Introduction:

Fibromyalgia that is diagnosed and labelled by physicians in clinical practice and even research interchangeably with Chronic Fatigue Syndrome is still a controversy by some, while a clear diagnostic entity by others. As the label of fibromyalgia denotes, it is a condition of generalized body (musculoskeletal) and joint pains. The Chronic Fatigue Syndrome label indicates the patient suffering from a general body fatigue. These two labels if they are two conditions may overlap as some patients and present with both generalized symptom clusters. That is why the two conditions are considered by some as one and inter-related. While these conditions were misdiagnosed or under-diagnosed in the past, they may be over-diagnosed in the recent years. Either way the diagnosis of these conditions often is clinical and by history and physical examinations (only if muscle and joint tenderness present) as any lab or imaging tests are often non-conclusive. Therefore the pathophysiology of these conditions is still known by many as idiopathic, without any known aetiology or pathologic pathway(s).

 More than a controversy, Fibromyalgia and Chronic Fatigue Syndrome (FCFS) are elusive and the diagnosis by many could be descriptive and clinical by symptoms counting like major depression. But there is at least one or more types of FCFS that are associated with many other medical conditions, e.g. IBS (Irritable Bowel Syndrome), non-ulcer dyspepsia, esophageal dysmotility, interstitial cystitis, chronic prostatitis, vulvodynia, vulvar vestibulitis, temporomandibular joint syndrome, sickle cell anaemia, osteoarthritis to name a few. The association with some of these comorbidities that are known as autoimmune disorders, could easily classify this type (s) of FCFS as an autoimmune condition(s) (1). The common conception behind the pathogenesis of FCFS is over-focussing on the pain symptoms that could be due to super-sensitivity or hyperalgesia of the nociceptive process in the central nervous system. But here the focus will be more on the type or types of FCFS that have some true underlying pathologies (1-2). This or these pathological condition (s) are inflammatory, systemic throughout the body and associated with one or more inflammatory or autoimmune disorders (e.g. 3-4).

In the Search of a True Pathologic Fibromyalgia & CFS:

A Chronic Pain Syndrome or A Systemic Musculoskeletal Inflammation?

The first thing to reach the truth of FCFS is to separate these two different conditions that currently are diagnosed under the generic umbrella of fibromyalgia and chronic fatigue syndrome. First of all since both a chronic pain syndrome due to hyperalgesia or super-sensitivity of the nociceptive receptors in the central nervous system, and a systemic musculoskeletal inflammation could cause chronic fatigue syndrome, this secondary or post-morbid condition in this article will be excluded and the literature on fibromyalgia is solely explored (5-8).

 Although a systemic musculoskeletal inflammatory condition could cause chronic generalized body pain, but the reason for the pain is not hyperalgesia or hyper-sensitivity of the nociceptive receptors in the central nervous system, but peripheral inflammations. This inflammatory condition is separated and searched for its underpinning pathology as the true pathological fibromyalgia, as pain even a generalized type could be subjective and not a true objective and pathological condition. Even tenderness of the muscles and joints without any proof of underlying pathology such as inflammation could be all subjective. Therefore this subjective condition or “Chronic Pain Syndrome” that could be due to a hyperalgesia or hyper-sensitivity of the nociceptive receptors of the brain or in a simpler word due to hyper-perception of pain by an individual is separated from a true fibromyalgia in this paper. This sole pain condition that is simply subjective could be perhaps associated more with other subjective conditions such as depression or being influenced by psychosocial processes (9-12).

Fibromyalgia: A Systemic Musculoskeletal Inflammatory Condition  

Unfortunately since most samples of fibromyalgia studies are mixed with chronic pain syndrome and other subjective conditions without any underlying physical pathology, the physical findings of any inflammatory biomarkers are below the real level of the pathological reality of the condition. But despite this limitation, there are studies that have been able to show the presence of an underlying inflammatory process in the true cases of fibromyalgia.

C-Reactive Protein (CRP) is a long-known reliable inflammatory index and positive in numerous inflammatory conditions and autoimmune disorders. This index has been reported to be positive in some Fibromyalgia cases (3). Increase sensitivity to pain in several inflammatory conditions such as fibromyalgia and Rheumatoid Arthritis (RA) has been demonstrated through the elevation of inflammatory indices such as CRP, Interleukins (IL-6, IL-1) and Tumor Necrosis Factor (TNF). In the case of CRP, the elevation has been observed more in high-sensitivity-CRP (hs-CRP) with levels >10mg/L (13-17).

