Qualitative Evaluation of Fatigue and Pruritus Among Patients with Primary Biliary Cholangitis

Abstract

Introduction

Primary biliary cholangitis (PBC) is a rare cholestatic autoimmune liver disease. We aimed to generate evidence of the signs, symptoms, and impacts of PBC considered important by patients through interviews with clinicians and patients.

Methods

This noninterventional, qualitative study involved a targeted literature review (TLR), clinician interviews, and patient interviews. The TLR identified relevant signs, symptoms, and impacts of PBC, as well as their reported prevalence data. This information was developed into a preliminary conceptual model (PCM) of PBC and refined via interviews with gastroenterology/hepatology clinicians, focusing on patients’ experiences. Next, PBC-related concepts were captured through patient interviews, and the PCM was finalized. A thematic approach was used to analyze data, and descriptive statistics were used to assess symptom and impact salience, ensuring a representative sample and achieving concept saturation.

Results

Fatigue and pruritus were confirmed as the most prevalent symptoms. Clinician interviews (n = 4) provided insights into biochemical abnormalities used for diagnosis and common symptoms. Patient interviews (n = 20) revealed 41 unique PBC signs and symptoms. Patients reported mental and/or physical fatigue, with both impacting daily activities and overall health-related quality of life. They also reported that pruritus interfered with sleep and social engagements. The final conceptual model could distinguish between salient and non-salient signs, symptoms, and impacts, reflecting patients’ attributions to PBC and its treatment.

Conclusions

PBC imposes a significant burden on patients’ lives. This study highlights unmet patient needs, contributing valuable qualitative evidence to support clinical and observational studies in PBC.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s12325-026-03691-4.

Plain Language Summary

Primary biliary cholangitis (PBC) is a rare disease where the immune system attacks and damages small bile ducts in the liver. PBC can get worse with time and can be potentially life-threatening. The main symptoms are tiredness and itchy skin (pruritus). We examined how people with PBC experience their condition, to better understand how it can be managed in the most useful way for patients. First, we used published studies to gather information on PBC, such as symptoms and ways in which PBC affects patients’ lives (impacts), allowing us to develop a model of PBC. Then, we interviewed medical professionals and patients to understand which symptoms and life impacts matter most to those living with PBC. The medical professionals discussed methods for diagnosing PBC. They reported that patients’ tiredness became worse as the day progressed. Medical professionals said that patients mostly had itchy skin on the soles of the feet or palms and found it to be very bothersome, greatly affecting patients’ daily lives and mental health. When interviewed, patients reported 41 different signs and symptoms, most commonly tiredness and itchy skin. Patients said they experienced mental and physical tiredness, making everyday tasks difficult, and they described how the itching disturbed their sleep and social lives. This study showed how much PBC affects patients’ quality of life. Our model of the most important symptoms and impacts for patients can guide research and improve care by helping us focus on what patients find most difficult about PBC.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s12325-026-03691-4.

Key Summary Points

Why carry out this study?

This study aimed to generate evidence of the signs, symptoms, and impacts of primary biliary cholangitis considered important by patients through interviews with clinicians and patients.

What was learned from the study?

Both patients and clinicians in this study confirmed fatigue and pruritus as the most prevalent symptoms.

Patients reported mental and/or physical fatigue, with both impacting daily activities and overall health-related quality of life. They also reported that pruritus interfered with sleep and social engagements.

The conceptual model developed in this study could distinguish between salient and non-salient signs, symptoms, and impacts, reflecting patients’ attributions to primary biliary cholangitis and its treatment.

Introduction

Primary biliary cholangitis (PBC) is a rare, autoimmune, cholestatic disease of the liver characterized by chronic inflammation in and destruction of the bile ducts [1]. Like other autoimmune conditions of the liver, PBC is associated with severe hepatic inflammation and fibrosis, including cellular alterations underlined by the inflammatory transcriptome [2]. If left untreated, it may slowly progress to cirrhosis, liver failure, and death, unless patients undergo a liver transplant [1, 3, 4]. PBC is more prevalent among women and usually develops in the fourth to sixth decade of life [5]. A systematic review and meta-analysis of epidemiological studies published up to October 2020 estimated the pooled global incidence and prevalence of PBC to be 1.76 and 14.60 per 100,000 persons, respectively [6]. Incidence and prevalence were higher in North America (2.75 and 21.81 per 100,000 persons) and Europe (1.86 and 14.59 per 100,000 persons) than in the Asia–Pacific region (0.84 and 9.82 per 100,000 persons). A recent claims database study conducted between 2014 and 2021 estimated that 105,506 adults had PBC in the USA, with an adjusted 2021 prevalence of 40.9 per 100,000 adults [7].

In PBC, symptoms have a poor correlation with disease stage, although patients with advanced disease usually have more symptoms [3]. Fatigue and pruritus are the most common symptoms [3, 8–10], and can occur independently of each other or coincide [11]. PBC-related fatigue may be constant or progress slowly over time, and may be exacerbated by comorbidities such as hypothyroidism, anemia, and type 2 diabetes [3, 12]. Fatigue significantly impacts patients’ health-related quality of life (HRQoL), and its severity can predict liver-related mortality and transplantation outcomes [3, 12]. Pruritus may be localized or diffuse, and can be aggravated by pregnancy, heat, or contact with clothes [3, 11]. It follows a circadian rhythm and worsens in the evening [3, 11]. The clinical course of pruritus may fluctuate with periods of aggravation and improvement; it has been reported to diminish during advanced disease [3]. Both fatigue and pruritus have been found to have detrimental effects on patients’ mental health and are commonly associated with depression [12, 13].

