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Introduction: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis and vascular abnormalities, often leading to the development of digital ulcers (DUs). DUs are painful and debilitating, significantly impacting patients' quality of life. Effective pain management during debridement is crucial, yet there is no consensus on the optimal approach. This study evaluates the efficacy and safety of digital nerve block (DNB) using lidocaine and mepivacaine for pain control during sharp debridement of DUs in SSc patients., Methods: This prospective observational study was conducted from September 2023 to May 2024 at the Rheumatology Operating Unit, University of Verona. Patients were randomized to receive either 1 mL of 2% lidocaine or 2% mepivacaine for DNB. Pain levels were assessed using a categorical grading scale during the injection and debridement. The outcomes were pain control and performance of lidocaine versus mepivacaine., Results: The cohort developed 46 ulcers. The pain was abolished in almost all patients. Lidocaine achieved faster anaesthesia (127.92 ± 34.32 s) compared with mepivacaine (252.65 ± 49.89 s, p  < 0.001). Mepivacaine resulted in less pain during injection ( p  = 0.006). No significant difference in pain levels during debridement was observed between the two anaesthetics. Three mild adverse effects (Raynaud's phenomenon) were reported. All procedures were completed successfully, and 35 ulcers healed with a mean time of 6.1 ± 7.77 weeks., Conclusions: DNB with mepivacaine provides effective pain control during DU debridement in SSc patients, with lower injection site pain and comparable efficacy to lidocaine. The procedure is safe, well-tolerated and facilitates successful ulcer healing. Further studies with larger cohorts are warranted to confirm these findings., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

Objectives: to evaluate over a 48-month follow-up period the: 1) long-term effectiveness and safety; 2) drug retention rate (DRR); 3) impact of comorbidities and bDMARDs line on MDA and DAPSA remission/low disease activity (LDA) of secukinumab in a multicenter Italian cohort of PsA patients., Methods: Consecutive PsA patients receiving secukinumab were followed prospectively in Italian centers between 2016 and 2023. Disease characteristics, previous/ongoing treatments, comorbidities and follow-up duration were recorded. Treatment response was evaluated at 6 and 12 months after initiation, and every year up to 48 months (T48). DRR was assessed according to clinical and demographic features, comorbidities and bDMARDs line. Adverse events (AE) were recorded., Results: Six hundred eighty-five patients [42.5% male] were enrolled; 32.9% naïve received secukinumab; 74.2% had ≥ 1 comorbidity. Overall, secukinumab yielded improved outcomes at T48: naïve maintained lower disease activity vs. non-naïve [DAPSA 4.0 (1.4-8.1) vs. 6.0 (2.2-10.4);p = 0.04]; 76.9% naïve and 66.2% non-naïve achieved MDA; MDA no comorbidities vs. 1-3 comorbidities 78.8% vs. 73.3% (p < 0.05), and MDA no comorbidities vs. > 3 comorbidities 78.8% vs. 48.7% (p < 0.001). DAPSA-REM and DAPSA-LDA rates were higher in naïve patients, albeit similar between those without comorbidities vs. 1-3 comorbidities, and slightly lower in those with > 3 comorbidities. Treatment was discontinued in 233 patients due to loss of effectiveness, and in 41 due to AE. The overall DRR at T48 was 66%, with differences according to bDMARDs line (p < 0.001), use of combined csDMARDs (p = 0.016), BMI (p = 0.037) and mono/oligoarthritis vs. polyarthritis (p = 0.012)., Conclusions: Secukinumab proved safe and effective, and patients achieved sustained remission with a notable drug retention rate at 4 years., (© 2024. The Author(s).)

Objective: The aim of the current study was to compare the clinical and treatment characteristics and dimensions of health-related quality of life between female and male patients with axial spondyloarthritis (SpA) and psoriatic arthritis (PsA)., Methods: The present study is cross-sectional and comprises 119 patients with axial SpA and 198 patients with PsA. Clinical data were collected by standardized and self-reported instruments. Disease activity was evaluated by the Ankylosing Spondylitis Disease Activity Score with C-reactive protein and the Disease Activity in PSoriatic Arthritis (for SpA and PsA, respectively). Health-related quality of life was assessed with the Medical Outcomes Study 36-item Short Form Survey. Patients were stratified by gender, and the socio-demographic, clinical, and quality-of-life data were compared., Results: Women with axial SpA and PsA had significantly lower education (p<0.001, p=0.004, respectively) and higher disease activity (p<0.001, p=0.003, respectively). Female patients with axial SpA were more frequently under second-line therapy (p=0.026) and glucocorticoid treatment (p=0.005), while women with PsA had more radiographic progression (p=0.006). Female patients with axial SpA and PsA had worse scores in the dimensions of quality of life regarding physical role, bodily pain, vitality, and mental health. Women with axial SpA had lower scores in general health, while women with PsA had lower scores in physical and social functioning., Conclusions: Women with axial SpA and PsA had worse scores than men in most clinical and treatment characteristics and health-related quality of life dimensions.

Background: Rheumatoid arthritis (RA) is characterized by bone loss. It is unclear whether JAK inhibitors can attenuate bone loss in RA by modulating bone metabolism. The main objective of our study is to investigate the effects of tofacitinib on serum levels of bone turnover markers and modulators. Secondary objectives were to assess changes in bone mineral density (BMD), metacarpal index, bone erosions., Methods: We conducted a prospective observational study on patients with active RA failure to bDMARDs or tsDMARDs initiating treatment with tofacitinib. We measured at baseline and after 1, 2, 3, 6, 9 and 12 months: serum bone turnover markers (CTX, P1nP, B-ALP), bone modulators (Dkk-1, sclerostin, vitamin D, PTH, OPG and RANKL), BMD and radiographic parameters (Sharp van der Heijde score [SvdH], bone health index [BHI] and metacarpal index [MCI])., Results: 30 patients were enrolled in the study of whom 21 completed the study through month 12. Tofacitinib was clinically effective by suppressing DAS28-CRP. Glucocorticoids daily dose significantly decreased from baseline. We found a negative correlation between pre-study cumulative and daily dose of glucocorticoids and baseline B-ALP serum levels (r -0.592, p 0.012). Sclerostin serum levels increased significantly during the study period, while P1nP and B-ALP (markers of bone formation) decreased significantly. BMD levels, BHI, MCI and SvdH score did not change., Conclusion: Treatment with tofacitinib was associated with a significant increase in sclerostin serum levels and a parallel decrease in markers of bone formation. However, no significant bone loss was observed., (© 2024. The Author(s).)

Background: Glucocorticoid sparing in rheumatoid arthritis (RA) treatment is crucial to minimizing adverse effects associated with long-term use. Janus kinase inhibitors (JAKi) could potentially offer a more potent glucocorticoid-sparing effect than biological Disease-Modifying Antirheumatic Drugs (bDMARDs)., Material and Methods: This is a single-center retrospective analysis of RA patients treated with JAKi or bDMARDs. Glucocorticoid tapering, rescue therapy and discontinuation were analyzed through mixed-effects models, Poisson regression, and multivariable logistic regression, respectively, adjusting for baseline disease activity, demographic factors, and treatment line., Results: A total of 716 RA patients treated with JAKi (n = 156) or bDMARDs (n = 560) were evaluated. JAKi treatment was associated with a more rapid reduction in glucocorticoid dose within the first 6 months and 60% higher odds of discontinuation compared with bDMARDs (adjusted odds ratio 1.63, 95% CI 1.02-2.60, p 0.039). Despite a higher baseline glucocorticoid dose, over 50% of JAKi-treated patients discontinued glucocorticoids after 12 months, vs ∼40% for bDMARDs. The need for glucocorticoid rescue therapy was significantly higher in the bDMARD group (rate ratio 2.66 (95% CI, 1.88-3.74))., Conclusion: Our findings indicate that JAK inhibitors facilitate more rapid glucocorticoid tapering compared with bDMARDs in RA patients. These results underscore the potential of JAK inhibitors to reduce long-term glucocorticoid exposure, highlighting their value in RA management strategies, including minimizing glucocorticoid-related adverse effects., (© The Author(s) 2024. 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: This study aims to evaluate in a real-life Italian multicenter cohort of axial spondyloarthritis (axSpA) (1) the 4-year effectiveness and safety of secukinumab, (2) the drug retention rate (DRR), and (3) the impact of the line of bDMARDs treatment, subtype of axSpA, and sex on achieving low disease activity (LDA) and very low disease activity (VLDA)., Methods: Consecutive axSpA patients receiving secukinumab between 2016 and 2023 were prospectively evaluated. Data on disease characteristics, previous/ongoing treatments, comorbidities, and follow-up duration were collected. Treatment response was evaluated at 6 and 12 months after initiation and yearly up to 48 months (T48). DRR and effectiveness outcomes were evaluated according to bDMARDs treatment, axSpA subtype, and sex. Infections and adverse events (AEs) were recorded., Results: We enrolled 272 patients (48.2% male; median age, 51; 39.7% HLA-B27+; 40.4% nr-axSpA), of whom 30.9% were naïve to secukinumab. Overall, secukinumab yielded improvement in effectiveness outcomes; the naïve patients maintained lower disease activity vs. the non-naïve ones. At T48, the LDA and VLDA rates were higher in naïve patients and in male individuals. Treatment was discontinued in 104 patients due to primary/secondary loss of effectiveness and in 34 patients due to AEs. The DRR at T48 was 67.4% in the whole population, regardless of treatment line, axSpA subtype, and sex., Conclusions: Secukinumab was safe and effective in all axSpA patients irrespective of treatment line, disease subtype, and sex. The patients achieved sustained 4-year remission and DRR., Competing Interests: RR has received honoraria and speaker fees from Novartis, Abbvie, Pfizer, MSD, and Janssen. CS has received consulting/speaker fees from AbbVie, Amgen, Alfa-Sigma, Biogen, Eli-Lilly, EUSA Pharma - Recordati, Galapagos, Janssen, Novartis, Octapharma, Pfizer, Recordati Rare Disease, SOBI and research support from AbbVie, Amgen, Janssen, Novartis, Pfizer. AM has received honoraria and speaker fees from Abbvie, Pfizer, MSD, UCB, Novartis, Janssen, and Eli-Lilly. LeS has received speaker fees from Jansen, Novartis, Pfizer, UCB, MSD, and Sanofi. AD has received honoraria and speaker fees from Novartis, AbbVie, Pfizer, MSD, Janssen.AC has received speaker fees from Novartis, Abbvie, Eli-Lilly and Janssen. The remaining 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 © 2024 Ramonda, Lorenzin, Chimenti, D’Angelo, Marchesoni, Selmi, Lubrano, Santo, Luchetti Gentiloni, Atzeni, Cauli, Manara, Rossini, Foti, Cozzi, Scagnellato, Ferraioli, Carriero, Luciano, Ruzzon, Fatica, Fracassi, Doria, Foti and Carletto.)

