Depression as a possible determinant of fatigue in patients with axial spondyloarthritis.

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.

Coping strategies, emotional distress and perceived disease severity in a cohort of patients with rheumatoid arthritis: a mediation analysis.

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.

Italian recommendations for influenza and pneumococcal vaccination in adult patients with autoimmune rheumatic diseases.

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.

Titer-Dependent Effect of Anti-Citrullinated Protein Antibodies On Systemic Bone Mass in Rheumatoid Arthritis Patients.

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.

Higher Level of Dickkopf-1 is Associated with Low Bone Mineral Density and Higher Prevalence of Vertebral Fractures in Patients with Ankylosing Spondylitis.

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.

Focal bone involvement in inflammatory arthritis: the role of IL17.

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.

Prevalence and Factors Associated with Subclinical Left Ventricular Systolic Dysfunction Evaluated by Mid-Wall Mechanics in Rheumatoid Arthritis.

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 ß 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.

In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density.

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.

Effects of intra-articular clodronate in the treatment of knee osteoarthritis: results of a double-blind, randomized placebo-controlled trial.

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.

Prednisone compared to methylprednisolone in the polymyalgia rheumatica treatment.

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 11ß-hydroxysteroid dehydrogenase activity.

Bisphosphonates vs infliximab in ankylosing spondylitis treatment.

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.

Sclerostin and DKK1 in primary hyperparathyroidism.

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.

Teriparatide treatment in adult patients with osteogenesis imperfecta type I.

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.

Changes in bone turnover markers and bone modulators during abatacept treatment.

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/cm2 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.

Comparison and potential determinants of health-related quality of life among rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis: A cross-sectional study.

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.

Dose-dependent short-term effects of single high doses of oral vitamin D(3) on bone turnover markers.

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.

Long-term effects of amino-bisphosphonates on circulating γδ T cells.

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.

Comparable long-term retention rates and effects on bone mineral density of denosumab treatment in patients with osteoporosis with or without autoimmune inflammatory rheumatic diseases: real-life data.

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.

Real-life short-term effectiveness of anti-osteoporotic treatments: a longitudinal cohort study.

Introduction: Randomized clinical trials have shown that anti-osteoporotic treatments can increase bone mineral density (BMD) and reduce the incidence of fragility fractures. However, data on the real-life effectiveness of anti-osteoporotic medications are still scarce. Methods: We conducted a cohort study on women at high risk of fracture. We retrieved clinical and densitometric data from the DeFRA database, which derives from the DeFRA tool, a web-based fracture risk assessment tool. Multivariable Cox regression survival models were employed to analyze the effectiveness of different anti-osteoporotic drugs on fracture. In sensitivity analyses, we conducted 1:1 propensity score matching analyses. Results: Data on 50,862 women were available. Among these, 3574 individuals had at least two consecutive visits. The crude fracture rate was 91.9/1000 person-year for non-treated patients. The crude fracture rate in bisphosphonate users was 72.1/1000 person-year, in denosumab users was 58.2/1000 person-year, and in teriparatide users was 19.3/1000 person-year. Overall, we found that bisphosphonate use was associated with a 30% lower risk of fracture compared to no treatment [adjusted hazard ratio (aHR): 0.70, 95% confidence interval (CI): 0.50-0.98]. Treatment with denosumab and teriparatide were associated with 60% and 90% lower risk of fracture, respectively (aHR: 0.43, 95% CI: 0.24-0.75 and aHR: 0.09, 95% CI: 0.01-0.70). Bisphosphonate use was associated with a lower risk of fracture only after 1 year of treatment. Conclusion: In conclusion, we found that all anti-osteoporotic medications considered in the study effectively reduced the risk of fracture in the real-life. The effect of bisphosphonate on fracture risk was apparent only after the first year of treatment. Our findings do not support the use of bisphosphonates in patients at imminent risk of fracture.

Association between long-term exposure to air pollution and immune-mediated diseases: a population-based cohort study.

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/m3 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/m3 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.