Clinical, Ultrasound, and Predictability Outcomes Following Certolizumab Pegol Treatment (with Methotrexate) in Patients with Moderate-to-Severe Rheumatoid Arthritis: 52-Week Results from the CZP-SPEED Study.

INTRODUCTION: To assess the impact of certolizumab pegol (CZP) treatment on clinical, patient-reported, and musculoskeletal ultrasound outcomes and to determine the treatment response time point most predictive of long-term outcomes in Italian patients with rheumatoid arthritis (RA). METHODS: CZP-SPEED (NCT01443364) was a 52-week, open-label, prospective, interventional, multicenter study. Biologic-naïve patients with moderate-to-severe active RA, who had failed at least one DMARD treatment, received CZP (400 mg at weeks 0, 2, and 4, then 200 mg every 2 weeks) concomitantly with methotrexate. The primary objective was to identify the time point of clinical response {decrease in 28-joint Disease Activity Score [DAS28(ESR)] ≥ 1.2} most predictive of a clinical response at week 52. Additional clinical and patient-reported outcomes were measured. Power Doppler (PD) ultrasound was used to assess synovial effusion, synovial proliferation, PD signal, cartilage damage, and bone erosion according to international guidelines. RESULTS: A total of 132 patients were enrolled and received CZP; 91/132 (69%) completed to week 52. Predicted 52-week responses for early responders (week 2 onwards) were between 65% and 70%. Rapid improvements in joint cavity widening and PD signal were observed to week 8 and maintained to week 52. Cartilage damage and bone erosion were stable over 52 weeks. No new safety signals were identified. CONCLUSION: In Italian CZP-treated patients with moderate-to-severe RA, week 12 clinical responses may be predictive of long-term response at week 52. Rapid improvements in clinical, patient-reported, and musculoskeletal ultrasound outcomes were maintained to week 52. These data may aid rheumatologists to make earlier treatment decisions. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01443364. FUNDING: UCB Pharma.

CD14++ CD16- monocytes are the main source of 11ß-HSD type 1 after IL-4 stimulation.

The anti-inflammatory actions of IL-4 are well established through earlier findings. However, the exact mechanism it uses to downregulate the pro-inflammatory cytokine production through monocytes and macrophages is poorly understood. In this study, we examined the effect of IL-4 in the induction of 11ß-HSD1 in the two main classes of monocytes, CD14++ CD16- (CD14) and CD14+ CD16+ (CD16). Peripheral Blood Mononuclear Cells (PBMCs) were isolated from 17 healthy donors and were sorted into CD14 and CD16 subpopulations using cell sorting. Effect of IL-4 on 11ß-HSD1-enzyme activity was measured in sorted and unsorted monocytes using Homogeneous Time-Resolved Fluorescence (HTRF) and M1/M2 polarization analysis was performed by flow cytometry. Our results indicate that CD14 cells are the major source of 11ß-HSD1 enzyme after IL-4 stimulation and that M2 phenotype is not a pre-requisite for its synthesis.

Rituximab increases peripheral natural killer cells in patients with rheumatoid arthritis.

OBJECTIVES: The clinical response of rituximab (RTX) is related to the degree of B cell depletion, although other circulating lymphocytes may be affected. We investigated the changes in lymphocyte sub-populations in rheumatoid arthritis (RA) patients treated with RTX and their relationship with the therapeutic response, with attention to natural killer (NK) cells. METHODS: In fifty-one RA patients peripheral blood B and T lymphocytes and NK cells subtypes were counted by flow cytometry before and 3, 6 and 12 months after RTX administration. Patients were evaluated for disease activity with DAS28-CRP and EULAR response criteria at each visit. RESULTS: RTX significantly increased from baseline values CD56+3- cells (28 %, 19 % and 25 %; p<0.001, p=0.009 and p=0.004 respectively for month 3, 6 and 12) and CD56dimCD16+ cells (41%, 24% and 36%; p<0.001, p=0.001 and p<0.001 respectively for month 3, 6 and 12). CD56bri16- cells were unaffected by RTX treatment. The increase in both CD56+3- and CD56dimCD16+ cells was significantly greater in patients who were re-treated with another course of RTX at month 6 (p=0.046 and p=0.010 respectively). An inverse correlation between disease activity score and increase in NK cells was demonstrated. No significant changes were observed in CD3+, CD4+ and CD8+ cells during the whole observation period. CONCLUSIONS: In RA patients, RTX treatment is associated with significant and persistent increase in CD56+3- and CD56dimCD16+ NK cells. A correlation with disease activity is probable, although the association with clinical response remains to be proved.

