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Management of Pruritus in Primary Biliary Cholangitis: A Narrative Review
Accepted Manuscript Management of pruritus in primary biliary cholangitis: a narrative review Hirsh D. Trivedi, M.D, Blanca Lizaola, M.D, Elliot B. Tapper, M.D, Alan Bonder, M.D PII:
S0002-9343(17)30157-2
DOI:
10.1016/j.amjmed.2017.01.037
Reference:
AJM 13930
To appear in:
The American Journal of Medicine
Received Date: 12 January 2017 Revised Date:
27 January 2017
Accepted Date: 30 January 2017
Please cite this article as: Trivedi HD, Lizaola B, Tapper EB, Bonder A, Management of pruritus in primary biliary cholangitis: a narrative review, The American Journal of Medicine (2017), doi: 10.1016/ j.amjmed.2017.01.037. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Management of pruritus in primary biliary cholangitis:
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a narrative review
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Hirsh D. Trivedi M.D. , Blanca Lizaola M.D. , Elliot B. Tapper M.D. , Alan Bonder M.D.
Liver Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 2
Department of Medicine, St. Elizabeth’s Medical Center, Brighton, MA Department of Hepatology, University of Michigan, Ann Arbor, MI
Corresponding author: Alan Bonder M.D. Address: 110 Francis Street, Suite 8E, Boston, MA 02215. Fax: 617-632-1065 Email: [email protected]
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There was no funding source for this manuscript. There are no conflicts of interest for all of the authors on this manuscript. All authors had access to the data and a role in writing the manuscript. Article type: Review Keywords: Primary biliary cholangitis, cholestatic pruritus, cholestasis, biliary injury, pruritus Running head: Pruritus Management in Primary Biliary Cholangitis
ACCEPTED MANUSCRIPT 2 Abstract
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Primary biliary cholangitis is an autoimmune condition characterized by destruction of intrahepatic bile ducts. It causes debilitating symptoms, which dramatically affect the patient’s quality of life. Pruritus affects 60% to 70% of individuals with primary biliary cholangitis and
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leads to sleep disturbances, fatigue, depression and suicidal ideation.
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A complete search was done with studies from PubMed, EMBASE, Web of Science, Cochrane database, Countway library and CINAHL with specific search terms. This narrative review was prepared after a comprehensive literature review.
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Treating patients with cholestatic pruritus is challenging and may have a profound impact on quality of life. The standard of therapy for primary biliary cholangitis, ursodeoxycholic acid (UDCA), does not have a beneficial effect in cholestatic pruritus. Patients often do not respond
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to conventional therapies such as cholestyramine, rifampicin, opioid antagonists, and sertraline. These therapies lack long-term efficacy and have side effects. Patients who have not responded
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to these initial treatments can be considered for experimental therapies or clinical trials. This review outlines the current and emerging treatment modalities for patients with primary biliary cholangitis who suffer from pruritus.
ACCEPTED MANUSCRIPT 3 Introduction
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Primary biliary cholangitis is an immune-mediated, cholestatic condition associated with debilitating symptoms. About 60% to 70% of patients with primary biliary cholangitis
experience pruritus, a potentially incapacitating symptom [1, 2]. It can occur at any stage and
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significantly affects quality of life [3, 4]. Pruritus leads to severe fatigue, sleep disturbance, depression and suicidal tendencies [4]. This often unbearable symptom requires close follow up
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with a focused and multidisciplinary management approach in addition to pharmacologic intervention. A heightened awareness of the treatment modalities for pruritus in primary biliary cholangitis is imperative in order for the treating clinician to optimize the quality of life for their
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patients.
Pharmacologic therapy is the main treatment modality for pruritus in primary biliary cholangitis. Ursodeoxycholic acid (UDCA), the current standard of therapy for primary biliary
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cholangitis, is not effective in the treatment of pruritus [3]. The treatments that are used in the management of pruritus in primary biliary cholangitis include bile acid sequestrants, rifampicin,
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opioid antagonists, and sertraline [3]. Although recommended by the American Association for the Study of Liver Disease (AASLD) and European Association for the Study of the Liver (EASL), these medications are often limited by their adverse effects and lack of efficacy. Alternate therapies must be considered in patients who have pruritus refractory to these treatments. This article reviews the literature of the current and emerging treatments for pruritus in primary biliary cholangitis.
ACCEPTED MANUSCRIPT 4 Pathogenesis of Pruritus in Primary Biliary Cholangitis
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The pathogenesis of pruritus within primary biliary cholangitis is multifaceted. Bile acids are thought to play a prominent role in mediating cholestatic pruritus. The uptake of bile acids in the ileum is increased in cholestatic environments [5]. These bile acids are brought back to the
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liver through the portal venous system and act as pruritogens, which may diffuse from the systemic circulation to the skin [5]. Sensory neurons associated with itch contain a plasma
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membrane receptor called TGR5, which is activated by bile acids and may play a role in cholestatic pruritus [6, 7].
Additional mechanisms of cholestatic pruritus have been proposed. One explanation involves
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the lysophosphatidic acid (LPA) and autotaxin pathway. LPA is formed from lysophosphatidylcholine by the enzyme autotaxin [8]. Autotaxin levels have been found to correlate with the intensity of pruritus in cholestasis compared to those without pruritus (P <
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0.0001) [8]. As a result, LPA, a pruritogen, is increased in patients with cholestatic liver diseases and pruritus [8]. Serum autotaxin levels can be measured to determine the therapeutic effect of
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antipruritic agents in cholestasis [9]. Other mechanisms exist, but are beyond the scope of this review.
ACCEPTED MANUSCRIPT 5 Initial Management of Pruritus
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The management of pruritus in primary biliary cholangitis is a sequential process with multiple steps. As an often presenting symptom of primary biliary cholangitis, pruritus is debilitating and leads to fatigue with sleep disturbance. It is estimated that 20% to 70% of patients with primary
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biliary cholangitis develop pruritus at some point in their illness [3, 10] and 75% of patients have pruritus preceding their diagnosis [11]. Regardless of its onset, the management of
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pruritus requires a multidimensional approach prior to initiating pharmacologic interventions.
Initial Evaluation
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Pruritus is a common manifestation of other systemic illnesses. Initially, an evaluation for other etiologies of pruritus must be considered. These conditions include but renal failure, psoriasis, atopic dermatitis, and a number of other diseases. Once the pruritus is determined to be
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secondary to primary biliary cholangitis, a multidisciplinary approach should be instituted to
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facilitate its treatment.