Objectives: Fatigue is a common comorbidity in patients with axial spondyloarthritis (axSpA), often reported also by those in clinical remission or with moderate disease activity. The aim of this study is to assess the prevalence of fatigue in patients with axSPA, and to investigate possible non-disease-related determinants, with a special focus on depression., Methods: Patients with axSpA were assessed using the Chalder's Fatigue Questionnaire (CFQ) for fatigue, and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) for depression. Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Functional Index (BASFI) and Health Assessment Questionnaire (HAQ) were also used to assess disease activities and disability. Univariate and multivariate linear regressions were performed to identify possible predictors of fatigue., Results: Out of 119 patients, 53 (44.5%) had fatigue. Patients with fatigue had higher HADS-D, ASDAS, BASFI, HAQ scores. HADS-D was predictive of CFQ score in univariate and multivariate regressions for total CFQ, and for mental and physical subscales. The correlation between HADS-D and CFQ total score was statistically significant also when taking into consideration only patients in clinical remission and with moderate disease activity. Depressed patients had higher CFQ score compared to non-depressed ones, and did not show any difference in CFQ scores when stratified for disease activity or systemic inflammation., Conclusions: The study found correlation between fatigue and disease activity and depression in patients with axSpA. These findings suggest that depression could represent the major determinant of fatigue in patients with axSpA, independently of clinical activity.

Objectives: This study aimed to compare the health-related quality of life scores among rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis and to evaluate socio-demographic and clinical determinantes of quality of life across diseases., Methods: The sample comprised 490 patients with rheumatoid arthritis, 198 with psoriatic arthritis, and 119 with spondyloarthritis who completed a series of health examinations and self-reported questionnaires. Quality of life was evaluated using the Short-Form 36 Health Survey, disease activity by DAS28-CRP, DAPSA, and ASDAS-CRP (for rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis, respectively), depression and anxiety using the Hospital Anxiety and Depression Scale. ANOVA was used to compare the quality of life dimensions and their physical and mental summary measures among rheumatic diseases, and multivariate analysis was used to explore their potential determinants., Results: Rheumatoid arthritis had significantly worse scores than spondyloarthritis in the following dimensions: physical functioning, role limitation due to physical health, physical component score, and mental health. Psoriatic arthritis was not significantly different from the other two diseases. Multivariate analysis revealed that physical quality of life was mainly associated with disease activity across rheumatic diseases, rheumatological treatment and depression in rheumatoid arthritis and psoriatic arthritis. Mental quality of life is primarily associated with depression and anxiety across rheumatic diseases., Conclusion: There were differences in quality of life among patients with inflammatory rheumatic diseases, but overall, approximately uniform factors explained the variance in quality of life across diseases. Clinicians should develop general approaches and strategies for inflammatory rheumatic diseases to improve patients' quality of life., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Rheumatoid arthritis (RA) causes bone loss, only partly related to inflammation. The impact of RA treatments on bone metabolism and their ability to mitigate bone loss remains uncertain. The primary goal of our study was to examine the influence of abatacept on serum levels of markers and regulators involved in bone turnover. Secondary objectives included evaluating changes in bone mineral density (BMD), bone health parameters, erosions, and exploring potential correlations among these parameters. We conducted a prospective observational study on patients with active seropositive RA failure to biological disease modifying anti-rheumatic drugs initiating treatment with abatacept. We measured at baseline and after 1, 2, 3, 6, 9 and 12 months: serum bone turnover markers (CTX, P1nP, B-ALP), bone modulators (Dkk-1, sclerostin, vitamin D, PTH, OPG and RANKL), BMD and radiographic parameters (modified Sharp van der Heijde score [mSvdH], bone health index [BHI] and metacarpal index [MCI]). Disease activity and glucocorticoid intake was monitored. 33 patients were enrolled in the study. We found a significant increase in markers of bone formation (B-ALP and P1nP) from baseline to M6 and M12. PTH increased significantly at M6 but not at M12. All other bone markers and modulators did not change. We found a significant decrease in BHI and MCI from baseline to M12 (median difference - 0.17 95% CI - 0.42 to - 0.10, p 0.001 and - 0.09 95% CI - 0.23 to - 0.07, respectively). BMD at femoral neck transitorily decreased at M6 (mean difference - 0.019 g/cm 2 95% CI - 0.036 to - 0.001 p 0.04). BMD at total hip, lumbar spine and mSvdH score did not change significantly. P1nP delta at M12 correlated with delta mSvdH. Treatment with abatacept was associated with a significant increase in bone formation markers. The secondary and transient increase in PTH serum levels may be responsible of the transitory bone loss., (© 2023. Springer Nature Limited.)

Psoriatic arthritis (PsA) is an inflammatory disease characterized by peripheral and axial involvement. Biological disease-modifying antirheumatic drugs (bDMARDs) are the mainstream treatment for PsA and bDMARDs retention rate is a proxy for the drug's overall effectiveness. However, it is unclear whether IL-17 inhibitors can have a higher retention rate than tumor necrosis factor (TNF) inhibitors, in particular in axial or peripheral PsA. A real-life observational study was conducted on bDMARD naïve PsA patients initiating TNF inhibitors or secukinumab. Time-to-switch analysis was carried out with Kaplan-Meyer curves (log-rank test) truncated at 3 years (1095 days). Sub-analyses of Kaplan-Meyer curves between patients presenting with prevalent peripheral PsA or prevalent axial PsA were also conducted. Cox regression models were employed to describe predictors of treatment switch/swap. Data on 269 patients with PsA naïve to bDMARD starting either TNF inhibitors (n=220) or secukinumab (n=48) were retrieved. The overall treatment retention at 1 and 2 years was similar for secukinumab and TNF inhibitors (log-rank test p NS). We found a trend towards significance in the Kaplan-Meyer at 3 years in favor of secukinumab (log-rank test p 0.081). Predominant axial disease was significantly associated with a higher chance of drug survival in secukinumab users (adjusted hazard ratio 0.15, 95% confidence interval = 0.04-0.54) but not in TNF inhibitor users. In this real-life, single-center, study on bDMARD naïve PsA patients, axial involvement was associated with longer survival of secukinumab but not of TNF inhibitors. Drug retention of secukinumab and TNF inhibitors were similar in predominantly peripheral PsA.

Objectives: Few data are available on the role of emotional distress as a possible mediator of the relationship between coping strategies and the Patient Global Assessment (PGA). This study aims to investigate, in a large cohort of patients affected by RA, the relationship between specific copying strategies and PGA, and the role of emotional distress as a mediator., Methods: A total of 490 patients with RA completed a set of standardized assessments including the self-reported PGA, the Coping Orientation to the Problems Experienced (COPE-NVI) and the Hospital Anxiety and Depression Scale (HADS). A mediation analysis was conducted to investigate the role of emotional distress., Results: The effect of coping strategies on the PGA score was significantly mediated by the emotional distress for religious (total effect mediated 42.0%), planning (total effect mediated 17.5%), behavioural disengagement (total effect mediated 10.5%), and focus on and venting of emotions (total effect mediated 9.8%). Seven coping strategies (acceptance, positive reinterpretation and growth, active coping, denial, humour, substance use-mental disengagement) resulted directly associated to PGA total score, but no mediation effect was found. The remaining four coping strategies were not associated to the PGA score., Conclusion: This study suggests that coping strategies could be an important factor in the perceived disease severity. Consequently, in order to reduce PGA in patients with RA, a useful tool could be represented by the implementation of psychological interventions aiming to modify the specific coping styles. Moreover, to prevent or treat emotional distress seems to further reduce PGA., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Identifying factors that influence problematic beliefs and behaviors related to pharmacotherapy may be useful for clinicians to improve the patients' adherence. The study aims to assess patients' beliefs about the necessity and concerns regarding pharmacotherapy in rheumatic diseases and attitude styles, and to investigate the association between clinical factors and negative beliefs about medication. A sample of 712 patients affected by Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis was enrolled. They were assessed using the Beliefs about Medicines Questionnaires-Specific (BMQ), the Simplified Disease Activity Index (SDAI), the Visual Analogue Scale for pain (VAS), the Chalder Fatigue Scale (CFQ) and the Health Assessment Questionnaire-Disability Index (HAQ-DI). The balance between benefits and costs in the BMQ-Specific was positive in the 79.4% of patients, negative in the 12.1% and equal in the 8.6%. SDAI, taking more than 5 medications, taking anti interleukin 6 (Anti-IL6) or biological disease-modifying antirheumatic drugs (bDMARDs), or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), pain, and fatigue were significantly associated to higher Concerns. Having a longer disease duration was significantly associated with a higher Necessity, together with the current pharmacological treatments and the disability. The multivariate regression models estimated that higher pain and fatigue were associated to higher Concerns (p < 0.001), while a longer disease duration (p < 0.001) and all pharmacological treatments for a rheumatologic disease (p = 0.001) were associated to higher Necessity levels. A high length of disease, a low level of remission, a high number of total medications, the prescription of an Anti-IL6/bDMARDs/tsDMARDs drug, a high level of pain, fatigue and disability identified patients potentially less adherent to pharmacotherapy to be carefully looked after by clinicians., (© 2022. The Author(s).)

