The Italian Society for Rheumatology clinical practice guidelines for the diagnosis and management of fibromyalgia Best practices based on current scientific evidence.

Fibromyalgia or fibromyalgia syndrome (FMS) is defined as a central sensitization syndrome characterized by the dysfunction of neurocircuits detecting, transmitting and processing nociceptive stimuli; the prevalent manifestation is musculoskeletal pain. In addition to pain, there are multiple accompanying symptoms, in common with other algo-dysfunctional syndromes, which are reflected in a broad spectrum of somatic, neurocognitive and neuro-vegetative manifestations. An evidence-based approach is essential in FMS management, in order to improve patient health and to reduce its social burden. Since in the last ten years new international guidelines for clinical practice (Clinical Practice Guidelines or CPGs) concerning FMS diagnosis and pharmacological/ non-pharmacological management have been published, the Italian Society of Rheumatology (SIR) has decided to adapt them to the Italian national setting. The framework of the Guidelines International Network Adaptation Working Group was adopted to identify, appraise (AGREE II), synthesize, and customize the most recent CPGs on FMS to the needs of the Italian healthcare context. A working group of rheumatologists from SIR epidemiology unit and FMS experts identified relevant clinical questions to guide the systematic review of the literature. The target audience of these CPGs included physicians and healthcare professionals who manage FMS. The adapted recommendations were finally assessed by an external multidisciplinary panel. From the systematic search in databases (Pubmed/Medline, Embase) and grey literature, 6 CPGs were selected and appraised by two independent raters. The combination of the scientific evidence underlying the original CPGs with expert opinion lead to the development of 17 recommendations. The quality of evidence for each recommendation was reported and their potential impact on clinical practice was assessed. These SIR recommendations are expected to be a valuable aid in the diagnosis and treatment of FMS, as they will contribute to disseminate the best practice on the basis of the current scientific evidence.

Accuracy of synovial fluid analysis compared to histology for the identification of calcium pyrophosphate crystals: an ancillary study of the OMERACT US Working Group - CPPD subgroup.

The aim of this study was to evaluate the accuracy of synovial fluid analysis in the identification of calcium pyrophosphate dihydrate crystals compared to microscopic analysis of joint tissues as the reference standard. This is an ancillary study of an international, multicentre cross-sectional study performed by the calcium pyrophosphate deposition disease (CPPD) subgroup of the OMERACT Ultrasound working group. Consecutive patients with knee osteoarthritis (OA) waiting for total knee replacement surgery were enrolled in the study from 2 participating centres in Mexico and Romania. During the surgical procedures, synovial fluid, menisci and hyaline cartilage were collected and analysed within 48 hours from surgery under transmitted light microscopy and compensated polarised light microscopy for the presence/absence of calcium pyrophosphate crystals. All slides were analysed by expert examiners on site, blinded to other findings. A dichotomic score (absence/ presence) was used for scoring both synovial fluid and tissues. Microscopic analysis of knee tissues was considered the gold standard. Sensitivity, specificity, accuracy, positive and negative predictive values of synovial fluid analysis in the identification of calcium pyrophosphate crystals were calculated. 15 patients (53% female, mean age 68 yo ± 8.4) with OA of grade 3 or 4 according to Kellgren-Lawrence scoring were enrolled. 12 patients (80%) were positive for calcium pyrophosphate crystals at the synovial fluid analysis and 14 (93%) at the tissue microscopic analysis. The overall diagnostic accuracy of synovial fluid analysis compared with histology for CPPD was 87%, with a sensitivity of 86% and a specificity of 100%, the positive predictive value was 100% and the negative predictive value was 33%. In conclusion synovial fluid analysis proved to be an accurate test for the identification of calcium pyrophosphate dihydrate crystals in patients with advanced OA.

Serum klotho concentrations inversely correlate with the severity of nailfold capillaroscopic patterns in patients with systemic sclerosis.

