Open access

Introductory Chapter: A Challenge to the Concept that Inflammation Plays a Prominent Pathogenic Role in Fibromyalgia

Written By

William S. Wilke

Published: March 14th, 2018

DOI: 10.5772/intechopen.72936

Chapter metrics overview

1,280 Chapter Downloads

View Full Metrics

1. Introduction

Among the chapters in this monograph are those that examine the treatment of fibromyalgia syndrome (FMS) using nonpharmacologic natural products and other relatively novel agents [1, 2, 3]. Although the modes of therapy described are diverse, a role for disordered immune mechanisms is implicit in each of the three chapters. These include reference to sulfur springs considered to inhibit interleukin-2 and interferon-gamma [1], introductory explanations of FMS pathogenesis that invokes inflammatory dysfunction [2], and mention of inflammatory cytokine production associated with autonomic nervous system dysfunction-stimulated microglial and astrocyte cell activation [3]. The discussion in the fourth chapter about the impact of FMS on the evaluation of inflammatory diseases assumes the opposite that clinically significant inflammation is not a feature of FMS [4].


2. Case (should have been previously) closed

Face validity favoring a major pathogenic role for cytokine-mediated inflammation in FMS has been addressed in the past. Although initial reports of intermuscular fibrous tissue inflammation by Stockman led Gowers to name the condition “fibrositis,” [5, 6], contemporary light and magnetic resonance imaging histological reports showed no evidence for peripheral muscle inflammation [7, 8]. These data should have closed the book on inflammation as a prominent etiopathogenic mechanism in FMS. Then along came inflammatory mediators.

In some contemporary reviews of FMS pathogenesis, inflammation is referenced in passing, as it is in these three chapters [9]. Whether this is done for “completeness,” after all, FMS is often misclassified as a “connective tissue disease” (a misnomer), most of which are inflammatory in nature, or that such reference adds a sort of “scientific patina” to the discussion is unclear.

This review examines the validity of the concept that cytokine- and chemokine-driven inflammation is relevant to the pathogenesis of FMS.


3. Background

At least three observations have been used to provide circumstantial or hypothesis-generating evidence to advance a role for inflammatory pathogenesis:

  1. The symptoms and signs of “sickness behavior” observed in FMS can be experimentally induced by inflammatory cytokines [10].

  2. Similar alteration of the hypothalamic–pituitary axis and autonomic nervous system observed in FMS has been etiopathogenically linked to elevated inflammatory cytokines, including interleukin-1 (IL-1), in a variety of clinical settings other than FMS [11, 12, 13, 14].

  3. Symptoms of disordered sleep, hyperalgesia, and cognitive dysfunction much like FMS were observed when patients with renal cell carcinoma were treated with interleukin-2 lymphokine-activated killer (IL-2 LAK) cell therapy and when chronic hepatitis patients were treated with interferon alpha [15].


4. Experimental evidence for cytokine/chemokine pathogenesis

  1. Previous inconsistent reports have demonstrated that C-reactive protein (CRP) can be marginally higher in FMS subjects than in parallel healthy controls [16]. In this analysis, however, serum inflammatory cytokines were not higher than in healthy controls.

  2. Inconsistent elevation of a variety of serum cytokines has, however, been observed in some studies [16, 17, 18, 19, 20, 21, 22, 23, 24]. In a meta-analysis of 25 FMS studies, 1255 FMS, and 800 healthy controls (HC), interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), and interleukin-8 (IL-8) were the most likely inflammatory cytokines to be elevated [25].

Three integrated reviews, although acknowledging discrepancies in the literature, attempted to associate cytokine abnormalities with core FMS symptoms [26, 27, 28]. The first concluded, “There are discrepant findings related to whether pro-inflammatory and anti-inflammatory cytokines are elevated or reduced in persons with FMS and whether they correlate with core symptoms.” [26]. The second [27] critiqued one of the more persuasive analysis, “….. may have cytokine driven abnormalities to explain their pain…IL-1ra and IL-6 were significantly higher after stimulating PBMC of FMS patients compared to controls [29].” The results of this study were not corroborated in a second study [24].

The third review of 12 separate analyses reported increased inflammatory cytokines IL-1ra, IL-6, and IL-8, and anti-inflammatory interleukin-10 (IL-10) or low anti-inflammatory interleukin-4 (IL-4) and IL-10 [24]. Among the inflammatory chemokines also linked to signs and symptoms, monocyte chemoattractant protein-1 (MCP-1), eotaxin among others, were elevated.