Objectives: To investigate whether concomitant autoimmune inflammatory rheumatic diseases (AIIRDs) represent a risk factor for denosumab discontinuation and to explore other possible predictors., Design: This is a real-life retrospective study conducted at our centre on consecutive patients who started treatment with denosumab from January 2014 to October 2021., Methods: Data on patients' characteristics, denosumab prescriptions and reason for discontinuation were collected from their medical electronic records. A log-rank test was run to assess differences in the denosumab retention rate between the not AIIRD and AIIRD patients. A backward stepwise logistic regression was used to identify possible predictors of denosumab discontinuation. When available, BMD data of the lumbar spine and total hip were collected., Results: Three hundred and sixty-three patients were included (265 not AIIRD and 98 AIIRD; median follow-up, 44 months). Sixty-nine patients discontinued denosumab at any time point (4 due to patient's decision, 3 due to medical decision, 62 were lost in follow-up). The log-rank test did not find a statistically significant difference for denosumab persistence between the two subgroups. In the binary logistic regression analysis, only older age at initiation and lower baseline serum 25-hydroxy vitamin D were confirmed as predictors for discontinuation. BMD significantly increased from baseline to the last prescription visit at both the lumbar spine and the total hip, without statistically significant differences in the not AIIRD and AIIRD patients., Conclusion: The present data seem to suggest that AIIRDs do not represent a risk factor for denosumab discontinuation. Furthermore, the presence of AIIRDs does not seem to impair its effectiveness in terms of BMD., Competing Interests: Competing interests: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Maurizio Rossini reports personal fees from AbbVie, Amgen, BMS, Galapagos, Eli Lilly, Menarini, Novartis, Pfizer, Theramex and UCB, outside the submitted work. Davide Gatti has received advisory board honoraria, consultancy fees and/or speaker fees from Amgen, Eli-Lilly, Msd-italia, Organon and Novartis, outside the submitted work. All the other authors have nothing to disclose., (© The Author(s), 2022.)

Objectives: To evaluate, in a multicentric Italian cohort of axial spondyloarthritis (axSpA) patients on Secukinumab (SEC) followed for 24 months: (1) the long-term effectiveness and safety of SEC; (2) the drug retention rate and low disease activity (LDA) measured as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) < 4/Ankylosing Spondylitis Disease Activity Score (ASDAS) < 2.1 and very low disease activity (VLDA) measured as BASDAI < 2/ASDAS < 1.3; (3) any differences in outcomes according to line of biological treatment (naïve/non-naïve), gender (male/female), subtype of axSpA [radiographic axSpA (r-axSpA)/non-radiographic axSpA (nr-axSpA)]., Methods: Consecutive axSpA patients treated with SEC were evaluated prospectively. Disease characteristics, previous/ongoing treatments, comorbidities, and follow-up duration were collected. Disease activity/functional/clinimetric scores and biochemical-values were recorded at baseline (T0), 6 (T6), 12 (T12), and 24 (T24) months. Effectiveness was evaluated over-time with descriptive statistics; multivariate Cox and logistic regression models were used to evaluate predictors of drug discontinuation and LDA at T6. Infections and adverse events were recorded., Results: A total 249 patients (47.8% male; median age 51) were enrolled; 40.9% had HLA-B27; 53.8% had r-axSpA, and 46.2% nr-axSpA. SEC was prescribed in 28.9% naïve and in 71.1% non-naïve patients. SEC effectiveness was shown as an improvement in several outcomes, such as ASDAS [T0 = 3.5 (2.9-4.4) versus T24 = 1.9 (1.2-2.4); p  = 0.02] and BASDAI [T0 = 6.5 (5.0-7.5) versus T24 = 2.8 (1.8-4.0); p  = 0.03]. At T24, naïve patients showed better physical functioning and lower disease activity than non-naïve. After 24 months of treatment, 90.7% of naïve and 75.3% of non-naïve patients achieved LDA (BASDAI < 4). Treatment was discontinued in 24.5% patients, mainly due to primary/secondary loss of effectiveness, and in 6.8% due to adverse events. Retention rate at T24 was 75% in the whole population, with some difference depending on gender ( p  = 0.002)., Conclusion: In a real-life clinical setting, SEC proved to be safe and effective in axSpA, mainly in naïve-patients, with a notable drug retention rate. No differences were observed between r-axSpA and nr-axSpA., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RR has received honoraria and speaker fees from Novartis, AbbVie, Pfizer, MSD, and Janssen. AM has received honoraria and speaker fees from AbbVie, Pfizer, MSD, UCB, Novartis, Janssen, and Eli-Lilly. LS received speaker fees from Jansen, Novartis, Pfizer, UCB, MSD, and Sanofi. The other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Objective: Environmental air pollution has been associated with disruption of the immune system at a molecular level. The primary aim of the present study was to describe the association between long-term exposure to air pollution and risk of developing immune-mediated conditions., Methods: We conducted a retrospective observational study on a nationwide dataset of women and men. Diagnoses of various immune-mediated diseases (IMIDs) were retrieved. Data on the monitoring of particulate matter (PM)10 and PM2.5 concentrations were retrieved from the Italian Institute of Environmental Protection and Research. Generalised linear models were employed to determine the relationship between autoimmune diseases prevalence and PM., Results: 81 363 subjects were included in the study. We found a positive association between PM10 and the risk of autoimmune diseases (ρ+0.007, p 0.014). Every 10 µg/m 3 increase in PM10 concentration was associated with an incremental 7% risk of having autoimmune disease. Exposure to PM10 above 30 µg/m3 and PM2.5 above 20 µg/m 3 was associated with a 12% and 13% higher risk of autoimmune disease, respectively (adjusted OR (aOR) 1.12, 95% CI 1.05 to 1.20, and aOR 1.13, 95% CI 1.06 to 1.20). Exposure to PM10 was associated with an increased risk of rheumatoid arthritis; exposure to PM2.5 was associated with an increased risk of rheumatoid arthritis, connective tissue diseases (CTDs) and inflammatory bowel diseases (IBD)., Conclusion: Long-term exposure to air pollution was associated with higher risk of developing autoimmune diseases, in particular rheumatoid arthritis, CTDs and IBD. Chronic exposure to levels above the threshold for human protection was associated with a 10% higher risk of developing IMIDs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Long-term environmental air pollution exposure was associated with osteoporosis' risk in a cohort of women at high risk of fracture. Cortical sites seemed to be more susceptible to the exposure's effect., Introduction: Environmental air pollution has been associated with disruption of bone health at a molecular level. Particulate matter (PM) exposure can simultaneously stimulate bone resorption and halt bone formation. The primary aim of the present study is to describe the association between long-term exposure to PM and osteoporosis in a large cohort of women at high risk of fracture., Methods: Clinical, demographic, and densitometric data were extracted from the DeFRAcalc79 dataset, which gathers data on women at risk for osteoporosis. Data on the monitoring of PM10 and PM2.5 concentrations were retrieved from the Italian institute of environment protection and research (Istituto Superiore per la Protezione e la Ricerca Ambientale, ISPRA). Generalized linear models with robust estimators were employed to determine the relationship between BMD and PM long-term exposure., Results: A total 59,950 women from 110 Italian provinces were included in the study. PM 2.5 exposure was negatively associated with T-score levels at the femoral neck (β -0.005, 95 CI -0.007 to -0.003) and lumbar spine (β -0.003, 95% CI -0.006 to -0.001). Chronic exposure to PM2.5 above 25 μg/m 3 was associated with a 16% higher risk of having osteoporotic T-score at any site (aOR 1.161, 95% CI 1.105 to 1.220), and exposure to PM10 above 30 μg/m 3 was associated with a 15% higher risk of having osteoporotic T-score at any site (aOR 1.148, 95% CI 1.098 to 1.200)., Conclusion: Long-term exposure to air pollution was associated with higher risk of osteoporosis. Femoral neck site seemed to be more susceptible to the detrimental effect of PM exposure than lumbar spine site., Key Message: Exposure to air pollution is associated with osteoporosis, mainly at femoral site., (© 2021. The Author(s).)

