Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial.

OBJECTIVES: Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. METHODS: 18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. RESULTS: taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. CONCLUSION: taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.

Autoantibodies are major predictors of arthritis development in patients with anti-citrullinated protein antibodies and musculoskeletal pain.

Objectives: Predictors of arthritis development are highly warranted among patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms to optimize clinical management. We aimed to identify clinical and laboratory predictors of arthritis development, including biochemically assessed alcohol consumption, among ACPA-positive patients with musculoskeletal pain.Method: 82 ACPA-positive individuals with musculoskeletal pain but no clinical arthritis were followed for a median of 72 months (interquartile range 57-81 months). We evaluated the prognostic value of baseline clinical and laboratory factors including smoking, symptom duration, age, gender, shared epitope, rheumatoid factor (RF), anti-carbamylated protein antibodies, ACPA levels, erythrocyte sedimentation rate, C-reactive protein levels, tender joint count, patient-reported general well-being, 28-joint Disease Activity Score, and alcohol consumption as measured by phosphatidyl ethanol (PEth) levels in whole blood.Results: During follow-up, 48% developed at least one arthritis. Multivariable analysis revealed an increased risk of arthritis development with RF positivity [hazard ratio (HR) = 2.3, 95% confidence interval (CI) 1.1-4.8, p = 0.028] and higher ACPA levels (HR = 1.0, 95% CI 1.000-1.001, p = 0.002). High levels of RF (HR = 4.4, 95% CI 1.7-11) entailed the highest HR in this ACPA-positive population. Neither clinical characteristics nor alcohol consumption measured by PEth conferred significant prognostic value.Conclusions: ACPA levels and concurrent presence of RF are independent predictors of arthritis development among ACPA-positive patients with musculoskeletal pain. The results are compatible with a dose-response relationship between RA-related autoantibodies and risk of arthritis development.

Enrichment of genomic pathways based on differential DNA methylation profiles associated with chronic musculoskeletal pain in older adults: An exploratory study.

Our study aimed to identify differentially methylated CpGs/regions and their enriched genomic pathways associated with underlying chronic musculoskeletal pain in older individuals. We recruited cognitively healthy older adults with (n = 20) and without (n = 9) self-reported musculoskeletal pain and collected DNA from peripheral blood that was analyzed using MethylationEPIC arrays. We identified 31,739 hypermethylated CpG and 10,811 hypomethylated CpG probes (ps ≤ 0.05). All CpG probes were clustered into 5966 regions, among which 600 regions were differentially methylated at p ≤ 0.05 level, including 294 hypermethylated regions and 306 hypomethylated regions (differentially methylated regions). Ingenuity pathway enrichment analysis revealed that the pain-related differentially methylated regions were enriched across multiple pathways. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e. antigen presentation, programed cell death 1 receptor/PD-1 ligand 1, interleukin-4, OX40 signaling, T cell exhaustion, and apoptosis) and gamma-aminobutyric acid receptor signaling. Further, Weighted Gene Correlation Network Analysis revealed a comethylation network module in the pain group that was not preserved in the control group, where the hub gene was the cyclic adenosine monophosphate-dependent transcription factor ATF-2. Our preliminary findings provide new epigenetic insights into the role of aberrant immune signaling in musculoskeletal pain in older adults while further supporting involvement of dysfunctional GABAergic signaling mechanisms in chronic pain. Our findings need to be urgently replicated in larger cohorts as they may serve as a basis for developing and targeting future interventions.

Association of CCL2 with systemic inflammation in Schnitzler syndrome.

BACKGROUND: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal gammopathy, which manifest mostly in the second half of life. It involves overactivation of the interleukin (IL)-1 system, but the exact pathophysiological pathways remain largely unknown. OBJECTIVES: To identify and characterize the pathogenetic players in SchS. METHODS: Blood parameters were quantified in patients with SchS compared with healthy controls and patients with psoriasis and hidradenitis suppurativa using enzyme-linked immunosorbent assay (ELISA). CCL2 expression in cultured primary cells was analysed by quantitative reverse-transcriptase polymerase chain reaction and ELISA. RESULTS: CCL2, a chemoattractant for monocytic and further mononuclear immune cells, was found to be significantly elevated in patients with SchS. CCL2 levels showed a positive association with global disease activity, especially with bone pain, but not disease duration, gammopathy, neutrophilia or skin disease. In vitro stimulation assays demonstrated a strong CCL2 production capacity of mononuclear immune cells and fibroblasts, but not epithelial or endothelial cells. Among a range of inflammatory mediators, only IL-1ß (immune cells, fibroblasts) and tumour necrosis factor (TNF)-α (fibroblasts) were important CCL2 inducers. TNF-α, but not IL-17, strengthened the CCL2-inducing effect of IL-1ß in fibroblasts. Accordingly, CCL2 levels positively correlated with both TNF-α and IL-1ß serum levels in patients with SchS. Therapeutic IL-1ß blockade decreased CCL2 blood levels in these patients as early as 1 week after the initiation of treatment. CONCLUSIONS: CCL2 may be an important component of the pathogenetic cascade leading to bone alterations, and a suitable marker of disease activity in patients with SchS.

