Open research questions

What is the antigen target of pathogenic IgG in Goebel-type FM?

Status: unanswered. Promotion of fm_autoimmune from emerging to established hinges on this.

Is glial activation (TSPO-PET signal) causal or downstream of central sensitization?

Status: unanswered. Determines whether glial modulators are upstream or symptomatic.

What fraction of FM-with-SFN is autoimmune-driven vs. metabolic vs. idiopathic?

Status: unanswered.

Does the gut-brain → glial pathway operate in FM patients in vivo?

Status: bridging. Closing requires longitudinal microbiome/TSPO data — see B2.

Is predictive_coding_failure a strict generalization of central_sensitization, or are they orthogonal mechanisms that co-occur?

Status: open, partially anchored. Updated 2026-05-08 after Strube 2026 + Herman 2026 ingestion: Strube positions the framework explicitly as distinct from CS with falsifiable predictions; Herman 2026 (emBODY task across two studies) provides direct FM-empirical evidence that interoceptive deficits are real and measurable — FM patients show lower LDA classification accuracy of body-state maps than controls, plus elevated alexithymia and negative ambiguous-sensation interpretation. The phenomenon is established; the relation to CS (subsumption vs. orthogonal vs. parallel) remains open. Closing requires either co-measurement (does interoceptive deficit predict TSPO-PET signal in the same patient?) or interventional contrast (does interoceptive retraining alter CS markers in the absence of glial/IgG-targeted therapy?).

Does serum_GRIN1_level track tspo_pet and ienfd in the same patient?

Status: open. If GRIN1 is high in FM but uncorrelated with TSPO/IENFD, it indexes a third subtype axis [pure central-glutamatergic]. If correlated, it's a redundant biomarker for an existing subtype. Either result tightens the subtype map.

Of the 9 distinct DRG-binding clusters identified by Seefried 2025, which (if any) correlate with the bile-acid elevations Jakobsson 2026 reports?

Status: open. This is the key intra-subtype-fractionation question — fm_autoimmune may be 9 sub-subtypes, and bile-acid stratification might map onto a subset of them. Tractable from existing samples if both groups collaborate.

Does the multi-ganglia SGC activation profile (DRG, TG, NG, SCG — Hanani 2026) correlate with patient symptom profile?

Status: open. If a patient has prominent autonomic symptoms, do they have stronger Sup-CG SGC activation specifically? If yes, ganglion-specific SGC binding could become a within-FM symptom router.

Does microbiome modulation (FMT, prebiotic, antibiotic, BA-receptor agonist) reduce anti-SGC IgG titers and FM symptoms?

Status: design drafted. The single highest-leverage cure-path experiment in the project right now. Full protocol-level design at Q17-microbiome-igg.md">research-design-Q17-microbiome-igg.md: crossover RCT of colesevelam in anti-SGC-IgG-positive FM patients, n=50, ~24 months, ~$700K-1M. Stage 1 of a 3-stage cure-path program. Closes bridge B2 fully if positive.

Does the Dogan 2026 biomarker panel (serum GRIN1, P2RX1, P2RY2) replicate in an independent FM cohort?

Status: open. Single-cohort AUCs typically inflate by 0.05–0.10 in replication. If P2RY2 holds AUC > 0.75 in a second cohort, it becomes a clinically useful FM diagnostic.

Do the three Dogan biomarkers correlate with TSPO-PET (inflammatory-central subtype) or anti-SGC IgG (autoimmune subtype) — i.e., which subtype do they index?

Status: open. Subtype-mapping question; closing tightens the three-axis biomarker panel.

Does thalamocortical decoupling (Hou 2026) correlate with TSPO-PET signal in the same FM patients?

Status: open. Tests whether the network-level finding is downstream of glial inflammation or independent.

Strube 2026's framework is explicitly falsifiable. What is the cleanest experimental test to estimate the "capacity hyperprior" update rate or precision-weighting parameters in FM patients vs. controls?

Status: open methodology question. If the framework is correct, these computational parameters should differ between groups; if they don't, the framework loses ground vs. CS-only.

Do interoceptive-retraining interventions (perceptual retraining, emotional state differentiation training, body-scan-as-differentiation rather than relaxation) reduce FM symptom impact?

