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Objectives: To study and compare the clinical and serological features of patients with elderly versus adult and younger onset of primary Sjögren's syndrome (pSS).Methods: We analyzed retrospectively 336 consecutive pSS patients followed at our unit. They were subdivided into three groups according to the age at disease onset: elderly (>65 years), adult (>40 and ≤65 years), and young (≤40 years). Clinical and immunological features of the disease, labial salivary glands biopsy, ocular and oral tests were collected at time of diagnosis and then compared among the three groups.Results: In 21 (6%) patients, disease onset occurred after the age of 65 years. At the time of diagnosis, 15 (71.4%) of these patients reported symptoms of dry mouth and 16 (76.1%) of dry eye. The most common extraglandular manifestation were arthralgias in 14 (66.7%), Raynaud's phenomenon in five (23.8%) and purpura in three (14.2%) cases. Ocular diagnostic tests (Schirmer's I and Rose-Bengal staining) were positive respectively in 17 (80%) and nine (44.4%) patients. In eight (38%) cases, unstimulated whole salivary flow showed normal values, while 12 patients (57.1%) showed positivity for salivary sialography. A focus score greater or equal to 1 per 4mm(2) was demonstrated in 11 (53.3%) of the 21 cases.Conclusion: Elderly onset of pSS was associated with similar incidence of the diagnostic tests positivity (parotid sialography, ocular tests, minor salivary gland biopsy) in comparison with adult and younger onset. Moreover, no statistical differences were found among the three groups concerning sex, disease duration, as well as ocular and oral symptoms. [ABSTRACT FROM AUTHOR]

Background and Objectives: The treatment landscape for Rheumatoid Arthritis (RA) has evolved significantly with the introduction of Janus kinase inhibitors (JAKi), such as Tofacitinib (TOFA), which offer a new therapeutic option for patients who have failed or are intolerant to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Safety concerns, particularly related to cardiovascular and cancer risks, prompted a need for additional investigation in real-world clinical settings. This study aimed to evaluate the long-term effectiveness and predictors of response to TOFA in two subpopulations of RA patients, categorized by differing cardiovascular risk profiles. Materials and Methods: This was a retrospective, multicenter observational study conducted as part of the BIRRA project, involving 23 Italian rheumatological referral centers. A total of 213 patients diagnosed with RA and treated with TOFA were included, with data collected on baseline demographics, clinical history, disease activity, and comorbidities. Patients were divided into high-risk and low-risk cardiovascular groups based on age (≥65 years) and the presence of at least one cardiovascular risk factor. Disease activity was assessed at baseline, 6 months, and 12 months using DAS28-ESR and DAS28-CRP. Treatment response was evaluated using intention-to-treat (ITT) and per-protocol (PP) approaches. Predictors of low disease activity (LDA) and remission were assessed through logistic regression, and clustering analyses were used to identify subgroups of patients with different therapeutic responses. Results: The study included 213 patients, with 129 classified as high-risk. For the overall cohort, patients achieving LDA and remission at 6 months were 20% and 12%, respectively, for the ITT analysis, and 29% and 14% for the PP analysis. At 12 months, 26% of patients reached LDA, and 17% achieved remission according to ITT, while for the PP analysis, these rates were 30% and 19%, respectively. No significant differences in remission or LDA rates were observed between the high-risk and low-risk groups. In the high-risk subgroup, 17% of patients reached LDA and 9% achieved remission at 6 months (ITT analysis), while these rates increased to 22% and 13%, respectively, in the PP analysis. At 12 months, 22% achieved LDA and 13% achieved remission in the ITT analysis, while 28% and 17% did so in the PP analysis. The reduction in DAS28-ESR and DAS28-CRP scores was significant ( p < 0.001) across all time points for both high-risk and low-risk patients. Logistic regression analyses revealed that none of the baseline characteristics-including age, sex, comorbidities, rheumatoid factor, anti-citrullinated protein antibody (ACPA) positivity, initial disease severity, or treatment history-were significant predictors of remission or LDA at 6 or 12 months. The clustering analysis suggested that older patients, particularly those with worse baseline DAS28 scores, tended to show a less favorable response to treatment, potentially indicating impacts of age-related factors such as immunosenescence on therapeutic outcomes. Conclusions: Tofacitinib demonstrated similar effectiveness in both high- and low-risk cardiovascular subgroups of RA patients, with significant reductions in disease activity observed at both 6 and 12 months. Despite safety concerns related to cardiovascular risk, TOFA remained an effective treatment option across patient subgroups, with no significant differences in remission or LDA rates based on cardiovascular risk profiles. Age appeared to negatively impact treatment response, highlighting the role of immunosenescence in RA management. These findings support the use of TOFA as a personalized therapeutic option for RA, emphasizing the need for careful evaluation of cardiovascular and age-related risks in clinical decision-making.