 A subgroup of Rheumatoid arthritis (RA), an autoimmune and inflammatory disorder with seronegative Rheumatoid Factor (RF) has been associated with fibromyalgia in a large sample of 2199 patients (4). A gnome-wide expression profiling study of the peripheral blood of patients with fibromyalgia, has identified 421 genes relevant to pathways for pain processing, such as glutamine/glutamate signaling and axonal development. But the study also showed up-regulation of several inflammatory pathways and down-regulation of pathways related to hypersensitivity and allergy (18). Behçet’s disease (BD), a chronic relapsing, inflammatory rheumatological disease has been shown to be associated with fibromyalgia up to 37.1% (19).

 Another support for the inflammatory pathology underlying fibromyalgia is elevated cytokine levels that could improve with progressive resistance exercise or relaxation therapy (20). Also an elevation of interleukin (IL)- 1β and proinflammatory cytokines (IL-18), along with coenzyme Q10 deficiency and mitochondrial dysfunction leading to inflammasome activation have been shown in the blood cells of fibromyalgia patients (21). Electromyography (EMG) and Nerve Conduction Studies (NCS) in fibromyalgia have resulted in 90% of the subjects showing peripheral large neuropathy in the forms of demyelinating and/or axonal, sensorimotor polyneuropathy, and 63% small fiber nerve neuropathy, suggesting a mixed fiber neuropathy in most patients. Furthermore, 61% of the patients have showed EMG findings suggestive of non-myotomal lower extremity axonal motor denervation, most likely due to a polyneuropathy, and 41% for “possible” chronic inflammatory demyelinating polyneuropathy (22).

Fibromyalgia: An Autoimmune Disorder

Small-fiber polyneuropathy (SFPN) causing and the pain and tenderness symptoms of Fibromyalgia, is caused by dysfunction and degeneration of peripheral small-fiber neurons. A recent study of skin biopsy in 27 fibromyalgia patients and 30 matched normal controls, showed 41% of fibromyalgia vs. 3% of control subjects were positive for SFPN. Out of 13 fibromyalgia subjects with SFPN-diagnostic skin biopsies, 8 subjects had dysimmune markers, 2 had hepatitis C serologies, and one family had apparent genetic causality (23). In a sample of 104 patients with both fibromyalgia and IBS (Irritable Bowel syndrome), 7 subjects or 6.7% of them displayed positive HLA-DQ2/HLA-DQ8, high tTG-2 serum levels and duodenal villous atrophy, concordant with Coeliac Disease (CD) (24).

 A logistic regression analysis of 219 female patients with fibromyalgia and 116 with chronic pain, revealed more autoimmune disorders in the first group compared with the second one. The autoimmune disorders were of endocrine, thyroid and diabetes and IBS (25). Seropositive antipolymer antibody has also been shown more in moderate to severe symptomatic fibromyalgia patients (26). While the prevalence of fibromyalgia in the general global population is between 2-7%, this is 30-40% in the population of Hashimoto thyroiditis (HT) with a structural pathology. In 2010, new classification criteria for FM were proposed, as an alternative to the American College of Rheumatology (ACR) 1990 criteria. In a recent study of 79 consecutive patients with HT with or without FM, the prevalence of FM in patients with HT was 62%. In this study, antithyroid peroxidase antibody (TPOAb) positivity, duration of disease, and waist circumference were significantly associated with concomitant FM (27).

 The prevalence of fibromyalgia has also been shown to be higher than the general population in autoimmune rheumatic diseases as follow: 6.6% in rheumatoid arthritis (RA), 13.4% for systemic lupus erythematosus (SLE), 12.6% for ankylosing spondylitis (AS), 10.1% for osteoarthritis (OA), 7.1% for familial Mediterranean fever (FMF), 5.7% for Behçet’s disease (BD), and 12% for Sjögren’s syndrome (SS), 25% for vasculitis, and 6.9% for polymyalgia rheumatica (PMR) (28). Other than rheumatic diseases, fibromyalgia has also been associated with other autoimmune disorders such as diabetes mellitus (29-30), vitiligo (31), autoimmune thyroiditis (27, 32) among others.

 ASIA (Autoimmune/Inflammatory Syndrome Induced by Adjuvants) have been an issue over the past decade, caused by post-vaccinations with HPV (Human Papilloma Virus) and Hepatitis B among others. Fibromyalgia (33-34) has been reported among these iatrogenic autoimmune and inflammatory syndromes post-hepatitis B vaccination, along the side with primary ovarian failure post-HPV vaccination (35), that is another evidence to the inflammatory/autoimmune nature of fibromyalgia.

