Dupilumab Treatment for Cholestatic Pruritus

Cholestatic pruritus (CP) is highly burdensome, observed in a multitude of hepatobiliary diseases (HBDs), difficult to treat given unclear etiopathogenesis, and may necessitate liver transplantation even in the absence of overt liver failure. We present a case of CP successfully treated with dupilumab, a fully human monoclonal antibody that targets the IL-4 receptor α subunit.

A 37-year-old man was in his usual state of health when hepatic cholestasis was noted on routine bloodwork. MRI/MRCP imaging revealed biliary ductal changes in the bilateral hepatic ducts, and liver biopsy showed prominent portal lymphoplasmacytic infiltrate, interface hepatitis, and stage II fibrosis – consistent with primary sclerosing cholangitis (PSC) / autoimmune hepatitis (AIH) overlap. The patient’s liver disease remained stable on azathioprine until age 39 when he developed worsening cholestasis (total bilirubin 7.8 mg/dL) with severe pruritus. ERCP revealed a markedly narrowed common bile duct, and a stent was placed. Cholestasis (total bilirubin 2.2 mg/dL) and pruritus improved over the next few months, and upon stent removal his pruritus was initially well controlled with daily rifampin and as-needed hydroxyzine. Over the next two years his pruritus progressively worsened despite therapy and stable bilirubin.

At age 41, dermatologic examination revealed linear excoriations intermixed with symmetric, hyperpigmented nodules on the chest, back, and arms and legs in areas of pruritus. Punch biopsy showed thick, compact orthohyperkeratosis, irregular epidermal hyperplasia, and fibrosis of the papillary dermis. These findings were consistent with prurigo nodularis (PN) secondary to the chronic itch-scratch cycle of CP. Over the next three years his symptoms were refractory to topical corticosteroids, intralesional corticosteroid injections, topical retinoids, bile acid sequestrants, anticonvulsants, doxepin, and antihistamines. Narrow-band UVB phototherapy (NBUVB) twice weekly (>50 sessions) provided minimal relief.

At age 44, subcutaneous dupilumab was initiated off-label with 600-mg loading dose followed by 300 mg every other week. At baseline, the patient reported severe and daily itch, sleep-related impairment and disturbance, and severe quality-of-life (QOL) impairment (Table 1). After three months of therapy all itch, sleep, and QOL scores improved, he experienced minimal itch, had resolution of the prurigo nodules, discontinued all other oral and topical therapies, and reduced NBUVB frequency. He has not experienced any adverse events on dupilumab, and liver function and cholestasis have remained stable.

Table 1.

Improvement in itch, sleep, and quality of life following dupilumab treatment

Variable	Baseline	3 Months of Dupilumab Treatment
Peak Pruritus NRS in the past 7 days (Itch intensity)	10/10 (severe)	2/10 (mild)
Average Pruritus NRS in the past 7 days (Itch intensity)	8/10 (severe)	1/10 (mild)
Number of days of itch in the past 7 days	7	2
PROMIS Itch – Quality (Subjective descriptions of itch)	Tingling Crawling sensation Throbbing Unpredictable Constant	Tingling Crawling sensation
PROMIS Itch – Interference (General QOL impairment from itch)	60.8 ± 2.3	39.7 ± 2.7
PROMIS Itch – Scratching Behavior (QOL impairment from scratching behavior)	54.6 ± 2.6	35.0 ± 3.8
PROMIS Sleep Related Impairment (Alertness, sleepiness, and tiredness during waking hours and perceived functional impairments)	63.3 ± 2.3	38.7 ± 4.2
PROMIS Sleep Disturbance (Sleep quality, depth, and restoration associated with sleep)	64 ± 2.6	42.4 ± 3.0
Dermatology Life Quality Index (Skin disease-related QOL impairment)	15/30 (very large effect)	4/30 (small effect)
ItchyQOL (Itch-specific QOL impairment)	3.7/5.0 (severe effect)	1.6/5.0 (mild effect)
Concurrent Treatments	NBUVB 2x/week Intralesional triamcinolone 20 mg/mL × 1 mL every other month Triamcinolone 0.1% ointment BID PRN Hydroxyzine 25 mg TID PRN	NBUVB 2x/week every other week
Alkaline phosphatase	642	668
Total Bilirubin	1.6	1.6
MELD	14	14

BID, twice daily; MELD, model for end-stage liver disease; NRS, numeric rating scale; NBUVB, narrowband ultraviolet B phototherapy; PROMIS, patient reported outcomes measurement information system (scored with T-scores ± standard error, calibrated to mean of 50 and standard deviation of 10 for the United States general population); PRN, as needed; QOL, quality of life; TID, three times daily

Pruritus is present in 20–40% of PSC patients at the time of diagnosis and increases with disease progression.¹ CP can be severely disabling and is associated with impaired QOL, fatigue, sleep disturbances, and mental health symptoms.^2,3 Current treatments include agents to reduce circulating bile acids, phototherapy, anti-depressants, and anticonvulsants – all of which have limited efficacy and increased risk for adverse events. Liver transplantation is often the only therapy for severe, refractory CP.

Prurigo nodularis (PN) is an uncommon chronic inflammatory skin disorder characterized by symmetrically distributed, hyperkeratotic, pruritic nodules. PN can be observed secondarily to poorly controlled chronic pruritis due to cholestasis, uremia, anemia, or malignancy.⁴ Aberrant neuroimmune signaling predominated by type 2 inflammation has been hypothesized to drive the chronic itch-scratch cycle in PN.⁵ While dupilumab is currently approved for atopic dermatitis, asthma, and rhinosinusitis with nasal polyposis, studies have described successful PN treatment with dupilumab – though none in patients with HBD.^6–8 While the direct role of type 2 neuroimmune signaling through IL-4 and IL-13 is not well described in CP, IL-13 contributes to hepatic fibrosis underlying CP, offering another potential target for dupilumab.⁹ Given a favorable safety profile with minimal concern for clinically apparent liver injury, early phase clinical trials for dupilumab in CP are currently underway (NCT04256759). Additional studies are required to characterize type 2 immune singling in CP and the mechanism of improved itch following dupilumab treatment.

Abbreviations used:

BID

twice daily

CP

cholestatic pruritus

MELD

model for end-stage liver disease

NRS

numeric rating scale

NBUVB

narrowband ultraviolet B phototherapy

PROMIS

patient reported outcomes measurement information system

QOL

quality of life

PRN

as needed

TID

three times daily