Background: Upadacitinib (UPA) is a selective, reversible Janus kinase inhibitor (JAKi) approved for the treatment of RA. However, there is still no solid evidence on the long-term efficacy of UPA in treated patients. The purpose of this study was to determine the efficacy of UPA to obtain remission or low disease activity (LDA) in a series of UPA patients in patients with RA after 6 and 12 months of treatment in a real-world setting., Methods: A series of 111 consecutive patients treated with UPA in 23 rheumatology centers were enrolled. Personal history, treatment history and disease activity at baseline, after 6 and 12 months were recorded. Intention-to-treat (ITT) and per-protocol (PP) analyses assessed achievement of remission or LDA or defined as DAS28 <2.6 and ≤3.2, respectively. Logistic regression analysis examined the role of several independent factors on the reduction of disease activity after 6 months of treatment., Results: Of the initial group of 111 subjects at baseline, 86 and 29 participants completed clinical assessments at 6 and 12 months. According to ITT analysis, the rates of remission and LDA were 18% and 18% at 6 months and 31.5% and 12.5% at 12 months, respectively. PP analysis showed higher rates of remission and LDA at 6 (23.3% and 19.8%) and 12 months (55.2% and 20.7%). Results of multivariate logistic regression analysis indicated that a low DAS28 score (P=0.045) was the only predictor of achieving remission at 6 months. None of the baseline factors predicted remission/LDA at 6 months., Conclusions: RA patients treated with UPA achieved a significant rate of disease remission or LDA in a real-world setting. The 6-month response was found to depend only on the baseline value of DAS28, while it was not influenced by other factors such as disease duration, line of treatment or concomitant therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids.

Background/Objectives: The Janus kinase inhibitors (JAKi) tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA), and filgotinib (FILGO) are effective drugs for the treatment of rheumatoid arthritis. However, the US Food and Drug Administration (FDA) raised concerns about the safety of TOFA after its approval. This prompted the European Medicines Agency (EMA) to issue two safety warnings for limiting TOFA use, then extended a third warning to all JAKi in patients at high risk of developing serious adverse effects (SAE). These include thrombosis, major adverse cardiac events (MACE), and cancer. The purpose of this work was to analyze how the first two safety warnings from the EMA affected the prescribing of JAKi by rheumatologists in Italy. Methods: All patients with rheumatoid arthritis who had been prescribed JAKi for the first time in a 36-month period from 1 July 2019, to 30 June 2022 were considered. Data were obtained from the medical records of 29 Italian tertiary referral rheumatology centers. Patients were divided into three groups of 4 months each, depending on whether the JAKi prescription had occurred before the EMA's first safety alert (1 July-31 October 2019, Group 1), between the first and second alerts (1 November 2019-29 February 2020, Group 2), or between the second and third alerts (1 March 2021-30 June 2021, Group 3). The percentages and absolute changes in the patients prescribed the individual JAKi were analyzed. Differences among the three groups of patients regarding demographic and clinical characteristics were also assessed. Results: A total of 864 patients were prescribed a JAKi during the entire period considered. Of these, 343 were identified in Group 1, 233 in Group 2, and 288 in Group 3. An absolute reduction of 32% was observed in the number of patients prescribed a JAKi between Group 1 and Group 2 and 16% between Group 1 and Group 3. In contrast, there was a 19% increase in the prescription of a JAKi in patients between Group 2 and Group 3. In the first group, BARI was the most prescribed drug (227 prescriptions, 66.2% of the total), followed by TOFA (115, 33.5%) and UPA (1, 0.3%). In the second group, the most prescribed JAKi was BARI (147, 63.1%), followed by TOFA (65, 27.9%) and UPA (33, 11.5%). In the third group, BARI was still the most prescribed JAKi (104 prescriptions, 36.1%), followed by UPA (89, 30.9%), FILGO (89, 21.5%), and TOFA (33, 11.5%). The number of patients prescribed TOFA decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 ( p ˂ 0.01). The number of patients who were prescribed BARI decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 ( p ˂ 0.01). In contrast, the number of patients prescribed UPA increased between Group 2 and Group 3 ( p ˂ 0.01). Conclusions : These data suggest that the warnings issued for TOFA were followed by a reduction in total JAKi prescriptions. However, the more selective JAKi (UPA and FILGO) were perceived by prescribers as favorable in terms of the risk/benefit ratio, and their use gradually increased at the expense of the other molecules.

Background/Objectives: Erosive hand osteoarthritis (EHOA) is an aggressive form of hand osteoarthritis (OA) and a severely disabling condition. Patients affected by OA frequently lament symptoms suggestive of neuropathic pain (NP). The aim of our study was to ascertain the presence and severity of NP in patients with EHOA and correlate its presence with EHOA clinical characteristics. Methods: In this retrospective study, we included all consecutive EHOA patients with NP symptoms who underwent upper limb electroneurography (ENoG) and nerve ultrasound. The presence of NP was screened using the ID pain neuropathic pain-screening questionnaire (ID-Pain). In addition, the following NP questionnaires were also used: Douleur Neuropathique en 4 Questions (DN4), PainDETECT, and Neuropathic Pain Symptom Inventory (NPSI). Moreover, patients completed the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) and Dreiser's algofunctional finger index questionnaires assessing EHOA disease activity. The following clinical and laboratory data were collected: age, sex, BMI, disease duration, intensity of pain (VAS 0-10), painful and swollen joints, and inflammatory indices, as well as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Results: Of the 34 patients studied, 24 (70.6%) presented NP to the ID-Pain questionnaire. According to DN4, 14 (41.2%) patients had NP, while using the PainDETECT questionnaire, 67.6% had NP. Patients with NP were statistically younger and had a higher VAS pain score compared to subjects without NP. The ENoG and median nerve ultrasound were normal in 81% of patients, while four patients had carpal tunnel syndrome. The ID-Pain questionnaire correlated with the number of painful joints (r = 0.48, p = 0.03) and with the AUSCAN questionnaire (r = 0.37, p = 0.05). The DN4 questionnaire correlated with PainDETECT (r = 0.58, p < 0.01). The PainDETECT questionnaire correlated with VAS pain (r = 0.49, p = 0.02), the DN4 questionnaire (r = 0.58, p < 0.01), and AUSCAN (r = 0.51, p = 0.02). The NPSI questionnaire correlated negatively with BMI (r = -0.53, p = 0.01) and positively with the PainDETECT questionnaire (r = 0.49, p = 0.02). Conclusions: Our study revealed that 32% to 70% of EHOA patients exhibited symptoms consistent with NP, with observed variability depending on the questionnaire utilized. Despite patients frequently exhibiting symptoms compatible with NP, only 19% of patients presented alterations on ENoG and ultrasound examinations confirming CTS. This suggests a probable nociplastic component for pain in patients with EHOA, which warrants tailored treatment. In the present study, NP correlated with clinical and functional indices of EHOA.

