CoChat
Sign Up
Cited by 213Fibromyalgia and Chronic Fatigue Syndrome ResearchPain Mechanisms and TreatmentsMyofascial pain diagnosis and treatment

A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis

Open access
Grayston, Rebecca, Czanner, Gabriela, Elhadd, Kareim, Goebel, Andreas, Frank, Bernhard, Üçeyler, Nurcan, Malik, Rayaz A, Alam, Uazman·2019·Seminars in Arthritis and Rheumatism
DOI 10.1016/j.semarthrit.2018.08.003
Open this paper in CoChat — free accountOpen PDF

Abstract

Fibromyalgia is a condition which exhibits chronic widespread pain with neuropathic pain features and has a major impact on health-related quality of life. The pathophysiology remains unclear, however, there is increasing evidence for involvement of the peripheral nervous system with a high prevalence of small fiber pathology (SFP). The aim of this systematic literature review is to establish the prevalence of SFP in fibromyalgia. An electronic literature search was performed using MEDLINE, EMBASE, PubMed, Web of Science, CINAHL and the Cochrane Library databases. Published full-text, English language articles that provide SFP prevalence data in studies of fibromyalgia of patients over 18years old were included. All articles were screened by two independent reviewers using a priori criteria. Methodological quality and risk of bias were evaluated using the critical appraisal tool by Munn et al. Overall and subgroup pooled prevalence were calculated by random-effects meta-analysis with 95% CI. Database searches found 935 studies; 45 articles were screened of which 8 full text articles satisfied the inclusion criteria, providing data from 222 participants. The meta-analysis demonstrated the pooled prevalence of SFP in fibromyalgia is 49% (95% CI: 38–60%) with a moderate degree of heterogeneity, (I2= 68%). The prevalence estimate attained by a skin biopsy was 45% (95% CI: 32–59%, I2= 70%) and for corneal confocal microscopy it was 59% (95% CI: 40–78%, I2= 51%). There is a high prevalence of SFP in fibromyalgia. This study provides compelling evidence of a distinct phenotype involving SFP in fibromyalgia. Identifying SFP will aid in determining its relationship to pain and potentially facilitate the development of future interventions and pharmacotherapy.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.semarthrit.2018.08.003

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Small fiber pathology was confirmed in 30% to 70% of women with fibromyalgia syndrome.

    “meanwhile small fiber pathology was confirmed in 30% to 70% of women with FMS.20”

    From Pain and small fiber pathology in men with fibromyalgia syndrome (2024) · cites this paper as [20]

    The Overall prevalence section reports small fiber pathology estimates of 30%–76% across eight studies of people with fibromyalgia, not 30%–70%. The paper does not present that range as an estimate specifically for women; its study table includes participants of both sexes (page numbers unavailable). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 63