Two potentially innovative separate controlled analyses described cytokine and chemokine concentrations in the supernatant after mitogen stimulation of cultured monocytes, using a logistical regression model to achieve statistically determined weighting for each chemokine and cytokine, and offered this score as diagnostic test for FMS [30, 31]. Of interest, the inflammatory cytokines and chemokines including IL-6 were lower in concentration compared to healthy controls or individuals with autoimmune disease. These findings suggest increased damping control of inflammation in FMS. The authors of both these studies, however, failed to determine the prevalence of depression or analyze its potential effects on cytokine concentrations.

Among the most novel analyses was a report of elevation of intrathecal IL-8 derived from glia cells supporting the hypothesis that FMS symptoms might be mediated by glial cell activation through sympathetic nervous system mechanisms [32].

In summary, in individuals with FMS, peripheral blood IL-6, IL-1ra, and IL-8 concentrations may be a bit higher and IL-4 and IL-10 lower, and IL-8 may be relatively higher in the cerebral spinal fluid than in healthy controls. Inflammatory chemokines may also be higher than in healthy control patients.


5. Depression and inflammation

Depression and FMS are very often comorbid and show a bidirectional association [19, 33, 34, 35, 36, 37, 38]. The prevalence of depression in FMS has been estimated to range from 20 to 80% in a detailed review [39]. Furthermore, the severity of comorbid depression correlates with FMS severity measures [40, 41, 42]. We have reported that depression, with a 73% prevalence, correlated better with core FMS symptoms than did any other variable in a cohort of 305 FMS patients [43].

As in FMS, similar mild elevation of CRP and inflammatory cytokines and chemokines have been demonstrated in depressed individuals in controlled analyses [44, 45, 46, 47, 48, 49, 50, 51, 52, 53]. Many primary analyses of FMS inflammation [15, 30, 31, 54, 55, 56] and reviews [23, 28], however, failed to control for depression. This is an unfortunate omission.

Maes and colleagues evaluated the serum concentrations of inflammatory cytokines in relationship to depression among 21 FMS patients compared to 33 healthy controls [57].

Serum soluble gp130, an important inflammatory cytokine signal transducer, and a soluble interleukin-6 receptor, Il-1 ra, were significantly higher in FMS patients with a Hamilton Depression Rating Scale score >16 than in FMS patients with scores of 16 or lower or in healthy controls. In the opinion of the Menzies’ integrated review, which included the Maes analysis, higher inflammatory cytokines in FMS, including IL6, were related to the degree of depression, although inconsistencies were common [26].

Of interest, higher body mass index partially explained cytokine differences as has been shown in depression [18, 52]. Therefore, inflammation in FMS, measured as higher serum concentrations of cytokines and chemokines, is multifactorial and not necessarily due solely to FMS pathophysiology.

Serum inflammatory cytokine concentrations correlate with the degree of depression and fall with effective treatment of depression [58]. Not surprisingly, inflammatory cytokine concentrations have also been shown to correlate with pain symptoms in primary depression alone [59].

This phenomenon even occurs when the treatment is nonpharmacological, suggesting an intrinsic etiopathophysiologic relationship of inflammatory cytokines with depression [46]. This analysis also demonstrated that despite a significant fall of cytokine concentration from baseline, the CRP was not significantly lower.

In summary, these two analyses demonstrate a pain symptom signature integral to depression and that cytokines, while slightly higher in depression than in healthy controls, are in fact trivial with respect to overall inflammation measured as CRP.


6. Different process mechanisms: RA versus FMS/depression

6.1. RA

In rheumatoid arthritis (RA) comorbid FMS is associated with disproportionately higher values for the subjective components, patient global assessment (PtGA), and tender joint count (TJC), which in turn inflate the disease activity score (DAS). This phenomenon is largely mediated by higher patient assessed pain, fatigue, and especially poor mood, and variables that define the criterion, distress, and the etiopathogenesis of FMS [60, 61, 62, 63, 64]. As a potential explanation, depression alone can disproportionately increase pain sensitivity, the tender joint count (TJC), and a patient’s sense of wellbeing, such as PtGA in RA [19, 65]. Higher subjective signs and symptoms then inflate the DAS. It is important to note that concomitant FMS and depression in RA are not associated with obvious, clinically significant increases of CRP or erythrocyte sedimentation rate [42, 62, 65].