Declining trends in the incidence of hip fractures in people aged 65years or over in years 2000-2011.

BACKGROUND: The aim of this study was to explore hip fracture (HFx) incidence in the Veneto Region of Italy, looking at potential differences with the national data. METHODS: We analyzed HFx incidence for people aged 65years or over, in years 2000-2011, using data from the Regional Hospitalization Database. Patients were stratified by sex, calendar year and 5-year age class. Data for the single provinces of the Region were also obtained. Absolute number of HFx, crude incidence for 10,000 inhabitants and age-standardized fracture rates were calculated. RESULTS: During the study period, there were 53,917 hospitalizations for HFx (77.7% in females). In the whole 11year period of observation, the absolute HFx number increased by 17.7% in males and 10.6% females, respectively. However, age-standardized incidence rates declined by 18% in the same period (IRR 0.82, 95% CI 0.78-0.87). This decreasing trend was almost identical through all the age-cohorts up to 84years. In the whole study period, HFx incidence was lower for Padova (IRR 0.63, 95% CI 0.60-0.66) and Verona (IRR 0.66, 95% CI 0.63-0.70) provinces as compared to the others. This regional profile was quite different with respect to the data published, for the same calendar years, for Italy as a whole, in spite of an almost identical demography of the population. CONCLUSIONS: HFx incidence is declining in the Veneto Region of Italy. Further studies, aimed to investigate factors involved in this figure are needed.

Effects of TNF Inhibitors on Parathyroid Hormone and Wnt Signaling Antagonists in Rheumatoid Arthritis.

Tumor necrosis factor α inhibitors (TNFi) are the major class of biologic drug used for the treatment of Rheumatoid arthritis (RA). Their effects on inflammation and disease control are well established, but this is not true also for bone metabolism, especially for key factors as parathyroid hormone and Wnt pathway. Those two pathways are gaining importance in the pathogenesis RA bone damage, both systemic and local, but how the new treatment affects them is still largely unknown. We studied 54 RA patients who were starting an anti-TNFα treatment due to the failure of the conventional synthetic disease-modifying antirheumatic drugs. Serum levels of Wnt/ßcatenin pathway inhibitors (Dickkopf-related protein 1, Dkk1, and Sclerostin), Parathyroid hormone (PTH), vitamin D, and bone turnover markers were measured at baseline in the morning after fasting and after 6 months of therapy. We found a significant percentage increase in serum PTH (+32 ± 55 %; p = 0.002) and a decrease in Dkk1 mean serum levels (-2.9 ± 12.1; p = 0.05). PTH percentage changes were positively correlated both with C-terminal telopeptide of type I collagen and Dkk1 percentage changes. Sclerostin serum levels showed no significant difference. TNFi treatment provokes in the short term a rise in PTH levels and a decrease in Dkk1 serum levels. The increase of PTH might promote bone resorption and blunt the normalization of Dkk1 serum levels in RA. Those data give a new insight into TNFi metabolic effects on bone and suggest new strategies to achieve better results in terms of prevention of bone erosions and osteoporosis with TNFi treatment in RA.

18F-fluoride PET/CT for detection of axial involvement in ankylosing spondylitis: correlation with disease activity.

OBJECTIVES: Aim of the current study was to evaluate the relationships between the findings of 18F-fluoride PET/CT (F-PET/CT) reflecting osteo-proliferative processes and the clinical indexes related to the disease activity. The clinical indexes are Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS). METHODS: We studied 29 AS patients aged 26-69 years with a wide range of disease activity using F-PET/CT. The number of regions of high bone turnover or osteoarthritis features at the spine and at sacroiliac joints was counted. RESULTS: The number of F-PET/CT positive sites was significantly higher in patients with severe functional impairment and higher disease activity and it was positively related to both BASDAI (r = 0.336; P = 0.036) and ASDAS (r = 0.408; P = 0.014) while the number of degenerative features (osteoarthritis) was related neither with functional impact nor with disease activity. CONCLUSIONS: With a single examination, F-PET/CT accurately identifies the functional impairment and the clinical involvement of AS. The good correlation we found between the number of F-PET/CT positive sites and disease activity candidates this technique also for follow-up of AS.

