Autoimmunity and Fibromyalgia: Common Pathogenesis and Promising Biomarkers
Abstract
Fibromyalgia (FM) is a complex and debilitating rheumatologic syndrome characterized by chronic widespread pain, fatigue, and cognitive disturbances. Despite extensive research, its pathogenesis remains poorly understood, and reliable biomarkers for diagnosis are lacking. Emerging evidence suggests a critical role of immune dysregulation in FM, highlighting its potential classification as an autoimmune-related disorder. This review explores the immunological aspects of FM pathogenesis, including its association with autoimmune comorbidities, the presence of autoantibodies, and the involvement of inflammatory cytokines. Additionally, we discuss recent findings that support an autoimmune basis for FM, such as the transfer of FM symptoms through patient-derived IgG in animal models. Recognizing these immunological connections may pave the way for improved diagnostic approaches and targeted therapeutic strategies for FM.
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2. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58(1):26-35.
3. Arnold LM, Bennett RM, Crofford LJ, Dean LE, Clauw DJ, Goldenberg DL, et al. AAPT Diagnostic Criteria for Fibromyalgia. J Pain. 2019;20(6):611-28.
4. Higgs JB. Fibromyalgia in Primary Care. Prim Care. 2018;45(2):325-41.
5. Siracusa R, Paola RD, Cuzzocrea S, Impellizzeri D. Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update. Int J Mol Sci. 2021;22(8):3891.
6. Choy E, Perrot S, Leon T, Kaplan J, Petersel D, Ginovker A, et al. A patient survey of the impact of fibromyalgia and the journey to diagnosis. BMC Health Serv Res. 2010;10(1):102.
7. Wolfe F, Clauw DJ, Fitzcharles M-A, Goldenberg DL, Häuser W, Katz RL, et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016;46(3):319–29.
8. Häuser W, Sarzi-Puttini P, Fitzcharles M-A. Fibromyalgia syndrome: under-, over- and misdiagnosis. Clin Exp Rheumatol. 2019;37 Suppl 116(1):90–7.
9. Annemans L, Wessely S, Spaepen E, Caekelbergh K, Caubere JP, Le Lay K, et al. Health economic consequences related to the diagnosis of fibromyalgia syndrome. Arthritis Rheum. 2008;58(3):895–902.
10. Annemans L, Le Lay K, Taieb C. Societal and patient burden of fibromyalgia syndrome. Pharmacoeconomics. 2009;27(7):547–59.
11. Smith HS, Harris R, Clauw D. Fibromyalgia: an afferent processing disorder leading to a complex pain generalized syndrome. Pain Physician. 2011;14(2):E217–45.
12. Fitzcharles M-A, Perrot S, Häuser W. Comorbid fibromyalgia: A qualitative review of prevalence and importance. Eur J Pain. 2018;22(9):1565–76.
13. Goebel A, Krock E, Gentry C, Israel MR, Jurczak A, Urbina CM, et al. Passive transfer of fibromyalgia symptoms from patients to mice. J Clin Invest. 2021;131(13):e144201.
14. Floreani A, Leung PS, Gershwin ME. Environmental basis of autoimmunity. Clin Rev Allergy Immunol. 2016;50(3):287–300.
15. Sharif K, Watad A, Coplan L, Lichtbroun B, Krosser A, Lichtbroun M, et al. The role of stress in the mosaic of autoimmunity: An overlooked association. Autoimmun Rev. 2018;17(10):967–83.
16. Martínez-Lavín M. Fibromyalgia in women: somatisation or stress-evoked, sex-dimorphic neuropathic pain. Clin Exp Rheumatol. 2021;39(2):422–5.
17. Yavne Y, Amital D, Watad A, Tiosano S, Amital H, editors. A systematic review of precipitating physical and psychological traumatic events in the development of fibromyalgia. Semin Arthritis Rheum. 2018;48(1):121–33.
18. Khoo T, Proudman S, Limaye V. Silicone breast implants and depression, fibromyalgia and chronic fatigue syndrome in a rheumatology clinic population. Clin Rheumatol. 2019;38(5):1271–6.
19. Agmon-Levin N, Zafrir Y, Kivity S, Balofsky A, Amital H, Shoenfeld Y. Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: Another angle of the ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ (ASIA). Immunol Res. 2014;60(2):376–83.