Quality of Life Assessment
A large proportion of patients with primary biliary cholangitis experience debilitating symptoms, which causes a dramatic impact on quality of life [3, 4, 12]. The symptoms that impair quality of life in primary biliary cholangitis patients include pruritus, fatigue, cognitive
ACCEPTED MANUSCRIPT 6 decline, social and emotional dysfunction, sleep disturbance and depression [4]. In a large UKprimary biliary cholangitis national cohort study, impaired health status and the perception of a
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poor quality of life was noted in 46% and 35% of primary biliary cholangitis patients, respectively, compared to their age-matched and sex-matched control groups (15% and 5%, P <0.0001 for both) [4]. Fatigue and depression showed to have significant impact on quality of
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life [4]. Close follow up and a multidisciplinary treatment approach in order to address issues of social isolation, cognitive decline, depression, and other associated symptoms, is imperative in
Assessment of the Severity of Pruritus
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the overall management of primary biliary cholangitis.
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Pruritus is a subjective complaint with individual threshold variations. Nonetheless, the monitoring of pruritus is essential in order to improve individual patient symptoms. The techniques used to measure the pruritus of primary biliary cholangitis in a research setting are
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grading scales or simple questionnaires, which can potentially be applied to a clinical scenario. The numerical grading scale, visual analogue scale (VAS) and 5-D itch scale are easy measuring
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tools but are not specific to primary biliary cholangitis. The PBC-40 and PBC-27 questionnaires are health related quality of life assessment tools validated specifically for primary biliary cholangitis used commonly in clinical trials [13, 14]. Of all of these modalities, the VAS is the most commonly used and grades the severity of pruritus by identifying a point on a line, which correlates to a numerical value between 0 and 10 (Figure 1) [15]. Regardless of the technique
ACCEPTED MANUSCRIPT 7 chosen to monitor pruritus, the clinician should individualize their approach for each patient
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and practice the selected modality in a consistent manner.
Medical Therapies for Pruritus
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Pharmacologic interventions can be considered once the initial management of pruritus is undergone. Determining the best medical therapy remains challenging. Commonly used
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therapies have limitations and side effects, and should be institute in a step-wise manner. Figure 2 illustrates a sequential approach in the treatment of pruritus in primary biliary cholangitis and table 1 provides the essential features of the individual medical therapies along with their recommended dosages. Often times, a combination approach with these therapies is
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Bile Acid Bindings Resins
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required to minimize pruritus, improve efficacy, and optimize patient comfort.
Bile acid binding resins are often used for pruritus in primary biliary cholangitis. Cholestyramine
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is recommended as first-line therapy [3, 10, 16, 17]. It has been proposed to exert its antipruritic effects by decreasing the reabsorption of bile acids and reducing their levels in the systemic circulation [18]. In one study, microporous cholestyramine was associated with a significant reduction in itch intensity (P < 0.01) and serum bile acids (P < 0.01) [19]. A systematic review evaluated the two randomized controlled trials (RCT) that studied cholestyramine and found the data to be insufficient to determine efficacy due to heterogeneity [20]. Its associated
ACCEPTED MANUSCRIPT 8 side effects include an unpleasant taste, diarrhea, constipation, and bloating [10, 17, 21]. It can also interfere with absorption of other medications and therefore be given 2 to 4 hours before
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or after UDCA [10].
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Rifampicin
Rifampicin has also shown benefit in treating cholestatic pruritus [20, 22]. It can be considered
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in those who are intolerant or refractory to bile-acid binding resins [3]. It’s safety and efficacy has been proven in RCTs and two separate meta-analyses [20, 22]. In a double-blind, randomized, crossover trial, rifampicin was associated with a significant reduction in the VAS score (P < 0.002) [23]. In one meta-analysis consisting of 5 randomized control trials with 61
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total patients, treatment with rifampicin led to complete resolution of pruritus in 77% of the patients and partial resolution in 20% of the patients (OR 5.2, confidence interval [CI] 5.2 to 45.6, P = 0.001) [22]. The adverse effects of rifampicin, which occasionally limit its use, include
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hepatotoxicity, nephrotoxicity, hemolysis, and drug interactions [24-26]. It is unclear which patient population is susceptible to these adverse reactions. However, short-term use of
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rifampicin is associated with a low risk of hepatotoxicity [22]. The guidelines recommend routine monitoring of liver function tests and blood counts to screen for adverse reactions during rifampicin therapy [10].
ACCEPTED MANUSCRIPT 9 Opioid Antagonists
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An increase in opioidergic tone has been observed in patients with pruritus [27]. This has culminated in the use of opioid antagonists as a therapeutic approach to cholestatic pruritus. In one study using naltrexone, the mean daytime VAS reduced from 6.29 ± 2.28 to 3.55 ± 2.39 (P =
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0.0003) and the night-time VAS reduced from 5.89 ± 2.49 to 3.55 ± 2.42 (P = 0.001) [28]. In a meta-analysis with a total of 84 patients, oral agents (naltrexone and nalmefene) and
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intravenous naloxone significantly decreased pruritus compared to the control intervention (standardized mean difference -1.62, 95% CI -3.05 to -0.18) [20]. A notable adverse effect associated with these medications is an opiate withdrawal-like reaction, which consists of hypertension, tachycardia, piloerection, abdominal pain and neuropsychiatric symptoms [29-
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32]. Patients with a more severe form of pruritus and higher opioidergic tone are suspected of being at higher risk for this reaction, although this has not been studied. If there is concern for this reaction, patients can be observed as an inpatient while starting intravenous naloxone and
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Sertraline
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subsequently transitioning to an oral regimen prior to discharge if it is well tolerated [10].
The serotonergic pathway may also play a role in the process of cholestasis pruritus [33, 34]. Sertraline, a selective serotonin reuptake inhibitor used mainly as an antidepressant, had a noteworthy effect in cholestatic pruritus in two trials [33, 34]. In one study, patients in the sertraline group improved by a mean of 1.86 points on the VAS, whereas those taking placebo
ACCEPTED MANUSCRIPT 10 worsened by 0.38 points (P = 0.009) [34]. The effect of sertraline on pruritus relief was independent from an improvement of depression [34]. Over all, sertraline was well tolerated
insomnia [34]. This therapy requires further investigation [10].
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Experimental Therapies for Pruritus
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with only a few patients experiencing mild side effects such as dizziness, loose stools and
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Patients who have pruritus refractory to the conventional therapies should be managed by a specialist and considered for experimental treatments. These interventions are regarded as salvage therapies and are available only in a limited number of centers. Enrollment of patients
Phototherapy
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into clinical trials should also be contemplated when these interventions are being considered.
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Ultraviolet B phototherapy exerts antipruritic effects through an unknown mechanism. In an observational case series, the median VAS score before and after treatment with phototherapy
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decreased from 8.0 to 2.0 (P < 0.001) [35]. The mean number of treatments that were required to achieve a significant reduction in pruritus was 26 ± 17 with the average duration of phototherapy being 8 weeks [35]. This therapy was over all well tolerated with only one patient developing erythema and another developing paresthesia [35].
