Immune reset in rheumatic autoimmune disease: from a tantalising metaphor to a measurable therapeutic state.

Abstract

Immune reset is increasingly invoked to describe the possibility that a one-off intervention is able to produce durable treatment-free control of rheumatic autoimmune diseases. However, the term remains imprecise and is often conflated with lymphodepletion or immune reconstitution. We argue that immune reset should denote a persistently normalised therapeutic state rather than an inferred consequence of profound immunodepletion. A credible immune reset claim should require sustained off-therapy clinical control beyond the expected pharmacodynamic window, stabilisation or improvement of the involved organs, and demonstrable reconfiguration of disease-relevant immune circuits in blood and accessible tissue. Importantly, restoration of immune competence, including protective immunoglobulins, vaccine responsiveness, and host defence against infection, is an essential part of immune reset. Naïve B-cell repopulation, serological improvement, repertoire rejuvenation, or transient clinical remission alone are insufficient to document immune reset because pathogenic compartments, irreversible organ damage, and acquired immune deficiency may persist. Until validated prospectively, the concept of immune reset should remain a hypothetical construct or perhaps a clinical aspiration rather than a therapeutic reality across treatment modalities and autoimmune disease entities.