Differential response to the treatment of the so-called subjective versus objective variables is a hallmark of comorbid FMS and/or depression in RA. In a prospective analysis of 668 RA patients, 18% with comorbid FMS had higher DAS and Health Assessment Disability Index at baseline compared to patients without FMS [66]. The TJC and PtGA were significantly higher, but the objective factors, ESR, and swollen joint count (SJC) were significantly lower in patients with FMS compared to patients with RA alone. Achievement of low disease activity and remission were significantly less likely in the comorbid FMS cohort. Others have confirmed these observations [67].

A very instructive, early, placebo-controlled trial showed that the pain of FMS did not respond to the treatment with prednisone 15 mg/day [68]. So too, unlike dose-related reduction of objective signs in RA such as the swollen joint count (SJC) and CRP, FMS-related inflated subjective signs and symptoms are resistant to aggressive anti-immune, anti-inflammatory RA treatment [69, 70, 71]. In fact, a treatment response resulting in remission in RA comorbid with FMS should not be expected because the higher, poorly responsive PtGA and TJC are not due to RA biological disease activity, but in fact to poorly responsive noninflammatory FMS central pain mechanisms [69].


7. Differential magnitude of inflammatory response

Mean CRP values, although reported elevated in some FMS populations compared to control populations, are still within the range of normal CRP [72]. Given this observation, it is both instructive and necessary to consider whether cytokines follow this same pattern.

7.1. Rewrite cytokine section

In RA, serum concentrations of IL-6 measured by enzyme immunoassay (ELISA) [73] in >900 patients demonstrated mean ~ 43 pg/ml, for all, and ~54–84 pg/ml for those with active disease [55]. In another population of 66 RA patients, using a similar assay, IL-6 levels declined to 22.5 pg/ml in low disease activity [74].

Contrast these serum levels with serum levels in depression and FMS. Using a different more sensitive ELISA assay, Grosse reported mean IL-6 serum concentration of 1.17 ± 2.59 for 214 patients with major depression disorder (MDD) and 0.66 ± 1.94 for healthy controls (HC) [50]. In another analysis of 64 MDD patients and 80 healthy controls, IL-6 levels were reported statistically higher in depression than in controls, 1.39 ± 0.35 versus 0.45 ± 0.28 pg/ml using yet another ELISA [47].

These same comparatively low serum levels were reported in FMS, with IL-6 in the range of 16 pg/ml in FMS and 1 pg/ml in healthy controls using yet another ELISA assay [75]. Although higher than HCs, the levels are very low when compared to those in RA.

This discussion apparently shows that inflammatory cytokines, even when relatively elevated in FMS, are much lower than in mildly active RA. If this is true, then the elevations in FMS may not be sufficiently high to initiate clinical signs or symptoms. Unfortunately, as can be seen, diverse assays that produce diverse serum and cellular concentrations and the lack of control for diurnal variation make precise comparisons between diseases difficult.

Fortunately, two papers do allow comparison. The authors of both studies used very similar ELISA methods. In 16 RA patients with varying disease activity, overnight IL-6 values ranged from a mean of ~40 pg/ml at 11 PM to a peak of ~60 at 8 AM with large individual variations [76].

In FMS, although the mean values for IL-6 were statistically significantly higher in FMS patients than in healthy controls at night (2.94 versus 2.14 pg/ml), these serum concentrations were at least 10 times lower in FMS than in RA [56]. Are these meager elevations of IL-6, ~0.80 pg/ml in FMS compared to HCs, sufficiently high enough to explain clinical differences?

Let us postulate that mildly elevated cytokines in the CNS such as IL-6 and IL-8 [32] produced by microglial and/or astrocyte cells are sufficient to interfere with processing and produce centrally mediated pain. We are still left with the lack of clinical response to moderate daily prednisone and even more aggressive antirheumatic, anti-inflammatory treatments which have been shown to reduce inflammation due to cytokines [67, 68, 71, 77].

There is little question that FMS does associate with mild cytokine change, such as reduced diurnal variation of IL-6 compared to healthy individuals [56]. Forensic objectivity, however, would seem to indicate that the described modest changes in inflammatory mediators, whether primary or secondary, do not seem sufficient to be responsible for clinically relevant FMS symptoms. Furthermore, in some very legitimate contemporary hypotheses of FMS etiopathogenesis, there is no role for chronic cytokine-mediated processes [78, 79].


