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The outcome of patients with COVID‐19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking. This study aimed to assess the outcome of patients with both SSc and COVID‐19 over several waves. Patients with both SSc and COVID‐19 who were registered in the European Scleroderma Trials and Research group (EUSTAR) were collected between April 2020 and April 2021. Patients were assigned to waves 1, 2, or 3 depending on the date of their COVID‐19 diagnosis. Primary endpoints were death, intensive care unit stay, or ventilatory support (severe outcome). Subgroup analyses of patients who were hospitalized or died were conducted. General and SSc‐specific characteristics and treatment were compared over the waves. Descriptive statistics and multivariate logistic regression were applied. A total of 333 patients were included; 57 patients (17%) had a severe outcome, and 30 patients (9%) died. Compared to wave 1, significantly fewer patients with SSc suffered from severe COVID‐19 in waves 2 and 3 (28.2% vs 9.8% and 12.7%; P< 0.001), fewer patients required hospitalization (46.7% vs 19.6% and 25.5%; P< 0.001) or ventilatory support (24.0% vs 8.7% and 10.9%; P =0.001), and fewer patients died (15.7% vs 5.0% and 7.5%; P =0.011). Patients were significantly younger, more often men, had less frequent arterial hypertension, and less SSc cardiac involvement over waves 1 to 3. Patients received significantly less medium to high doses of corticosteroids as they did SSc treatment. The outcome of patients with both SSc and COVID‐19 improved significantly over time because of intrinsic and extrinsic factors.

ABSTRACTIntroductionThe advent of biological disease-modifying anti-rheumatic drugs (bDMARDs), and more recently of Janus kinase inhibitors (JAKi), has had a major impact on the herpes zoster (HZ) reactivation, which represents an important clinical challenge in the treatment of inflammatory arthritis (IA) in patients with a complete pharmacological control of peripheral inflammation.Areas coveredIn this review, we provide an overview on the effects of conventional DMARDs/ bDMARDs and JAKi on HZ reactivation. Furthermore, we underline the controversial findings and the potential management strategies. We searched PubMed, Medline, and the Cochrane Library for papers published between 1995 and November 2022.Expert opinionThe overall data showed a slightly higher risk of HZ in patients treated with bDMARDs, and more pronounced for those treated with JAKi. As management strategies, we suggest an effective vaccination campaign and a focus on early diagnosis.

ABSTRACTIntroductionThe advent of biological disease‐modifying anti‐rheumatic drugs (bDMARDs) and, more recently, of Janus kinase inhibitors (JAKi) has had a major impact on the long-term outcomes of chronic inflammatory arthritis (IA). However, the persistence of pain, even in patients with a complete pharmacological control of peripheral inflammation, represents an important clinical challenge in the treatment of IA.Areas coveredIn this review, we provide an overview of possible mechanisms underlying pain in IA and its assessment, as well as the effects of bDMARDs and JAKi on pain management.Expert opinionThe overall data showed a good effect of bDMARDs and JAKi on pain, which is more pronounced for JAKi. However, it is challenging to distinguish the effect on the different types of pain (nociceptive, neuropathic, and nociplastic).

ABSTRACTIntroductionInterleukin 23 (IL-23) is a pro-inflammatory cytokine that plays a protective role against bacterial and fungal infections. However, the dysregulation of the IL-23/IL-17 axis provides a solid substrate for the development of various inflammatory diseases, such as psoriatic arthritis (PsA) and ankylosing spondylitis (AS).Areas coveredIn different clinical trials, several drugs against IL-23 have shown efficacy and safety toward PsA, with excellent results on skin and joint scores. However, the same drugs did not show the same efficacy in AS, suggesting that IL-23 may not be a relevant driver of the pathobiology and clinical symptoms of active axial spondyloarthritis (axSpA).Expert opinionThese drugs have shown an excellent efficacy and a good safety profile toward PsA, while in AS the efficacy of the IL-23 blockade is lacking for reasons not yet known. Several hypotheses have been reported, but further studies will be needed for a greater understanding. This suggests the involvement of pathways or mechanisms for the development of SpA that remain unknown. In order to allow a wide use of IL-23 inhibitors, further clinical trials and long-term prospective studies are necessary.

The risk of cardiovascular disease is increased in patients with rheumatoid arthritis compared with the general population owing to the influence of traditional and non-traditional risk factors. Inflammation has a pivotal contribution and can accelerate the atherosclerotic process. Although dampening inflammation with DMARDs should theoretically abrogate this process, evidence suggests that these drugs can also promote atherosclerosis directly and indirectly, hence adding to an increased cardiovascular burden. However, the extent and direction of the effects largely differ across drugs. Understanding how these drugs influence endothelial damage and vascular repair mechanisms is key to understanding these outcomes. NSAIDs and glucocorticoids can increase the cardiovascular risk. Conversely, conventional, biologic and targeted DMARDs control inflammation and reduce this risk, although some of these drugs can also aggravate traditional factors or thrombotic events. Given these data, the fundamental objective for clinicians should be disease control, in an individualized approach that considers the most appropriate drug for each patient, taking into account joint and cardiovascular outcomes. This Review provides a comprehensive analysis of the effects of DMARDs and other approved drugs on cardiovascular involvement in rheumatoid arthritis, from a clinical and mechanistic perspective, with a roadmap to inform the research agenda.

ABSTRACTIntroductionSARS-CoV-2 is a novel coronavirus that was first isolated from a group of patients hospitalized with pneumonia in China at the end of 2019, and, in February 2020, the syndrome it caused was named coronavirus disease 2019 (COVID-19) by the World Health Organization. In the absence of specific antiviral treatments capable of neutralizing the etiological agent, one therapeutic approach is to control the cytokine storm responsible for the most severe forms of the disease. The characteristic cytokine profile of severely affected patients is increased levels of interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor alpha (TNF-α).Areas coveredThis article discusses the pathogenesis of COVID-19 as a rationale for using the biological and targeted synthetic drugs used in rheumatology (anti-TNF, anti-IL-1 and anti-IL-6 agents and baricitinib) to treat the disease, and provides key information concerning their potential benefits and adverse effects.Expert opinionInterleukin inhibition seems to be a promising means of treating COVID-19 patients when respiratory function declines (or even earlier) if there are laboratory data indicating the presence of a cytokine storm because the interleukins are key drivers of inflammation. However, it is important to consider the risks and benefits of biological agents carefully, and critically analyze the evidence concerning their use in COVID-19 patients.

Introduction: Gender equity and gender medicine are opportunities not to be missed, and this Expert Group Opinion Paper on pain in women aims to review the treatment of pain conditions mainly affecting women, as well as the fundamental aspects of the different clinical response to drug treatment between the genders, and what can be done for gender-specific rehabilitation. Methods: Perspective review. Results: Genotypic and phenotypic differences in pain between the sexes are conditioned by anatomical, physiological, neural, hormonal, psychological, social, and cultural factors, such as the response to pharmacological treatment to control pain. The examination of these factors shows that women are affected by pain diseases more frequently and severely than men and that they report pain more frequently and with a lower pain threshold than men. Some forms of pain are inherently related to gender differences, such as pain related to the genitourinary system. However, other forms of chronic pain are seen more frequently in women than men, such as migraine, rheumatological, and musculoskeletal pain, in particular fibromyalgia. Discussion: Research is needed into the pathophysiological basis for gender differences in the generation of acute pain and maintenance of chronic pain, including the factors that put women at higher risk for developing chronic pain. In addition, different specialties need to collaborate to develop gender-related diagnostic and therapeutic guidelines, and healthcare professionals need to upskill themselves in the appropriate management of pain using existing diagnostic tools and therapeutic options.

