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Introduction: The 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 Covered: In 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 Opinion: The 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).

Objectives: In this study, we aimed at describing the clinical characteristics, life-threatening complications occurrence, and mortality of adult-onset Still's disease (AOSD) patients with elderly onset., Methods: A multicentre retrospective study of prospectively followed-up AOSD patients included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort was performed., Results: Out of 221 assessed patients, 37 (16.7%) had an onset of the disease aged over 60 years. When compared with younger patients, these were characterised by a higher prevalence of pericarditis (p=0.008), comorbidities (p<0.0001), and mortality (p=0.023). Age predicted the presence of serositis in both univariate (HR: 1.02, 95%CI: 1.01-1.03, p=0.007) and multivariate analyses (HR: 1.02, 95%CI: 1.01-1.04, p=0.007). Age was also a significant predictor of parenchymal lung disease in both univariate (HR: 1.03, 95%CI: 1.01-1.05, p=0.017) and multivariate analyses (HR: 1.03, 95%CI: 1.00-1.05, p=0.048). Furthermore, age resulted to be a negative predictor of polycyclic pattern only in univariate analysis (HR: 0.99, 95%CI: 0.97-1.00, p=0.048). Finally, age significantly predicted the mortality in both univariate (HR: 1.03, 95%CI: 1.00-1.06, p=0.034) and multivariate analyses (HR: 1.05, 95%CI: 1.01-1.08, p=0.012)., Conclusions: Clinical features of AOSD patients in the elderly were described in our cohort. Although the main clinical characteristics were similar comparing older and younger patients, patients aged over 60 years at disease onset were characterised by an increased prevalence of serositis, comorbidities, mostly cardiometabolic, and a higher mortality rate. Age predicted the presence of parenchymal lung disease and mortality, and it could be considered a negative prognostic factor in AOSD.

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory condition characterized by skin and joints involvement, and with a great burden of comorbidity that could affect the choice of treatment. Chronic obstructive pulmonary disease (COPD) is one of the primary causes of morbidity and mortality. Medical therapy can improve symptoms and the frequency and severity of exacerbations. A variety of evidence showed an increasing association between COPD and PsA., Areas Covered: Psoriatic disease and COPD appear to have a possible pathophysiologic link. The inhibition of intracellular molecules responsible for pro-inflammatory responses could be a therapeutic approach for both psoriatic diseases and COPD. Inhibitors of phosphodiesterase 4 (PDE-4) were developed to treat chronic inflammatory conditions such as psoriasis, PsA and COPD. Roflumilast has been used to treat COPD and asthma, while Apremilast to treat psoriasis and PsA. Given the efficacy and safety of these treatments, we can speculate that blocking PDE-4 might also provide clinical benefits in patients with co-existing COPD and PsA., Expert Opinion: This hypothesis could offer the opportunity to screen patients for both diseases. Furthermore, this approach would increase the involvement of other specialists in the management of PsA, and it would improve the use of a tailored treatment for each patient.

Introduction: Interleukin 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 Covered: In 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 Opinion: These 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.

Objective: To develop recommendations for cardiovascular risk (CVR) management in gout, vasculitis, systemic sclerosis (SSc), myositis, mixed connective tissue disease (MCTD), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS)., Methods: Following European League against Rheumatism (EULAR) standardised procedures, a multidisciplinary task force formulated recommendations for CVR prediction and management based on systematic literature reviews and expert opinion., Results: Four overarching principles emphasising the need of regular screening and management of modifiable CVR factors and patient education were endorsed. Nineteen recommendations (eleven for gout, vasculitis, SSc, MCTD, myositis, SS; eight for SLE, APS) were developed covering three topics: (1) CVR prediction tools; (2) interventions on traditional CVR factors and (3) interventions on disease-related CVR factors. Several statements relied on expert opinion because high-quality evidence was lacking. Use of generic CVR prediction tools is recommended due to lack of validated rheumatic diseases-specific tools. Diuretics should be avoided in gout and beta-blockers in SSc, and a blood pressure target <130/80 mm Hg should be considered in SLE. Lipid management should follow general population guidelines, and antiplatelet use in SLE, APS and large-vessel vasculitis should follow prior EULAR recommendations. A serum uric acid level <0.36 mmol/L (<6 mg/dL) in gout, and disease activity control and glucocorticoid dose minimisation in SLE and vasculitis, are recommended. Hydroxychloroquine is recommended in SLE because it may also reduce CVR, while no particular immunosuppressive treatment in SLE or urate-lowering therapy in gout has been associated with CVR lowering., Conclusion: These recommendations can guide clinical practice and future research for improving CVR management in rheumatic and musculoskeletal diseases., Competing Interests: Competing interests: GCD, DV, EH, LB, SB, DTB, NB, GK, FM, CM, MR-C, KS, SS, VPvH, GJM, MMW and MN have nothing to declare. FA: research grants from BMS, Celgene, Novartis and Sandoz and consulting fees from AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and Sanofi-Aventis, all unrelated to this manuscript; INB: grant from GSK paid to institution, consulting fees from Astra Zeneca, GSK, Eli lilly, UC, MSD paid to institution, support for attending meetings and/or travel from GSK, participation on a data safety monitoring board/or advisory board from Aurinia, Astra Zeneca and ILTOO paid to institution, all unrelated to this manuscript; MÁG-G: grants/research support from AbbVie, MSD, Jansen and Roche paid to institution and personal consulting fees/participation in company sponsored speakers bureau from AbbVie, Pfizer, Roche, Celgene, MSD, Novartis, SOBI and Sanofi, all unrelated to this manuscript; SJ: grants from BMS paid to institution, personal consulting fees from Astra Zeneca, and personal fees from Danish Medicolegal Council, all unrelated to this manuscript; NS: grants paid to institution from Astrazeneca, Boehringer Ingelheim and Roche Diagnostics, personal consulting fees from Afimmune, Amgen, Astrazeneca, Boehringer Ingelheim, Eli-Lilly, Hanmi Pharamceuticals, MSD, Novartis, Novo Nordisk, Pfizer and Sanofi, all unrelated to this manuscript; ES: grant from Merck and honoraria from Janssen, all unrelated to this manuscript; ZS: research grants from Pfizer paid to institution and personal consulting fees from Pfizer, MSD, Lilly, Novartis, Roche, Gedeon Richter, Boehringer Ingelheim, Abbvie, all unrelated to this manuscript; A-KT: speakers fee from Berlin Chemie Menarini, Novarti and personal fees and non-financial support from AstraZeneca and Grünenthal, all unrelated to this manuscript; AT: consulting fees from Magenta Therapeutics and personal fees from Novartis and Idorsia for participation on a Data Safety Monitoring Board or Advisory Board, all unrelated to this manuscript; AV: personal consulting fees from Astra Zeneca and GS, all unrelated to this manuscript; MGT: research grants from Genesis, GSK, MSD, Pfizer and UCB paid to institution, and personal consulting fees from Genesis, GSK and Novartis, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Fibromyalgia (FM) is a chronic musculoskeletal pain syndrome of unknown aetiopathogenesis. Its development and maintenance are related to the interplay of biological, psychological, and contextual factors. Among the contextual factors, sociodemographic aspects are poorly elucidated. This study aimed to evaluate the relationships between sociodemographic/clinical factors and symptom severity measures using a web-based registry of patients with FM., Methods: Adult patients with an ACR 2010/2011 diagnosis of FM underwent a clinical evaluation and were asked to complete questionnaires covering their sociodemographic data (gender, age, marital status, educational level), and disease-specific measures (the revised Fibromyalgia Impact Questionnaire (FIQR), and the Polysymptomatic Distress Scale (PDS))., Results: Data relating to 3,221 patients (3001 women and 220 men) was collected. The ANOVA showed significant difference in mean FIQR scores when the five marital conditions (cohabiter, married, separated/divorced, single, widowed) were compared (F 3.321, p<0.01). While males and females were found to have comparable FIQR scores, the interaction between gender and marital status indicated that separated/divorced males have higher FIQR scores (F 5.684, p=0.001). The multiple regression analysis demonstrated that patients who reported lower educational level experienced more severe FM symptoms, as scored with FIQR (p<0.0001)., Conclusions: Our results indicated that being male and separated/divorced is associated to higher severity of FM symptoms, as rated with FIQR. Furthermore, a relationship between educational level and FIQR scores has been detected. This study supports the importance of collecting simple SES measures to identify environmental risk factors for FM severity.

