Fibromyalgia syndrome – a case report and pathogenetic role of immune processes

Introduction

Fibromyalgia is a chronic pain illness characterized by widespread musculoskeletal pain (any body part can be involved), diffuse pain in „tender points”, stiffness, soft tissue tenderness, general fatigue, sleep disturbances and other several systemic symptoms such as headaches and migraines, dizziness, irritable bowel and bladder, restless legs syndrome, skin sensitivities and rashes, vision problems, Raynaud’s syndrome, paresthesias, anxiety, impaired memory and concentration, depression. During the course of this disorder a new symptoms may be developed and current symptoms become more intensive [1, 2]. In industrialized countries FS affects approximately 2-4% of the population [3]. Although a higher percentage (80-90%) of women in the middle-age is affected, it does strike men [4], women and children of all ages and races [5, 6]. About 25% of patients have early FM symptoms before the age of 15 [7]. Diagnosis and management of FS are usually difficult and long-lasting with periods of remission. The average time from onset to diagnosis was 5 to 8 years. There are no laboratory tests that can confirm
a diagnosis of FS. Etiology and pathogenesis of this disease are unclear. The multiplicity of factors that may cause or contribute to FS and most of different symptoms has led to a multiplicity of treatments. Treatment must be tailored individually according to the needs of each patient. Fibromyalgia has a serious impact on the quality of live of patients, patients’ family and friends.
On the basis of case reports described previously [8], we present a short clinical presentation of our patient in this study, with the stress put on the data of immunological parameters performed in our patient. In this article, based on review of the literature, current view on the FM pathogenesis is also discussed with the stress put on the immunologic response.

Case report

The subject of the study was a girl from the second pregnancy, and an uncomplicated born. There was no family history of serious disease. The child’s psychomotor development in infancy was normal. In the childhood period she was suffering from upper respiratory system diseases and occasionally urinary tract infections. At the age of 11 adenotomy was performed. This procedure was complicated by high fever, face and neck swelling. During the next three months after adenotomy she was admitted to the hospital several times because of lymphadenopathy, parotid and submandibular gland swelling, recurrent of tonsillitis and maxillary sinusitis, herpes of the lips, urinary tract infection and an unclear episode of fever. Also were observed myofascial pains, musculoskeletal discomfort, lack of sleep and unrefreshing sleep, psychological stressors, easy fatigability from physical exertion. At the age of 11.5 she was admitted to the Clinic of Children Immunology, Medical University of Wroclaw with the suspicion of disorders in immune systems because after 4 months there was no effect of antiinflammatory, analgesic and antibiotic treatment. On admission the girl’s general condition was good. The physical examination did not reveal any deviations. Since then the girl many times had been admitted to the department because of increase in the severity pathological signs. Periodically, she had irritable bowel syndrome, dysuria, abdominal pain, difficulties with breathing, dry cough, various joints pain (without local changes such as swelling and heat), morning stiffness, fatigue, Raynaud’s phenomen, headache and recurrent aphthous ulcer. On the skin disseminated maculopapules and nodular skin lesion and ulcerations located on the forearms and face occurred. We also observed sensitivity to changes in the weather and noise. Results of
a physical examination were unremarkable, she was well-developed and well nourished girl, also mental development was normal, but she was less active than usual. During the next months the pain was expanding including the occiput, neck, back, thoracic and lumbar paraspinous regions, shoulders, pelvic girdle, elbows, hands and knees. On physical examination, the pain on palpation of tender points was observed. After about 2.5 year-long observation of our patient, at the age of 14, we established diagnosis of fibromyalgia syndrome on the basis of the American College of Rheumatology criteria [1]. Routine laboratory investigation revealed normal values. Only at the time of infection diseases, verified by microbiology and/or serological investigations (Staphylococcus aureus, Streptococcus pyogenes, E. coli, Mycoplasma pneumoniae, Herpes simplex 1/2, Coxsackie B2, Candida albicans), it were slightly elevated. Infections with HAV, HBV, HCV, CMV, EBV, HIV, Borelia burgdorferi, Chlamydia pneumoniae and trachomatis, Yersinia enterocolica, Helicobacter pylori, Toxoplasma gondi, Listeria monocytogenes, Mycobacterium tuberculosis, Pneumocystis carinii were excluded. Performed salivary gland, thyroid and abdominal ultrasonography, chest radiograph, scintigraphy of bone and renum, electromyography, computed tomography scan and magnetic resonance of the head and cervical spine were normal. We performed the wide immune system diagnosis. The following parameters of the immune system were evaluated: serum concentration of immunoglobulins IgG, IgA, IgM and IgE total, complement hemolytic activity with C3 and C4 components, percentage and number of lymphocytes B (CD19+), T lymphocytes and subset CD4+, CD8+,CD4+/CD8+ ratio and their function estimated by the test of blastic transformation after stimulation with PHA and ConA. Also bactericidal capacity and metabolic activity of neutrophils (chemiluminescence of isolated neutrophils, phagocytosis index, total phagocytosis capacity, percentage of phagocytic cells) were examined. All of them were within normal range. Circulating immune complexes were found only once in the onset our investigations. Serum levels of
IL-8, TGF-β were normal. Autoantibody screening was negative for ANA (antinuclear antibodies), ANCA (antineutrophil cytoplasmatic antibodies), antibodies against mitochondria, and microsomes, anti-smooth muscle antibodies and anti-striated muscle antibodies, thyroid autoantibodies (against thyreoglobulin and peroxidase). We found the elevated serum levels of antielastin antibodies in IgG and IgM classes, whereas in IgA class they were within normal range (table 1). In HLA typing DR15 and DRw 51 were present. TSH, fT3, fT4, growth hormone, cortisole, alpha-1 antitrypsin, procollagen III deficiency was excluded.
Various classes of medications were used in the treatment, including non-steroidal anti-inflammatory mediactions, antidepressants – tricyclic anti-depressants and selective serotonin reuptake inhibitors, neuroleptics, muscle relaxant, sedatives, opioids, immunosupresive drugs – prednisolone and azathioprine, antihistamines, immunomodulating drugs (including sublingual use of human interferon-alpha), melatonin, antioxidant vitamins, homeopathic drugs. In the course of treatment we also employed a wide range of non- medicinal modalities – exercise and physical therapy and also family and individual psychotherapy. But no significant subjective response to the treatment was noted.