20. Qassem R, Watad A. The role of infection and immunization in the induction of fibromyalgia. In: Fibromyalgia Syndrome. Springer; 2021. p. 267–72.
21. Ursini F, Ciaffi J, Mancarella L, Lisi L, Brusi V, Cavallari C, et al. Fibromyalgia: A new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey. RMD Open. 2021;7(3):e001735.
22. Mahroum N, Shoenfeld Y. Autoimmune autonomic dysfunction syndromes: Potential involvement and pathophysiology related to complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms and post-COVID syndrome. Pathophysiology. 2022;29(3):414–25.
23. Hayden MR. Hypothesis: Neuroglia activation due to increased peripheral and CNS proinflammatory cytokines/chemokines with neuroinflammation may result in Long COVID. Neuroglia. 2021;2(1):7–35.
24. Littlejohn G, Guymer E, editors. Neurogenic inflammation in fibromyalgia. Semin Immunopathol. 2018;40(3):291–300.
25. Martínez-Lavín M. Dorsal root ganglia: Fibromyalgia pain factory? Clin Rheumatol. 2021;40(2):783–7.
26. Haliloglu S, Carlioglu A, Akdeniz D, Karaaslan Y, Kosar A. Fibromyalgia in patients with other rheumatic diseases: Prevalence and relationship with disease activity. Rheumatol Int. 2014;34(9):1275–80.
27. Levy O, Segal R, Maslakov I, Markov A, Tishler M, Amit-Vazina M. The impact of concomitant fibromyalgia on visual analogue scales of pain, fatigue and function in patients with various rheumatic disorders. Clin Exp Rheumatol. 2016;34(2 Suppl 96):S120–4.
28. Huang FF, Fang R, Nguyen MH, Bryant K, Gibson KA, O'Neill SG. Identifying co-morbid fibromyalgia in patients with systemic lupus erythematosus using the Multi-Dimensional Health Assessment Questionnaire. Lupus. 2020;29(11):1404–11.
29. Staud R. Are patients with systemic lupus erythematosus at increased risk for fibromyalgia? Curr Rheumatol Rep. 2006;8(6):430–5.
30. Park DJ, Takahashi Y, Kang JH, Yim YR, Kim JE, Lee JW, et al. Anti-N-methyl-D-aspartate receptor antibodies are associated with fibromyalgia in patients with systemic lupus erythematosus: A case-control study. Clin Exp Rheumatol. 2017;35 Suppl 105(3):54–60.
31. Kılıçarslan A, Yurdakul FG, Bodur H. Diagnosing fibromyalgia in rheumatoid arthritis: The importance of assessing disease activity. Turk J Phys Med Rehabil. 2018;64(2):133.
32. Provan SA, Austad C, Halsaa V, Hammer HB, Kvien TK, Uhlig T. Fibromyalgia in patients with rheumatoid arthritis. A 10-year follow-up study, results from the Oslo Rheumatoid Arthritis Register. Clin Exp Rheumatol. 2019;37 Suppl 116(1):58-62.
33. McWilliams DF, Walsh DA. Factors predicting pain and early discontinuation of tumour necrosis factor-alpha-inhibitors in people with rheumatoid arthritis: results from the British society for rheumatology biologics register. BMC Musculoskelet Disord. 2016;17:337.
34. Basu N, Kaplan CM, Ichesco E, Larkin T, Harris RE, Murray A, et al. Neurobiologic Features of Fibromyalgia Are Also Present Among Rheumatoid Arthritis Patients. Arthritis Rheumatol. 2018;70(7):1000-7.
35. Durmaz Y, İlhanlı İ. Comparison of ankylosing spondylitis patients with and without fibromyalgia syndrome according to the disease activation scores and response to treatment. Turk J Phys Med Rehabil. 2021;67(4):509.
36. Gau SY, Lee YH, Tsou HK, Huang JY, Chen X, Ye Z, et al. Patients With Ankylosing Spondylitis Are Associated With High Risk of Fibromyalgia: A Nationwide Population-Based Cohort Study. Front Med (Lausanne). 2021;8:618594.
37. Choi BY, Oh HJ, Lee YJ, Song YW. Prevalence and clinical impact of fibromyalgia in patients with primary Sjögren’s syndrome. Clin Exp Rheumatol. 2016;34(2 Suppl 96):S9-13.
