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Summary 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/m3 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/m3 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.

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.

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.

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.

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 &lt, 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 &lt, 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:Many patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) are in their childbearing years. Concerns exist regarding the interplay between the rheumatic diseases and the pregnancy (1).Objectives:Actually, there are contradictory data regarding the pregnancy outcome in patients with RA and SpA (2). Thus, we performed this longitudinal retrospective study to evaluate the effect of RA and SpA on pregnancy outcome.Methods:The data of 78 pregnancies of 60 women followed from April 2017 to December 2020 at pregnancy clinic of Internal Medicine Unit, San Bortolo Hospital, Vicenza and Rheumatology Unit, University of Verona were reviewed. Fifty (64.1%) women were affected by RA and 28 (35.9%) by SpA. Information regarding demographic data, disease activity, drug exposure and maternal/foetal outcomes were collected in an electronic database. Details concerning pregnancy complications and congenital malformation were also collected. We compared pregnancy and foetal/neonatal outcome, medication use and disease activity between women affected by RA and SpA. Moreover, we evaluated the effect of disease activity on pregnancy outcome.Results:Overall, there were 70 (86.4%) live births, 10 (12.3%) miscarriages and 1 (1.2%) foetal death. There were three twin pregnancies. Even there was a higher rate of glucocorticoids and bDMARDs use in RA than in SpA group, respectively 40% vs 21% and 70% vs 57,1%, there were no statistical differences regarding drug exposure at conception. Moreover, there were no differences concerning disease activity at conception. Still, a higher rate of glucocorticoids and bDMARDs, respectively 26% vs 10.7% and 46% vs 39.3% were used in RA than in SpA patients during pregnancy. Furthermore, we did not find any statistical differences regarding maternal and foetal/neonatal outcome between pregnancies in the RA and those in the SpA groups. There were four (4.9%), congenital malformation, two (3.8%) in RA group and two (6.9%) in SpA group. About one-third of patients 24 (30.7%) presented a moderate disease activity at conception as evaluated by DAS28PCR and BASDAI. However, there were no significant differences, on maternal and foetal/neonatal outcome in patients with moderate activity disease with respect of those in clinical remission.Conclusion:Even a higher rate of glucocorticoids and bDMARDs were used in RA than in SpA patients, there was no differences on pregnancy outcome between them.References:[1]Ostensen M. Nat Rev Rheumatol. 2017;13:485-493. doi: 10.1038/nrrheum.2017.102.[2]Polachek et al. J Rheumatol 2020;47:161-163. doi: 10.3899/jrheum.190631.Disclosure of Interests:None declared

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

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. CHABetween 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.Patients were divided into LOWscore and HIGHscore groups if CHACHA

Background Occult left ventricular (LV) systolic dysfunction (LVSD) is associated with worse cardiovascular outcomes in asymptomatic patients with arterial hypertension and/or diabetes mellitus. In these patients, LV systolic function may worsen or improve overtime. However, little is known about the changes in LV function during follow up of patients with rheumatoid arthritis (RA). Objectives This prospective study analyzed incidence and factors associated with changes in LV systolic function in patients with RA without known cardiovascular disease. Methods One-hundred-forty outpatients with RA without overt cardiac disease were recruited between March and December 2014. Patients underwent clinical and echocardiographic evaluation at baseline and after a median period [min-max] of 35 [23-47] months of follow up. Stress-corrected midwall fractional shortening (sc-MFS) was used as measure of LVSD and considered impaired if Results Impaired sc-MFS at follow up (sc-MFS-FU) was detected in 60/140 (43%) patients who were compared with 80 patients with normal sc-MFS-FU. Baseline sc-MFS did not differ significantly between the two groups, which appeared to diverge significantly soon after 1-year of follow up (figure). Baseline anti-citrullinated protein antibodies (ACPA) positivity, high disease activity (CDAI>10) and duration of RA were independently associated with impaired sc-MFS-FU at multiple logistic regression analysis. Among these parameters, ACPA had the highest sensitivity (80%) whereas high disease activity had the highest specificity (89%) for sc-MFS-FU. A predictive score including all three predictors (ACPA status, CDAI>10 and duration of RA) detected impaired sc-MFS-FU with a sensitivity of 78% and specificity of 82% (AUC 0.80 [IC 0.72-0.88], p Conclusion This study supports the hypothesis that changes overtime in LVSF in patients with RA are associated with ACPA, high disease activity and duration of disease. Disclosure of Interests: Alessandro Giollo: None declared, Giovanni Cioffi: None declared, Giovanni Orsolini Speakers bureau: Grunenthal, Luca Idolazzi: None declared, Antonio Carletto Speakers bureau: Roche, Novartis, MSD, Abbvie, Bristol, Jannsen, Celgene, Pfizer, Andrea Dalbeni: None declared, Federica Ognibeni: None declared, Elena Fracassi Speakers bureau: Novartis, Davide Gatti Speakers bureau: Abiogen, Amgen, Janssen-Cilag, Mundipharma, Pfeizer, Maurizio Rossini: None declared, Ombretta Viapiana Speakers bureau: Novartis, Abbvie, Eli-Lilly, Sanofi Genzyme