Discussion

Although many studies have described the clinical symptoms associated with this disorder, the primary mechanisms underlying the etiology of fibromyalgia are still unclear. It is a non-inflammatory, non-progressive and non-degenerative complex syndrome. Fibromialgia patients may have different pain processing mechanisms. Most data indicated that psycho-neuro-endocrinological dysfunctions systems including biochemical substances such as neurotransmitters, hormones and peptides are the main disorders [9]. Peripheral and central abnormalities of nociceptor systems have been described [10]. In 2005 Julien et al. [11] reported that in fibromyalgia may be a deficit of endogenous pain inhibitory systems. Stress, injuries, infections, allergy, physical and psychological trauma from many causes can begin the neurotransmitter cascade and may act by inducing a self-perpetuating vicious cycle [12]. No genetic component has been found yet but some of studies have demonstrated familiar occurrence of fibromyalgia [13].
The interplay between FS and immune disorders has also become a focus of researches. These abnormalities may contribute to abnormal pain sensitivity in FS patients, but many aspects of FS are not yet clear. The interference between the immune and neuro- endocrine systems has been considered by many authors [14]. It is a well-know fact that physical or psychical stress causes changes in the immune system as well [15]. It is very significant because of the contribution of injury and stress in pathogenesis of FS [16, 17]. The role of immune mechanisms is also an important area of investigation in FS patients. The cellular and humoral immune response systems may be depressed or activated on different cells and molecules. Changes in immune system function found in FS, are generally in the direction of increased activity. One of the major regulatory mechanisms of the immune system is a control of the balance of cytokines. Cytokine also plays an important role in nervous system. For example, it may be responsible for long-term activation of spinal cord glia and dorsal horn neurons, thus resulting in central sensitization. Researches indicate that IL-6 may promote hyperalgesia, fatigue and depression and IL-8 – sympathetic pain. The analysis of serum concentration of IL-1, IL-2, IL-6, IL-10, soluble IL-2 receptor (sIL-2R), interferon-g (INF-g) and tumor necrosis factor (TNF-a) did not show any significant differences compared to normal value in FS patients. But simultaneously serum levels of IL-R antibody (IL-Ra) and IL-8 were above normal range. In supernatant of non-stimulated and stimulated in vitro by lectins and phorbol myristate acetate (PMA) peripheral blood mononuclear cells IL-1Ra and IL-6 were elevated. These data may suggest that IL-6 and IL-8 may play important role in modulation of such symptoms as pain, hyperalgesia, fatigaue and depression [18]. Salemi et al. [19] reported that in aproximally 30% of skin biopsies from FS women messenger RNA for inflammatory cytokines – IL-1beta, IL-6 and TNF-a was present. These authors postulated that there may be local disorder of collagen metabolism and neurogenic inflammation in these cases. In the other study the disturbance in the production of IL-2 by lymphocyte T was found. Only the addition of phorbol myristate acetate induced normal secretion of IL-2 [20]. The research conducted by Thompson et al. [21] demonstrated that in patients with FS serum concentration of IL-2, IL-2 receptor, IL-8 and IL-1 receptor antagonist were elevated. The analysis of this group revealed that in patients with FS lasting longer than 2 years IL-1 and IL-6 levels were increased and in patients who are depressed increased soluble IL-6 receptor and soluble IL-1 receptor antagonist levels were found. In skin biopsies of some patients IL-1b, IL-6, and TNF-a were present. But on the other hand, the research using flow cytometry showed the normal production of inflammatory cytokines [22]. According to these results it is difficult to evaluate the cytokines role in ethiopathological terms because increased cytokine, soluble cytokine receptors or cytokine receptor antagonist concentration are observed in many inflammatory and non-inflammatory diseases and disorders.
