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Objective We wished to determine bone alterations in systemic sclerosis (SSc) patients by conventional densitometry (DXA), peripheral quantitative computed tomography (pQCT), and bone biomarkers. Methods We included 44 SSc patients and 33 age-matched healthy controls. Lumbar spine and femoral neck bone mineral density (BMD) was assessed by DXA. Volumetric BMD was measured by pQCT at the radius. FRAX, 25-hydroxyvitamin-D 3 (25-OH-D 3 ), parathyroid hormone, osteocalcin, C-terminal collagen telopeptide, and procollagen type I amino-terminal propeptide were also assessed. Results SSc patients had lower L2–4 BMD (0.880 ± 0.108 vs. 0.996 ± 0.181 g/cm 2 ; p  = 0.019) and femoral neck (FN) BMD (0.786 ± 0.134 vs. 0.910 ± 0.090 g/cm 2 ; p  = 0.007) by DXA. In SSc vs. controls, pQCT indicated lower mean cortical (328.03 ± 103.32 vs. 487.06 ± 42.45 mg/cm 3 ; p  < 0.001) and trabecular density (150.93 ± 61.91 vs. 184.76 ± 33.03 mg/cm 3 ; p  = 0.037). Vitamin D 3 deficiency was more common in SSc vs. controls (60.0% vs. 39.3%; p  = 0.003). L2–4 ( p  = 0.002) and FN BMD ( p  = 0.015) positively correlated with BMI. pQCT assessments confirmed an inverse correlation between pulmonary manifestation and total ( p  = 0.024), trabecular ( p  = 0.035), and cortical density ( p  = 0.015). Anti-Scl70 positivity inversely correlated with pQCT total density ( p  = 0.015) and the presence of digital ulcers with cortical density ( p  = 0.001). We also found that vertebral and FN BMD as determined by DXA significantly correlated with pQCT total, trabecular, and cortical density ( p  < 0.05). Conclusion The results of our study suggest that bone loss in SSc patients may be associated with lower BMI, anti-Scl70 positivity, and the presence of pulmonary manifestations and digital ulcers. Both DXA and pQCT are appropriate tools to evaluate the bone alterations in SSc patients.

Cardiovascular (CV) disease and osteoporosis (OP) have become increasing challenges in the aging population and even more in patients with inflammatory rheumatic diseases, such as rheumatoid arthritis, spondyloarthropathies, and systemic lupus erythematosus. In this review, we discuss how the epidemiology and pathogenesis of CV events and OP are overlapping. Smoking, diabetes mellitus, physical inactivity as conventional risk factors as well as systemic inflammation are among the modifiable risk factors for both CV events and bone loss. In rheumatic patients, systemic “high-grade” inflammation may be the primary driver of accelerated atherogenesis and bone resorption. In the general population, in which some individuals might have low-grade systemic inflammation, a holistic approach to drug treatment and lifestyle modifications may have beneficial effects on the bone as well as the vasculature. In rheumatic patients with accelerated inflammatory atherosclerosis and bone loss, the rapid and effective suppression of inflammation in a treat-to-target regime, aiming at clinical remission, is necessary to effectively control comorbidities.

Background Skeletal manifestations are predominant in psoriatic arthritis (PsA). The aim of this cross-sectional, case-control study is the complex assessment of areal and volumetric bone mineral density (BMD), fracture risk, vitamin D status and bone turnover markers, and its association with disease-related variables. Methods Lumbar spine (L1-L4) and femoral neck (FN) areal, and distal radius (DR) volumetric BMD, 10-year probability of major and hip osteoporotic fracture as assessed by the fracture risk assessment (FRAX) tool, markers of bone metabolism and disease activity were assessed. Results Upon comparison of the disease and age- and sex-matched control groups, there was a statistically significant difference in FN areal (0.952 (0.607–1.292) g/cm 2 vs. 1.016 (0.760–1.550) g/cm 2 ; p  = 0.001) and DR total volumetric (284.3 (138.9–470.3) mg/cm 3 vs. 367.0 (287.0–412.0) mg/cm 3 ; p  < 0.001) BMD, 10 year probability for major osteoporotic (3.7% (0.7–32%) vs. 2.6% (0–17.5%); p  = 0.003) and hip (0.4% (0–16%) vs. 0.05% (0–6.1%); p  = 0.002) fracture and 25-hydroxyvitamin D status (47.5 (10–120) nmol/L vs. 64 (10–137; p  < 0.001) nmol/L). As compared to areal assessment, volumetric BMD measurements identified a significantly higher number of patients with low bone mineral density (T-Score ≤ − 1.00) (34% vs. 88%, p  < 0.001). Upon multiple linear regression analysis, disease activity score, as determined by DAS28 assessment, was an independent predictor of 10-year probability for major osteoporotic fracture ( B (95%CI) = 1.351 (0.379–2.323); p  = 0.007). Conclusion In the studied PsA cohort, disease activity was an independent predictor of 10-year probability for a major osteoporotic fracture, and complemented assessment of volumetric and areal BMD assured better efficacy at identifying those with low bone mineral density.