Ursodeoxycholic acid (UDCA) is recommended as the first-line treatment for patients with PBC in the USA and Europe [14], and it has been found to significantly reduce mortality (adjusted hazard ratio 0.57; 95% CI 0.52–0.64) [15, 16]. However, a substantial proportion of the population (40%) may have an incomplete response to the drug, and 3–5% of patients are intolerant to it [17]. Obeticholic acid (OCA) is one of the medications used as second-line treatment for such patients [3]. However, treatment with OCA increases the incidence or severity of pruritus among patients with PBC [18–20]. Further, in 2024, the European Medicines Agency recommended that marketing authorization for OCA be removed, based on research showing that its benefits do not outweigh the risk of liver damage [21]. Two recently approved, second-line peroxisome proliferator-activated receptor agonist-based therapies—elafibranor and seladelpar—have not only demonstrated biochemical improvements in clinical trials but have also been seen to reduce pruritus among patients [22, 23]. To measure elafibranor’s treatment effect on patients’ experience of fatigue and pruritus, the ELATIVE trial utilized four patient-reported outcome (PRO) instruments, namely, Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 – Fatigue 7a, the PBC Worst Itch Numeric Rating Scale (WI NRS), PBC-40 questionnaire, and 5-D itch scale.

This article discusses a qualitative study undertaken to generate the evidence necessary to establish the content validity of the PROMIS Short Form v1.0 – Fatigue 7a and PBC WI NRS clinical outcome assessment measures for use in PBC study populations as per guidance from the US Food and Drug Administration (FDA). We conducted a literature review and developed a conceptual model, followed by interviews with clinicians and patients with PBC to generate qualitative evidence regarding the signs, symptoms, and impacts of PBC that are relevant and important to patients. Interviews with patients included cognitive debriefings of PROMIS Short Form v1.0 – Fatigue 7a and PBC WI NRS.

Methods

Study Design

This noninterventional qualitative study, based on grounded theory and content analysis, involved three phases. The first phase was a targeted literature review (TLR), followed by interviews with clinicians (phase 2) and patients (phase 3). All interviews were conducted by FGS (PhD), a scientific advisor with 23 years’ qualitative research experience. Participants were informed of who the interviewer’s employer was, and that the interviewer was a researcher and not a medical professional.

Targeted Literature Review

A PubMed search was conducted in 2018 for full-length articles published between 2008 and 2018 using specific search terms (Table S1) to identify publications describing the most relevant signs, symptoms, and impacts among patients with PBC. An updated review was conducted to cover additional publications until March 2021. Additional gray literature searches were also conducted. Publications referring to conditions other than PBC, describing studies using animal models, and/or not pertaining to patients’ experiences with PBC with a focus on its signs, symptoms, and/or impacts were excluded. Frequency of reports of the concepts were captured where available, and concepts were categorized as high (> 50%), medium (≥ 25% to ≤ 50%), or low (< 25%) prevalence. This phase led to the development of a preliminary conceptual model (PCM) of PBC that was subsequently revised based on interviews with clinicians and patients in the second and third phases of the study, respectively.

Clinician Interviews

Between May 25, 2021 and July 22, 2021, semi-structured telephonic interviews in English lasting approximately 75 min were conducted with four clinicians with expertise in PBC diagnosis and treatment to refine the PCM and to gain their perspectives on the experiences and treatments of patients with PBC who were experiencing PBC-related pruritus. Clinicians (Doctor of Medicine) were purposively selected if they specialized in gastroenterology or hepatology, had several years of experience in front-line diagnosis and treatment of patients with PBC, and had spent a majority (> 80%) of their professional time on clinical patient care.

A discussion guide (developed during the first phase based on knowledge gathered from the TLR) was used to steer clinician interviews to focus on five major topics: (1) background and experience in caring for patients with PBC; (2) their perspectives on the signs, symptoms, and impacts that patients reportedly experience because of PBC; (3) their review of and feedback on the PCM developed during the first phase; (4) their perspectives on patients’ experiences of pruritus and their description of mild, moderate, and severe pruritus levels; and (5) their descriptions of the improvement and worsening of pruritus and their qualitative assessments of a meaningful change in improvement and worsening of pruritus from a patient’s perspective, that is, what constitutes an improvement or worsening in patients’ experience of mild, moderate, and severe pruritus.

Interview audio recordings were transcribed, and transcripts were analyzed using ATLAS.ti based on a thematic approach. Representative quotes were extracted to illustrate the study findings.

Patient Interviews

The third phase of the study involved concept-elicitation interviews with patients with two objectives: (1) to further improve our understanding of PBC-related signs, symptoms, and impacts and capture the words and phrases commonly used by patients to describe their disease and treatment burden; and (2) to update the PCM revised during the second phase and finalize it based on patients’ inputs regarding their experiences of PBC-related symptoms and HRQoL impacts. Twenty patients with PBC were interviewed by phone during August 12, 2021 to June 3, 2022. Purposive recruitment of eligible patients from a network of physicians in private and university clinics, social media, and patient advocacy groups was managed by a patient recruitment agency (Global Perspectives) based on criteria defined below. Two patient advocacy groups provided inputs on participant eligibility criteria and patient outreach strategy; raised awareness among their members of the potential opportunity to participate; and supported with interpretation of study data. This study was conducted in accordance with the Declaration of Helsinki. The protocol and study documents were approved by Western Institutional Review Board-Copernicus Group institutional review board (reference number 20213616).