Objectives: The role of age in influencing the severity of fibromyalgia (FM) is still controversial. The aim of this study is to define the contribution of age in the severity of FM from data from a large national database., Methods: This cross-sectional study included adult patients with FM diagnosed according to the 2010/2011 American College of Rheumatology criteria. Disease severity was assessed with the revised Fibromyalgia Impact Questionnaire (FIQR) and the modified Fibromyalgia Assessment Status (FAS 2019mod). Patients were grouped into five age categories (between 18-40 years, between 41-50 years, between 51-60 years, between 61-70 years, and ≥71 years). Differences in disease severity between groups were assessed by one-way analysis of variance (ANOVA)., Results: The study included 2889 patients (199 males and 2690 females), mean age of 52.58 (±11.82) years, with a mean FIQR score of 59.22 (±22.98) and a mean FAS 2019mod of 25.50 (±8.66). Comparing the mean values of the various indices between age categories, there were no statistically significant differences between the groups for FIQR total score and FAS 2019mod. However, the 60-70 years category showed the lowest scores for both scales. The main difference emerged for the FIQR physical function subscale, where the ≥71 years category showed significantly higher scores (p<0.05) compared the 18-40 years category., Conclusions: The severity of FM has a significant level of stationarity according to age categories. Patients between 60-70 years have a lower disease burden. Physical function is the health domain with the most significant difference between the groups.

Objectives: Fibromyalgia (FM) is a syndrome of unknown aetiology characterised by chronic widespread musculoskeletal pain and associated with high rates of psychiatric comorbidities, mainly mood and anxiety disorders.This study aims to determine the age at onset (AAO) and temporal sequencing patterns of FM and its frequent and distinguishable psychiatric comorbidities, the major depressive episode/s (MDE), and panic disorder (PD)., Methods: Diagnosis of MDE and PD were assigned using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV). The AAO of FM, MDE, and PD was defined using the event history calendar. All patients completed a sociodemographic data form, self-report questionnaires measuring FM-related symptoms and function, and the Childhood Trauma Questionnaire-28 (CTQ-28)., Results: 98 (83%) of the 118 recruited patients with FM had at least one psychiatric comorbidity. Two main temporal patterns were identified among the 83 patients (70.3 %) who could reliably report the age at onset of FM and psychiatric comorbidities. In the concurrent comorbidity pattern (CCP), MDE and/or PD co-occurred with the onset of FM. In the sequential pattern (SP), the patients first developed PD, then MDE, and finally FM. FM patients with SP are overweight and younger than those with a CCP (FM concurrent with MDE and PD) and reported more childhood adversities, mainly sexual abuse. AAO of psychiatric comorbidities significantly differed between the two patterns., Conclusions: The presence of different temporal comorbidity patterns may suggest prevention/early treatment interventions, especially in patients with childhood adversities and early-onset PD.

Spondyloarthritis are chronic inflammatory diseases affecting spine, peripheral joints and enthesis, as well as extra-articular sites (bowel, eyes, skin). Diagnosis of spondyloarthritis often is slow and requires a multidisciplinary approach. The "Early SpA Clinic" project aimed at improving the patient care and journeys, by solving some organizational issues existing in Rheumatology Clinics. The "Early SpA Clinic" involved 19 Italian Rheumatology Centers using in-depth organizational analyses to identify areas for improvement. From the results of the analyses, some organizational solutions were suggested, and their impact measured at the end of the project through specific KPI. With the implementation of the suggested organizational solutions, Centers achieved relevant results, positively impacting on all the phases of the patient journey: decrease in waiting lists (-23%) and in the time length to transit the Center (-22%), increase in the percentage of new diagnoses (+20%), in the saturation of outpatient clinic capacity (+16%), and in the patient satisfaction (+4%). Centers involved in the "Early SpA Clinic" implemented several organizational actions based on an overall assessment of their activities and on solutions that required no additional resources. Overall, the Centers achieved the "Early SpA Clinic" objectives in terms of better management of resources, personnel, spaces, equipment, in relation to the volumes of patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 D'Angelo, Afeltra, Atzeni, Baldissera, Caminiti, Ciccia, D'Agostino, Dagna, Erre, Franceschini, Fusaro, Giacomelli, Gremese, Guggino, Lomater, Lubrano, Padula, Pagano Mariano, Russo, Sarzi Puttini, Scarpa, Selmi, Tirri, Ferri and Iannone.)

Sjögren Syndrome (SS) seems to be associated with a greater "overall risk" of cardiovascular (CV) and cerebrovascular events. Although not conventionally considered a feature of the disease, CV events represent a major burden in SS patients. CV risk is the consequence of a complex combination of multiple factors, including traditional risk factors and disease-related mechanisms. A complex relationships between disease-related features, endothelial dysfunction and traditional risk factor has been suggested. Several drugs are available for treating the systemic manifestations of SS, however they have shown positive effects on different outcomes of the disease, but until today the data on the role of these drugs on CV events are scarse. Given these data, the aim of this review was to evaluate the risk of CV risk in primary SS and the effect of the drugs on this manifestation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Atzeni, Gozza, Cafaro, Perricone and Bartoloni.)