Background Given the data on efficacy and safety of biologic treatment in rheumatoid arthritis (RA), more and more patients older than 65 years are starting these drugs. Objectives This study aims to evaluate safety and efficacy of biologics in elderly patients. Methods: four-hundred and thirteen patients with RA were enrolled and divided in two group, i.e. older or younger than 65 years old. Data on disease characteristics, treatment and adverse reactions were collected. In addition, comorbidities were evaluated by the Rheumatic Disease Comorbidity index (RDCI). Results Seventy-seven patients were male and 87 were older than 65 years. The elderly patients had a higher RDCI as compared to those younger than 65 years (1.0 ± 3.0 vs. 0.0 ± 10 respectively, p Conclusion RA patients aged over 65 years have been found to have even a better retention rate at first biologic than youngers one, probably because of less strict targets in disease control and a more frequent follow up. In addition, safety has been found to be as good as in younger patients. Comorbidities do not seem to affect retention rate. Disclosure of Interests Cristian Caimmi: None declared, Federica Martinis: None declared, Ilaria Montanari: None declared, Alice Dellaidotti: None declared, Elena Fracassi Speakers bureau: Novartis, Ombretta Viapiana Speakers bureau: Novartis, Abbvie, Eli-Lilly, Sanofi Genzyme, Domenico Biasi: None declared, Maurizio Rossini: None declared, Antonio Carletto Speakers bureau: Roche, Novartis, MSD, Abbvie, Bristol, Jannsen, Celgene, Pfizer

Background: Secukinumab is a novel treatment for psoriatic arthritis (PsA) but data from real life are still missing. Objectives: The aim of this study is to evaluate a wide cohort of PsA patients on secukinumab followed in 7 Italian rheumatologic centers. Methods: Two-hundred and seventy-nine patients affected by PsA and on secukinumab were enrolled. Data on disease characteristics, previous and ongoing treatments, comorbidities and duration of follow-up were collected. In particular DAPSA and aSDAS were used to assess articular and axial disease activity. Results: Mean age of our cohort was 53±11 years and BMI 26.4±5.1 kg\m2 with the majority of patients being female (63.8%). Mean disease duration was 9.7±7.5 years and mean follow-up was 10.9±6.8 years. For 100 patients (35.8%) secukinumab was their first line biologic treatment and 41 (50.5%) were in monotherapy. DAPSA was 25.9±10.5 at baseline, 15.9±9.7 at M3, 12.9±8.4 at M6, 9.8±7.1 at M12 with a significant downward decrease at every visit as compared to baseline (p Forty patients (14.3%) stopped the treatment during the follow up mainly because of primary or secondary loss of efficacy (18 and 10, respectively). Only 9 patients suspended the treatment because of adverse events, of which 5 because of reactions at site of injection. The retention rate at 12 months was very good in the whole population (figure), and in particular in patients with entesitis at the baseline (10.5 vs, 11.2, p=0.038). No differences in survival were found when dividing patients accordingly to BMI, although overweight or obese patients showed a trend for a better retention rate (10.6 vs 10.9, p=0.089). Interestingly no differences were found between naive and non-naive patients (p=0.895) and between those in monotherapy or in combination therapy (p=0.925). Conclusion: This is one of the first real life studies on secukinumab and shows a very good efficacy and safety of this treatment in PsA patients, also for the articular manifestations, as shown by a significant decrease of DAPSA over a 12-months follow up. Disclosure of interests: Federica Martinis: None declared, Cristian Caimmi: None declared, Rosario Foti: None declared, Elisa Visalli: None declared, Giorgio amato: None declared, Roberta Ramonda: None declared, augusta Ortolan: None declared, Mariagrazia Lorenzin: None declared, angelo Semeraro: None declared, Leonardo Santo: None declared, Emanuela Praino: None declared, Maria Sole Chimenti: None declared, Roberto Perricone: None declared, Favia Sunzini: None declared, Raffaele Scarpa: None declared, Francesco Caso: None declared, Luisa Costa: None declared, Elena Fracassi Speakers bureau: Novartis, Maurizio Rossini: None declared, antonio Carletto Speakers bureau: Roche, Novartis, MSD, abbvie, Bristol, Jannsen, Celgene, Pfizer

