Elevated Rheumatoid Factor in ME/CFS

sec-bib-rf-elevated-mecfs-duplicate

1 Hashimoto1992 — RF Positivity in Japanese CFS Cohort

Full Citation:: Hashimoto N, Kura F, Taniguchi I. Chronic fatigue syndrome — 51 cases in the Jikei University School of Medicine. Nihon Rinsho. 1992;50(11):2796–2800. (Hashimoto et al. 1992) PMID:: 1287241 Key Findings::

- 6/51 (11.8%) CFS patients were rheumatoid factor positive
- 16/51 (31.3%) were ANF positive
- No specific EBV antibody pattern
- 77.5% had flu-like onset (5 with acute infectious mononucleosis)
- 56.8% generally improved at follow-up

Conclusion:: First report of elevated RF in CFS patients. Suggests autoimmune features in a subset of CFS, particularly post-infectious onset. Limitations:: Small single-center case series without healthy controls. Japanese language, English abstract only. No RF isotype or titer details. Certainty:: 0.30

2 Kerr2002 — Parvovirus B19 CFS: No Characteristic Autoantibody Pattern

Full Citation:: Kerr JR, Bracewell J, Laing I, Mattey DL, Tyrrell DAJ. Chronic fatigue syndrome and arthralgia following parvovirus B19 infection. Journal of Rheumatology. 2002;29(3):595–602. (Kerr et al. 2002) PMID:: 11911112 Key Findings::

- 5/39 (13%) of follow-up patients met CDC CFS criteria after B19 infection
- No characteristic pattern of B19 markers or autoantibodies (including RF) distinguished CFS
- Chronic B19 fatigue associated only with acute B19 fatigue (p=0.011)
- CFS attribution to B19 infection extremely difficult without serology at onset

Conclusion:: RF and other autoantibodies are not reliable markers for post-parvovirus CFS. Limitations:: Small number of CFS outcomes (n=5). Single-center. B19-specific, not generalizable to all CFS. Certainty:: 0.50

3 Liñán Ponce2024 — Fibromyalgia with Elevated RF: Poor Treatment Response

Full Citation:: Liñán Ponce F, Yampufe Canani J, et al. Fibromyalgia with elevated rheumatoid factor is associated with poor therapeutic response but not with progression to rheumatoid arthritis. Reumatología Clínica (English Edition). 2024;20(10):535–542. (Liñán Ponce, Yampufe Canani, et al. 2024) DOI:: 10.1016/j.reumae.2024.10.001 PMID:: 39455297 Key Findings::

- 124 FM patients: 62 high RF (>20 U/mL) vs 62 RF negative
- High RF group: significantly poorer treatment response (24 vs 45 improved at 6 months)
- Progression to RA: 5 vs 4 (NS) — RF does not predict RA conversion in FM
- First prospective identification of RF+ FM as a distinct phenotype

Conclusion:: Elevated RF in fibromyalgia identifies a severe, treatment-refractory subgroup without RA progression. Limitations:: Moderate sample (n=124). Single center. Not replicated. FM-specific, not ME/CFS. Certainty:: 0.50

4 Bergman2009 — Fatigue Is Not an Inflammatory Variable in RA

Full Citation:: Bergman MJ, Shahouri SH, Shaver TS, et al. Is fatigue an inflammatory variable in rheumatoid arthritis (RA)? Analyses of fatigue in RA, osteoarthritis, and fibromyalgia. Journal of Rheumatology. 2009;36(12):2788–2794. (Bergman et al. 2009) DOI:: 10.3899/jrheum.090561 PMID:: 19918042 Key Findings::

- Inflammatory markers (ESR, SJC) contributed 9.2% to fatigue variance in RA
- Patient global assessment explained 43.1% of fatigue variance
- RA and OA fatigue levels did not differ (4.5 vs 4.4, NS) after age/sex adjustment
- FM fatigue (7.6) was substantially higher than RA/OA (~4.8)
- RF seropositivity not associated with fatigue level

Conclusion:: Fatigue in RA is not driven by inflammation. RF status does not predict fatigue severity. Limitations:: Cross-sectional, VAS fatigue measurement, multiple cohorts with different methodologies. Certainty:: 0.75

5 Germain2025 — Comprehensive Autoantibody Profiling: Null Result

Full Citation:: Germain A, Jaycox JR, Emig CJ, Ring AM, Hanson MR. An in-depth exploration of the autoantibody immune profile in ME/CFS using novel antigen profiling techniques. International Journal of Molecular Sciences. 2025;26(6):2799. (Germain et al. 2025) DOI:: 10.3390/ijms26062799 PMID:: 40141440 Key Findings::