Background : Tofacitinib (TOFA) was the first Janus kinase inhibitor (JAKi) to be approved for the treatment of rheumatoid arthritis (RA). However, data on the retention rate of TOFA therapy are still far from definitive. Objective : The goal of this study is to add new real-world data on the TOFA retention rate in a cohort of RA patients followed for a long period of time. Methods : A multicenter retrospective study of RA subjects treated with TOFA as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was conducted in 23 Italian tertiary rheumatology centers. The study considered a treatment period of up to 48 months for all included patients. The TOFA retention rate was assessed with the Kaplan-Meier method. Hazard ratios (HRs) for TOFA discontinuation were obtained using Cox regression analysis. Results : We enrolled a total of 213 patients. Data analysis revealed that the TOFA retention rate was 86.5% (95% CI: 81.8-91.5%) at month 12, 78.8% (95% CI: 78.8-85.2%) at month 24, 63.8% (95% CI: 55.1-73.8%) at month 36, and 59.9% (95% CI: 55.1-73.8%) at month 48 after starting treatment. None of the factors analyzed, including the number of previous treatments received, disease activity or duration, presence of rheumatoid factor and/or anti-citrullinated protein antibody, and presence of comorbidities, were predictive of the TOFA retention rate. Safety data were comparable to those reported in the registration studies. Conclusions : TOFA demonstrated a long retention rate in RA in a real-world setting. This result, together with the safety data obtained, underscores that TOFA is a viable alternative for patients who have failed treatment with csDMARD and/or biologic DMARDs (bDMARDs). Further large, long-term observational studies are urgently needed to confirm these results.

Spondyloarthritis (SpA) encompasses a heterogeneous group of chronic inflammatory diseases that can affect both axial and peripheral joints, tendons and entheses. Among the extra-articular manifestations, inflammatory bowel disease (IBD) is associated with considerable morbidity and effects on quality of life. In everyday clinical practice, treatment of these conditions requires a close collaboration between gastroenterologists and rheumatologists to enable early detection of joint and intestinal manifestations during follow-up and to choose the most effective therapeutic regimen, implementing precision medicine for each patient's subtype of SpA and IBD. The biggest issue in this field is the dearth of drugs that are approved for both diseases, as only TNF inhibitors are currently approved for the treatment of full-spectrum SpA-IBD. Janus tyrosine kinase inhibitors are among the most promising drugs for the treatment of peripheral and axial SpA, as well as for intestinal manifestations. Other therapies such as inhibitors of IL-23 and IL-17, phosphodiesterase 4 inhibitor, α4β7 integrin blockers and faecal microbiota transplantation seem to only be able to control some disease domains, or require further studies. Given the growing interest in the development of novel drugs to treat both conditions, it is important to understand the current state of the art and the unmet needs in the management of SpA-IBD., (© 2023. Springer Nature Limited.)

Our study aimed to evaluate the association between fetuin-A levels and the presence of radiographic sacroiliitis and syndesmophytes in patients with early axial spondyloarthritis (axSpA) and to identify potential predictors of radiographic damage in the sacroiliac joints (SIJs) after 24 months. Patients diagnosed with axSpA in the Italian cohort of the SpondyloArthritis-Caught-Early (SPACE) study were included. Physical examinations, laboratory tests (including fetuin-A), SIJ,+ and spinal X-rays and MRIs at T0 (diagnosis) and at T24 were considered. Radiographic damage in the SIJs was defined according to the modified New York criteria (mNY). Fifty-seven patients were included in this analysis (41.2% male, median (interquartile range), chronic back pain [CBP] duration of 12 (8-18) months). Fetuin-A levels were significantly lower in patients with radiographic sacroiliitis compared to those without at T0 (207.9 (181.7-215.9) vs. 239.9 (217.9-286.9), respectively, p < 0.001) and at T24 (207.6 (182.5-246.5) vs. 261.1 (210.2-286.6) µg/mL, p = 0.03). At T0, fetuin-A levels were significantly higher in non-smokers, in patients with heel enthesitis and in those with a family history of axSpA; fetuin-A levels at T24 were higher in females, in patients with higher ESR or CRP at T0 and in those with radiographic sacroiliitis at T0. Fetuin-A levels at T0 were independently negatively associated with the likelihood of radiographic sacroiliitis (OR = 0.9 per 10-unit increase (95% CI 0.8, 0.999), p = 0.048); but not with the presence of syndesmophytes. After adjustment for confounders, fetuin-A levels at T0 and T24 were also negatively associated with mNY at T0 (β -0.5, p < 0.001) and at T24 (β -0.3, p < 0.001), respectively. Among other variables at T0, fetuin-A levels did not achieve statistical significance in predicting mNY at T24. Fetuin-A levels were negatively associated with radiographic damage of the SIJs, but not of the spine, in early axSpA and after 2 years of follow-up. Our findings suggest that fetuin-A levels may serve as a biomarker to identify patients with a higher risk of developing severe disease and early structural damage.