8. Conclusions

The key points from this discussion are:

  1. Although a minority of studies found CRP elevated in FMS compared to healthy controls, the mean high value was still within the normal range.

  2. Depression, which is very often comorbid with FMS, was not well controlled in many cytokine/chemokine analyses. When it was, it was shown to significantly contribute to higher cytokine values.

  3. Fibromyalgia symptoms, whether as the primary diagnosis or as comorbid in RA, do not respond to anti-inflammatory, anti-immune therapy.

  4. Both stimulated and unstimulated cytokine and chemokine studies have employed a variety of methods of measurements that make cytokine levels difficult to analyze between diseases. A few comparisons have shown relatively trivial values in FMS compared to proven inflammatory disease such as RA.


  1. 1. Kocak FA, Kurt EE. Nonpharmacologic Treatment of Fibromyalgia. InTech
  2. 2. Brito RG, Santos PL, Olivera MA, et al. Natural Products as Promising Pharmacological Tools for the Management of Fibromyalgia Symptoms: A Review. InTech
  3. 3. Miranda-Diaz AG, Odriguez-Lara SQ. The Role of Oxidants/Antioxidants, Mitochondrial Dysfunction, Autophagy in Fibromyalgia. InTech
  4. 4. Wilke WS. Recognize Comorbid Fibromyalgia Syndrome in Order to Better Evaluate Rheumatic Diseases. InTech
  5. 5. Stockman R. The causes, pathology and treatment of chronic rheumatism. Edinburgh Medical School. 1904;15:107-116
  6. 6. Gowers WR. Lumbago. Its lessons and analogues. British Medical Journal. 1904;114:117-121
  7. 7. Fassbender HG, Wegner K. Morphologic and pathogenese des Weichteil rheumatismmus. Zeitschrift Fur Rheumaforsh. 1973;32:355-374
  8. 8. Yunus MB, Kalyan-Raman UP, Masi AT, Aldag JC. Electron microscopic studies of muscle biopsy in primary fibromyalgia syndrome: A controlled and blinded study. The Journal of Rheumatology. 1989;16:97-101
  9. 9. Arranz L-I, Canela M-A, Rafecas M. Fibromyalgia and nutrition, what do we know? Rheumatology International. 2010;30:1417-1427
  10. 10. Dantzer R. Cytokine-induced sickness behavior a neuroimmune response to activation of innate immunity. European Journal of Pharmacology. 2004;500:399-411
  11. 11. Dunne AJ. Cytokine activation of the HPA axis. Annals of the New York Academy of Sciences. 2000;917:608-617
  12. 12. Wingenfeld K, Heim C, Schmidt I, et al. HPA axis reactivity and lymphocyte glucocorticoids sensitivity in fibromyalgia and pelvic pain. Psychosomatic Medicine. 2008;242:33-38
  13. 13. Gur A, Oktayoglu P. Status of immune mediators in fibromyalgia. Current Pain Headache Reports. 2008;12:175-181
  14. 14. Pillemer SR. The neuroscience and endocrinology of fibromyalgia. Arthritis & Rheumatism. 1997;40:1928-1939
  15. 15. Wallace DJ, Margolin K, Waller P. Fibromyalgia and interleukin-2 therapy for malignancy. Annals of Internal Medicine. 1988;106:906
  16. 16. Bazzichi L, Rossi A, Massimetti G, et al. Cytokine patterns in fibromyalgia and their correlation with clinical manifestation. Clinical and Experimental Rheumatology. 2007;25:225-230
  17. 17. Hader N, Rimon D, Kinarty A, Lahat N. Altered interleukin-2 secretion in patients with primary fibromyalgia syndrome. Arthritis & Rheumatism. 1991;34:866-872
  18. 18. Xiao Y, Haynes WL, Michalek JE, Russell IJ, et al. Elevated serum high-sensitivity C-reactive protein levels in fibromyalgia syndrome patients correlated with body mass index, interleukin-6, interleukin-8, erythrocyte sedimentation rate. Rheumatology International. May 2012;33(5):1259-1264. DOI: 10.1007/s00296-012-2538-6
  19. 19. Toussaint LL, Vincent A, McSllister SJ, et al. Original experimental: A comparison of fibromyalgia symptoms in patients with Healthy versus depressive, low and reactive affect balance styles. Scandinavian Journal of Pain. 2014;5:161-166