ACCEPTED MANUSCRIPT 11 Plasmapheresis
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Plasmapheresis may also have a role in patients with primary biliary cholangitis and debilitating pruritus [36]. It removes pruritogens from the systemic circulation and reduces pruritus [37]. A recent study with 17 patients with primary biliary cholangitis (9 with cirrhosis) showed a mean
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decrease in pruritus score on a 10-point numerical scale from 8.3 ± 1.4 to 3.1 ± 2.2 (P < 0.0001) [38]. The antipruritic effect lasted throughout the 90-days follow-up period (P < 0.0001) and
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was not affected by the presence of cirrhosis [38].
Albumin Dialysis
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Albumin dialysis using molecular adsorbent recirculating system (MARS) can be considered in uncontrollable cholestatic pruritus, although long-term data is lacking. Similar to plasmapheresis, MARS exerts its antipruritic effects by removing pruritogens from the systemic
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circulation [37]. In a study of 21 patients with cholestatic liver disease, the VAS score decreased from 70.2 ± 4.8 to 20.1 ± 4.2 (P < 0.001) [39]. Over all, the VAS score decreased by 72%
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immediately after treatment and by 51% one month after treatment [39]. No major adverse effects were noted in any of the patients [39]. In another study with 15 patients, the VAS and itch severity scale improved significantly (P < 0.001) [40]. It was safe and associated with an immediate and complete response in 11 of the patients [40]. In the remaining 4 patients, two had a partial response and two had no response [40].
ACCEPTED MANUSCRIPT 12 Nasobiliary Drainage
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Nasobiliary drainage of bile salts reduces pruritus and serum autotaxin levels, but effects are only transient [8, 9, 41]. In one study, it decreased pruritus by 80% (P < 0.01) [9]. In another multicenter retrospective study, nasobiliary drainage reduced pruritus in 89.6% of cases with
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the VAS score decreasing from 10.0 to 0.3 (P < 0.0001) [42]. Significant reductions in alkaline phosphatase (ALP) levels (P = 0.001) and serum bilirubin (P = 0.03) were also noted, but not in
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total serum bile salts [42]. The most commonly observed complication of nasobiliary drainage was mild post-endoscopic retrograde cholangiopancreatography pancreatitis [42].
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Liver Transplantation
Although the number of patients requiring liver transplantation for primary biliary cholangitis has declined, it remains the sixth leading indication in the United States [10]. Transplantation
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improves symptoms of pruritus and fatigue [10]. It should only be considered when all other
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measures have failed or if urgently required [10].
Ileal Bile Acid Transporter Inhibitors
The ileal bile acid transporter (IBAT) inhibitors are a novel drug class currently undergoing investigation for pruritus in primary biliary cholangitis. IBAT, also known as apical sodiumdependent bile acid transporter (ASBT), is a protein in the terminal ileum which is responsible
ACCEPTED MANUSCRIPT 13 for the intestinal reabsorption of bile acids to the liver. IBAT inhibitors reduce the reabsorption of bile acids facilitating their excretion into the stool and disrupting the enterohepatic
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circulation [43]. Experimental studies have shown beneficial effects of IBAT inhibitors in cholestasis [44, 45]. In a phase 2, multicenter, double-blinded, placebo-controlled, crossover trial presented at AASLD in November of 2016, IBAT inhibitor was associated with a significant
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reduction in pruritus when compared to placebo [43]. The reduction in pruritus was noted using the following scales: numerical rating scale [-23% (-1% to -45%)], PBC-40 itch domain [-14% (-
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1% to -26%)], and 5-D itch [-20% (-7% to -34%)] [43]. The use of the IBAT inhibitor was also associated with a decrease in total bile acid levels and autotaxin activity [43]. The adverse effects were mild and included diarrhea and headache [43]. Further investigation is required.
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Fibrates
Recent evidence on fibrate therapy suggests that it improves biochemical parameters, such as
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ALP, in those who are unresponsive to UDCA therapy [46-48] and may have a possible antipruritic effect [49]. In a recent study of 46 patients with pruritus from UDCA-refractory
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primary biliary cholangitis, there was a significant reduction in the VAS with the use of bezafibrate (from 4.4 ± 0.5 to 0.8 ± 0.2, p<0.001) [49]. This effect was only transient and dissipated once it was discontinued [49].
ACCEPTED MANUSCRIPT 14 Methotrexate and Colchicine
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Methotrexate has shown benefit in treating pruritus [50, 51]. In one trial, pruritus had decreased significantly (P = 0.0001) in patients receiving combination therapy with UDCA, colchicine and methotrexate [50]. However, colchicine for pruritus treatment remains
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controversial. One trial showed significant benefit (P = 0.001) compared with placebo group [52], whereas another study showed no difference [53]. Further investigation of these therapies
Obeticholic Acid-Induced Pruritus
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is required before clinical application.
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Obeticholic acid (OCA), a farnesoid X receptor agonist, is a recently approved medication that improves biochemical parameters in patients with primary biliary cholangitis and a suboptimal response to UDCA [54]. Pruritus is the most common side effect of OCA and requires dose
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adjustments. Certain pretreatment baseline characteristics have been found to be associated with higher risk of OCA-induced pruritus [55]. These include higher baseline levels of gamma-
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glutamyl transferase (GGT), direct bilirubin or ALP, as well as age at primary biliary cholangitis diagnosis and free triiodothyronine levels [55]. In a phase III clinical trial called POISE trial, the group that started off at a lower (5 mg) dose of OCA had the lowest risk of developing pruritus [54]. OCA can be reduced to 5 mg every other day for patients who were taking 5 mg daily and to 5 mg once a day to those who were on 10 mg daily [56]. Another option is to stop therapy completely and restart 2 weeks later at a lower dose [56].
ACCEPTED MANUSCRIPT 15 Conclusion
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Pruritus is a debilitating symptom of primary biliary cholangitis and dramatically affects the patient’s quality of life [1, 57]. It can lead to sleep disturbances, fatigue, depression and
suicidality [4]. UDCA, the mainstay of therapy in primary biliary cholangitis, does not have an
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effect on pruritus [3]. Although multiple therapies currently exist, their long-term antipruritic effects have yet to be established. These therapies are often ineffective and have adverse
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effects. In cases of refractory pruritus, patients should be referred to a specialized facility where they can be considered for experimental therapies or clinical trials. Liver transplantation should only be considered when the all therapies have failed in patients with severe intractable
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pruritus [3, 58].
Treating pruritus in primary biliary cholangitis remains difficult. Despite the different therapeutic options, a significant proportion of patients are still suffering from this unbearable
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symptom [1, 2]. The absence of effective long-term therapeutic modalities is a result of the incomplete understanding behind the mechanism of cholestatic pruritus. Our ongoing learning
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of this multifaceted symptom will hopefully lead to the development of more effective therapies and improve the quality of life for patients with primary biliary cholangitis.
