Fatigue in Primary Biliary Cholangitis: No Place for Rituximab
Authors: Ulrich Beuers, Simon Hohenester
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. See Article on Page 1646 Patients with primary biliary cholangitis (PBC) have experienced major therapeutic progress during the last four decades. An effective first‐line therapy, ursodeoxycholic acid (UDCA), is available from which all patients, responders as well as "incomplete" responders, appear to benefit according to the newest data.1 Increasing insight into the mechanisms and sites of action of UDCA has meanwhile been gained.2 Potential second‐line treatments are also available when UDCA alone is not effective enough: the farnesoid X receptor agonist obeticholic acid,3 conditionally approved by North American (US Food and Drug Administration) and European (European Medicines Agency) authorities as a second‐line treatment in PBC, or the nonspecific peroxisomal proliferator–associated receptor agonist bezafibrate.4 Other nuclear receptor agonists and therapeutic bile acids await further evaluation as second‐line or third‐line therapy (in combination with UDCA) for PBC in the upcoming years.2 Finally, liver transplantation has been the standard of care in end‐stage PBC for four decades, but the numbers of patients in need of liver transplantation are markedly decreasing, suggesting that we are increasingly able to treat the underlying disease. This therapeutic progress has led to the global name change from "primary biliary cirrhosis" to "primary biliary cholangitis" as the majority of patients do not develop cirrhosis anymore5 and have a normal life expectancy.1 Notably, all of the above‐mentioned therapeutic agents strengthen defense mechanisms of biliary epithelia against hydrophobic human bile acids and appear to contribute to stabilization of a "biliary bicarbonate umbrella"6 or increased biliary micelle formation, thereby dampening the toxicity of millimolar hydrophobic bile acid monomers in the bile. In striking contrast, immunosuppressive strategies in PBC have largely failed during previous decades. These observations have contributed to a conceptual shift for some investigators from interpreting PBC as a pure autoimmune disease to a disease potentially based on defective biliary bicarbonate secretion7 and, thereby, impaired defense of biliary epithelia against toxic human bile acids,6 leading to secondary immune activation in genetically predisposed individuals.8 While progress is being made in understanding the pathogenesis of PBC and developing effective treatment strategies for the underlying disease process, adequate therapy of clinical symptoms is still far behind our patients' expectations. Fatigue and pruritus are the leading, but nonspecific, symptoms in PBC: fatigue is reported by patients with various immune‐mediated/autoimmune disorders including Sjoegren's syndrome, rheumatoid arthritis, and multiple sclerosis, whereas pruritus of cholestasis is observed in different cholestatic disorders affecting hepatocytes and/or cholangiocytes. While next to guideline‐approved antipruritic strategies (cholestyramine, rifampicin, naltrexone, sertraline) new therapeutic agents including apical sodium‐bile salt transporter inhibitors9 and fibrates4 (results of a randomized, placebo‐controlled trial [FITCH, "Fibrates for Itch"] will be reported later this year) appear promising, no convincing strategy has been developed to adequately treat fatigue in PBC. In the present issue of hepatology, David Jones and his group from Newcastle present data from a phase 2, randomized, placebo‐controlled trial for treatment of fatigue in PBC with the monoclonal anti–cluster of differentiation 20 (CD20) B cell–depleting antibody rituximab.10 The authors had previously studied the pathophysiology of fatigue in PBC and had identified both central and peripheral components potentially contributing to fatigue in PBC.10 Among their findings in patients with PBC suffering from debilitating fatigue were muscle bioenergetic abnormalities and a reduced anaerobic threshold. Increased muscle acidosis with exercise and impaired recovery of muscle acidosis following discontinuation of exercise were linked to antimitochondrial antibodies, which are diagnostic for PBC and particularly directed against the E2 subunit of the mitochondrial pyruvate dehydrogenase complex (anti‐PDC). PDC is crucial for linking cytosolic glycolysis (Embden‐Meyerhof pathway) to the mitochondrial Krebs cycle by forming the Krebs cycle substrate acetyl coenzyme A from pyruvate after uptake of pyruvate into the mitochondria. The authors speculated that interaction of anti‐PDC