  20. 20. Tsiloni I, Russell IJ, Stewart JM, et al. Neuropeptides CRH, SP, HK-1, and inflammatory cytokines IL-6 and TNF are increased in serum of patients with fibromyalgia syndrome, implicating mast cells. Journal of Pharmacology and Experimental Therapeutics. 2016;356:664-672
  21. 21. Gur A, Erdogan S, Nas K, et al. Regional cerebral blood flow and cytokines in young females with fibromyalgia. Clinical and Experimental Rheumatology. 2002;20:753-760
  22. 22. Ortega E, Bote ME, Giraldo E, García JJ. Aquatic exercise improves the monocytes pro-and anti-inflammatorycytokine production balance in fibromyalgia patients. Scandivanian Journal of Medical Science and Sports. 2012;22:104-112
  23. 23. Üçeyler N, Valenza R, Stock M, Schedel R, Sprotte G, Sommer C. Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis & Rheumatism. 2006;54:2656-2664 [PubMed: 16871547]
  24. 24. Kashipaz MRA, Swindon D, Todd I, et al. Normal production of inflammatory cytokines in chronic fatigue and fibromyalgia syndromes determined by intracellular cytokine staining in short-term cultured blood mononuclear cells. Clinical and Experimental Immunology. 2003;132:360-365
  25. 25. Uceyler N, Hauser W, Sommer C. Systemic review with meta-analysis: Cytokines in fibromyalgia syndrome. BMC Musculoskeletal Disorders. 2011;12:245-260
  26. 26. Menzies V, Lyon DE. Integrated review of the association of cytokines with fibromyalgia and fibromyalgia core symptoms. Biological Research for Nursing. 2010;11:387-394
  27. 27. Staud R. Cytokine and immune system abnormalities in fibromyalgia and other central sensitivity syndromes. Current Rheumatology Review. 2015;11:109-115
  28. 28. Rodriguez-Pinto I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia and cytokines. Immunology Letters. 2014;161:200-203
  29. 29. Wallace DJ, Linker-Israeli M, Hallegua D, et al. Cytokines play an aetiopathogenetic role in fibromyalgia: A hypothesis and pilot study. Rheumatology. 2001;40:743-749
  30. 30. Behm FG, Gavin IW, Karpenko O, et al. Unique immunologic patterns in fibromyalgia. BMC Clinical Pathology. 2012;12:25-32
  31. 31. Wallace DJ, Gavin IG, Karpenko O, et al. Cytokine and chemokine profiles in fibromyalgia, rheumatoid arthritis and systemic lupus erythematosus: A potentially useful tool in differential diagnosis. Rheumatology International. 2015;35:991-996
  32. 32. Kadetoff D, Lampa J, Westman M, et al. Evidence of central inflammation in fibromyalgia—Increased cerebrospinal fluid interleukin-8 levels. Neuroimmunology. 2012;242:33-38
  33. 33. Krag NJ, Norregaard J, Larsen JK, Danneskiold-Samsoe B. A blinded controlled evaluation of anxiety and depressive symptoms in patients with fibromyalgia, as measured by standardized psychometric interview scales. Acta Psychiatrica Scandinavica. 1994;89:370-375
  34. 34. Hudson JI, Hudson MS, Pliner LF, Goldenberg DL, Pope, HG Jr. Fibromyalgia and major affective disorder: A controlled phenomenology and family history study. American Journal of Psychiatry. 1985;142:441-446
  35. 35. Hudson JI, Pope HG. Fibromyalgia and psychopathology: Is fibromyalgia a form of affective spectrum disorder? Journal of Rheumatology (suppl.). 1989;19:15-22
  36. 36. Hudson JI, Goldenberg DL, Pope HG, Keck PE, Schlesinger L. Comorbidity of fibromyalgia with medical and psychiatric disorders. American Journal of Medicine. 1992;92:363-367
  37. 37. Gruber AJ, Hudson JI, Pope HG. The management of treatment-resistant depression in disorders on the interface of psychiatry and medicine. Fibromyalgia, chronic fatigue syndrome, migraine, irritable bowel syndrome, a typical facial pain, and premenstrual dysphoric disorder. Psychiatry Clinics of North America. 1996;19:351-369
