Background

Primary biliary cholangitis (PBC) is a rare, chronic, autoimmune, cholestatic liver disease that can lead to end-stage liver disease and necessitate liver transplantation [1]. Cholestatic pruritus (referred to by patients as itch) is commonly seen in PBC [2], affecting up to 81% of patients at some point during their disease course [2,3,4,5]. It can impair daily activities, adversely impact quality of life, contribute to fatigue, and lead to depression and, in extreme cases, suicidal ideation [5,6,7,8]. Patients with PBC who experience pruritus report worse fatigue scores than those who do not report pruritus [9, 10].

Pruritus in PBC tends to increase throughout the day and is often worse at night [11, 12]. When assessed at five timepoints (from wake time to sleep time), patients with PBC (n = 74) showed an increase in perceived pruritus over the course of a day, with the peak reported at bedtime [12].

In a study of patient perspectives by the PBCers organization, 65% of respondents with PBC and pruritus (n = 164) reported that their pruritus was worse at night [11]. One of the most prominent effects of pruritus is sleep disturbance, with 74% of patients in the same study reporting that pruritus interferes with their sleep [11]. Up to 20% of patients with PBC in the UK-PBC cohort reported that pruritus frequently or always affected their sleep [2]. In addition, patients with PBC who have higher pruritus scores have longer sleep latency, earlier wake times and increased daytime somnolence [12, 13], which in turn correlates with fatigue [13].

In a series of qualitative interviews with 20 patients with PBC and at least moderate pruritus, the symptoms reported by patients as having most impact fell into the subdomains ‘changes in daily performance’, ‘emotional functioning’, and ‘sleep difficulties caused by itching or other symptoms’ [14]. Thus, it is clear, sleep disturbance has a negative impact on the daily lives of patients with PBC.

An effective treatment for cholestatic pruritus in PBC may influence patient wellbeing by improving quality of life, which is affected by both pruritus and its impact on sleep. Current treatments for PBC, such as the first-line US Food and Drug Administration (FDA)-approved ursodeoxycholic acid (UDCA), have not been shown to improve either pruritus or sleep [15, 16]. Obeticholic acid, a conditionally approved adjunctive therapy to UDCA or monotherapy for those unable to tolerate UDCA for the treatment of PBC, has been associated with a greater incidence of severe pruritus in clinical studies than placebo, a reaction listed as a warning and precaution within the US and EU prescribing information [17,18,19]. Guideline-recommended anti-pruritic strategies for PBC include the bile acid-binding resin cholestyramine and off-label therapies including rifampicin, naltrexone, and sertraline [20]. Off-label fibrates have also been used to manage cholestatic itch [1). Similar findings were found for impact of pruritus on sleep measured by 5-D itch sleep item score and PBC-40 item 8 (“Itching disturbed my sleep”) (Table 1).

Table 1 Patient clinico-demographics and sleep scores by baseline pruritus severity for all patients in GLIMMER (N = 147)†
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Relationship between pruritus and sleep

To evaluate the relationship between pruritus and sleep, this post-hoc analysis was conducted utilizing the GLIMMER study data to assess whether improvements in pruritus correlated with improvements in sleep. At Week 16, a strong correlation was observed between change from baseline in weekly sleep score and change from baseline in weekly itch score (r = 0.88 [95% CI: 0.83; 0.91]) (Fig. 1). Similar correlations were observed between change from baseline in monthly sleep score and monthly itch score (Fig. S1). Post-hoc analysis using the Bland–Altman statistical method showed a correlation between change from baseline in monthly itch score and change from baseline in monthly sleep score (Months 1–3) (r = 0.84 [95% CI: 0.80; 0.87]) (Fig. 2), indicating that the worsening of pruritus may contribute to increased sleep interference, and that the improvement of pruritus may contribute to decreased sleep interference.

