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Cholestatic Pruritus

CME

The Impact of Cholestatic Pruritus in PBC

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: June 18, 2024

Expiration: June 17, 2025

Christopher L. Bowlus
Christopher L. Bowlus, MD
CME/CE Information

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Nonpharmacologic Treatments for PBC Pruritus22

The management of cholestatic pruritus can be challenging for healthcare professionals given the limited tools we have available to us.

Typically we start with the nonpharmacologic treatments of PBC, which will work in patients with very mild pruritus or those who do not want to take medications for their itching.

Because itching is typically worse at night, having patients use light bedding and be cool when they go to bed can sometimes help with the nighttime itch.

Avoiding other causes of itch, such as dry skin, means topical moisturizers can be helpful. Furthermore, cool showers (rather than hot showers) will help prevent the exacerbation of itch from heat.

Avoiding fragrance or other irritants in soaps and laundry detergents, as well as avoiding irritating fabrics such as wool, also can sometimes mitigate the itch.

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Drug and Nondrug Management of Pruritus19,23

However, in patients with moderate to severe itch, simple nonpharmacologic measures are unlikely to give them much relief, so we have to think about pharmacologic measures instead.

We could think about the different modalities of treating PBC pruritus as reducing the production of pruritogen, increasing the excretion/elimination of the pruritogen, blocking the signaling of the pruritogen, or modifying the perception of itch locally.

  • We can increase the excretion/elimination of the pruritogens with bile acid–binding resins such as cholestyramine. Experimental medications such as ileal bile acid transport (IBAT) inhibitors block the reabsorption of the pruritogens. Plasmapheresis can be used in more severe cases to increase elimination or drainage of bile.
  • We can try to reduce the production of the pruritogen with antibiotics such as rifampin.
  • We can block the itch signal from reaching the brain with drugs such as naltrexone and sertraline.
  • We can modify the itch perception locally with UV light therapy.

Antihistamines are not included because the itch in cholestatic pruritus is not related to histamine release. Antihistamines may help with sedation at bedtime but also can cause intolerable adverse events.

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First-line PBC Pruritus Treatment: Bile Acid Resins3,24-26

According to the American Association for the Study of Liver Diseases guidelines, first-line treatment of PBC pruritus is bile acid resins. This class includes cholestyramine, colesevelam, and colestipol, of which cholestyramine is the only agent approved by the FDA for this indication.

Cholestyramine generally is given 2 times daily; of importance, each of the drugs in this class must be separated by 2-4 hours from other drugs, including ursodeoxycholic acid, which can be very inconvenient for patients.

In addition, cholestyramine can be unpalatable for patients. The other bile acid resins can cause constipation and bloating, neither of which are well-tolerated.

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Your patient with PBC has been experiencing increasingly bothersome pruritus and is starting cholestyramine for treatment. Which is a key counseling point to cover?

Beyond First-line Treatments for PBC Pruritus3

Other treatments for PBC pruritus include the antibiotic rifampin, which is limited by a relatively frequent incidence of significant hepatotoxicity; it is contraindicated in people with severe liver disease at baseline. Rifampin is fraught with important drug–drug interactions that must be considered. If you are prescribing rifampin, it is important to counsel your patient that it can change the color of their urine and tears.27

Naltrexone—an oral opioid antagonist—is a next-line therapy that can be used, but there are concerns about possible withdrawal syndromes and development of abdominal pain when used chronically.28

Sertraline, a selective serotonin reuptake inhibitor, also may be effective for pruritus, independent of its antidepressant effects.

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PPAR Agonists for PBC Pruritus29

More recently, a lot of attention has been paid to PPAR agonists for the treatment of pruritus and PBC. This has included older fibrate medications such as bezafibrate, as well as newer PPAR agonists, including elafibranor and seladelpar.

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ELATIVE: Elafibranor for PBC30

Elafibranor has been evaluated in the phase III ELATIVE study, and there are signals to suggest that it can improve pruritus symptoms in people with moderate to severe itching.

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ENHANCE and RESPONSE: Seladelpar for PBC31,32

In two phase III studies of seladelpar, patients with moderate to severe pruritus experienced improved symptoms based on improvements in Numerical Rating Scale scores.

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FITCH Trial: Bezafibrate33,34

In addition, there is a randomized, controlled study of the fibrate bezafibrate, which is not available in the United States but has been used extensively in Japan and Europe.

In this study, which enrolled patients with PBC, primary sclerosing cholangitis, or secondary sclerosing cholangitis who had moderate to severe itch, bezafibrate was found to have a significant effect on reducing pruritus in patients with cholestatic pruritus.

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Ileal Bile Acid Transport Inhibitors For PBC Pruritus35-37

The IBAT inhibitors are what the future appears to hold for us.

Maralixibat and odevixibat currently are approved for treatment of cholestatic pruritus associated with Alagille syndrome and progressive familial intrahepatic cholestasis.

There are phase II data demonstrating their efficacy in PBC pruritus, and there is an ongoing study of linerixibat, another IBAT inhibitor, in the GLISTEN trial to determine if it is effective for PBC.

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GLIMMER Trial: Linerixibat37

In the phase IIb GLIMMER trial, patients with PBC who had moderate to severe pruritus were randomized to receive one of several doses of linerixibat or placebo.

In addition, there was found to be a significant dose-dependent itch reduction in patients who received the linerixibat.

The most frequent adverse events observed in patients who received linerixibat were—similar to other IBAT inhibitors—diarrhea or abdominal pain, but generally linerixibat was well-tolerated.

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Take-home Points

In summary, cholestatic pruritus is a frequent and often severe symptom associated with PBC that can dramatically reduce the patient’s quality of life.

Evaluating pruritus at each visit with our patients with PBC is key to understanding its impact on their life and if treatments are achieving symptom control.

There are nonpharmacologic options including moisturizers, cool showers, and avoiding irritant fabrics or soaps. These measures may be effective in those with mild pruritus.

Pharmacologic options, including bile acid–binding resins, PPAR agonists, rifampin, naltrexone, and sertraline, may be appropriate in patients with more moderate to severe pruritus.

In the future, we hope to have additional medications, such as IBAT inhibitors, to add to our tools to help relieve pruritus symptoms in our patients with PBC.

Do you plan to make any changes in your clinical practice based on what you learned in today’s program?
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