Status: open. Herman 2026 proposes this on mechanistic grounds; no trial yet exists. Mechanism-anchored non-pharmacological therapy candidate — would be tractable and inexpensive to test.

Is the alexithymia ↔ FPN-VAN circuit (Hou 2026) the neural substrate of the body-map differentiation deficit (Herman 2026)?

Status: open. Co-measurement experiment: emBODY task + rs-fMRI in same FM cohort — would directly test whether body-map-LDA performance correlates with FPN-VAN FC.

Are anti-SGC-IgG-positive FM patients and mast-cell-activation FM patients the same patients, overlapping, or distinct subtypes?

Status: open. The Morcos & Theoharides 2026 mast-cell axis is a candidate parallel mechanism alongside the autoimmune axis. If overlap is high, mast-cell-directed therapy might benefit anti-SGC IgG positive patients via different mechanism. If distinct, this is a fifth subtype dimension to add to the project subtype map.

Does FMT specifically reduce anti-SGC IgG titers in FM patients?

Status: open. Martín Pérez 2024 systematic review shows FMT reduces FM symptoms but no included study measured anti-SGC IgG specifically. This is BASIS-FM stage-2 territory; if positive, the chain microbiome → BA → IgG → SGC → symptoms is closed end-to-end as a cure path.

Verify the primary citation for the Journal of Pain 2025 paper "Altered lipid concentrations associated with disease symptom severity and anti-SGC IgG antibodies."

Status: project-internal action item. Currently staged with incomplete metadata; full text retrieval needed before tier promotion or specific lipid-entity addition. Note (2026-05-08): Seefried 2025 citation separately verified via the H1/H2/H3 search pass — PubMed 39907533, with 9 binding clusters identified including FABP7+ satellite glial cells. The lipid-paper citation remains unverified; the Seefried verification is logged here for context only.

What fraction of anti-SGC-IgG-positive FM patients ALSO have elevated serum tryptase / chromogranin A (MC markers)?

Status: open. Single observational study would populate the H1×H2 2×2 subtype map proposed in causal-chain-hypotheses.md.

Do interoceptive-retraining responders cluster in the H3-only quadrant (no IgG, no MC), or across all quadrants?

Status: open. Tests whether interoceptive retraining is mechanism-specific or works on the systems-level deficit regardless of upstream biology.

Is there a fifth quadrant — vagal/autonomic-dominant FM — that the H1×H2 2×2 misses?

Status: open. Q6 originally raised this; the new chain framework formalizes the test.

Does HERV-W ENV positivity correlate with anti-SGC IgG positivity in the same FM patients?

Status: open. Tests whether HERV reactivation is the upstream cause of the autoimmune subtype, or a parallel mechanism. Oltra 2023 reports 33.3% HERV-W-ENV-positive in FM; Seefried 2025 reports ~37% anti-SGC-IgG-positive; suggestively similar fractions but overlap unmeasured.

Does the HERV-W-positive FM subset respond to anti-HERV-W ENV therapy (e.g., temelimab, in MS clinical development by GeNeuro)?

Status: open. Direct cure-path test for an HERV-defined FM subtype. Most actionable if HERV reactivation is the project's correctly-identified upstream cause.

Does EBV reactivation status predict response to plasma-cell-directed therapy (daratumumab) in FM-autoimmune subtype?

Status: open. Tests whether EBV-driven B-cell reprogramming is the upstream cause of anti-SGC IgG production. Cheap to add as secondary endpoint to BASIS-FM.

Is post-COVID FM an HERV-driven or RNA-integration-driven phenomenon?

Status: open. Distinguishes between viral-genome-modification mechanisms 1 and 3 — see synthesis/viral-genome-modification-hypothesis.md. Tractable in a post-COVID FM cohort with HERV-W ENV ELISA + LINE-1-mediated SARS-CoV-2 sequence detection.

Are anti-SGC IgG and β2-AR/M3-muscarinic autoantibodies present in the same FM patients or in different patients?

Status: open. Analog of Q24 for the autoimmune axis itself — i.e., is the autoimmune subtype heterogeneous across multiple autoantibody species? Oesch-Régeni 2025 used β2-AR/M3 as inclusion criteria; project's other anchor papers used anti-SGC IgG. Co-measurement in the biomarker-mapping cohort would directly resolve.