Testing patients with non-specific symptoms for antibodies against Borrelia burgdorferi sensu lato does not provide useful clinical information about their aetiology.

The aim of this study was to determine whether patients with antibodies against Borrelia burgdorferi sensu lato or who report a history of erythema migrans (EM) or tick bite are more likely to have non-specific symptoms such as musculoskeletal pain, fatigue, sensory disorder, and headache. The study group comprised 423 subjects with non-specific symptoms tested for antibodies against B. burgdorferi sensu lato between July 2012 and December 2014 because of suspicion of Lyme borreliosis (LB). Of these, 285 were females (67%) and 138 were males (33%); the median age was 53 years (range, 7-89 years). Patients with a confirmed diagnosis of LB and patients with a known underlying disease that could influence the development of the symptoms were excluded from the evaluation. Subjects were assigned to the seronegative group or to one of three seropositive groups, and the history of EM and tick bite was also recorded. Statistical analysis was performed with single chi-square tests of independence and multiple logistic regression models. No differences in the occurrence of non-specific symptoms were observed between patients grouped according to antibody status. A history of EM showed no significant effect on any of the non-specific symptoms. A history of tick bite was weakly correlated with joint pain and joint swelling (p <0.05). In conclusion, it is highly unlikely that the complaints are related to a previous infection with B. burgdorferi sensu lato. The results show that testing patients with non-specific symptoms for antibodies against B. burgdorferi sensu lato in the everyday clinical setting does not provide any useful information about their aetiology.

Sex differences in upper respiratory symptoms prevalence and oral-respiratory mucosal immunity in endurance athletes.

The purpose of this study was to examine sex differences in oral-respiratory mucosal immunity and the incidence, severity and duration of upper respiratory symptoms (URS) episodes in endurance athletes during a 16-week winter training period. Blood was collected from 210 subjects (147 men and 63 women) at the start and end of the study for determination of differential leukocyte counts. Timed collections of unstimulated saliva were obtained at the start and at 4-week intervals during the study period. Saliva samples were analysed for salivary antimicrobial peptides and proteins (AMPs). Weekly training and daily illness logs were kept using validated questionnaires. Training loads averaged 11 h/week of moderate-vigorous physical activity and were not different for males and females. The salivary concentration of lysozyme and lactoferrin (both P < 0.04) but not salivary immunoglobulin A (SIgA) or amylase were higher in males than females. Saliva flow rates were significantly higher in males than females (P < 0.03) and consequently so were the salivary secretion rates of lysozyme, lactoferrin and amylase (all P < 0.01) but not SIgA (P = 0.097). Total blood leukocyte, monocyte and lymphocyte counts were not different between the sexes but females had higher numbers of circulating neutrophils (P = 0.040). The average number of URS episodes was 0.6 +/- 0.8 (mean +/- SD) in males and 0.8 +/- 1.0 in females (P = 0.103) and the number of URS days was higher in females (4.7 vs 6.8 days, P < 0.02). The duration of URS episodes was longer in females (11.6 vs 15.5 days, P < 0.03). The findings of this study concur with recent reports of illness incidence at major competitive games indicating that female athletes may be more susceptible than their male counterparts to URS and that lower oral-respiratory mucosal immunity may, in part, account for this.

Physiopathology of pain in rheumatology.

Pain is the main manifestation of many rheumatic diseases (be they overtly inflammatory such as rheumatoid arthritis or dysfunctional such as fibromyalgia) but, at least initially, the mechanisms involved in the genesis, amplification and chronicisation of the persistent pain characterising the various conditions can be very different. The main peripheral mechanism underlying acute nociceptive pain is a change in the activity of the nociceptors located in the affected anatomical structures (joints, tendons and ligaments), which makes them more sensitive to normally painful stimuli (hyperalgesia) or normally non-painful stimuli (allodynia). This physiopathological mechanism of peripheral sensitisation plays a primary role in rheumatic diseases characterised by acute inflammation, such as the arthritides due to microcrystals. In the case of chronic rheumatic diseases that do not regress spontaneously, functional and structural central nervous system changes cause a generalised reduction in the pain threshold that is not limited to the anatomical structures involved, thus leading to the appearance of hyperalgesia and allodynia in many, if not all body districts. This is the physiopathological basis of chronic, widespread musculoskeletal pain.

Basal inflammation and innate immune response in chronic multisite musculoskeletal pain.