Background: The adoption of Computed tomography (CT)-defined sarcopenia to risk stratify transcatheter aortic valve implantation (TAVI) candidates remains limited by a lack of both standardized definition and evidence of independent value over currently adopted mortality prediction tools., Methods: 391 consecutive TAVI patients with pre-procedural CT scan were included (81 ​± ​6 years, 57.5% male, STS-PROM score 4.4 ​± ​3.6%) and abdominal muscle retrospectively quantified. The two definitions of radiologic sarcopenia previously adopted in TAVI studies were compared (psoas muscle area [PMA] at the L4 vertebra level: "PMA-sarcopenia"; indexed skeletal muscle area at the L3 vertebra level: "SMI-sarcopenia"). The primary endpoint was longer available-term all-cause mortality. Secondary endpoints were Valve Academic Research Consortium-2-defined in-hospital and 30-day outcomes., Results: SMI- and PMA-sarcopenia were present in 192 (49.1%) and 117 (29.9%) patients, respectively. After a median of 24 (12-30) months follow-up, 83 (21.2%) patients died. PMA-(adj-HR 1.81, 95%CI 1.12-2.93, p ​= ​0.015), but not SMI-sarcopenia (adj-HR 1.23, 95%CI 0.76-2.00, p ​= ​0.391), was associated with all-cause mortality independently of age, sex and in-study outcome predictors (atrial fibrillation, hemoglobin, history of peripheral artery disease, cancer and subcutaneous adipose tissue). PMA-defined sarcopenia provided additive prognostic value over current post-TAVI mortality risk estimators including STS-PROM (p ​= ​0.001), Euroscore II (p ​= ​0.025), Charlson index (p ​= ​0.025) and TAVI2-score (p ​= ​0.020). Device success, early safety, clinical efficacy and 30-day all-cause death were unaffected by sarcopenia status regardless of definition., Conclusions: PMA-sarcopenia (but not SMI-sarcopenia) is predictive of 2 year mortality among TAVI patients. The prognostic information provided by PMA-sarcopenia is independent of the tools currently adopted to predict post-TAVI mortality in clinical practice., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2021 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Introduction: To date, four Janus kinase inhibitors (JAKis) are licensed for the treatment of rheumatoid arthritis (RA) and/or psoriatic arthritis (PsA) in North America and/or Europe: tofacitinib, baricitinib, upadacitinib, and filgotinib. Most DMARDs have cardioprotective potential, yet for some of them, including JAKi, the modulatory effect on cardiovascular risk remains undetermined. Since their commercialization, the risk of venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) is taking on a relevant role in RA patients., Areas Covered: In this article, we will review the effect of JAKi on CV risk and atherosclerosis process as major contributor to MACE. Furthermore, we will present the effect of JAKi on thromboembolic risk., Expert Opinion: Although the effect of JAKi on CV and thrombosis is one of the most relevant topic regarding RA patients, it is necessary to underline that these patients have an increased risk of these comorbidities due to the inflammation process, and further study are needed in order to understand the real role of JAKi in controlling or inducing these complications.

The objective of this study is to describe the possible prognostic impact of smoking habit on adult-onset Still's disease (AOSD) patients, by the assessment of clinical characteristics, life-threatening complications occurrence, and mortality in smokers than non-smokers. A multicentre retrospective study of prospectively followed-up AOSD patients included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort was conducted. Out of 185 AOSD assessed patients, 45 smokers were identified. These showed a higher frequency of pericarditis (35.5% vs 16.4%, p = 0.011), pleuritis (33.3% vs 14.3%, p = 0.008), and abdominal pain (17.7% vs 6.4%, p = 0.035). Furthermore, smokers showed higher values of systemic score (6.4 ± 2.2 vs 5.4 ± 1.8, p = 0.004), an increased rate of macrophage activation syndrome (MAS) (28.9% vs 6.4%, p < 0.0001) and of parenchymal lung disease (17.7% vs 12.6%, p = 0.035). Although not significant, these patients more frequently experienced a poor prognosis (13.3% vs 4.3%, p = 0.074). Smoking habit predicted MAS occurrence in both univariate (HR: 5.98, 95% CI: 2.45-14.57, p < 0.0001) and multivariate regression models (HR: 6.21, 95% CI: 2.46-15.70, p < 0.0001). Smokers had a significant higher risk of parenchymal lung disease in both univariate (HR: 3.97, 95% CI: 1.43-11.02, p = 0.008) and multivariate regression models (HR: 3.90, 95% CI: 1.36-11.23, p = 0.012). Smoking habit also increased the risk of mortality in univariate regression model (HR: 4.25, 95% CI: 1.33-13.55, p = 0.015). Smoking habit resulted to be a negative prognostic factor on AOSD patients. Smokers were characterised by a higher frequency of serositis and higher values of systemic score. Additionally, these patients were more frequently burdened by MAS and parenchymal lung disease associated with a poor prognosis. Key points • Smoking habit resulted to be a negative prognostic factor on AOSD. • Smokers were characterised by an increased frequency of serositis and higher values of systemic score. • Cigarette exposure was associated with MAS and parenchymal lung disease in AOSD., (© 2021. International League of Associations for Rheumatology (ILAR).)

Objective: Patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA) commonly develop renal dysfunction due to either systemic inflammation or drug-related nephrotoxicity. This study compared renal function parameters in patients with PsA versus those with RA and examined the impact of clinical remission or disease relapse on renal function., Methods: This single-center retrospective study was conducted at the University Hospital of Messina, Italy. Adult patients (aged ≥18 years) with PsA or RA who attended the rheumatology clinic within the past 6 months were identified from electronic medical records., Results: In total, 45 patients with PsA ( n = 23) or RA ( n = 22) were included. The mean (standard deviation) age was 55.6 (15.9) years, and 78% of participants were female. Patient age, renal function, and medical history were generally similar between the two disease groups, although significantly more RA patients were smokers, and more PsA patients had comorbid hypertension. The prevalence of estimated glomerular filtration rate [eGFR] ≤90 mL/min/1.73 m 2 at 1, 6, and 12 months of treatment ranged from 38.5% to 58.3% in the PsA group and from 45.5% to 54.5% in the RA group and did not significantly differ between disease groups. Clinical remission did not appear to affect renal function parameters in either disease group; however, relapse was associated with significantly higher serum creatinine levels in PsA patients at the same timepoint., Conclusion: In this study, patients with PsA and RA had a similar prevalence of renal function parameter abnormalities over 12 months of treatment. Disease relapse may impact renal function in patients with PsA.

Background: Several cardiovascular (CV) risk algorithms are available to predict CV events in the general population. However, their performance in patients with rheumatoid arthritis (RA) might differ from the general population. This cross-sectional multicentre study aimed to estimate the 10-year CV risk using two different algorithms in a large RA cohort and in patients with osteoarthritis (OA)., Methods: In a consecutive series of RA patients and matched OA controls without prior CV events, clinical and serologic data and traditional CV risk factors were recorded. The 10-year CV risk was assessed with the Systematic COronary Risk Evaluation (SCORE) and the "Progetto Cuore" algorithms., Results: 1,467 RA patients and 342 OA subjects were included. RA patients were more frequently diabetic (9.9% vs 6.4%; p=0.04) and smokers (20.4% vs 12.5%; p=0.002) but had lower prevalence of obesity (15% vs 21%; p=0.003). Dyslipidaemia was more prevalent in OA (32.5% vs 21.7%; p<0.0001). The 10-year estimated CV risk was 1.6% (95%CI 1.3-1.9) in RA and 1.4% (95%CI 1.3-1.6) in OA (p=0.002) according to SCORE and 6.5% (95%CI 6.1-6.9) in RA and 4.4% (95%CI 3.9-5.1) in OA (p<0.001) according to "Progetto Cuore". Regardless of the score used, RA patients had a 3- to-4-fold increased 10-year risk of CV events compared to OA subjects., Conclusion: RA patients have a significantly higher 10-year risk of CV events than OA subjects. In addition to effective disease control and joint damage prevention, specific protective measures targeting modifiable traditional CV risk factors should be implemented in RA., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjögren's syndrome (pSS)., Methods: By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression., Results: There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R2 0.87) and the frequency of abnormal oral tests (adjusted R2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.18%), and constitutional, cutaneous, and haematological involvements (the frequency decreased by 0.09% for each 1-year increase). In contrast, other domains showed an ascending pattern, especially pulmonary involvement (for each 1-year increase in the age at diagnosis, the frequency of activity increased by 0.22%), and peripheral nerve involvement (the frequency increased by 0.09% for each 1-year increase)., Conclusions: The influence of the age at diagnosis on the key phenotypic features of pSS is strong, and should be considered critical not only for designing a personalised diagnostic approach, but also to be carefully considered when analysing the results of diagnostic tests and immunological parameters, and when internal organ involvement is suspected at diagnosis.