Eligibility Criteria

Adult patients (18–65 years) residing in the USA or Canada with a confirmed PBC diagnosis and experiencing PBC-related pruritus were eligible for the third phase of the study. Patients needed to be able to speak, write, and read fluently in English. They also had to be willing and able to provide informed consent and participate in a 90-min telephonic interview, and have access to a computer/tablet and a stable internet connection.

Patients with a history of significant neurological events (such as a major stroke) or a mental condition rendering them unable to understand the nature, scope, and possible consequences of the study were excluded. Similarly, those diagnosed with other liver diseases (i.e., alcohol liver disease, hepatitis A, autoimmune hepatitis, non-alcoholic steatohepatitis, hepatocellular carcinoma, Gilbert’s syndrome, alpha-1 antitrypsin deficiency, and primary sclerosing cholangitis), atopic dermatitis, or psoriasis, as well as those with a history of liver transplantation or awaiting liver transplantation, were also excluded. Lastly, patients enrolled in any clinical trials evaluating elafibranor (in the past or at the time of the study) were excluded.

Eligible patients who provided written informed consent were recruited once physicians provided written confirmation of their diagnosis or copies of medical records that indicated a PBC diagnosis. Patients received compensation based on fair market value upon completion of the interviews.

Data Collection and Analysis

A sample size of 20 patients was deemed appropriate to achieve concept saturation regarding the health-related experiences of patients in this study. This approach was in alignment with similar studies evaluating the requirements of sample size for achieving saturation during concept-elicitation interviews [24]. The sample size was derived based on achieving a representative sample of the study population and generalization of results, and it follows the US FDA’s guidance regarding PRO measures, which states that the quality of the interview and diversity of the patient sample are more critical than the number of patients in relation to the intended clinical trial population characteristics [25].

A semi-structured discussion guide containing open-ended questions and probes was used to steer the interviews, which lasted approximately 75–90 min. The questions in the discussion guide focused on capturing the patient experience with the signs, symptoms, and impacts of PBC, including fatigue and pruritus. Various probes were used to gain deep insights into patients’ experiences of PBC symptoms (e.g., “How do you experience [sign/symptom]? How would you describe it?”, “How often does it occur?”, “Any triggers?”, “What makes it better/worse?”). For all concepts, follow-up questions were asked in order to obtain a bothersome/disturbance rating between 0 (not at all bothersome/disturbing) and 10 (very bothersome/disturbing).

The interview approach was in line with the recommendations of the International Society for Pharmacoeconomics and Outcomes Research PRO Good Research Practices Task Force. Interview recordings were transcribed, and the qualitative data were coded using a qualitative analysis software (ATLAS.ti v8.0). A codebook was tested and refined by two coders, and transcripts were double coded to ensure consistency and quality of the data until intercoder agreement was reached. Concept saturation, that is, the point in the data collection process after which no new relevant information is elicited, was assessed after each wave of five interviews.

The cognitive debriefing section of the interview aimed to explore the relevance and clarity of PROMIS Short Form v1.0 – Fatigue 7a and PBC WI NRS questions and rating scales to the patient’s experience of PBC and to confirm the appropriateness of the recall period, response options, and response labels. Patients were also asked to describe what rating on both instruments would reflect a meaningful treatment benefit, as compared with how they answered the question (supplementary methods).

For concept-elicitation data, a thematic approach was used to identify and categorize patient concept expressions around the themes and topics of interest based on the study objectives. Descriptive statistics were used to describe the frequency and proportion of concepts elicited, and to describe patients’ demographic and clinical characteristics. Symptom and impact saliencies were determined by plotting the average disturbance rating of each symptom or impact against the frequency of its mentions. Saliency was defined as ≥ 50% of respondents reporting the item as relevant (either “probed” or “spontaneous”) with an average disturbance rating of ≥ 6.5. Analysis of cognitive debriefing data is described in the supplementary methods.

Results

Targeted Literature Review

Our search strategy (end date March 2021) yielded 1070 articles that were further screened based on their titles, followed by their abstracts, to identify the top 100 most relevant articles. Subsequent screening, based on articles pertaining to patients’ experiences and PBC symptoms and impacts, led to the shortlisting of 22 articles. Of these, 11 (two independent surveys, two clinical trial publications with a patient survey component, six literature reviews, and a qualitative study) were selected for a full-text review to extract relevant signs, symptoms, and impacts of PBC (Table S2). Almost all articles mentioned fatigue and pruritus as the main PBC symptoms; one article primarily focused on fatigue, and four focused on pruritus, although they also mentioned other signs, symptoms, and impacts of PBC.

The TLR identified 20 signs and symptoms of PBC, which were organized in the PCM based on their relation to the disease (n = 8), its treatment (n = 10), or both (n = 2). The most prevalent (≥ 50%) symptoms in the literature were fatigue, pruritus, pain/discomfort, and gastrointestinal symptoms. While pain or discomfort is attributed to the disease, gastrointestinal symptoms only result from treatment. Fatigue and pruritus, on the other hand, can be attributed to both the disease and its treatment. These signs and symptoms were organized in the PCM with these considerations in mind.

The TLR also identified 17 impacts (immediate, 6; distal, 9; broader, 2) of PBC. The most prevalent (≥ 50%) immediate impacts were on physical activity, scratching due to itching, sleep deprivation/abnormal sleep patterns, and diet changes. Emotional dysfunction, social isolation/social disturbance, and the inability to work were the most frequently reported distal impacts. The broader impacts (decreased HRQoL and limitations in lifestyle) were also highly prevalent in the literature.