Klotho is a transmembrane and soluble glycoprotein that governs vascular integrity. Previous studies have demonstrated reduced serum klotho concentrations in patients with systemic sclerosis (SSc), and it is known that klotho deficiency can impair the healing of digital ulcers related to microvessel damage. The aim of this study was to evaluate the association between serum klotho levels and nailfold capillaroscopic abnormalities in SSc patients. We retrospectively enrolled 54 consecutive patients with SSc diagnosed on the basis of the 2013 EULAR/ACR criteria [11 with diffuse SSc; 47 females; median age 68.0 years (IQ 18); median disease duration 11.0 years (IQ 7)]. Serum klotho concentrations were determined by means of an enzyme-linked immunosorbent assay. On the basis of the 2000 classification of Cutolo et al., 14 patients had normal nailfold capillaroscopic findings, 8 had an early scleroderma pattern, 21 an active scleroderma pattern, and 11 a late scleroderma pattern. The median serum klotho concentration was 0.29 ng/mL (IQ 1). Regression analysis of variation showed an inverse correlation between serum klotho concentrations and the severity of the capillaroscopic pattern (p=0.02; t -2.2284), which was not influenced by concomitant treatment. Logistic regression did not reveal any significant association between the risk of developing digital ulcers and nailfold capillaroscopic patterns, serum klotho levels, or concomitant medications. The presence of avascular areas significantly correlated with calcinosis (p=0.006). In line with previous studies, our findings confirm that klotho plays a role in preventing microvascular damage detected with nailfold capillaroscopy.

Real-world experience of tocilizumab in rheumatoid arthritis: sub-analysis of data from the Italian biologics' register GISEA.

To assess the long-term effectiveness and safety of tocilizumab, abatacept, and tumor necrosis factor-α inhibitors (TNFi), in the Italian real-world setting of rheumatoid arthritis (RA). The records of adult RA patients from the Italian biologics' registry Gruppo Italiano Studio Early Arthritis (GISEA) were analyzed. Demographic and clinical data were obtained at entry. The disease remission rate (28-joint disease activity score calculated using the erythrocyte sedimentation rate [DAS28-ESR] ≤ 2.6) and frequency of adverse events (AEs) were evaluated at 2 years. From 1999 to 2014, 7539 patients were treated with biologics (61.3% in first- and 22.6% in second-line), 68% of cases received TNFi, 9.1% tocilizumab, and 8.6% abatacept. Treatment groups showed a similar DAS28 at entry. As first-line, tocilizumab induced a significantly higher remission rate than abatacept or TNFi at 6 (51 vs 23.3 and 26.2%, respectively; p < 0.0001) and 24 months (52.3 vs 33.3 and 34.4%, respectively; p < 0.01). A similar pattern was observed in later lines. The most common AEs reported were infections, reactions to biologics (more frequent among TNFi-treated patients), increased transaminase (more frequent among TCZ-treated patients), and cardiovascular events. In clinical practice, TCZ induced a rapid and long-lasting remission and in a higher percentage of patients compared to abatacept and TNFi, with a good safety profile.

The clinical impact of Anti-DFS70 antibodies in undifferentiated connective tissue disease: case reports and a review of the literature.

Anti-nuclear antibody (ANA) positivity suggests CTD but can also lead to a diagnosis of UCTD when a patient does not fulfill the CTD diagnostic criteria. An anti-dense fine speckled (DFS) immunofluorescence (IIF) pattern can be observed when using an ANA test on HEp-2 cells and is due to the presence of antibodies to the nuclear DFS70 antigen that has rarely found in CTD. Serological testing for anti-DFS70 antibodies could therefore play a very interesting negative predictive role in stratifying patients on the basis of the evolution of UCTD to CTD. We described two patients ANA and anti-DFS70 positive in which the use of new method allowing the immunoadsorption of anti-DFS70 antibodies has permitted to exclude the incorrect diagnosis of CTD.