Introduction: Patients with rheumatoid arthritis (RA) or other rheumatic diseases say that pain and stiffness are symptoms affecting their quality of life. Ketoprofen and ibuprofen are the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs) to reduce inflammation and manage mild-to-moderate pain. The aim of this new systematic review of the literature and meta-analysis of randomized controlled trials (RCTs) was to compare the clinical efficacy of ketoprofen and ibuprofen in patients with RA. Methods: The MEDLINE and EMBASE scientific databases were systematically searched from their inception to November 2020 to identify RCTs directly comparing the recommended therapeutic doses of oral ketoprofen (50–200 mg/day) with ibuprofen (600–1800 mg/day) for RA pain relief. The meta-analysis was made using the standardized mean differences (SMD) of each of the identified RCTs using a fixed effects model. Results: Four RCTs involving 456 patients met the inclusion criteria. The results of the meta-analysis showed a statistically significant difference in efficacy in favor of ketoprofen (0.33, 95% CI 0.14–0.52, p= 0.0005) at all point-estimates of the mean-weighted size effect. The heterogeneity test for the efficacy outcome (the hypothesis was χ2= 3.57%, df= 3, pvalue = 0.31 and the chance of a test effect was 3.49, p= 0.0005) was not significant, and this was confirmed by a Higgins percentage of 16%. The studies included in the meta-analysis did not reveal any significant differences between the two drugs in terms of tolerability or safety. Conclusions: The result of this meta-analysis shows that ketoprofen is more effective than ibuprofen in managing RA pain at therapeutic doses, thus supporting its use in clinical practice.

Fibromyalgia is characterized by chronic widespread pain, fatigue, sleep disturbances and functional symptoms. The etiopathogenesis, diagnostic criteria and classification criteria of fibromyalgia are still debated and, consequently, so are the strategies for treating this condition. Fibromyalgia is the third most frequent musculoskeletal condition, and its prevalence increases with age. However, although diagnosis has improved with the evolution of more accurate diagnostic criteria, a considerable proportion of physicians still fail to recognize the syndrome. Many factors contribute to the development of fibromyalgia in a unique manner: genetic predisposition, personal experiences, emotional–cognitive factors, the mind–body relationship and a biopsychological ability to cope with stress. The multiple components of the pathogenesis and maintenance of the condition necessitate a multi-modal treatment approach. Individually tailored treatment is an important consideration, with the increasing recognition that different fibromyalgia subgroups exist with different clinical characteristics. Consequently, although an evidence-based approach to fibromyalgia management is always desirable, the approach of physicians is inevitably empirical, and must have the aim of creating a strong alliance with the patient and formulating shared, realistic treatment goals.

The increased risk of cardiovascular disease (CVD) among patients with autoimmune rheumatic diseases such as rheumatoid arthritis, spondyloarthritis and systemic lupus erythematosus has been extensively documented. Sub-clinical atherosclerosis can be assessed using various non-invasive imaging techniques. However, the mechanisms underlying the higher risk of atherosclerotic CVD in patients with autoimmune rheumatic diseases are not fully known, although they seem to include chronic low-grade systemic inflammation leading to prolonged endothelial activation, accompanied by a pro-thrombotic/pro-coagulant and autoantibody state. Furthermore, sub-clinical atherosclerosis is also influenced by other traditional risk factors for CVD. Including the individual components of the metabolic syndrome (MetS: obesity, impaired glucose metabolism, dyslipidemia and high blood pressure), the degree of which is higher in these patients than in controls. The aim of this narrative review is to discuss the CV manifestations and risk factors involved in the increased risk of CVD among patients with autoimmune rheumatic diseases.

ABSTRACTIntroductionStudies in vitroand in vivohave identified several peptides that are potentially useful in treating systemic lupus erythematosus (SLE). The rationale for their use lies in the cost-effective production, high potency, target selectivity, low toxicity, and a peculiar mechanism of action that is mainly based on the induction of immune tolerance. Three therapeutic peptides have entered clinical development, but they have yielded disappointing results. However, some subsets of patients, such as those with the positivity of anti-dsDNA antibodies, appear more likely to respond to these medications.Areas coveredThis review evaluates the potential use of therapeutic peptides for SLE and gives an opinion on how they may offer advantages for SLE treatment.Expert opinionGiven their acceptable safety profile, therapeutic peptides could be added to agents traditionally used to treat SLE and this may offer a synergistic and drug-sparing effect, especially in selected patient populations. Moreover, they could temporarily be utilized to manage SLE flares, or be administered as a vaccine in subjects at risk. Efforts to ameliorate bioavailability, increase the half-life and prevent immunogenicity are ongoing. The formulation of hybrid compounds, like peptibodies or peptidomimetic small molecules, is expected to yield renewed treatments with a better pharmacologic profile and increased efficacy.

ABSTRACTIntroductionThe first-line treatment of axial spondyloarthritis (SpA) is with non-steroidal anti-inflammatory drugs (NSAIDs) and is followed by tumor necrosis factor (TNF) inhibitors (the main treatment for patients not responding to NSAIDs) or drugs targetting the IL-23/IL-17 pathway. The efficacy of disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and sulfasalazine (SSZ) has not been demonstrated, although SSZ can be considered in patients with concomitant peripheral arthritis.Areas coveredThis review describes the beneficial and toxicological effects of the drugs used to treat axial SpA.Expert commentaryGrowing concerns about the safety of anti-TNF drugs underline the need to ensure that all clinicians are capable of taking appropriate preventive action and adequately treating affected patients.

ABSTRACTIntroductionMore than 15 years after its introduction, there is still no agreement as to whether anti-TNF treatment increases the risk of developing infections, cardiovascular or neurological diseases, or auto-antibodies. Anti-TNF drugs reduce inflammation and sub-clinical atherosclerosis in rheumatoid arthritis (RA) patients, but they also alter their lipid profiles and can lead to the development of severe infections. Furthermore, as they increase the risk of developing demyelinating diseases, are not recommended in patients with multiple sclerosis or related disorders. The authors searched the Medline database for English language articles concerning the adverse events of anti-TNF drugs published between 1998 and December 2019, and have summarized their contents relating to infections, malignancies, cardiovascular diseases, autoimmunity and neurological diseases. Patients should be fully informed of the increased risks associated with anti-TNF drugs, and physicians should know how to treat them.Areas coveredThis review considers these safety concerns, their possible underlying causes, and other aspects that are important in clinical practice.Expert opinionGrowing concern about the safety of anti-TNF drugs underlines the need to ensure that all clinicians are capable of taking appropriate preventive and therapeutic action.