- 7542 antibody-antigen interactions analyzed: Luminex (1134 autoantigens) + REAP (6183 extracellular + 225 viral proteins)
- No significant differences in autoantibody reactivities between ME/CFS (n=172) and controls
- GPCRs and β-adrenergic receptors: no group differences
- Subtle male-female trends and herpesvirus reactivation patterns observed
- Largest and most comprehensive autoantibody study in ME/CFS

Conclusion:: No evidence for ME/CFS-specific autoantibody reactivity. Previous positive reports may reflect assay limitations or subgroup effects. Limitations:: Cross-sectional; does not rule out autoantibodies to rare antigens or conformational epitopes. Certainty:: 0.65

6 Ryabkova2023 — Altered Natural Autoantibody Signatures in ME/CFS and FM

Full Citation:: Ryabkova VA, Churilov LP, Shoenfeld Y. Autoantibody correlation signatures in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: association with symptom severity. Biomedicines. 2023;11(2):257. (Ryabkova, Churilov, and Shoenfeld 2023) DOI:: 10.3390/biomedicines11020257 PMID:: 36830795 Key Findings::

- 33 natural autoantibodies measured in 11 ME/CFS+FM, 11 ME/CFS-FM, 11 HC
- GABA-receptor immunoreactivity deviated in patients
- Correlation patterns between AAb levels and symptom severity differed across groups
- No RF measured
- Authors: homeostasis of natural autoimmune relationships is disrupted

Conclusion:: Altered autoantibody network homeostasis found, but no specific autoantibody (including RF) emerged as a biomarker. Limitations:: Tiny pilot (n=33 total). Single center. No RF data. Certainty:: 0.30

7 Batham2024 — Autoimmunity in ME/CFS: Systematic Review

Full Citation:: Batham J, Marshall-Gradisnik S. Autoimmunity’s enigmatic role: exploring the connection with myalgic encephalomyelitis/chronic fatigue syndrome. BMC Immunology. 2024;25:66. (Batham and Marshall-Gradisnik 2024) DOI:: 10.1186/s12865-024-00657-5 PMID:: 39354352 Key Findings::

- PRISMA systematic review of 10 papers on autoimmunity in ME/CFS
- 6 investigated autoantibodies, 3 genetics, 1 cytokine
- Inconsistent and insufficient evidence to classify ME/CFS as autoimmune
- Autoantibody evidence deemed limited and conflicting
- Difficulty distinguishing autoreactivity from deregulatory processes

Conclusion:: Current evidence insufficient to support an autoimmune classification for ME/CFS. Limitations:: Only 10 papers included; narrow scope; autoantibody methods heterogeneous. Certainty:: 0.65

8 Sirois2001 — Sjögren’s Syndrome in a Subset of CFS

Full Citation:: Sirois DA, Natelson BH. Clinicopathological findings consistent with primary Sjögren’s syndrome in a subset of patients diagnosed with chronic fatigue syndrome: preliminary observations. Journal of Rheumatology. 2001;28(1):126–131. (Sirois and Natelson 2001) PMID:: 11196514 Key Findings::

- 13/25 (52%) CFS patients reported mucosal dryness
- 8/25 (32%) met full diagnostic criteria for primary SS (p=0.05)
- 10/25 (40%) had low Schirmer test (p=0.01 vs 6% controls)
- 0/18 controls met SS criteria
- CFS-Sjögren overlap documented with histology

Conclusion:: A subset of CFS patients may have primary Sjögren’s syndrome. RF would be expected in this subset. Limitations:: Small sample (n=25+18). Preliminary. Single center. No RF measurement concurrent with sicca evaluation. Certainty:: 0.45

9 Azcue2026 — GPCR Autoantibodies in ME/CFS and PCC

Full Citation:: Azcue N, Prada A, Del Pino R, et al. Involvement of autoantibodies against G protein-coupled receptors in post-COVID condition and chronic fatigue syndrome. Scientific Reports. 2026;16:49131. (Azcue et al. 2026) DOI:: 10.1038/s41598-026-49131-9 PMID:: 42082542 Key Findings::

- ME/CFS (n=59): significantly higher β2 adrenergic AAb than PCC (n=96) and HC (n=36)
- β2 AAb correlated with sympathovagal imbalance in ME/CFS (r=0.45, p=0.001)
- M1, M3, M4 muscarinic AAb positively correlated with memory in ME/CFS
- RF not measured — competing mechanism via GPCR AAb

Conclusion:: GPCR autoantibodies (especially β2 adrenergic) are relevant to ME/CFS pathophysiology, not RF. Limitations:: Cross-sectional; moderate sample; no RF comparison. Certainty:: 0.55