Background Targeted synthetic therapeutics, such as Janus kinase (JAK) inhibitors, have opened up a new platform for the treatment of various diseases, including rheumatoid arthritis (RA). As with all drugs, the efficacy of different medicine may vary from patient to patient, and there may be different side effects if the expected effect is not achieved. In addition to the uncertain success of treatments, they also place a heavy burden on the health care system, making the identification of potential predictive biomarkers for drug optimisation highly valuable. Methods In order to identify potential predictive biomarkers, 28 patients with RA were recruited and blood samples were taken twice–before medical treatment and after 6 months of continuous therapy. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples and after RNA isolation, RNA sequencing was performed using high throughput sequencing technology to generate global gene expression data. Validation of target genes was conducted using real-time quantitative PCR methods. Results After data analyses we examined the gene expression changes between the two sampling time points and responder versus non-responder groups. 225 genes showed significantly different expression between T6 and T0 samples, while 60 and 66 genes showed differential expression between the responder and non-responder patients at T0 and T6 sampling points, respectively. 13 differentially expressed genes were common between two time points and showed the same direction in regulation. Conclusions Based on our results, several RA-relevant genes were identified, as a result of the JAK-inhibitor treatments in comparison of T6 versus T0 samples. At both time points, the differentially expressed genes between responder and non-responder groups could separate the samples, however, the separation was not clear. The identified 13 common genes could also partially separate the responder and non-responder groups from each other. These sets of genes could be the source of potential biomarkers, which could help predict the responsiveness of patients to JAK inhibitor therapy.

ObjectivesRheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss. We conducted a comprehensive study using imaging (dual-energy X-ray absorptiometry, DXA) and laboratory biomarkers in order to determine bone health and to study the effects of anti-tumor necrosis factor (TNF) biologics in RA and AS.Patients and methodsThirty-six RA and 17 AS patients undergoing 1-year etanercept (ETN) or certolizumab-pegol (CZP) therapy were studied. Bone density was assessed by DXA at baseline and after 12 months. Serum C-reactive protein (CRP), calcium, phosphate, parathyroid hormone (PTH), vitamin D3, osteocalcin, procollagen type I N-propeptide (P1NP), C-terminal telopeptide (βCTX), osteoprotegerin, sclerostin (SOST), Dickkopf-1 (DKK-1), soluble receptor activator nuclear kappa B ligand (sRANKL), and cathepsin K (cathK) levels were determined at baseline and after 6 and 12 months.ResultsTNF-α inhibition was clinically effective. Anti-TNF-α halted further bone loss over 1 year. In general, anti-TNF therapy significantly increased P1NP, SOST levels, and the P1NP/βCTX ratios, while decreased DKK-1 and CathK production at different time points in most patient subsets. In the full cohort and in RA, baseline and/or 12-month bone mineral density (BMD) at multiple sites exerted inverse relationships with CRP and βCTX, and positive correlation with SOST. In AS, L2-4 BMD after 1-year biologic therapy inversely correlated with baseline βCTX, while femoral neck BMD rather showed inverse correlations with CRP.ConclusionsAnti-TNF therapy slowed down generalized bone loss, in association with clinical improvements, in both diseases. TNF blockade may enhance bone formation and suppress joint destruction. Anti-TNF therapy may act inversely on DKK-1 and SOST. Independent predictors of BMD were SOST and βCTX in RA, whilst CRP in AS.Key Points• One-year anti-TNF therapy halted generalized bone loss in association with clinical improvement in arthritides.• Anti-TNF therapy may inversely act on DKK-1 and SOST.• Independent predictors of BMD were SOST and βCTX in RA, while CRP in AS.