ABSTRACTIntroduction: Cardiovascular (CV) mortality is increased in patients with ankylosing spondylitis (AS), but little is known about CV morbidity beyond the fact that they have a two-fold higher prevalence of ischemic heart disease than controls due to the inflammatory pattern of the disease itself, and a higher prevalence of traditional CV risk factors than the general population. Anti-TNF drugs reduce inflammation and a number of studies have reported a reduction in sub-clinical atherosclerosis in AS patients treated with anti-TNF drugs, thus suggesting that inflammation contributes to their higher CV risk. Anti-TNF drugs also alter the lipid profiles of AS patients, although these changes may reflect their normalization secondary to inflammation control, and improve their other myocardial alterations.Areas covered: This review concentrates on the risk of cardiovascular morbidity and mortality among AS patients and the effect of anti-TNF drugs on this risk, with particular emphasis on the putative causes involved and the aspects that are relevant in clinical practice.Expert opinion: The growing evidence of CV disease in AS means that all clinicians need to know how to prevent it and treat patients appropriately. It is important to bear in mind the EULAR guidelines, which state that a rheumatologist is responsible for monitoring all AS patients for signs of CV involvement because this is essential in order to ensure that they are treated properly. As there is little clinical evidence concerning the effects of biological drugs other than anti-TNF agents, treatment should be decided on the basis of the clinical aspects of the type of AS and the CV co-morbidity: for example, patients who are hypertensive or dyslipidemic should immediately start treatment with an anti-hypertensive agent and/or a statin. All of the patients should be educated to prevent CV events by keeping to a balanced healthy diet, avoiding tobacco smoking, and maintaining normal blood pressure, LDL-cholesterol and glucose levels. Finally, all clinicians (but particularly rheumatologists) should always bear in mind CV complications in order to guarantee that the quality of life of AS patients is as good as possible.

Objective.To evaluate the prevalence and factors associated with the neuropathic pain features in a cohort of patients with psoriatic arthritis (PsA).Methods.A cross-sectional evaluation was conducted in consecutive patients having PsA with prevalent peripheral joint involvement, referred to 3 rheumatological centers. For each patient, a comprehensive assessment of disease activity, physical function, and disease effect was carried out. The presence of comorbid fibromyalgia syndrome (FMS) was evaluated. Acute-phase reactants were also recorded. The neuropathic pain features were investigated through the PainDETECT Questionnaire (PDQ). A logistic regression analysis was therefore conducted using the PDQ as the dependent variable.Results.The final evaluation included 118 patients. A comorbid FMS was detectable in 30 of the 118 patients with PsA (25.4%). Probable characteristics of neuropathic pain (PDQ ≥ 19) were found in 30 (25.4%) patients overall, ambiguous (PDQ > 12 and < 19) in 21 (17.8%) patients, and unlikely (PDQ ≤ 12) in 67 (56.8%) patients. Using logistic regression analysis, the only independent variable among those investigated that could explain the neuropathic pain features was the presence of a comorbid FMS (p = 0.0127). Excluding patients with comorbid FMS, an association with disability (measured by Health Assessment Questionnaire–Disability Index) emerges (p = 0.0489). In patients with PsA and comorbid FMS, PDQ scores were significantly higher than in patients without comorbid FMS.Conclusion.Neuropathic pain features are common in patients with PsA, and the presence of pain sensitization (comorbid FMS) seems to be its main predictor.

Rheumatoid arthritis (RA) is associated with an increased risk of morbidity and mortality, when compared with general population, largely due to enhanced atherosclerotic disease. In this work, we aimed at assessing both occurrence and predictive factors of subclinical and clinical atherosclerosis in RA. From January 1, 2015, to December 31, 2015, consecutive participants with RA, admitted to Italian Rheumatology Units, were assessed in the GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) cohort. After that, those participants were followed up in a 3-year, prospective, observational study, assessing the occurrence of subclinical and clinical atherosclerosis and possible predictive factors. McNemar test was employed to assess the changes in subclinical and clinical atherosclerosis, and regression analyses exploited the ORs for the occurrence of those comorbidities. We analysed 841 participants, mostly female (82.2%) and with median age of 60 years (range 21–90). The remission was achieved and maintained by 41.8% of participants during the follow-up. We observed an increased rate of subclinical atherosclerosis at the end of follow-up (139 vs 203 participants, p< 0.0001), particularly in participants with a disease duration less than 5 years at baseline (70 participants vs 133 participants, p< 0.0001). Type 2 diabetes (T2D) (OR 4.50, 95%CI 1.74–11.62, p= 0.002), high blood pressure (OR 2.03, 95%CI 1.04–4.14, p= 0.042), ACPA (OR 2.36, 95%CI 1.19–4.69, p= 0.014) and mean values of CRP during the follow-up (OR 1.07, 95%CI 1.03–1.14, p= 0.040) were significantly associated with higher risk of subclinical atherosclerosis. We observed an increased rate of clinical atherosclerosis at the end of follow-up (48 vs 76 participants, p< 0.0001). T2D (OR 6.21, 95%CI 2.19–17.71, p= 0.001) was associated with a significant risk of clinical atherosclerosis. The achievement and the maintenance of remission reduced the risk of subclinical (OR 0.25, 95%CI 0.11–0.56, p= 0.001) and clinical atherosclerosis (OR 0.20, 95%CI 0.09–0.95, p= 0.041). We reported an increased prevalence and incidence of both subclinical and clinical atherosclerosis in 3-year prospectively followed participants, mainly in the subset with a duration of disease less than 5 years. The achievement and the maintenance of remission are associated with a reduction of the risk of subclinical and clinical atherosclerosis. Among “traditional” cardiovascular risk factors, participants with T2D showed a higher risk of clinical and subclinical atherosclerosis.

La fibromialgia (FM) è una condizione a eziologia sconosciuta, caratterizzata da dolore muscoloscheletrico diffuso e da polimorfi sintomi extra-scheletrici, in particolare l’astenia, i disturbi del sonno, le difficoltà cognitive, l’ansia e la depressione. La vasta gamma e la grande variabilità intra- e interindividuale dei sintomi extra-scheletrici, associate all’assenza di specifici esami di laboratorio o radiologici, rendono complessi l’iter diagnostico e la diagnosi differenziale, in particolare con l’ipertiroidismo, con il quale condivide la stanchezza, le mialgie diffuse, le difficoltà di memoria e concentrazione, la sensazione persistente di freddo. Si ritiene che alla base della sintomatologia fibromialgica vi sia una “sensibilizzazione centrale” cioè un’aumentata risposta dei neuroni del cervello e del midollo spinale agli stimoli. Sono inoltre riconoscibili diversi fattori di tipo predisponente e precipitante, sia di tipo fisico (infezioni, traumi), sia di tipo psicologico. Il trattamento della fibromialgia deve essere multimodale e integrare interventi farmacologici e non farmacologici, in particolare l’attività fisica aerobica e la psicoterapia cognitivo-comportamentale. Tra i farmaci, le maggiori evidenze di efficacia sostengono gli antidepressivi, gli anticonvulsivanti e alcuni analgesici. In ogni caso, è essenziale che l’intervento terapeutico sia altamente individualizzato e costruito tenendo conto delle specifiche esigenze del paziente, le sue risorse, l’ambiente che lo circonda.

Diclofenac is widely used to manage chronic inflammatory and degenerative joint diseases such as osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis, and extra-articular rheumatism. Its various mechanisms of action make it particularly effective in treating nociceptive pain, but it is also an alternative for treating spinal and chronic central pain. Osteoarthritis and rheumatoid arthritis are the most frequently encountered arthritic conditions in adults. The management of nociceptive pain requires a sequential hierarchical approach, with the initial NSAID treatment being characterized by the replacement of one drug with another, or complete discontinuation usually because of insufficient pain control. OA- and RA-related pain is complex and multifactorial, and due to physiological interactions between the signaling of the central and peripheral nervous systems. The mechanisms of action of diclofenac make it particularly effective in treating both nociceptive pain and chronic central pain. This review underlines the mechanisms of diclofenac involved in chronic and acute joint pain, the most relevant adverse events.