Clinician Interviews

Background and Experience

The clinicians included in this study had 20–30 years of experience, and all of them specialized in hepatology; one clinician also specialized in gastroenterology (Table S3). Clinicians reported that their patients were mostly White, female, and in their 50s.

Signs and Symptoms of PBC Based on Clinicians’ Experience of Managing the Condition

During the interviews, clinicians reported that most patients were asymptomatic at diagnosis, and those who reported symptoms were often diagnosed at an advanced stage (Table S4). The presence of biochemical abnormalities (abnormally high levels of gamma-glutamyl transpeptidase, alkaline phosphatase, and bilirubin) and a positive anti-mitochondrial antibodies test were typically used by clinicians to confirm diagnosis. They reported that UDCA was generally well tolerated by patients. According to one clinician, younger patients tended to have aggressive disease and experienced disease progression faster than older patients, who were less likely to experience symptoms and develop complications (liver stiffness, liver fibrosis, ductopenia, cirrhosis, decompensated liver disease, liver cancer, and end-stage liver disease/liver failure). Any changes in therapy in the younger cohort were aimed at prolonging the time to clinical events.

Clinicians stated that patients with PBC commonly experienced fatigue, which tended to worsen as the day progressed. According to the clinicians, severe fatigue is generalized and could be described as an extreme exhaustion that patients associated with mental fatigue or “brain fog.” It can also be related to sleep disturbances due to nighttime pruritus.

“The patients are embarrassed, and other people are telling them, ‘Stop itching. Stop scratching,’ as if they could control it. So that leads to social isolation … they’re exhausted because they didn’t sleep, so that adds to their fatigue. That leads to depression.” – CLIN04

“Frequently, with the fatigue, they will report they have to take naps in the middle of the day, and they will get progressively more tired, such that they’re able to work or maybe do the minimal household activities, but not have energy for doing any kind of extra activities.” – CLIN02

“Of course, fatigue can be overwhelming, and people can’t do anything, right? They barely can get out of bed, and they have real trouble doing their activities of daily living, and so it can be really overwhelming. I mean that’s severe disease, but it’s not life-threatening.” – CLIN06

Clinicians reported that patients who were symptomatic at diagnosis commonly experienced pruritus, although it did not correlate with the histological stage of PBC. Further, there was no consensus on whether pruritus is related to disease progression, as it can subside when patients become more cholestatic and require liver transplants. A higher alkaline phosphatase level was associated with a greater likelihood of experiencing pruritus. According to the clinicians, patients commonly developed pruritus in the extremities (soles of the feet, palms of the hands); it was associated with skin drying and tended to be worse during winters and at night. Clinicians reported that patients were bothered by the pruritus, and discussions with them on the impact of pruritus on their daily lives were critical to make decisions regarding treatment. Patients could develop serious mental health issues if the pruritus was refractory to medical therapy, and liver transplantation may be indicated when the patient is suicidal as a result of pruritus.

“Pruritus can bring patients to become suicidal, and that is an indication for liver transplantation when pruritus is refractory to everything, and patients are that distressed.” – CLIN04

Apart from fatigue and pruritus, other common PBC symptoms reported by clinicians included dry eyes, dry mouth, portal hypertension, abdominal discomfort in the right upper quadrant, and muscle weakness (or muscle dysfunction/muscle wasting).

Impacts of PBC Based on Clinicians’ Experience of Managing the Condition

During the interviews, clinicians reported that pruritus resulted in excessive scratching, which led to scarring and skin discoloration (Table S4). Consequently, patients tended to change their clothing style to hide their damaged skin and to even wear gloves to avoid scratching themselves while sleeping. Pruritus also interfered with the patients’ ability to sleep at night, due to which they felt tired during the day. Further, the clinicians reported potential emotional impacts, such as anxiety and depression resulting from social isolation and embarrassment, frustration, stress, and the feeling of not being understood by others.

Clinicians reported that dry mouth caused dental problems, such as tooth decay in patients with PBC, and the dry eyes could lead to corneal ulcerations. They reported that patients experienced a decline in physical and cognitive function over time and found it difficult to perform daily chores; patients also often found it difficult to keep up with others due to a need to rest during the day. Clinicians noted that, consequently, patients often reported to them that they experienced reduced working hours, employment loss, and financial stress. Clinicians also stated that patients with PBC experienced social isolation, as they were unable to perform recreational activities and avoided going out.

“Because of the depression and anxiety that is very tightly interconnected with fatigue, many patients are unable to work. I have prescribed disability for many patients, total disability.” – CLIN02

Clinicians’ perspectives regarding changes in pruritus are described in the supplementary results.

Conceptual Model

Clinicians’ review of the PCM resulted in the addition of 13 signs and symptoms and the elimination of four signs and symptoms—obstructive sleep apnea, piloerection, urine frequency change, and neuropsychiatric symptoms (e.g., visual hallucinations). In total, there were 28 signs and symptoms included. Further, eight immediate impacts (scarring/excoriation of the skin due to scratching, clothing changes, needing rest during the day, eating challenges, difficulty with dental hygiene/dental loss, urge to drink/sucking, corneal ulcerations, and inability to wear contact lenses) and three distal impacts (inability to engage in recreational activities, impacts on activities of daily living, and difficulty taking care of family) were added to the conceptual model.

