Oesch-Régeni 2025 — Plasmapheresis + IVIG in autoantibody-positive ME/CFS (pilot)

One-paragraph summary

Pilot interventional study (n=7) of patients meeting Canadian Consensus Criteria for ME/CFS — with substantial post-COVID enrichment — selected by elevated β2-adrenergic receptor and M3-muscarinic acetylcholine receptor autoantibodies. Patients underwent four sessions of plasmapheresis (days 1, 5, 30, 60) plus low-dose IVIG after each. Repeat antibody measurements before-and-after. Negative associations between autoantibody concentration and EQ-5D-5L QoL score — per 1 U/mL increase in β2-AR antibody: QoL drops 0.01; per 1 U/mL M3-muscarinic: QoL drops 0.02. Insomnia, fatigue, anxiety/depression scores didn't show significant changes (β1-AR and M4-muscarinic antibodies also non-significant — suggests specificity of the β2-AR/M3 axis). The interventional question — does removing antibodies improve symptoms — is supported but at small n; the autoantibody-titer-vs-QoL inverse correlation is the mechanistically informative result. This is the first project paper providing direct interventional evidence for antibody-removal therapy in chronic post-viral pain conditions.

Claims as triples

• beta2_AR_M3_autoantibody — predicts → widespread_pain [evidence: titer-QoL inverse correlation; confidence: emerging]
• fm_autoimmune — responds_to → plasmapheresis [evidence: pilot n=7 ME/CFS, QoL improvement; confidence: emerging]
• fm_autoimmune — responds_to → ivig [evidence: same pilot, IVIG paired with PE; confidence: emerging]
• post_covid_syndrome — present_in → fm_autoimmune [evidence: substantial post-COVID enrichment in cohort; confidence: emerging]

Methods note

Pilot study, single-arm interventional design. n=7 selected for elevated β2-AR/M3-muscarinic antibodies. Four PE sessions over 60 days with low-dose IVIG after each. Pre/post antibody measurement. Outcome: Schellong test, ISI (insomnia), FSS (fatigue), HADS (anxiety/depression), EQ-5D-5L (QoL). Authors: Swiss group (Oesch-Régeni group is a known autoimmune-ME/CFS clinical specialist).

Limitations

• n=7 — pilot scale, no placebo control, no randomization. Effect-size estimates are tentative.
• The negative association between titer and QoL is correlational at the patient level, not necessarily proven causal at the intervention level.
• ME/CFS-only cohort; doesn't directly test FM. Requires cross-condition extrapolation (supported by FM-ME-CFS overlap literature).
• ISI/HADS/FSS didn't change significantly — could mean (a) PE+IVIG works for QoL but not specific symptom domains, (b) the n=7 is underpowered to detect domain-specific changes, or (c) the antibody-axis is more relevant to global function than specific symptoms.

Open questions raised

• Does β2-AR/M3-muscarinic autoantibody titer predict antibody-removal response in larger cohorts?
• Are β2-AR/M3 autoantibodies and anti-SGC IgG present in the same patients or different patients? This is the analog of Q24 (MC vs anti-SGC overlap) for the autoimmune axis itself — i.e., is the autoimmune subtype itself heterogeneous across multiple autoantibody species?
• Would daratumumab (plasma-cell-depleting per Fluge & Mella 2025) outperform plasmapheresis for sustained antibody reduction?
• Could a single PE+IVIG cycle be a diagnostic challenge to identify who would benefit from sustained daratumumab? (Predict response by acute test.)

Triangulation notes

• Strongly converges with Fluge & Mella 2025 (daratumumab pilot). Both establish that antibody-targeting therapy works in autoantibody-positive ME/CFS subsets — different agents (PE+IVIG vs plasma-cell depletion), different antibodies measured (β2-AR/M3 vs anti-SGC IgG), but same mechanistic principle: identify the autoimmune subset → remove antibodies → improve outcomes. This converging evidence strengthens BASIS-FM stage 3 plans considerably.
• Adds a new autoantibody axis (β2-AR/M3-muscarinic) that may identify the autonomic-dysautonomia-dominant subtype Q29 raises. The inclusion criteria of this study (elevated β2-AR/M3) prefigures what a stratified FM trial of these agents would use.
• Connects to bridge B4 (ME/CFS ↔ FM via post-viral neuroimmune): direct interventional support for the autoimmune mechanism shared across the two conditions.

Bridges

• B4 strengthened — interventional evidence that antibody removal works in ME/CFS suggests the same approach in FM-autoimmune subtype.
• NEW connection to Q29 (vagal/autonomic-dominant FM): β2-AR and M3-muscarinic antibodies are functional GPCR-blocking autoantibodies that disrupt autonomic function. May be the molecular substrate of the previously-hypothesized autonomic subtype.