with PDC‐E2 (in mitochondria?) might impair the function of PDC and mitochondrial aerobic respiration. Thus, depletion of anti‐PDC‐producing B cells by rituximab might shut down the production of anti‐PDC, correct impaired mitochondrial respiration in muscle cells, and possibly improve fatigue. The authors performed a phase 2, double‐blind, randomized, controlled trial for which they screened 71 patients with PBC and moderate to severe fatigue as defined by a score of ≥33 (2 standard deviations above the mean) of the fatigue domain in the PBC‐40 questionnaire. They randomized 57 patients (73% of a priori planned 78 patients) with mostly early‐stage definite or probable PBC (67% with normal serum alkaline phosphatase!) to either rituximab (1,000 mg intravenously on days 1 and 15) or placebo and followed them for up for 3, 6, 9, and 12 months. All patients received conditioning with 100 mg methylprednisolone, acetaminophen, and chlorphenyramine. The primary endpoint, a relevant decrease of ≥5 points in the fatigue domain of the PBC‐40 questionnaire after 3 months, was reached by 59% and 36% of patients, respectively, and was not different between the groups. Also, fatigue diaries and other secondary outcome measures including validated measures of anxiety and depression, daytime somnolence, vasomotor autonomic symptoms, and cognitive functionality did not differ between the groups. Notably, fatigue was reduced in both groups to the same extent after 3 months, suggesting a considerable placebo effect. The authors proved that rituximab was effective at depleting CD20‐positive cells, an effect seen after 3 and 6 months and then slowly fading out. Consequently, anti‐PDC antibodies decreased in the rituximab‐treated group, confirming effective immunomodulation by rituximab. Notably, the low anaerobic threshold as determined by conventional cardiopulmonary exercising improved in rituximab‐treated, but not placebo‐treated, patients. This effect, however, was not associated with improvement of fatigue. Minor favorable effects on serum alkaline phosphatase were also observed in the rituximab group but not the placebo group, whereas other measures including muscle bioenergetic function and additional serum parameters were largely unchanged. The authors have to be congratulated for their effort to extensively characterize all patients. Still, a number of concerns may be addressed. (1) The study was underpowered, and the investigators randomized only 73% of the patients planned a priori. The aim of randomizing 78 PBC patients with moderate to severe fatigue in a single center within a limited time period was indeed ambitious. Involvement of additional centers could have enhanced patient recruitment and would possibly have better balanced patient expectations (see the impressive placebo effect on fatigue). Still, the multitude of analyses performed in each patient before, during, and after the trial certainly did not make it easy to transfer the whole "fatigue test battery" established in Newcastle to other centers. The investigators' decision to terminate recruitment after 3 years appears, therefore, understandable. (2) The study cohort did not represent a "real‐world" PBC cohort: 67% of patients had a normal serum alkaline phosphatase at inclusion, suggesting a mainly early‐stage cohort responding well to UDCA. It remains unclear whether patients in more advanced disease stages would have shown diverging responses to rituximab. (3) The authors focused on fatigue in PBC, although similar complaints are reported by patients with other chronic immune‐mediated diseases including Sjoegren's syndrome, rheumatoid arthritis, and multiple sclerosis. Thus, the underlying hypothesis of a component of peripheral fatigue explained by the interaction of PBC‐specific anti‐PDC with mitochondrial PDC‐E2 appears attractive but questionable considering that anti‐PDC or other antimitochondrial antibodies are not expressed in patients with chronic inflammatory conditions other than PBC who present with comparable characteristics of fatigue. It remains unclear by which molecular mechanisms improvement of the low anaerobic threshold was achieved after treatment with rituximab but not placebo. The negative results of this trial are disappointing from a patient's, a clinician's, and an investigator's perspective. Still, the investigators' efforts have to be praised as they show that the anti‐CD20 antibody rituximab, occasionally overused in diverse immune‐mediated diseases, has no place in the armamentarium of physicians taking care of patients with PBC. Thus, the simplified message is at this moment: no rituximab for PBC.