Patient Interviews

Demographic and Clinical Characteristics

Concept-elicitation interviews were conducted with 19 women and one man (average age, 50 years; range, 29–68 years; Tables S5 and S6); of the 20 patients, 16 were from the USA, and four were from Canada. Due to difficulty in recruiting patients, one patient was recruited despite being 3 years older than the upper age limit of 65 years. Physicians confirmed the PBC diagnosis and specified the disease stage. During the interviews, all patients reported that they had received UDCA (n = 20) for PBC; six patients had received OCA, and four patients had received cholestyramine. Two patients reported receiving ondansetron, and one patient reported receiving dextroamphetamine and levoamphetamine for symptomatic treatment. Overall, patients received their PBC diagnosis at a median of 5 years preceding the interview. During the study, almost half of the patients had stage 1 disease and reported experiencing moderate pruritus in the past month (n = 9 for both). Consistent with the literature [26, 27], no association was observed between disease stage and severity of pruritus.

Signs and Symptoms of PBC Experienced by Patients

Patients reported 41 unique signs and symptoms during the interviews; 11 symptoms were mentioned by more than half the patients. Fatigue (n = 19) and pruritus (n = 20) were the most frequently reported symptoms; dry eyes and sensitivity to cold (n = 14 for both) were other common symptoms. The most salient symptoms identified by patients were fatigue, pruritus, dry eyes, dry mouth, skin surface change, and pain (Fig. 1).

Fig. 1.

Saliency map of patient-reported signs and symptoms

Patients’ Experience of Fatigue

Nineteen patients reported experiencing fatigue (Table S7). Patients stated that fatigue was “the worst thing,” that they were “extremely tired” all the time, or that it varied from day to day and worsened with increased activity. One patient rarely experienced fatigue. Patients also reported having mental fatigue and/or physical fatigue and that both types of fatigue impacted their daily lives.

“The worst thing is the fatigue. The fatigue is the worst thing because I still work full time. There’s days I can barely function I’m so tired.” – P04

“It’s just the overall feeling of basically being very tired all the time. It doesn’t really seem to matter how much sleep I get. I don’t sleep a lot, but during the times that I do manage to get sleep, I’m still extremely tired … I haven’t found anything yet that helps.” – P02

When patients were asked to describe what made their fatigue worse, they usually responded by attributing it to PBC or to a comorbidity (e.g., Hashimoto’s disease). Others stated that the fatigue was due to the medicine they took for PBC or other symptoms, such as nausea.

“I think it’s the disease. I think it is the PBC. They tell me it is. I have expressed to my doctors about the fatigue, but because where I had the bleed, my blood is extremely low and, for some reason they can’t get it back up. She said that with low blood and the disease, it’s something basically I gotta live with. There’s not much they can do for it.” – P04

Patients’ Experience of Pruritus

Patients described pruritus as “unbearable” or “torturous,” like a “burning sensation,” “bugs underneath the skin,” or “falling into a beehive” (Table S7). They reported that it occurred at different locations, such as the head or scalp, in the upper or lower body (including the extremities), or around the torso (including the waist and groin). Pruritus varied from one patient to another, from being constant to occurring occasionally. Each patient experienced day-to-day variation in the occurrence and severity of pruritus, which interfered with their sleep and caused stress. The most bothersome aspect of pruritus was that it was not relieved by scratching. In fact, scratching caused bleeding and prevented patients from engaging in different activities. Patients described pruritus as an annoyance, and reported being anxious (n = 19) and embarrassed (n = 11) by the itching. For almost all patients (n = 19), pruritus was the worst at night and interfered with their sleep. Patients reported that changes in environmental temperatures tended to worsen pruritus. Two patients mentioned that OCA made their pruritus worse, and one patient reported that UDCA made it worse. Two patients reported that hydroxyzine provided relief from pruritus; six patients said antihistamines helped them feel sleepy at night. Although patients tried different over-the-counter solutions, most reported that creams and lotions did not provide any relief.

Impacts of PBC Experienced by Patients

Patients reported 31 unique impacts of PBC during their interviews, categorized as physical impacts, emotional impacts, cognitive impacts, role functioning impacts, social impacts, and other impacts (e.g., lifestyle changes). The most frequently reported physical impacts were scratching (n = 20), sleep problems (n = 19), and diet changes (n = 14). Of these, sleep problems (average disturbance rating 8.0/10) and scratching (7.9/10) were the most disturbing to patients. Anxiety/worry (n = 19), stress and sadness/depression (n = 15 for both), embarrassment (n = 11), and frustration (n = 10) were the most common emotional impacts, of which frustration was the most disturbing (7.8/10). The most common cognitive impacts were memory problems (n = 12) and attention problems (n = 10); and patients found the latter most disturbing (7.6/10). Twelve patients reported that PBC affected their work productivity (average disturbance rating 6.3/10); seven reported financial impacts (average disturbance rating 9.5/10). Thirteen patients also stated that PBC impacted their ability to spend time with others, especially because of their fatigue, and 10 patients explained that their relationship with their partner/family was affected. An inability to spend time with others was the most disturbing social impact (8.4/10), followed by the impact on their relationships (6.5/10). Finally, 17 patients stated that they had experienced a deterioration in HRQoL, and 15 patients said they had made lifestyle changes after being diagnosed with PBC. The impact on overall HRQoL was most disturbing to patients (6.6/10). Overall, the most salient impacts identified by patients were scratching, sleep problems, physical activities, activities of daily living, sadness/depression, frustration, attention problems, spending time with others, impacts on their relationships with their partner and family members, and HRQoL impacts (Fig. 2).

Fig. 2.