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

Background:Secukinumab (SEC) is a novel treatment for psoriatic arthritis (PsA),but data from real life are still missing.Objectives:1)to evaluate the effectiveness and safety of a wide cohort of PsA patients on SEC followed in 7 Italian rheumatologic centers for 24 months;2)to compare the features and disease activity indices of SEC-treated PsA patients subdivided in naïve biological drugs (group A) and in TNF-inhibitors (TNFi) failure patients (group B).Methods:Consecutive patients with moderate-severe PsA,who begun SEC treatment were evaluated prospectively.Data on disease characteristics,previous and ongoing treatments,comorbidities and duration of follow-up were collected.Disease activity,functional and clinimetric scores and biochemical values were recorded at baseline (t0),at 6 (t6),12 (t12),and 24 (t24) months.Anova (Kruskal Wallis) and generalized linear models were used to compare variables over time.Infections and adverse events were also collected.Results:PsA345patients [38.84% men;mean age 52.9 (11.27) years] were enrolled;mean treatment duration was 18.53 (9.97) years.SEC was prescribed as first line biologic treatment in 133 (38.55%) patients and as second or more line biological treatment in 212 (61.45%) patients. Enthesitis was present as a prominent manifestation in 61.44% of patients (Figure 1).In all population significant decrease in tender/swollen joints;Visual Analogue Scale of pain (VASp) and general health (VASgh);Psoriasis Area Severity Index (PASI);Leeds Enthesitis Index (LEI);number of dactylitis;Health Assessment Questionnaire modified for spondyloarthritis (HAQ-S);Bath Ankylosing Spondylitis Disease Activity Index (BASDAI);Bath Ankylosing Spondylitis Functional Index (BASFI);C-reactive protein (CRP) was achieved.Effectiveness of all PsA patients was associated to an improvement in Ankylosing Spondylitis disease activity score (ASDAS) [t0=3.45 (0.69) vs t24=1.48 (0.23);pgroup Bhad a more erosive (p=0.04) and polyarticular pattern (p=0.04),a longer disease duration (p=0.001),a greater prevalence (p=0.04) of psoriasis and dactylitis (p=0.01),a higher PASI score (p=0.01),while no significant difference was observed for uveitis,inflammatory bowel diseases,enthesitis.At t24group Ashowed better physical functioning and lower disease activity compared togroup B[HAQs A vs B=0.03 (0.16) vs 0.69 (0.73);BASDAI A vs B=2.37 (0.66) vs 4.27 (2.33);ASDAS A vs B=1.4 (0.62) vs 1.99 (0.86);CRP A vs B=2.03 (1.94) vs 3.11 (1.55) mg/L;DAPSA A vs B=7.03 (3.57) vs 12.41 (8.05)].After t24 of treatment 74.6% ofGroup Aand 72.8% ofGroup Barticular had an inactive\low disease activity (MDA),accordingly to ASDAS and DAPSA respectively.Forty-three patients (12.46%) stopped the treatment during the follow-up mainly because of primary or secondary loss of efficacy (29 and 24, respectively).Only 14 patients suspended SEC because of adverse events (of which 9 for reactions at site of injection).A low number of episodes of mild infections (16) occurred;SEC was instead permanently discontinued in 7 cases for:oral refractory mucositis (3);recurrent aphthosis (2);diverticulitis (2).The retention rate at t24 was good in the whole population.Interestingly no differences were found betweenGroup AandB(p=0.815).Conclusion:In a real life clinical setting,SEC was safe and effective in PsA. as shown by a significant decrease of DAPSA and ASDAS over a 24-months follow up.Disclosure of Interests:Mariagrazia Lorenzin: None declared, Antonio Carletto: None declared, Rosario Foti Consultant of: lilly, sanofi, MSD, Janssen, Abbvie, BMS, celgene, roche, Speakers bureau: lilly, sanofi, MSD, Janssen, Abbvie, BMS, celgene, roche, Maria Sole Chimenti: None declared, Angelo Semeraro: None declared, Luisa Costa: None declared, Leonardo Santo: None declared, Elena Fracassi: None declared, Ilaria Montanari: None declared, Mara Felicetti: None declared, Giulia Lavinia Fonti: None declared, Francesco Caso: None declared, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Augusta Ortolan: None declared, Roberta Ramonda Speakers bureau: Novartis, Celgene, Janssen, Pfizer, Abbvie, Lilly

Background Secukinumab has been approved for the treatment of active ankylosing spondilytis (AS) and psoriatic arthritis (PsA). Its efficacy has been demonstrated in phase III trials where eligibility criteria ensured a homogeneous population. Although this strategy reduces confounding factors, it does not guarantee the same results in the real world, where clinicians deal with advanced disease, comorbidities, adherence and persistence challenges. Objectives Aim of this study was to assess efficacy and safety of Secukinumab in real-world clinical practice. Methods Patients received Secukinumab (150 or 300 mg) at weeks 0,1,2,3 and 4 as induction therapy and then every 4 weeks as manteinance therapy. Assessment of disease acrivity was done at months 0,6 and 12 using DAPSA, ASDAS, BASDAI, BASFI, pain VAS. Results 61 patients affected by PsA (65% females, 35% males) and 29 affected by AS (70% males, 30% females) were included. 64% of patients reached 12 months follow up. Baseline characteristics of both groups are shown in the tables below. In the PsA cohort, the median DAPSA at baseline was 19.5 (IQR 9.6), at 6 months 9.09 (IQR 6.5, p In the AS cohort, the median BASDAI at baseline was 5.5 (IQR 2.2), at 6 months 3.6 (IQR 1.2, p 4 patients switched therapy at 6 months due to partial response, 1 patient experienced an expected adverse event (Candida infection). Overall, no serious side effects were observed and none resulted in Secukinimab discontinuation. Conclusions In this first real-world cohorts of patients with PsA and AS Secukinumab has proven to be effective, regardless of PsA subtype, radiographic progression in AS and previous exposure to biologic therapy. The safety profile was favourable and similar to previous studies. Reference [1] Baeten D, et al. Secukinumab, an Interleukin-17 A Inhibitor, in Ankylosing Spondylitis. NEJM2015; 373 (26): 2534–48. Disclosure of Interest None declared