EULAR revised recommendations for the management of fibromyalgia.

OBJECTIVE: The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were 'expert opinion'. METHODS: A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations. RESULTS: 2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only 'strong for' therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as 'weak for' based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability). CONCLUSIONS: These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.

The role of klotho in systemic sclerosis.

The aim was to evaluate the role of klotho in the pathogenesis of systemic sclerosis (SSc), through the measurement of its serum concentration in SSc patients compared to healthy controls, and to assess the association with cutaneous and visceral involvement. Blood samples obtained from both SSc patients and healthy controls were analysed by an ELISA assay for the detection of human klotho. SSc patients were globally evaluated for disease activity and assessed through the modified Rodnan's Skin Score, Medsger's scale, pulmonary function tests, 2D-echocardiography, nailfold capillaroscopy and laboratory tests. Our cohort consisted of 69 SSc patients (61 females, mean age 64.5±12.5 years, median disease duration 9.0 (IQR 8) years) and 77 healthy controls (28 females, mean age 49.7±10.2 years). In the group of SSc patients, 19 (27.5%) suffered from a diffuse form of SSc. All patients were receiving IV prostanoids, and some of them were concomitantly treated with immunosuppressive drugs (prednisone, hydroxychloroquine, mofetil mycophenolate, methotrexate, cyclosporin A and azathioprine). The median serum concentration of klotho was significantly lower in patients compared to controls (0.23 ng/mL vs 0.60 ng/mL; p<0.001). However, Spearman's test showed no significant association between klotho serum levels and disease activity, concerning either clinical, laboratory or instrumental findings. Our data show a significant deficit of klotho in SSc patients although any significant association was detected between klotho serum concentration and the clinical, laboratory or instrumental features of the disease. However, due to the limits of the study, further investigations are required.

Evaluation of Th9 lymphocytes in peripheral blood of rheumatoid arthritis patients and correlation with anti-tumor necrosis factor therapy: results from an in vitro pivotal study.

The aim of this study was to determine the prevalence of T helper 9 (Th9) lymphocytes in rheumatoid arthritis (RA) patients and to identify a possible association between the percentage of Th9 and the discontinuation of a biological treatment with an anti-tumor necrosis factor (TNF) (infliximab). We collected peripheral blood mononuclear cells (PBMCs) from 55 consecutive RA outpatients and 10 healthy controls. Among RA patients, 15 were not receiving any immunosuppressive drug, 20 were successfully treated with infliximab and 20 discontinued infliximab because of adverse events or inefficacy and were treated with other biological agents. PBMCs were cultured with/without infliximab 50 mg/L for 18 h, and the percentage of Th9 cells was assessed by means of flow cytometry. Th9 lymphocytes were identified as interferon gamma, interleukin (IL)4-, IL17-, IL9-secreting cluster of differentiation 4 (CD4)+ T cells. Cytometric analysis revealed no significant decrease in the percentage of Th9 cells after infliximab exposure in any of the groups, although it was lower in healthy controls than RA patients either before and after the infliximab stimulation assay. Th9 cells are IL-9-secreting T helper lymphocytes whose role in RA is still poorly known. IL-9 levels are increased in RA patients, in whom this cytokine plays a crucial role. Th9 cells are the major producers of IL-9, and their prevalence is higher in RA patients than in healthy subjects; however our experiment in vitro does not demonstrate an association between Th9 lymphocytes and the response to infliximab. Further studies are required to evaluate the real involvement of Th9 population in the immunogenicity of anti-TNF agents.

Possible relationship between certolizumab pegol and arrhythmias: report of two cases.