Adult-onset Still's disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients.

Adult-onset Still's disease (AOSD) is a systemic inflammatory condition of unknown aetiology characterized by typical episodes of spiking fever, evanescent rash, arthralgia, leukocytosis and hyperferritinemia. Given the lack of data in Italian series, we promote a multicentric data collection to characterize the clinical phenotype of Italian patients with AOSD. Data from 245 subjects diagnosed with AOSD were collected by 15 centres between March and May 2013. The diagnosis was made following Yamaguchi's criteria. Data regarding clinical manifestations, laboratory features, disease course and treatments were reported and compared with those presented in other published series of different ethnicity. The most frequent features were the following: arthritis (93 %), pyrexia (92.6 %), leukocytosis (89 %), negative ANA (90.4 %) and neutrophilia (82 %). As compared to other North American, North European, Middle Eastern and Far Eastern cohorts, Italian data show differences in clinical and laboratory findings. Regarding the treatments, in 21.9 % of cases, corticosteroids and traditional DMARDs have not been able to control the disease while biologics have been shown to be effective in 48 to 58 patients. This retrospective work summarizes the largest Italian multicentre series of AOSD patients and presents clinical and laboratory features that appear to be influenced by the ethnicity of the affected subjects.

Clinical profile and outcome of patients with rheumatoid arthritis and abnormally high aortic stiffness.

OBJECTIVES: Ascending aorta has an increased stiffness (AoSI) in rheumatoid arthritis (RA) patients due to their chronic inflammatory status. We assessed prevalence and factors associated with increased AoSI and its prognostic role in a large cohort of RA patients. METHODS: We prospectively analysed 226 RA patients without overt cardiac disease compared with 226 non-RA patients matched for cardiovascular risk factors (non-RA controls). Abnormally high AoSI was diagnosed if AoSI > 6.07% (95th percentile of the AoSI detected in our reference healthy population). AoSI was assessed at the level of the aortic root by two-dimensional guided M-mode evaluation as part of a thorough echocardiography performed in all patients. RESULTS: AoSI was significantly higher in the RA patients than non-RA controls (6.3 ± 4.5% vs. 4.6 ± 3.5%, p < 0.001); it was related to older age, higher systolic blood pressure and RA disease. Predictors of AoSI in RA patients were older age, higher systolic blood pressure and the non-prescription of non-steroidal anti-inflammatory drug and/or immunomodulatory/anti-cytotoxic agents. Abnormally high AoSI was diagnosed in 41% RA patients and 21% non-RA controls (p < 0.001). The RA phenotype with abnormally high AoSI was a > 60 years old subject with systolic blood pressure > 129 mmHg, mitral annular calcification who was not receiving non-steroidal anti-inflammatory drug. By multivariate Cox regression analysis abnormally high AoSI independently predicted death or all-cause hospitalization (hazard ratio 2.85 (95% confidence interval 1.03-7.85)) at 12-month follow-up. CONCLUSIONS: Increased AoSI is common, can be predicted by an ordinary clinical assessment and is a strong predictor of adverse clinical outcome at mid-term follow-up in patients with RA.

Combined Circumferential and Longitudinal Left Ventricular Systolic Dysfunction in Patients with Rheumatoid Arthritis without Overt Cardiac Disease.