 

Conclusion:

Fibromyalgia as generalized musculoskeletal pain and tenderness that could be associated with chronic fatigue seems to be an inflammatory condition. This condition that seems to have an underlying pathological inflammation in the musculoskeletal system that causes a generalized body tenderness on examination, needs to be differentiated from a chronic generalized body pain that could be subjective without any underlying pathology such as inflammation. This secondary subjective pain condition could be perhaps due to hyperalgia or supersensitivty of pain perception by the nociceptive receptors of the brain. This chronic subjective pain condition that still is mixed up in the study samples of fibromyalgia, could be associated with other subjective conditions such as depression, and needs not to be mixed up with the true fibromyalgia that is a pathologic physical/medical condition.

 As discussed and showed some evidence in the available scarce research, the inflammatory fibromyalgia is often associated with other inflammatory/autoimmune conditions such as a vast group of arthritic conditions, e.g. Rheumatoid Arthritis that could denote that inflammatory fibromyalgia to be an autoimmune disorder as well. Not only arthritic conditions but other inflammatory/autoimmune disorders have been observed to be associated with inflammatory fibromyalgia such as autoimmune and Hashimoto’s thyroiditis. Not just involving musculoskeletal system, but the underlying vessels and peripheral nerves could also be involved in this general inflammation, as association with vasculitis has been shown to as frequent as 25% and small fiber neuropathy has been evidenced in the inflammatory fibromyalgia.

 In summary the inflammatory fibromyalgia if separated from other similar subjective conditions that are without any true physical pathologies such as chronic pain syndrome, could be an autoimmune disorder of inflammatory type. This separation of a true objective medical condition from other similar subjective conditions, needs to be done at both research and also clinical level. At the research arena, such inclusion of a true inflammatory fibromyalgia with physical tenderness could lead the researchers to identifying more inflammatory and autoimmune indices associated with this condition and also any other comorbid inflammatory/autoimmune disorders. At the clinical stage, simple blood tests such as measuring CRP, cytokines and interleukins could identify these subjects who could benefit from anti-inflammatory or immune fostering agents and end to their sufferings.    

 Dr. Mostafa Showraki, MD, FRCPC

Lecturer, School of Medicine, University of Toronto

Author: ADHD: Revisited Book

Adhdrevisited.com/medicinerevisited.com      

References:

1. Sluka KA, Clauw DJ. Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience. 2016;338:114-129.
2. Coghill RC, McHaffie JG, Yen YF. Neural correlates of interindividual differences in the subjective experience of pain. Proc Natl Acad Sci USA. 2003;100:8538–8542.
3. Feinberg T, Sambamoorthi U, Lilly C, Innes KK. Potential Mediators between Fibromyalgia and C-Reactive protein: Results from a Large U.S. Community Survey. BMC Musculoskelet Disord. 2017;18(1):294. Published 2017 Jul 7. doi:10.1186/s12891-017-1641-y
4. Doss J, Mo H, Carroll RJ, Crofford LJ, Denny JC. Phenome-Wide Association Study of Rheumatoid Arthritis Subgroups Identifies Association Between Seronegative Disease and Fibromyalgia. Arthritis Rheumatol. 2017;69(2):291-300.
5. Tanasescu R, Cottam WJ, Condon L, Tench CR, Auer DP. Functional reorganisation in chronic pain and neural correlates of pain sensitisation: A coordinate based meta-analysis of 266 cutaneous pain fMRI studies. Neurosci Biobehav Rev. 2016;68:120-133.
6. Abaei M, Sagar DR, Stockley EG, Spicer CH, Prior M, Chapman V, Auer DP. Mol Pain. 2016; 12. Epub 2016 Apr 11.
7. Friebel U, Eickhoff SB, Lotze M. Neuroimage. 2011 Oct 15; 58(4):1070-80. Epub 2011 Jul 20.
8. Edwards RR, Dworkin RH, Sullivan MD, Turk DC, Wasan AD. The Role of Psychosocial Processes in the Development and Maintenance of Chronic Pain. J Pain. 2016;17(9 Suppl):T70-92.
9. McIntosh AM, Hall LS, Zeng Y, et al. Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis. PLoS Med. 2016;13(8):e1002090. Published 2016 Aug 16. doi:10.1371/journal.pmed.1002090
10. Jaracz J, Gattner K, Jaracz K, Górna K. Unexplained Painful Physical Symptoms in Patients with Major Depressive Disorder: Prevalence, Pathophysiology and Management. CNS Drugs. 2016;30(4):293-304.
11. Sheng J, Liu S, Wang Y, Cui R, Zhang X. The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain. Neural Plast. 2017;2017:9724371.
12. Meints SM, Edwards RR. Evaluating psychosocial contributions to chronic pain outcomes. Prog Neuropsychopharmacol Biol Psychiatry. 2018;87(Pt B):168-182.
13. Afari N, Mostoufi S, Noonan C, et al. C-reactive protein and pain sensitivity: findings from female twins. Ann Behav Med. 2011;42(2):277-83.
14. Lund Haheim L, Nafstad P, Olsen I, Schwarze P, Ronningen KS. C-reactive protein variations for different chronic somatic disorders. Scand J Public Health. 2009;37:640–646.
15. Kushner I, Rzewnicki D, Samols D. What does minor elevation of C-reactive protein signify? Am J Med. 2006;119(166):e117–e128.
16. Petzke F, Clauw DJ, Ambrose K, Khine A, Gracely RH. Increased pain sensitivity in fibromyalgia: effects of stimulus type and mode of presentation. 2003;105:403–413.
17. White KP, Harth M, Speechley M, Ostbye T. Testing an instrument to screen for fibromyalgia syndrome in general population studies: The London Fibromyalgia Epidemiology Study Screening Questionnaire. J Rheumatol. 1999;26:880–884.
18. Jones KD, Gelbart T, Whisenant TC, et al. Genome-wide expression profiling in the peripheral blood of patients with fibromyalgia. Clin Exp Rheumatol. 2016;34(2 Suppl 96):S89-98.
19. Jobanputra C, Richey RH, Nair J, Moots RJ, Goebel A. Fibromyalgia in Behçet’s disease: a narrative review. Br J Pain. 2017;11(2):97-101.
20. Ernberg M, Christidis N, Ghafouri B, et al. Plasma Cytokine Levels in Fibromyalgia and Their Response to 15 Weeks of Progressive Resistance Exercise or Relaxation Therapy. Mediators Inflamm. 2018;2018:3985154. Published 2018 Apr 18.
21. Cordero MD, Alcocer-Gómez E, Culic O, et al. NLRP3 inflammasome is activated in fibromyalgia: the effect of coenzyme Q10. Antioxid Redox Signal. 2014;20(8):1169-80.
22. Caro XJ, Galbraith RG, Winter EF. Evidence of peripheral large nerve involvement in fibromyalgia: a retrospective review of EMG and nerve conduction findings in 55 FM subjects. Eur J Rheumatol. 2018;5(2):104-110.
23. 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.
24. Rodrigo L, Blanco I, Bobes J, de Serres FJ. Remarkable prevalence of coeliac disease in patients with irritable bowel syndrome plus fibromyalgia in comparison with those with isolated irritable bowel syndrome: a case-finding study. Arthritis Res Ther. 2013;15(6):R201.
25. Brooks L, Hadi J, Amber KT, Weiner M, La Riche CL, Ference T. Assessing the prevalence of autoimmune, endocrine, gynecologic, and psychiatric comorbidities in an ethnically diverse cohort of female fibromyalgia patients: does the time from hysterectomy provide a clue?. J Pain Res. 2015;8:561-9.
26. Bazzichi L, Giacomelli C, De Feo F, et al. Antipolymer antibody in Italian fibromyalgic patients. Arthritis Res Ther. 2007;9(5):R86.
27. 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 Jul;36(7):1617-1621.
28. 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 Sep; 34(9):1275-80. Epub 2014 Mar 4.
29. Yanmaz MN, Mert M, Korkmaz M. The prevalence of fibromyalgia syndrome in a group of patients with diabetes mellitus.Rheumatol Int. 2012 Apr; 32(4):871-4. Epub 2011 Jan 8.
30. Lichtenstein A, Tiosano S, Comaneshter D, Amital H, Cohen AD, Amital D. Cross-sectional analysis of the associations between fibromyalgia and diabetes mellitus. Reumatologia. 2018;56(5):275-278. doi: 10.5114/reum.2018.79496. Epub 2018 Oct 31.
31. Khudhair OS, Gorial FI, Hameed AF. Fibromyalgia Syndrome and Vitiligo: A Novel Association. Arch Rheumatol. 2017 Oct 16;33(2):174-180.
32. Bazzichi L, Rossi A, Zirafa C, Monzani F, Tognini S, Dardano A, Santini F, Tonacchera M, De Servi M, Giacomelli C, et al. Thyroid autoimmunity may represent a predisposition for the development of fibromyalgia? Rheumatol Int. 2012 Feb; 32(2):335-41. Epub 2010 Nov 18.
33. Agmon-Levin N(1), 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 Dec;60(2-3):376-83.
34. Nancy AL, Shoenfeld Y. Chronic fatigue syndrome with autoantibodies–the result of an augmented adjuvant effect of hepatitis-B vaccine and silicone implant. Autoimmun Rev. 2008 Oct; 8(1):52-5.
35. Gruber N, Shoenfeld Y. A link between human papilloma virus vaccination and primary ovarian insufficiency: current analysis. Curr Opin Obstet Gynecol. 2015 Aug; 27(4):265-70.