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Krawczyk, M., et al., Plasmapheresis exerts a long-lasting antipruritic effect in severe cholestatic itch. Liver Int, 2016. Pares, A., et al., Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers. J Hepatol, 2010. 53(2): p. 307-12. Leckie, P., et al., 'Out-patient' albumin dialysis for cholestatic patients with intractable pruritus. Aliment Pharmacol Ther, 2012. 35(6): p. 696-704. Kremer, A.E., et al., Autotaxin is a potential mediator of cholestatic pruritus. Acta Dermato-Venereologica, 2009. 89(6): p. 702. Hegade, V.S., et al., The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study. Aliment Pharmacol Ther, 2016. 43(2): p. 294-302. Hegade, V.S., et al., BAT117213: Ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: Study protocol for a randomised controlled trial. BMC Gastroenterology, 2016. 16(1). Baghdasaryan, A., et al., Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis. J Hepatol, 2016. 64(3): p. 674-81. Graffner, H., et al., The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation. Aliment Pharmacol Ther, 2016. 43(2): p. 303-10. Lens, S., et al., Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int, 2014. 34(2): p. 197203. Levy, C., et al., Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther, 2011. 33(2): p. 235-42. Hazzan, R. and R. Tur-Kaspa, Bezafibrate treatment of primary biliary cirrhosis following incomplete response to ursodeoxycholic acid. J Clin Gastroenterol, 2010. 44(5): p. 371-3. Reig, A., P. Sese, and A. Pares, Bezafibrate: A novel and effective alternative for relieving pruritus in patients with primary biliary cirrhosis. Hepatology, 2015. 62: p. 508A. Kaplan, M.M., et al., Methotrexate in patients with primary biliary cirrhosis who respond incompletely to treatment with ursodeoxycholic acid. Dig Dis Sci, 2010. 55(11): p. 320717. Babatin, M.A., F.M. Sanai, and M.G. Swain, Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy. Aliment Pharmacol Ther, 2006. 24(5): p. 813-20. Vuoristo, M., et al., A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid. Gastroenterology, 1995. 108(5): p. 1470-1478. Almasio, P.L., et al., Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis. Alimentary Pharmacology and Therapeutics, 2000. 14(12): p. 1645-1652. Nevens, F., et al., A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl J Med, 2016. 375(7): p. 631-43.
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Malecha, E.S., et al., Baseline factors predicting obeticholic acid induced pruritus in patients with PBC. Gastroenterology, 2016. 150(4): p. S1058. Intercept Pharmaceuticals, I., Ocaliva (obeticholic acid) [prescribing information]. New York, NY. May 2016. Hegade, V.S., et al., A comparative study of cholestatic pruritus in primary biliary cirrhosis cohorts from USA,UK and Italy. Gastroenterology, 2015. 148(4): p. S1059S1060. Neuberger, J. and E.A. Jones, Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy. Eur J Gastroenterol Hepatol, 2001. 13(11): p. 1393-4.
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Therapy
Mechanism
Naltrexone: 50 mg daily
Opioid withdrawal-like reaction, Rare: hepatotoxicity
Sertraline: 75 100 mg daily
Minimal: dizziness, insomnia, loose stools
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SSRI*
Reduces opiodergic tone in cholestasis Affects serotonergic pathways
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Opiate Antagonists (naltrexone, naloxone)*
References [10, 17, 21]
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Table 1. Management of Pruritus in Primary Biliary Cholangitis Drug Mechanism Recommended Limitations Dosages Cholestyramine* Removes 4 - 16 g/day, given diarrhea, constipation, pruritogenic 2-4 hours before bloating, unpleasant taste substances or after UDCA Rifampicin* PXR agonist 150 - 300 mg hepatic failure, renal and enzyme twice daily failure, hemolysis and inducer drug interactions
Experimental therapies Pruritus Relief
[10, 20, 22, 24-26, 59] [10, 20, 28, 29, 6064] [10, 34, 65]
Statistical Significance
References
2.0
P < 0.001
[35]
3.1 ± 2.2 (GS)
P < 0.0001
[66]
VAS (or GS) before
VAS (or GS) after
8.0
8.3 ± 1.4 (GS)
Unknown
Plasmapheresis
Removes pruritogens
Albumin dialysis
Removes pruritogens
70.2 ± 4.8
20.1 ± 4.2
P < 0.001
[39]
Nasobiliary drainage Fibrates
Reduces circulating bile Acts of PPARs family
10.0
0.3
P < 0.0001
[42]
4.4 ± 0.5
0.8 ± 0.2
P < 0.001
[49]
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Phototherapy
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Table 1. Pharmacologic interventions used for the management of pruritus of primary biliary cholangitis. UDCA: Urosdeoxycholic acid, PXR: Pregnane X Receptor, PPAR: Peroxisome Proliferator Activated Receptor, SSRI: Selective Serotonin Reuptake Inhibitor, VAS: visual analogue scale, GS: grading scale *Randomized controlled trials provide higher level of evidence for these agents
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Figure 1. Visual Analogue Scale. 0 = no pruritus, 1-3 = mild pruritus, 4-6 = moderate pruritus, 7-8 = severe pruritus, and 9-10 = very severe pruritus.
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Figure 2. Step-wise approach to managing pruritus in primary biliary cholangitis. *Opioid antagonists include naltrexone and naloxone. **Experimental therapies include phototherapy, plasmapheresis, albumin dialysis, nasobiliary drainage, or clinical trials (all should be performed at a specialized facility).
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Clinical Significance
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Pruritus affects 60 to 70% of patients with primary biliary cholangitis. It is a potentially debilitating symptom that directly reduces the quality of life. Conventional therapies are limited by adverse effects and lack of long-term efficacy, making pruritus a challenging symptom to treat. Clinicians should be aware of the emerging experimental therapies in order to reduce pruritus and optimize the quality of life in patients with primary biliary cholangitis.
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S0002-9343(17)30157-2
DOI:
10.1016/j.amjmed.2017.01.037
Reference:
AJM 13930
To appear in:
The American Journal of Medicine
Received Date: 12 January 2017 Revised Date:
27 January 2017
Accepted Date: 30 January 2017
Please cite this article as: Trivedi HD, Lizaola B, Tapper EB, Bonder A, Management of pruritus in primary biliary cholangitis: a narrative review, The American Journal of Medicine (2017), doi: 10.1016/ j.amjmed.2017.01.037. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Management of pruritus in primary biliary cholangitis:
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a narrative review
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Hirsh D. Trivedi M.D. , Blanca Lizaola M.D. , Elliot B. Tapper M.D. , Alan Bonder M.D.
Liver Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 2
Department of Medicine, St. Elizabeth’s Medical Center, Brighton, MA Department of Hepatology, University of Michigan, Ann Arbor, MI
Corresponding author: Alan Bonder M.D. Address: 110 Francis Street, Suite 8E, Boston, MA 02215. Fax: 617-632-1065 Email: [email protected]
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There was no funding source for this manuscript. There are no conflicts of interest for all of the authors on this manuscript. All authors had access to the data and a role in writing the manuscript. Article type: Review Keywords: Primary biliary cholangitis, cholestatic pruritus, cholestasis, biliary injury, pruritus Running head: Pruritus Management in Primary Biliary Cholangitis
ACCEPTED MANUSCRIPT 2 Abstract
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Primary biliary cholangitis is an autoimmune condition characterized by destruction of intrahepatic bile ducts. It causes debilitating symptoms, which dramatically affect the patient’s quality of life. Pruritus affects 60% to 70% of individuals with primary biliary cholangitis and
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leads to sleep disturbances, fatigue, depression and suicidal ideation.
