Alessandro Giollo

Strong relationship between vitamin D status and bone mineral density in anorexia nervosa

BACKGROUND Anorexia nervosa (AN) is associated with impaired bone health and low bone mineral density (BMD) as a consequence of an inadequate peak bone mass in adolescence and bone loss in young adulthood. The vitamin D status with its implications for bone health in patients affected by AN has only been examined previously in small studies. OBJECTIVE To evaluate the prevalence of vitamin D deficiency and test the hypothesis that patients with AN and vitamin D deficiency might have worse bone metabolism and lower bone density as compared with AN with adequate vitamin D repletion. DESIGN We analysed the vitamin D status and bone metabolism in a large cohort (n=89) of untreated patients affected by AN, with amenorrhoea. RESULTS Vitamin D deficiency is widespread in untreated patients with AN: 16.9% had 25OH vitamin D levels below 12 ng/ml, 36% below 20 ng/ml and 58.4% below 30 ng/ml. PTH values were higher and BMD at both femoral sites were lower in patients with vitamin D<20 ng/ml. Progressively higher values of BMD were observed by 4 ranks of 25 OH vitamin D values (severe deficiency: <12 ng/ml, deficiency: ≥12 ng/ml and <20 ng/ml, insufficiency: ≥20 and <30 ng/ml and normal: ≥30 ng/ml). In patients with severe vitamin D deficiency BMD at the hip were significantly lower than that measured in groups with values over 20 ng/ml (p<0.001 for trend). The level of significance did not change for values adjusted for BMI or body weight. CONCLUSION We found a strong relationship between vitamin D status and hip BMD values with additional benefits for those with 25OHD levels above 20 ng/ml. Our results support the design of a randomized placebo-controlled clinical trial on the effect of vitamin D on BMD in patients with AN. The second point, whether 25OHD should be above 20 or 30 ng/ml remains a discussion point.

Osteoporosis: an Independent Determinant of Bone Erosions in Rheumatoid Arthritis?

We read with great interest the article by Simon and colleagues “Ageand Sex-Dependent Changes of Intra-Articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis.” The postmenopausal state and rheumatoid arthritis (RA) lead to a significant decrease of both cortical and trabecular intra-articular bone density. This process in RA patients is a sign for a severe disease course predicting erosive disease. Bone erosion is an important complication of RA and is associated with deformities and disabilities. Insufficient inhibition of structural joint damage by disease-modifying antirheumatic drugs (DMARDs) represents an unsolved problem and was reported despite clinical improvement. Erosion mainly affects intra-articular cortical bone and results from unpaired bone resorption and formation. It is clear that the main trigger of articular bone erosions is inflammation. Proinflammatory cytokines such as TNF-a, interleukin 1 (IL-1), and interleukin 6 (IL-6) play a pivotal role in bone complications throughout the activation of osteoclasts, mainly via the RANK/ RANKL/osteoprotegerin system. Moreover, Dickkopf-1 (DKK-1), a Wnt system inhibitor, hasanemerging role inbonemetabolismand bone complications of RA. DKK-1 is implicated in joint remodeling and in inflammation-induced bone loss. DKK-1 serum levels have been found to be elevated in RA and related with erosions and lower bone mineral density (BMD). Recent evidence has also linked higher parathyroid hormone (PTH) levels to bone damage in RA, and we have observed that PTH appears to be an important determinant of bone resorption and DKK-1 serum levels in RA patients. It is well known that chronic high serum levels of PTH decreases thickness and increases porosity of cortical bone. Simon and colleagues showed that the alterations of bone quantity and microstructure of intra-articular bone, measured with high-resolution peripheral quantitative computed tomography (HR-pQCT), could be not only secondary to RA disease, but also secondary to aging and/or loss of estrogen. Indeed, intra-articular bone in RA has similar composition as in postmenopausal women older than 60 years. The latter evidence suggests a new hypothesis: osteoporosis, as well as RA, may be an independent determinant in the development of erosions. Simon and colleagues found a strong correlation between intra-articular bone in the metacarpal heads and extra-articular bone in the radius, which is in accordance with previous findings. It is known that low BMD, measured with digital X ray techniques or dual-energy X-ray absorptiometry (DXA), is significantly associated with bone erosions in RA patients. Recently, cortical thinning and fenestration have been observed before the clinical onset of arthritis in subjects with anti-citrullinated protein antibodies (ACPAs), and ACPAs have a negative titer-dependent effect on BMD. ACPA titer is a well-known risk factor for bone erosions in RA. Many other factors are related with higher risk of erosions in RA, includingdisease activity, cigarette smoking, alcohol consumption, hypovitaminosis D, low body mass index (BMI), corticosteroid use, andaging; all of thesearewell-known risk factors forosteoporosis too! Therefore, we could speculate that the correlation with bone erosions might also be mediated by osteoporosis. On the other hand, the described protective effect of obesity on radiographic joint damage might be due to the wellknown positive correlation between BMI and BMD. Denosumab, a drug for osteoporosis treatment, achieved important results in the prevention of erosions in RA; of note, denosumab has no effect on inflammation but only positive effects on cortical BMD and porosity. In conclusion, osteoporosis might be an important and independent determinant of bone erosions in RA. We need a deeper bone investigation in RA patients. The poor response to the DMARDs, in terms of progression of bone erosions, might depend on the concomitant osteoporosis and on other risk factors of bone loss.

