Antibody-mediated autoimmunity in symptom-based disorders: position statement and proceedings from an international workshop.

A 2-day closed workshop was held in Liverpool, United Kingdom, to discuss the results of research concerning symptom-based disorders (SBDs) caused by autoantibodies, share technical knowledge, and consider future plans. Twenty-two speakers and 14 additional participants attended. This workshop set out to consolidate knowledge about the contribution of autoantibodies to SBDs. Persuasive evidence for a causative role of autoantibodies in disease often derives from experimental "passive transfer" approaches, as first established in neurological research. Here, serum immunoglobulin (IgM or IgG) is purified from donated blood and transferred to rodents, either systemically or intrathecally. Rodents are then assessed for the expression of phenotypes resembling the human condition; successful phenotype transfer is considered supportive of or proof for autoimmune pathology. Workshop participants discussed passive transfer models and wider evidence for autoantibody contribution to a range of SBDs. Clinical trials testing autoantibody reduction were presented. Cornerstones of both experimental approaches and clinical trial parameters in this field were distilled and presented in this article. Mounting evidence suggests that immunoglobulin transfer from patient donors often induces the respective SBD phenotype in rodents. Understanding antibody binding epitopes and downstream mechanisms will require substantial research efforts, but treatments to reduce antibody titres can already now be evaluated.

Unexpectedly high prevalence of primary immune deficiency in fibromyalgia: serologic features and clinical correlates.

OBJECTIVES: We sought laboratory evidence of primary immune deficiency (PID), a condition known to be associated with recurrent infections and autoimmunity, in fibromyalgia (FM). We correlated laboratory findings with a clinical history of recurrent infections and reduced epidermal nerve fiber density (ENFD). METHODS: We prospectively measured serum total and subclass concentrations for IgA, IgG, IgM, IgE, and mannose-binding lectin in 72 adult FM subjects (31 "FM only;" 41 "FM+RA") and compared those results against historical controls. We also administered a novel "Lifetime History of Infections" questionnaire to all FM subjects and 40 apparently healthy, community volunteers matched for age, race, and gender. ENFD values available for 49/72 FM subjects were also correlated with immunoreactant levels. RESULTS: Of FM subjects, 96% (69/72) had ≥3 and 85% (61/72) had ≥4 of 9 immunoreactants below or within the lowermost quartile of historical normal values. Recurrent sinus infections occurred more often in "FM only" (p=0.06), and "FM+RA" subjects (p=0.02) than controls. "FM+RA" subjects had a significantly greater history of recurrent, severe non-sinus infections (p=0.04). The prevalence of total IgA deficiency was significantly greater in "FM only" than in "FM+RA" subjects (p=0.04). We also found a direct correlation between total IgA (p=0.02), IgA1 (p=0.005), and IgG1 (p=0.04) concentrations and ENFD in "FM only" subjects. CONCLUSIONS: Serologic evidence of PID in FM is common and correlates with a clinical history of recurrent sinus and non-sinus infections, and reduced ENFD. This study suggests that PID may be important to diagnostic and therapeutic considerations in FM.

Evidence of peripheral large nerve involvement in fibromyalgia: a retrospective review of EMG and nerve conduction findings in 55 FM subjects.

OBJECTIVE: Whereas small fiber neuropathy (SFN) is now a recognized part of fibromyalgia (FM), surprisingly little attention has been paid to any findings of large fiber neuropathy (LFN) in this disorder. Since 90% to 95% of FM subjects seen in our outpatient facility routinely undergo EMG and nerve conduction studies (NCS) we elected to retrospectively review the EMG/NCS results garnered from a large cohort of unselected subjects in order to describe the electrodiagnostic features of LFN in FM. METHODS: Records from 100 consecutive, unselected clinic patients meeting the 1990 ACR criteria for FM, who had undergone EMG/NCS, were reviewed. The same electromyographer tested all subjects. After exclusion of FM patients with any other clinically relevant condition that might influence EMG results (e.g., familial neural degenerative conditions, diabetes mellitus, Vitamin B-12 deficiency, etc.) fifty-five FM subjects remained: 29 subjects with "FM Only," and 26 subjects with FM+Rheumatoid Arthritis ("FM+RA"). All subjects had also undergone ankle area skin biopsy for determination of epidermal nerve fiber density (ENFD). Fourteen other subjects, without FM or RA, examined by the same electromyographer, were used as an EMG/NCS comparison group. RESULTS: Ninety percent of the "FM Only" subjects demonstrated a demyelinating and/or axonal, sensorimotor polyneuropathy, and 63% had findings of SFN (ENFD ≤7 fibers/mm), suggesting a mixed fiber neuropathy in most. Furthermore, 61% of the "FM Only" subjects showed EMG findings suggestive of non-myotomal lower extremity axonal motor denervation, most likely due to a polyneuropathy, and 41% satisfied published criteria for "possible" chronic inflammatory demyelinating polyneuropathy (CIDP). There was surprisingly little difference in the EMG/NCS findings between the "FM Only" and the "FM+RA" groups. With the exception of carpal tunnel syndrome, our EMG/NCS comparison group showed few to none of these findings. CONCLUSION: Our review of the EMG/NCS results, gleaned from the largest FM cohort yet studied with these modalities, shows that electrodiagnostic features of polyneuropathy, muscle denervation, and CIDP are common in FM. Furthermore these electrodiagnostic findings are often seen coincident with SFN, and are not significantly influenced by the presence of RA. These results, particularly when taken as a whole, suggest that EMG/NCS may be clinically useful in detecting LFN in FM and help in better understanding the etiopathogenesis of this painful disorder.

The Role and Importance of Small Fiber Neuropathy in Fibromyalgia Pain.