Background: The aim of the study was to examine the relationship among patients' characteristics, intraoperative pathology and pre/post-operative symptoms in a cohort of patients undergoing arthroscopic partial meniscectomy for symptomatic meniscal tears., Methods: Clinical data were collected (age, sex, body mass index, time to surgery, trauma). Intraoperative cartilage pathology was assessed with Outerbridge score. Meniscal tears were graded with the ISAKOS classification. Synovial inflammation was scored using the Macro-score. Patient symptoms were assessed pre/post-operatively using the KOOS instrument., Results: In the series of 109 patients (median age 47 years), 50% of the meniscal tears were traumatic; 85% of patients showed mild to moderate synovitis; 52 (47.7%) patients had multiple cartilage defects and 31 (28.4%) exhibited a single focal chondral lesion. Outerbridge scores significantly correlated with patient age, BMI and synovial inflammation. There was a correlation between severity of chondral pathology and high-grade synovial hyperplasia. Pre-operative KOOS correlated with BMI, meniscal degenerative changes and symptom duration. Obesity, time to surgery, presence of high-grade synovial hyperplasia and high-grade cartilage lesions were independent predictors of worse post-operative pain and function., Conclusion: We demonstrated that pre-operative symptoms and post-operative outcomes correlate with synovitis severity and cartilage pathology, particularly in old and obese patients that underwent arthroscopic partial meniscectomy. Importantly, patients with a degenerative meniscal pattern and with longer time to surgery experienced more severe cartilage damage and, consequentially, pain and dysfunction. These findings are fundamental to identify patients suitable for earlier interventions., Competing Interests: The authors declare no conflict of interest.

Background: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA)., Methods: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC., Results: Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach., Conclusion: These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA., Competing Interests: Competing interests: KM: honoraria from Abbvie, Eli Lilly & Co and UCB; grants from Eli Lilly & Co and Gilead. HJS: none declared. AK: speakers bureau, consultancy: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly & Co, Gilead, Merck Sharp and Dohme, Novartis and Pfizer. DAR: scientific advisor for GSK. AIC, JDC and APC: none declared. CID: honoraria from Roche, Chugai, Pfizer, BMS, MSD, Biogen, Abbvie, Sandoz, Janssen, Novartis, Fresenius Kabi and Sanofi; research grants from Pfizer, MSD and Schwa Medico. KR: speaker fees from Abbvie. PE: expert advice to Pfizer, Abbvie, Amgen, MSD, Roche, Sanofi, BMS, Novartis, Eli Lilly & Co, Gilead, Samsung and Celltrion; grants from Abbvie, Eli Lilly & Co, BMS and Samsung., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Little evidence is available about the impact of diet on disease activity of axial spondyloarthritis (axSpA). This study evaluated the impact of a 6-month nutritional advice based on the Mediterranean diet on the disease activity of axSpA., Methods: We prospectively collected the information of a group of axSpA patients who were offered nutritional advice for a 6-month period, who were compared to axSpA patients followed at the same center who were not on a specific diet. A nutritionist gave suggestions for dietary modification at baseline and thereafter every 2 months until month 6. Adherence to the Mediterranean diet was evaluated with the PREDIMED questionnaire ranging from 0 (no adherence) to 10 (optimal adherence); disease activity was evaluated with ASDAS-CRP. A multivariable regression analysis was conducted to identify independent predictors of PREDIMED and of ASDAS-CRP improvement (improvement ≥ 20% of each score)., Results: A total of 161 patients were included: 81 receiving nutritional advice and 80 controls; 47 in the nutritional group and 63 controls had complete information until month 6. Overall, 40 (36.4%) were females, the mean age was 51.7 ± 1.3 years, and 58 (52.7%) were affected with psoriasis. No relevant change of anthropometric or laboratory measures was observed in either group. Adherence to the Mediterranean diet was moderate (PREDIMED score 6.7 ± 1.8 at baseline; 7.6 ± 2.1 at month 6) and improved more in the nutritional group compared to controls (p = 0.020). Predictors of a PREDIMED improvement ≥ 20% were receiving nutritional advice (OR 4.53, 1.36-15.1, p = 0.014), age (per 10-year increase OR 1.05, 1.02-1.68, p = 0.007), and BMI (OR 0.77, 0.63-0.9, p = 0.006). An ASDAS-CRP improvement ≥ 20% was more frequent in the nutritional group compared to controls (p = 0.020). A PREDIMED improvement ≥ 20% was associated with a ASDAS-CRP improvement ≥ 20% (OR 6.75,1.8-25.3, p = 0.005). Psoriasis and disease duration were negatively but not significantly associated to the ASDAS-CRP improvement., Conclusions: Improving adherence to the Mediterranean diet may have a beneficial impact on the activity of axSpA. Patients with a lower BMI and older patients are less prone to modify their diet towards the Mediterranean diet following nutritional advice. Patients with psoriasis may have a limited benefit from dietary improvement., Study Registration: Protocol No. 52723, Padova Hospital Medical Ethical Committee (October 11, 2010)., (© 2021. The Author(s).)