Lymphocyte phenotype is a one way of determination of cellular immunity. The wide investigation of lymphocyte performed by Hernanz et al. [23] indicates that most of them were normal and only CD69 and CD25 were above normal range. Samborski et al. [24] reported that the positive correlation between CD3 and CD3DR, CD3DR and CD8, and a negative correlation between CD4 and CD8 were found in patients with primary fibromyalgia. Recently, the attention has been drawn to the connection between natural killer cell activity in serum FS patients and occurrence pain, psychological variables, sleep quality. But then no associations were observed between these parameters [25]. Russel et al. [26] conducted a 6-week study to test the concentration of peripheral blood mononuclear leukocyte subpopulations and natural killer activity, after administration of low-dose, sublingually use of human interferon-alpha in FS patients. They concluded that in observed cases immunological disorders do not appear.
Many studies have documented that reactive oxygen species and oxidant – antioxidant imbalance may play an important role in the pathogenesis of various diseases and disorders. Elevated nitric oxide production has also been found in patients with FS [27]. In 2005 Bagis et al. [28] reported that in primary fibromyalgia patients there was an increased concentration of malonyldialdehyde – a toxic of lipid peroxidation products and simultaneously depressed level of superoxide dismutase - an intracellular antioxidant enzyme. The results of these studies indicate that oxidative stress may occur in fibromyalgia patients.
Because of the fact that some fibromyalgia patients may develop co-existing autoimmune diseases or patients with autoimmune condition may develop FS the research on this subject is being continued. In autoimmune diseases, the body’s immune system attacks its own cells. One theory, concerning the question why the immune system starts to injure, is that a virus, bacteria or persistent infection might trigger the response. In some cases an acute onset of symptoms may indicate an infection being an early event in the pathogenesis of FMS [29]. Significant elevated (in 45% cases) serum specific circulating IgM antibodies against enterovirus in patients with acute FS onset compared to healthy controls (10%) [30], and compared to 15% of the slow onset fibromyalgia patients [31] were detected. Douche--Aourik et al. [32] found of enterovirus RNA in 13% of specimens of skeletal muscle biopsy from patients with FS. Those investigations may indicate that persistent infection may cause immune system disorder in some patients with FS. In our patient we found also antibodies against Coxsackie B2 in serum. In contrast, there are other studies in which no correlation between parvovirus B19 infection and FS could be found [33]. Studies in recent years reported that the association between FS and hepatitis C infection [21] and HIV infection [34] may occur. Results of the other clinical reports indicate also a connection between Borrelia burgdorferi [35] or Mycoplasma [36] infection and FS.
The interference between autoantibodies and FS has been regarded by many authors as the cause of the FS. Most studies have shown that the presence of antinuclear antibodies (ANA) in FS patients and healthy control were similar (about 10%) [37, 38], although Smarti et al. [39] found, that ANA were positive in 30% of all FS patients. Al-Allaf et al. [38], found only one FM patient with ANA-positive group, who fulfilled the criteria for systemic lupus erythematosus (SLE). The results of these studies show that ANA is not a good predictor of the future development of other connective tissue disease in FS patients. Results of the investigations reported that 25% women suffering from FS had anti-smooth muscle antibodies and 40% had anti-striated muscle antibodies [40]. In contrast, there are reports of other studies [41, 42] in which no statistical difference in presence of antibodies directed against cell nuclei (ANA), smooth muscle, mitochondria, microsomes and antigens against liver, kidney and stomach tissue in FS patients compared to healthy controls were found.
Extremely interesting is the presence of antibodies against serotonin and gangliosides in 74% FS patients [42]. Klein et al. in other study [43] reported that 73% of the FS and 62% of the chronic fatigue syndrome (CFS) patients had antibodies to serotonin, 71% or 43% to gangliosides, 54% or 38%to phospholipids. 49% of FS and 17% of the CFS patients had all three antibodies in parallel, 70% and 55% respectively had at least two of these antibody types. 21% of FS and 29% of CFS patients were completely negative for these antibodies. These data may suggest that FS and CFS may belong to the same autoimmune diseases group. Other clinical evaluation showed that FS patients [44] had a significantly higher percentage of autoantibodies against serotonin and thromboplastin (43% vs 9%; p < 0.001), but not against ganglioside Gm1. Also no association between autoantibody pattern and pain, depression, pain related anxiety, and activities of daily living were found.