Objectives: To ascertain if the use of hydroxychloroquine(HCQ)/cloroquine(CLQ) and other conventional DMARDs (cDMARDs) and rheumatic diseases per se may be associated with COVID-19-related risk of hospitalization and mortality., Methods: This case-control study nested within a cohort of cDMARD users was conducted in the Lombardy, Veneto, Tuscany and Lazio regions and Reggio Emilia province. Claims databases were linked to COVID-19 surveillance registries. The risk of COVID-19-related outcomes was estimated using a multivariate conditional logistic regression analysis comparing HCQ/CLQ vs MTX, vs other cDMARDs and vs non-use of these drugs. The presence of rheumatic diseases vs their absence in a non-nested population was investigated., Results: A total of 1275 patients hospitalized due to COVID-19 were matched to 12 734 controls. Compared with recent use of MTX, no association between HCQ/CLQ monotherapy and COVID-19 hospitalization [odds ratio (OR) 0.83 (95% CI 0.69, 1.00)] or mortality [OR 1.19 (95% CI 0.85, 1.67)] was observed. A lower risk was found when comparing HCQ/CLQ use with the concomitant use of other cDMARDs and glucocorticoids. HCQ/CLQ was not associated with COVID-19 hospitalization as compared with non-use. An increased risk for recent use of either MTX monotherapy [OR 1.19 (95% CI 1.05, 1.34)] or other cDMARDs [OR 1.21 (95% CI 1.08, 1.36)] vs non-use was found. Rheumatic diseases were not associated with COVID-19-related outcomes., Conclusion: HCQ/CLQ use in rheumatic patients was not associated with a protective effect against COVID-19-related outcomes. The use of other cDMARDs was associated with an increased risk when compared with non-use and, if concomitantly used with glucocorticoids, also vs HCQ/CLQ, probably due to immunosuppressive action., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To stratify adult-onset Still's disease (AOSD) patients in distinct clinical subsets to be differently managed, by using a multi-dimensional characterization., Methods: AOSD patients were evaluated by using a hierarchical unsupervised cluster analysis comprising age, laboratory markers systemic score and outcomes. The squared Euclidean distances between each pair of patients were calculated and put into a distance matrix, which served as the input clustering algorithm. Derived clusters were descriptively analysed for any possible difference., Results: Four AOSD patients clusters were identified. Disease onset in cluster 1 was characterized by fever (100%), skin rash (92%) and arthritis (83%), with the highest ferritin levels [mean (S.D.) 14 724  (6837) ng/ml]. In cluster 2, the onset was characterized by fever (100%), arthritis (100%) and liver involvement (90%), together with the highest CRP levels [288.10  (46.01) mg/l]. The patients in cluster 3 presented with fever (100%), myalgia (96%) and sore throat (92%). The highest systemic score values [8.88  (1.70)] and the highest mortality rate (54.2%) defined cluster 3. Fever (100%) and arthritis (90%) were the symptoms at the onset in cluster 4, which was characterized by the lowest ferritin and CRP levels [1457  (1298) ng/ml and 54.98  (48.67) mg/l, respectively]., Conclusion: Four distinct phenotypic subgroups in AOSD could be suggested, possibly associated with different genetic background and pathogenic mechanisms. Our results could provide the basis for a precision medicine approach in AOSD in an attempt to find a clinical and laboratory multidimensional stratification and characterization, which would drive a tailored therapeutic approach in these patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aim: To evaluate the convergent and discriminative validity of many continuous composite disease activity indices and patient-reported outcome measures (PROMs) in rheumatoid arthritis (RA)., Methods: In consecutive RA patients in moderate or high disease activity, according to the Simplified Disease Activity Index (SDAI) definition, were computed four additional composite disease activity indices, the 28-joint Disease Activity Score - erythrocyte sedimentation rate (DAS28-ESR), the Clinical Disease Activity Index (CDAI), the Chronic Arthritis Systemic Index (CASI), and the Mean Overall Index for RA (MOI-RA), and five PROMs, the Patients' Activity Scale (PAS), the Rheumatoid Arthritis Impact of Disease (RAID), the 5-item RA Disease Activity Index (RADAI-5), the Routine Assessment of Patient Index Data (RAPID3), and the Clinical Arthritis Activity (PRO-CLARA). Spearman's rho correlation coefficients were determined to assess their convergent validity, and discriminative performance was calculated by the area under the receiver-operating curve (AUC-ROC). The patients' opinion of their symptomatic status (PASS) was used as the external criterion., Results: 246 RA patients with moderate (29.3%) or high disease activity (70.7%) have been assessed. The indices all showed a significant correlation (p <0.0001 for all). Among the composite disease activity indices, the CDAI was the one that showed the best discriminating ability compared to the PASS (AUC = 0.962), while among the PROMs the RAID was the most performing (AUC = 0.879)., Conclusions: CDAI as composite index of disease activity, and RAID as PROM, are the two instruments with the best performances in relation to PASS. The use of validated disease activity measures can help in clinical practice to adopt treat-to-target strategies in RA patients. (www.actabiomedica.it).

Objectives: In rheumatoid arthritis (RA), "traditional" cardiovascular (CV) risk factors continue to be underdiagnosed and undertreated, thus increasing the risk of developing atherosclerosis. In this work, we evaluated the occurrence and predictive factors of "traditional" cardiovascular risk factors, with a focus on high blood pressure (HBP), type 2 diabetes (T2D), and metabolic syndrome (MetS), in participants with RA, in a 3-year, multicentre, prospective, observational study., Methods: To assess the occurrence and predictive factors of HBP, T2D, and MetS, consecutive participants with RA, admitted to Italian Rheumatology Units, were evaluated in the GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) cohort, a 3-year, multicentre, prospective, observational study., Results: In the present evaluation, 841 participants, who were fully followed up with 3-year of prospective follow-up were assessed. At the end of follow-up, a significant increased incidence of HBP, T2D, and MetS was recorded. Assessing predictive factors, the mean values of C-reactive protein during the follow-up were independent predictors of occurrence of those comorbidities, whereas participants maintaining remission showed a significant lower risk. Furthermore, therapy with hydroxychloroquine (HCQ) reduced the risk of occurrence of T2D and MetS., Conclusions: An increased incidence of HBP, T2D, and MetS was observed in assessed participants, prospectively followed-up. Furthermore, the analysis of predictive factors suggested that the rheumatoid pro-inflammatory process could increase the occurrence of these comorbidities. Conversely, metabolic and cardiovascular benefits of maintaining remission as well as of therapy with HCQ were reported.