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A complete search was done with studies from PubMed, EMBASE, Web of Science, Cochrane database, Countway library and CINAHL with specific search terms. This narrative review was prepared after a comprehensive literature review.
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Treating patients with cholestatic pruritus is challenging and may have a profound impact on quality of life. The standard of therapy for primary biliary cholangitis, ursodeoxycholic acid (UDCA), does not have a beneficial effect in cholestatic pruritus. Patients often do not respond
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to conventional therapies such as cholestyramine, rifampicin, opioid antagonists, and sertraline. These therapies lack long-term efficacy and have side effects. Patients who have not responded
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to these initial treatments can be considered for experimental therapies or clinical trials. This review outlines the current and emerging treatment modalities for patients with primary biliary cholangitis who suffer from pruritus.
ACCEPTED MANUSCRIPT 3 Introduction
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Primary biliary cholangitis is an immune-mediated, cholestatic condition associated with debilitating symptoms. About 60% to 70% of patients with primary biliary cholangitis
experience pruritus, a potentially incapacitating symptom [1, 2]. It can occur at any stage and
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significantly affects quality of life [3, 4]. Pruritus leads to severe fatigue, sleep disturbance, depression and suicidal tendencies [4]. This often unbearable symptom requires close follow up
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with a focused and multidisciplinary management approach in addition to pharmacologic intervention. A heightened awareness of the treatment modalities for pruritus in primary biliary cholangitis is imperative in order for the treating clinician to optimize the quality of life for their
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patients.
Pharmacologic therapy is the main treatment modality for pruritus in primary biliary cholangitis. Ursodeoxycholic acid (UDCA), the current standard of therapy for primary biliary
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cholangitis, is not effective in the treatment of pruritus [3]. The treatments that are used in the management of pruritus in primary biliary cholangitis include bile acid sequestrants, rifampicin,
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opioid antagonists, and sertraline [3]. Although recommended by the American Association for the Study of Liver Disease (AASLD) and European Association for the Study of the Liver (EASL), these medications are often limited by their adverse effects and lack of efficacy. Alternate therapies must be considered in patients who have pruritus refractory to these treatments. This article reviews the literature of the current and emerging treatments for pruritus in primary biliary cholangitis.
ACCEPTED MANUSCRIPT 4 Pathogenesis of Pruritus in Primary Biliary Cholangitis
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The pathogenesis of pruritus within primary biliary cholangitis is multifaceted. Bile acids are thought to play a prominent role in mediating cholestatic pruritus. The uptake of bile acids in the ileum is increased in cholestatic environments [5]. These bile acids are brought back to the
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liver through the portal venous system and act as pruritogens, which may diffuse from the systemic circulation to the skin [5]. Sensory neurons associated with itch contain a plasma
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membrane receptor called TGR5, which is activated by bile acids and may play a role in cholestatic pruritus [6, 7].
Additional mechanisms of cholestatic pruritus have been proposed. One explanation involves
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the lysophosphatidic acid (LPA) and autotaxin pathway. LPA is formed from lysophosphatidylcholine by the enzyme autotaxin [8]. Autotaxin levels have been found to correlate with the intensity of pruritus in cholestasis compared to those without pruritus (P <
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0.0001) [8]. As a result, LPA, a pruritogen, is increased in patients with cholestatic liver diseases and pruritus [8]. Serum autotaxin levels can be measured to determine the therapeutic effect of
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antipruritic agents in cholestasis [9]. Other mechanisms exist, but are beyond the scope of this review.
ACCEPTED MANUSCRIPT 5 Initial Management of Pruritus
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The management of pruritus in primary biliary cholangitis is a sequential process with multiple steps. As an often presenting symptom of primary biliary cholangitis, pruritus is debilitating and leads to fatigue with sleep disturbance. It is estimated that 20% to 70% of patients with primary
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biliary cholangitis develop pruritus at some point in their illness [3, 10] and 75% of patients have pruritus preceding their diagnosis [11]. Regardless of its onset, the management of
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pruritus requires a multidimensional approach prior to initiating pharmacologic interventions.
Initial Evaluation
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Pruritus is a common manifestation of other systemic illnesses. Initially, an evaluation for other etiologies of pruritus must be considered. These conditions include but renal failure, psoriasis, atopic dermatitis, and a number of other diseases. Once the pruritus is determined to be
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secondary to primary biliary cholangitis, a multidisciplinary approach should be instituted to
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facilitate its treatment.
Quality of Life Assessment
A large proportion of patients with primary biliary cholangitis experience debilitating symptoms, which causes a dramatic impact on quality of life [3, 4, 12]. The symptoms that impair quality of life in primary biliary cholangitis patients include pruritus, fatigue, cognitive
ACCEPTED MANUSCRIPT 6 decline, social and emotional dysfunction, sleep disturbance and depression [4]. In a large UKprimary biliary cholangitis national cohort study, impaired health status and the perception of a
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poor quality of life was noted in 46% and 35% of primary biliary cholangitis patients, respectively, compared to their age-matched and sex-matched control groups (15% and 5%, P <0.0001 for both) [4]. Fatigue and depression showed to have significant impact on quality of
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life [4]. Close follow up and a multidisciplinary treatment approach in order to address issues of social isolation, cognitive decline, depression, and other associated symptoms, is imperative in
Assessment of the Severity of Pruritus
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the overall management of primary biliary cholangitis.
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Pruritus is a subjective complaint with individual threshold variations. Nonetheless, the monitoring of pruritus is essential in order to improve individual patient symptoms. The techniques used to measure the pruritus of primary biliary cholangitis in a research setting are
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grading scales or simple questionnaires, which can potentially be applied to a clinical scenario. The numerical grading scale, visual analogue scale (VAS) and 5-D itch scale are easy measuring
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tools but are not specific to primary biliary cholangitis. The PBC-40 and PBC-27 questionnaires are health related quality of life assessment tools validated specifically for primary biliary cholangitis used commonly in clinical trials [13, 14]. Of all of these modalities, the VAS is the most commonly used and grades the severity of pruritus by identifying a point on a line, which correlates to a numerical value between 0 and 10 (Figure 1) [15]. Regardless of the technique
ACCEPTED MANUSCRIPT 7 chosen to monitor pruritus, the clinician should individualize their approach for each patient
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and practice the selected modality in a consistent manner.