Background Depression and anxiety disorders are more common in chronic inflammatory arthritides (CIA) than in the general population.1 In rheumatoid arthritis (RA), depressive and anxiety symptoms have been associated with disease activity and pain perception,1 physical disability,2 health care costs,3 and mortality.4 To our knowledge, data on the prevalence of depression in Italian patients with RA are scarce. Objectives To estimate the prevalence and factors associated with depression among patients affected by RA. Methods During an one year period, patients affected by RA have been consecutively enrolled. For each patient demographics and disease characteristics were recorded; the Hospital Anxiety and Depression Scale (HADS) was administered. HADS is a validate questionnaire to assess depressive and anxiety symptoms in patients affected by somatic disorders admitted to general hospital. An HADS ≥11 was considered diagnostic for depression. Results The table summarises the main results. We recruited 231 patients affected by RA, finding a prevalence of depression of 13.9% (95% CI 9.4%–18.3%). Overall, patients with depression, when compared with patients without, were older, more frequently females, with a lower education, higher physician global assessment and patient global assessment, more comorbidities. In particular, they had any cardiovascular, neurologic or musculoskeletal issue (p=0.018, p=0.032, p=0.014, respectively) and more often used glucocorticoids or NSAIDs. Conversely, no association was found between depressive symptoms and the use of biologic therapies or the presence of inflammatory markers. Interestingly, a positive history of depression was present only in few patients with an HADS ≥11. Conclusions These preliminary results suggest that more than one every seven patients with RA could suffer from depression, thus depression might be undiagnosed in a significant number of patients. Comorbidities, anti-inflammatory medications and both physician- and patient- driven evaluation of disease burden were the most striking factors associated with depression in this cohort of patients with RA. References [1] Kojima M, et al. Arthritis and rheumatism2009Aug 15;61(8):1018–24. [2] Peck JR, et al. Arthritis and rheumatism1989Sep;32(9):1100–6. [3] Joyce AT, et al. J Rheumatol2009Apr;36(4):743–52. [4] Ang DC, et al. J Rheumatol2005Jun;32(6):1013–9. Disclosure of Interest None declared

Background Since 2013, in Veneto9s Region, data registration is mandatory for all patients affected by Rheumatoid arthritis (RA), Psoriatic Arthritis (PA), Ankylosing Spondylitis (AS) in treatment with biologic agents. The biologic DMARDs currently marketed in Italy are: anti-TNF (originator and biosimilar infliximab, etanercept, adalimumab, certolizumab and golimumab), anti-IL6 (tocilizumab), anti-CD20 (rituximab), CTLA-4 like (abatacept) and anti IL-12/23 (ustekinumab). Objectives The aim of this study was first to describe the characteristics of patients with RA, PA, AS under biologics and then, to extract and analyze real-life data regarding rheumatic treatments in Verona9s cohort. Methods The study has been carried out on behalf of Regione del Veneto, Giunta regionale- Ricerca Sanitaria Finalizzata-Venezia-Italy. Data used for analysis were retrieved from Veneto9s Region Biologics Register (VRBR). VRBR provides that core variables such as onset and type of disease, anthropometric characteristics (age, sex, body weight, height) are registered at the beginning. Furthermore, prior and concomitant rheumatic treatment (conventional and biologic DMARDs, corticosteroids, NSAIDs), disease activity indicators (DAS 28-PCR, ASDAS-PCR, pain-NRS), prognostic factors (positivity for rheumatoid factor and/ or anti-citrulline antibodies in AR, presence of radiological erosions) were assembled at baseline, every 6 months and at the time of biologic9s switch or swap. Results A total of 983 patients under biologics were examined; 543 (55,2%) with AR, 272 (27,7%) with AP and 168 (17,1%). Between these, 262 (27,2%) patients were naive to biologics, 128 with AR, 84 with AP, 50 with SA. Mean duration of disease was of 15,3, 10,7 and 12,6 years respectively for RA, PA and AS. Radiological erosions were present in 73% of RA-patients and the percentage was higher in those with positivity for rheumatoid factor and/ or anti-citrulline antibodies (84,4% versus 56,2%). More than half of the patients in this cohort were treated at least with one biologic agent; anti-TNFs were the main biologic used (RA:54,8%, PA:92,7%, AS: 100%) followed by Abatacept (25,4%), tocilizumab (12,3%) and rituximab (5,9%) in patients with RA. Methotrexate (MTX) was the prevalent associated c-DMARDs (41,8% in RA and 34,2% in PA) with mean dose of 11,9 mg/week in RA and 12,1 mg/week in PA. The optimal dose of methotrexate was not achieved prevalently because of drug intolerance. Conclusions Profile of both conventional and biological DMARDs looks very different according to the type of rheumatic disease. The first data show an underuse of MTX in patients with RA and PA under biologics with a low mean dosage due to intolerance. Next step is to evaluate long-term outcomes in clinical practice. Disclosure of Interest None declared

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

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.