Although psoriatic arthritis (PsA) primarily leads to joint and skin damage, it is associated with higher prevalence of metabolic syndrome (MetS) and its components, namely hypertension, dyslipidemia, obesity, and type II diabetes. Additionally, chronic inflammation is known to aggravate these cardiometabolic factors, thus explaining the enhanced cardiovascular (CV) morbidity and mortality in RA. Furthermore, emerging evidence suggest that some risk factors can fuel inflammation, thus pointing to a bidirectional crosstalk between inflammation and cardiometabolic factors. Therefore, dampening inflammation by disease-modifying anti-rheumatic drugs (DMARDs) may be thought to ameliorate MetS burden and thus, CV risk and disease severity. In fact, recommendations for PsA management emphasize the need of considering comorbidities to guide the treatment decision process. However, the existing evidence on the impact of approved DMARDs in PsA on MetS and MetS components is far from being optimal, thus representing a major challenge for the clinical setting. Although a beneficial effect of some DMARDs such as methotrexate, TNF inhibitors and some small molecules is clear, no head-to-head studies are published and no evidence is available for other therapeutic approaches such as IL-23 or IL-17 inhibitors. This narrative review summarizes the main evidence related to the effect of DMARDs on MetS outcomes in PsA patients and identify the main limitations, research needs and future perspectives in this scenario., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Atzeni, Gerratana, Francesco Masala, Bongiovanni, Sarzi-Puttini and Rodríguez-Carrio.)

Medical cannabis (MC) describes the usually inhaled or ingested use of a cannabis plant or cannabis extract for medicinal purposes. The action of whole cannabis plants is extremely complex because their large number of active compounds not only bind to a plethora of different receptors but also interact with each other both synergistically and otherwise. Renewed interest in the medicinal properties of cannabis has led to increasing research into the practical uses of cannabis derivatives, and it has been found that the endocannabinoid system (particularly CB2 receptor activation) is a possible target for the treatment of inflammatory and the autoimmune diseases related to immune cell activation. However, in vivo findings still lack, creating difficulties in applying translational cannabinoid research to human immune functions. In this review, we summarized the main mechanisms of action of medical cannabis plant especially regarding the immune system and the endocannabinoid system, looking at preliminary clinical data in three most important autoimmune diseases of three different specialities: rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease., Competing Interests: All of the authors declare that they have no conflict of interest in relation to this paper., (© 2021 Giorgi et al.)

Background: There is a lack of real-life clinical data for biosimilar etanercept, an anti-TNF blocking fusion protein. We describe the comparable efficacy and safety of originator and biosimilar etanercept in rheumatoid arthritis (RA) patients in a real-life clinical setting. Our data confirm that a biosimilar etanercept can be safely used as first-line treatment as well as in patients switched from a previous originator compound., Objectives: To compare the efficacy and safety of originator and biosimilar etanercept in a cohort of RA patients attending two Italian hospitals., Methods: The study involved 81 consecutive adult RA patients treated for at least 6 months with originator or biosimilar etanercept and considered their clinical and laboratory data, concomitant medications, and adverse events at baseline, and after 3 and 6 months of treatment., Results: Group 1 included 51 patients taking originator etanercept; group 2 included 30 taking biosimilar etanercept, including 19 who had been switched from the reference product. Despite a significant baseline difference in clinical disease activity, one-way analysis of variance showed that the two groups were clinically comparable after 6 months of treatment, and the same was true when only those receiving etanercept as first-line biological treatment were considered. Nine patients discontinued the treatment due to inefficacy or adverse events, which were never serious and were only reported in group 1., Conclusions: The efficacy and safety profiles of originator and biosimilar etanercept are comparable in RA patients in a real-life clinical setting. Further studies are needed to confirm these preliminary findings.

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 χ 2  = 3.57%, df = 3, p value = 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.

Axial spondyloarthritis (axSpA) describes a group of chronic inflammatory rheumatic diseases primarily involving the axial skeleton. IL-17 is involved in the pathogenesis of numerous inflammatory diseases, including inflammatory arthritis. Until a few years ago, the only biological agents licensed for the treatment of axSpA and nr-axSpA were TNF inhibitors. However, as some patients did not respond to TNF inhibition or experienced secondary failure, the introduction of the first two IL-17 inhibitors (secukinumab [SEC] and ixekizumab [IXE]) has extended the treatment options, and there are now three others (bimekizumab, brodalumab and netakimab) in various stages of clinical development. The last ten years have seen the development of a number of therapeutic recommendations that aimed at improving the management of axSpA patients. The aim of this narrative review of the published literature concerning the role of IL-17 in the pathogenesis of SpA, and the role of IL-17 inhibitors in the treatment of axSpA, is to provide a comprehensive picture of the clinical efficacy and safety of the drugs themselves, and the treatment strategies recommended in the international guidelines., Competing Interests: Dr Salvatore D’Angelo reports personal fees from Abbvie, Eli Lilly, Novartis, and UCB, outside the submitted work. The authors reported no other potential conflicts of interest for this work., (© 2021 Atzeni et al.)

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.

Fibromyalgia syndrome is one of the most common causes of chronic widespread pain, but pain accompanies a wide range of ancillary symptoms. To date, its aetiopathogenesis remains elusive, and diagnosis is exquisitely clinical, due to the lack of biomarkers or specific laboratory alterations in fibromyalgia patients. This position paper has the purpose to summarise the current scientific knowledge and expert opinions about the main controversies regarding fibromyalgia syndrome, namely: (i) fibromyalgia definition and why it is still not recognised in many countries as a distinct clinical entity; (ii) fibromyalgia severity and how to evaluate treatment outcome; (iii) how to treat fibromyalgia and which is a correct approach to fibromyalgia patients.

Objectives: Fibromyalgia syndrome (FM) is a complex disease that is mainly characterised by chronic widespread pain, fatigue and sleep disturbances and may be precipitated or worsened by many stressors. The aim of this study was to observe the behaviour of FM symptoms during the course of coronavirus disease 2019 (COVID-19)., Methods: Patients who had been diagnosed as having FM for ≥3 months were recruited between February and May 2020. The collected data were age, sex, educational level and marital status; height and weight; and the scores of the revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromyalgia Assessment Status 2019 (FASmod), and the Polysymptomatic Distress Scale (PDS). The patients were divided into those with or without concomitant COVID-19 infection., Results: Eight hundred and ninety-seven (93%) of the 965 patients (881 women [91.3%] and 84 men [8.7%]) were followed up on an outpatient basis because of FM and 68 (7.0%) were either followed up as out-patients or hospitalised because of COVID-19. There was no difference in the sociodemographic data of the two groups, but there were statistically significant between-group differences in the results of the clinimetric tests. The major differences between the score of the items (those with the greatest disease impact) were the following related symptoms: sleep quality (FIQR15), fatigue/energy (FIQR13), pain (FIQR12), stiffness (FIQR14)., Conclusions: The mean total and subdomain scores of all the tests were significantly higher in the patients with COVID-19, which suggests that global FM symptoms are more severe in patients with infection. Further studies of the post-COVID19 patients are being carried out in order to discover whether the worsened symptomatology continues because of their hypersensitised state.