Does HERV-W-positive FM respond to temelimab while HERV-W-negative HERV-altered FM responds to rituximab?

Status: open. Martín-Martínez 2025 case shows rituximab efficacy in HERV-W-negative HERV-altered patient; suggests HERV stratification at the family level — not just HERV-W presence — is needed for trial design. Stratified retrial in HERV-positive ME/CFS / FM populations is candidate next study.

Does post-COVID FM have detectable axonal injury (NfL elevation) that idiopathic FM doesn't?

Status: open. Giménez-Orenga 2025 panel includes NfL — testing whether post-COVID FM has a neurodegenerative component absent in idiopathic FM, with substantively different cure-path implications.

Does FM symptom severity show menstrual-cycle correlation in MC-active FM patients?

Status: open. Wang 2025 mechanism predicts cyclic estrogen → MC activation → symptom flare. If confirmed, (a) explains FM female predominance via H2 chain, (b) hormonal modulation [progesterone-only contraceptives, GnRH agonists] becomes a candidate H2-targeted intervention with established safety profiles, (c) suggests H2 chain may need to split into "post-viral H2" and "endocrine-MC H2" sub-axes.

What's the right RCT design for MCAS-stratified high-dose continuous cromolyn in FM?

Status: open. Christoforou 2026 n=5 case series suggests an MC-stratified retrial after the Ang 2014 negative ketotifen RCT in unstratified FM. Inclusion: FM + MCAS comorbidity. Intervention: cromolyn 1600-2400 mg/d continuous-sip regimen. Comparator: placebo. Primary endpoint: serum tryptase reduction + FIQ-R change with mediation analysis. Sample-size estimation needed; pilot effect size from Christoforou is uninformative for design.

Do HERV-W-positive FM patients show elevated plasma cell-free mtDNA + Type I IFN ISG signature compared to HERV-W-negative FM patients?

Status: open. Single most direct test of the HERV-Mitochondrial-Inflammation Loop in FM — see synthesis/herv-mitochondrial-inflammation-loop.md. Tractable with stored plasma + standard RT-qPCR; ~$200/patient. Belongs in the biomarker-mapping cohort as the 11th-13th dimensions.

Of the AlphaFold-predicted HERV-encoded protein structures, which are predicted to localize to or interact with mitochondria?

Status: scoped 2026-05-08 — full bioinformatic-pipeline scope document at q40-bioinformatic-pipeline-scope.md. 8-step pipeline: HERV protein universe → AlphaFold structures → ensemble mito-localization prediction → membrane-interaction features → MitoCarta cross-reference → AlphaFold-3 docking against cGAS/STING/TLR4 → composite scoring → manual triage of top 20. Resource estimate: 4-6 weeks for an experienced bioinformatician, ~$15-30K. Output: ranked candidate list + technical report. Validation against HERV-W ENV positive control.

Does temelimab (anti-HERV-W ENV) reduce plasma mtDNA / ISG signature in MS patients in GeNeuro Phase 2 trials?

Status: open. Secondary-analysis collaboration with GeNeuro could provide proof-of-concept evidence for in-vivo loop interruption — without requiring FM-specific trial.

Do mitochondrial-protective agents (idebenone, MitoQ, elamipretide) reduce FM symptoms preferentially in HERV-W-positive vs HERV-W-negative patients?

Status: open. Cheap to test in stratified pragmatic trial; existing safety profiles bypass IND requirements for idebenone/CoQ10. Would be candidate adjunct therapy while temelimab/STING-inhibitor evidence accumulates.

Do the top FM GWAS loci (HTT, GPR52, CAMKV, DCC, DRD2/NCAM1, MDGA2, CELF4 — Kerrebijn 2025) define a biological substrate for predictive-coding failure that maps onto Strube 2026's computational framework?

Status: open. Would unify the H3 chain at the gene-product level. Functional follow-up via expression-QTL analysis in brain regions associated with interoceptive inference is tractable. Differential weighting in H3-only vs H1/H2/HERV+ subsets would refine the cube.