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.

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.

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

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 turnov...

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

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.

Neridronic acid (6-amino-1-idroxyesilidene-1,1-bisphosphonate) is a nitrogen-containing bisphosphonate licensed in Italy for the treatment of osteogenesis imperfecta and Paget's disease of bone. The pharmacodynamic profile is similar to that of other nitrogen-containing bisphosphonates and is characterized by its high affinity for bone tissue particularly at sites undergoing a process of remodeling. In growing children affected by osteogenesis imperfect, neridronic acid rapidly increases bone mineral density as measured by dual X-ray absortiometry and this is associated with a significant decrease in fracture cumulative number. Similar results have been obtained also in newborns (12 month old) and in adult patients. In Paget's disease of bone, 200 mg intravenous neridronic acid is associated with a 65% rate of full remission and a biochemical response (decrease of75% of bone turnover markers) in 95% of the patients. Neridronic acid treatment has been reported to be effective also in other skeletal diseases such as osteoporosis, algodystrophy, hypercalcemia of malignancy and bone metastasis. Neridronic acid has been developed only for parenteral use, and it is the only one used as intramuscular injection. This avoids all the limitations of oral bisphosphonates and may be offered for a home treatment with simple nursing assistance.

Background Vitamin D deficiency is very common in elderly people while there are very few reports on its incidence, determinants and metabolic consequences in young subjects. Results In 608 young healthy premenopausal women participating in the BONTURNO study, levels of 25-hydroxyvitamin D [25(OH)D] below 20 ng/ml were found in almost a third of the women. Its levels were inversely ( P 2 ) and directly with sunlight exposure during the summer time, and latitude: i.e. the higher the latitude over Italy, the higher the 25(OH)D level. In women on contraceptive pill the mean 25(OH)D level was significantly increased even when the data were adjusted for age, BMI and sun exposure. 25(OH)D levels, adjusted for age and BMI, were significantly and positively related with serum C-telopeptide of type 1 collagen, serum phosphate and spine bone mineral density (BMD) and negatively with serum PTH, serum magnesium, serum bone alkaline phosphatase (bone AP). Conclusion Vitamin D deficiency is rather common in young otherwise healthy Italian women and particularly among those living in the Southern part of the country. The most close determinants of vitamin D deficiency were BMI and sunlight exposure. Vitamin D insufficiency is associated with low spine BMD and increased bone AP even in young individuals.

L’osteogenesi imperfetta comprende un gruppo di patologie ereditarie del collagene di tipo I che si esprime clinicamente con fragilita ossea e fratture ricorrenti. L’unica terapia che abbia dimostrato di essere in grado di ridurre significativamente l’incidenza di nuove fratture sono i bisfosfonati. Il neridronato e l’unico bisfosfonato registrato al momento in Italia per l’osteogenesi imperfetta.

Anorexia nervosa (AN) is a life-threatening eating disorder characterized by an inability to maintain a normal body weight and amenorrhoea, often associated with osteoporosis and increased risk of fragility fractures. Bone metabolism, including markers of bone turnover (serum total alkaline phosphatase, bone alkaline phosphatase [bone AP], osteocalcin [OC] and type I collagen C-telopeptide breakdown products [sCTX]) and bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) at the spine and at the hip, were evaluated in 55 consecutive women with AN undergoing a 3-month intensive nutritional rehabilitation program. The control group was constituted of 25 healthy young medical students. In AN patients body weight increased during the 3-month nutritional program from 37.8+/-5.1 (mean+/-SD) to 51.5+/-4.5 kg. The corresponding BMI rose to values17.5 kg/m(2) in all patients. Mean BMD significantly rose by 2.6+/-3.5% and 1.1+/-3.6% at the hip and at the spine, respectively. The markers of bone formation, serum bone AP and osteocalcin, significantly rose by two-folds, while sCTX decreased by 16%. The changes in hip BMD were positively related (p0.005) to changes in body weight and in bone AP (p0.02) while the changes in spine BMD were positively related to changes in serum osteocalcin (p0.05). In the 25 patients who attended the 12-month posttreatment control, mean body weight significantly decreased by 3.6+/-6.0 kg and this was not associated with any significant change in BMD values. In the patients in whom BMI fell again below 17.5 kg/m(2) hip BMD values decreased significantly. On the contrary, in the patients who maintained BMI17.5 kg/m(2), BMD values continued to rise up to values over the 15-month observation of 4.8+/-6.2 and 7.1+/-12.1 at the spine and hip, respectively. In conclusion, we have demonstrated that substantial gains in weight in women with chronic AN are associated with remarkable increases in BMD at both the hip and the spine. If weight is maintained, the overall improvement approach 1 SD within 1 year. The changes in both weight and BMD are correlated with improvements in bone formation markers and diminutions in a marker of bone resorption.