Saliency map of patient-reported impacts. HRQoL health-related quality of life

Patients’ Experience of Scratching

Pruritus led to excessive scratching for all patients (n = 20); four patients referred to “scratching” as “itching” (Table S7). It was described as “maddening” by two patients, while two patients reported being less aware of their scratching. Five patients described scratching as causing skin bleeding and marks on the skin. Five patients stated that they were embarrassed by the scratching and its effects on their skin and were self-conscious about scratching in front of others.

Sleep Problems

Problems with sleep were reported by 19 patients. They often reported having problems falling asleep as a result of itching that would intensify at night (Table S7). Three patients stayed awake at night due to scratching, which interfered with their sleep. According to the patients, the lack of sleep and persistent fatigue made them feel helpless, emotional, and unable to function during the day.

“Literally, I sit at my desk, and I could fall asleep. When it hits, I just want to cry, I’m so tired. There’s days I just sit there with tears in my eyes saying, ‘I need to go to sleep.’ I take naps on my lunch. I go in the boardroom and just take a nap just to get me through the day, I’m so tired sometimes.” – P04

Concept Saturation

Of the 41 unique signs and symptoms reported by patients during the interviews, 33 symptoms (80%) emerged during the first wave of interviews. During wave 2, five new symptoms (12%) were elicited (hypertension, swelling, skin pain, taste issues, and odor sensitivity), and three new symptoms (7%) were elicited in wave 3 (appetite issues, breathing issues, and hair loss/thinning). No additional symptoms were elicited in wave 4. Thus, symptom saturation was reached after 15 interviews.

Of 31 unique impacts reported during the patient interviews, 28 impacts (90%) emerged in the first wave of interviews. In wave 2, two new impacts (6%) were elicited (emotional impact [guilt] and role functioning impact [change in employment status]), and one new impact (3%) was elicited in wave 3 (cognitive impacts [difficulty finding words]). No new impacts emerged in wave 4. Thus, impact saturation was reached after 15 interviews.

Revision and Finalization of the Conceptual Model

A comprehensive account of all symptoms and impacts reported by participants was summarized in the conceptual model. New symptoms that emerged from the patient interviews that were not reported in the literature or mentioned by clinicians were skin pain, nail problems, bleeding, nosebleeds, weight change, early satiety, swelling, odor sensitivity, breathing issues, difficulty tolerating cold or hot water (temperature sensitivity), dizziness, and vomiting. Similarly, new impacts included self-consciousness, not being understood by others, and change in alcohol consumption. In addition, patients mentioned having difficulty finding words and issues with work productivity as impacts of PBC. The conceptual model was revised based on feedback from patients, wherein patient-reported symptoms were added (e.g., weight change, skin pain, dizziness, and temperature sensitivity) and clinician-reported symptoms were removed (e.g., vaginal dryness, CK elevation, and discoloration of urine), except portal hypertension, which was retained. Amendments were made to the impacts as well (e.g., work productivity, difficulty finding words, and changes in alcohol consumption were added; corneal ulcerations, difficulty taking care of family, and liver transplant were removed). The final conceptual model is presented in Fig. 3.

Fig. 3.

Final conceptual model. Black text represents concepts reported by patients and clinicians. Blue text represents patient-reported concepts. Green text represents clinician-reported important concepts. Bold text represents concepts reported as salient (≥ 50% mentions and ≥ 6.5 average disturbance rating). HRQoL health-related quality of life, TLR targeted literature review

Cognitive Debriefing Results

Table 1 shows the results of the cognitive debriefing section of the interviews with patients, along with illustrative quotes. Overall, patients found both tools to be relevant and comprehensive. Details of patients’ perspectives on meaningful improvements or worsening in fatigue and pruritus are provided in the supplementary results.

Table 1.

Cognitive debriefing results (N = 20)