Background & Aims: Hydroxychloroquine (HCQ) and chloroquine (CQ) are anti-malarial drugs frequently used in the rheumatologic field. They were recently identified as potential therapeutic options for Coronavirus Disease (COVID-19). The present study aims to map and grade the diverse health outcomes associated with HCQ/CQ using an umbrella review approach., Methods: Umbrella review of systematic reviews of observational and intervention studies. For observational studies, random-effects summary effect size, 95% confidence interval, and 95% prediction interval were estimated. We also assessed heterogeneity, evidence for small-study effect, and evidence for excess significance bias. The quality of evidence was then graded using validated criteria from highly convincing to weak. The evidence from randomized controlled trials (RCTs) was graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool., Results: From 313 articles returned in the literature search, six meta-analyses were included (n = 25 outcomes). Among meta-analyses (MAs) of observational studies, HCQ/CQ are weakly associated with a reduced risk for cardiovascular events and diabetes when used for autoimmune diseases and with spontaneous abortion; they are also associated with a higher risk of death in COVID-19 patients. Among MAs of RCTs, HCQ/CQ are associated with an improvement of articular manifestations of rheumatic diseases., Conclusions: There is high evidence of the efficacy of HCQ/CQ in the rheumatologic field. The lack of evidence for efficacy and the risk of death associated with the use of HCQ/CQ for COVID-19 indicate the inappropriateness of their inclusion in recent COVID-19 therapy guidelines and the urgent need for RCTs to determine eventual appropriateness as a COVID-19 therapy., (Copyright © 2020. Published by Elsevier Ltd.)

Objectives: We aimed to evaluate trends of rheumatoid arthritis (RA) mortality reported as the underlying cause of death (UCD) and as multiple causes of death (MCD) in Italy between 2003 and 2015., Methods: Analyses were carried out on the Italian National Cause of Death Register, managed by the Italian National Institute of Statistics (ISTAT). Deaths from January 1, 2003 to December 31, 2015 with any mention of RA were included. Diseases are coded according to the International Classification of Diseases, 10th Edition (ICD- 10, 2009 version). Time trends of age-standardised rates were analysed for RA both as UCD and MCD, and the annual percent change (APC) was estimated., Results: Overall, 26,564 deaths with a mention of RA were retrieved out of 7,595,214 deaths (0.35% of all certificates). The mention of RA as MCD increased throughout the study period, meanwhile the selection as the UCD decreased. RA mortality rates based on the UCD declined (males APC -3.1%, CI -3.9, -2.3; females APC -3.3%, CI -4.1, -2.4); while rates based on the MCD were stable. Specifically, rates were stable or declined among younger subjects and increased in subjects aged ≥80 years., Conclusions: RA was found to be increasingly reported in death certificates in the last two decades in Italy, although it is less frequently reported as the UCD. Due to the increased survival of patients, we observed a shift of RA-related mortality towards the elderly, making RA a comorbidity contributing to death in these patients.

The educational needs assessment tool (ENAT) is a seven-domain questionnaire assessing the educational needs (EN) of patients with rheumatoid arthritis (RA). The aim of this study was to validate the Italian version of the ENAT and to identify factors associated with EN in people with RA. The original English ENAT version was translated into Italian according to Beaton's method and subjected to Rasch analysis for validity testing. Socio-demographic and clinical variables were tested for associations with the ENAT domain scores using a multivariable linear regression model. The ENAT translated well into Italian and retained its construct validity. Some adjustments were needed when pooling the Italian and English datasets. The overall score of the ENAT had a high median: 82.8 (interquartile range (IQR): 57.5 to 100) i.e., 72.4% of the maximum score. The highest score was observed in the domain "Arthritis process" and the lowest was in "Support systems". Only gender was independently associated with EN (females having higher EN than males). The Italian ENAT is feasible for the use in the clinical setting and may help the health care practitioners to tailor educational interventions for RA patients. The characteristics of the patients, particularly female gender, may be associated with higher EN.

Axial spondyloarthritis (axSpA) is a group of debilitating, chronic, rheumatic conditions characterized by inflammation and new bone formation, mainly involving the spine and the sacroiliac joints. The lack of biomarkers in axSpA is well known. Despite significant treatment advances in recent years thanks to the introduction of drugs with a new mode of action, such as new biologic and targeted synthetic disease-modifying antirheumatic drugs, no relevant improvement in the identification of disease biomarkers has been achieved. Common parameters, such as erythrocyte sedimentation rate and C-reactive protein, which are routinely used to measure systemic inflammation, are the sole markers available to date and are not adequate to assess disease activity in all patients. The aim of this study is to review the most promising serum biomarkers that may help treatment decision in axSpA via a proper assessment of disease activity and identification of negative prognostic factors., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Objectives: The 5-item Compliance Questionnaire for Rheumatology (CQR5) proved reliability and validity in respect of identification of patients likely to be high adherers (HAs) to anti-rheumatic treatment, or low adherers (LAs), i.e. taking<80% of their medications correctly. The objective of the study was to validate an Italian version of CQR5 (I-CQR5) in rheumatoid arthritis (RA) patients and to investigate factors associated with high adherence., Methods: RA patients, undergoing treatment with ≥1 self-administered conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) or biological DMARD (bDMARD), were enrolled. The cross-cultural adaptation and validation of I-CQR5 followed standardised guidelines. I-CQR5 was completed by patients on one occasion. Data were subjected to factor analysis and Partial Credit model Parametrisation (PCM) to assess construct validity of I-CQR5. Analysis of factors associated with high adherence included demographic, social, clinical and treatment information. Factors achieving a p<0.10 in univariate analysis were included in multivariable analysis., Results: Among 604 RA patients, 274 patients were included in the validation and 328 in the analysis of factors associated with adherence. Factor analysis and PCM confirmed the construct validity and consistency of I-CQR5. HAs were found to be 109 (35.2%) of the patients. bDMARD treatment and employment were found to be independently associated with high adherence: OR 2.88 (1.36-6.1), p=0.006 and OR 2.36 (1.21-4.62), p=0.012, respectively., Conclusions: Only one-third of RA patients were HAs according to I-CQR5. bDMARDs and employment status increased by almost 3-fold the likelihood of being highly adherent to the anti-rheumatic treatment.