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.

It is a matter of fact that the inflammatory pathogenesis does not explain all the skeletal manifestations of Rheumatoid Arthritis (RA), and the development of bone involvement is sometimes unconnected from the clinical scores of inflammation. On the basis of recent studies, we would like to make a point of the new available evidence about the metabolic pathogenic component of bone erosions. We assume that in this process an additional role could be played by metabolic factors, such as the parathyroid hormone (PTH), DKK1 (the inhibitor of the Wnt/β catenin pathway) and cortical bone mineral density. The result is a new pathogenic hypothesis for bone erosion in RA, which supplements the inflammatory one: the reduction of osteoblasts activity and the increase of the osteoclasts one, involved in the pathogenesis of bone erosions and osteoporosis, are not only the consequence of the action of inflammatory cytokines, but also of increased levels of DKK1 and PTH. On the other hand, osteoporosis, in particular at the cortical sites, facilitates the appearance of erosions.

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.

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.

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.

Objective—The reflex sympathetic dystrophy syndrome (RSDS) is a painful limb disorder, for which a consistently eVective treatment has not yet been identified. The disease is associated with increased bone resorption and patchy osteoporosis, which might benefit from treatment with bisphosphonates, powerful inhibitors of bone resorption. Methods—Twenty patients with RSDS of foot and hand, were randomly assigned to blind administration of either alendronate intravenously (Istituto Gentili, Pisa, Italy) 7.5 mg dissolved in 250 ml saline solution or placebo saline infusions daily for three days. Two weeks later all patients had an identical treatment course with open labelled alendronate (7.5 mg/day for three days), independent from the results of the first blind treatment. Results—In the patients treated with blind alendronate the diminution in spontaneous pain, tenderness, and swelling (circumference of the aVected limb) and the improvement in motion were significantly diVerent from baseline (p

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.

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).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.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; p0.0001). DKK1 serum levels were positively correlated with age (p0.05) only in the healthy controls, while they were correlated with PTH serum levels only in the RA patients (p0.0001). 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; p0.05). DKK1 levels adjusted for age and PTH were negatively correlated with total hip BMD (p0.05). In the RA patients not on treatment with bisphosphonates, DKK1 serum levels positively correlated with C-terminal telopeptides of type I collagene serum levels (p0.05).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.

Bone densitometry has become a major tool for osteoporosis risk assessment. The traditional dual-energy X-ray absorptiometry (DXA) methods are able to evaluate the bone mineral content (BMC; mg/cm) and the areal density (BMD; mg/cm2), but only quantitative computed tomography (QCT) has the potential to measure the true volumetric bone density in the sense of mass per unit volume (mg/cm3). Peripheral QCT (pQCT) measurements were carried out at the non-dominant radius using a Stratec XCT 960 (Unitrem, Roma) in 241 postmenopausal and 29 premenopausal women. The sites of evaluation were both the ultradistal and the proximal radius. The technique used has a coefficient of variation of 2% and it allows separation of the bone section into trabecular and cortical bone on the basis of density threshold. Bone mass of radius, hip and spine was also evaluated by DXA procedures. The bone density data obtained by pQCT were significantly correlated with all DXA measurements. The correlation coefficients between their respective BMD values ranged from 0.48 to 0.75, but for the BMC values of the radius the correlation coefficients ranged from 0.82 to 0.93. The BMD values measured by DXA, but not by pQCT, were positively related with patient heights. All pQCT density measurements, including those obtained at the proximal radius and containing exclusively cortical bone, where negatively related with age and years since menopause. A partial volume effect, which is increasingly relevant the thinner are the bone cortices, might explain that. However, by applying increasing density thresholds, cortical bone density seems to decrease with age as a consequence of a gradual density diminution from the inner part of the bone cortex outwards. Trabecular bone density decreases with aging, but its overall mass does not change as a consequence of an age-related enlargement of trabecular area. Thus, the proportion of trabecular bone over total bone rises, and this might be relevant for our understanding of the age-related changes in bone turnover and rate of bone loss.