Dysregulation of the immune system may play a role in chronic pain, although study findings are inconsistent. This cross-sectional study examined whether basal inflammatory markers and the innate immune response are associated with the presence and severity of chronic multisite musculoskeletal pain. Data were used on 1632 subjects of the Netherlands Study of Depression and Anxiety. The Chronic Pain Grade questionnaire was used to determine the presence and severity of chronic multisite musculoskeletal pain. Subjects were categorized in a chronic multisite musculoskeletal pain group (n=754) and a control group (n=878). Blood levels of the basal inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were determined. To obtain a measure of the innate immune response, 13 inflammatory markers were assessed after lipopolysaccharide (LPS) stimulation in a subsample (n=707). Subjects with chronic multisite musculoskeletal pain showed elevated levels of basal inflammatory markers compared with controls, but statistical significance was lost after adjustment for lifestyle and disease variables. For some LPS-stimulated inflammatory markers, we did find elevated levels in subjects with chronic multisite musculoskeletal pain both before and after adjustment for covariates. Pain severity was not associated with inflammation within chronic pain subjects. An enhanced innate immune response in chronic multisite musculoskeletal pain may be examined as a potential biomarker for the onset or perpetuation of chronic pain.

Prevalence of antinuclear antibodies in schoolchildren during puberty and possible relationship with musculoskeletal pain: a longitudinal study.

OBJECTIVE: The role of antinuclear antibodies (ANA) in children has still to be elucidated. The aim of our study was to evaluate the prevalence and persistence of ANA in schoolchildren during the puberty switch, and the possible relationship with chronic noninflammatory musculoskeletal pain (MSP). METHODS: Children aged 8-13 years and attending 4 public schools underwent a clinical examination, focusing on pubertal stage and presence of chronic noninflammatory MSP. Laboratory tests to determine the autoantibody-profile were also performed. Subjects with ANA positivity (titer ≥ 1:80) and/or chronic noninflammatory MSP were re-evaluated 3 years later. RESULTS: Two hundred sixty-one subjects enrolled in the study and 12.3% were ANA-positive, equally distributed in terms of sex and pubertal status. Three years later, in the group of patients studied for chronic noninflammatory MSP (n = 67), ANA positivity significantly increased from 13.4% to 44.8%. In the ANA-positive cohort at baseline (n = 28), 92.9% of subjects were confirmed as being ANA-positive with a significantly increased titer. No association between ANA positivity and chronic noninflammatory MSP was found. CONCLUSION: ANA prevalence and titers increase during puberty, especially in females, but have no relationship with chronic noninflammatory MSP. This finding may be related to the complex hormonal changes during the puberty switch period and opens new insights into autoimmunity.

[Cytokines in psychoneuroendocrine immunological context of nonspecific musculoskeletal pain]. / Zytokine im psychoneuroendokrin-immunologischen Kontext unspezifischer muskuloskeletaler Schmerzen.

Cytokines are coordinators of immune homeostasis. Evidence for the participation of cytokines in neurogenic inflammation, peripheral and central sensitization and hyperalgesia as well as for induction of inflammatory immune responses by pain-related catastrophizing is well documented. A disproportion of proinflammatory and anti-inflammatory cytokines is known to be a contributory cause of pain and pain behavior. Embedded into psychoneuroendocrine immunological feedback control systems cytokines are able to perpetuate a virtuous circle between local inflammation and systemic pain behavior (pain/sickness behavior) thus contributing to chronification of nonspecific musculoskeletal pain.In this model avoidance and pain-related nonrecognition as key components of systemic pain behavior lead to maintenance of the virtuous circle by generating of a local inflammation with local and systemic consequences. This model can explain the success of established therapy concepts from the point of view of psychoneuroimmunology, such as fear avoidance, which are effectively used as principal components in multimodal pain therapy.

Rarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects.

OBJECTIVE: Statins, among the most commonly prescribed medications, are associated with a wide range of musculoskeletal side effects. These include a progressive autoimmune myopathy with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies that requires immunosuppression. However, it remains unknown whether these antibodies are found in statin users with and without self-limited musculoskeletal side effects; this limits their diagnostic utility. The current work assessed the prevalence of anti-HMGCR antibodies in these groups of statin users. METHODS: We determined the prevalence of anti-HMGCR antibodies in 1,966 participants (including 763 current statin users) in a substudy of the community-based Atherosclerosis Risk in Communities (ARIC) Study and 98 French Canadian subjects with familial hypercholesterolemia, including 51 with documented statin intolerance. RESULTS: No participant in the ARIC substudy, including those with past or current statin exposure at the time of sample collection, had anti-HMGCR antibodies. Similarly, none of 51 patients with self-limited statin intolerance or 47 statin-tolerant patients receiving maximal statin therapy were anti-HMGCR positive. CONCLUSION: The majority of patients with and without statin exposure, including those with self-limited statin intolerance, do not develop anti-HMGCR antibodies. Therefore, anti-HMGCR antibodies are highly specific for those with an autoimmune myopathy.