BACKGROUND: Patients with rheumatoid arthritis have an increased risk for cardiovascular disease. Because of accelerated atherosclerosis and changes in left ventricular (LV) geometry, circumferential and longitudinal (C&L) LV systolic dysfunction (LVSD) may be impaired in these patients despite preserved LV ejection fraction. The aim of this study was to determine the prevalence of and factors associated with combined C&L LVSD in patients with rheumatoid arthritis. METHODS: One hundred ninety-eight outpatients with rheumatoid arthritis without overt cardiac disease were prospectively analyzed from January through June 2014 and compared with 198 matched control subjects. C&L systolic function was evaluated by stress-corrected midwall shortening (sc-MS) and tissue Doppler mitral annular peak systolic velocity (S'). Combined C&L LVSD was defined if sc-MS was <86.5% and S' was <9.0 cm/sec (the 10th percentiles of sc-MS and S' derived in 132 healthy subjects). RESULTS: Combined C&L LVSD was detected in 56 patients (28%) and was associated with LV mass (odds ratio, 1.03; 95% CI, 1.01-1.06; P = .04) and concentric LV geometry (odds ratio, 2.76; 95% CI, 1.07-7.15; P = .03). By multiple logistic regression analysis, rheumatoid arthritis emerged as an independent predictor of combined C&L LVSD (odds ratio, 2.57; 95% CI, 1.06-6.25). The relationship between sc-MS and S' was statistically significant in the subgroup of 142 patients without combined C&L LVSD (r = 0.40, F < 0.001), having the best fitting by a linear function (sc-MS = 58.1 + 3.34 × peak S'; r(2) = 0.19, P < .0001), absent in patients with combined C&L LVSD. CONCLUSIONS: Combined C&L LVSD is detectable in about one fourth of patients with asymptomatic rheumatoid arthritis and is associated with LV concentric remodeling and hypertrophy. Rheumatoid arthritis predicts this worrisome condition, which may explain the increased risk for cardiovascular events in these patients. NOTICE OF CLARIFICATION: The aim of this "notice of clarification" is to analyze in brief the similarities and to underline the differences between the current article (defined as "paper J") and a separate article entitled "Prevalence and Factors Associated with Subclinical Left Ventricular Systolic Dysfunction Evaluated by Mid-Wall Mechanics in Rheumatoid Arthritis" (defined as "paper E"), which was written several months before paper J, and recently accepted for publication by the journal "Echocardiography" (Cioffi et al. http://dx.doi.org/10.1111/echo.13186). We wish to explain more clearly how the manuscript described in "paper J" relates to the "paper E" and the context in which it ought to be considered. Data in both papers were derived from the same prospective database, so that it would appear questionable if the number of the enrolled patients and/or their clinical/laboratory/echocardiographic characteristics were different. Accordingly, both papers reported that 198 patients with rheumatoid arthritis (RA) were considered and their characteristics were identical, due to the fact that they were the same subjects (this circumstance is common and mandatory among all studies in which the patients were recruited from the same database). These are the similarities between the papers. In paper E, which was written several months before paper J, we focused on the prevalence and factors associated with impaired circumferential left ventricular (LV) systolic function measured as mid-wall shortening (corrected for circumferential end-systolic stress). We found that 110 patients (56% of the whole population) demonstrated this feature. Thus, these 110 patients were the object of the study described in paper E, in which we specifically analyzed the factors associated with the impairment of stress-corrected mid-wall shortening (sc-MS). The conclusions of that paper were: (i) subclinical LV systolic dysfunction (LVSD) is detectable in more than half RA population without overt cardiac disease as measured by sc-MS, (ii) RA per se is associated with LVSD, and (iii) in RA patients only LV relative wall thickness was associated with impaired sc-MS based upon multivariate logistic regression analysis. Differently, in the paper J, we focused on the prevalence and factors associated with combined impairment of circumferential and longitudinal shortening (C&L) in 198 asymptomatic patients with RA. We found that 56 patients (28% of the whole population) presented this feature. Thus, these 56 patients were analyzed in detail in this study, as well as the factors associated with the combined impairment of C&L shortening. In paper J, we evaluated sc-MS as an indicator of circumferential systolic LV shortening, and we also determined the average of tissue Doppler measures of maximal systolic mitral annular velocity at four different sampling sites ( S') as an indicator of longitudinal LV systolic shortening. This approach clearly demonstrates that in paper J, we analyzed data deriving from the tissue Doppler analysis, which were not taken into any consideration in paper E. The investigation described in paper J made evident several original and clinically relevant findings. In patients with RA: (i) the condition of combined C&L left ventricular systolic dysfunction (LVSD) is frequent; (ii) these patients have comparable clinical and laboratory characteristics with those without combined C&L LVSD, but exhibit remarkable concentric LV geometry and increased LV mass, a phenotype that can be consider a model of compensated asymptomatic chronic heart failure; (iii) RA is an independent factor associated with combined C&L LVSD; (iv) no relationship between indexes of circumferential and longitudinal function exists in patients with combined C&L LVSD, while it is statistically significant and positive when the subgroup of patients without combined C&L LVSD is considered, having the best fitting by a linear function. All these findings are unique to the paper J and are not presented (they could not have been) in paper E. It appears clear that, starting from the same 198 patients included in the database, different sub-groups of patients were selected and analyzed in the two papers (they had different echocardiographic characteristics) and, consequently, different factors emerged by the statistical analyses as covariates associated with the different phenotypes of LVSD considered. Importantly, both papers E and J had a very long gestation because all reviewers for the different journals found several and important issues that merited to be addressed: a lot of changes were proposed and much additional information was required, particularly by the reviewers of paper E. Considering this context, it emerges that although paper E was written well before paper J, the two manuscripts were accepted at the same time (we received the letters of acceptance within a couple of weeks). Thus, the uncertainty about the fate of both manuscripts made it very difficult (if not impossible) to cite either of them in the other one and, afterward, we just did not think about this point anymore. Of note, the idea to combine in the analysis longitudinal function came therefore well after the starting process of revision of the paper E and was, in some way inspired by a reviewer's comment. That is why we did not put both findings in the same paper. We think that our explanations provide the broad audience of your journal a perspective of transparency and our respect for the readers' right to understand how the work described in the paper J relates to other work by our research group. Giovanni Cioffi On behalf of all co-authors Ombretta Viapiana, Federica Ognibeni, Andrea Dalbeni, Davide Gatti, Carmine Mazzone, Giorgio Faganello, Andrea Di Lenarda, Silvano Adami, and Maurizio Rossini.