Does TPSAB1 ddPCR genotyping in an FM cohort identify a cleanly definable MC-active subgroup, independent of the variable serum-tryptase clinical assay?

Status: open. Tractable in any FM cohort with stored DNA; ~$30/sample. Operationalizes Q24 with a heritable stratifier. Should be added to the biomarker-mapping cohort as a 14th dimension.

Does heartbeat-detection IAc (Sci Rep 2025) track HERV-W ENV / anti-SGC IgG / MC markers, or vary independently?

Status: open. Determines whether the H3 interoceptive-inference deficit is upstream-coupled to H1/H2/HERV biology or an independent therapy axis. ~5 min/patient cohort addition.

Do FM patients show elevated microglial P2X7 expression on TSPO-PET-positive scans, or on PBMC monocyte panels?

Status: open. He et al 2026 establishes P2X7 → mtDNA → cGAS-STING in mouse chronic-stress model — a parallel upstream entry to the HERV-mito loop. If P2X7 is elevated in stress-trigger-onset FM, P2X7 antagonism becomes a candidate adjunct therapy. Pilot tractable in any FM cohort with stored PBMCs + monocyte-isolation protocol.

Are the three persistent HERV loci identified by Koo & Morrow 2025 in PASC monocytes (notably the JAKMIP2-intronic locus) also amplified in FM-HERV-W-positive PBMCs, or are FM and PASC HERV signatures distinct?

Status: open. Direct Q40 input expansion — these loci should be added to the q40_pipeline seed-protein universe. Tractable with stored FM PBMC scRNA-seq + WHA method.

Does FcRn blockade with efgartigimod or rozanolixizumab attenuate pain in autoantibody-positive FM patients?

Status: open. Shi & Clark 2025 establishes that pan IgG Fc-receptor blockade reverses chronic pain in IgG-mediated mouse model. FcRn blockers clinically approved for myasthenia gravis since 2021/2023 — investigator-initiated stratified pilot in anti-SGC-IgG-positive FM is feasible without IND. Adds a fourth antibody-removal arm to the H1 cure-path program alongside daratumumab, plasmapheresis+IVIG, rituximab.

Does resveratrol reduce plasma cell-free mtDNA or ISG signature in HERV-W-positive FM patients?

Status: open. Duan 2026 establishes resveratrol blocks STING ER-Golgi translocation + TBK1 phosphorylation in mouse aging model. Cheap OTC pragmatic pilot; existing safety profile bypasses IND. Could be tested ahead of clinical-stage STING inhibitors. Adds a candidate STING-pathway interrupter to the white paper §7.4 cure-path arms.

If completed metformin MS trials (n=7) report positive efficacy via NfL or remyelination, what's the right design for an investigator-initiated stratified pilot in HERV+/EBV+ FM?

Status: open watch-list. Trial readouts expected 2026-2028. AMPK-pathway activation may intersect with HERV-mito-loop's mitochondrial-quality-control step. Drug-repurposing tier; generic; established safety.

Does the HERV-K10 MAG1 domain have predicted mitochondrial-localization signal or cgas/STING binding affinity?

Status: open. Direct Q40 extension — Özer & Vincendeau 2025 establishes HERV-K10/MAG1 is operationally immunomodulatory in chronic HBV patients with elevated IL-6/IL-1β. Adding MAG1 to the q40_pipeline seed-protein universe is a one-line edit; the bioinformatician's TargetP/MitoFates/DeepMito ensemble run will score it for mitochondrial localization in Step 3.

Do anti-MAG1 antibodies cross-react with neuronal or satellite-glial antigens in FM-autoimmune subset?

Status: open. If positive, MAG1 becomes a candidate antigen target alongside FABP7+ satellite glial cells (Seefried 2025) for the FM-autoimmune subset, narrowing the 9-binding-cluster Seefried space.

Why does metformin produce sex-specific neurotransmitter modulation in the AboTaleb 2024 Cells FM mouse model (effects in males but not females) despite both sexes showing similar pain and mood improvements?

Status: open. Methodologically critical for FM trials given 80% female predominance. Female-mechanism axis candidates: anti-inflammatory IL-1β reduction; mitochondrial-quality-control improvement; AMPK/AKT/mTOR/STAT3 pathway. Pharmacological dissection in female animals would resolve.