Introduction: Depression is a quite common comorbidity in patients with rheumatoid arthritis (RA) and is thought to influence its severity. This study aims to estimate, in a large cohort of Italian patients with RA, the prevalence of depression and to investigate the clinical correlates of depression in terms of disease activity and disability., Methods: This is a cross-sectional study enrolling 490 outpatients with RA (80% female, mean age 59.5). The Hospital Anxiety and Depression Scale (HADS) was used to assess the presence of depression with a cut-off of 11. We collected data about disease activity and disability with DAS28, TJC-68, PhGA, PGA, VAS, DAS28, SDAI, CDAI and HAQ., Results: Prevalence of depression was 14.3% (95% CI: 11-17%). Depressed patients, when compared with not depressed ones, were found to have higher scores for TJC-68 (p = 0.011), PhGA (p = 0.001), PGA (p = 0.001), VAS (p = 0.001), DAS28 (p = 0.007), SDAI (p = 0.001), CDAI (p = 0.001) and HAQ (p = 0.001). Out of the 70 depressed patients, 30 subjects, already known to be depressed in the past, were still depressed at the time of the assessment, with only 11 (15.7%) under antidepressants. A multivariate analysis showed that male sex, higher PGA score, use of antidepressants and higher HAQ score were significantly associated with an increased risk of depression., Conclusions: Our study shows that depression is common in RA and may affect its activity mainly via an alteration in the perception of the disease. Although its important implications, depression is still under-diagnosed and its management is inadequate., (© 2021. The Author(s).)

Comparative pharmacodynamic (PD) analyses on different dosing schedules for cholecalciferol supplementation are limited. This was an open-label, randomized, parallel-group study involving 75 healthy individuals deficient in vitamin D (baseline 25OHD < 20 ng/mL) receiving oral cholecalciferol with three different dosing regimens: Group A: 10,000 IU/day for 8 weeks followed by 1000 IU/day for 4 weeks; Group B: 50,000 IU/week for 12 weeks and Group C: 100,000 IU every other week for 12 weeks. Regulators of calcium and phosphate homeostasis, bone turnover markers and Wnt inhibitors were measured at baseline, Day 28, 53, 84, and 112. The 1,25OH2D increased at each time point. The increase was greater ( p < 0.05) for group A vs. B and C at Day 28, and vs. group B at Day 56. No significant difference among groups was observed for the other biomarkers. The 24,25OH2D remained stable over time. PTH decreased at Day 84 and FGF-23 increased at all time points. CTX-I and PINP increased slightly at Day 28. BALP decreased from Day 56 onward. Dkk-1 increased from Day 56 onward, while sclerostin did not show significant changes. In healthy individuals deficient in vitamin D, vitamin D supplementation exerted effects on multiple regulators of calcium, phosphate and bone metabolism, without marked differences using the three regimens.

Background: There is increasing evidence that environmental air pollution is associated with the development of chronic inflammatory arthritides (CIA). The role of air pollutants on the biological treatment (biological disease-modifying antirheumatic drugs [bDMARDs]) response of CIA is still unclear., Methods: We retrieved longitudinal data on patients affected by CIA on biological therapies and on the daily concentration of air pollutants in the Verona area. We designed a case-crossover study to compare the exposure to pollutants in the 60-day period preceding a drug switch or swap due to disease progression referent to the 60-day period preceding a visit with stable treatment for at least 6 months., Results: A total of 1257 patients with CIA (863 with rheumatoid arthritis, 256 with psoriatic arthritis, and 138 with ankylosing spondylitis) with 5454 follow-up visits were included in the study (median follow-up 2.09 years [interquartile range: 0.82-2.58 years]). A total of 282 patients were included in the case-crossover study. We retrieved 13 636 daily air pollution records. We found that air pollutants' concentrations were higher in the 60-day period before a failure of bDMARD response and prior to a switch or swap compared with the period preceding a visit with stable bDMARD therapy for at least 6 months., Conclusion: We found that environmental air pollution was a determinant of poor response to bDMARDs in a cohort of patients with CIA followed over a 5-year period. An intervention aimed at decreasing fossil combustion emissions might have beneficial effects on biologic persistence rates of patients with CIA and economic expenditures related to switches and swaps., (© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: To evaluate in a multicentric Italian cohort of patients with psoriatic arthritis (PsA) on secukinumab followed for 24 months: (1) the long-term effectiveness and safety of secukinumab, (2) the drug retention rate and minimal disease activity (MDA), (3) differences in the outcomes according to the biological treatment line: biologic-naïve patients ( group A ) versus multifailure ( group B ) patients., Methods: Consecutive patients with PsA receiving secukinumab were evaluated prospectively. Disease characteristics, previous/ongoing treatments, comorbidities and follow-up duration were collected. Disease activity/functional/clinimetric scores and biochemical values were recorded at baseline (T0), 6(T6), 12(T12) and 24(T24) months. Effectiveness was evaluated overtime with descriptive statistics; multivariate Cox and logistic regression models were used to evaluate predictors of drug-discontinuation and MDA at T6. Infections and adverse events were recorded., Results: 608 patients (41.28% men; mean (SD) age 52.78 (11.33)) were enrolled; secukinumab was prescribed as first-line biological treatment in 227 (37.34%) patients, as second (or more)-line biological treatment in 381 (62.66%). Effectiveness of secukinumab was shown with an improvement in several outcomes, such as Ankylosing Spondylitis Disease Activity Score (T0=3.26 (0.88) vs T24=1.60 (0.69) ;p=0.02) and Disease Activity Index for Psoriatic Arthritis (T0=25.29 (11.14) vs T24=7.69 (4.51); p<0.01). At T24, group A showed lower Psoriasis Area Severity Index (p=0.04), erythrocyte sedimentation rate and C reactive protein (p=0.03 ;p=0.05) and joint count (p=0.03) compared with group B . At T24, MDA was achieved in 75.71% of group A and 70.37% of group B . Treatment was discontinued in 123 (20.23%) patients, mainly due to primary/secondary loss of effectiveness, and in 22 due to adverse events. Retention rate at T24 was 71% in the whole population, with some difference depending on secukinumab dosage (p=0.004) and gender (p=0.05)., Conclusions: In a real-life clinical setting, secukimumab proved safe and effective in all PsA domains, with notable drug retention rate., Competing Interests: Competing interests: RR has received honoraria and speaker fees from Novartis, AbbVie, Pfizer, MSD, Janssen. AM has received honoraria and speaker fees from AbbVie, Pfizer, MSD, UCB, Novartis, Janssen, Eli-Lilly. LS speaker from Jansen, Novartis, Pfizer, UCB, MSD, Sanofi., (© 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.)

Objective: To evaluate the clinical effectiveness of golimumab in biologic inadequate responder (IR) patients with Rheumatoid arthritis (RA), Spondyloarthritis (SpA), and Psoriatic arthritis (PsA)., Methods: We analyzed 1424 patients on golimumab from the GISEA registry. Drug survival was estimated by Kaplan-Meier analysis in biologic-naïve, 1-biologic IR, ≥2-biologics IR patients. Hazard ratios (HRs) of discontinuing golimumab at 2 years were assessed by multivariate Cox regression. Patients achieving CDAI based low disease activity (LDA) or BASDAI<4 were calculated at 6 and 12 months., Results: In RA (n.370), the 2-years survival on golimumab was 61.4% in 1-biologic IR, 51.9% in≥2-biologics IR, and 73.1% in biologic-naive patients (P=0.002 vs≥2-biologics IR). In SpA (n.502), the survival was similar among 1-biologic IR (80%), ≥2-biologics IR (76.5%), and biologic-naive (74.6%) patients (P>0.05). In PsA (n.552) the survival was 72% in 1-biologic IR, 72.5% in≥2-biologics IR, and 71.8% in naïve-biologic (P>0.05). Predictors of golimumab discontinuation were monotherapy (HR 1.65) for RA, female gender for SpA (HR 2.48) and PsA (HR 1.57). In RA, patients on CDAI-LDA were lower in 1-biologic IR (40%) or≥2 biologics IR (40%) than in biologic-naïve (60%) group at 6 months (P=0.02), but no difference was observed at 12 months. In PsA and SpA, the percentage of patients on CDAI-LDA or BASDAI<4 at 6 months was almost identical across the subgroups., Conclusions: Golimumab had similar effectiveness in biologic-failure and biologic-naïve SpA and PsA, but seems to be less effective in multi-failure RA patients, especially as monotherapy. The best outcomes were seen in male patients., (Copyright © 2020 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: This prospective study was designed to analyze the incidence and the factors associated with impairment in left ventricular systolic function (LVSF) overtime in patients with rheumatoid arthritis (RA) without overt cardiac disease. In particular, we verified the hypothesis that a relationship between worsening of LVSF and markers of RA disease activity exists., Methods: One hundred forty outpatients with RA without overt heart disease underwent clinical, laboratory, and echocardiographic evaluation at baseline and after 35 (interquartile range [IQR] 23-47) months of follow-up. A clinical Disease Activity Index (CDAI) score greater than 10 indicated the presence of moderate-high RA disease activity; data on anticitrullinated peptide antibody (ACPA) positivity were recorded at baseline. Stress-corrected midwall fractional shortening (sc-MFS) was used as a measure of LVSF and was considered impaired if less than 86.5%., Results: At 36 (IQR 23-47) months follow-up, impaired sc-MFS was detected in 60 of 140 (43%) patients, compared with 80 patients with normal sc-MFS. Disease duration and activity, ACPA positivity, inflammatory markers, cardiovascular and antirheumatic therapies, and sc-MFS were similar between the two groups at baseline. A multiple logistic regression analysis showed ACPA positivity, moderate-high disease activity (CDAI greater than 10), and disease duration as independent predictors of impaired sc-MFS at follow-up. Finally, a simple clinical score to predict worsening of LVSF at midterm was built (area under the curve of 0.80, with a sensibility and specificity of 78% and 82%, respectively)., Conclusion: Disease duration, ACPA positivity, and moderate-high disease activity are independent prognosticators of LVSF impairment in RA. Adverse changes in heart function could be prevented by good control of inflammation and modulation of autoimmunity., (© 2020 The Authors. ACR Open Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objectives: To provide evidence-based recommendations for vaccination against influenza virus and S. pneumoniae in patients with autoimmune rheumatic diseases (ARDs)., Methods: A Consensus Committee including physicians with expertise in rheumatic and infectious diseases was established by two Italian scientific societies, Società Italiana di Reumatologia (SIR) and Società Italiana di Malattie Infettive e Tropicali (SIMIT). The experts were invited to develop evidence-based recommendations concerning vaccinations in ARDs patients, based on their clinical status before and after undergoing immunosuppressive treatments. Key clinical questions were formulated for the systematic literature reviews, based on the clinical pathway. A search was made in Medline (via PubMed) according to the original MeSH strategy from October 2009 and a keyword strategy from January 2016 up to December 2017, updating existing EULAR recommendations. Specific recommendations were separately voted and scored from 0 (no agreement with) to 100 (maximal agreement) and supporting evidence graded. The mean and standard deviation of the scores were calculated to determine the level of agreement among the experts' panel for each recommendation. Total cumulative agreement ≥70 defined consensus for each statement., Results: Nine recommendations, based on 6 key clinical questions addressed by the expert committee, were proposed. The aim of this work is to integrate the 2011 EULAR recommendations on vaccination against influenza and S. pneumoniae in ARDs patients. An implementation plan was proposed to improve the vaccination status of these patients and their safety during immunosuppressive treatments., Conclusions: Influenza and pneumococcus vaccinations are effective and safe in patients with ARDs. More efforts should be made to translate the accumulated evidence into practice.