Background Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular (CV) disease, despite preserved left ventricular (LV) ejection fraction (EF). Changes in LV geometry, LV systolic dysfunction (LVSD) and the development of excessive left ventricular mass (LVM) are closely and consistently associated with CV disease in several settings of patients such as those with arterial hypertension or type 2 diabetes mellitus, with preserved LVEF. Objectives The aim of this study was the evaluation of this subclinical parameters in patients with RA. Methods 198 outpatients with RA without overt cardiac disease were prospectively analyzed with echocardiography and compared with 198 matched controls. In all patient LV geometry (concentric remodeling or hypertrophy), LVEF, circumferential and longitudinal LVSD (respectively by stress-corrected midwall shortening [sc-MS] and Tissue Doppler mitral annular peak systolic velocity [S9]) and the presence of inappropriately high LVM (iLVM)were evaluated. Results The patients with RA present higher prevalence respect to controls ofconcentric remodeling or hypertrophy, circumferential or/and longitudinal LVSD and iLVM as reported on table. By multiple logistic regression analysis, rheumatoid arthritis emerged as independent predictor of all this echocardiography alterations. Conclusions The patients with RA without overt cardiac disease have the same echocardiographyc characteristics what are associated with CV disease in hypertension and in diabetes mellitus. These findings may be clinically useful for identifying a subgroup of patients with RA at very high risk for adverse CV events (mostly heart failure). Longitudinal studies are needed to assess the prognostic role of this conditions in these patients and to test conceivable and useful pharmacological and/or non-pharmacological treatments. Disclosure of Interest None declared

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 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 (iv) 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. © 2012 American Society for Bone and Mineral Research

The effect of teriparatide (TPD) on bone turnover is initially exuberant but then diminishes. TPD is thought to stimulate bone formation by down-regulating the expression of specific Wnt antagonists, such as of sclerostin and Dickkopf-1 (DKK1).Our objective was to determine whether long-term treatment with TPD is associated with increasing serum levels of either sclerostin or DKK1.Ancillary observation was made of patients participating in a randomized clinical trial. PATIENTS, INTERVENTION, AND OUTCOMES: Fifty-five women with postmenopausal osteoporosis were randomly allocated to treatment for 18 months with either TPD 20 μg daily or placebo.In the TPD group, both N-propeptide of type I collagen and C-terminal telopeptide of type I collagen rose significantly by 108 and 175% within the first 6 months. At month 18, the mean values decreased significantly compared with month 12 (-10 and -12%, respectively), but they were still significantly higher than baseline (+84 and 152%, respectively). Sclerostin remained stable over the entire study period in both groups. DKK1 did not change during the first 6 month of treatment, but only in the active group, it rose significantly at month 12 (median change +26.9%) and remained elevated at month 18 (+29.7%), at the time when the pharmacological effect of treatment with TPD appeared to be declining.Long-term (12 months) treatment with TPD is associated with an increase in serum levels of DKK1 that might be associated with the appearance of declining effect on bone formation markers.

Bone turnover markers (BTM) progressively decrease in young adult women. This might be linked to changes in insulin-like growth factor-1 (IGF-I). Four serum BTMs [serum C-telopeptide of type 1 collagen (CTX), osteocalcin (OC), N-terminal propeptide of type 1 procollagen (P1NP), and bone alkaline phosphatase (bone AP)], serum calcium (sCa), phosphate (sPO(4)), magnesium, 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (PTH) and IGF-I were measured in 531 young healthy premenopausal women aged 20-50 years participating in the BONTURNO study. In all subjects bone mineral density (BMD) was measured at the spine and at the hip by dual-energy X-ray densitometry. Hip BMD, IGF-I, the four BTMs, sCa and sPO(4) progressively decreased with advancing age and this was associated with proportional increases in PTH. IGF-I levels were significantly and positively correlated with sCa, sPO(4), CTX, OC, P1NP, bone AP, spine BMD, femoral neck BMD and total hip BMD and negatively with age, BMI and serum PTH. When the IGF-I levels were adjusted for age and BMI, the only correlations maintaining a statistical significance were those with serum PTH, P1NP and bone AP. These associations were weak and IGF-I accounted for a only a small proportion of the BTM variance. The mean, age-adjusted IGF-I values were significantly higher in women practicing physical exercises for more then 60 min per week than in sedentary women. In conclusion, in this study we provide evidence of an association between the age-related decline in IGF-I with the progressive decrease in bone formation markers in premenopausal women.

Vitamin D deficiency is a relevant problem particularly in south Europe and in over 65 year old subjects, that is often underestimated. Vitamin D deficiency represents a real medical emergency also for its role in the patho-physiology of muscular-skeletal diseases. Chronic vitamin D deficiency leads to severe bone and muscular outcomes including: osteoporosis, osteomalacia and proximal limb myopathy. These increase the risk of falling and fractures. The efficacy of vitamin D treatment in decreasing the fracture risk has been reporting in several studies. The negative results of some recent studies questioned the clinical vitamin D efficacy. However these studies have a number of methodological problems and even the interpretation of the results is questionable. In this paper we review all these aspects. This analysis permits to confirm that vitamin D treatment can be extremely cost-effective when given to people at high risk of deficiency. An acceptable compliance is obviously of critical importance.