Central nervous system (CNS) involvement is quite unusual in patients with rheumatoid arthritis (RA), although cerebral vasculitis, rheumatoid nodules and meningitis have all been reported, and patients with RA may also have CNS comorbidities such as stroke and neuro-degenerative and demyelinating syndromes. It has been found that biological drugs, especially anti-tumour necrosis factor-alpha (anti-TNF-α) drugs, slightly increase the risk of developing demyelinating diseases, and they are consequently discouraged in patients with multiple sclerosis and related disorders. Furthermore, the risk of opportunistic CNS infections is increased in immunosuppressed patients.

Measurement of lymphocyte subpopulations is a crucial parameter in the diagnosis and monitoring of therapy in a wide variety of clinical conditions. We compared different flow cytometry‐based methods to determine lymphocyte subsets counts of routine samples by volumetric AQUIOS CL (Beckman Coulter) and bead‐based FACS CANTO II (BD Biosciences) cytometers. We evaluated the possible decrease of the labor intensive technical work using the fully automated AQUIOS CL system in the pre and post analytical steps in comparison with our routine flow cytometer FACS CANTO II, toward the reduction of laboratory analytical turnaround time (TAT). The analytical performance of AQUIOS CL flow cytometer compared with FACS CANTO II was evaluated testing 224 routine samples, attending the Immunology and Allergology Laboratory Unit, S. Giovanni di Dio Hospital, (Florence, Italy) between September and October 2015. Bland–Altman plot of the differences between the two methods showed an excellent agreement for absolute and percentage counts. Furthermore, the study showed that automated AQUIOS CL system is simple to be used during all analytical steps with a reduction of TAT. In routine conditions, AQUIOS CL flow cytometer could be a suitable tool for subpopulations subset analysis. © 2017 International Clinical Cytometry Society

The role of pericytes in systemic sclerosis (SSc) is unclear because of the difficulty in phenotyping them. They are mainly distributed in the pre-capillary, capillary and post-capillary abluminal side of non-muscular micro-vessels, express platelet-derived growth factor receptors (PDGFRs), and preside over vascular integrity and regeneration. By establishing close contact with many endothelial cells, a single pericyte can regulate ion influx, mechanical stress, leukocyte diapedesis, and platelet activation. Moreover, under pathological conditions such as SSc, pericytes may acquire a contractile phenotype and respond to various stimuli, including endothelin, angiotensin II and reactive oxygen species. The pericytes of SSc patients share some molecular patterns with myofibroblasts or fibroblasts, including A disintegrin and metalloproteinase domain 12 (ADAM-12), α-smooth muscle actin (α-SMA), the extra domain A (ED-A) variant of fibronectin, and Thy-1. Following stimulation with PDGF-β or transforming growth factor-β (TGF-β), pericytes may acquire a myofibroblast phenotype, and produce extracellular matrix or indirectly promote fibroblast activation. They may also contribute to fibrosis by means of epigenetic regulation. The pericyte plasmalemma is particularly rich in caveolae containing caveolin-1, a deficit of which has been associated with defective vessel tone control and lung fibrosis in mice. Consequently, dysfunctional pericytes may underlie the microangiopathy and fibrosis observed in SSc patients. However, given its variability in biological behaviour and the lack of a pan-pericyte marker, the exact role of these cells in SSc warrants further investigation.

ABSTRACTIntroduction: Fibromyalgia (FM) is a chronic disorder whose symptoms of pain, fatigue, sleep disturbances and depression have a devastating effect on patients’ lives as it limits their ability to engage in everyday working and social activities, and make it difficult to maintain normal relationships with family, friends and employers. None of the currently available drugs are fully effective against the whole spectrum of symptoms. The aim of this narrative review is to summarise the data relating to the new therapeutic options that have become available over the last few years.Areas covered: Increasing efforts by the pharmaceutical industry have led to the introduction of new investigational drugs and new formulations of older drugs, and studies have been carried out in order to investigate the possibility of using drugs that are currently used for other diseases.Expert opinion: Slight improvements in the health of FM patients treated with drugs targeting a range of molecular mechanisms have been observed, but there is still no single drug that is capable of offering substantial efficacy against all of the characteristic symptoms of FM. The identification of new and improved therapies for FM requires consideration of the heterogeneity of the condition, which suggests the existence of different patient subgroups, a relationship between central and peripheral aspects of the pathophysiology, and the need for combined treatment with drugs targeting multiple molecular mechanisms.

To examine the relationship between smoking, smoking cessation, and disease characteristics and quality of life (QoL) in spondyloarthritis. The Scotland Registry for Ankylosing Spondylitis collects data from clinically diagnosed patients with spondyloarthritis. Clinical data, including Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) scores, were obtained from medical records. Mailed questionnaires contained information on smoking status and QoL (Ankylosing Spondylitis QoL questionnaire [ASQoL]). Linear and logistic regression were used to quantify the effect of smoking, and smoking cessation, on various disease‐specific and QoL outcomes, with adjustments for age, sex, deprivation, education level, and alcohol use. Results are presented as regression coefficients (β) or odds ratios (ORs) with 95% confidence intervals (95% CIs). Data were obtained from 946 participants (73.5% male, mean age 52 years). Current smoking was reported by 22%, and 38% were ex‐smokers. Ever smokers had poorer BASDAI (β = 0.5 [95% CI 0.2, 0.9]) and BASFI scores (β = 0.8 [95% CI 0.4, 1.2]), and reported worse QoL (ASQoL β = 1.5 [95% CI 0.7, 2.3]). Compared to current smokers, ex‐smokers reported less disease activity (BASDAI β = −0.5 [95% CI −1.0, −0.04]) and significantly better QoL (ASQoL β = −1.2 [95% CI −2.3, −0.2]). They also were more likely to have a history of uveitis (OR 2.4 [95% CI 1.5, 3.8]). Smokers with spondyloarthritis experience worse disease than those who are never smokers. However, this study provides new evidence that, among smokers, smoking cessation is associated with lower disease activity and better physical function and QoL. Clinicians should specifically promote smoking cessation as an adjunct to usual therapy in patients with spondyloarthritis.

ABSTRACTIntroduction:Pregabalin is indicated for the treatment of fibromyalgia and pregabalin-treated subjects have shown improved pain, sleep and functional measures in placebo-controlled and open-label studies. This article reviews pregabalin’s safety profile.Areas covered:The safety findings in pregabalin clinical trials were accessed by a PubMed search using the key words ‘pregabalin’ or ‘anti-epilectics drug’ or ‘gabapentinoids’ or ‘anticonvulsants’ and ‘fibromyalgia’. Although frequent, the side effects of pregabalin therapy are usually mild to moderate, well tolerated in the long term, and can be monitored in a primary care setting.Expert opinion:Pregabalin therapy may be associated with somnolence, dizziness, weight gain and periphereal edema. Potential drug interactions are not common, and pregabalin seems to be well tolerated in combination with antidepressants. The demonstrated efficacy of pregabalin suggests that the risk/benefit ratio favours its use.

