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Rheumatology 2001; 40: 743-749
© 2001 British Society for Rheumatology

Original Papers

Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study

D. J. Wallace, M. Linker-Israeli, D. Hallegua, S. Silverman, D. Silver and M. H. Weisman

Department of Medicine/Division of Rheumatology, Cedars–Sinai Medical Center/UCLA School of Medicine, Los Angeles, CA, USA


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To measure soluble factors having a possible role in fibromyalgia (FM) and compare the profiles of patients with recent onset of the syndrome with patients with chronic FM.

Methods. The production of cytokines, cytokine-related molecules, and a CXC chemokine, interleukin (IL)-8, was examined. Fifty-six patients with FM (23 with <2 yr and 33 with >2 yr of symptoms) were compared with age- and sex-matched healthy controls. Cytokines and cytokine-related molecules were measured in sera and in supernatants of peripheral blood mononuclear cells (PBMC) that were incubated with and without lectins and phorbol myristate acetate (PMA).

Results. No differences between FMS and controls were found by measuring IL-1ß, IL-2, IL-10, serum IL-2 receptor (sIL-2R), interferon {gamma} (IFN-{gamma}), and tumour necrosis factor {alpha} (TNF-{alpha}). Levels of IL-1R antibody (IL-1Ra) and IL-8 were significantly higher in sera, and IL-1Ra and IL-6 were significantly higher in stimulated and unstimulated FM PBMC compared with controls. Serum IL-6 levels were comparable to those in controls, but were elevated in supernatants of in vitro-activated PBMC derived from patients with >2 yr of symptoms. In the presence of PMA, there were additional increases in IL-1Ra, IL-8 and IL-6 over control values.

Conclusions. In patients with FM we found increases over time in serum levels and/or PBMC-stimulated activity of soluble factors whose release is stimulated by substance P. Because IL-8 promotes sympathetic pain and IL-6 induces hyperalgesia, fatigue and depression, it is hypothesized that they may play a role in modulating FM symptoms.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Fibromyalgia (FM) is felt to be a syndrome characterized by abnormal central sensory processing of pain signals and is thought to arise from a combination of interactions between neurotransmitters, external stressors, behavioural constructs, hormones and the sympathetic nervous system. Although cytokines are suspected to play a role in FM, their precise dynamics has escaped elucidation [1–4]. Recent evidence linking sleep disorders, hyperalgesia, cognitive dysfunctions, fatigue, stress and anxiety to cytokines led us to re-examine their expression in FM. We performed these analyses in context, by stratifying the patients according to onset of symptoms [5]. This line of inquiry was further bolstered by suggestions that these factors and cytokines interact with chemokines, the autonomic nervous system and immunoregulatory molecules.

Fibromyalgia may have different pathophysiological features in its acute and chronic forms. A variety of epidemiological surveys showed that when FM was correctly identified within its first 2 yr of presentation (‘early’) and was managed appropriately, 24 months later over 50% of patients no longer met the ACR criteria for the syndrome [6, 7]. Suboptimally managed regional pain can also lead to fibromyalgia [8]. In contrast, in chronic, stable FM patients managed at tertiary centres, over 95% still met the American College of Rheumatology (ACR) criteria at 2 yr, with no detectable improvement [9, 10]. In this study, we asked whether early FM could be different from chronic FM and therefore associated with a different cytokine profile. We examined both constitutive (serum levels, spontaneous in vitro production) and induced (lectin-stimulated) cytokine expression.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients with FM seen in the office practices of DJW, DH, SS and DS and who fulfilled the ACR criteria for FM [11] signed informed consent approved by the Cedars–Sinai Institutional Review Board and agreed to participate in the present study. The patients filled out a questionnaire (results are tabulated in Table 1Go) and were assigned to one of three groups: onset of FM symptoms within 2 yr, onset more than 2 yr previously, patients with systemic lupus erythematosus or rheumatoid arthritis who also had FM symptoms. As very few patients had verifiable FM of less than 2 yr duration, the Fibromyalgia Network sent a mailing to its members residing in Los Angeles County, which enhanced participation. Thirty-nine healthy, unrelated, controls matched for age, sex and ethnic background were studied from a family practice seen at the same facility on the same morning.