Serious investigators of fibromyalgia (FM) realize the profound implications of finding features of small fiber neuropathy (SFN) in this disorder. For the first time, an easily reproducible and generally agreed upon, peripheral tissue lesion has been reported from multiple investigative centers. Understanding how this discovery relates to other features of FM, and how one might utilize it to better comprehend, and care for, afflicted patients' painful complaints remains a challenge, however. In this article we review how the SFN seen in FM may be placed in context, and suggest how such a tissue abnormality might be used to better understand the pathophysiology of FM, and plan for its effective treatment. We also suggest how finding SFN in FM implies the need for continued focused research within the area of neuropathic disease in FM.

Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications.

OBJECTIVE: A subset of patients with fibromyalgia (FM) exhibit a large fiber demyelinating peripheral polyneuropathy akin to that seen in chronic inflammatory demyelinating polyneuropathy (CIDP). It has been suggested that this demyelinating process is likely to be immune mediated. Because it is known that similar large fiber neuropathic lesions may be associated with a cutaneous small fiber neuropathy, we sought to determine the prevalence of small fiber neuropathy, as measured by epidermal nerve fiber density (ENFD), in a series of patients with FM and clinically healthy control subjects. METHODS: Forty-one consecutive patients with FM and 47 control subjects underwent a 3-mm punch skin biopsy at the proximal thigh and distal leg near the ankle, for analysis of the ENFD. Patients with FM who had clinical evidence of a disorder known to be associated with small fiber neuropathy were excluded. The patients with FM also underwent pinwheel testing and vibratory testing for hypesthesia and serologic testing for a series of cytokine, circulating immune complex, and complement measurements. RESULTS: All patients with FM had evidence of stocking hypesthesia. The ENFD of patients with FM was lower than that of control subjects at both the calf (mean ± SD 5.8 ± 2.8 versus 7.4 ± 1.9; P = 0.0002) and thigh (9.3 ± 3.2 versus 11.3 ± 2.0; P = 0.0007). There was an inverse correlation between calf ENFD and age at the time of skin biopsy in patients with FM (r = -0.29, P = 0.03) but not in control subjects; however, analysis of covariance showed that this relationship could not be explained by aging alone. Serologic evaluation showed an inverse correlation between calf ENFD in patients with FM and the interleukin-2 receptor (IL-2R) level (r = -0.28, P = 0.04). However, an inverse correlation between thigh ENFD and serum IL-2R levels did not reach significance (P = 0.08). Analysis of thigh-to-calf ENFD ratios suggested that the ENFD decline in FM is affected by both a diffuse and a length-dependent process. CONCLUSION: The calf and thigh ENFD in patients with FM is significantly diminished compared with that in control subjects. Advancing age alone cannot explain this finding. Calf ENFD was inversely correlated, although weakly, with serum levels of IL-2R. These findings suggest that small fiber neuropathy is likely to contribute to the pain symptoms of FM; that pain in this disorder arises, in part, from a peripheral immune-mediated process; and that measurement of ENFD may be a useful clinical tool in FM.

Immunoglobulin g for the treatment of chronic pain: report of an expert workshop.

BACKGROUND: The treatment of chronic pain is still unsatisfactory. Despite the availability of different drugs, most patients with chronic pain do not receive satisfactory pain relief or report side effects. Converging evidence implicates involvement of the immune system in the pathogenesis of different types of nociceptive and neuropathic chronic pain. DESIGN: At a workshop in Liverpool, UK (October 2012), experts presented evidence suggesting immunological involvement in chronic pain and recent data supporting the concept that the established immune-modulating drug, polyvalent immunoglobulin G (IgG), either given intravenously (IVIg) or subcutaneously (SCIg), may reduce pain in some peripheral neuropathies and a range of other pain disorders. Workshop's attendees discussed the practicalities of using IVIg and SCIg in these disorders, including indications, cost-effectiveness, and side effects. RESULTS: IgG may reduce pain in a range of nociceptive and neuropathic chronic pain conditions, including diabetes mellitus, Sjögren's syndrome, fibromyalgia, complex regional pain syndrome, post-polio syndrome, and pain secondary to pathological autoantibodies. CONCLUSIONS: IgG is a promising treatment in several chronic pain conditions. IgG is a relatively safe therapeutic strategy, with uncommon and mild side effects but high costs. Randomized, controlled trials and predictive tests are needed to better support the use of IgG for refractory chronic pain.

EEG biofeedback treatment improves certain attention and somatic symptoms in fibromyalgia: a pilot study.

Fibromyalgia (FMS) is a chronic, painful disorder often associated with measurable deficiencies in attention. Since EEG biofeedback (EEG-BF) has been used successfully to treat attention problems, we reasoned that this modality might be helpful in the treatment of attention problems in FMS. We also speculated that improvement in central nervous system (CNS) function might be accompanied by improvement in FMS somatic symptoms. We studied fifteen FMS patients with attention problems, demonstrated by visual and auditory continuous performance testing (CPT), while completing 40 or more EEG-BF sessions. Training consisted of a "SMR protocol" that augmented 12-15 Hz brainwaves (sensory motor rhythm; SMR), while simultaneously inhibiting 4-7 Hz brainwaves (theta) and 22-30 Hz brainwaves (high beta). Serial measurements of pain, fatigue, psychological distress, morning stiffness, and tenderness were also obtained. Sixty-three FMS patients who received standard medical care, but who did not receive EEG-BF, served as controls. Visual, but not auditory, attention improved significantly (P < 0.008). EEG-BF treated subjects also showed improvement in tenderness, pain and fatigue. Somatic symptoms did not change significantly in controls. Visual attention parameters and certain somatic features of FMS appear to improve with an EEG-BF SMR protocol. EEG-BF training in FMS deserves further study.