Rheumatoid arthritis (RA) with concomitant hepatitis B virus (HBV) infection represents a therapeutic challenge due to the risk of HBV reactivation under immunosuppressive treatment. To date there are few data coming from anecdotal case reports that concern HBV reactivation following treatment with abatacept. This observational retrospective study was aimed to assess the safety profile of abatacept in this particular clinical setting. Eleven Italian rheumatologic centers provided data from patients with RA and positive HBV serology treated with intravenous abatacept. HBV markers and clinical and laboratory data were checked at followup visits every 3 months. In total, 72 patients were included in the study: 47 inactive carriers, 21 occult carriers, and 4 chronic active carriers for HBV. At baseline all of the patients had normal liver function tests and low or undetectable HBV DNA levels, except for those with chronic active hepatitis. Thirteen patients received prophylaxis with lamivudine, and 4 received treatment with adefovir or tenofovir. At the end of the 24‐month followup period, 49 patients were being treated. Data from 316 followup visits showed that abatacept was safe. No patients experienced reactivation of hepatitis B. Treatment withdrawals (23 patients) were due to lack of efficacy, subject decision/lost at followup, or adverse events not related to HBV infection. Our study provides reassuring data about the safety profile of abatacept in RA with concomitant HBV infection without universal antiviral prophylaxis. Further prospective studies are needed to confirm these preliminary results.

Objective.Patients with resolved hepatitis B virus (HBV) infection, i.e., hepatitis B surface antigen (HBsAg)-negative/antihepatitis B core antigen (anti-HBc)-positive, undergoing rituximab (RTX)-based chemotherapy for hematological malignancies without anti-HBV prophylaxis are at risk of HBV reactivation, but the risk in such patients receiving RTX for rheumatological disorders is not clear. We evaluated this risk in HBsAg-negative/anti-HBc–positive patients with rheumatoid arthritis (RA) undergoing RTX without prophylaxis.Methods.Thirty-three HBsAg-negative/anti-HBc–positive outpatients with RA with undetectable HBV DNA by sensitive PCR assay [73% women, median age 60 years, 85% with HBsAg antibodies (anti-HBs), 37% with antihepatitis B envelope antigen] received a median of 3 cycles of RTX (range 1–8) over 34 months (range 0–80) combined with disease-modifying antirheumatic drugs (DMARD) without prophylaxis. All underwent clinical and laboratory monitoring during and after RTX administration, including serum HBsAg and HBV DNA measurements every 6 months or whenever clinically indicated.Results.None of the patients seroreverted to HBsAg during RTX treatment, but 6/28 (21%) showed a > 50% decrease in protective anti-HBs levels, including 2 who became anti-HBs–negative. One patient (3%) who became HBV DNA-positive (44 IU/ml) after 6 months of RTX treatment was effectively rescued with lamivudine before any hepatitis flare occurred. Among the 14 patients monitored for 18 months (range 0–70) after RTX discontinuation, no HBV reactivation was observed.Conclusion.The administration of RTX + DMARD in patients with RA with resolved HBV infection leads to a negligible risk of HBV reactivation, thus suggesting that serum HBsAg and/or HBV DNA monitoring but not universal anti-HBV prophylaxis is justified.

Ro52 is an interferon-inducible protein of the tripartite motif family. Antibodies against Ro52 have been described in patients with different autoimmune diseases, such as systemic lupus erythematosus and Sjögren’s syndrome, that are often associated with anti-Ro60 antibodies. The Ro52 autoantigen is extraordinarily immunogenic, and its autoantibodies are directed against both linear and conformational epitopes. The aim of this study was to evaluate the prevalence of antibodies to the five Ro52 domains, as well as to Ro52 176– to 196–amino acid (aa) and 200–239-aa peptides, in different systemic autoimmune rheumatic diseases (SARDs). We also aimed to verify whether antibodies to a single domain or domain association could increase their diagnostic specificity for any SARD. Serum samples were obtained from 100 anti-Ro52 antibody–positive patients with SARDs and from 68 controls (50 healthy donors and 18 patients with other autoimmune or allergic diseases). A special line immunoassay was created containing a full-length Ro52 antigen expressed in insect cells using the baculovirus system, five recombinant Ro52 antigen fragments [Ro52-1, Ro52-2, Ro52-3, Ro52-4 (partly overlapping Ro52-1 and Ro52-2), and Ro52-5 (partly overlapping Ro52-2 and Ro52-3)], and two Ro52 peptides (176–196 aa and 200–239 aa), all expressed in Escherichia coli. In patients with SARDs, fragment prevalence rates were as follows: Ro52-1 = 3 %, Ro52-2 = 97 %, Ro52-3 = 0 %, Ro52-4 = 9 %, Ro52-5 = 28 %, Ro52 175–196-aa peptide = 6 %, and Ro52 200–239-aa peptide = 74 %. All control samples were negative for the full-length Ro52 and for the five fragments tested. The main epitope of the Ro52 antigen was localized on fragment 2 (aa 125–267), and the majority (97 %) of SARD sera had antibodies that target this fragment. As most of the samples were positive for fragment 2 and only some for fragments 4 or 5, which partially overlap fragment 2, it seems that the target epitope is localized in the middle of fragment 2 or in the area between fragments 4 and 5. No antibody against a single epitope or a combination of epitopes was linked to any of the single SARDs.

IL-9, which may be an inflammatory or regulatory cytokine, can be experimentally produced in a Th17 or modified Th2 context in the presence of T cell receptor (TCR) stimulation. The primary aim of this study was to measure serum IL-9 levels in patients with inflammatory bowel disease (IBD), and evaluate their relationships with the patients’ clinical characteristics. The secondary aim was to determine the levels of interferon-? (IFN (interferon)-?), Th2 cytokines (IL-4, IL-5 and IL-13), and IL-6 in order to clarify the context of detectable peripheral cytokines in which IL-9 is produced.Venous blood samples of 43 IBD patients (20 with Crohn’s disease [CD] and 23 with ulcerative colitis [UC]) were analysed by means of quantitative enzyme-linked immunosorbent assays using purified anti-human IL-4, IL-5, IL-13, IFN-?, IL-9 and IL-6 antibodies, and the laboratory findings were statistically correlated with their clinical expression.None of the patients showed the peripheral presence of IL-4, IL-5 and IL-13. Forty (93%) were positive for IFN-?, thus confirming the presence of Th1 in both UC and CD, and IFN-? levels correlated with disease activity (P= 0.045). Eighteen patients (41%) were positive for IL-9, which was associated with a severe prognosis (P<0.001), and 72.2% of the IL-9-positive patients were also IL-6 positive. There was a significant correlation between disease severity and IL-9 in the CD patients (P<0.001), but not in the UC patients (P= 0.1).Our findings confirm the presence of common Th1 cytokines in UC and CD. However the IL-9 positivity indicates the presence of an alternative population of T cells that respond to antigen stimulation and condition the prognosis of IBD. The fact that the same serum IL-9 levels were differentially associated with clinical measures of CD and UC activity suggest that the same cytokine can be produced in different contexts.