Does metformin reduce plasma cell-free mtDNA or ISG signature in HERV-W-positive FM patients?

Status: open. Direct test of metformin's intersection with Hypothesis 1. Connects Kazakou 2025 Nat Commun mitochondrial mechanism to the project's HERV-mito loop biomarker prediction. Tractable in any FM cohort with stored plasma + RT-qPCR after metformin pilot run.

Does metformin's PCC-prevention effect (Chaichana 2026 Clin Infect Dis, HR 0.36 in 624K cohort) extend to normal-BMI populations and to FM-pattern-PCC specifically?

Status: open. The cohort study is restricted to BMI ≥ 25 kg/m² and PCC is broadly defined. Subtype-stratified re-analysis or replication in unrestricted populations would close the generalizability gap. If yes, metformin becomes a candidate prophylactic for at-risk post-COVID populations.

Is the parsimonious unified read of the metformin literature correct — that metformin works prophylactically / in early-window (Chaichana 2026) but has limited efficacy in established neurodegenerative disease (Abdelgaied 2026 negative pilot)?

Status: open. Determines whether FM metformin trials should be designed as therapeutic-of-established-FM (likely null result) or as early-onset / post-trigger prophylactic (likely positive result). Critical for v0.3.1 §12.9 trial design.

Does green-light therapy modulate V2M (medial secondary visual cortex) ↔ thalamic LP (lateral posterior nucleus) functional connectivity in FM patients?

Status: open. Direct test of the candidate circuit mechanism for green-light analgesia in FM. Pre-post green-light functional-imaging study in stratified FM patients. Tan et al 2025 establishes the circuit in mice; O'Brien et al 2026 establishes human green-light analgesia in OA; Hou 2026 establishes FM thalamocortical decoupling. The unified test connects all three.

Are N-acyl-glycines elevated in plasma of human FM patients receiving green-light therapy?

Status: open. Direct biomarker test of the green-light analgesic mechanism in human FM. O'Brien et al 2025 PAIN identifies N-acyl-glycine endolipid upregulation as required for green-light analgesia in OA rats. Lipidomic assay in stored plasma from any FM cohort with pre-post green-light treatment would close the mechanism gap. Cheap, standard LC-MS.

Does the β2-AR-high ME/CFS subset (Azcue 2026) overlap with the vasoconstrictive-FM-subtype empirical findings (Sotzny 2022 / Wirth & Scheibenbogen 2020 framework)?

Status: open. Tests whether the β2-AR AAb phenotype defines a vasoconstrictive cure-path arm distinct from the cognitive-AAb (M1/M3/M4 muscarinic) arm. Could split H3 cure-tractable subset into two interventional substrata with different downstream symptom profiles and likely different responder rates to plasmapheresis+IVIG vs FcRn blockade.

Would FcRn blockade with efgartigimod or rozanolixizumab proportionally reduce the muscarinic and β-adrenergic AAb titers measured by Azcue 2026 in PCC and ME/CFS patients?

Status: open. Operationalizes Q48 with specific quantitative AAb endpoints. If FcRn blockade preferentially clears β2-AR or M3-muscarinic AAbs in proportion to their pathological roles, the AAb panel becomes both a stratifier and an outcome measure for the FcRn-blocker cure-path arm.

What fraction of established FM cohorts are M2R/β2AR-AAb seropositive at the van der Spek 2026 threshold (~44% in "other chronic pain" category, 22% in HCs)?

Status: open. Directly tractable by re-running the ELISA on stored FM serum samples already collected for anti-SGC IgG measurement. If FM seropositivity is in the 40-60% range, autonomic-receptor AAbs become a candidate co-stratifier alongside anti-SGC IgG; if FM is closer to the 22% HC baseline, the chronic-pain AAb signal is selective for non-FM conditions.

Has Tempol (or another ROS-scavenger) been tested in FM, ME/CFS, post-COVID, or HERV+ cohorts at chronic dosing?

Status: open watch-list. Tempol has been studied in oncology and radioprotection trials at higher doses; chronic-pain pharmacokinetics need review. If a chronic-dose-tolerable formulation exists, this is a low-cost candidate OTC-tier loop-interrupter arm alongside resveratrol §12.6.

