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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.

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.

The 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.This review describes the beneficial and toxicological effects of the drugs used to treat axial SpA.Growing 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.

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.

Fibromyalgia syndrome (FMS) is a condition included within the functional somatic syndromes (FSS), with whom frequently is associated and shares part of the etiopathogenetic hypotheses.

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.

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.To compare the efficacy and safety of originator and biosimilar etanercept in a cohort of RA patients attending two Italian hospitals.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.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.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.

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).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.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.

More 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.This review considers these safety concerns, their possible underlying causes, and other aspects that are important in clinical practice.Growing 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.

Post-marketing surveillance activities are essential to detect the risk/benefit profile of biologic disease-modifying antirheumatic drugs (bDMARDs) in inflammatory arthritis. The aim of this study was to evaluate adverse events (AEs) in patients treated with bDMARDs in rheumatology during a prospective pharmacovigilance study from 2016 to 2018. Descriptive statistical analyses were performed to evaluate bDMARDs-related variables of patients without AEs/failures vs patients with AEs and failures. The risk profile among biologics was assessed by comparing patients treated with each bDMARD to patients treated with etanercept. A total of 1155 patients were enrolled, mostly affected by rheumatoid arthritis (46.0%). AEs and failures were experienced by 8.7% and 23.3%, respectively. The number of comorbidities significantly influenced the onset of AEs, while anxiety-depressive, gastrointestinal disease, and fibromyalgia influenced onset of failures. The probability of developing an AE was significantly lower in patients treated with secukinumab, while the probability of developing treatment failure was significantly lower in patients treated with golimumab, secukinumab and tocilizumab. A total of 216 AEs were reported (25.5% serious), mostly regarding infections (21.8%), musculoskeletal (17.6%) and skin (16.2%) disorders. Serious AEs included neutropenia (12.7%), lymphocytosis (9.1%) and uveitis (7.3%). The obtained results revealed known AEs but real-world data should be endorsed for undetected safety concerns.

A new class of oral synthetic drugs has been developed for the treatment of rheumatoid arthritis (RA) with the aim of blocking the Janus kinase/signal transducer and activator of transcription (JAK-STAT) system. Tofacitinib and baricitinib have been approved for the treatment RA patients who inadequately respond to methotrexate or anti-tumor necrosis factor drugs. The aim of this narrative review is to summarize the data concerning the drugs' basic mechanisms and clinical trial results in order to inform clinicians about the serious and non-serious adverse events associated with JAK inhibitors. Areas covered: The mechanisms, adverse events, and clinical trial data associated with the use of JAK inhibitors in RA patients were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1999 and April 2018 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: Management of the adverse events of JAK inhibitors is challenging because of the lack of robust treatment data used and the heterogeneity of the events themselves. Treatment decisions are often made clinically on the basis of age and the burden of comorbidities, and require the multidisciplinary collaboration of rheumatologists and other specialists.