Background: Inflammatory arthritis including rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are disorders at increased risk of morbidity and mortality for which a validated prognostic tool for facilitating clinical management is needed. CHA 2 DS 2 -VASc (congestive heart failure/hypertension/age diabetes/stroke/vascular disease/age/sex category) score was initially conceived and used to estimate thromboembolic risk in non-valvular atrial fibrillation, and then successfully applied in community populations with sinus rhythm. We tested CHA 2 DS 2 -VASc-score as a prognosticator of adverse outcomes in patients in sinus rhythm with RA/AS/PsA., Methods: Between March 2014 and March 2015, 414 patients (214 RA, 75 AS, 125 PsA) in sinus rhythm without cardiac disease were consecutively analyzed and prospectively followed-up. Primary and co-primary end-points were a composite of all-cause death/all-cause hospitalization and CV death/CV hospitalization, respectively., Results: Patients were divided into LOWscore and HIGHscore groups if CHA 2 DS 2 -VASc was = 0/1 point or greater than 1 point, respectively. The HIGHscore group comprised 190 patients who were older with higher prevalence of CV risk factors and arthritis disease activity than 224 LOWscore patients. During a follow up of 36 months, the event rate for primary and co-primary end-point was 37% and 12% in the HIGHscore vs 22% and 4% in LOWscore group (P = .001 and .002 respectively). At multivariate Cox regression analysis CHA 2 DS 2 -VASc-score was related to primary end-point (hazards ratio [HR] 1.30 [1.07-1.59], P = .009) and co-primary end-point (HR 1.35 [1.01-1.79], P = .04) independently of traditional CV risk factors analyzed individually and indexes of inflammation or disease duration., Conclusion: CHA 2 DS 2 -VASc-score accurately identifies in the mid-term patients in sinus rhythm with RA/AS/PsA at different risks for CV and non-CV mortality and hospitalization., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: The duration of treatment with glucocorticoids (GC) in polymyalgia rheumatica (PMR) is often longterm. Amino bisphosphonates (N-BP) are used in PMR for the prevention of GC-induced osteoporosis, but they coulsd also have immunomodulatory properties. Whether they can be effective as an adjuvant treatment in PMR is unknown. We aimed to establish whether the use of N-BP in our PMR cohort may be associated with GC discontinuation., Methods: We conducted a retrospective review of all patients diagnosed with PMR recorded in our electronic medical notes. Cox regression analyses were used to examine the association between the use of N-BP and discontinuation of GC., Results: Data were retrieved for 385 patients (mean age 71 ± 10 yrs, 64% females, mean initial prednisone dose 19 ± 9 mg/day). The median followup time was 38 months (range 9-57); more than 60% of patients were exposed to N-BP. GC were discontinued in 47% of patients after a median time of 20 months (range 14-27), but subsequently restarted in 39%. Overall, 276/385 patients (72%) were actively treated at their last available evaluation (mean prednisone dose 4.9 ± 5.5 mg/day), while 123/205 (60%) were still receiving GC after 24 months of followup. The use of N-BP was associated with the discontinuation of GC (adjusted HR 0.66, 95% CI 0.50-0.88), independent of age, initial GC dose, and osteoporosis., Conclusion: Unlike current guidelines, longterm treatment with GC is often necessary. These preliminary data suggest that N-BP may be involved in the management of PMR.

Climate change communication efforts grounded in the information deficit model have largely failed to close the gap between scientific and public understanding of the risks posed by climate change. In response, simulations have been proposed to enable people to learn for themselves about this complex and politically charged topic. Here we assess the impact of a widely-used simulation, World Climate, which combines a socially and emotionally engaging role-play with interactive exploration of climate change science through the C-ROADS climate simulation model. Participants take on the roles of delegates to the UN climate negotiations and are challenged to create an agreement that meets international climate goals. Their decisions are entered into C-ROADS, which provides immediate feedback about expected global climate impacts, enabling them to learn about climate change while experiencing the social dynamics of negotiations. We assess the impact of World Climate by analyzing pre- and post-survey results from >2,000 participants in 39 sessions in eight nations. We find statistically significant gains in three areas: (i) knowledge of climate change causes, dynamics and impacts; (ii) affective engagement including greater feelings of urgency and hope; and (iii) a desire to learn and do more about climate change. Contrary to the deficit model, gains in urgency were associated with gains in participants' desire to learn more and intent to act, while gains in climate knowledge were not. Gains were just as strong among American participants who oppose government regulation of free markets-a political ideology that has been linked to climate change denial in the US-suggesting the simulation's potential to reach across political divides. The results indicate that World Climate offers a climate change communication tool that enables people to learn and feel for themselves, which together have the potential to motivate action informed by science., Competing Interests: The authors declare the following competing interests: The funder provided support in the form of salaries for authors JRV and KM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author KR is employed by SageFox Consulting Group, which provided support in the form of KR’s salary, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. There are no patents, products in development or marketed products to declare. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Patients with psoriasis may be at higher risk of Candida spp . infection. Interleukin (IL)-17 acts in the prevention of those infections; it is also involved in the pathogenesis of psoriasis. Therefore, anti-IL17 antibodies - which have an established role in the treatment of psoriasis - may be associated with an increased incidence of Candida spp . infection, as it has been suggested in pivotal trials. Patients and Results: We report the occurrence of those infections in psoriatic patients receiving secukinumab 300 mg. Sixteen patients, treated with secukinumab 300 mg, for one year, and documented by mycological examinations, did not present any increase in the occurrence of Candida spp . infection, even asymptomatic. Moreover, 2 patients, after secukinumab treatment, became negative for candida detection, without any additional anti-fungal therapy. Conclusion: Although this case series is limited in size, our results may be reassuring on the low risk of candida infection in psoriatic patients, during secukinumab therapy.

Bone loss in rheumatoid arthritis (RA) is a key feature both local and systemic. Anti-citrullinated protein antibodies (ACPA) have recently been found to directly induce differentiation and activation of osteoclasts and therefore contribute to periarticular bone loss. The aim of this study was to analyze the effect of ACPA on systemic bone mineral density (BMD) in patients with established RA. This is a cross-sectional study with a single-center RA population. BMD was measured with Dual X-ray absorptiometry at lumbar and femoral sites. ACPA were measured by EIA. Multivariate analysis was performed adjusting for the main confounding variables. One hundred twenty-seven RA patients were enrolled. In univariate analysis, ACPA-positive patients showed lower BMD Z-score (SD below the age- and gender-matched mean reference value) at femoral sites (p < 0.01). A negative correlation between ACPA titer and BMD Z-score at all sites was observed (p < 0.01). The multivariate analysis adjusted for the main confounding variables confirmed the negative effect of ACPA at femoral sites (p < 0.05), but not at lumbar spine BMD. No significant effect of rheumatoid factor has been observed. ACPA have a negative titer-dependent effect on BMD at femoral sites, mainly constituted by cortical bone. ACPA-positive patients, especially if at high titer, should undergo bone investigations and be treated with bone protecting agents. Disease-modifying anti-rheumatic drugs lowering ACPA titer might have positive effects on systemic bone mass.