These results are remarkable because anti-serotonin antibodies are not present in such diseases of connective tissue as rheumatoid arthritis or polymyalgia rheumatica. Serotonin (5-HT) is a key neurotransmitter in the central nervous system and plays a role in the regulation of pain perception. On the other hand gangliosides are important components of the serotonin receptor. The presence of anti-serotonin antibodies may be associated with lover serum and cerebrospinal fluid concentration of serotonin in FS patients [45]. In contrast, there are reports of other studies in which no correlation could be found between fibromyalgia symptoms and disturbances in serotonin metabolism [46] or with T102C polymorphism of the
5-HT2A receptor gene [47]. Further research is required to do the clinical and diagnostic significance of anti-serotonin and anti-gangliosides antibodies with potential pathophysiologic and therapeutic implications for these reasons.
Maes et al. [48] found a higher serum concentration of soluble gp130, the common signal transducer protein of various neurotrophic cytokines, serum soluble IL-6 receptor (sIL-6R) and soluble IL-1 receptor antagonis (sIL-1RA) in patients with an increased the Hamilton Depression Rating Scale. Whereas, the serum CD8 was significantly lower. Severity of FS was also measured with several pain scales and dolorimetry. Based on these data, authors suggest that pain and stiffness may be accompanied by a suppression of some aspects of the inflammatory response system. The presence of clinically significant depressive symptoms may be associated with some signs of inflammatory response system activation in fibromyalgia patients. Results of the other investigation also suggest the connection between FS and thyroid autoantibodies, and depression [49].
The results of our own investigation regarding antielastin antibodies are interesting. Antibodies in IgM subset were elevated during our observation all the time, and in IgG mainly in the early stage. Antibodies in IgA class remained within normal range. It may to suggest the active parcitipation of the elastin fibres in described cases. But the importance of the presence of these antibodies in FS is unclear and further investigation is required, especially because no similar studies were found in the literature.
Simultaneously, concentration of procollagen type III in serum of our patient was within normal range in contrast to investigation performed by Jacobsen el al. [50]. They reported lower serum levels concentration of procollagen type III in FS patients. They also had more symptoms and lower dynamic muscle strength.
Although family occurrence is reported in FS patients, weak linkage with HLA phenotype was described [51, 52]. However, in our patient we found HLA DR 15 and DRw 51 markers. The pathophysiological significance of this finding remains unknown.
Clinical evaluation showed that 35% to 50% of FS patients had positive allergy skin tests [53]. In some cases, but not statistically significant, serum IgE- total levels were elevated [54, 55]. Samborski et al. [55] found also a negative correlation between CD3DR and IgE, and between CD8 and IgE concentration.
The question whether there is a significant role of immune system in pathogenesis FS is difficult to answer because the data presented above demonstrate that FS patients differ in their immune response.

Conclusions

Based on the data available from the literature and from our own observations we concluded that fibromyalgia is
a very complex a long lasting condition and is one of the major health problems. The onset of disorder appears to follow physiological and/or psychological stressors. We also think that probably adenotomy and recurrent infection were a great injury for our patient. Elevated serum levels of antielastin antibodies in IgG and IgM classes may suggest that the contribution of elastic fibers took place in the presented case.
The possibilities of influence of the changes in the immune system on clinical duration of FS require further investigations

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