Would combined-arm Tempol + resveratrol produce additive HERV-mito-loop interrupter effects, given the upstream (ROS scavenging) + downstream (STING ER-Golgi translocation) mechanistic separation?

Status: open. Cheap pragmatic-pilot design in HERV-W+ FM patients, both compounds available OTC. If additive, the combined arm becomes the project's first "loop-interrupter cocktail" candidate.

Do AGT-related cardiovascular medications (ACE inhibitors, ARBs) modify FM phenotype in retrospective EHR analyses?

Status: open. Gowri Gopal 2026 identifies AGT as an FM hub gene in bioinformatic PPI analysis. RAS-targeting drugs are generic, FDA-approved, and have established chronic-dosing safety profiles; if EHR re-analysis shows a signal, this becomes a cheap-to-test repurposing-tier arm. If null, the AGT hub-gene finding is interpreted as a downstream-marker rather than a therapeutic target.

Does the SNCA-FM-association (Gowri Gopal 2026) replicate in FM brain tissue (post-mortem) or animal-model proteomics, and does it open a Parkinson's-disease cross-condition bridge?

Status: open. α-synuclein is the Parkinson's-defining aggregation-prone protein; if FM-brain α-synuclein is meaningfully elevated, this opens both a candidate biomarker dimension (CSF or serum α-synuclein) and a cross-condition bridge (FM ↔ Parkinson's via shared synaptic-dysfunction substrate).

Would EZH2 inhibitors (tazemetostat at sub-oncology dose, or experimental EZH2 degraders) interrupt the central-sensitization pain phenotype in FM animal models?

Status: open. Gowri Gopal 2026 highlights EZH2 as a candidate druggable epigenetic regulator. Clinical-stage EZH2 inhibitors exist (tazemetostat, FDA-approved 2020 for epithelioid sarcoma) but at oncology dosing levels — chronic-pain repurposing requires substantial dose-finding work. Long-shot but high-value if positive.

Does the Gowri Gopal 2026 estrogen-pathway gene-expression pattern (ESR2↓, ABHD2↓, SULT1E1↑) replicate in the postmenopausal-FM subset specifically?

Status: open. Direct test of whether the estrogen-pathway dysregulation pattern is hormone-status-dependent. If positive, anchors a sub-cube cell for postmenopausal FM with a transcriptome-level dysregulation signal — and provides a candidate target for hormone-replacement-protocol modifications.

Are AGT, SNCA, EZH2 SNP variants enriched in the Kerrebijn 2025 GWAS top loci?

Status: open. Direct cross-reference between Gowri Gopal 2026's transcriptome hub-gene set and Kerrebijn 2025's GWAS top loci. Tractable from existing data — Kerrebijn supplementary tables likely available on medRxiv. If positive, the bioinformatic hub-gene approach is validated at the population-genetic level; if null, hub genes are downstream consequence rather than heritable substrate.

Does the Azcue 2026 β2-AR-AAb-elevated ME/CFS subset overlap with the Wirth & Scheibenbogen sympathetic-hyperactive subset at the patient level?

Status: open — DIRECT EXTENSION OF Q59. The β2-adrenergic AAbs are functional agonists, plausibly the molecular mediators of the noradrenergic hyperactivity Wirth & Scheibenbogen frame as one of three excitatory drivers. Co-measurement in the biomarker-mapping cohort would directly resolve. If overlap is high, the β2-AR-AAb assay becomes a stratifier for the neurotransmitter-imbalance subset.

Is skeletal-muscle cell-free mtDNA elevated in PEM-active ME/CFS or FM patients, and does it correlate with the type-I IFN ISG signature?

Status: open. Direct test of the Wirth & Scheibenbogen → H1 amplifier connection. Tractable with stored serum + standard cf-mtDNA RT-qPCR + ISG signature panel; ~$200-300/patient. If positive, neurotransmitter-imbalance-driven skeletal-muscle calcium overload becomes a confirmed fifth upstream entry to H1's mtDNA-cGAS-STING amplifier alongside HERV-W ENV, P2X7-stress, LINE-1, and oxidative stress.

Does tissue-based Western blotting against cardiac, pulmonary, and vascular antigens detect a higher AAb-positive fraction in FM cohorts than ELISA-based panels?