Early diagnosis and timely and appropriate treatments positively influence the history of fibromyalgia syndrome (FM), with favourable repercussions at clinical, psychological, social and economic levels. Notwithstanding, there are still significant problems with timeliness of diagnosis, access to pharmacological therapies - particularly to innovative ones - and appropriate and effective taking in charge of patients. All the aforementioned factors have a great impact on FM patients' quality of life. Indeed, even though the World Health Organisation recognised FM as a chronic condition in the International Classification of Diseases 10th edition (ICD-10), many countries still fail to recognise the syndrome, and this negatively influences the capability to appropriately protect and care for patients. This is the case in several European Countries. In Italy, a few Regions have started to put in place precise indications for people suffering from FM, aiming at the implementation of diagnostic-therapeutic pathways. The Diagnostic-Therapeutic Care Pathway (DTCP) provides an important tool to meet the needs of patients suffering from chronic diseases. They present the organisation of an integrated assistance network. This includes a seamless path for disease prevention, diagnosis and treatment, by means of cooperation among physicians and other healthcare professionals.

Fibromyalgia (FM) is a syndrome of unknown aetiology characterised by chronic pain, fatigue, and disturbed sleep. This review presents and summarises the 2020 literature on FM by retrieving all articles indexed in PubMed between 1 January 2020 and 31 December 2020. The attention of the scientific community towards FM is constantly growing, and this year's review is focused on the diagnostic, pathogenetic and therapeutic aspects of this syndrome. In particular, the treatment options for FM, both pharmacological and non-pharmacological, have been extensively studied.

Behçet disease (BD) is a complex, multi-systemic inflammatory condition mainly hallmarked by oral and genital ulcers which can also affect the vessels, gastrointestinal tract, central nervous system and even the axial skeleton. Without a clear classification among autoimmune or autoinflammatory conditions, BD has been recently classified as a MHC-I-opathy. BD aetiology is still obscure, but it is thought that certain microorganisms can elicit an aberrant adaptive immune response in the presence of a permissive genetic background. Altered T-cell homeostasis, mostly Th1/Th17 expansion and Treg impairment, could lead to an overactivation of the innate immunity, which underlies tissue damage and thus, signs and symptoms. Immunosuppression and/or immunomodulation are central to the BD management. A complex armamentarium ranging from classical synthetic disease-modifying antirrheumatic drugs to new-era biologic agents or small molecules is available in BD, with different therapeutic outcomes depending on disease manifestations. However, the precise disease mechanisms that underlie BD symptoms are not fully deciphered, which may limit their therapeutic potential and add a significant layer of complexity to the treatment decision-making process. The aim of the present review is to provide an exhaustive overview of the latest breakthroughs in BD pathogenesis and therapeutic options., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: This study aimed to validate Italian versions of Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale and Pain DETECT questionnaire (PD-Q) and evaluate the ability of these questionnaires to discriminate between nociceptive and neuropathic pain., Design: Multicenter prospective validation cohort study. Subjects and Setting. One hundred patients were included with a diagnosis formulated by a specialist in outpatient settings (50 affected by knee osteoarthritis as nociceptive pain and 50 affected by trigeminal or postherpetic neuralgia as neuropathic pain)., Methods: The Italian versions of both questionnaires according to Italian cultural characteristics were performed according to the following steps: (1) translation of the questionnaires from English into Italian; (2) review by a bilingual individual for consistency; (3) proposed version after a mail round between experts; (4) backward translation; (5) comparison with the original English version by the experts; (6) approved version of the questionnaires. One hundred patients were enrolled and completed the two questionnaires administered by a specialist or blinded nursing staff, at the baseline and after 24/48 hours. Internal consistency, stability, validity, and discriminative power were analyzed., Results: Statistically significant differences were reported about the ability of both questionnaires to discriminate between patients affected by neuropathic or nociceptive pain. Internal consistency for the Italian version of the LANSS was 0.76, and for PD-Q, it was 0.80, assessed by Cronbach's α ; LANSS showed a good test-retest reliability with an ICC of 0.76, and PD-Q showed a high test-retest reliability with an ICC of 0.96. For interrater reliability, there was a concordance rate of 83.3% between reference diagnosis and LANSS (Cohen's kappa = 0.67, CI 95% 0.52-0.75)., Conclusions: This study validated the Italian versions of LANSS and PD-Q as reliable instruments with good psychometric characteristics, for pain evaluation, discriminating between nociceptive and neuropathic pain. Our findings were similar to those observed in the original study. Furthermore, we have reported the test-retest reliability for both questionnaires, not addressed in original validation studies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Alberto Migliore et al.)

Fibromyalgia (FM) was frequently observed in patients with rheumatoid arthritis (RA). We aimed to evaluate the differences in psychiatric comorbidities and life adversities between patients with Rheumatoid arthritis + FM (secondary fibromyalgia [SFM]) and people with primary FM (PFM). In a cross-sectional, observational study, patients with PFM and SFM underwent a structured interview for the lifetime diagnosis of major depression (MDD), panic disorder (PD) and post-traumatic stress disorder (PTSD) and were assessed for childhood/adulthood adversities and FM-related symptoms severity. Thirty patients with PFM and 40 with SFM were recruited. The univariate analysis showed that the lifetime rates of MDD were significantly higher in PFM versus SFM (76.7 % and 40%, respectively, p < 0.003), as well as the rates of PD (50 % and 15%, respectively, p < 0.003), whereas there was no difference in PTSD rates. The rates of sexual abuse and physical neglect were significantly higher in PFM patients versus SFM patients (p < 0.005 and p < 0.023). Life events occurring before FM onset were different in PFM and SFM groups. In the logistic regression model, lifetime PD and physical neglect remain independent risk factors for PFM. PFM and SFM differ in psychiatric comorbidities and environmental adversities, suggesting that common pathogenesis may develop through different pathways., (© 2020 John Wiley & Sons Ltd.)