  38. 38. Chang M-H, Hsu J-W, Huang K-I, et al. Bidirectional association between depression and fibromyalgia syndrome: A nationwide longitudinal study. Journal of Pain. Sep 2015;16(9):895-902. DOI: 10.1016/j.jpain.2015.06.004
  39. 39. Fieta P, Manganelli P. Fibromyalgia and psychiatric disorders. Acta Biomedica. 2007;78:88-95
  40. 40. Hawley DJ, Wolfe F. Depression is not more common in rheumatoid arthritis: A 10-year longitudinal study of 6153 patients with rheumatic disease. Journal of Rheumatology. 1993;20:2025-2031
  41. 41. Arnold LM, Hudson JI, Keck PE, et al. Comorbidity of fibromyalgia and psychiatric disorders. Journal of Clinical Psychiatry. 2006;67:1219-1225
  42. 42. Brown D, Mulvey M, Cordingley L, et al. The relationship between psychological distress and multiple tender points across the adult lifespan. Archives of Gerontology and Geriatrics. 2016;63:102-107
  43. 43. Gota CE, Kauok S, Wilke WS. The impact of depressive and bipolar symptoms on socioeconomic status, core symptoms, function and severity of fibromyalgia. International Journal of Rheumatic Diseases. 2015;20(3):326-339
  44. 44. Wium-Andersen MK, Orsted MD, Nielsen SF, Nordestgaard BG. Elevated C-reactive protein levels, psychological distress, and depression in 73131 individuals. JAMA Psychiatry. 2013;70:176-184
  45. 45. Berk M, Wadee AA, Kruschke RH, O’neil-Kerr A. Acute phase proteins in major depression. Journal of Psychosomatic Research. 1997;43:529-534
  46. 46. Dahl J, Ormstad H, HCD A, et al. The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. Psychoneuroendocrinology. 2014;45:77-86
  47. 47. Fan N, Luo Y, Ou Y, He H. Altered serum levels of TNF-alpha, IL-6, and IL-18 in depressive disorder patients. Human Psychopharmacology Clinical and Experiment. 2017;32:e2588.
  48. 48. Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder and depression. Molecular Psychiatry. 2016;21(12):1696-1709
  49. 49. Davami MH, Baharlou R, Vasmehjani AA, et al. Elevated IL-17 and TGF-β serum levels: A positive correlation between T-helper 17 cell-related pro-inflammatory responses with major depressive disorder. Basic and Clinical Neuroscience. 2015;7(2):137-142
  50. 50. Grosse L, Ambree O, Jorgens S, et al. Cytokine levels in major depression are related to childhood trauma but not to recent stressors. Psychoneuroendocrinology. 2016;73:24-31
  51. 51. Eyre HA, Air T, Pradham A, et al. A meta-analysis of chemokines in major depression. Progress in Neuro-psychopharmacology & Biological Psychiatrtry. 2016;68:1-8. DOI: 10.1016/j.pnpbp.2016.02006
  52. 52. Howren B, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: A meta analysis. Psychosomatic Medicine. 2009;71:171-186
  53. 53. Dowlati Y, Hermann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biological Psychiatry. 2010;67:446-457
  54. 54. Zhang Z, Cherryholmes G, Mao A, et al. High plasma levels of MCP-1 and eotaxin provide evidence for an immunological basis of fibromyalgia. Experimental Biology and Medicine (Maywood). 2008;233:1171-1180
  55. 55. Wang J, Platt A, Upmanyu R, et al. IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis. BMJ Open. 2013;3:e003199. DOI: 10.1136/bmjopen-2013-003199
  56. 56. Fatima G, Mahdi AA, Das SK, et al. Lack of circadian pattern of serum TNF-a and IL-6 in patients with fibromyalgia syndrome. Indian Journal of Clinical Biochemistry. 2012;27:(4)340-343 (October–December 2012)
  57. 57. Maes M, Libbrect I, Van Hunsel F, et al. The immune-inflammatory pathophysiology of fibromyalgia: Increased serum soluble gp130, the common signal transducer protein of various neurotrophic cytokines. Psychoneuroendocrinology. 1999;24:371-383
  58. 58. Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: A meta-analysis. Neuropsychopharmacology. 2011;36:2452-2459
  59. 59. Bai Y-A, Chou W-F, Su T-P, et al. Pro-inflammatory cytokine associated with somatic and pain symptoms in depression. Journal of Affective Disorders. 2014;155:28-34
