Understanding the biological basis of symptoms in primary biliary cholangitis

Abstract

Background and Aims: Symptoms of pruritus, fatigue and cognitive impairment are common in Primary Biliary Cholangitis (PBC) with a significant impact on patients’ quality of life. The biological mechanisms underpinning these are poorly understood. Management of symptomatic PBC remains a significant unmet need, with no effective treatment for fatigue or cognition and only partially effective treatments for pruritus. This study explored markers associated with the pathogenesis of PBC and their relationship to symptoms. Method: Study 1 (exploratory) investigated 19 O-link serum proteomic markers in 289 fully characterised PBC patients from the UK-PBC cohort. Markers were compared to ‘clinically significant’ (c/s) symptoms, as assessed using the PBC-40. Study 2 (validation) compared a multiplex of 11 markers to a symptom-heavy cohort of 160 PBC patients and 40 healthy controls. Study 3 explored the neurosteroid allopregnanolone in 120 PBC patients and 40 healthy controls, comparing serum levels to c/s symptoms. Results: Interleukin-6 (IL-6) was positively associated with c/s fatigue, as compared with ‘not clinically significant’ (nc/s) fatigue (exploratory: median 2.63(IQR 0.80) pg/ml vs 2.42(0.89); p=0.047; validation: 1.62(0.89) vs 1.06(0.86); p=0.01), while Interluekin-4 Receptor Alpha (IL-4RA) was associated with c/s pruritus, as compared with nc/s pruritus (exploratory: 3.27(1.30) pg/ml vs 3.09(1.01); p=0.032; validation: 1081(173) vs 1000(200); p=0.022). Allopregnanolone was elevated in c/s cognitive (0.037 (0.04) vs 0.023(0.036); p=0.044) and emotional symptoms (0.039(0.056) vs (0.027(0.036); p=0.01). Conclusion: IL-6 was elevated in two distinct PBC groups with fatigue and has previously been implicated in skeletal muscle fatigability. IL-6 blockade therapies may present a new therapeutic strategy for fatigue. IL-4RA demonstrated positive associations for pruritus across both groups. An ongoing IL-4RA receptor antagonist trial may prove effective in treating cholestatic pruritus. Elevated serum allopregnanolone is associated with severe cognitive and emotional symptoms in PBC and may be amenable to novel compounds targeting GABA-A receptors