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.

Short-Term Effects of TNF Inhibitors on Bone Turnover Markers and Bone Mineral Density in Rheumatoid Arthritis.

TNFα inhibitors (TNFαI) exert positive effects on disease activity in rheumatoid arthritis (RA). Bone involvement is a major determinant of functional impairment in this disease. Here we investigated the short-term effects of TNFαI therapy on bone metabolism and density. We studied 54 patients with RA starting a TNFαI biologic drug, in whom any factor known to interfere with bone metabolism was excluded or rigorously accounted for. We measured at baseline and after 6-month therapy bone turnover markers: N-propeptide of type I collagen (P1NP), and bone alkaline phosphates for bone formation and serum C-terminal telopeptide of type I collagen (CTX) for bone resorption. We also evaluated bone mineral density (BMD) at hip and lumbar by dual-energy X-ray absorptiometry. All bone markers rose significantly and these changes were not dependent on steroid dosage. A significant decrease in femoral neck BMD was also observed. These results indicate that TNFαI therapy in RA over 6 months is associated with an early increase in bone turnover and a decline in hip BMD.

Bone Metabolism in a Large Cohort of Patients with Systemic Sclerosis.

The aim of this study was to evaluate in a large size cohort of SSc patients bone mineral density (BMD) and to analyze its possible determinants. 106 consecutive outpatients affected by SSc were enrolled and completely evaluated for bone metabolism and SSc characteristics. For the statistical analysis, we preferred Z score to BMD or T score since the population was composed of patients of different ages and of both sexes. Mean neck Z score was significantly lower than 0. No significant differences were found for other sites. Female patients were shown to have a total femur and neck Z score significantly lower than 0 (p = 0.028 and p < 0.001, respectively). 13 % of patients had at least one morphometric non-clinical vertebral fracture. In univariate analysis, total femur Z score was lower in female (p = 0.050) and positively correlates with BMI (p = 0.001), neck Z score positively correlates with age (p = 0.016), and whole body Z score positively correlates with BMI (p < 0.001). No correlations were found for lumbar Z score. The multivariate analysis confirmed the positive correlation between BMI and total femur and whole body Z score and between age and neck femur Z score (p = 0.005, p < 0.001 and p = 0.040, respectively). Lung involvement was shown to correlate with a lower whole body Z score in multivariate analysis (p = 0.037). We found a modest risk of low BMD in patients with SSc and the important protective role of BMI. Patients with lung involvement showed lower whole body Z score.