  1. Belt NK, Kronholm E, Kauppi MJ. Sleep problems in fibromyalgia and rheumatoid arthritis compared with the general population. Clin Exp Rheumatol 2009;27(1): 35-41.
  2. Bellato E, Marini E, Castoldi F, Barbasetti N, Mattei L, Bonasia DE, et al. Fibromyal- gia syndrome: etiology, pathogenesis, diagnosis, and treatment. Pain Res Treat 2012;2012:426130.
  3. Schmidt-Wilcke T, Clauw DJ. Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol 2011;7(9):518-27.
  4. Levine TD, Saperstein DS. Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients. Clin Rheumatol 2015;34(3):413-7.
  5. Kindler LL, Bennett RM, Jones KD. Central sensitivity syndromes: mounting path- ophysiologic evidence to link fibromyalgia with other common chronic pain dis- orders. Pain Manag Nurs: Off J Am Soc Pain Manag Nurses 2011;12(1):15-24.
  6. Cagnie B, Coppieters I, Denecker S, Six J, Danneels L, Meeus M. Central sensitiza- tion in fibromyalgia? A systematic review on structural and functional brain MRI. Semin Arthritis Rheum 2014;44(1):68-75.
  7. Foerster BR, Petrou M, Harris RE, Barker PB, Hoeffner EG, Clauw DJ, et al. Cerebral blood flow alterations in pain-processing regions of patients with fibro- myalgia using perfusion MR imaging. AJNR Am J Neuroradiol 2011;32(10): 1873-8.
  8. Kwiatek R, Barnden L, Tedman R, Jarrett R, Chew J, Rowe C, et al. Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evi- dence of reduction in the pontine tegmentum and thalami. Arthritis Rheum 2000;43(12):2823-33.
  9. Guedj E, Taieb D, Cammilleri S, Lussato D, de Laforte C, Niboyet J, et al. 99mTc-ECD brain perfusion SPECT in hyperalgesic fibromyalgia. Eur J Nucl Med Mol Imaging 2007;34(1):130-4.
  10. Okifuji A, Hare BD. Management of fibromyalgia syndrome: review of evidence. Pain Ther 2013;2(2):87-104.
  11. Pyke TL, Osmotherly PG, Baines S. Measuring glutamate levels in the brains of fibromyalgia patients and a potential role for glutamate in the pathophysiology of fibromyalgia symptoms: a systematic review. Clin J Pain 2017;33(10):944-54.
  12. Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, et al. Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neu- rosci 2007;25(12):3576-82.
  13. Alnigenis MN, Barland P. Fibromyalgia syndrome and serotonin. Clin Exp Rheu- matol 2001;19(2):205-10.
  14. Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008;131(7):1912-25.
  15. Koroschetz J, Rehm SE, Gockel U, Brosz M, Freynhagen R, T€ olle TR, et al. Fibromy- algia and neuropathic pain À differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia. BMC Neurol 2011; 11(1):55.
  16. Rehm SE, Koroschetz J, Gockel U, Brosz M, Freynhagen R, T€ olle TR, et al. A cross- sectional survey of 3035 patients with fibromyalgia: subgroups of patients with typical comorbidities and sensory symptom profiles. Rheumatology 2010;49(6):1146-52.
  17. Berglund B, Harju E-L, Kosek E, Lindblom U. Quantitative and qualitative percep- tual analysis of cold dysesthesia and hyperalgesia in fibromyalgia. Pain 2002; 96(1):177-87.
  18. Geisser ME, Casey KL, Brucksch CB, Ribbens CM, Appleton BB, Crofford LJ. Percep- tion of noxious and innocuous heat stimulation among healthy women and women with fibromyalgia: association with mood, somatic focus, and catastroph- izing. Pain 2003;102(3):243-50.
  19. Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small- fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 2013;154(11):2310-6.
  20. Harte SE, Clauw DJ, Hayes JM, Feldman EL, St Charles IC, Watson CJ. Reduced intraepidermal nerve fiber density after a sustained increase in insular glutamate: a proof-of-concept study examining the pathogenesis of small fiber pathology in fibromyalgia. Pain Rep 2017;2(3):e590.
  21. Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small- fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 2013;154(11):2310-6.
  22. Giannoccaro MP, Donadio V, Incensi A, Avoni P, Liguori R. Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve 2014;49(5): 757-9.
  23. Caro XJ, Winter EF. Evidence of abnormal epidermal nerve fiber density in fibro- myalgia: clinical and immunologic implications. Arthritis Rheumatol 2014; 66(7):1945-54.
  24. Oudejans L, He X, Niesters M, Dahan A, Brines M, van Velzen M. Cornea nerve fiber quantification and construction of phenotypes in patients with fibromyalgia. Sci Rep 2016;6:23573.
  25. Ramirez M, Martinez-Martinez LA, Hernandez-Quintela E, Velazco-Casapia J, Var- gas A, Martinez-Lavin M. Small fiber neuropathy in women with fibromyalgia. An in vivo assessment using corneal confocal bio-microscopy. Semin Arthritis Rheum 2015;45(2):214-9.
  26. Doppler K, Rittner HL, Deckart M, Sommer C. Reduced dermal nerve fiber diame- ter in skin biopsies of patients with fibromyalgia. Pain 2015;156(11):2319-25.
  27. € Uçeyler N. Reply Pain 2017;158(5):989-90.
  28. Peters MJ, Bakkers M, Merkies IS, Hoeijmakers JG, van Raak EP, Faber CG. Inci- dence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology 2013;81(15):1356-60.
  29. Wolfe F. New American College of Rheumatology criteria for fibromyalgia: a twenty-year journey. Arthritis Care Res 2010;62(5):583-4.
  30. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis Rheum 1990;33(2):160-72.
  31. Katrak P, Bialocerkowski AE, Massy-Westropp N, Kumar S, Grimmer KA. A sys- tematic review of the content of critical appraisal tools. BMC Med Res Methodol 2004;4:22.
  32. Lauria G, Cornblath DR, Johansson O, McArthur JC, Mellgren SI, Nolano M, et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropa- thy. Eur J Neurol 2005;12(10):747-58.