Introduction Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are associated with osteoporosis. There have not been many peripheral quantitative computed tomography (QCT) studies in patients receiving biologics. We assessed volumetric and areal bone mineral density (BMD) by forearm QCT and dual-energy X-ray absorptiometry (DXA), respectively in addition to laboratory biomarkers in these arthritides. Methods Forty RA and AS patients treated with either etanercept (ETN) or certolizumab pegol (CZP) were undergoing follow-ups for one year. Volumetric and areal BMD, as well as parathyroid hormone (PTH), osteocalcin, RANKL, 25-hydroxyvitamin D (VITD), P1NP, CTX, sclerostin (SOST), Dickkopf 1 (DKK-1) and cathepsin K (CATHK) were determined. Results We did not observe any further bone loss during the 12-month treatment period. Volumetric and areal BMD showed significant correlations with each other (p<0.017 after Bonferroni’s correction). Trabecular QCT BMD at baseline (p=0.015) and cortical QCT BMD after 12 months (p=0.005) were inversely determined by disease activity at baseline in the full cohort. Trabecular QCT BMD at baseline also correlated with CTX (p=0.011). In RA, CRP negatively (p=0.014), while SOST positively (p=0.013) correlated with different QCT parameters. In AS, RANKL at baseline (p=0.014) and after 12 months (p=0.007) correlated with cortical QCT BMD. In the full cohort, 12-month change in QTRABBMD was related to TNF inhibition together with elevated VITD-0 levels (p=0.031). Treatment and lower CATHK correlated with QCORTBMD changes (p=0.006). In RA, TNF inhibition together with VITD-0 (p<0.01) or CATHK-0 (p=0.002), while in AS, treatment and RANKL-0 (p<0.05) determined one-year changes in QCT BMD. Conclusions BMD as determined by QCT did not change over one year of anti-TNF treatment. Disease activity, CATHK, RANKL and VITD may be associated with the effects of anti-TNF treatment on QCT BMD changes. RA and AS may differ in this respect.

Cardiovascular (CV) disease and osteoporosis (OP) have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Bone and vascular biomarkers and parameters along with the effect of 1-year anti-TNF therapy on these markers were assessed in order to determine correlations between vascular pathophysiology and bone metabolism in RA and AS. Thirty-six patients treated with etanercept or certolizumab pegol and 17 AS patients treated with ETN were included in a 12-month follow-up study. Bone and vascular markers were previously assessed by ELISA. Bone density was measured by DXA and quantitative CT (QCT). Flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) were assessed by ultrasound. Multiple correlation analyses indicated associations between bone and vascular markers. Osteoprotegerin, sclerostin and cathepsin K were significantly associated with FMD, IMT and PWV, respectively (p < 0.05). Moreover, total and trabecular BMD determined by QCT inversely correlated with IMT (p < 0.05). On the other hand, among vascular parameters, platelet-derived growth factor BB and IMT correlated with DXA femoral and QCT total BMD, respectively (p < 0.05). In the RM-ANOVA analysis, anti-TNF treatment together with baseline osteocalcin, procollagen 1 N-terminal propeptide (P1NP) or vitamin D3 levels determined one-year changes in IMT (p < 0.05). In the MANOVA analysis, baseline disease activity indices (DAS28, BASDAI), the one-year changes in these indices, as well as CRP exerted effects on multiple correlations between bone and vascular markers (p < 0.05). As the pattern of interactions between bone and vascular biomarkers differed between baseline and after 12 months, anti-TNF therapy influenced these associations. We found a great number of correlations in our RA and AS patients undergoing anti-TNF therapy. Some of the bone markers have been associated with vascular pathophysiology, while some vascular markers correlated with bone status. In arthritis, systemic inflammation and disease activity may drive both vascular and bone disease.