Cryoglobulinaemic syndrome (CS) includes clinical signs and symptoms that range from the classic triad of Meltzer and Franklin (purpura, weakness and arthralgias) to multiple organ involvement, and it may be characterised by nociceptive or neuropathic pain. Both types of pain use the same pathways and neurotransmitters, but nociceptive pain has an adaptive system and biological function whereas neuropathic pain does not. Managing CS means dealing with often very different clinical patterns, activity and severity with the aim of preventing irreversible organ damage, reducing pain, improving the patients' quality of life and reducing social costs. However, treatment is still largely empirical, and it is often delayed. The Italian Group for the Study of Cryoglobulinaemia (GISC) strongly recommended a low-antigen-content diet and colchicine for all symptomatic CS patients. Patients with mild–moderate symptoms (such as purpura, weakness, arthralgia and initial neuropathy) have been treated with low or medium doses of steroids, and, in the presence of chronic hepatitis C virus (HCV)-related hepatitis, an attempt has been made to eradicate HCV with pegylated interferon plus ribavirin. In the case of severe or rapidly progressive disease (glomerulonephritis, neuropathy, leg ulcers, widespread vasculitis or hyperviscosity syndrome), more aggressive treatment should be used (e.g., high doses of corticosteroids, plasma exchange plus cyclophosphamide or rituximab). Pain management in CS therefore depends on the type of pain (nociceptive, neuropathic or mixed), the characteristics of the patients and their co-morbidities. Drug therapy should be carefully monitored in order to obtain prompt and beneficial results.

Complex regional pain syndrome (CRPS) encompasses a wide range of painful conditions, but it is characterised by continuing (spontaneous and/or evoked) limb pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional, with distal predominance usually but not related to a specific nerve territory or dermatome, and it is usually associated with abnormal sensory, motor, sudomotor, vasomotor and/or trophic findings. The complexity of the aetiopathogenetic factors making up the clinical picture of CRPS is mirrored by the inconsistency of almost all of the monotherapies used to treat it so far.

The sometimes intense, persistent and disabling pain associated with rheumatoid arthritis (RA) and spondyloarthritis frequently has a multifactorial, simultaneously central and peripheral origin, and it may be due to currently active inflammation or joint damage and tissue destruction caused by a previous inflammatory condition. The symptoms of inflammatory pain symptoms can be partially relieved by non-steroidal anti-inflammatory drugs, but many patients continue to experience moderate pain due to alterations in central pain regulation mechanisms, as in the case of the chronic widespread pain (CWP) characterising fibromyalgia. The importance of distinguishing CWP from inflammatory pain is underlined by the fact that drugs such as tumour necrosis factor inhibitors are expensive, and direct costs are higher in patients with concomitant CWP than in those without. The management of pain requires a combination approach that includes pharmacological analgesia, and biological and non-biological treatments because, although joint replacement surgery can significantly improve RA-related pain, it may only be available to patients with the most severe advanced disease.

Pain is associated with the different types of rheumatic syndromes because it is often the most troubling symptom of patients affected by any of these diseases. Some risk factors clearly play a major role in the clinical expression of pain and related syndromes, including genetics, age, gender, co-morbidities, traumas and psychological patterns, but there are no specific clinical, laboratory or neuroimaging markers that can indicate why and when a patient's localised pain will become chronic and widespread. Any type of pain must be treated not only appropriately, but also rapidly because the likelihood of developing some form of chronic pain is related to the duration of the peripheral pain stimulus. Chronic pain inevitably has a major impact on patients' quality of life because the loss of function undermines their ability to do everyday activities. Pain can be most effectively treated by carefully selecting various pharmacological and non-pharmacological interventions based on the characteristics of the pain itself, disease factors, psychological coping abilities, and lifestyle.

Pain is frequent in patients with connective tissue diseases (CTDs), particularly those affected by systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) in which it is virtually ubiquitous and can have different causes. The SLE classification criteria include pain associated with musculoskeletal involvement, which are frequently the initial symptom of SLE and can include arthralgia, arthritis and/or myalgia. Chronic widespread pain, the cornerstone of fibromyalgia (FM), is also frequently associated with CTDs.

The assessment of chronic pain and its impact on physical, emotional and social functions requires the use of multidimensional qualitative and health-related quality of life instruments, but there is still little agreement concerning what these may be or which approach to adopt. Increasing focus on patient-reported outcomes in medicine has had the positive effect of giving prominence to the views and experiences of patients with chronic pain, and the ecological momentary assessment (EMA) approach allows patients' symptoms to be assessed in their natural environment in real time without the need for recall. Computerised EMA symptom diaries are now generally regarded as the ‘gold standard’ in the field of pain medicine, and they have recently attracted increasing attention as an essential component of health-care monitoring systems based on the information and communication technology. A web/Internet-based diary and patient terminal seem to provide a ubiquitous, easy-to-use and cost-efficient solution for patient-centred data acquisition. In addition, telemonitoring is increasingly seen as an effective means of supporting shared decision-making as it can inform patients about typical symptoms, treatment options and prognosis, and it is widely accepted as an additional source of information. This article reviews some of the instruments used to assess chronic pain, including newly developed and well-established validated multidimensional instruments and health-care monitoring systems based on information and communication technology, and it discusses their advantages and limitations.

Serum cartilage oligomeric matrix protein (COMP) level is a new marker of joint destruction in patients with rheumatoid arthritis (RA), and a new means of identifying patients with progressive joint damage. To evaluate the effect of tocilizumab (TCZ) on serum COMP levels, and whether there is any difference in this effect between patients failing on anti-TNF treatment and those failing on disease-modifying anti-rheumatic drugs (DMARDs). Fifty-one patients with long-standing RA (42 F, 9 M; mean age 62±14 years; disease duration 4.5±1.2 years) unresponsive to DMARDs and anti-TNF drugs were treated with TCZ 8 mg/kg/month. Serum COMP levels were measured by means of an ELISA at baseline and after six months of TCZ treatment; the patents’ DAS28 scores and levels of RF (IgM, IgG, IgA), anti-CCP autoantibodies, ESR, CRP and IL-6 were evaluated at the same times. After six months of TCZ treatment, there was a significant decrease from baseline in ESR (46.1 [28.7-68.9] vs 34.3 [4.1- 58.8] mm/h, P <0.0001), CRP (2.2 [0.8-4.4] vs 1.3 [0.7-3.8] mg/dL, P <0.0001), TNF-α (21.3 [7.6-29.8] vs 17.4 [3.4-28.6] pg/mL, P=0.0408), IL-6 (6.9 [3.5-9.6] vs 3.4 [3.0-9.6] pg/mL, p<0.0001); anti-CCP (55.1 [30.2-273.0] vs 54.7 [30.1- 269.8] IU/mL, P=0.9683), RF-IgM (142.0 [48.0-260.0] vs 138.0 [42.0-243.0] IU/mL, P=0.4828), RF-IgA (81.0 [20-140] vs 108.0 [20-175] U/mL, P=0.0003), and RF-IgG (65.2 [30-158] vs 58.3 [38.0-158.0] U/mL, P=0.2671). There was also a significant decrease in DAS28 scores (4.3 [3.2-5.9] vs 3.7 [2.3-5.4], P <0.0001), and a non-significant decrease in serum COMP levels (0.95 [0.04-2.90] vs 0.98 [0.05-2.36] μg/mL; P = 0.9856). A decrease in serum COMP levels was observed in the patients failing on anti-TNF treatment or anti-DMARDs without any difference. TCZ therapy in patients with long-standing RA is associated with a significant decrease in ESR, CRP, IL-6, TNF and DAS28 values, and a decrease in serum COMP levels, particularly in patients failing on previous anti-TNF therapy. These findings suggest that TCZ has an effect on cartilage joint destruction after only six months of treatment.