  33. Muller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res 2003;76(5):521-42.
  34. Petropoulos IN, Alam U, Fadavi H, Asghar O, Green P, Ponirakis G, et al. Corneal nerve loss detected with corneal confocal microscopy is symmetrical and related to the severity of diabetic polyneuropathy. Diabetes Care 2013; 36(11):3646-51.
  35. Petropoulos IN, Manzoor T, Morgan P, Fadavi H, Asghar O, Alam U, et al. Repeat- ability of in vivo corneal confocal microscopy to quantify corneal nerve morphol- ogy. Cornea 2013;32(5):e83-9.
  36. Petropoulos IN, Alam U, Fadavi H, Marshall A, Asghar O, Dabbah MA, et al. Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal con- focal microscopy. Investig Ophthalmol Vis Sci 2014;55(4):2071-8.
  37. Alam U, Riley DR, Jugdey RS, Azmi S, Rajbhandari S, D'Aout K, et al. Diabetic neuropathy and gait: a review. Diabetes Therapy: Res Treat Educ Diabetes Relat Disord 2017;8(6):1253-64.
  38. Chen X, Graham J, Dabbah MA, Petropoulos IN, Ponirakis G, Asghar O, et al. Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneurop- athy: comparing corneal confocal microscopy with intraepidermal nerve fiber density. Diabetes Care 2015;38(6):1138-44.
  39. Alam U, Jeziorska M, Petropoulos IN, Asghar O, Fadavi H, Ponirakis G, et al. Diag- nostic utility of corneal confocal microscopy and intra-epidermal nerve fibre den- sity in diabetic neuropathy. PLoS One 2017;12(7):e0180175.
  40. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21(11):1539-58.
  41. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-60.
  42. de Tommaso M, Nolano M, Iannone F, Vecchio E, Ricci K, Lorenzo M, et al. Update on laser-evoked potential findings in fibromyalgia patients in light of clinical and skin biopsy features. J Neurol 2014;261(3):461-72.
  43. Leinders M, Doppler K, Klein T, Deckart M, Rittner H, Sommer C, et al. Increased cutaneous miR-let-7d expression correlates with small nerve fiber pathology in patients with fibromyalgia syndrome. Pain 2016; 157(11):2493-503.
  44. Jones GT, Atzeni F, Beasley M, Fluss E, Sarzi-Puttini P, Macfarlane GJ. The preva- lence of fibromyalgia in the general population: a comparison of the American College of Rheumatology 1990, 2010, and modified 2010 classification criteria. Arthritis Rheumatol 2015;67(2):568-75.
  45. Kim S-K, Kim S-H, Lee C-K, Lee H-S, Lee S-H, Park Y-B, et al. Effect of fibromyalgia syndrome on the health-related quality of life and economic burden in Korea. Rheumatology 2013;52(2):311-20.
  46. Williams DA, Gracely RH. Biology and therapy of fibromyalgia. Functional mag- netic resonance imaging findings in fibromyalgia. Arthritis Res Therapy 2006; 8(6):224.
  47. Hsu MC, Harris RE, Sundgren PC, Welsh RC, Fernandes CR, Clauw DJ, et al. No con- sistent difference in gray matter volume between individuals with fibromyalgia and age-matched healthy subjects when controlling for affective disorder. Pain 2009;143(3):262-7.
  48. Hsieh PC, Tseng MT, Chao CC, Lin YH, Tseng WY, Liu KH, et al. Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connec- tivity of the limbic system after peripheral nerve degeneration. Pain 2015; 156(5):904-16.
  49. Wei SY, Chao HT, Tu CH, Li WC, Low I, Chuang CY, et al. Changes in functional con- nectivity of pain modulatory systems in women with primary dysmenorrhea. Pain 2016;157(1):92-102.
  50. Kim SH, Kim DH, Oh DH, Clauw DJ. Characteristic electron microscopic findings in the skin of patients with fibromyalgiaÀpreliminary study. Clin Rheumatol 2008;27(3):407-11.
  51. Salemi S, Rethage J, Wollina U, Michel BA, Gay RE, Gay S, et al. Detection of inter- leukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in skin of patients with fibromyalgia. J Rheumatol 2003;30(1):146-50.
  52. Tian D, Tian M, Zhang L, Zhao P, Cui Y, Li J. High fat diet sensitizes fibromyalgia- like pain behaviors in mice via tumor necrosis factor alpha. PLoS One 2018;13(2): e0190861.
  53. Oza MJ, Garud MS, Gaikwad AB, Kulkarni YA. Chapter 7 À fibromyalgia syndrome: role of obesity and nutrients A2. In: Watson R R, ed. Nutrition and functional foods for healthy aging, Academic Press; 2017:53-63.
  54. Smith AG, Singleton JR. Impaired glucose tolerance and neuropathy. Neurologist 2008;14(1):23-9.
  55. Lodahl M, Treister R, Oaklander AL. Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber poly- neuropathy. Pain Rep 2018;3(1):e633.
  56. Oaklander AL. What is the meaning of "small-fiber polyneuropathy" in fibromyal- gia? An alternate answer. Pain 2016;157(6):1366-7.
  57. Gemignani F. Fibromyalgia syndrome and small-fiber neuropathy: comment on the article by Caro and Winter. Arthritis Rheumatol 2014;66(12):3526-7.
  58. Littlejohn G. Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome. Nat Rev Rheumatol 2015;11(11):639-48.
  59. Albrecht PJ, Hou Q, Argoff CE, Storey JR, Wymer JP, Rice FL. Excessive peptidergic sensory innervation of cutaneous arteriole-venule shunts (AVS) in the palmar gla- brous skin of fibromyalgia patients: implications for widespread deep tissue pain and fatigue. Pain Med 2013;14(6):895-915.
  60. Dori A, Lopate G, Keeling R, Pestronk A. Myovascular innervation: axon loss in small-fiber neuropathies. Muscle Nerve 2015;51(4):514-21.
  61. Stewart JM, Medow MS, Messer ZR, Baugham IL, Terilli C, Ocon AJ. Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome. Am J Physiol À Heart Circ Physiol 2012;302(5):H1185-94.
  62. Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain 2004;127(7):1606-15.
  63. Tavakoli M, Mitu-Pretorian M, Petropoulos IN, Fadavi H, Asghar O, Alam U, et al. Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes 2013;62(1):254-60.