Objectives: The aim of our study was to investigate cause-specific mortality in rheumatoid arthritis (RA) subjects living in Italy., Methods: We identified in the electronic archive of the Veneto Region patients aged 20-89 years who were exempt from co-payment for RA in January 2010, and linked them with the archive of causes of deaths of the period 2010-2015. Causes of death were coded according to the International Classification of Diseases, 10th Edition. Standardised mortality ratios (SMRs) with 95% confidence intervals were computed as the ratios between deaths observed in the cohort, and those expected according to age- and gender-specific regional mortality rates., Results: Overall, 16,098 residents diagnosed with RA and aged 20-89 years were enrolled in the cohort. The overall follow-up amounted to 88,599 person-years, with 2,142 registered decedents. The most common causes of death were circulatory diseases (36.6%), neoplasms (24.2%), and respiratory diseases (8.3%). Overall mortality was increased in RA subjects (SMR=1.42, confidence interval 1.36-1.48). Mortality was significantly increased from circulatory (SMR=1.56, 1.45-1.67), respiratory (SMR=1.83, 1.57-2.12), digestive (SMR=1.93, 1.60-2.32), infectious (SMR=2.34, 1.88-2.89), haematological diseases (SMR=3.22, 2.04-4.83), and falls (SMR=1.95, 1.19-3.01). RA was the underlying cause of death in 6.1% of all deaths in the cohort and was mentioned in 25.4% of death certificates., Conclusions: In our study, a 42% excess risk of death was observed among subjects with RA compared with the general population. Cardiovascular disease is the primary cause of premature death in RA. Adverse effects of therapy and comorbidities should be adequately monitored in RA subjects.

Loading macroalgae into existing anaerobic digestion (AD) plants allows us to overcome challenges such as low digestion efficiencies, trace elements limitation, excessive salinity levels and accumulation of volatile fatty acids (VFAs), observed while digesting algae as a single substrate. In this work, the co-digestion of the brown macroalgae Saccharina latissima with mixed municipal wastewater sludge (WWS) was investigated in mesophilic and thermophilic conditions. The hydraulic retention time (HRT) and the organic loading rate (OLR) were fixed at 19 days and 2.1 g l -1  d -1 of volatile solids (VS), respectively. Initially, WWS was digested alone. Subsequently, a percentage of the total OLR (20%, 50% and finally 80%) was replaced by S. latissima biomass. Optimal digestion conditions were observed at medium-low algae loading (≤50% of total OLR) with an average methane yield close to [Formula: see text] and [Formula: see text] in mesophilic and thermophilic conditions, respectively. The conductivity values increased with the algae loading without inhibiting the digestion process. The viscosities of the reactor sludges revealed decreasing values with reduced WWS loading at both temperatures, enhancing mixing properties.

Objectives: To investigate power Doppler (PD) signal, grade and location and their association with radiographic progression in RA patients in remission., Methods: A prospective observational study was conducted in 125 consecutive RA patients in stable 28-joint DAS (DAS28) remission (⩾6 months) achieved on anti-TNF-α. At baseline, patients in stable remission underwent radiographic and US examination of the wrists and MCP, PIP and MTP joints. Semi-quantitative PD scoring (0-3) was recorded. We scored PD according to two locations: capsular or within synovial tissue without bone contact (location 1) and with bone contact or penetrating bone cortex (location 2). Radiographic progression was evaluated at the 1 year follow-up and defined as a change in van der Heijde-modified total Sharp score >0. Risk ratios (RRs) of radiographic progression according to presence, grade and location of PD were calculated., Results: Four patients were excluded because of missing data. At baseline, 59/121 (48.7%) patients had a PD signal in one or more joints. PD location 2 was found in 74.6% patients (44/59). At the 1 year follow-up, 17/121 patients experienced radiographic progression: all had PD signal in one or more joints at baseline (RR 2.47, P < 0.0001). Radiographic progression was associated with the following baseline US features: PD grade 2 (RR 4.58, P < 0.01), PD grade 3 (RR 3.49, P < 0.05), total PD score ⩾2 (sum of all PD scores) (RR 3.19, P < 0.0001) and PD location 2 (RR 3.49, P < 0.0001)., Conclusion: Higher PD grades and PD in contact with/or penetrating bone are associated with radiographic progression in patients in DAS28 remission., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Calprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-α inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker. Impact statement Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment.