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  		TABLE 1. Clinical characteristics of patients with fibromyalgia (n=56) and controls (n=36)

 
Venous blood was drawn between 9 and 11.30 a.m. into plain or heparin-containing vacutainers (BDIS, San Jose, CA, USA) for separation of serum, plasma and peripheral blood mononuclear cells (PBMC). Interleukin (IL)-1ß, IL-2, IL-6, IL-8, IL-10, serum IL-2 receptor (sIL-2R), IL-1 receptor antibody (IL-1Ra), interferon {gamma} (IFN-{gamma}), and tumour necrosis factor {alpha} (TNF-{alpha}) were measured by ELISA in sera diluted between 1:5 and 1:20. We used capture and detection (horseradish peroxidase-conjugated) antibody pairs as well as standards purchased from BioSource International (Camarillo, CA, USA). Serum and plasma levels were calculated in relation to the standard curve, and results were expressed as ratios of individual patients' levels (without autoimmune disease) to the mean level of the control group. PBMCs were isolated on Ficoll density gradients (Histopaque, Sigma, St Louis, MO). After extensive washing, PBMC (2x106/ml) were incubated at 37°C, under 5% carbon dioxide with medium only, phytohaemagglutinin (PHA) (1:100), and lipopolysaccharide (LPS) (10 µg/ml) with and without phorbol myristate acetate (PMA) (<1 ng/ml). Supernatants were harvested after 72 h, centrifuged, filtered to remove cells and cell debris, and stored at -70°C until used. The cytokine content of the supernatants, diluted between 1:2 and 1:5, was measured by ELISA, as detailed previously [12]. Results were expressed as the ratios of individual cytokine levels of patient-derived sera/supernatants to the mean of control-derived sera/supernatants. P values for determining statistical significance were calculated using an unpaired two-tailed Student's t-test (Excel, Microsoft Office). Values less than 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Fibromyalgia patients (n=56) and controls matched for age, sex and ethnic background (n=36) were studied. The mean age of the patients was 50.4 yr, and 92.9% were female. The patients were all Caucasian (including three Latinos and three Iranians), and their clinical profile as judged by patient interview and chart abstraction by DJW, is shown in Table 1Go. The findings appear to be typical for a community-based rheumatology practice. One control patient was male and all were Caucasian. The two study groups are shown in Table 2Go. Twenty-three patients were confirmed to have had less than 2 yr of symptoms; in 69% of them, the onset of symptoms could be related to trauma or infection. Ten patients had had >2 yr of FM symptoms concurrent with rheumatoid arthritis or systemic lupus erythematosus and were excluded from the FM groups for further comparisons. The remainder (n=23) had had >2 yr of FM symptoms, and 39% could relate the onset of their syndrome to trauma or infection. Analysis of possible correlations between clinical findings listed in Table 1Go and symptom duration revealed the only significant difference (P=0.05) to be that the recent onset group had less post-exercise fatigue.


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  		TABLE 2. Self-reported FM-inducing trigger

 
Serum and plasma findings
Nine cytokines and associated molecules were studied. No statistically significant differences between control and patient groups were found for IL-1ß, IFN-{gamma}, sIL-2r, IL-10, TNF-{alpha} and IL-2 (negative results not shown). In contrast, FM patients had an average increase of 55% in serum levels of IL-1Ra compared with healthy controls (Fig. 1Go). Elevated IL-1Ra titres were seen in the sera of most patients, regardless of syndrome duration (P=0.002 for <2 yr and P=0.001 for >2 yr). Plasma IL-8 levels were three times higher than those of controls (P=0.01). However, this difference was due mainly to the high IL-8 levels observed in the plasma of FM patients having at least 2 yr of symptoms (P=0.01) (Fig. 1Go). IL-6 levels in FM sera were similar to those in control sera.



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  		FIG. 1. IL-1Ra and IL-8 plasma levels are increased in FM patients. Plasma concentrations of IL-1Ra, IL-8 and IL-6 were measured by ELISA. comb, combined; fms/aid, fibromyalgia with autoimmune disease (pg/ml+S.E.M.) (stacked columns).

 
To evaluate whether the pattern of serum findings could be related to the spontaneous in vitro production of FM PBMC, the latter were incubated for 72 h without deliberate stimulation. The production of both IL-1Ra and IL-6 by PBMC was higher in FM patients compared with control PBMC, but attained statistical significance only in patients having >2 yr of symptoms (P=0.01) (Fig. 2Go). In newly diagnosed patients, the values appeared to be increased but did not attain statistical significance. In contrast to the high IL-8 plasma levels, spontaneous IL-8 production in vitro was low and similar to that in controls.



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  		FIG. 2. The spontaneous in vitro production of IL-1Ra and IL-6 by FM PBMC is increased. PBMC of FM and controls were incubated with no deliberate stimulation for 72 h, when supernatants were harvested and measured by ELISA. Results are expressed as pg/ml+S.E.M. (stacked columns).