Fig. 1
figure 1

Correlation between change from baseline in weekly sleep and itch scores at Week 16. n = 135 patients. Pearson product-moment correlation was used. BID twice daily, CI confidence interval, QD once daily

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Fig. 2
figure 2

Correlation of CFB in monthly sleep and itch scores at Week 16. N = 147 patients (intent-to-treat population). Bland–Altman repeated measures correlation. Each colored dot and corresponding line is associated with an individual patient. CFB change from baseline, CI confidence interval

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Relationship between improvement in pruritus and sleep

The relationship between improvement in pruritus and improvement in sleep was examined post-hoc by assessing whether reported improvements in pruritus severity categories (i.e., mild, moderate, severe) were associated with reduced sleep interference due to pruritus. Patients who experienced improvements in weekly itch score severity category from baseline at Week 16 also demonstrated improved weekly sleep score at Week 16 (Fig. 3). The extent of improvement in pruritus over the course of the study also seemed to have an impact, as patients who improved by two or more pruritus severity categories from baseline (i.e., severe to mild; moderate to none) reported greater improvements in sleep interference scores at Week 16 compared with those who only improved by one category.

Fig. 3
figure 3

Reduction in sleep interference by pruritus severity improvements from baseline at Week 16. n = 135 patients. Improvement by two severity categories corresponds to change in pruritus from severe to mild or moderate to none

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To further characterize the relationship between improvements in pruritus and sleep, weekly sleep score was assessed post-hoc in patients with improvements in pruritus (i.e., itch responders). Patients were considered itch responders if they exhibited weekly itch score improvement of ≥2 points from baseline at Week 16. Patients who demonstrated itch response experienced greater improvements in weekly sleep score, in the sleep items from the 5-D itch scale and in the PBC-40 sleep measure, compared with itch non-responders (Fig. 4). Exploring different thresholds to define itch responders, improvements from baseline of ≥3 or ≥4 points showed consistent and greater improvements in weekly sleep score, as well as in the sleep items from 5-D itch and PBC-40 measures, compared with itch non-responders (Fig. S2). Similar findings were observed with monthly sleep score (Fig. S3).

Fig. 4
figure 4

Itch responders analysis: CFB in weekly sleep score (n = 135), 5-D itch (n = 134), and PBC-40 itch domain sleep item (n = 134). A weekly sleep score; B 5-D itch scale impact of itch on sleep (disability domain sleep item) and C PBC-40 itch domain sleep item 8, impact of itch on sleep. A patient was considered an itch responder if they had a weekly itch score improvement from baseline of at least 2 points on the itch NRS at Week 16. Changes from baseline in continuous endpoints by itch responder groups are presented as box plots with mean (diamond), median, interquartile range, minimum, maximum, and outliers plotted. CFB change from baseline, PBC-40 quality of life measure for primary biliary cholangitis, 5-D 5-dimension

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Discussion

Pruritus and fatigue are two of the most common and debilitating conditions impacting patients with PBC. To reduce the negative impact of these conditions on patients and their quality of life, it is essential to understand the relationship between pruritus and sleep and to determine whether improvements in pruritus have the potential to result in improved sleep. Although several studies have investigated the association between pruritus and sleep [11, 12, 39,40,41,42], this relationship has not previously been well characterized in patients with PBC. This post-hoc analysis of GLIMMER was the first and largest trial to extensively explore the directional relationship between pruritus and sleep in PBC in the entire population, regardless of treatment, using robust methodology [34]. The findings from this analysis demonstrate that there is a clear correlation between pruritus severity and the impact of pruritus on sleep interference in patients with PBC. Sleep interference was worse in patients with moderate or severe pruritus compared with those with mild pruritus, with a strong correlation between changes from baseline in weekly itch score and weekly sleep score at Week 16. Patients who reported an improvement in pruritus severity category from baseline to Week 16 exhibited improvements in sleep as measured by weekly sleep score. Further, mean improvement in weekly sleep score was greater in those with more substantial improvements in pruritus. Itch responders on average showed improved sleep compared with itch non-responders, which was confirmed by multiple different measures (weekly sleep score, reduced 5-D itch impact on sleep scores, and decreased PBC-40 sleep disturbance scores) across a range of itch response thresholds. Indeed, the reduction in pruritus-related sleep interference in patients with a ≥ 2-category improvement in pruritus was more than twice that in those with a 1-category improvement. Thus, improvement in pruritus is likely to lead to a concomitant reduction in sleep interference in patients with PBC.