Objective: Patients with rheumatoid arthritis (RA) have an increased cardiovascular event rate, mainly due to the arterial stiffness which leads to coronary atherosclerosis and concentric left ventricular (LV) geometry. These conditions predispose to LV systolic dysfunction (LVSD), which can be detected by stress-corrected mid-wall shortening (sc-MS), an early prognosticator of cardiovascular events in asymptomatic patients with arterial hypertension and/or diabetes. In these subjects, sc-MS is frequently impaired even though LV ejection fraction (LVEF) is preserved. In this study, we analyzed the prevalence and the factors associated with asymptomatic LVSD measured by sc-MS among patients with RA and verified whether RA per se was independently related to LVSD., Methods: We prospectively recruited 198 outpatients with RA without overt cardiac disease between January and June 2014 and compared them to 198 controls matched for age, gender, body mass index, and prevalence of hypertension and diabetes. sc-MS was taken as index of LVSD and considered impaired if <86.5%., Results: Impaired sc-MS was detected in 110 (56%) RA patients and in 30 (15%) controls (P < 0.001), whereas LVEF was impaired (value <50%) in six (3%) RA patients and in two (1%) controls (P = ns). Multiple logistic regression analysis revealed that RA was independently associated with impaired sc-MS (Exp β 2.01 [CI 1.12-3.80], P = 0.02) together with increased LV mass and concentric geometry., Conclusions: More than half RA patients without overt cardiac disease have LVSD detectable by sc-MS. RA emerges as a condition closely related to LVSD. These findings might explain the high risk for adverse cardiovascular events in RA patients., (© 2016, Wiley Periodicals, Inc.)

Patients with ankylosing spondylitis (AS) have an increased risk of bone loss and vertebral fractures. In this study, we explored the hypothesis that the excess bone loss and vertebral fractures might be related with the activity of the Wingless signaling pathway, and in particular with the serum levels of its circulating inhibitors, Sclerostin and Dickkopf-1 (DKK1). We recruited 71 patients diagnosed with AS. Lateral radiographs of the total spine were analyzed to detect the presence of vertebral fractures, and bone mineral density (BMD) was assessed in all patients using dual X-ray absorptiometry at lumbar spine and proximal femoral site. Blood samples were obtained and levels of C-reactive protein (CRP), DKK1, and Sclerostin were measured. Blood samples from 71 healthy sex- and age-matched volunteers were collected to be used as controls. Vertebral fractures were detected more commonly among men than in women (29 vs 8 %, respectively). DKK1, but not Sclerostin serum levels, were inversely correlated to lumbar spine Z-score BMD. Patients with one or more prevalent vertebral fractures had significantly higher DKK1 levels, without significant difference in Sclerostin serum levels. A significant positive correlation was found between DKK1 serum levels and CRP (r = 0.240, p = 0.043). The association we found between serum DKK1 levels and BMD values and vertebral fracture prevalence suggests that DKK1 might contribute to the severity of osteoporosis in AS.

Conditions such as rheumatoid arthritis (RA) and spondyloarthritis (SpA, such as psoriatic arthritis, PsA, and ankylosing spondylitis, AS) are characterized by an imbalance between osteoclast (OC) bone resorption and osteoblast (OB) bone formation. The two conditions present substantial differences in bone involvement, which is probably related to the different expression of IL17 and TNFα, two cytokines that strongly promote osteoclastogenesis and focal bone erosions. TNFα is the major inflammatory cytokine in RA. It acts by both triggering OC bone erosion via the RANK-RANKL system, and suppressing OB bone formation through the overexpression of DKK1, a powerful inhibitor of the WNT bone anabolic signaling pathway. Differing from TNFα, IL17 promotes also osteogenesis, particularly at inflamed sites undergoing mechanical stress, such as entheses. Therefore, in RA, where overexpression of TNFα is higher than IL17, OC bone resorption largely prevails upon bone formation. In PsA and AS, the prevailing inflammatory cytokine is IL17, which promotes also osteogenesis. Given the prevalent involvement of entheses poor of OC, excess bone formation may even prevail over excess bone resorption. The results of clinical trials support the different pathophysiology of bone involvement in chronic arthritis. Inflammation control through anti-TNFα agents has not resulted in incomparable effects on radiographic progression and excess bone formation in both AS and PsA. Clinical trials investigating IL17 inhibitors, such as secukinumab, in patients with psoriatic disease are underway. The preliminary results on inflammation and symptoms appear positive, while long-term studies are required to demonstrate an effect on excess bone formation.

Glucocorticoids (GLs) are the sole therapeutic approach in polymyalgia rheumatica (PMR). An undefined proportion of patients respond only to very high doses of GLs and some seem to respond better to methylprednisolone (MPONE) than to prednisone (PN) or vice versa. Fifty-two PMR patients were randomized (ratio 1/1) to a fixed daily dose of PN (25 mg) or MPONE (20 mg), and the dose was tapered with a fixed scheme at the time of symptomatic relief. The clinical and biochemical assessments were obtained at fixed time points: 2 weeks, and 3, 6, 12 months. A clinical and biochemical remission of PMR was observed in 100 % of the patients on MPONE and in 89 % of the patients on PN. The mean time to achieve full remission after the first dose was significantly (p < 0.05) longer for PN (20.3 days) than for MPONE (15.2 days). This difference was mainly driven by 3 patients in whom the remission was achieved after 26-49 days. The mean levels of serum ACTH and cortisol were very similar in both treatment groups as the slope of their correlations for equivalent steroid doses. PN and MPONE have a similar therapeutic effect on suppression of the HPA axis in PMR patients. The results of this preliminary study suggest that a delayed response to PN may occur. Further studies are warranted in order to verify whether this might be related to variations in 11β-hydroxysteroid dehydrogenase activity.

Golimumab is an anti-TNF monoclonal antibody administred subcutaneously once a month and produced with an innovative technology that minimizes immunogenicity. This paper reviews and updates the main studies on the efficacy, safety and pharmacoeconomic aspects of treatment with golimumab of psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis.

Aim of this study was to evaluate the efficacy and tolerability of intra-articular (IA) clodronate, compared to saline solution, in patients with symptomatic knee osteoarthritis (KOA). In this double-blind phase 3 randomized clinical trial, patients were randomized to receive once weekly IA injection of 2 mg clodronate or placebo for 4 weeks with 12 weeks of follow-up. The primary objective was the sum of spontaneous, on passive movement, and at digital pressing pain relief assessed by visual analogue score (VAS) of 0-100 at 5 weeks after the final injection. Improving in Western Ontario MacMaster (WOMAC) scale, Lequesne index, consumption of acetaminophen, and physician or patient overall judgment were secondary objectives. Study population included 80 patients, 67 women and 13 men aged 66 ± 6 (SD) years. A significant improvement for all efficacy parameters was observed at all-time points in both groups. A significant difference in favor to clodronate in VAS for pain was observed 5 weeks after the last injection (-114.6 vs. -87.2 for clodronate and placebo group, respectively; p < 0.05). The improvements in Lequesne index, global KOA evaluation from both patients and investigators, and the WOMAC pain subscale were significantly greater in the clodronate group. The proportion of patients that did not require acetaminophen was significantly greater in the clodronate group (about 10 vs. 30 % for clodronate and placebo group, respectively; p < 0.05). IA 2 mg clodronate is associated with small and transient symptomatic and functional benefits and it is safe in KOA patients.

Objectives: The objective of this study is to compare the serum levels of Dickkopf-1 (DKK1), a natural inhibitor of Wnt signalling, with parathyroid hormone (PTH) and bone involvement in patients with rheumatoid arthritis (RA)., Methods: This cross-sectional study includes 154 postmenopausal women with RA and 125 healthy controls. DKK1, 25OH vitamin D (25OHD), bone turnover markers, and PTH serum levels were measured by ELISA; lumbar spine and hip bone mineral density (BMD) and the erosion score were obtained., Results: The RA patients and healthy controls were not significantly different in terms of age, body mass index, and 25OHD serum levels. The mean level of DKK1 and PTH were significantly higher in patients with RA than in healthy controls (172±68 [SD] vs. 96±55 pmoL/L, and 30±15 vs 22±11, respectively; p<0.0001). DKK1 serum levels were positively correlated with age (p<0.05) only in the healthy controls, while they were correlated with PTH serum levels only in the RA patients (p<0.0001). Among the RA patients, DKK1 levels adjusted for age, PTH and disease duration were significantly higher in patients with bone erosions (176 vs. 167 pmoL/L, respectively; p<0.05). DKK1 levels adjusted for age and PTH were negatively correlated with total hip BMD (p<0.05). In the RA patients not on treatment with bisphosphonates, DKK1 serum levels positively correlated with C-terminal telopeptides of type I collagene serum levels (p<0.05)., Conclusions: In patients with RA, serum levels of DKK1 are significantly increased, correlate with PTH and are associated with increased risk of bone erosions and osteoporosis. However, this finding deserves confirmation in a larger and more selected population.