Introduction: Tumour-associated antigens (TAA) have been implicated in cell adhesion and cancer metastasis formation, but also in inflammatory processes, such as rheumatoid arthritis (RA). There has been little information about the possible associations of TAAs with RA-related clinical and laboratory parameters, with impaired vascular pathophysiology in RA, as well as about the effects of antirheumatic drugs on TAA production. Therefore, we determined the effects of one-year tofacitinib treatment on TAA levels, as well as correlations of TAA levels with various RA-associated and vascular parameters. Patients and methods: Altogether, 26 RA patients received 5 mg bid or 10 mg bid tofacitinib treatment for 12 months. Ultrasound-based functional vascular assessments, such as common carotid intima-media thickness (ccIMT), brachial artery flow-mediated vasodilation (FMD) and carotid-femoral pulse-wave velocity (cfPWV), were determined at various timepoints. Serum concentrations of TAAs, including carcinoembryonic antigen (CEA), CA15-3, CA19-9, CA125, CA72-4, human epididymis protein 4 (HE4) and tissue polypeptide antigen (TPA), as well as various cytokines (TNF-α, IL-6, IL-8, VEGF) and PECAM-1 were determined by flow cytometry using a bead-based multiplex assay (LEGENDplex). Results: As previously determined and published, one-year tofacitinib treatment effectively suppressed disease activity and inflammation. Serum CA15-3 and HE4 levels significantly decreased both after 6 and 12 months compared to baseline (p < 0.05). CA19-9 levels significantly increased both after 6 and 12 months, while CEA levels transiently increased after 6 months versus baseline (p < 0.05). CA125, CA72-4 and TPA levels did not change over time. In various regression analyses, TAA levels showed variable, significant, positive associations with the 28-joint disease activity score (DAS28), CRP, ESR, RF, IL-6, TNF-α, IL-8 and PECAM-1 (p < 0.05). In addition, TAAs variably correlated with ccIMT and cfPWV (p < 0.05). Moreover, one-year changes in TAA levels variably correlated with DAS28, RF and some cytokines (p < 0.05), as well as with changes in DAS28, HAQ, CRP, ESR, IL-6, VEGF and ccIMT from baseline to 12 months (p < 0.05). Conclusions: JAK inhibition might decrease the levels of some TAAs and increase those of others. TAA levels might be associated with RA-related and vascular biomarkers. These results suggest that TAAs might play a role in inflammatory processes and vascular pathology underlying RA.

IntroductionRheumatoid arthritis (RA) has been associated with changes in lipid, arginine and NO metabolism with increased cardiovascular (CV) risk. The aim of this study is to evaluate the effect of tofacitinib, a Janus kinase (JAK) inhibitor, on arginine and methionine metabolism in correlation with inflammation, functional and pathological vascular changes during one-year treatment of patients with RA.Materials and methodsThirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound at baseline and after 6 and 12 months. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels at these time points.ResultsTwenty-six patients (13 on each arm) completed the study. CRP, ESR and DAS28 decreased significantly during one-year treatment with tofacitinib. Arginine and ADMA showed a negative univariate correlation with CRP but not with FMD, PWV or IMT. Tofacitinib at 10 mg bid significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. ADMA and SDMA levels did not change in our study. Methionine showed negative correlation with FMD at baseline and positive correlation with PWV after 12 months. No change was observed in FMD and PWV but a significant increase was measured in IMT at 6 and 12 months. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with anti-CCP after one-year treatment. With respect to vascular pathophysiology, only PWV and methionine correlated with each other.ConclusionOne-year tofacitinib treatment suppressed systemic inflammation and improved functional status in RA. FMD, PWV have not been affected by one-year tofacitinib treatment., while IMT increased further despite treatment. Increased arginine and methionine might contribute to the anti-inflammatory effects of tofacitinib. Increased arginine availability with no changing ADMA may protect FMD and PWV from deterioration. The increase of IMT in the anti-inflammatory environment cannot be explained by arginine or methionine metabolism in this study.