In GLIMMER, daily sleep scores improved in all groups, including placebo, and there was a high concordance between improvements in itch and sleep scores [34]. The high placebo response is not unusual in pruritus studies [28, 43, 44], as well as studies that rely on subjective patient-reported outcomes [45]. GLIMMER was a dose-ranging study; changes in sleep score over the treatment period were more notable for the BID dose groups, concordant with significant improvements in pruritus. As such, this analysis was performed to further explore the relationship between pruritus severity and sleep-interference due to pruritus in patients with PBC, regardless of treatment group. The Phase 3 GLISTEN trial will further examine the effect of an optimized dose of linerixibat (40 mg BID) on sleep interference due to pruritus.

This post-hoc analysis of the GLIMMER study builds on results from a Phase 2a randomized, double-blind trial of 22 patients with PBC and pruritus, which demonstrated a significant improvement in pruritus and sleep NRS with 2 weeks of linerixibat treatment compared with placebo [24]. Two small open-label studies have shown improvements in pruritus-related sleep disturbance in patients with PBC; however, neither included a placebo comparator. The first was a Phase 2b study where 4 out of 10 patients treated with odevixibat reported improvements in pruritus as assessed by the PBC-40 itch domain and no longer experienced sleep disturbance due to pruritus [29]. The second was a Phase 2 open-label study of seladelpar in 101 patients with PBC where improvements in pruritus-related sleep disturbance, measured using the PBC-40 sleep item, were reported after 1 year [46]. Two earlier studies did include a placebo arm, including an analysis on the efficacy of sertraline in patients with cholestatic pruritus [47]. Fifty-seven percent of patients had PBC, and while sleep disturbance due to pruritus was reduced with open-label sertraline, improvements were similar in the sertraline and placebo arm when patients received double-blind treatment. The second study assessed the antipruritic effect of naltrexone in 16 patients with PBC or primary sclerosing cholangitis. Patients treated with naltrexone experienced reduced daytime and nighttime pruritus which correlated with reduced sleep disturbance [48]. While it is unclear whether improvements were associated with the specific study drug or a placebo effect, a commonality in each of these studies was that the improvement in pruritus resulted in an improvement in sleep in patients with chronic liver disease.

Despite the differences in study design and the variety of measures used to assess pruritus and sleep, there is arguably a suggestion in the published literature of an association between pruritus and sleep interference in PBC, as seen in other conditions [39, 40]. Although this post-hoc analysis demonstrates the potential clinical utility of PRO measures of sleep, the patient-reported nature of these measures may lead to a level of self-report bias. Other methods, such as actigraphy technology, monitor rest/activity cycles during sleep, may allow for an objective daily measure of sleep and sleep disturbance. Actigraphy was initially utilized in the GLIMMER trial as an optional component of the study but was discontinued due to negative patient feedback on the wearable device. The continued advancement in tools that can accurately and objectively assess sleep may provide more effective and practical means of measuring sleep in future studies [49]. Additionally, these analyses used simple correlations to assess the strength of the relationship between itch and sleep. These relationships could be further explored using modeling to adjust for covariates.

Lastly, one limitation of the current post-hoc analysis was the use of a single-item NRS for assessing sleep in GLIMMER, as it only evaluated sleep interference and was not able to differentiate which aspects of sleep were affected, such as quantity, quality, and effects on daily activities. In addition, since the protocol permitted patients with itch NRS ≥ 3 at baseline (Week 4) to be randomized, approximately 25% of the population with mild pruritus entered the treatment period [34]. Thus, the ability to fully detect an impact on pruritus, and any corresponding improvement in sleep in such patients, may have been limited. However, inclusion of patients with a wider range of pruritus is expected to have minimized the confounding effect of pruritus severity.

Conclusions

In conclusion, this post-hoc analysis of GLIMMER demonstrates a strong correlation between pruritus and sleep in patients with PBC, with the presence of worse pruritus correlating with worse sleep. Furthermore, reduction in PBC pruritus led to improved sleep, with greater improvements in pruritus associated with greater improvements in sleep. This is likely to have a beneficial impact on quality of life in patients with PBC. Future larger studies, such as the ongoing Phase 3 GLISTEN trial, will aim to better understand the effect of linerixibat on pruritus and sleep.