tried to reduce potential barriers to participation by translating the English survey into other languages, engaging with known PSC and liver patient organisations such as the European Liver Patients Association as well as the ERN RARE-LIVER physicians for dissemination. There is an urgent need to raise awareness of PSC in countries where patient engagement is low or nonexistent. Recall bias is an obvious problem. The low figures reported on investigations may be underreported. We did not use a validated questionnaire and the translated versions did also not undergo a validation process. Parents/caregivers responded on behalf of the youngest patients, and misinterpretation of symptoms and confidence may not accurately reflect the child's view. It was not possible to estimate the survey response rate due to the openly distributed invitations to take part.

Despite the number of limitations, this study has some strengths. The survey was open globally and translated into 11 languages, allowing more people with PSC to access the survey in their native languages, rather than English-only questions.

5 CONCLUSION

Our findings show that symptom burden in PSC is high, and areas of improvement are disease monitoring with more widespread use of elastography, bone density scanning and colonoscopy, and treatment for itch. Personalised prognostic information should be offered to all individuals with PSC and include information on diet and how they can improve their health. Current practice needs to improve and change if current clinical practice recommendations are to be universally followed. The rarity of PSC means that extensive clinical experience can be limited and timely referral to centres of expertise is critical.

AUTHOR CONTRIBUTIONS

MW, AB, NJ, NC, AL and CS contributed to concept and design. MW, NC, AL, AM, HL, MC, JM, AL, NJ, CS and AB contributed to survey development. DT contributed to statistical analysis. MW and AB contributed to first draft. All authors contributed to revision of manuscript.

CONFLICT OF INTEREST STATEMENT

The authors do not have any disclosures to report.

CLINICAL TRIAL NUMBER

NA.