Background Evaluating psoriatic arthritis (PsA)-related enthesitis is diagnostically and therapeutically essential, but may be very complex because of the wide range of signs and symptoms that partly overlap or co-exist with the clinical features of fibromyalgia (FM) [1,2]. Objectives The primary aim was to compare the prevalence of clinical and ultrasonographic signs of enthesitis in patients with PsA, FM, or both. The secondary aim was to assess the impact of FM on disease activity and clinimetric scores. Methods This single-centre, observational cross-sectional study involved 101 consenting patients: 39 with PsA (CASPAR criteria), 23 with FM (2016 criteria), and 39 with both. Standard PsA and FM clinical, laboratory and clinimetric data were recorded. Disease activity in PsA and PsA-FM patients was assessed using BASDAI and ASDAS. The entheses were assessed using LEI and MASES score. All of the patients underwent B mode (grey scale) ultrasonography, the US findings were scored using the GUESS. Results The mean age of the patients was 53.6 years, SD ± 9.47. Females accounted for 64.1% of the PsA patients (disease duration 9.13 years, SD ± 5.9), 95.6% of FM patients (disease duration 5.09 years, SD ± 3.6), and 92.3% of the patients with PsA-FM (disease duration 7.9 years, SD ± 5.5). There were no between-group differences in the patients’ BMI. None of the FM subjects reported any personal or family history of psoriasis. The mean PASI was 2.3 ± 3.1 in the PsA group, and 1.2 ± 2.45 in the PsA-FM group. The median BASDAI was significantly higher in PsA-FM vs PsA group (7.7 [IQR 2.1] vs 5.0 [IQR 3.8]; p Conclusion The use of a clinical examination and clinimetric scores alone may overestimate active enthesitis in FM patients. As US was more frequently positive in patients with PsA and PsA-FM than in those with FM, it may be useful in differentiating pain due to enthesitis from entheseal pain due to FM. References [1] Marchesoni A, et al. The problem in differentiation between psoriatic-related polyenthesitis and fibromyalgia. Rheumatology. 2018;57:32-40 [2] McGonagle D. Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease.J Eur Acad Dermatol Venereol2009;23:9–13 Disclosure of Interests Alessia Fiorenza : None declared, Gianluca Bonitta Consultant for: Sanofi, Elisabetta Gerratana : None declared, Francesca Marino: None declared, Pietro Muto: None declared, Donatella Sangari: None declared, Piercarlo Sarzi-Puttini Speakers bureau: Novartis, Fausto Salaffi Grant/research support from: Abbvie, Roche, Novartis, BMS, Pfizer, Sanofi, Speakers bureau: Abbvie, Roche, Novartis, Pfizer, Sanofi, BMS, Fabiola Atzeni: None declared

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.

Background:Patients with rheumatic arthritis (RA) continue to report significant pain despite apparent disease control by immunosuppressive drugs (1), leading to the hypothesis that central sensitisation (CS) plays a role in the chronic musculo-skeletal pain defining fibromyalgia (FM).Objectives:The aim of our study was to evaluate the differences in psychiatric comorbidities and life adversities between patients with AR+FM and patients with primary FM (PFM).Methods:In a observational cross- sectional study patients with PFM and AR+FM were consecutively recruited. The inclusion criteria were an age of 18-70 years; a diagnosis of RA according to the 2010 ACR classification criteria and FM according to the 1990 ACR criteria and 2016 ACR criteria. Lifetime diagnoses of major depression disorder (MDD), panic disorder (PD) and post-traumatic stress disorder (PTSD), three of the most frequently described psychiatric disorders among FM patients, were made with the Structured Clinical Interview for DSM-5. Depressive symptoms were measured using the Zung Self-rating Depression Scale (ZSDS). Childhood trauma was measured using the short form of the Childhood Trauma Questionnaire (CTQ) and stressful events were assessed using the Paykel’s Interview for Recent Life Events. Pain was assessed using a visual analogue scale (VAS). The Fibromyalgia Impact Questionnaire (FIQ) was also used.Results:Seventy-seven patients were originally screened, but seven were excluded because of current depressive episode or having a ZSDS of ≥60 or categorized as minimizers of childhood maltreatment at CTQ. The final analysis therefore involved 70 patients, all Caucasians: 30 with PFM and 40 with AR+FM. All patients with PFM and 38 (95%) of the 40 with AR+FM were treated for FM symptoms (antidepressants, pregabalin). The lifetime rates of MDD were significantly higher in PFM vs AR+FM (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 PFM patients reported significantly higher levels of physical (p=0.020) and sexual abuse (p=0.011) and physical neglect (pConclusion:PFM and SFM differ in psychiatric co-morbidities and environmental adversities, suggesting that the putative common pathogenetic condition of CS may develop through different pathways.References:[1]McWilliams DF, Walsh DA. BMC Musculoskelet Disord 2016; 17, 337.Disclosure of Interests: :None declared