10 Kim2023 — Sjögren Fatigue vs ME/CFS: Distinct Phenotypes

Full Citation:: Kim L, Freitag H, Sotzny F, et al. Characterizing Sjögren-associated fatigue: a distinct phenotype from ME/CFS. Journal of Clinical Medicine. 2023;12(15):4994. (Kim et al. 2023) DOI:: 10.3390/jcm12154994 PMID:: 37568396 Key Findings::

- Sjögren fatigue and ME/CFS fatigue are distinct phenotypes
- Different immunological and clinical dimensions
- Important for differential diagnosis in RF+ patients

Conclusion:: Fatigue in Sjögren’s (where RF is often elevated) has a different profile from ME/CFS fatigue. Limitations:: Moderate sample size; cross-sectional. Certainty:: 0.50

11 Sotzny2022 — Dysregulated Autoantibodies in Post-COVID Syndrome

Full Citation:: Sotzny F, Filgueiras I, Kedor C, et al. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. Frontiers in Immunology. 2022;13:981532. (Sotzny et al. 2022) DOI:: 10.3389/fimmu.2022.981532 PMID:: 36238301 Key Findings::

- AAb targeting GPCR, vasoregulatory and immunoregulatory receptors elevated in post-COVID
- AAb levels correlated with symptom severity
- Establishes autoantibody dysregulation in post-viral fatigue
- RF not measured — competing non-RF autoantibody mechanism

Conclusion:: Post-viral fatigue involves autoantibodies, but to GPCR receptors, not classical RA-associated autoantibodies like RF. Limitations:: Post-COVID specific; cross-sectional; no RF comparison. Certainty:: 0.50

12 Berwick2025 — Anti-Satellite Glial Cell IgG in FM and Post-COVID

Full Citation:: Berwick RJ, Andersson DA, Goebel A. Postacute COVID-19 syndrome and fibromyalgia syndrome are associated with anti-satellite glial cell IgG serum autoantibodies but only fibromyalgia syndrome serum-IgG is pronociceptive. Pain. 2025;166(10):e121–e135. (Berwick, Andersson, and Goebel 2025) DOI:: 10.1097/j.pain.0000000000003629 PMID:: 40408228 Key Findings::

- Both post-COVID and FM patients had anti-satellite glial cell autoantibodies
- Only FM IgG was pronociceptive in passive transfer
- Autoantibody target distinct from RF (not classical RA-linked)

Conclusion:: Autoantibody-mediated mechanisms in FM and post-viral fatigue target glial cells, not the RF/RA pathway. Limitations:: Animal passive transfer; in vitro; post-COVID and FM, not ME/CFS specifically. Certainty:: 0.60

13 Kozłowska2022 — Fatigue in RA: RF Not a Predictor

Full Citation:: Kozłowska KA, Bączyk G. The link between the demographic and clinical factors and fatigue symptoms among rheumatoid arthritis patients. International Journal of Environmental Research and Public Health. 2022;19(22):14681. (Kozłowska and Bączyk 2022) DOI:: 10.3390/ijerph192214681 PMID:: 36429400 Key Findings::

- 128 RA patients: fatigue assessed by FACIT-F and SF-36 vitality
- Fatigue associated with pain, morning stiffness, DAS28, low hemoglobin
- RF not a significant predictor of fatigue in multivariate analysis
- Null context: RF seropositivity does not independently cause fatigue even in RA

Conclusion:: Even in RA (where RF is highly prevalent and pathogenic), RF does not independently predict fatigue. Limitations:: Cross-sectional; moderate sample; single center; RA-specific. Certainty:: 0.40

14 Wohlrab2025 — Autoantibody-Targeting Therapies in ME/CFS

Full Citation:: Wohlrab F, Eltity M, Ufer F, Paul F, Scheibenbogen C, Bellmann-Strobl J. Autoantibody targeting therapies in Post COVID syndrome and myalgic encephalomyelitis/chronic fatigue syndrome. Expert Opinion on Biological Therapy. 2025;25(5):621–634. (Wohlrab et al. 2025) DOI:: 10.1080/14712598.2025.2492774 PMID:: 40211686 Key Findings::

- Immunoadsorption, B-cell depletion, IVIG being trialled in post-COVID and ME/CFS
- Rationale: β2-adrenergic and M3 muscarinic AAb are elevated in subsets
- RF not discussed as a therapeutic target
- Ongoing RCT: EXTINCT (NCT05954325), IMPACT (NCT07529197)

Conclusion:: Autoantibody-targeting therapies are under investigation for ME/CFS, but target GPCR AAb, not RF. Limitations:: Narrative review; no new data; ongoing trials not yet reported. Certainty:: 0.45

References

Azcue, N., A. Prada, R. Del Pino, M. Acera, L. Lasaosa, et al. 2026. “Involvement of Autoantibodies Against G Protein-Coupled Receptors in Post-COVID Condition and Chronic Fatigue Syndrome.” Scientific Reports 16: 49131. https://doi.org/10.1038/s41598-026-49131-9.