 
We compared the production of cytokines and IL-1Ra by PBMC from FM patients in response to in vitro stimulation with PHA or LPS, with or without PMA, with that of controls (Fig. 3Go). LPS-stimulated FM PBMC produced IL-6 and IL-1Ra in similar amounts to controls; however, in the presence of PMA, lectin-stimulated FM PBMC behaved differently from controls. IL-Ra levels in LPS+PMA-stimulated PBMC of FM patients having >2 yr of symptoms were significantly higher than levels for either controls (P=0.025) or those with <2 yr of symptoms (P=0.05). PMA co-stimulation also increased IL-6 production by PBMC from both groups of FM patients significantly above that of control PBMC (P=0.05).



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  		FIG. 3. PMA co-stimulation markedly increases the lectin-induced production of IL-1Ra, IL-8 and IL-6 by PBMC of FM patients in vitro. PBMC of FM and controls were incubated with LPS+PMA (IL-Ra and IL-6), PWM+PMA (IL-8) and PHA+PMA (IL-2). Cell culture supernatants were harvested 72 h after culture initiation and analysed by ELISA. pg/ml+S.E.M.; stacked columns. PBMC donors were: controls (light), FM <2 yr (hatched left), FM >2 yr (hatched right).

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Our group's interest in the potential influence of cytokines on fibromyalgia dates from 1988, when it was observed that patients given IL-2 LAK cell therapy for either terminal renal cell carcinoma or melanoma developed transient myalgias, arthralgias, cognitive impairment and tender points [1]. Similar FM-like symptoms appeared in patients receiving IFN-{alpha} for chronic hepatitis [13]. Because brain cells express cytokine receptors and lymphocytes express opiate receptors and bind substance P, we hypothesized that there was a neuroimmune–cytokine link relevant to fibromyalgia [3]. As a result of these speculations, we performed a controlled study of lymphocyte markers, the expression of IL-1, IL-2, IL-2R, TNF-{alpha}, IFN-{alpha} and IFN-{gamma}, proliferative responses, natural killer cell activity, IgG subclasses and circulating immune complexes. Although no gross differences between FM and healthy individuals were detected, the FM group showed higher individual variability in proliferative responses to PHA and concanavalin A than the controls [2, 14]. Our data suggested to us that the survey was limited by small number of patients and the potential failure to recognize FM subsets.

In the present study, using a new cohort of FM patients and healthy controls, we investigated a battery of cytokines and cytokine-related molecules based upon speculation that certain cytokines might be expressed differently in FM subsets. There were no obvious differences in the levels of most of these markers. In contrast, levels of serum IL-8 and IL-1Ra, as well as spontaneous in vitro IL-6 and IL-1Ra and in vitro-induced IL-1Ra, IL-6 and IL-8, were significantly higher than normal. These three molecules are important in inflammation, the hypothalamic–pituitary axis (HPA) and the sympathetic nervous system (SNS). In addition, and relevant to aetiopathogenesis of FM, these levels appeared to increase with symptom duration.

Neuroimmune–hormone–cytokine links in healthy people
It is now apparent that cytokines are only one component of proposed FM paradigms. The HPA axis and SNS are linked to cytokines and T lymphocytes [5]. Catecholamines and neurokinin K promote the release of IL-1, IL-6 and TNF-{alpha}, which activate the axis. HPA axis activation can also be promoted by acetylcholine and serotonin, but is blocked by IL-2, {alpha}-IFN, {gamma}-aminobutyric acid (GABA) and opiates. The SNS innervates lymphocytes, especially T cells [summarized in reference 15]. ß-Agonists can decrease natural killer cell activity and lymphocyte proliferative responses. IL-1 and TNF-{alpha} can uncouple ß-adrenergic receptors, IL-6 can activate the SNS and IL-8 is a mediator of sympathetic pain [16].