Cited by

Sorted by citations

Authors
Grayston, R., Czanner, G., Elhadd, K., Goebel, A., Frank, B., Üçeyler, N., Malik, R. A., & Alam, U.
Affiliations
  • University of Liverpool (GB)
  • Walton Centre (GB)
  • University of Würzburg (DE)
  • Weill Cornell Medical College in Qatar (QA)
Corresponding author
Alam, Uazman
ORCID
Venue
Seminars in Arthritis and Rheumatism
Publisher
Elsevier BV
Published
2019-04
Volume
48
Issue
5
Pages
933-940
ISSN
0049-0172 (ISSN-L)
DOI
10.1016/j.semarthrit.2018.08.003
OpenAlex
W2888150073
Cited by
213
References
8
Citations by year
2026: 21 · 2025: 30 · 2024: 23 · 2023: 27 · 2022: 38 · 2021: 28 · 2020: 32 · 2019: 12 · 2014: 1
FWCI
2.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Seminars in Arthritis and Rheumatism (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
  • Liverpool John Moores University (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Myofascial pain diagnosis and treatment
Keywords
fibromyalgia, prevalence, peripheral nervous system, neuropathic pain, chronic widespread pain, skin biopsy, corneal confocal microscopy, pain phenotypes
MeSH terms
Small Fiber Neuropathy, Female, Fibromyalgia, Humans, Male, Skin, Case-Control Studies, Nerve Fibers, Unmyelinated

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review