	Number of patients	Illustrative quotes
PROMIS Short Form v1.0 – Fatigue 7a
Instructions were clear	Y = 18/18a	Yes. Very well worded, clear, able to understand, not confusing at all. – P03 I’m extremely exhausted, I have no desire to even cook dinner, do my normal things. I don’t even want to read, and I’m a voracious reader. I don’t want to read. I don’t want to do anything, honestly. – P07 Running out of energy. You just do not have the capacity to… you’re just done. You’re physically done. You just don’t have the energy to keep going on, keep doing what you got to do. – P08
Items were clear	Y = 18/18
Response options were easy to use	Y = 19/19b	It is. I think sometimes I had a… I was going between “sometimes” and “often” or “rarely” and “sometimes”. There was almost something in between those. I wouldn’t quite say “rarely”, but I wouldn’t say “sometimes”. I feel like there could be something in between those. – P12
Recall period was appropriate	Y = 16/20	I think 7 days is good because then it kind of normalizes any spikes. You’re asking just generally. In a general, you might’ve had one bad day, but in a general, how are things? – P01 Yes, it’s relevant and appropriate. Like I said, when I plan to do anything, it’s based on how I’m feeling that day pretty much. That’s how many answers I gave you are appropriate for the past 7 days for me. I haven’t done a lot. I haven’t been able to go out or anything because I haven’t had a lot of energy and stuff like that. – P08 Yes and no because for me the fatigue is always there. It doesn’t matter if it’s this past week or the week before or 2 months ago. – P15
Meaningful improvementc
1-point change	12/18	Jumping from “sometimes” to “rarely” would be significant change. – P11
2-point change	6/18	My eyes lit up when you said that. It would be great to go to “never,” but even to just be at “sometimes,” to have more days available where I wasn’t feeling fatigued, so overly exhausted, so “sometimes,” “rarely,” or “never” would be great… That would be awesome. – P08
Meaningful worseningd
1-point change	11/16	Well, to me it would be noticeable to jump to “often,” and, definitely be going towards “always,” but, yeah, if you jumped to “often,” it would be noticeable. – P08 I think the same for going up, especially if I’m going from “never” to now I’m like 2 days a week I feel fatigued. That’s a big deal. That can be a very big deal. – P14
2-point change	5/16
PBC WI NRS
Instructions were clear	Y = 20/20	They’re good [instructions]. I think just the only thing I didn’t understand was the ‘NRS’. – P12
Items were clear	Y = 20/20	[‘Worst itch imaginable’ means] that I’m tearing my skin apart and I can’t sleep. – P04
Response options were easy to use	Y = 19/20e	Yes, it is [clear]. Obviously, over the last 24 h, since yesterday at this time. Or within a 24-h period. – P05 Well, it’s kind of hard, really, for an itch because it’s not constant. There are days that it can be really bad and there are days that you’re not going to itch. Then there are days that you itch a little, which is affected, really, by your environment. If it’s a hot, sticky day and I’m outside, I’m going to itch and it’s going to be more so than when it’s cold. You don’t feel it as much. – P09
Recall period was appropriate	Y = 15/19e	I think that’s how we should evaluate how our day is, and 24 h is a day. Combine too many days and it gets lost, so yeah, 24 h. – P10 For me, it’s variable not only week to week, but like month to month. Like I said at the beginning, for me, time of year can affect it… Time of the month can affect it. So, it really varies. You’re catching me today where I’m like, oh yeah, no, I’m feeling pretty good and no I don’t have any itch vs if you would have called me 3 weeks ago, I maybe would have had a completely different answer… I would say I’ve had a 1 probably 3-plus weeks now. – P18
Meaningful improvementf
1-point change	3/18	I think a meaningful change from a 7 would be anything that got it beneath a 4, so 4 or lower. If 1 is I’ve only itched occasionally, 4 would be either I’ve had frequent periods of pruritus, but they’re a very either shortened duration or they weren’t very painful? Or I had 1 or 2 decently bad episodes, but they weren’t super frequent or. All of those being ones that didn’t interfere with my sleep. – P11 I'm so used to it at this point that once it gets to like a 5, it’s tolerable. Anything beyond a 5, it starts getting more severe. I guess, for me to take another medication, it would definitely have to significantly make a difference. – P02 Yeah, I mean anything from 0 to 5 is probably something I would really notice. I would say from the 5 to 10 is when it starts and then it can go either to 10. It can go to 9. It just depends on how bad it is. But I think 5 and below, to me, is just not really crazy itchy, not the worst itch. – P09
2-point change	2/18
3-point change	10/18
4-point change	3/18
Meaningful worseningf
1-point change	7/19	Well, if I think about taking that Ocaliva before, I gave it about 3 days and I was itching like a crazy nut. I mean, my hair itched, my inside of my ears, everything itched. I’m not going to give it, but about 1. I mean, I’m going to go from a 2 to a 3. – P17
2-point change	8/19	If I’m at a 2 and I’m moving upward, I think once it starts getting about a 4, I know I’m headed in the wrong direction. I think beyond 4…beyond 4. – P08
3-point change	4/19	Yes. It might have something to do with how long it was going on. If it was just a day’s worth of an itch, it is certainly different than a continuous itch for weeks. – P12 It would be still occasional, but more, so like a 0, I’m having no itch, a 1 would be probably every couple of days, but a 2 would probably be getting more into…closer to almost every day, and then 3 would be longer periods each day. Then, as it intensified up to 5 and up, it intensifies in the itch itself. – P04
4-point change	0

PROMIS Patient-Reported Outcomes Measurement Information System, PBC WI NRS Primary Biliary Cholangitis Worst Itch Numeric Rating Scale

^aTwo patients were not asked if the instructions and items were clear

^bOne patient was not asked to comment on the response options

^cTwo patients were not able to provide a clear answer for meaningful improvement

^dFour patients were unable to provide a clear answer for meaningful worsening

^eOne patient was not asked to comment on the PBC WI NRS recall period

^fOne patient was not asked the question, and one patient did not understand the improvement question but was able to respond to the worsening question

Discussion

This qualitative study contributes to the existing knowledge base on PBC while focusing on the signs, symptoms, and impacts considered important and meaningful by patients. The TLR confirmed that fatigue and pruritus were among the most prevalent symptoms of PBC, and that scratching and sleep problems were the most prevalent impacts. Clinician interviews helped ascertain the impacts patients experience from fatigue and pruritus, which often led to mental health issues and poor sleep. A 20% change in pruritus following treatment was regarded as meaningful from the clinicians’ perspective; in contrast, any worsening of pruritus was deemed meaningful and warranted a discussion with patients about the potential benefit–risk profiles of PBC treatment options. On the other hand, patients considered a 1-point improvement on the PROMIS Short Form v1.0 – Fatigue 7a 5-point Likert scale and a 3-point change in the PBC WI NRS rating as meaningful. In terms of worsening, patients reported a 1-point decrease for PROMIS Short Form v1.0 – Fatigue 7a and a 1- or 2-point decrease for PBC WI NRS as meaningful.

Evidence from the present study supported the content validity of the well-established PROMIS Short Form v1.0 – Fatigue 7a instrument. Further, the content validity of the PBC WI NRS was established via a deep dive into the experience of pruritus. The qualitative evidence generated during patient interviews improved our understanding of patients’ experiences with PBC. Pruritus was described as “unbearable” and interfered with sleep, prevented social engagement, and contributed to stress. Patients experienced both mental and physical fatigue, which was either constant or varied from day to day, and impacted their HRQoL. Scratching was excessive and “maddening,” caused skin bleeding, and contributed to embarrassment in social settings. Sleep problems were often attributed to pruritus during the night. Lack of sleep and persistent fatigue were linked to feelings of helplessness and the inability to function during the day.