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.

Rheumatoid arthritis, γδ T cells and bisphosphonates

We read with great interest the results of the study of Mo et al .1 The authors suggest that γδ T cells are involved in the pathogenesis of rheumatoid arthritis (RA). The study showed a significant reduction, in patients with RA, of peripheral total γδ T cells (particularly Vδ2 T cells, the major population of peripheral blood γδ T cells). The percentage of peripheral Vδ2 T cells of RA was negatively correlated with the levels of inflammatory markers, including C-reactive protein, erythrocyte sedimentation rate as well as the Disease Activity Score in 28 joints. The peripheral reduction of Vδ2 …

Prognostic Role of Subclinical Left Ventricular Systolic Dysfunction Evaluated by Speckle-Tracking Echocardiography in Rheumatoid Arthritis

Background: Speckle‐tracking echocardiography allows early detection of subclinical left ventricular systolic dysfunction (LVSD) in patients with rheumatoid arthritis (RA). In this prospective study, we assessed the prevalence and the prognostic role of subclinical LVSD detected by speckle‐tracking echocardiography in RA patients. Methods: Two‐dimensional global longitudinal strain (GLS) and global circumferential strain (GCS) were measured in 209 RA patients without overt cardiac disease. LVSD was defined as low GLS (> −16.0%), low GCS (> −17.8%), or both. The primary end point was all‐causes hospitalization; the coprimary end point was hospitalization for cardiovascular causes. Results: The study population had a mean age of 58 ± 11 years; 67% were female, 52% had hypertension, and the RA duration was 14 ± 10 years. Low GLS was detected in 51 patients (24%), low GCS in 42 patients (20%), and combined low GLS and GCS in 18 patients (9%). During a median follow‐up time of 16 months (range, 10–21 months), a primary end point occurred in 50 patients (24%), and 25 patients were hospitalized for a cardiovascular event. Multiple Cox regression analyses revealed that combined low GLS and GCS was independently associated with the end point defined as all‐causes hospitalization together with higher aortic stiffness. Examined individually, neither low GCS nor low GLS showed an independent association with this typology of clinical outcome. Conversely, both low GCS and low GLS (examined individually or as combined low GLS and GCS) emerged as strong independent prognosticators of cardiovascular events. Conclusions: Subclinical LVSD defined as low GLS, GCS, or both is common in RA patients without overt cardiac disease and provides additional prognostic information in these individuals. HighlightsA significant proportion of asymptomatic rheumatoid arthritis patients without history of cardiac disease have subclinical left ventricular systolic dysfunction detected by speckle‐tracking echocardiography and defined as low global longitudinal strain (GLS) and/or low global circumferential strain (GCS).In rheumatoid arthritis subjects analyzed in primary prevention, all‐causes hospitalizations are independently related to the condition of combined low GLS and GCS.The combined low GLS and GCS status is characterized by older age, left ventricular diastolic dysfunction, and left ventricular hypertrophy, all of which are factors predisposing patients toward the development of overt heart failure.Low GCS, low GLS, and combined low GLS and GCS are strong independent predictors of cardiovascular events at mid‐term follow‐up.

Effects of secukinumab on serum adipocytokines: preliminary data

Psoriatic arthritis (PsA) is a chronic inflammatory disease that affects joints, connective tissues and the axial skeleton. Metabolic syndrome is an independent risk factor for psoriasis (Pso) development and is associated with more severe forms of Pso. Adipocytokines are secreted by white adipose tissue and are thought to link obesity with the development of metabolic and cardiovascular diseases. Secukinumab is a new monoclonal antibody with a different mechanism of action. This antibody selectively binds to and neutralizes interleukin-17 (IL-17) and it has shown efficacy in the treatment of PsA. The aim of this study was to evaluate the possible interferences of secukinumab on different adipocytokines. We enrolled 28 patients with PsA, classified with the CASPAR criteria. Serum samples were stored at baseline and then at the first, the third and the sixth month of therapy. Resistin, chemerin, adiponectin and C-reactive protein (CRP) were dosed. When tested globally, none of the adipokine tested showed any statistically significant variation. However, when the male group was tested, both resistin and chemerin at M6 showed a significant decrease from baseline. CRP did not show any variation at any time point. Our study demonstrated that treatment with secukinumab has little influence on the levels of adipokines tested within the first six months of treatment even though it might exert different influence between males and females from a metabolic perspective. Further studies with greater numbers of patients are needed to determine whether these preliminary results have clinical relevance.