  60. 60. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Research. 2010;62:600-610
  61. 61. Fifield J, Tennen H, Reisine S, McQuillan J. Depression and the long-term risk of pain, fatigue, and disability in patients with rheumatoid arthritis. Arthritis & Rheumatism. 1998;41:1851-1857
  62. 62. Kapoor SR, Hider SJ, Brownfield A, et al. Fibromyalgia in patients with rheumatoid arthritis. Clinical and Experimental Rheumatology. 2011;29(Suppl. 69):S88-S91
  63. 63. Wolfe F, Michaud K, Busch RE, et al. Polysymptomatic distress in patients with rheumatoid arthritis: Understanding disproportionate response and its spectrum. Arthritis Care Research (Hoboken). 2014;66(10):1465-1471
  64. 64. Lee YC, Bingham CO III, Edwards RR, et al. Pain sensitization is associated with disease activity in rheumatoid arthritis patients: A cross-sectional study. Arthritis Care and Research. 2017; Accepted Article. DOI: 10.1002/acr.23266
  65. 65. Matcham F, Ali S, Irving K, et al. Are depression and anxiety associated with disease activity in rheumatoid arthritis? A prospective study. BMC Musculoskeletal Disorder. 2016;17:155
  66. 66. Kim H, Cui J, Frits M, et al. Fibromyalgia predicts two-year changes in functional status in rheumatoid arthritis patients. Arthritis Care Research. Dec 2017;69(12):1871-1877. Accepted Article’. DOI: 10.1002/acr.23216
  67. 67. Duran J, Combe B, Niu J, et al. The effect on treatment response of fibromyalgic symptoms in early rheumatoid arthritis patients: Results from the ESPOIR cohort. Rheumatology. 2015;54:2166-2170
  68. 68. Clark S, Tindall E, Bennett RM. A double blind crossover trial of prednisone versus placebo in the treatment of fibrositis. Journal of Rheumatology. 1985;12:980-983
  69. 69. Lee YC, Cui J, Lu B, et al. Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: A longitudinal observational study. Arthritis Research & Therapy. 2011;R13:R83
  70. 70. Lage-Hansen PR, Chrysidis S, Lage-Hansen M, et al. Concomorbid fibromyalgia in rheumatoid arthritis is associated with the more frequent use of biological therapy: Across-sectional study. Scandinavian Journal of Rheumatology. Jan 2016;45(1):45-48
  71. 71. Altawil R, Saevarsdottir S, Wedren S, et al. Remaining pain in early rheumatoid arthritis patients treated with methotrexate. Arthritis Care Research. 2016;68:1061-1068
  72. 72. 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 Musculoskeletal Disorders. 2017;18:294. DOI: 10.1186/s12891-017-1641-y
  73. 73. Fraunberger P, Pfeiffer M, Cremer P. et al, Validation of an automated enzyme immunoassay for iInterleukin-6 for routine clinical use. Clinical Chemical and Laboratory Medicine. 1998;36:797-801
  74. 74. Robak T, Gladalska A, Stepien H, et al. Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. Mediators Inflammation. 1998;7:347-353
  75. 75. Hernandez ME, Becerril E, Perez M, et al. Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index. BMC Research Notes. 2010;3:156
  76. 76. Perry MG, Kirwan JR, Jessop DS, Hunt LP. Overnight variations in cortisol, interleukin 6, tumour necrosis factor alpha and other cytokines in people with rheumatoid arthritis. Annals of the Rheumatic Diseases. 2009;68:63-68
  77. 77. Vermeer M, Kuper HH, van der Bijl AE, et al. The provision al ACR/EULAR definition of remission in RA: A comment on the patient global assessment criterion. Rheumatology. 2012;51:1076-1080
  78. 78. Gracely RH, Schweinhardt P. Key mechanisms mediating fibromyalgia. Clinical and Experimental Rheumatology. 2015;33(Suppl. 88):S3-S6
  79. 79. Cagnie B, Coppieters I, Denecker S, et al. Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI. Seminars Arthritis Rheumatism. 2014;44:68-75

Written By

William S. Wilke

Published: March 14th, 2018