We thank Dr. Hernández-Evole et al. for their positive evaluation of our manuscript regarding the uptake of anticholestatic therapy in the Dutch population with primary biliary cholangitis (PBC) 1, 2. They agreed that ursodeoxycholic acid (UDCA) dosing should be optimised according to body weight before classifying a patient as insufficient responder and initiation of second-line therapy. It was rightfully questioned, however, whether the dose of UDCA also needs to be optimised in patients who have already achieved complete biochemical response without evidence of disease progression. One may argue that Dutch hepatologists tend to agree as lower UDCA dosages were more frequently prescribed to patients with a complete biochemical response according to Paris II. In this subgroup with a relatively good prognosis, it may be difficult to imagine and/or document an absolute prognostic gain of minor UDCA dose adjustments, at least within the registered follow-up of current (inter-)national datasets. Availability of detailed data on the UDCA dosages over time will most likely be an important hurdle for such an assessment as well. Still, we believe we should continue to promote a uniform UDCA dosage recommendation of at least 13 mg/kg/day for all people affected by PBC. From a scientific perspective, as pointed out by dr. Hernández-Evole as well, the Global PBC cohort showed that the clinical benefit of UDCA (in terms of liver transplantation or death) was stronger among those treated with > 13 mg/kg/day (hazard ratio HR 0.29) as compared to those treated with < 13 mg/kg/day (HR 0.50) 3. This survival benefit was independent of the patient's biochemical profile. Follow-up analyses of this study showed a favourable LT-free survival with UDCA even among those without any decline of alkaline phosphatase (ALP) or bilirubin 4. This suggests that the mechanisms of action of UDCA other than its anti-cholestatic properties may indeed be clinically relevant 5. However, it remains unknown how this hypothesis would apply to those with a complete biochemical response. At the same time, waiting for disease progression to optimise first-line therapy feels counterproductive, especially as UDCA is generally affordable and has a very favourable safety profile. A uniform message on the UDCA dosage is easy to communicate and understand. While UDCA has been available for more than 30 years, recent reports still identify ‘gaps’ in the quality of this aspect of PBC care 6-8. In part this may be explained by difficulties to stay up to date on a rare disease. Especially over the past 10 years, PBC treatment strategies have rapidly evolved, adding to the complexity of today's (international) guidelines. Through a general survey among physicians, such complexity was identified as one of the three major barriers to guideline adherence next to a high number of weak or conditional recommendations and time constraints due to clinical responsibilities 9. Thus, instead of searching for difficult-to-prove conditional recommendations with respect to UDCA therapy, the cornerstone in the treatment of PBC, we believe the population with PBC is best served by a one-size-fits-all UDCA dose recommendation of 13–15 mg/kg/day. Ellen Werner: conceptualization, writing – original draft, investigation. Maria C. B. van Hooff: conceptualization, writing – review and editing. Adriaan J. van der Meer: writing – review and editing, conceptualization, supervision. The authors have nothing to report. Adriaan J. van der Meer received grants from: CymaBay Therapeutics, Intercept Pharmaceuticals, Gilead Sciences, MSD and Zambon Nederland B.V.; is consultant for Intercept Pharmaceuticals, Advanz Pharma, AOP Health, CymaBay Therapeutics, and Ipsen, and receives speakers fee from Zambon Nederland B.V. and AOP Health. All other authors report no potential conflicts of interest for this manuscript. This article is linked to Werner et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70669 and https://doi.org/10.1111/apt.70703. All collaborating authors of the Dutch PBC Study Group. Sunje Abraham; Rob P. R. Adang; Huseyin Aktas; Yasser A. Alderlieste; Maria N. Aparicio-Pages; L. (Bert) C. Baak; Martine A. M. C. Baven-Pronk; A. (Sander) van der Beek; Frank C. Bekkering; Jeroen D. van Bergeijk; Ulrich Beuers; Menno Beukema; Tiki D. Blom; Wink de Boer; Femke Boersma; Kirsten Boonstra; Frank ter Borg; Martijn J. ter Borg; Pieter C. J. ter Borg; Gijs J. de Bruin; Paul J. Bus; Djuna L. Cahen; Marcel Cazemier; Frans J. C. Cuperus; Lisette J. H. van Dam; Maaike J. Denters; Remco van Dijk; Joost P. H. Drenth; Ludger S. M. Epping; Nicole S. Erler; Hajo J. Flink; Philip W. Friederich; Nicole F. M. van Gerven; Tom J. G. Gevers; Bettina E. Hansen; Sven J. van den Hazel; Bart van Hoek; Maria C. van Hooff; Daphne M. Hotho; Harry L. A. Janssen; Hendrik J. M. de Jonge; Matthias C. Jurgens; J. (Netty) van Kemenade; Marjo J. Kerbert-Dreteler; Michael Klemt-Kropp; Ingrid C. A. W Konings; Sander de Kort; Matthijs Kramer; Edith M. M. Kuiper; Johan P. H. Kuyvenhoven; Adriaan J. van der Meer; Suzanne van Meer; Susanne L. Onderwater; Leendert H. Oterdoom; Cyriel Y. Ponsioen; Paul G. van Putten; Janne E. van Rooij; Robert Roomer; Johannes Schmidt-Böhmer; Stephan Schmittgens; Tim C. M. A. Schreuder; Jerome Sint Nicolaas; Hanneke van Soest; Khalida Soufidi; Stephan H. C. van Stiphout; Hans H. K. Thio; Merel M. Tielemans; Sigrid Vandebosch; Rozanne C. de Veer; Bart J. Veldt; Robert C. Verdonk; J. Marleen de Vree; Elsemieke de Vries; Anne Vrieze; Jan Maarten Vrolijk; Laurens A. van der Waaij; Gemma X. Weijsters; Ellen Werner; Ulrike de Wit; Frank H. J. Wolfhagen. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Werner et al. (Fri,) studied this question.