Medical Therapies for Pruritus
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Pharmacologic interventions can be considered once the initial management of pruritus is undergone. Determining the best medical therapy remains challenging. Commonly used
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therapies have limitations and side effects, and should be institute in a step-wise manner. Figure 2 illustrates a sequential approach in the treatment of pruritus in primary biliary cholangitis and table 1 provides the essential features of the individual medical therapies along with their recommended dosages. Often times, a combination approach with these therapies is
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Bile Acid Bindings Resins
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required to minimize pruritus, improve efficacy, and optimize patient comfort.
Bile acid binding resins are often used for pruritus in primary biliary cholangitis. Cholestyramine
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is recommended as first-line therapy [3, 10, 16, 17]. It has been proposed to exert its antipruritic effects by decreasing the reabsorption of bile acids and reducing their levels in the systemic circulation [18]. In one study, microporous cholestyramine was associated with a significant reduction in itch intensity (P < 0.01) and serum bile acids (P < 0.01) [19]. A systematic review evaluated the two randomized controlled trials (RCT) that studied cholestyramine and found the data to be insufficient to determine efficacy due to heterogeneity [20]. Its associated
ACCEPTED MANUSCRIPT 8 side effects include an unpleasant taste, diarrhea, constipation, and bloating [10, 17, 21]. It can also interfere with absorption of other medications and therefore be given 2 to 4 hours before
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or after UDCA [10].
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Rifampicin
Rifampicin has also shown benefit in treating cholestatic pruritus [20, 22]. It can be considered
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in those who are intolerant or refractory to bile-acid binding resins [3]. It’s safety and efficacy has been proven in RCTs and two separate meta-analyses [20, 22]. In a double-blind, randomized, crossover trial, rifampicin was associated with a significant reduction in the VAS score (P < 0.002) [23]. In one meta-analysis consisting of 5 randomized control trials with 61
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total patients, treatment with rifampicin led to complete resolution of pruritus in 77% of the patients and partial resolution in 20% of the patients (OR 5.2, confidence interval [CI] 5.2 to 45.6, P = 0.001) [22]. The adverse effects of rifampicin, which occasionally limit its use, include
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hepatotoxicity, nephrotoxicity, hemolysis, and drug interactions [24-26]. It is unclear which patient population is susceptible to these adverse reactions. However, short-term use of
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rifampicin is associated with a low risk of hepatotoxicity [22]. The guidelines recommend routine monitoring of liver function tests and blood counts to screen for adverse reactions during rifampicin therapy [10].
ACCEPTED MANUSCRIPT 9 Opioid Antagonists
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An increase in opioidergic tone has been observed in patients with pruritus [27]. This has culminated in the use of opioid antagonists as a therapeutic approach to cholestatic pruritus. In one study using naltrexone, the mean daytime VAS reduced from 6.29 ± 2.28 to 3.55 ± 2.39 (P =
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0.0003) and the night-time VAS reduced from 5.89 ± 2.49 to 3.55 ± 2.42 (P = 0.001) [28]. In a meta-analysis with a total of 84 patients, oral agents (naltrexone and nalmefene) and
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intravenous naloxone significantly decreased pruritus compared to the control intervention (standardized mean difference -1.62, 95% CI -3.05 to -0.18) [20]. A notable adverse effect associated with these medications is an opiate withdrawal-like reaction, which consists of hypertension, tachycardia, piloerection, abdominal pain and neuropsychiatric symptoms [29-
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32]. Patients with a more severe form of pruritus and higher opioidergic tone are suspected of being at higher risk for this reaction, although this has not been studied. If there is concern for this reaction, patients can be observed as an inpatient while starting intravenous naloxone and
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Sertraline
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subsequently transitioning to an oral regimen prior to discharge if it is well tolerated [10].
The serotonergic pathway may also play a role in the process of cholestasis pruritus [33, 34]. Sertraline, a selective serotonin reuptake inhibitor used mainly as an antidepressant, had a noteworthy effect in cholestatic pruritus in two trials [33, 34]. In one study, patients in the sertraline group improved by a mean of 1.86 points on the VAS, whereas those taking placebo
ACCEPTED MANUSCRIPT 10 worsened by 0.38 points (P = 0.009) [34]. The effect of sertraline on pruritus relief was independent from an improvement of depression [34]. Over all, sertraline was well tolerated
insomnia [34]. This therapy requires further investigation [10].
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Experimental Therapies for Pruritus
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with only a few patients experiencing mild side effects such as dizziness, loose stools and
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Patients who have pruritus refractory to the conventional therapies should be managed by a specialist and considered for experimental treatments. These interventions are regarded as salvage therapies and are available only in a limited number of centers. Enrollment of patients
Phototherapy
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into clinical trials should also be contemplated when these interventions are being considered.
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Ultraviolet B phototherapy exerts antipruritic effects through an unknown mechanism. In an observational case series, the median VAS score before and after treatment with phototherapy
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decreased from 8.0 to 2.0 (P < 0.001) [35]. The mean number of treatments that were required to achieve a significant reduction in pruritus was 26 ± 17 with the average duration of phototherapy being 8 weeks [35]. This therapy was over all well tolerated with only one patient developing erythema and another developing paresthesia [35].
ACCEPTED MANUSCRIPT 11 Plasmapheresis
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Plasmapheresis may also have a role in patients with primary biliary cholangitis and debilitating pruritus [36]. It removes pruritogens from the systemic circulation and reduces pruritus [37]. A recent study with 17 patients with primary biliary cholangitis (9 with cirrhosis) showed a mean
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decrease in pruritus score on a 10-point numerical scale from 8.3 ± 1.4 to 3.1 ± 2.2 (P < 0.0001) [38]. The antipruritic effect lasted throughout the 90-days follow-up period (P < 0.0001) and
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was not affected by the presence of cirrhosis [38].
Albumin Dialysis
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Albumin dialysis using molecular adsorbent recirculating system (MARS) can be considered in uncontrollable cholestatic pruritus, although long-term data is lacking. Similar to plasmapheresis, MARS exerts its antipruritic effects by removing pruritogens from the systemic
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circulation [37]. In a study of 21 patients with cholestatic liver disease, the VAS score decreased from 70.2 ± 4.8 to 20.1 ± 4.2 (P < 0.001) [39]. Over all, the VAS score decreased by 72%
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immediately after treatment and by 51% one month after treatment [39]. No major adverse effects were noted in any of the patients [39]. In another study with 15 patients, the VAS and itch severity scale improved significantly (P < 0.001) [40]. It was safe and associated with an immediate and complete response in 11 of the patients [40]. In the remaining 4 patients, two had a partial response and two had no response [40].
ACCEPTED MANUSCRIPT 12 Nasobiliary Drainage
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Nasobiliary drainage of bile salts reduces pruritus and serum autotaxin levels, but effects are only transient [8, 9, 41]. In one study, it decreased pruritus by 80% (P < 0.01) [9]. In another multicenter retrospective study, nasobiliary drainage reduced pruritus in 89.6% of cases with
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the VAS score decreasing from 10.0 to 0.3 (P < 0.0001) [42]. Significant reductions in alkaline phosphatase (ALP) levels (P = 0.001) and serum bilirubin (P = 0.03) were also noted, but not in
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total serum bile salts [42]. The most commonly observed complication of nasobiliary drainage was mild post-endoscopic retrograde cholangiopancreatography pancreatitis [42].