Batham, J., and S. Marshall-Gradisnik. 2024. “Autoimmunity’s Enigmatic Role: Exploring the Connection with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” BMC Immunology 25: 66. https://doi.org/10.1186/s12865-024-00657-5.

Bergman, M. J., S. H. Shahouri, T. S. Shaver, J. D. Anderson, D. N. Weidensaul, R. E. Busch, S. Wang, and F. Wolfe. 2009. “Is Fatigue an Inflammatory Variable in Rheumatoid Arthritis (RA)? Analyses of Fatigue in RA, Osteoarthritis, and Fibromyalgia.” Journal of Rheumatology 36 (12): 2788–94. https://doi.org/10.3899/jrheum.090561.

Berwick, R. J., D. A. Andersson, and A. Goebel. 2025. “Postacute COVID-19 Syndrome and Fibromyalgia Syndrome Are Associated with Anti-Satellite Glial Cell IgG Serum Autoantibodies but Only Fibromyalgia Syndrome Serum-IgG Is Pronociceptive.” Pain 166 (10): e121–35. https://doi.org/10.1097/j.pain.0000000000003629.

Germain, A., J. R. Jaycox, C. J. Emig, A. M. Ring, and M. R. Hanson. 2025. “An in-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques.” International Journal of Molecular Sciences 26 (6): 2799. https://doi.org/10.3390/ijms26062799.

Hashimoto, N, Y Kuraishi, T Yokose, N Tajima, and S Mochio. 1992. “Chronic Fatigue Syndrome—51 Cases in the Jikei University School of Medicine.” Nihon Rinsho 50 (11): 2796–2801.

Kerr, Jonathan R, Janice Bracewell, Ian Laing, Derek L Mattey, Robert M Bernstein, and Ian N Bruce. 2002. “Chronic Fatigue Syndrome and Arthralgia Following Parvovirus B19 Infection.” The Journal of Rheumatology 29 (3): 595–602.

Kim, L., H. Freitag, F. Sotzny, M. Tölle, P. Grabowski, and C. Scheibenbogen. 2023. “Characterizing Sjögren-Associated Fatigue: A Distinct Phenotype from ME/CFS.” Journal of Clinical Medicine 12 (15): 4994. https://doi.org/10.3390/jcm12154994.

Kozłowska, K. A., and G. Bączyk. 2022. “The Link Between the Demographic and Clinical Factors and Fatigue Symptoms Among Rheumatoid Arthritis Patients.” International Journal of Environmental Research and Public Health 19 (22): 14681. https://doi.org/10.3390/ijerph192214681.

Liñán Ponce, F., J. Yampufe Canani, et al. 2024. “Fibromyalgia with Elevated Rheumatoid Factor Is Associated with Poor Therapeutic Response but Not with Progression to Rheumatoid Arthritis.” Reumatologı́a Clı́nica (English Edition) 20 (10): 535–42. https://doi.org/10.1016/j.reumae.2024.10.001.

Ryabkova, V. A., L. P. Churilov, and Y. Shoenfeld. 2023. “Autoantibody Correlation Signatures in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Association with Symptom Severity.” Biomedicines 11 (2): 257. https://doi.org/10.3390/biomedicines11020257.

Sirois, D. A., and B. H. Natelson. 2001. “Clinicopathological Findings Consistent with Primary Sjögren’s Syndrome in a Subset of Patients Diagnosed with Chronic Fatigue Syndrome: Preliminary Observations.” Journal of Rheumatology 28 (1): 126–31.

Sotzny, F., I. Filgueiras, C. Kedor, H. Freitag, K. Wittke, S. Bauer, et al. 2022. “Dysregulated Autoantibodies Targeting Vaso- and Immunoregulatory Receptors in Post COVID Syndrome Correlate with Symptom Severity.” Frontiers in Immunology 13: 981532. https://doi.org/10.3389/fimmu.2022.981532.

Wohlrab, F., M. Eltity, F. Ufer, F. Paul, C. Scheibenbogen, and J. Bellmann-Strobl. 2025. “Autoantibody Targeting Therapies in Post COVID Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” Expert Opinion on Biological Therapy 25 (5): 621–34. https://doi.org/10.1080/14712598.2025.2492774.