Newer insights have suggested that cytokines may have a role in FM symptoms. For example Go (Table 4Go), IL-1 produces somnolence [17]. IL-1 produced by the liver promoted hyperalgesia by vagal afferents, which can be blocked by the administration of IL-1Ra [18]. It clearly regulates substance P gene expression [19] and is associated with fever and antinociception [20]. Substance P induces IL-8 expression, which can also be blocked by IL-1Ra. IL-8 is a pro-inflammatory chemokine which induces neutrophil trafficking across the vascular wall [21]. TNF-{alpha} promotes rapid eye movement sleep and allodynia, induces pain-producing excitatory amino acids, and regulates substance P expression [20, 22]. IL-6 produces fatigue and pain in healthy people, decreases cognitive function, correlates with depression, influences the hyperalgesia of corticosteroid withdrawal and promotes B- and T-cell proliferation [23–25]. Substance P, whose spinal fluid levels are increased in FM, stimulates the release of IL-6 [26]. On the other hand, IL-10 can block pain. It increases B-cell levels, promotes energy by down-regulating type 1 responses and decreases IL-6 and TNF-{alpha} production by monocytes [27]. IFN-{alpha} and -{gamma} lower substance P levels and produce arthralgias, myalgias and cognitive impairment as well as stress and anxiety. A study among 38 healthy medical students showed that psychological stress stimulated the production of TNF-{alpha}, IL-6, IL-1Ra, {alpha}-IFN and IL-10 [28]. Those who admitted to being more anxious had decreased IL-10 and IL-4 production.


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  		TABLE 3. Serum levels of cytokines

 

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  		TABLE 4. Cytokines and associations potentially relevant to fibromyalgia

 

Neuroimmune–hormone–cytokine links in FM and chronic fatigue syndrome
A limited number of surveys have looked at immune function and cytokines in FM. Serum levels of the gp130 receptor and sIL-1Ra were increased among 21 FM patients compared with 33 controls [4]. We confirmed the IL-1Ra results and showed that the increases are seen mainly in patients with >2 yr of symptoms. Hernanz et al. [29] reported that levels of the activation markers CD69, CD25 and IL-2R were diminished in FM [29]. Hader et al. [3] reported a reduction in mitogen-induced IL-2 secretion in FM patients [3]. However, in support of our results, another report found no differences in serum levels of IL-1, IL-2 and IL-6 in irritable colon patients who also had fibromyalgia, compared with healthy controls [30]. A recent report from the National Institutes of Health on 13 FM patients and eight controls showed no differences in IL-6 serum levels, but excessive norepinephrine levels and delayed release of adrenocorticotrophic hormone after the administration of the cytokine [31].

Efforts to examine lymphocyte markers and cytokine levels in chronic fatigue syndrome have been incomplete and contradictory. Most of these studies are hampered by small numbers, differing selection criteria and lack of control groups. The best surveys demonstrated that a subgroup of patients may have early postinfectious markers for immune activation [32, 33].

The autonomic nervous system may function abnormally in FM. Neuronally mediated hypotension, livedo reticularis, mitral valve prolapse, numbness, tingling, headache and cognitive impairment have been linked to dysautonomia [34].

Is fibromyalgia an evolving process with different pathogenetic mechanisms over time?
Many patients with FM start out with regional myofascial pain and ultimately develop individual four-quadrant tenderness [35]. Evidence cited above suggests that patients may evolve a response to repetitive central sensory stimuli over time, and that intervening early in an effective manner is associated with an improved outcome [36]. The increased central repetitive sensitization of sensory inputs via afferent C fibres and autonomically derived B fibres into the dorsal root ganglion associated with FM initially leads to a greater proliferative response in IL-6 and IL-8, factors that mediate sympathetic pain. IL-1Ra could be released as a compensatory mechanism, because of its reputed role as a protective acute-phase reactant in decreasing inflammation. Figure 4Go provides a pictorial glimpse of such a schema. Over time, the level of response to mitogenic stimulation increases as the FM patients’ protective dampening mechanisms are exhausted or overwhelmed. In a few very extreme cases, reflex sympathetic dystrophy could evolve in this scheme. IL-6 could then induce many fibromyalgia symptoms, such as hyperalgesia, fatigue and depression. The proposed model underscores the argument for earlier, aggressive intervention to prevent a chronic pain pattern from developing. It is our suggestion that FM needs to be viewed through a biomedical model as a heterogeneous syndrome characterized by multifactorial pain amplification. This pilot study has generated a hypothesis, but not tested it. The fact that our data were cross-sectional and not prospective is a potential confounding factor. Cytokine changes in FM may be not causative but secondary to other factors. Because our patients with >2 yr of FM were recruited differently from those with early FM, this introduces an additional selection bias. The work described above is preliminary and we hope it will enhance interest in studying the role of cytokines in FM.



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  		FIG. 4. Hypothetical schema showing how some cytokines might play a role in fibromyalgia.

 


   Acknowledgments
 
This project is supported by the American Fibromyalgia Syndrome Association.


   Notes
 
Correspondence to: D. J. Wallace, 8737 Beverly Blvd Suite 203, Los Angeles, CA 90048, USA Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 3 May 2000; Accepted 21 December 2000


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