Upstream of the immune response: beta-hydroxybutyrate as a candidate intervention in the preclinical phase of rheumatoid arthritis
Year: 2026
Type: preprint
Study design: Study Protocol
Abstract: Rheumatoid arthritis has a measurable preclinical phase. Anti-citrullinated protein antibodies (ACPA) appear in serum years before the first synovitis, and the individuals whocarry them can be identified before any joint is damaged. Six randomised trials have now tested whether treatment started in that window prevents or delays the disease: rituximab(PRAIRI), abatacept (APIPPRA, ARIAA), methotrexate (TREAT EARLIER), hydroxychloroquine (StopRA) and atorvastatin (STAPRA). They differ in agent, population andendpoint, and their results are mixed, with delay more consistently achieved than prevention. They share one feature: each acts on the immune response. None acts on theproduction of the antigen that the response is directed against.This preprint sets out the reason for that gap and a candidate way to close it. Under the AHDI framework, ACPA are a correct response to epitopes that persistent tissue damagehas made visible and chemically modified, and extracellular citrullination by PAD2 and PAD4 is the step that generates them. The junction between inflammasome activity andPAD release — until recently the one undocumented link in that chain — has now been described: NLRP3 activation promotes PAD2/PAD4 release and protein citrullination inrheumatoid arthritis. What remains untested is whether that junction can be reached pharmacologically in humans.Beta-hydroxybutyrate (BHB) inhibits NLRP3 assembly at concentrations an oral dose can produce. It is proposed here in preference to butyrate on pharmacokinetic rather thanpharmacodynamic grounds: the two share HCAR2 agonism and histone deacetylase inhibition, but butyrate is consumed by colonocytes and intercepted by the liver, while BHB ismanufactured by the liver for export to the periphery.The design proposed is a twelve-week, placebo-controlled, dose-escalation proof-of-mechanism study in ACPA-positive adults without synovitis, with two co-primary endpoints— serum PAD activity and the circulating burden of citrullinated proteins — and an internal dose-response analysis within the active arm. The duration is set by the limit ofavailable human safety data, and is adequate for both primary measures. The decision criteria, fixed before any data exist, are stated in full. Coeliac disease is offered as theexisting precedent for an antigen-directed therapy in an immune-mediated condition, and as the source of the one prediction that distinguishes this proposal from those already tested.
Author: Trovato, Giuseppe
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7222986455
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