Objective.To evaluate 4-year retention rates of tumor necrosis factor-α (TNF-α) inhibitors adalimumab, etanercept, and infliximab among patients with longstanding rheumatoid arthritis (RA), as derived from an Italian national registry.Methods.The clinical records of 853 adult patients with RA in the GISEA (Gruppo Italiano Studio Early Arthritis) registry were prospectively analyzed to compare drug survival rates and the baseline factors that may predict adherence to therapy.Results.In 2003 and 2004, 324 patients started treatment with adalimumab, 311 with etanercept, and 218 with infliximab. After 4 years, the global retention rate of anti-TNF-α therapy was 42%. Etanercept survival (51.4%) was significantly better than that of infliximab (37.6%) or adalimumab (36.4%; p < 0.0001). Accordingly, the mean duration of therapy was significantly longer for etanercept (3.1 ± 2 yrs) than for adalimumab (2.6 ± 2 yrs) or infliximab (2.7 ± 2 yrs; p < 0.05). The use of concomitant disease-modifying antirheumatic drugs, mainly methotrexate, and the presence of comorbidities significantly predicted drug continuation (p < 0.01), whereas a high Disease Activity Score did not.Conclusion.The 4-year global drug survival of adalimumab, etanercept, and infliximab was lower than 50%, with etanercept having the best retention rate. The main positive predictor of adherence to anti-TNF-α therapy was the concomitant use of methotrexate. Our study provides further evidence that the real-life treatment of patients with RA may be different from that of randomized clinical trials.

OBJECTIVE: To identify the clinical features that can help to distinguish between psoriatic arthritis (PsA) and fibromyalgia (FM). METHODS: Our cross-sectional study was carried out in 10 Italian rheumatology centers between January and September 2009, and enrolled all consecutive patients with PsA and FM who agreed to participate. Standard clinical and laboratory data for PsA and FM were collected from all patients. Records were made of somatic symptoms, response to nonsteroidal antiinflammatory drugs (NSAID), self-evaluated pain, general health, disability, and responses to the Fibromyalgia Impact Questionnaire. Data were statistically analyzed by univariate and multivariate analyses, and receiver-operating characteristic curves. The analysis concentrated on the clinical features shared by the 2 conditions. RESULTS: Two hundred sixty-six patients with PsA (mean age 51.7 yrs; disease duration 10.2 yrs) and 120 patients with FM (mean age 50.2 yrs; disease duration 5.6 yrs) were evaluated. Univariate analysis showed that patients with FM had higher mean tender point and enthesitis scores, more somatic symptoms, and responded less to NSAID. Multivariate analysis showed that the presence of ≥ 6 FM-associated symptoms and ≥ 8 tender points was the best predictor of FM. CONCLUSION: The shared clinical features of PsA and FM that had the greatest discriminating power for FM were the number of FM-associated symptoms and tender point count.

OBJECTIVE: To identify the presence of subclinical atherosclerosis in patients with psoriatic arthritis (PsA) and healthy controls using intima-media thickness (IMT), coronary flow reserve (CFR), and the plasma concentration of asymmetric dimethylarginine (ADMA), to evaluate the correlations among ADMA, IMT, and CFR. METHODS: The study involved 22 patients who fulfilled the ClASsification of Psoriatic ARthritis study group criteria for PsA and a cohort of 35 healthy controls with no history or current signs of coronary artery disease (CAD). Common carotid IMT was measured using high-resolution B-mode ultrasonography. Dipyridamole transthoracic stress echocardiography was used to evaluate CFR. Blood samples were obtained to assess ADMA levels. The clinical manifestations were recorded. All patients were treated with disease-modifying antirheumatic drug, but none had received any biological or steroid therapy. RESULTS: Plasma ADMA levels were significantly higher in the patients with PsA (0.71 ± 0.07 µmol/l vs 0.48 ± 0.07 µmol/l; p = 0.00) and CFR was significantly reduced in that group (2.86 ± 0.70 vs 3.3 ± 0.43; p < 0.01) compared to controls. Common carotid IMT was greater in the patients with PsA, but the difference was not significant (0.64 ± 0.26 mm vs 0.62 ± 0.5 mm; p = 0.65). There was a significant correlation between CFR and plasma ADMA levels in the PsA group (R = 0.28; p < 0.01), but no correlation between plasma ADMA levels and IMT (R = 0.02; p = 0.32), Disease Activity Score 28 (p = 0.52), or Psoriasis Area and Severity Index (p = 0.98). CONCLUSION: Our patients with PsA showed a profile of subclinical atherosclerosis. ADMA may be a useful marker of endothelial dysfunction in PsA.

Fibromyalgia (FM) is a rheumatic disease that is characterised by chronic musculoskeletal pain, stiffness, fatigue, sleep and mood disorder. FM patients demonstrate dysregulation of pain neurotransmitter function and experience a neurohormone-mediated association with sleep irregularities. There are currently no instrumental tests or specific diagnostic markers for FM, and many of the existing indicators are only significant for research purposes. Anti-depressants, non-steroidal anti-inflammatory drugs (NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have all been used to treat FM with varying results. It has been shown that interdisciplinary treatment programmes lead to greater improvements in subjective pain and function than monotherapies. Physical exercise and multimodal cognitive behavioural therapy are the most widely accepted and beneficial forms of non-pharmacological therapy.

Assessing chronic widespread pain (CWP) and its impact on physical, emotional and social function requires multidimensional qualitative and health-related quality of life (HRQL) instruments. The recommendations of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) concerning outcome measurements for pain trials are useful for making routine assessments, the most significant of which include pain, fatigue, disturbed sleep, physical functioning, emotional functioning, patient global ratings of satisfaction and HRQL. However, despite the growing spread of instruments and theoretical publications devoted to measuring the various aspects of chronic pain, there is little widespread agreement, and no unified approach has yet been devised. There is therefore still considerable scope for the development of consensus around a core set of measures and response criteria, as well as for the development and refinement of the related instruments, standardised assessor training, the cross-cultural adaptation of health status questionnaires, electronic data capture and the introduction of valid, reliable and responsive standardised quantitative measurements into routine clinical care. Clinicians need to be aware of the psychometric properties of the instruments used, including their levels of imprecision and minimum clinically important differences (those indicating a meaningful change in clinical status). This article reviews a selection of the instruments used to assess CWP patients, including validated newly developed and well-established screening instruments, and discusses their advantages and limitations.

Fibromyalgia (FM) is a rheumatic disease characterised by musculoskeletal pain, chronic diffuse tension and/or stiffness in joints and muscles, fatigue, sleep and emotional disturbances and pressure pain sensitivity in at least 11 of 18 tender points. There are currently no instrumental tests or specific diagnostic markers, and the characteristic symptoms of the disease overlap those of many other conditions classified in a different manner. FM is often associated with other diseases that act as confounding and aggravating factors, including primary Sjögren’s syndrome (pSS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). It has been reported to coexist in 25% of patients with RA, 30% of patients with SLE and 50% of patients with pSS.

Chronic pain can be classified as localised, regional or widespread, and its high prevalence in the general population seems to increase with age. The majority of cases present with musculoskeletal pain. The conditions associated with chronic widespread pain (CWP) are highly burdensome as their characteristic symptoms may include multifocal pain, fatigue, insomnia, memory difficulties and a higher rate of concomitant mood disorders. After many years of debate, it is still unclear whether CWP (central sensitisation) is an entirely explainable neurotransmitter-related process or is partially or totally due to individual cognitive experiences and evaluations. The two models (neurochemical and biopsychosocial) also affect our ability to find therapeutic answers.