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.

Safety issues and adverse reactions with osteoporosis management.

INTRODUCTION: Osteoporosis is a disease that has spread worldwide and has become a relevant public health problem. Over the last 2 decades, a number of drugs have been licensed for its treatment owing to their efficacy in preventing fragility fractures. The safety profiles of these drugs are well defined with data from extensive programs of pharmacovigilance to support it. AREAS COVERED: In this article we reviewed the long-term safety of Bisphosphonates, Calcium, Vitamin D, Selective Estrogen Receptor Modulators, Teriparatide and Denosumab. We excluded hormone replacement therapy that lost its indication for the treatment of osteoporosis. The license for the treatment of osteoporosis of Calcitonin was recently withdrawn and that of Strontium ranelate was severely limited. For both drugs, we report EMA statements about their safety profile. EXPERT OPINION: The safety profile of most available drugs for the treatment of osteoporosis is well defined and the most serious adverse events are either rare or predictable. Osteoporosis treatment is a favorable choice in patients at moderate-high risk of fracture, while in patients at low risk pharmacological prevention should involve consideration of the balance between the beneficial effects of treatment, the probability of adverse effects and costs.

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.

The use of bisphosphonates in women: when to use and when to stop.

INTRODUCTION: Bisphosphonates (BPs) are the most commonly used drugs in osteoporosis. AREAS COVERED: This review focuses on the criteria for identifying patients who should be treated with BPs and also the rational for the duration of treatment. EXPERT OPINION: BPs remain the mainstay for the treatment of osteoporosis. For their low cost, the treatment threshold is related exclusively to the ratio between expected benefits and the risk of side effects. This is the case of patients with prior fragility fracture or with low bone density and the presence of other relevant risk factors. The treatment should continue for 3 - 5 years or until fracture risk is no longer high. Afterward a treatment holiday should be considered on the light of the increasing risk of side effects but its duration is still controversial. The duration of this treatment holiday depends on the drug used. Discontinuation of risedronate and ibandronate is associated with the quick loss of the acquired benefits and with these two BPs discontinuation should not exceed 6 months. Alendronate and zoledronate are characterized by a persistent effect after discontinuing treatment and this would allow a more prolonged drug holiday.

Prevalence and factors related to inappropriately high left ventricular mass in patients with rheumatoid arthritis without overt cardiac disease.

OBJECTIVES: Due to the chronic inflammatory status, specific neuro-hormones and progression of arterial stiffness, patients with rheumatoid arthritis (RA) are exposed to the development of excessive left ventricular mass disproportionate to the need to compensate left ventricular load. This condition, named inappropriately high left ventricular mass (iLVM), is associated with unfavorable prognosis in patients with hypertension, aortic stenosis or diabetes. In this study, we assessed prevalence and factors associated with iLVM in a large cohort of patients with RA and tested the hypothesis that RA per se is a condition related to iLVM. METHODS: We prospectively analyzed 235 RA patients without overt cardiac disease recruited between January and December 2014, who were compared with 235 controls matched for age, sex, BMI, prevalence of hypertension and diabetes. iLVM was defined as measured/predicted LVM ratio above 123%. LVM was predicted in each individual by using a simple equation considering height, sex and left ventricular work. RESULTS: iLVM was detected in 150 RA patients (64%) and in 30 controls (15%; P < 0.001). In patients with RA, the variables independently associated with iLVM emerged by multivariate logistic regression analysis were left ventricular systolic dysfunction measured as mid-wall shortening and concentric left ventricular geometry. Considering both groups of patients with RA and matched controls, RA was the strongest variable related to iLVM (odds ratio 3.37, 95% confidence interval 1.37-8.31, P = 0.008). CONCLUSIONS: Two-thirds of patients with RA without overt cardiac disease have iLVM, which is associated with left ventricular systolic dysfunction and concentric geometry. RA per se is a condition closely related to iLVM.