It is still unknown whether there is an association between the use of certolizumab pegol (CZP) in rheumatic patients and the onset of cardiac arrhythmias. We describe the cases of two patients with rheumatoid arthritis (RA) treated with CZP as the first-line biological drug and methotrexate (MTX), who developed an arrhythmic event. The first was a 60-year-old, hypertensive male smoker, the second a 66-year-old dyslipidemic female non-smoker. Both were diagnosed as having RA in 2010, and started treatment with MTX plus CZP. The first patient developed undatable atrial fibrillation, which was resistant to pharmacological treatment and electrical cardioversion. The second patient developed an atrial flutter, which was treated with a betablocker. In both cases, we set a cautious interval between two consecutive administrations of CZP and, in the first case, also reduced the dose of MTX without any worsening of RA activity. Although many studies have shown that tumor necrosis factor (TNF)-alpha plays a pathogenetic role in inducing an arrhythmogenic substrate that is apparently rescued by anti-TNF drugs, there is still a lack of conclusive data. We suggest caution in any patient developing a cardiac event (including rhythm disorders) during treatment with a conventional or biological disease-modifying anti-rheumatic drug.

Cardiovascular and autoimmune diseases in females: The role of microvasculature and dysfunctional endothelium.

Cardiovascular (CV) diseases are becoming increasingly frequent and associated with a high incidence of CV events, disability and death. It is known that there is a relationship between CV burden and systemic autoimmune diseases (SADs) that is mainly due to inflammation and autoimmunity, but the other mechanisms underlying the high CV risk of SAD patients have not yet been fully clarified. The aim of this review article is to discuss some of the specific factors associated with the accelerated atherosclerosis (ATS) characterising SADs (female sex, the microcirculation and the endothelium) in order to highlight the importance of an early diagnosis and the prompt implementation of preventive measures, as well as the possible role of new therapeutic strategies such as vaccine immunomodulation. Finally, as the natural history of ATS begins with endothelial injury (a potentially reversible process that is influenced by various factors) and microvascular damage plays a central role in the etiopathogenesis of SADs, it underlines the crucial need for the development of reliable means of detecting sub-clinical abnormalities in the microcirculation, particularly coronary microcirculation dysfunction.

Polymyalgia rheumatica: inflammation suppression with low dose of methylprednisolone or modified-release prednisone.

OBJECTIVE: Polymyalgia rheumatica (PMR) is an inflammatory disease that affects people aged > 50 years, and is characterised by pain and morning stiffness in the shoulder and pelvic girdle with synovitis of the proximal joints and extra-articular synovial structures. It is currently mainly treated with glucocorticoids (GCs). The aim of the study was to evaluate changes in inflammatory markers and their correlations with cortisol levels after treatment with 6-methylprednisolone (6-MP) or modified-release prednisone (MR-P) in patients with "early" PMR. PATIENTS AND METHODS: The study involved 81 GC-naïve with "early" PMR diagnosed on the basis of the 2012 EULAR/ACR criteria: 38 treated with 6-MP at a starting dose of 12 mg at 8.00 a.m, gradually tapered to 8, 4 and 2 mg/day, and 43 treated with MR-P at a starting dose of 10 mg at 10 p.m, tapered to 7, 5, 3, 2 and 1 mg. The markers of inflammation (ESR mm/h, CRP mg/dL and fibrinogen mg/dL), the circulating serum levels of cytokines (TNFa and IL-6), and morning serum cortisol levels were evaluated at baseline and during GC treatment. RESULTS: There were significant differences between baseline and the end of treatment in the serum levels of IL-6 (5.3 ± 9.3 vs 2.8 ± 3.3 pg/mL; p < 0.05) and CRP (2.1 ± 3.3 vs 0.9 ± 1.7 mg/dL; p < 0.01) in the patients treated with MR-P, and in serum cortisol levels (15.8±6.4 vs 13.6+5.6 µg/dL; p < 0.01) in the patients treated with 6-MP. After the first month of treatment, 76.7% of the patients treated with MR-P had IL6 levels at or below the upper normal limit, whereas 52.6% of those treated with 6-MP had normal IL6 levels (p < 0.05). There was also a significant difference in the percentage of patients in whom the daily GC dose was tapered within eight months (6.7% in the MR-P group vs 25% in the 6-MP group; p < 0.001) and, by the end of the study, respectively 59.5% vs 35.1% patients were receiving a low GC dose or had discontinued treatment altogether (OR 2.7, 95% CI 1.0-6.77; p < 0.001). After six and 12 months, respectively 10.3% and 14.3% of the patients had discontinued MR-P, as against none of the patients treated with 6-MP (p < 0.05). CONCLUSIONS: In this prospective observational study of PMR patients receiving low-dose GCs, the changes in inflammatory markers were similar in those treated with 6-MP or MR-P, whereas morning cortisol levels remained unchanged only in the MR-P group. During the first month of treatment, MR-P chronotherapy given at bedtime significantly decreased IL-6 levels. The percentage of patients stopping GC treatment was higher in the MR-P group than in the 6-MP group.

Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study.

OBJECTIVES: To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. METHODS: SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patient's global health component (DAS28-3)-erythrocyte sedimentation rate (ESR) over 6 months. RESULTS: 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3-ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3-ESR at 6 months was significantly greater in rituximab than TNFi patients: -1.5 (0.2) vs -1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (-1.7 vs -1.3; p=0.017) but not intolerance (-0.7 vs -0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3-ESR with rituximab than with TNFi (-1.6 (0.3) vs -1.2 (0.3); p=0.011), particularly those switching because of inefficacy (-1.9 (0.3) vs -1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. CONCLUSIONS: These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy.

Three-dimensional morphological condylar and mandibular changes in a patient with juvenile idiopathic arthritis: interdisciplinary treatment.

Temporomandibular joint (TMJ) involvement is common but usually delayed in patients with juvenile idiopathic arthritis (JIA). We describe the case of a JIA patient with bilateral TMJ involvement, mandibular retrognathia, bone erosion, and severely restricted mouth opening. The use of cone beam computed tomography and a 3D diagnostic protocol in young patients with JIA provides reliable, accurate and precise quantitative data and images of the condylar structures and their dimensional relationships. Analgesics and conventional disease modifying antirheumatic drugs were ineffective, but interdisciplinary treatment with etanercept and a Herbst functional appliance improved functional TMJ movement and bone resorption.

Pain in rheumatic diseases: how relevant is it?

Pain, a complex phenomenon influenced by a series of genetic, biological, psychological and social factors, is a major component of many rheumatological conditions and the result of physiological interactions between central and peripheral nervous system signalling. It may be acute or chronic (generally defined as lasting ≥ three months): acute pain is often primarily attributable to inflammation and/or damage to peripheral structures (i.e. nociceptive input), whereas chronic pain is more likely to be due to input from the central nervous system (CNS). The many different aspects of pain mean that rheumatologists and other clinicians need to have enough expertise to diagnose the type of pain correctly and treat it appropriately. However, most rheumatologists receive little formal training concerning contemporary theories of pain processing or management, and this may affect the clinical results of any specific target therapy.

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.

Pain in rheumatoid arthritis: a critical review.

Patients with rheumatoid arthritis (RA) are frequently afflicted by pain, which may be caused by joint inflammation (leading to structural joint damage) or secondary osteoarthritis, and may be increased by central sensitisation. Non-inflammatory pain may also confuse the assessment of disease activity, and so the aim of treatment is not only to combat inflammatory disease, but also relieve painful symptoms. In order to ensure effective treatment stratification, it is necessary to record a patients medical history in detail, perform a physical examination, and objectively assess synovitis and joint damage. The management of pain requires various approaches that include pharmacological analgesia and biological and non-biological treatments. Although joint replacement surgery can significantly improve RA-related pain, it may only be available to patients with the most severe advanced disease.

Chronic widespread pain in spondyloarthritis.

