Rituximab Is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A Phase 2 Randomized Controlled Trial 2019 Khanna et al

Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. Half of patients experience debilitating fatigue, which is currently untreatable. Previous studies have shown muscle bioenergetic abnormalities in PBC, including increased muscle acidosis with exercise linked to the antimitochondrial antibody (AMA) diagnostic of the disease, and reduced anaerobic threshold.

In this study we addressed the hypothesis that fatigue in PBC is driven by muscle bioenergetic abnormality related to AMA, and that AMA reduction with B-cell depletion therapy will improve fatigue. In our single-center phase 2 randomized controlled trial, 57 participants aged 18 years or older with PBC and moderate to severe fatigue were randomized to receive two doses of either rituximab (1000 mg) or saline (placebo). The primary outcome measure was fatigue severity assessed using the PBC-40 fatigue domain at 3 months. Secondary outcome measures included patient-reported outcomes and immunological and bioenergetics disease parameters. Experimental outcomes included biochemical markers of disease severity.

Improvement in fatigue score at 3 months was seen in both arms, with no significant difference (adjusted mean difference -0.9 [95% confidence interval -4.6 to 3.1]). Little difference was observed in other patient-reported outcomes or physical activity. Significant anaerobic threshold improvement was seen in the rituximab group, only but this was not associated with fatigue improvement. No treatment-emergent serious adverse events were seen.

Conclusions: Rituximab was safe over the 12-month study period but showed no evidence of effectiveness for the treatment of fatigue in PBC. Anaerobic threshold improvement was seen, potentially linking AMA with muscle bioenergetics dysfunction; however, this was not related to improvement in fatigue. Rituximab had some evidence of a beneficial effect on alkaline phosphatase levels in this largely ursodeoxycholic acid (UDCA)-responding, early-disease stage cohort.

Open access PDF, https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.30099

 

Interesting to see what Julia Newton is working on these days.

 

Not sure if you missed it but this was from 2019, so may not represent what she is currently working on.

 

This trial was getting going in 2014. I never caught up with the publication. But at the time I thought Newton's argument that if rituximab worked for fatigue in one illness it ought to work in others was weak. Primary biliary cirrhosis is obviously antibody mediated. So its manifestations, including fatigue, might respond to rituximab. But other conditions like heart failure, which includes fatigue, would not. So it would tell us nothing about ME/CFS. Fortunately Fluge and Bella were able to set up their phase 3 at that point.

A lot of autoimmune conditions with antibodies to nuclear proteins do not respond to rituximab well and that may be because the antibody levels do not go down much (likely produced by long lived plasma cells). So a failure here is not surprising anyway.

 

Ah ok. I wonder if she's currently working on ME/CFS. I think perhaps not. I can't see any publications on ME/CFS since 2020.

 

My memory is that Newton said that she had made a decision not to continue working on ME/CFS because she could not get funding - maybe 3-4 years ago.

 

Prospective open-label trial with rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy not responding to conventional immune therapies
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