Status: open. Direct test of the Tatai 2026 methodology in FM. Tractable on stored Seefried 2025 or Krock 2023 cohort serum samples. If FM shows the same ~30 percentage point methodology gap Long COVID does, the H3 cure-tractable subset expands beyond the Seefried ~37% anti-SGC IgG fraction — and the biomarker-mapping cohort protocol needs to incorporate tissue-Western methodology before data collection begins.

Of the 18 PRISMA-included gene-therapy studies in Jaffal & Jaffal 2026, which specifically address FM versus which address CRPS / neuropathy / arthritis, and is there any HERV-targeted strategy (e.g., CRISPR knockdown of HERV-W ENV transcription) among them?

Status: open. Needs full-text read for FM-specific subset identification + HERV-target screening. If a HERV-targeted preclinical study exists, it provides preclinical anchor for the H1-via-§12.10 cure-path-arm intersection that would otherwise be theoretical.

Are TREM2 expression / soluble TREM2 (sTREM2) levels and SYK phosphorylation altered in FM patient PBMCs, serum, or post-mortem brain tissue?

Status: open. Direct test of the Tian 2026 microglial-receptor-signaling axis in FM. Tractable: serum sTREM2 by ELISA in stored Seefried 2025 or Krock 2023 cohort serum; PBMC monocyte SYK phosphorylation by flow cytometry if fresh-blood collection. If positive, the TREM2/SYK/NF-κB axis becomes a candidate FM-specific microglial-state biomarker + intervention target.

Does fostamatinib (FDA-approved SYK inhibitor for chronic ITP) attenuate central sensitization or microglial activation in FM animal models?

Status: open. Direct cure-path-arm-candidate test. Tractable in the Dahl SS rat FAM-index platform (Ferrari 2026), already predictive-validity-validated; or in the reserpine FM mouse model (AboTaleb 2024). If positive, fostamatinib becomes a candidate repurposing-tier arm — clinical-stage with 8+ years of safety data, oral administration, established chronic dosing protocols — that bypasses the upstream gut-dysbiosis driver by acting directly on microglial M1 polarization.

Does anti-SGC IgG ELISA titer correlate with MRGPRX2-activating capacity of the same patient serum (Sanchez 2025 LAD2 assay)?

Status: open. Direct test of whether the two main FM-autoimmune biomarker assays are measuring related quantities. If yes, anti-SGC IgG remains a clinically useful stratifier and either assay can route patients to MRGPRX2-antagonist arm. If no, the H1 chain bifurcates downstream of "FM-IgG production" and the two assays index independent biomarker axes — would require both for adequate stratification.

Do existing MRGPRX2 antagonists (barzolvolimab, CDX-0159, class) attenuate FM symptoms in anti-SGC-IgG-positive patients?

Status: open. The most direct cure-path test enabled by Sanchez 2025. Clinical-stage compounds in Phase 2/3 for chronic urticaria — investigator-initiated stratified pilot trial in anti-SGC-IgG-positive FM is feasible without IND barrier. Adds a third receptor-level arm to the H1×H2 cure-path program alongside FcRn blockade and plasmapheresis+IVIG.

Is the MRGPRX2 mechanism FM-specific, or does it also operate for long COVID IgG (Mignolet 2026 passive transfer paradigm) and CRPS IgG (Goebel earlier work)?

Status: open. If yes, MRGPRX2 antagonism becomes a cross-condition cure-path arm for autoantibody-mediated post-infectious chronic pain — tractable via LAD2 cell assay comparison across patient serum panels.

Does long-COVID-pain IgG operate through MRGPRX2/mast cells (parallel to Sanchez 2025) or through direct sensory-neuron binding (Mignolet 2026 DRG immunostaining)?

Status: open. Highest-priority follow-up to Mignolet 2026 ingestion. Determines whether LC pain shares the H1×H2 unified mechanism with FM or operates through a distinct sensory-neuron-targeting mechanism. Co-investigation in Goebel/Sanchez/Dong lab is plausible given the ACR conference framing.

Are LC-pain patients distinguished from LC-brain-fog patients by IgG / autoantibody status?