Aims: Permanent pacemaker implantation (PPI) may be required after transcatheter aortic valve implantation (TAVI). Evidence on PPI prediction has largely been gathered from high-risk patients receiving first-generation valve implants. We undertook a meta-analysis of the existing literature to examine the incidence and predictors of PPI after TAVI according to generation of valve, valve type, and surgical risk., Methods and Results: We made a systematic literature search for studies with ≥100 patients reporting the incidence and adjusted predictors of PPI after TAVI. Subgroup analyses examined these features according to generation of valve, specific valve type, and surgical risk. We obtained data from 43 studies, encompassing 29 113 patients. Permanent pacemaker implantation rates ranged from 6.7% to 39.2% in individual studies with a pooled incidence of 19% (95% CI 16-21). Independent predictors for PPI were age [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01-1.09], left bundle branch block (LBBB) (OR 1.45, 95% CI 1.12-1.77), right bundle branch block (RBBB) (OR 4.15, 95% CI 3.23-4.88), implantation depth (OR 1.18, 95% CI 1.11-1.26), and self-expanding valve prosthesis (OR 2.99, 95% CI 1.39-4.59). Among subgroups analysed according to valve type, valve generation and surgical risk, independent predictors were RBBB, self-expanding valve type, first-degree atrioventricular block, and implantation depth., Conclusions: The principle independent predictors for PPI following TAVI are age, RBBB, LBBB, self-expanding valve type, and valve implantation depth. These characteristics should be taken into account in pre-procedural assessment to reduce PPI rates. PROSPERO ID CRD42020164043., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objective: Various studies have shown that overweight and obesity are central features of FM, but the real impact of a high BMI on clinical severity in patients with FM is still controversial. The aim of this study was to analyse the relationships between BMI categories and measures of symptom severity and functional impairment using data from a Web-based registry of patients with FM., Methods: Adult patients with an ACR 2010/2011 diagnosis of FM underwent a complete physical examination and laboratory tests and were asked to complete a package of questionnaires covering their sociodemographic and treatment details, in addition to the following disease-specific questionnaires: the revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromyalgia Assessment Status questionnaire (ModFAS) and the Polysymptomatic Distress Scale (PDS)., Results: A total of 2339 patients were recruited and divided into two weight categories, underweight/normal (U/N, n  = 1127, 48.2%) and overweight/obese (O/O, n  = 1212, 51.8%). The total and subscales of FIQR, ModFAS and PSD scores were significantly higher in the O/O patients, as were all the mean scores of the individual FIQR items ( P  < 0.001 for all)., Conclusion: Our findings demonstrate that O/O patients with FM are significantly more impaired than U/N patients in all the symptomatological and functional domains as measured using the FIQR, ModFAS and PDS, thus suggesting that being O/O has an additional effect on symptoms and function., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: While waiting for the development of specific antiviral therapies and vaccines to effectively neutralize the SARS-CoV2, a relevant therapeutic strategy is to counteract the hyperinflammatory status, characterized by an increase mainly of interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor (TNF)-α, which hallmarks the most severe clinical cases. 'Repurposing' immunomodulatory drugs and applying clinical management approved for rheumatic diseases represents a game-changer option. In this article, we will review the drugs that have indication in patients with COVID-19, including corticosteroids, antimalarials, anti-TNF, anti-IL-1, anti-IL-6, baricitinib, intravenous immunoglobulins, and colchicine. The PubMed, Medline, and Cochrane Library databases were searched for English-language papers concerning COVID-19 treatment published between January 2020 and October 2020. Results were summarized as a narrative review due to large heterogeneity among studies. In the absence of specific treatments, the use of immunomodulatory drugs could be advisable in severe COVID-19 patients, but clinical outcomes are still suboptimal. An early detection and treatment of the complications combined with a multidisciplinary approach could allow a better recovery of these patients.

Background: Central sensitization (CS) is a condition characterized by a disproportionate response to pain stimuli. We sought to investigate the prevalence of CS in patients with inflammatory arthritides and its association with measures of disease activity and functional disability., Methods: We conducted an observational retrospective study in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) patients. We administered to all the subjects in the study the CS inventory (CSI), a questionnaire that has been used for the diagnosis of CS. Demographic and clinical characteristics were collected as well as measures or disease activity [i.e. Simple Disease Activity Index, Disease Activity Score in PsA (DAPSA)] and functional disability [Health Assessment Questionnaire Disability Index (HAQ-DI)]. Patients with fibromyalgia were excluded from the analyses. The primary outcome measure was the presence of functional disability as assessed by HAQ-DI >1., Results: We enrolled 150 patients with inflammatory arthritides (78 PsA and 72 RA). Prevalence of CS was observed in 35.3% of the overall sample (29% in RA, 42.9% in PsA). Binary logistic regressions showed a strong, independent and linear association between functional disability and CS in both PsA and RA patients. The strength of this association was greater in PsA than in RA., Conclusion: CS is an important determinant of functional disability in patients with chronic inflammatory arthritides. PsA appeared to be more vulnerable to CS. In addition, in the presence of CS, DAPSA did not adequately capture the occurrence of functional disability. Therefore, special attention should be paid to PsA patients, in whom the concomitant diagnosis of CS should be routinely ruled out., Competing Interests: Conflict of interest statement: Angelo Fassio reports personal fees from Abiogen, Novartis, Neopharmed, outside the submitted work. Luca Idolazzi reports personal fees from Eli-Lilly, Merck Sharp & Dohme, Novartis, Sanofi, Celgene, UCB outside the submitted work. Maurizio Rossini reports personal fees from AbbVie, Abiogen, Eli-Lilly, Merck Sharp & Dohme, Novartis, Sanofi, UCB, outside the submitted work. Davide Gatti has received advisory board honoraria, consultancy fees and/or speaker fees from Abiogen, Celgene, Eli-Lilly, Neopharmed-Gentili, Pfizer, UCB. All other authors do not have anything to disclose., (© The Author(s), 2021.)

Comorbidities in patients with rheumatoid arthritis (RA) are often associated with poor health outcomes and increased mortality. Treatment decisions should take into account these comorbidities due to known or suspected associations with certain drug classes. In clinical practice, it is critical to balance potential treatment benefit against the possible risks for comorbidities as well as the articular manifestations of RA. This review summarises the current literature relating to prevalence and risk factors for the important comorbidities of cardiovascular disease, infections, lymphomas and nonmelanoma skin cancers in patients with RA. The impact on patient outcomes and the interplay between these comorbidities and the therapeutic options currently available, including tumour necrosis factor inhibitors and newer biological therapies, are also explored. As newer RA therapies are developed, and patients gain wider and earlier access to advanced therapies, in part due to the emergence of biosimilars, it is important to consider the prevention or treatment of comorbidities as part of the overall management of RA.

Objective: To establish optimal cut-off values for the scores of the revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromialgia Assessment Scale (FAS 2019mod), and the Polysymptomatic Distress Scale (PDS) in order to distinguish five levels of FM disease severity., Methods: Consecutive FM patients were evaluated with the three clinimetric indices, and each patient was required to answer the anchor question: 'In general, would you say your health is 1 = very good, 2 = good, 3 = fair, 4 = poor, or 5 = very poor?'-which represented the external criterion. Cut-off points were established through the interquartile reconciliation approach., Results: The study sample consisted of 2181 women (93.2%) and 158 men (6.8%), with a mean age of 51.9 (11.5) years, and mean disease duration was 7.3 (6.9) years. The overall median FIQR, FAS 2019 mod and PDS scores (25th-75th percentiles) were respectively 61.16 (41.16-77.00), 27.00 (19.00-32.00) and 19.0 (13.00-24.00). Reconciliation of the mean 75th and 25th percentiles of adjacent categories defined the severity states for FIQR: 0-23 for remission, 24-40 for mild disease, 41-63 for moderate disease, 64-82 for severe disease and >83 for very severe disease; FAS 2019 mod: 0-12 for remission, 13-20 for mild disease, 21-28 for moderate disease, 29-33 for severe disease and >33 for very severe disease; PDS: 0-5 for remission, 6-15 for mild disease, 16-20 for moderate disease, 21-25 for severe disease and >25 for very severe disease., Conclusions: Disease severity cut-offs can represent an important improvement in interpreting FM., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: SARS-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 Covered: This 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 Opinion: Interleukin 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.