38. Gau S-Y, Leong P-Y, Lin C-L, Tsou H-K, Wei JC-C. Higher Risk for Sjögren’s Syndrome in Patients With Fibromyalgia: A Nationwide Population-Based Cohort Study. Front Immunol. 2021;12:640618.
39. Applbaum E, Lichtbroun A. Novel Sjögren's autoantibodies found in fibromyalgia patients with sicca and/or xerostomia. Autoimmun Rev. 2019;18(2):199-202.
40. Melikoglu M, Melikoglu MA. The prevalence of fibromyalgia in patients with Behçet’s disease and its relation with disease activity. Rheumatol Int. 2013;33(5):1219-22.
41. Lee S, Yoon H, Chang H, Park K. Fibromyalgia in Behçet's disease is associated with anxiety and depression, and not with disease activity. Clin Exp Rheumatol. 2005;23(4):S.
42. Tagoe CE. Rheumatic symptoms in autoimmune thyroiditis. Curr Rheumatol Rep. 2015;17(2):5.
43. Giuffrida G, Bagnato G, Campennì A, Giovinazzo S, Keller K, Alibrandi A, et al. Non-specific rheumatic manifestations in patients with Hashimoto’s thyroiditis: a pilot cross-sectional study. J Endocrinol Invest. 2020;43(1):87-94.
44. Haliloglu S, Ekinci B, Uzkeser H, Sevimli H, Carlioglu A, Macit PM. Fibromyalgia in patients with thyroid autoimmunity: prevalence and relationship with disease activity. Clin Rheumatol. 2017;36(7):1617-21.
45. Aleksi V, Elise K, Koskela TH. Excess use of thyroid hormone treatment among patients with fibromyalgia: a cross-sectional study in primary health care. BMC Res Notes. 2022;15(1):1-5.
46. Groenewegen KL, Mooij CF, van Trotsenburg AP. Persisting symptoms in patients with Hashimoto’s disease despite normal thyroid hormone levels: Does thyroid autoimmunity play a role? A systematic review. J Transl Autoimmun. 2021;4:100101.
47. Watt T, Hegedüs L, Bjorner JB, Groenvold M, Bonnema SJ, Rasmussen ÅK, et al. Is thyroid autoimmunity per se a determinant of quality of life in patients with autoimmune hypothyroidism? Eur Thyroid J. 2012;1(3):186-92.
48. Slim M, Calandre EP, Rico-Villademoros F. An insight into the gastrointestinal component of fibromyalgia: clinical manifestations and potential underlying mechanisms. Rheumatol Int. 2015;35(3):433-44.
49. Almansa C, Rey E, Sanchez RG, Sanchez AA, Diaz-Rubio M. Prevalence of functional gastrointestinal disorders in patients with fibromyalgia and the role of psychologic distress. Clin Gastroenterol Hepatol. 2009;7(4):438-45.
50. Lebwohl B, Sanders DS, Green PH. Coeliac disease. Lancet. 2018;391(10115):70-81.
51. Tovoli F, Giampaolo L, Caio G, Monti M, Piscaglia M, Frisoni M, et al. Fibromyalgia and coeliac disease: a media hype or an emerging clinical problem? Clin Exp Rheumatol. 2013;31(6 Suppl 79):S50-2.
52. García-Leiva JM, Carrasco JLO, Slim M, Calandre EP. Celiac symptoms in patients with fibromyalgia: a cross-sectional study. Rheumatol Int. 2015;35(3):561-7.
53. Zipser RD, Patel S, Yahya KZ, Baisch DW, Monarch E. Presentations of adult celiac disease in a nationwide patient support group. Dig Dis Sci. 2003;48(4):761-4.
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| Files | ||
| Issue | Vol 8, No 2 (2025) | |
| Section | Review Article | |
| DOI | https://doi.org/10.18502/igj.v8i2.18000 | |
| Keywords | ||
| Antibody Autoimmunity Autoimmune Disease Biomarker Cytokine Fibromyalgia | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Yousefi S, Mansouri V. Autoimmunity and Fibromyalgia: Common Pathogenesis and Promising Biomarkers. Immunol Genet J. 2025;8(2):203-212.