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Liver Transplantation
Although the number of patients requiring liver transplantation for primary biliary cholangitis has declined, it remains the sixth leading indication in the United States [10]. Transplantation
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improves symptoms of pruritus and fatigue [10]. It should only be considered when all other
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measures have failed or if urgently required [10].
Ileal Bile Acid Transporter Inhibitors
The ileal bile acid transporter (IBAT) inhibitors are a novel drug class currently undergoing investigation for pruritus in primary biliary cholangitis. IBAT, also known as apical sodiumdependent bile acid transporter (ASBT), is a protein in the terminal ileum which is responsible
ACCEPTED MANUSCRIPT 13 for the intestinal reabsorption of bile acids to the liver. IBAT inhibitors reduce the reabsorption of bile acids facilitating their excretion into the stool and disrupting the enterohepatic
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circulation [43]. Experimental studies have shown beneficial effects of IBAT inhibitors in cholestasis [44, 45]. In a phase 2, multicenter, double-blinded, placebo-controlled, crossover trial presented at AASLD in November of 2016, IBAT inhibitor was associated with a significant
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reduction in pruritus when compared to placebo [43]. The reduction in pruritus was noted using the following scales: numerical rating scale [-23% (-1% to -45%)], PBC-40 itch domain [-14% (-
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1% to -26%)], and 5-D itch [-20% (-7% to -34%)] [43]. The use of the IBAT inhibitor was also associated with a decrease in total bile acid levels and autotaxin activity [43]. The adverse effects were mild and included diarrhea and headache [43]. Further investigation is required.
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Fibrates
Recent evidence on fibrate therapy suggests that it improves biochemical parameters, such as
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ALP, in those who are unresponsive to UDCA therapy [46-48] and may have a possible antipruritic effect [49]. In a recent study of 46 patients with pruritus from UDCA-refractory
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primary biliary cholangitis, there was a significant reduction in the VAS with the use of bezafibrate (from 4.4 ± 0.5 to 0.8 ± 0.2, p<0.001) [49]. This effect was only transient and dissipated once it was discontinued [49].
ACCEPTED MANUSCRIPT 14 Methotrexate and Colchicine
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Methotrexate has shown benefit in treating pruritus [50, 51]. In one trial, pruritus had decreased significantly (P = 0.0001) in patients receiving combination therapy with UDCA, colchicine and methotrexate [50]. However, colchicine for pruritus treatment remains
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controversial. One trial showed significant benefit (P = 0.001) compared with placebo group [52], whereas another study showed no difference [53]. Further investigation of these therapies
Obeticholic Acid-Induced Pruritus
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is required before clinical application.
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Obeticholic acid (OCA), a farnesoid X receptor agonist, is a recently approved medication that improves biochemical parameters in patients with primary biliary cholangitis and a suboptimal response to UDCA [54]. Pruritus is the most common side effect of OCA and requires dose
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adjustments. Certain pretreatment baseline characteristics have been found to be associated with higher risk of OCA-induced pruritus [55]. These include higher baseline levels of gamma-
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glutamyl transferase (GGT), direct bilirubin or ALP, as well as age at primary biliary cholangitis diagnosis and free triiodothyronine levels [55]. In a phase III clinical trial called POISE trial, the group that started off at a lower (5 mg) dose of OCA had the lowest risk of developing pruritus [54]. OCA can be reduced to 5 mg every other day for patients who were taking 5 mg daily and to 5 mg once a day to those who were on 10 mg daily [56]. Another option is to stop therapy completely and restart 2 weeks later at a lower dose [56].
ACCEPTED MANUSCRIPT 15 Conclusion
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Pruritus is a debilitating symptom of primary biliary cholangitis and dramatically affects the patient’s quality of life [1, 57]. It can lead to sleep disturbances, fatigue, depression and
suicidality [4]. UDCA, the mainstay of therapy in primary biliary cholangitis, does not have an
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effect on pruritus [3]. Although multiple therapies currently exist, their long-term antipruritic effects have yet to be established. These therapies are often ineffective and have adverse
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effects. In cases of refractory pruritus, patients should be referred to a specialized facility where they can be considered for experimental therapies or clinical trials. Liver transplantation should only be considered when the all therapies have failed in patients with severe intractable
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pruritus [3, 58].
Treating pruritus in primary biliary cholangitis remains difficult. Despite the different therapeutic options, a significant proportion of patients are still suffering from this unbearable
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symptom [1, 2]. The absence of effective long-term therapeutic modalities is a result of the incomplete understanding behind the mechanism of cholestatic pruritus. Our ongoing learning
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of this multifaceted symptom will hopefully lead to the development of more effective therapies and improve the quality of life for patients with primary biliary cholangitis.
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References:
6. 7. 8. 9. 10. 11. 12. 13.
14. 15. 16. 17. 18. 19.
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Hegade, V.S., et al., Patient experience and characteristics of cholestatic pruritus in the UK-PBC research cohort. Hepatology, 2014. 60: p. 362A-363A. Hegade, V.S., et al., A comparative study of pruritus in pbc cohorts from UK, USA and Italy. Journal of Hepatology, 2015. 62: p. S785. Beuers, U., et al., EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. Journal of Hepatology, 2009. 51(2): p. 237-267. Mells, G.F., et al., Impact of primary biliary cirrhosis on perceived quality of life: the UKPBC national study. Hepatology, 2013. 58(1): p. 273-83. Lanzini, A., et al., Intestinal absorption of the bile acid analogue 75Se-homocholic acidtaurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration. Gut, 2003. 52(9): p. 1371-5. Alemi, F., et al., The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest, 2013. 123(4): p. 1513-30. Lieu, T., et al., The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology, 2014. 147(6): p. 1417-28. Kremer, A.E., et al., Autotaxin but not bile salts correlate with itch intensity in cholestasis. Journal of Hepatology, 2010. 52: p. S1. Kremer, A.E., et al., Autotaxin levels mirror efficacy of treatment of cholestatic pruritus. Hepatology, 2010. 52: p. 481A. Lindor, K.D., et al., Primary biliary cirrhosis. Hepatology, 2009. 50(1): p. 291-308. Rishe, E., A. Azarm, and N.V. Bergasa, Itch in primary biliary cirrhosis: a patients' perspective. Acta Derm Venereol, 2008. 88(1): p. 34-7. Poupon, R.E., et al., Quality of life in patients with primary biliary cirrhosis. Hepatology, 2004. 40(2): p. 489-94. Jacoby, A., et al., Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut, 2005. 54(11): p. 1622-9. Montali, L., et al., A short version of a HRQoL questionnaire for Italian and Japanese patients with Primary Biliary Cirrhosis. Dig Liver Dis, 2010. 42(10): p. 718-23. Reich, A., et al., Visual analogue scale: evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol, 2012. 92(5): p. 497-501. Oster, Z.H., et al., RELIEF OF PRURITUS BY CHOLESTYRAMINE IN CHRONIC LIVER DISEASE. Israel Journal of Medical Sciences, 1965. 1(4P1): p. 599-&. Datta, D.V. and S. Sherlock, Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis. Gastroenterology, 1966. 50(3): p. 323-32. An antipruritic agent for primary biliary cirrhosis and cholestatic jaundice. Cholestyramine resin (cuemid). JAMA (Chicago, Ill.), 1966. 197(4): p. 261-262. Di Padova, C., et al., Double-blind placebo-controlled clinical trial of microporous cholestyramine in the treatment of intra- and extra-hepatic cholestasis: relationship between itching and serum bile acids. Methods Find Exp Clin Pharmacol, 1984. 6(12): p. 773-6.