Purpose of Review: Diffuse Idiopathic Skeletal Hyperostosis (DISH) is considered a metabolic condition, characterized by new bone formation affecting mainly at entheseal sites. Enthesitis and enthesopathies occur not only in the axial skeleton but also at some peripheral sites, and they resemble to some extent the enthesitis that is a cardinal feature in spondyloarthritis (SpA), which is an inflammatory disease., Recent Findings: We review the possible non-metabolic mechanism such as inflammation that may also be involved at some stage and help promote new bone formation in DISH. We discuss supporting pathogenic mechanisms for a local inflammation at sites typically affected by this disease, and that is also supported by imaging studies that report some similarities between DISH and SpA. Local inflammation, either primary or secondary to metabolic derangements, may contribute to new bone formation in DISH. This new hypothesis is expected to stimulate further research in both the metabolic and inflammatory pathways in order to better understand the mechanisms that lead to new bone formation. This may lead to development of measures that will help in earlier detection and effective management before damage occurs.

Fibrosing interstitial lung disease (ILD) is one of the most important causes of morbidity and mortality in patients with connective tissue diseases (CTDs), which include systemic sclerosis, rheumatoid arthritis, Sjögren's syndrome, idiopathic inflammatory myositis and systemic lupus erythematosus. The treatment of CTD-ILDs is challenging due to the paucity of proven effective treatments. Recently, two antifibrotic drugs conditionally approved for use in patients with idiopathic pulmonary fibrosis, nintedanib and pirfenidone, have been trialled in CTD-ILDs based on overlapping pathological and clinical features between the two diseases. In this narrative review, we discuss the experimental evidence and clinical trials investigating the efficacy and safety of antifibrotic drugs in patients with CTD-ILDs and the potential mechanisms of action involved. Results from clinical trials suggest that nintedanib use retards lung function decline in progressive fibrotic CTD-ILDs. By contrast, the evidence for the efficacy of pirfenidone in these groups is not equally compelling. Further, well-designed randomized clinical trials are needed to evaluate the efficacy and safety of individual antifibrotic drugs in specific CTD-ILD subgroups., Competing Interests: Disclosure and potential conflicts of interest: The authors declare no conflicts of interest. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2020/11/dic.2020-8-6-COI.pdf, (Copyright © 2021 Erre GL, Sebastiani M, Manfredi A, Gerratana E, Atzeni F, Passiu G, Mangoni AA.)

Interstitial lung diseases (ILDs) are some of the first and most serious complications of connective tissue diseases (CTDs). However, the pathogenesis of CTD-related ILDs (CTD-ILDs) is still unclear and their treatment often depends on functional and radiographic disease progression as well as on patient age and comorbidities. It can be difficult to manage CTD-ILDs due to their heterogeneous nature, the lack of robust therapeutic data, and the few well-defined outcome measures. This review focuses on cyclophosphamide due to its crucial role in the treatment of systemic sclerosis-related ILD, particularly in the case of patients with progressive ILD. This narrative review was performed using PubMed, Medline, and Cochrane Library databases to retrieve English language papers published between 2000 and April 2020 concerning the treatment of CTD-ILDs with cyclophosphamide., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no potential conflicts of interest with respect to the research, authorship, or publication of this article. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2020/11/dic.2020-9-1-COI.pdf, (Copyright © 2021 Nucera V, Gerratana E, Giallanza M, La Corte L, Sangari D, Atzeni F.)

Rituximab (RTX) represents a milestone in the treatment of mixed cryoglobulinemic vasculitis (MCV). Despite usually well-tolerated, RTX may induce different types of adverse drug reactions, including exacerbation of vasculitis. Recently, RTX biosimilar CT-P10 has been approved in Europe for the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of CT-P10 in the treatment of MCV. In this multicenter open-label study, we analyzed the safety of CT-P10 in patients with MCV treated in first-line or after a shift by RTX originator. Fifty-one consecutive MCV patients (females/males 35/16, median age 68 years, median disease duration 42 months, 51% HCV positive) were included in the study between July and December 2018 and were treated with CT-P10 (group 1). Safety and effectiveness of CT-P10 were compared with a retrospective group (group 2) including 75 consecutive patients treated with RTX originator between July 2017 and July 2018. Thirty-six patients were treated with CT-P10 for the first time, while the other 15 switched from RTX originator. RTX was administrated with high or dosage schemes (375 mg/m 2 four times a week apart/1000 mg twice one week apart or 250 mg/m 2 twice one week apart). During a month period after the last infusion, 13/51 adverse events (AE) were observed in group 1 and 17/75 in group 2 (p not significant). Among them, 7/13 and 6/17 (in group 1 and 2, respectively) could be considered immune-mediated AE (p not significant). At univariate analysis patients with IM-AE were more frequently males (p = 0.04) and with a lower disease duration (p = 0.03), but both the parameters were not significant at logistic regression. About clinical response after 6 months by the end of the treatment, no differences were observed between patients treated with originator and CT-P10 regarding the response to the therapy. No differences were observed in safety and effectiveness between patients naïve at RTX or switching from originator. Despite the higher prevalence of immune-mediated AE among patients treated with CT-P10 than originator, we have observed no significant differences between the 2 groups. The use of a low-dosage regimen is more common in group 1 than in group 2, representing a possible bias of the study, possibly influencing the appearance of AE. Considering the cost/efficacy ratio of biosimilars, their use could be helpful to treat a large number of MCV patients with an effectiveness and safety comparable to originator. Multicenter studies including a large number of patients and the new RTX biosimilars could be useful to fully elucidate the possible risk of immune-mediated adverse events with biosimilar drugs. Considering the cost/efficacy ratio of CT-P10, its use could help to treat a large number of MCV patients with an effectiveness and safety comparable to originator.

About half of the patients with fibromyalgia (FM) had a lifetime major depression episode and one third had a panic disorder (PD). Because the co-morbidity between bipolar disorder (BD) and PD marks a specific subtype of BD we aimed to investigate if co-morbid BD/PD (comBD/PD) occurs more frequently than the single disorder in FM patients and evaluate the clinical significance and timing of this co-morbidity. Further, we explored the role of co-morbid subthreshold BD and PD. In 118 patients with FM, lifetime threshold and sub-threshold mood disorders and PD were diagnosed with Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR) Clinical Interview. Demographic and clinical variables were compared in co-morbid BD/PD (comBD/PD) and not co-morbid BD/PD (nocomBD/PD) subgroups. The co-morbidity BD/PD was seen in 46.6% of FM patients and in 68.6% when patients with minor bipolar (MinBD) and sub-threshold panic were included. These rates are higher than those of the general population and BD outpatients. There were no statistically significant differences between threshold and sub-threshold comBD/PD and nocom-BD/PD subgroups in demographic and clinical parameters. In the majority of patients (78.2%), the onset of comBD/PD preceded or was contemporary with FM. These findings support the hypothesis that comBD/PD is related to the development of FM in a subgroup of patients.

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.