Neutrophils are known to be targets for the biological activity of tumour necrosis factor (TNF)-α in the pathogenensis of rheumatoid arthritis (RA). Therefore, these cells may be among the targets of anti-TNF-α therapy. In this study we evaluated the effect of therapy with adalimumab (a fully human anti-TNF-α mAb; dosage: 40 mg subcutaneously every other week) on certain phenotypic and functional aspects of neutrophils obtained from 10 selected patients with RA and 20 healthy control individuals. Peripheral blood neutrophils were obtained at baseline and during anti-TNF-α therapy (2, 6 and 12 weeks after the first administration of adalimumab). All patients had been receiving a stable regimen of hydroxychloroquine, methotrexate and prednisone for at least 3 months before and during the study. Baseline neutrophil chemotaxis was significantly decreased in RA patients when compared with control individuals (P < 0.001). Two weeks after the first administration of adalimumab, chemotactic activity was completely restored, with no differences noted between patients and control individuals; these normal values were confirmed 6 and 12 weeks after the start of anti-TNF-α therapy. Phagocytic activity and CD11b membrane expression on neutrophils were similar between RA patients and control individuals; no modifications were observed during TNF-α neutralization. The production of reactive oxygen species, both in resting and PMA (phorbol 12-myristate 13-acetate)-stimulated cells, was significantly higher in RA patients at baseline (P < 0.05) and was unmodified by anti-TNF-α mAb. Finally, we showed that the activation antigen CD69, which was absent on control neutrophils, was significantly expressed on neutrophils from RA patients at baseline (P < 0.001, versus control individuals); however, the molecule was barely detectable on cells obtained from RA patients during adalimumab therapy. Because CD69 potentially plays a role in the pathogenesis of arthritis, our findings suggest that neutrophils are among the targets of anti-TNF-α activity in RA and may provide an insight into a new and interesting mechanism of action of anti-TNF-α mAbs in the control of inflammatory arthritis.

OBJECTIVE: Fibromyalgia (FM) is a syndrome characterized by widespread musculoskeletal pain. Symptoms of orthostatic intolerance may also be present, suggesting underlying abnormalities of cardiovascular neural regulation. We tested the hypothesis that FM is characterized by sympathetic overactivity and alterations in cardiovascular autonomic response to gravitational stimulus. METHODS: Sixteen patients with primary FM and 16 healthy controls underwent electrocardiography examination, finger blood pressure, respiration, and muscle sympathetic nerve activity (MSNA) recordings at rest and during stepwise tilt test, up to 75°. The autonomic profile was assessed by MSNA, plasma catecholamine, and spectral indices of cardiac sympathetic (LFRR in normalized units, NU) and vagal (HFRR both in absolute and NU) modulation and of sympathetic vasomotor control (LFSAP) computed by spectrum analysis of RR and systolic arterial pressure (SAP) variability. Arterial baroreflex function was evaluated by the SAP/RR spontaneous-sequences technique, the index a, and the gain of MSNA/diastolic pressure relationship during stepwise tilt test. RESULTS: At rest, patients showed higher values of heart rate, MSNA, LFRR NU, LF/HF, LFSAP, and reduced HFRR than controls. During tilt test, lack of increase of MSNA, less decrease of HFRR, and excessive rate (44%) of syncope were found in patients, suggesting reduced capability to enhance the sympathetic activity to vessels and withdraw the vagal modulation to sino-atrial node. Baroreflex function was similar in both groups. CONCLUSION: Patients with FM have an overall enhancement of cardiovascular sympathetic activity while recumbent. Lack of increased sympathetic discharge to vessels and decreased cardiac vagal activity characterize their autonomic profile during tilt test, and might account for the excessive rate of syncope.

OBJECTIVE: Androgens such as dehydroepiandrosterone sulfate (DHEAS) and testosterone are markedly lower in postmenopausal women with rheumatoid arthritis (RA) than in controls. In contrast, compared to controls, serum levels of estrogens are normal or elevated in women with RA. Since tumor necrosis factor (TNF) alters production of these hormones, we investigated changes of these hormones during anti-TNF antibody (anti-TNF) therapy with adalimumab in longstanding RA. METHODS: In this longitudinal anti-TNF therapy study in 13 patients with long-standing RA without prior prednisolone (7 infusions of anti-TNF: Week 0, 2, 4, 6, 8, 10, and 12), we measured serum concentrations of interleukin 6 (IL-6), androstenedione, DHEA, DHEAS, free testosterone, estrone, and 17ß-estradiol. Levels of these hormones in patients were compared to serum levels of 31 age and sex matched healthy controls. RESULTS: Upon treatment with anti-TNF, there was an impressive decrease of clinical markers of inflammation, erythrocyte sedimentation rate, and serum levels of IL-6. Serum levels of DHEAS and free testosterone were markedly lower at baseline in patients compared to controls, but this did not change during anti-TNF therapy. Serum levels of DHEA and 17ß-estradiol were significantly elevated in patients compared to controls, but similarly, anti-TNF therapy did not change initially increased levels. Molar ratios of hormones, which reflect hormone shifts via converting enzymes, showed typical alterations at baseline, but did not change markedly during anti-TNF therapy. CONCLUSION: Longterm therapy with anti-TNF did not change altered serum levels of typical sex hormones in patients with RA, although baseline values were largely different. In patients with RA, this indicates that alterations of sex hormones and altered activity of respective converting enzymes are imprinted for a long-lasting period over at least 12 weeks.

OBJECTIVE: In the dynamic organization of sleep, cyclic alternating pattern (CAP) expresses a condition of instability of the level of vigilance that manifests the brain's fatigue in preserving and regulating the macrostructure of sleep. We evaluated the presence of CAP in patients with fibromyalgia (FM) compared to healthy controls. METHODS: Forty-five patients with FM (42 women) were studied and compared with 38 healthy subjects (36 women) matched for age, sex, and body mass index. Entry criteria were diagnosis of FM according to 1990 American College of Rheumatology criteria; willingness to participate in the study; and having no other diagnosis of autoimmune, neoplastic, or other possible causes of secondary diffuse musculoskeletal pain. Patients in the study underwent polysomnography recordings and a sleep questionnaire. Hypersomnolence was evaluated according to the Epworth Sleepiness Scale. RESULTS: FM patients had less sleep efficiency (sleep time/time in bed) than controls (79 ± 10 vs 89 ± 6; p < 0.01), a higher proportion of stage 1 non-rapid eye movement (non-REM) sleep (20 ± 5 vs 12 ± 5; p < 0.001), and twice as many arousals per hour of sleep (9.7 ± 3.3 vs 4.1 ± 1.9; p < 0.01). The CAP rate (total CAP time/non-REM sleep time) was significantly increased in FM patients compared to controls (68 ± 6% vs 45 ± 11%; p < 0.001). CAP rate seemed to correlate with the severity of clinical symptoms in FM patients (tender points index; p < 0.01) and with less efficiency of sleep (p < 0.01). CONCLUSION: The increase of CAP rate indicates a worse quality of sleep in patients with FM. These data are strongly correlated to the severity of symptoms.