The coupling of bone formation to bone resorption during treatment of postmenopausal osteoporosis with antiresorbers might be related to changes in Wnt/b-catenin signaling. We compared the effects of two bisphosphonate treatments on two Wnt-inhibitors Sclerostin (SOST) and Dickkopf-related protein 1 (DKK1). The study population included 74 women with postmenopausal osteoporosis participating simultaneously in two multicenter, placebo controlled trials. The patients were randomized to: intramuscular clodronate 100mg/week (CLO) (N=36), and yearly intravenous therapy with 5mg zoledronate (ZOL) (N=18) and placebo (N=20). Bone turnover markers (intact N-propeptide of type I collagen [P1NP], C-terminal telopeptide of type I collagen [CTX]) remained unchanged in the placebo group while they significantly decreased during treatment with the two bisphosphonates, versus both placebo and baseline. In CLO treated patients serum DKK1 remained stable over the entire period of observation while serum SOST levels increased significantly after 12months of treatment both versus placebo group (p<0,005), baseline (p<0,001) and ZOL treated group. In the ZOL group, DKK1 levels increased significantly within one month and for the following 6months and it fell back to baseline values at 12months. The second ZOL infusion was again associated with an increase in DKK1 a month later, although to a lesser extent. In conclusion, in this study we have found that the treatment of postmenopausal osteoporosis with intermittent yearly ZOL is associated with transient and declining increases in DKK1 while continuous treatment with CLO, results in a late increase in serum SOST. These preliminary results and further ad hoc studies might contribute to shed light on our understanding of the bone coupling effects taking place during treatment of osteoporosis with different anti-resorbers or with different treatment regimens., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Vitamin D has some well-known effects on calcium, phosphate and bone metabolism, but it has recently shown to have many other effects, which may potentially be relevant to patients with extra-skeletal rheumatic diseases. Such effects may be justified by: 1) the presence of the vitamin D receptors also on extra-osseous cells, such as cartilage cells, sinoviocytes, muscle cells; 2) the proven role of vitamin D in the control of the transcription of genes involved in rheumatic diseases; 3) the evidence that vitamin D has multiple endocrine effects not only on calcium homeostasis; 4) the activation of vitamin D not only in the kidneys, but also in monocyte-macrophage and lymphocytic cell lines and in some epithelial cells with additional intracrine and paracrine effects. Vitamin D deficiency has been reported in numerous metabolic, degenerative, inflammatory and autoimmune rheumatic diseases. In some cases this association was also related to the risk of developing a rheumatic disease or the degree of disease activity. However there is no conclusive evidence of the efficacy of a preventive or therapeutic strategy based on vitamin D supplementation in extra-skeletal rheumatic diseases. This review aims to provide an overview of the latest evidence concerning the relationship between vitamin D and the most relevant rheumatic diseases.

Objective: The objective of this study was to evaluate if the anti-inflammatory properties of bisphosphonates and their effect on bone turnover could be useful in the treatment of AS., Methods: Sixty patients were consecutively assigned in a 1:1 ratio in a 6-month open-label, single-centre study on active AS to receive monthly i.v. neridronate (100 mg) or standard infliximab (5 mg/kg) therapy., Results: A significant reduction in the mean BASDAI was observed over 6 months of either neridronate (-1.72) or infliximab (-1.62) administration. The BASFI decreased significantly at 3 and 6 months in the neridronate arm, while in the infliximab group a significant reduction at 3 months but not 6 months was observed. The 10-cm visual analogue scale for axial pain decreased significantly and comparably at 3 and 6 months in both groups. No significant differences between treatment arms for all these changes were observed at both 3 months and the final assessment. The BASMI was not significantly modified in the neridronate or infliximab group. No significant variations of BMD were observed in the infliximab group, while in patients treated with neridronate a significant increase was observed at the lumbar spine., Conclusion: High i.v. doses of the amino-bisphosphonate neridronate are as effective as infliximab therapy in reducing disease activity in AS patients, with additional benefits on BMD changes. Further studies to confirm these results over a longer time frame are warranted together with the possibility to explore the long-term efficacy of a combination of lower anti-TNF doses with bisphosphonates.

A number of effective therapies for the treatment of osteoporosis have become available in recent years. However, uncertainty exists regarding their long-term use and effectiveness. Bisphosphonate treatment, unlike hormone replacement, denosumab or teriparatide, is associated with benefits extended even after treatment discontinuation. The extended benefits are most apparent for alendronate (ALN) and zoledronate (ZOL). A drug holiday might be considered in patients at low-moderate risk and who have been fully compliant with treatment, and who have had a response to treatment. In patients at low-moderate risk of fractures the decision to consider a drug holiday should be balanced also with the safety profile of each treatment.

Osteogenesis imperfecta (OI) is a hereditary disease characterized by low bone mass, increased bone fragility, short stature, and skeletal deformities. This study focuses on OI type I, the mildest form of the disease. Bisphosphonates represent the prevailing standard of care in patients with OI. Teriparatide (TPD) is a PTH analog with bone-anabolic actions which has been approved for osteoporosis treatment. Thirteen postmenopausal women with type I OI who had been on treatment with neridronate for at least 2 years and who incurred new vertebral fracture during treatment were treated with TPD for 18 months. Bone mineral density (BMD) increased significantly over 18 months up to 3.5 % at the lumbar spine (p = 0.001), while no significant changes were noted in hip BMD. Serum markers of bone formation and of bone resorption increased significantly during the treatment. The Wnt inhibitors serum dickkopf-1 (DKK1) and sclerostin were also measured. A nonsignificant increase was seen in serum sclerostin levels, while serum DKK1 rose gradually and significantly during TPD treatment. In patients affected by type I OI, TPD treatment is associated with a remarkable response in markers of bone formation. This suggests a normal osteoblastic response to TPD. However, the observed increases in BMD were somewhat lower than those in postmenopausal or senile osteoporosis treated with TPD for the same lag time. Our results open the possibility to develop TPD for the treatment of adult type I OI, but particularly for the lack of a control group, a properly designed controlled study is warranted.

Decreasing levels of estrogens during menopause are associated with reduced bone density and an increased risk of osteoporosis. Many women also experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Results of systematic reviews and meta-analyses of randomized controlled trials have shown that both systemic estrogen therapy or hormone therapy (estrogen combined with a progestin) are useful to prevent bone loss, and they are the most effective treatment for such climacteric symptoms as hot flushes, sweating, vaginal dryness, and dyspareunia. Unfortunately, estrogen therapy and hormone therapy increase the risk of endometrial and breast cancer, respectively. The selective estrogen receptor modulators (SERMs) result in positive estrogenic effects on bone, with no negative effects on the endometrium and breast but do not provide relief from postmenopausal symptoms. The combination of a SERM with estrogen as a tissue selective estrogen complex (TSEC) is a new strategy for the prevention of bone loss and the treatment of climacteric symptoms. This combination is particularly interesting from a clinical point of view, taking into account that estrogen alone did not increase breast cancer risk by the Women's Health Initiative. TSEC is hypothesized to provide the benefits of estrogen-alone therapy, with an improved tolerability profile because the SERM component can make possible the elimination of progestin. The objective of this review was to critically evaluate the evidence from the reports published to date on the use of bazedoxifene (a third-generation SERM) in combination with conjugated estrogens in postmenopausal women. The conclusion is that effectively, the combination of bazedoxifene and conjugated estrogens may be a promising alternative to hormone therapy for the prevention of osteoporosis and the treatment of postmenopausal symptoms in non-hysterectomized postmenopausal women.

Bone formation is influenced by the Wnt pathway through effects on osteoblast functionality, and these actions are opposed by two antagonists: sclerostin and Dickkopf-1 (DKK1). Decreased levels of serum sclerostin were found after treatment with the PTH analogue teriparatide and in patients with primary hyperparathyroidism (PHPT), while treatment with teriparatide of postmenopausal osteoporosis is associated with increases in serum DKK1. We studied mineral metabolism and Wnt pathway in 21 postmenopausal women affected by PHPT and in 42 age-matched healthy women. Mean serum calcium and PTH were significantly higher and serum phosphates significantly lower in the PHPT group compared with the control group. Serum 25-OH-vitamin D (25OHD) was lower in PHPT patients and 1,25 dihydroxy-vitamin D [1,25(OH)2D] was significantly higher. Patients with PHPT had significantly higher levels of bone alkaline phosphatase (BAP) and of serum C-terminal telopeptides of type I collagene (sCTX). Serum sclerostin in PHPT was significantly lower (-26 %) and serum DKK1 significantly higher (+57 %) than in healthy control subjects. Serum PTH was positively correlated with 1,25OH2D (p < 0.001), BAP (p = 0.036), sCTX (p = 0.003), and DKK1 (p = 0.007) and negatively with 25OHD (p = 0.002) and sclerostin (p = 0.02). In PHPT patients, serum sclerostin was negatively correlated with BAP (p = 0.038) and sCTX (p = 0.07). Patients with PHPT have significantly lower sclerostin and higher DKK1 levels compared with healthy postmenopausal control subjects. Further studies are warranted in order to verify whether the balance between these two opposite effects on Wnt function might help explain the variable bone involvement among patients with PHPT.

The aim of this study was to explore whether desensitization to the occurrence of the acute-phase response (APR) in patients previously treated with amino-bisphosphonates (N-BPs) is due to a long-lasting reduction in the number of circulating γδ T cells. Circulating lymphocyte subpopulation counts were obtained from 63 patients with postmenopausal or senile osteoporosis at baseline and after 2 days and 12 months of the first intravenous (IV) 5 mg zoledronic acid (ZOL) infusion. At baseline both the proportion and absolute number of circulating γδ T cells were significantly higher in patients who had never used N-BPs vs. previous users, either oral or IV. A typical APR was observed in none of the patients given IV ZOL a year earlier, in 6 (22 %) of the patients previously treated with oral N-BPs, and in 13 (57 %) of the patients naive to any N-BP treatment. In patients naive to N-BPs, a significant reduction in both total lymphocytes and their subsets was observed 2 days after ZOL infusion; all these changes returned to baseline values 1 year later with the exception of γδ T cells, which remained significantly lower in terms of both proportion and absolute number. These results indicate for the first time that both IV and oral N-BP treatments are associated with a long-lasting decrease in circulating γδ T cells, and this may explain the lower incidence of APR in patients previously exposed to N-BPs. Other clinical implications of this sustained effect of N-BPs on immune-regulatory cells might be important.