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Tandon, P., et al., The efficacy and safety of bile Acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus. Am J Gastroenterol, 2007. 102(7): p. 1528-36. Van Itallie, T.B., et al., The treatment of pruritus and hypercholesteremia of primary biliary cirrhosis with cholestyramine. N Engl J Med, 1961. 265: p. 469-74. Khurana, S. and P. Singh, Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver Int, 2006. 26(8): p. 943-8. Ghent, C.N. and S.G. Carruthers, Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology, 1988. 94(2): p. 488-93. Talwalkar, J.A., et al., Natural history of pruritus in primary biliary cirrhosis. Clin Gastroenterol Hepatol, 2003. 1(4): p. 297-302. Bachs, L., et al., Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis. Lancet, 1989. 1(8638): p. 574-6. Prince, M.I., A.D. Burt, and D.E. Jones, Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut, 2002. 50(3): p. 436-9. Ballantyne, J.C., A.B. Loach, and D.B. Carr, The incidence of pruritus after epidural morphine. Anaesthesia, 1989. 44(10): p. 863. Terg, R., et al., Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol, 2002. 37(6): p. 717-22. Bergasa, N.V., et al., Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med, 1995. 123(3): p. 161-7. Thornton, J.R. and M.S. Losowsky, Opioid peptides and primary biliary cirrhosis. Bmj, 1988. 297(6662): p. 1501-4. Bergasa, N.V., et al., Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study. J Am Acad Dermatol, 1999. 41(3 Pt 1): p. 4314. Bergasa, N.V., et al., Open-label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology, 1998. 27(3): p. 679-84. Browning, J., B. Combes, and M.J. Mayo, Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol, 2003. 98(12): p. 2736-41. Mayo, M.J., et al., Sertraline as a first-line treatment for cholestatic pruritus. Hepatology, 2007. 45(3): p. 666-74. Decock, S., et al., Cholestasis-induced pruritus treated with ultraviolet B phototherapy: an observational case series study. J Hepatol, 2012. 57(3): p. 637-41. Cohen, L.B., E.P. Ambinder, and A.M. Wolke, Role of plasmapheresis in primary biliary cirrhosis. Gut, 1985. 26(3): p. 291-294. Kremer, A.E., et al., Pathogenesis and Management of Pruritus in PBC and PSC. Dig Dis, 2015. 33 Suppl 2: p. 164-75.
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Malecha, E.S., et al., Baseline factors predicting obeticholic acid induced pruritus in patients with PBC. Gastroenterology, 2016. 150(4): p. S1058. Intercept Pharmaceuticals, I., Ocaliva (obeticholic acid) [prescribing information]. New York, NY. May 2016. Hegade, V.S., et al., A comparative study of cholestatic pruritus in primary biliary cirrhosis cohorts from USA,UK and Italy. Gastroenterology, 2015. 148(4): p. S1059S1060. Neuberger, J. and E.A. Jones, Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy. Eur J Gastroenterol Hepatol, 2001. 13(11): p. 1393-4.
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Therapy
Mechanism
Naltrexone: 50 mg daily
Opioid withdrawal-like reaction, Rare: hepatotoxicity
Sertraline: 75 100 mg daily
Minimal: dizziness, insomnia, loose stools
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SSRI*
Reduces opiodergic tone in cholestasis Affects serotonergic pathways
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Opiate Antagonists (naltrexone, naloxone)*
References [10, 17, 21]
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Table 1. Management of Pruritus in Primary Biliary Cholangitis Drug Mechanism Recommended Limitations Dosages Cholestyramine* Removes 4 - 16 g/day, given diarrhea, constipation, pruritogenic 2-4 hours before bloating, unpleasant taste substances or after UDCA Rifampicin* PXR agonist 150 - 300 mg hepatic failure, renal and enzyme twice daily failure, hemolysis and inducer drug interactions
Experimental therapies Pruritus Relief
[10, 20, 22, 24-26, 59] [10, 20, 28, 29, 6064] [10, 34, 65]
Statistical Significance
References
2.0
P < 0.001
[35]
3.1 ± 2.2 (GS)
P < 0.0001
[66]
VAS (or GS) before
VAS (or GS) after
8.0
8.3 ± 1.4 (GS)
Unknown
Plasmapheresis
Removes pruritogens
Albumin dialysis
Removes pruritogens
70.2 ± 4.8
20.1 ± 4.2
P < 0.001
[39]
Nasobiliary drainage Fibrates
Reduces circulating bile Acts of PPARs family
10.0
0.3
P < 0.0001
[42]
4.4 ± 0.5
0.8 ± 0.2
P < 0.001
[49]
EP
TE D
Phototherapy
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Table 1. Pharmacologic interventions used for the management of pruritus of primary biliary cholangitis. UDCA: Urosdeoxycholic acid, PXR: Pregnane X Receptor, PPAR: Peroxisome Proliferator Activated Receptor, SSRI: Selective Serotonin Reuptake Inhibitor, VAS: visual analogue scale, GS: grading scale *Randomized controlled trials provide higher level of evidence for these agents
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Figure 1. Visual Analogue Scale. 0 = no pruritus, 1-3 = mild pruritus, 4-6 = moderate pruritus, 7-8 = severe pruritus, and 9-10 = very severe pruritus.
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Figure 2. Step-wise approach to managing pruritus in primary biliary cholangitis. *Opioid antagonists include naltrexone and naloxone. **Experimental therapies include phototherapy, plasmapheresis, albumin dialysis, nasobiliary drainage, or clinical trials (all should be performed at a specialized facility).
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Clinical Significance
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Pruritus affects 60 to 70% of patients with primary biliary cholangitis. It is a potentially debilitating symptom that directly reduces the quality of life. Conventional therapies are limited by adverse effects and lack of long-term efficacy, making pruritus a challenging symptom to treat. Clinicians should be aware of the emerging experimental therapies in order to reduce pruritus and optimize the quality of life in patients with primary biliary cholangitis.
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