The final conceptual model developed in our study distinguishes between salient and non-salient PBC signs, symptoms, and impacts that were reported by patients, and it reflects patients’ sign/symptom attributions to PBC, treatment, or to both. Overall, there was consensus among the patients that both fatigue (n = 16) and pruritus (n = 20) were attributed to PBC; however, three patients also attributed these salient symptoms to treatment. In addition, the conceptual model includes several immediate impacts (e.g., scratching, physical activity, sleep deprivation/abnormal sleep patterns), distal impacts (e.g., emotional dysfunction, social impacts, impacts on activities of daily living, and sadness/depression), and broader impacts (e.g., poor HRQoL and limitations in lifestyle).

This study has certain limitations. First, PBC-related pruritus was an inclusion criterion for patients, but fatigue was not mentioned. Thus, fatigue may be under-represented in the study sample. Next, the patient cohort comprised mostly White women, so the findings may not reflect the experiences of patients in other demographic groups. Although future studies with a larger and more diverse patient cohort are needed in terms of race or ethnicity, the sample in this study is representative of the real-world population, at least in terms of sex [16]. Of the 20 patients, 18 had early-stage disease (stages 1 and 2). To better understand the evolution and progression of disease burden and how pruritus manifests itself over time, more patients with later-stage disease should be recruited in future studies. The TLR only included full-length articles from PubMed, so other signs, symptoms, and impacts not reported in these publications were not included in the PCM of PBC. However, given the iterative process used to develop the conceptual model, which involved both clinicians and patients, the final conceptual model is likely to be adequately comprehensive. Lastly, although the questions in the discussion guides and conceptual model focused on comprehensively capturing patients’ experiences of PBC, including both fatigue and pruritus, the experience of pruritus was examined in greater detail in order to establish the content validity of the PBC WI NRS. Nonetheless, the content validity of the PROMIS Short Form v1.0 – Fatigue 7a was also supported by evidence from this research.

Conclusions

This qualitative research study, including a TLR as well as clinician- and patient-focused interviews, helped generate evidence to support clinical and observational studies in PBC. The findings of this research highlight the significant impact of PBC on patients’ lives, underscoring the unmet needs of this patient population. Notably, pruritus often disrupts patients’ sleep quality, and mental and physical fatigue—which patients attribute to PBC—impacts their ability to function during the day. The compounding effects of pruritus and fatigue contribute to significant social and emotional stress.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Cynthia Levy: Conceptualization and writing – review & editing. Betsy Williams: Conceptualization, investigation, methodology, project administration, supervision, visualization, writing – original draft, and writing – review & editing. France Ginchereau Sowell: Conceptualization, data curation, formal analysis, funding acquisition, methodology, project administration, validation, visualization, writing – original draft, and writing – review & editing. Julie Dietrich: Conceptualization, funding acquisition, methodology, project administration, supervision, visualization, writing – review & editing. Elaine A Böing: Writing – review & editing. Gail Wright: Writing – review & editing. Jörn M Schattenberg: Writing – review & editing.

Disclosures

Julie Dietrich’s current affiliation is Eli Lilly and Company. Elaine A Böing’s current affiliation is Insmed Incorporated.

Funding

Sponsorship for this study, the Rapid Service Fee, as well as the journal’s open access fee, were provided by Ipsen.

Data Availability

Qualified researchers with a valid research question may request anonymized patient-level data by contacting an Ipsen representative. Further information on Ipsen’s Data Sharing policy is available at http://ipsen.com/science/clinical-trials/clinical-data-transparency/ .

Declarations

Conflict of Interest

Cynthia Levy: Received grants from Calliditas, CymaBay, Gilead, GlaxoSmithKline, Intercept, Ipsen, Kowa, Mirum, Pliant, Target RWE, and Zydus; is an associate editor for Hepatology; Chair for the AASLD Practice Guidelines Committee. Betsy Williams: Employee of IQVIA at the time of the study. France Ginchereau Sowell: Employee of IQVIA. Julie Dietrich: Employee of Genfit at the time of the study and holds stock/stock options with Genfit. Elaine A Böing: Employee of Ipsen at the time of the study and holds stock/stock options with Ipsen. Gail Wright: Is President of the Canadian PBC Society (unpaid role). Jörn M Schattenberg: Received consulting fees from Akero, Alentis, Alexion, Altimmune, Astra Zeneca, 89Bio, Boehringer Ingelheim, Gilead Sciences, GSK, Ipsen, Inventiva Pharma, Madrigal Pharmaceuticals, Kríya Therapeutics, Eli Lilly, eTherapeutics, Merck, MSD Sharp & Dohme GmbH, Novo Nordisk, and Roche; received payment or honoraria from AbbVie, Boehringer Ingelheim, Gilead Sciences, Ipsen, Lilly, Madrigal Pharmaceuticals, MSD, and Novo Nordisk; received support for attending meetings and/or travel from Boehringer Ingelheim and Ipsen; holds stock/stock options with Hepta Bio.

Ethical Approval

This study was conducted in accordance with the Declaration of Helsinki. The protocol and study documents were approved by Western Institutional Review Board-Copernicus Group institutional review board (reference number 20213616). Informed consent was obtained from all individual participants whose PRO data were evaluated in the analysis.