Objectives: Orthostatic hypotension is a common condition among older adults and is associated with a range of deleterious outcomes. Recently, interest has developed in hypovitaminosis D (defined as low 25 hydroxiyvitamin D levels) as a potential risk factor for orthostatic hypotension. We conducted a systematic review and meta-analysis examining the association of orthostatic hypotension between study participants with and without hypovitaminosis D, including the adjustment of potential confounders (age, sex, BMI, renal function, comorbidities, seasonality, use of antihypertensive medications, and supplementation with cholecalciferol)., Methods: A systematic literature search of major electronic databases from inception until 09/2015 was made for articles providing data on orthostatic hypotension and hypovitaminosis D. A random effects meta-analysis of cross-sectional studies investigating orthostatic hypotension prevalence comparing participants with vs. those without hypovitaminosis D was undertaken, calculating the odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Of 317 initial hits, five cross-sectional studies were meta-analysed including 3646 participants (1270 with hypovitaminosis D and 2376 without). The participants with hypovitaminosis D had a higher prevalence of orthostatic hypotension (OR = 1.88; 95% CI: 1.25-2.84; I = 68%) that was not affected by adjusting for a median of five potential confounders (OR = 2.03; 95% CI: 1.13-3.68; I = 73%). People with orthostatic hypotension had significantly reduced serum vitamin D concentrations (standardized mean difference = -0.42; 95% CI: -0.72 to -0.12). One longitudinal study confirmed the association between hypovitaminosis D and orthostatic hypotension., Conclusion: Our meta-analysis highlights that hypovitaminosis D is associated with orthostatic hypotension, independent of potential confounders. Further longitudinal studies and clinical trials are required to confirm these findings.

Background: Disease flares are common in rheumatoid arthritis (RA) and are related to structural damage. However, few data on the impact of flares reported by patients on radiographic progression are available. Our aim was to investigate whether overall flares (OF), self-reported flares (SRF) and short flares assessed at the visit (SF) predict radiographic progression in RA patients in DAS28 (28-joint disease activity score) remission., Methods: We reviewed the records of RA patients included in our database. We considered all patients who had a period of at least 24 months in remission (DAS28 < 2.6), stable biologic and synthetic disease-modifying anti-rheumatic drug treatment, no missing follow-up visits and hands and feet radiographs at the start and at the end of the 24-month follow up. Radiographic progression was considered as an increase in the van der Heijde modified total Sharp score >0. Patients were assessed every 3 months and flares were recorded. We defined SRF as any worsening of the disease reported by patients occurring in the time between visits and SF as an increase in DAS28 ≥ 2.6 or >0.6 from the previous visit assessed by the physician in one isolated visit. The impact of SRF, SF and OF on radiographic progression was assessed through multivariate regression analysis., Results: One hundred forty-nine patients were included. The median number (interquartile range) of OF was 1.00/year (0.50; 1.38), of SRF was 0.50/year (0.14; 1.00), and of SF was 0.34/year (0; 0.50). Eighteen patients (12.1 %) experienced a progression of radiographic damage. OF and SRF were significant predictors of radiographic progression: OR 3.27, 95 % CI 1.30, 8.22 and OR 3.63, 95 % CI 1.16, 11.36, respectively., Conclusions: OF and SRF are predictors of structural damage. Flares assessed at the visit, SF, do not impact on radiographic progression as they might underestimate the actual number of flares.

Microalgae have demonstrated the ability to remediate wastewater nutrients efficiently, with methods to further enhance performance through species selection and biomass concentration. This work evaluates a freshwater species remediation characteristics through analysis of internal biomass N:P (nitrogen:phosphorus) and presents a relationship between composition and nutrient uptake ability to assist in species selection. Findings are then translated to an optimal biomass concentration, achieved through immobilisation enabling biomass intensification by modifying bead concentration, for wastewaters of differing nutrient concentrations at hydraulic retention times (HRT) from 3 h to 10 d. A HRT <20 h was found suitable for the remediation of secondary effluent by immobilised Scenedesmus obliquus and Chlorella vulgaris at bead concentrations as low as 3.2 and 4.4 bead·mL(-1). Increasing bead concentrations were required for shorter HRTs with 3 h possible at influent concentrations <5 mgP L(-1)., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This prospective long-term follow-up study evaluated the effects of half-dose etanercept (25 mg weekly) on clinical remission and radiographic progression in a large cohort of patients with rheumatoid arthritis (RA) in clinical remission after etanercept 25 mg bi-weekly., Methods: 524 biologic-naïve RA patients were treated with etanercept 25 mg bi-weekly after failure of conventional drugs. Patients achieving remission (DAS28 <2.6) for ≥12 months were randomised to receive etanercept 25 mg weekly or 25 mg bi-weekly. Patients were assessed at baseline and every 12 weeks. Remission rates, radiographic progression, incidence of infections and costs of the regimens were compared., Results: After a mean follow-up of 18±11 months, 347 patients (66.2%) achieved DAS28 remission; 323 were randomised to one of two dose regimens: etanercept 25 weekly (group A, 159 patients) and etanercept 25 mg bi-weekly (group B, 164 patients). At the end of follow-up, 81.8% patients of group A maintained remission for a mean of 3.6±1.5 years. Radiographic progression occurred in a small number of patients of group A and the rate of radiographic progression (TSS >0) was not significantly different in the two groups (18.85% vs. 19.0% after the first year and 16.9% vs. 21.6% after the second year, respectively). The incidence ratio of severe infections was 2.3/1.000 patient-years in group A. Etanercept half-dose regimen resulted in a saving of €3.190.545 with a cost saving up to €827.318 per year., Conclusions: Clinical remission and arrest of radiographic progression persisted in a substantial percentage of patients with RA even after reduction of standard-dose etanercept.