Disease activity and left ventricular systolic function in rheumatoid arthritis

We have read with interest the recent paper by Midtbo et al .1 The authors evaluated 119 patients with rheumatoid arthritis (RA), and found that patients with RA active disease (Simplified Disease Activity Index (SDAI) >3.3) compared with those in remission (SDAI<3.3) had lower left ventricular (LV) systolic myocardial function, assessed by stress-corrected mid-wall shortening (scMWS) and global longitudinal strain (GLS). Data from Midtbo et al are in line with our previous work, in which we demonstrated that RA per se is a condition closely related to LV systolic dysfunction (LVSD) assessed by scMWS.2 Furthermore, similar to other pathophysiological models (systemic hypertension, diabetes mellitus and aortic stenosis), we showed that the LVSD in patients with RA is closely …

Drug-Induced Interstitial Lung Disease: A Systematic Review

Background: Drug-induced interstitial lung disease (DIILD) occurs as a result of numerous agents, but the risk often only becomes apparent after the marketing authorisation of such agents. Methods: In this PRISMA-compliant systematic review, we aimed to evaluate and synthesise the current literature on DIILD. Results: Following a quality assessment, 156 full-text papers describing more than 6000 DIILD cases were included in the review. However, the majority of the papers were of low or very low quality in relation to the review question (78%). Thus, it was not possible to perform a meta-analysis, and descriptive review was undertaken instead. DIILD incidence rates varied between 4.1 and 12.4 cases/million/year. DIILD accounted for 3–5% of prevalent ILD cases. Cancer drugs, followed by rheumatology drugs, amiodarone and antibiotics, were the most common causes of DIILD. The radiopathological phenotype of DIILD varied between and within agents, and no typical radiological pattern specific to DIILD was identified. Mortality rates of over 50% were reported in some studies. Severity at presentation was the most reliable predictor of mortality. Glucocorticoids (GCs) were commonly used to treat DIILD, but no prospective studies examined their effect on outcome. Conclusions: Overall high-quality evidence in DIILD is lacking, and the current review will inform larger prospective studies to investigate the diagnosis and management of DIILD.

Cardiovascular outcomes of patients with rheumatoid arthritis prescribed disease modifying anti-rheumatic drugs: a review

ABSTRACT Introduction: Rheumatoid arthritis (RA) is associated with a heightened risk of cardiovascular disease (CVD), with both traditional CV risk factors and inflammation contributing to this risk. Areas covered: This review highlights the burden of CVD in RA and associated traditional CV risk factors, including the complexity of dyslipidemia in RA and the so-called ‘lipid paradox.’ Furthermore, the recognized RA-disease-specific factors associated with higher risk of CVD and the role of systemic inflammation in the pathogenesis of CVD in RA will be addressed. With the advent of biologic and targeted synthetic therapies in the treatment of RA, the effect of conventional and newer generation disease modifying anti-rheumatic therapies (DMARDs) on CV risk and associated risk factors will also be discussed. Expert opinion: Identifying the RA phenotype at greatest risk of CVD, understanding the interplay of increased traditional risk factors, common inflammatory processes and RA-specific factors, and personalized use of DMARDs according to disease phenotype and comorbidity to reduce this risk are key areas for future research.

GP2015 as a promising therapy for rheumatoid arthritis

ABSTRACT Introduction: Rheumatoid arthritis is a common inflammatory joint disease with a myriad of systemic manifestations. Over the last 20 years its treatment has been revolutionised by the introduction of a number of different biologic drugs, including the TNF-receptor Fc fusion protein, Etanercept. However, these drugs are expensive and their widespread use puts a financial burden on healthcare systems. As many biologic treatments begin to come off patent new ‘biosimilar’ versions are being developed which can lead to significant cost savings. GP2015 (Erelzi®) is the second biosimilar version of Etanercept which is licensed for the treatment of rheumatoid arthritis. Areas covered: We discuss the Chemistry, pharmacokinetics and pharmacodynamics of GP2015 in relation to reference Etanercept. Preclinical trials have shown pharmacokinetic equivalence between GP2015 and the reference drug. The recently completed Phase III, randomised, double blind EQUIRA study has shown equivalent efficacy and safety between GP2015 and Etanercept in patients with rheumatoid arthritis. Expert opinion: GP2015 has shown equivalent efficacy and safety to reference Etanercept. With a growing number of biosimilar medications becoming available and another biosimilar Etanercept already being widely prescribed it is likely to be the cost of the drug that will determine if it is used widely.