Status: open. Mignolet 2026's clean sensory-only phenotype (no cognitive, anxiety, depression behavior in mice) predicts that anti-DRG IgG positivity should be a discriminator within the LC syndrome. Operationalizes the LC subtype-mapping problem.

What fraction of FM patients are HαT-positive (TPSAB1 duplication)?

Status: open — direct extension of Q44 with the Simeone 2026 MRGPRX2-mechanism context. Population baseline is ~5%; FM enrichment at 2-3× baseline would establish HαT as a heritable risk factor for the H1×H2 unified subtype. ddPCR in any FM cohort, ~$30/sample, tractable within BASIS-FM cohort design.

Do HαT-positive FM patients show enhanced response to MRGPRX2 antagonists vs HαT-negative FM patients in stratified trial design?

Status: open. Direct test of the heritable-amplifier hypothesis. If HαT amplifies the Sanchez-mechanism, HαT-positive FM patients should respond more strongly to MRGPRX2 blockade. Could be a stratification dimension within a Q76 trial.

Are FM-comorbid lipedema patients more likely to be anti-SGC-IgG-positive, or do they cluster in a distinct H2-MC subtype operating via estrogen-MC mechanism (Amato 2026) rather than the IgG-MRGPRX2 mechanism (Sanchez 2025)?

Status: open. If lipedema-FM has lower IgG positivity than non-lipedema-FM, lipedema marks a distinct MC entry point — different cure-path arm (estrogen-modulating therapy ± direct MC stabilization rather than MRGPRX2 antagonism). Stratified anti-SGC IgG ELISA in lipedema-FM vs non-lipedema-FM cohorts would directly test.

Does CSF substance P elevation in FM correlate with serum tryptase, anti-SGC IgG titer, and HαT status in the same patient?

Status: open. Direct test of the H1×H2 unified mechanism predictions. If all four biomarkers correlate, they index a single mechanism axis (the IgG-MRGPRX2-MC chain) and any one can serve as a stratifier. If they don't all correlate, the chain has multiple parallel entry points and multi-axis stratification is required. Tractable in stored CSF + serum cohorts (Krock 2023 stored samples may suffice).

Does aprepitant (FDA-approved NK1R antagonist) attenuate FM symptoms in CSF-SP-elevated patients?

Status: open. Drug-repurposing-tier cure-path test. NK1R blockade interrupts the SP arm of the MC-SP loop (Aitella 2026) independent of MRGPRX2 antagonism. Established chronic-dosing safety profile (since 2003). Stratified retrial would be cheap to mount; if positive, NK1R blockade becomes a second receptor-level arm of the H1×H2 cure-path program with a parallel mechanism.

Are SFN-positive and TSPO-positive populations the same patients, overlapping, or distinct?

Status: unanswered. Determines whether the subtype map is bucketed or multi-axial.

Is there a vagal / autonomic-dominant subtype that biomarkers don't yet cleanly capture?

Status: speculative.

Does post-COVID FM cluster in fm_autoimmune subtype, or does it span subtypes?

Status: unanswered. Highly tractable given existing post-COVID cohorts.

Does IVIG benefit antibody-positive FM patients in a controlled trial?

Status: unanswered. Would close B3.

Does subtype-stratification rescue the effect size of existing FDA-approved therapies?

Status: unanswered. Would justify retrospective re-analysis of trial data.

What's the cleanest single-blood-draw biomarker panel that could route a patient to a subtype?

Status: open. Would unlock prospective trial design. Tooling component: a script that scans the ontology for biomarker → subtype edges.

Build a small Python script that loads ontology.yaml and (a) lists entities touched by ≥N papers, (b) flags entities only seen in non-FM-tagged papers (bridge candidates), (c) outputs A → B → C chains where direct A → C is not yet asserted.

Status: partial — research_agent/research_agent.py (2026-05-08) implements the inverse: it uses ontology.yaml to drive paper discovery via Europe PMC, with bridge-relationship queries + bridging-tier-entity queries + curated cluster queries. Triangulation chain analysis (the A → B → C output) is the remaining piece.

Add citation-graph expansion to the research agent (Semantic Scholar API) so we don't miss influential papers that the keyword/bridge queries don't surface.

Status: not started; see research_agent/README.md "Adding a new source".