Background:Central sensitization (CS) is an important feature of patients with chronic pain, especially rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients. CS might interfere with the clinical evaluation of inflammation. Central Sensitization Inventory (CSI) is a validated instrument for assessing central sensitization.Objectives:We seek to investigate the inference of central sensitization (assessed with the CSI) on clinical (disease activity scores) and ultrasound parameters (US 7-joints score) in RA and PsA patients.Methods:We conducted a cross-sectional analysis on patients with an established diagnosis of RA or polyarticular PsA. Demographic, anamnestic and clinical parameters were collected. Disease activity was measured with SDAI in RA patients and with DAPSA in PsA patients. The presence and severity of synovitis was measured with the US 7-joints score. Exclusion criteria included: diagnosis of fibromyalgia, depression and patients with PsA with enthesitis predominant and/or spondylitis subtypes. Differences between variables were analysed with t-test and ANOVA for multiple comparisons. Correlation between continuous variables was analysed with Pearson correlation. CSI was analysed either as positive\negative (threshold 40 points) or divided in four categories, i.e., subclinical (≤29), mild (30-39), moderate (40-49), severe (50-59) and extreme (≥60).Results:We enrolled 42 patients in the study. Descriptive characteristics of the study population are presented in table 1. We found no difference in clinical parameters between diseases, sex or age. Women had a higher CSI score compared to men (mean 39.3 vs 26.7 p=0.005). We found a correlation between CSI score and DAPSA (r20.39, p =0.001), number of tender joints (r20.13, p=0.02) and HAQ (r20.47, p20.33, p=0.03), number of swollen joints (r20.28, p=0.002) and disease duration (r20.35, pTable 1.Descriptive characteristics of the study populationAge (mean, SD in years)55.9 (12.3)BMI25.9 (3.9)CSI questionnaire score (mean)35 (16)CSI categories (n, %)Subclinical18 (42.9%)Mild9 (21.4%)Moderate8 (19.0%)Severe4 (9.5%)Extreme3 (7.1%)Diagnosis (n, %)PsA 52.4%9 men 13 womenRA 47.6%2 men 18 womenCSI score in PsA (mean, SD)34.4 (16.5)CSI score in RA (mean, SD)34.8 (15.5)CRP (median, IQR in mg/L)1.85 (1.0-4.6)Tender joints (mean, SD)2 (2)Swollen joints (mean, SD)1 (2)SDAI categories (n, %)Remission4 (20.0%)Low disease activity8 (40.0%)Moderate disease activity7 (35.0%)Severe disease activity1 (5.0%)DAPSA categories (n, %)Remission6 (33.3%)Low disease activity4 (22.2%)Moderate disease activity7 (38.9%)Severe disease activity1 (5.6%)US 7-joints score (mean, SD)6 (7)HAQ (mean, SD)0.6 (0.6)Prednisone equivalent (mean, SD in mg/day)1.47 (3.2)Biological DMARD (n, %)No15 (35.7%)Yes27 (64.3%)Conventional DMARD (n, %)No13 (31.0%)Yes29 (69.0%)Figure 1.Correlation between DAPSA score and CSI score and between HAQ and CSI scoreConclusion:We found an association between CS and sex, functional disability, tender joints count and disease activity score in PsA patients while there was no correlation between RA disease activity and central sensitization. US 7-joints score was associated with swollen joints count, disease duration and disease activity in RA patients but not in PsA patients. In PsA patients, DAPSA might be more influenced by central sensitization, especially in female individuals.Disclosure of Interests:Giovanni Adami: None declared, Elisabetta Gerratana: None declared, Alessandro Giollo: None declared, Camilla Benini: None declared, Elisabetta Vantaggiato: None declared, Denise Rotta: None declared, Luca Idolazzi: None declared, Davide Gatti Speakers bureau: Davide Gatti reports personal fees from Abiogen, Amgen, Janssen-Cilag, Mundipharma, outside the submitted work., Maurizio Rossini Speakers bureau: AbbVie, Abiogen, Amgen, BMS, Eli-Lilly, Novartis, Pfizer, Sanofi, Sandoz and UCB, Angelo Fassio Speakers bureau: Angelo Fassio reports personal fees from: Abiogen and Novartis, outside the submitted work.