Background Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular adverse events, favored by the progression of arterial stiffness leading to coronary atherosclerosis and concentric left ventricular (LV) geometry. These conditions can lead to LV systolic dysfunction (LVSD) that can be expressed by different parameters such as stress-corrected midwall shortening (sc-MS), a prognostic of CV events in patients with arterial hypertension and diabetes. Objectives To evaluate the prevalence of LVSD in RA patients. Methods From January to June 2014, 198 recruited RA patients were investigated and compared with 198 controls matched for age, gender, body mass index, prevalence of hypertension and diabetes. Echocardiography was performed measuring many parameters expressing LV systolic function: sc-MS (impaired if 123% of measured/predicted ratio). This last parameter has been evaluated in a group of 235 patient. Results LVSD defined by S9 reduction was found in 45% of RA patient, by sc-MS in 56% of patients vs 15% of controls (p Conclusions In conclusion we demonstrate through different parameters that among RA patients there is a significant prevalence of LVSD that precedes LVEF impairment. RA has turn to be an independent risk factor for LVSD. These data confirm the need for a careful evaluation of CV risk in RA patients. Disclosure of Interest None declared

Osteogenesis imperfecta (OI) is a heritable disease of connective tissue, characterized by increased bone fragility. Bisphosphonates currently seems to be the most promising therapy, at least in children. We tested IV neridronate, an amino-bisphosphonate structurally similar to alendronate and pamidronate in adults with OI. Twenty-three men and 23 premenopausal women with OI were randomized to either iv neridronate (100 mg infused intravenously for 30 minutes every 3 months) or no treatment with a ratio of 2 to 1. Control patients were given the same bisphosphonate therapy at the end of the first year. Clinical evaluation included bone densitometry measurements using dual energy X-ray absorptiometry (DXA), fasting serum and urinary biochemistry every 6 months, and radiographs of the spine taken at baseline and after 12 and 24 months of follow-up. Spine and hip bone mineral density rose by 3.0 +/- 4.6% (SD) and by 4.3 +/- 3.9%, respectively, within the first 12 months of treatment, whereas small insignificant changes were observed in the control group. During the second year of follow-up, additional 3.91% and 1.49% increases were observed at the spine and hip, respectively. Markers of skeletal turnover significantly fell during neridronate treatment. Fracture incidence during neridronate treatment was significantly lower than before therapy and compared with controls. Neridronate iv infusions, administered quarterly, significantly increase bone mineral density and lowered the risk of clinical fracture in adults with OI. Bisphosphonate therapy seems to provide clinical benefits, not only to children with OI, but also to adult patients.

Background Recently data strengthens the concept that treatment with bisphosphonates may be associated with beneficial symptomatic effects and perhaps structural benefits in people with osteoarthritis. Objectives 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). Methods 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 14 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. Improving in Western Ontario MacMaster (WOMAC) scale, Lequesne Index, consumption of acetaminophen, and physician or patient overall judgment were secondary objectives. Results 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 3 and 5 weeks after the last injection. The improvements in Lequesne index, global KOA evaluation from both patients and investigators, and the WOMAC pain subscale were significantly greater in clodronate group 3-5 weeks after the last injection. The proportion of patients that did not require acetaminophen was significantly greater in the clodronate group. Conclusions IA 2 mg clodronate is safe and is associated with small and transient symptomatic and functional benefits in KOA patients in addition to those seen with saline solution. The opportunity to further investigate this therapeutic option is questionable. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4532

Background 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. Objectives The aim of this study is to compare MPONE to PN in terms of clinical response and on their effect on HPA axis in patients initiating GL treatment for PMR. Methods 53 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 assessment and the measurement of ESR, CRP, fibrinogen, serum cortisol and ACTH were obtained at fixed time point (two weeks, and 3, 6, 12 months). Results A significant and comparable reduction of ESR and CRP levels was observed in both groups of patients. 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 longer for PN (20.3 days) than with 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 well as the slopes relating equivalent steroid dose. Conclusions PN and MPONE have a similar therapeutic effect and 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 with different expression of 11β-HSD activity. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4564

Background Ankylosing spondylitis (AS) is a chronic, inflammatory rheumatic disease characterised by inflammatory back pain due to sacroiliitis and spondylitis. TNF-α blocking agents (infliximab, etanercept, adalimumab and golimumab) are effective in controlling inflammation and pain and improving functionality in AS but are much more expensive than conventional treatments and they are contraindicated in some conditions. Objectives Recognition of the importance of subchondral bone marrow inflammation in AS, together with in vitro and animal model data indicating that bisphosphonates may possess anti-inflammatory properties, constitute a theoretical rationale for their evaluation in this disease. Methods This was a 6-month open randomized study on active AS conducted in a single center. After a 4-week run-in period, sixty patients were consecutively randomized in a 1:1 ratio to receive either neridronate (100 mg in 250 mL over 2 hours) or infliximab (5 mg/kg in 250 ml of sodium clorure 9% solution over 2 hours). Results A significant reduction in the mean BASDAI was observed over 6 month neridronate or infliximab administration. BASDAI decreased by 1,54 (30,7%) (p Conclusions In this study we have shown that high IV doses of the amino-bisphosphonate neridronate are effective in reducing symptoms of disease in AS patients. The size effect at 6 months is similar to that obtained with standard infliximab therapy with additional benefits on BMD changes. Further studies to confirm these results over considerably longer timeframe are warranted together with the possibility to explore the long-term efficacy of a combination of anti-TNF and bisphosphonates. Disclosure of Interest None Declared