The pain associated with spondyloarthritis (SpA) can be intense, persistent and disabling. It frequently has a multifactorial, simultaneously central and peripheral origin, and may be due to currently active inflammation, or joint damage and tissue destruction arising from a previous inflammatory condition. Inflammatory pain symptoms can be reduced by non-steroidal anti-inflammatory drugs, but many patients continue to experience moderate pain due to alterations in the mechanisms that regulate central pain, as in the case of the chronic widespread pain (CWP) that characterises fibromyalgia (FM). The importance of distinguishing SpA and FM is underlined by the fact that SpA is currently treated with costly drugs such as tumour necrosis factor (TNF) inhibitors, and direct costs are higher in patients with concomitant CWP or FM than in those with FM or SpA alone. Optimal treatment needs to take into account symptoms such as fatigue, mood, sleep, and the overall quality of life, and is based on the use of tricyclic antidepressants or selective serotonin reuptake inhibitors such as fluoxetine, rather than adjustments in the dose of anti-TNF agents or disease-modifying drugs.

Pain and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by heterogeneous clinical manifestations involving virtually the entire body. The pain in SLE can have different causes. The SLE classification criteria include mainly the musculoskeletal manifestations of pain, which are commonly reported as initial symptoms of SLE, such as arthralgia, arthritis and/or myalgia. Chronic widespread pain, which is typical of fibromyalgia (FM), is frequently associated with SLE. The aim of this review is to describe widespread pain and fatigue in SLE, and the association of SLE and FM. Although secondary FM is not correlated with the disease activity, it may interfere with the daily activities of SLE patients. Therefore it is necessary to identify its symptoms and treat them promptly to improve the quality of life of patients. In conclusion, it is essential to identify the origin of pain in SLE in order to avoid dangerous over-treatment in patients with co-existing widespread pain and FM.

Pain in systemic sclerosis.

Chronic pain is a healthcare problem that significantly affects the mental health, and the professional and private life of patients. It can complicate many disorders and represents a common symptom of rheumatologic diseases, but the data on its prevalence is still limited. Pain is a ubiquitous problem in systemic sclerosis (SSc). SSc-related pain has been studied on the basis of biomedical models and is considered a symptom caused by the disease activity or previous tissue damage. Effective pain management is a primary goal of the treatment strategy, although this symptom in SSc has not yet been investigated in detail. However, these patients do not all respond adequately to pharmacological pain therapies, therefore in these cases a multimodal approach needs to be adopted. This paper must be considered as retracted due to a plagiarism misconduct. See the Retraction note at: https://doi.org/10.4081/reumatismo.2018.1171

Pain in fibromyalgia and related conditions.

Pain is the hallmark symptom of fibromyalgia (FM) and other related syndromes, but quite different from that of other rheumatic diseases, which depends on the degree of damage or inflammation in peripheral tissues. Sufferers are often defined as patients with chronic pain without an underlying mechanistic cause, and these syndromes and their symptoms are most appropriately described as "central pain", "neuropathic pain", "nonnociceptive pain" or "central sensitivity syndromes". The pain is particular, regional or widespread, and mainly relates to the musculoskeletal system; hyperalgesia or allodynia are typical. Its origin is currently considered to be distorted pain or sensory processing, rather than a local or regional abnormality. FM is probably the most important and extensively described central pain syndrome, but the characteristics and features of FM-related pain are similar in other disorders of particular interest for rheumatologists, such as myofascial pain syndromes and temporo-mandibular joint disorders, and there is also an intriguing overlap between FM and benign joint hypermobility syndrome. This suggests that the distinctive aspects of pain in these idiopathic or functional conditions is caused by central nervous system hypersensitivity and abnormalities. Pharmacological and non-pharmacological therapies have been suggested for the treatment of these conditions, but a multidisciplinary approach is required in order to reduce the abnormal cycle of pain amplification and the related maladaptive and self-limiting behaviours.