We investigated the short-term effects on bone turnover markers of high doses of vitamin D(3) in order to identify what initial therapeutic dose can be safely administered in vitamin D-deficient subjects. Thirty-seven elderly subjects [mean age 75 ± 3 (SD) years] were consecutively randomized to the administration of a single oral bolus of 600000, 300000, or 100000 IU vitamin D(3). Blood samples were taken at baseline and 1, 3, 7, 14, 30, 60, and 90 days after vitamin D(3) administration. Twenty-four subjects served as controls. No relevant changes in bone turnover markers [C-terminal telopeptides of type I collagen (sCTX) and bone-specific alkaline phosphatase (BAP)] were observed in the controls. In treated patients a dose-dependent effect on sCTX was observed. With the administration of 600,000 IU vitamin D(3) a significant increase of sCTX was observed already at day 1, and it was sustained for 2 months. The changes in sCTX with smaller doses were considerably lower and reached statistical significance only within the first 3 days with the 300,000 IU dose. BAP remained unchanged in patients given 300,000 and 600,000 IU vitamin D(3), while it significantly rose by 15-23 % throughout the observation period in patients given 100,000 IU. Our results indicate that the use of a vitamin D bolus exceeding 100,000 IU may be associated with acute increases of sCTX.

The bone mass benefits of antiresorbers in postmenopausal osteoporosis are limited by the rapid coupling of decreasing bone resorption with bone formation. Wnt signaling is involved in this coupling process during treatment with bisphosphonates, whereas its role during treatment with the anti-receptor activator of NF-κB ligand (RANKL) antibody denosumab is unknown. The study population includes patients participating in a placebo-controlled trial lasting 36 months: 19 women were on placebo and 24 on subcutaneous 60 mg denosumab every 6 months. All measured parameters (serum C-terminal telopeptide of type I collagen [sCTX], serum bone alkaline phosphatase [bAP], Dickkopf-1 [DKK1], and sclerostin) remained unchanged during the observation period in the placebo group. sCTX and bAP were significantly suppressed by denosumab treatment over the entire follow-up. Denosumab treatment was associated with significant (p < 0.05) increases (28% to 32%) in serum sclerostin over the entire study follow-up. Serum DKK1 significantly decreased within the first 6 months with a trend for further continuous decreases, which reached statistical significance (p < 0.05) versus placebo group from the 18th month onward. The changes in DKK1 were significantly and positively related with the changes in sCTX and bAP and negatively with hip bone mineral density (BMD) changes. The changes in sclerostin were significantly and negatively related only with those of bAP. The changes in bone turnover markers associated with denosumab treatment of postmenopausal osteoporosis is associated with significant increase in sclerostin similar to those seen after long-term treatment with bisphosphonates and significant decrease in DKK1. This latter observation might explain the continuous increase over 5 years in BMD observed during treatment of postmenopausal osteoporosis with denosumab., (Copyright © 2012 American Society for Bone and Mineral Research.)

Context: Vitamin D deficiency is often treated or prevented by high intermittent doses of vitamin D to achieve a better treatment adherence, but treatment outcomes were contradictory, and even a transient increase in fracture and fall risk was reported., Objective: The objective of the study was to investigate the short-term effects on bone turnover markers of a single bolus of vitamin D₃., Design, Setting, Patients, and Intervention: Twelve elderly subjects (eight women, four men; mean age 76 ± 3 yr) were given a single oral bolus of 600,000 IU vitamin D₃. Blood samples were taken at baseline and 1, 3, 7, 14, 30, 60, and 90 d after vitamin D₃ administration. Twenty-four subjects served as controls., Main Outcome Measures: Changes in serum levels of 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D, PTH, C-terminal-telopeptides of type I collagen, cross-linked N-telopeptide of type I collagen (sNTX), osteocalcin, and bone-specific alkaline phosphatase., Results: No relevant changes in 25OHD and bone turnover markers were observed in the controls. In treated subjects, serum 25OHD attained a peak increment to 67.1 ± 17.1 ng/ml (P < 0.001) at d 3. Subsequently it slowly decreased to 35.2 ± 5.8 ng/ml (P <0.01 vs. a baseline value of 21.7 ± 5.6 ng/ml). Mean serum PTH concentration decreased by 25-50% and serum 1,25-dihydroxyvitamin D rose by 25-50%. Serum CTX and sNTX rose significantly at d 1 (P < 0.01), they attained a peak increment greater than 50% at d 3, and they subsequently decreased almost back to baseline values at d 90. Serum osteocalcin slightly rose within the first 3 d and then declined by d 60. No changes were observed in serum bone-specific alkaline phosphatase., Conclusions: Our results indicate that the use of large doses of vitamin D may be associated with acute increases in C-terminal-telopeptides of type I collagen and sNTX, which may explain the negative clinical results obtained by using intermittent high doses of vitamin D to treat or prevent vitamin D deficiency.

The benefits coming from long-term treatment of postmenopausal osteoporosis with bisphophonates are limited by a coupled decrease in bone formation. The objective of this study is to determine whether this decrease in bone formation is associated with changes in serum levels of the WNT signaling antagonist sclerostin or Dickkopf-1 (DKK1). This is an ancillary observation from patients participating in a 12 months, phase 2, randomized clinical trial. We analyzed 107 patients given either monthly intramuscular neridronate (12.5, 25 or 50 mg) or placebo. Serum C-terminal telopeptide of type I collagen (sCTX, a bone-resorption marker) decreased by 61%, 75% and 73% in the 12.5, 25 and 50 mg dose groups, respectively. Mean changes in bone alkaline phosphatase (bAP) at 12 months were -47%, -60.0% and -52.6% in the groups receiving 12.5, 25 or 50 mg neridronate, respectively. Serum DKK1 remained unchanged at all time points in the 3 groups. Serum sclerostin increased versus placebo group gradually and significantly only in patients treated with 25 or 50 mg neridronate monthly, reaching 138-148% of baseline values (P<0.001). Changes in serum sclerostin at 12 months were negatively correlated with changes in bAP (P<0.001) even when data were adjusted for sCTX changes and only treated patients were included. In conclusions, decreased bone formation after several months of bisphosphonate therapy is associated with increased serum levels of sclerostin. This might suggest that Wnt signaling may play a role in the coupling between resorption and formation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The use of intravenous nitrogen-containing bisphosphonates (N-BPs) is associated with the appearance of an acute phase response (APR) in a proportion of the patients for reasons that are poorly understood. The APR was attributed to the indirect activation of γδ T cells with the release of interferon-γ and tumor necrosis factor (TNF). Forty patients with postmenopausal or senile osteoporosis (age range = 53-91 years) never previously treated with intravenous (i.v.) bisphosphonate, received a single 5-mg zoledronic acid (ZOL) iv infusion over 15 minutes. White blood cells were counted and analyzed with an automated hematology analyzer (ADVIA 2120i Siemens, New York, USA) and by flow cytometer (BD FACSCanto, Becton Dickinson). The occurrence of APR was defined by the occurrence of fever (>37 °C) during the next 2 days. Forty-two percent of patients (17 of 40) receiving the infusion of ZOL experienced an APR. Compared with the others they were younger (69 ± 7 years versus 74 ± 8 years; p = 0.06), and both the proportion and absolute number of γδ T cells were significant higher (p = 0.02 and p = 0.013, respectively). Nonsignificant differences were found between the two groups for white blood cells and for the other circulating lymphocyte subpopulations. Age was inversely correlated with circulating γδ T cells (p = 0.003) but the difference between the two groups in circulating γδ T cells persisted for age-adjusted values and vice versa. In conclusion, the results of this study indicate that the number of circulating γδ T cells, together with age, are important determinant of the occurrence of APR after intravenous infusion of ZOL and possibly of any other N-BPs., (Copyright © 2012 American Society for Bone and Mineral Research.)

In patients with primary hyperparathyroidism (PHPT) not suitable for surgical correction, a skeletal protection with bisphosphonates is considered a reasonable option, but the long-term effects after treatment discontinuation are not well known. Sixty postmenopausal women with PHPT were given 400-600 IU vitamin D(3) daily and 100 mg neridronate IV every 2 months for 2 years with 2 additional years of follow-up without antiresorptive therapies. Bone mineral density (BMD) progressively rose by 6.7 ± 7.6% (SD) and by 2.9 ± 4.5% at the spine and femoral neck, respectively. During follow-up, mean BMD progressively fell, but after 2 years it was still 3.9 ± 5.5% higher than baseline values at the spine. Bone alkaline phosphatase and serum C-telopeptide of type I collagen decreased significantly within 6 months (28 and 49% versus baseline, respectively) and rose to baseline values within 6-12 months during follow-up. Serum PTH significantly rose from baseline during treatment, but it remained significantly higher than baseline during follow-up. The PTH changes were significantly correlated with serum 25-hydroxyvitamin D (25OHD) levels. In conclusion, in this study we observed that in patients with mild PHPT treatment with bisphosphonates is associated with the expected changes in bone-turnover markers and that the significant increases of both hip and spine BMD are partially maintained for at least 2 years after treatment discontinuation at the vertebral site. The marked increases in serum PTH levels, particularly in subjects with low 25OHD levels, persist after treatment discontinuation and this raises the suspicion that this might reflect a worsening of PHPT.