Anaerobic digestion (AD) of microalgae is primarily inhibited by the chemical composition of their cell walls containing biopolymers able to resist bacterial degradation. Adoption of pre-treatments such as thermal, thermal hydrolysis, ultrasound and enzymatic hydrolysis have the potential to remove these inhibitory compounds and enhance biogas yields by degrading the cell wall, and releasing the intracellular algogenic organic matter (AOM). This work investigated the effect of four pre-treatments on three microalgae species, and their impact on the quantity of soluble biomass released in the media and thus on the digestion process yields. The analysis of the composition of the soluble COD released and of the TEM images of the cells showed two main degradation actions associated with the processes: (1) cell wall damage with the release of intracellular AOM (thermal, thermal hydrolysis and ultrasound) and (2) degradation of the cell wall constituents with the release of intracellular AOM and the solubilisation of the cell wall biopolymers (enzymatic hydrolysis). As a result of this, enzymatic hydrolysis showed the greatest biogas yield increments (>270%) followed by thermal hydrolysis (60-100%) and ultrasounds (30-60%)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Dissolved Air Flotation (DAF) is a well-known coagulation-flotation system applied at large scale for microalgae harvesting. Compared to conventional harvesting technologies DAF allows high cell recovery at lower energy demand. By replacing microbubbles with microspheres, the innovative Ballasted Dissolved Air Flotation (BDAF) technique has been reported to achieve the same algae cell removal efficiency, while saving up to 80% of the energy required for the conventional DAF unit. Using three different algae cultures (Scenedesmus obliquus, Chlorella vulgaris and Arthrospira maxima), the present work investigated the practical, economic and environmental advantages of the BDAF system compared to the DAF system. 99% cells separation was achieved with both systems, nevertheless, the BDAF technology allowed up to 95% coagulant reduction depending on the algae species and the pH conditions adopted. In terms of floc structure and strength, the inclusion of microspheres in the algae floc generated a looser aggregate, showing a more compact structure within single cell alga, than large and filamentous cells. Overall, BDAF appeared to be a more reliable and sustainable harvesting system than DAF, as it allowed equal cells recovery reducing energy inputs, coagulant demand and carbon emissions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Ankylosing spondylitis (AS) is presented with axial and peripheral articular involvement. Uveitis is a severe and rather specific manifestation of AS. Biologics targeting tumor necrosis factor (TNF) α are effective on both articular and ocular manifestations of disease. The occurrence of uveitis in patients that never had eye involvement or the relapse of uveitis is described during anti-TNF α treatment. The frequency of these events is slightly higher during therapy with etanercept. The available TNF α blockers show different pharmacokinetics and pharmacodynamics yielding different biological effects. There is an ongoing debate whether uveitis during anti-TNF α has to be considered as paradoxical effect or an inadequate response to therapy. Here, we present a case report and review what the evidences for the two hypotheses are.

Pemphigus foliaceus (PF) and Behçet's disease (BD) are immune-mediated conditions which are usually treated with corticosteroids, immunosuppressants, and, when refractory, with biologic agents. In both diseases, interleukin (IL)-6 serum levels are increased driving the immune-mediated inflammatory process. Tocilizumab is a humanized monoclonal antibody, targeting IL6-receptor, used in the treatment of rheumatoid arthritis. Besides the current indication, it has been recently administered to patients with refractory immune inflammatory diseases as an off-label treatment. Here, we report the case of a woman affected with PF and BD, who did not respond to corticosteroids, immunosuppressants, and biologic agents including adalimumab, anakinra, and infliximab. A complete, long-lasting, clinical, and serological remission was achieved only with tocilizumab. To the best of our knowledge, the association between PF and BD has never been reported. Moreover, only two cases of BD and no cases of PF treated with tocilizumab have been described to date. A literature review on the use of biologic agents on patients with PF and BD was also carried out.

The aim of the treatment in rheumatoid arthritis (RA) is to prevent articular damage and functional loss by decreasing the activity of the disease. The overall goal is the full suppression of the activity of the disease, also called clinical remission. The most reliable indices to assess RA activity were defined by the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR) and the International League Against Rheumatism (ILAR) and are habitually used for the evaluation of remission. The Food and Drug Administration (FDA) established three increasingly restrictive categories of disease remission: complete clinical response, major clinical response, and remission. Then, OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) advanced the concept of low disease activity state (LDAS) or minimal disease activity (MDA). Thus, those reported by FDA are the only criteria for remission which consider radiographic arrest of the disease. This review aims to describe the criteria for RA remission and to discuss their advantages and limitations., (Copyright 2009 Elsevier B.V. All rights reserved.)

Patients suffering from rheumatoid arthritis have increased risk of infections when compared with general population. The risk depends directly from disease activity and severity. Furthermore, risk increases with aging, immunosuppressive agents and comorbidities such as diabetes, pulmonary and cardiac diseases. In particular corticosteroids, even at low doses, are a major risk factor. Due to disease related risk it is difficult to separate the risk deriving from the use of TNF alpha blockers. Data from clinical trials, meta-analysis and national registers are somewhat contradictory. In patients with rheumatoid arthritis on routine follow-up, treatment with TNF alpha blockers seems to carry an increased risk of infections compared to traditional DMARDs but not associated with increased risk of overall serious infection. Physicians should carefully monitor for signs of infection when using TNF alpha blockers, particularly shortly after treatment initiation.