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Objectives: Inflammatory rheumatic and musculoskeletal diseases (iRMDs) are associated with increased systemic bone loss that is mediated by chronic inflammation, treatment with glucocorticoids (GCs) and other factors. Our objective was to analyse the impact of variables that influence osteoporosis (OP) in patients with iRMD treated with GC.Methods: Rh-GIOP (acronyme) is a prospective observational cohort study investigating bone health in consecutive patients with iRMD and current or prior GC treatment. We present an analysis of the patients' baseline data here. Bone mineral density (BMD) measured by dual X-ray absorptiometry was the primary outcome. Multivariable linear regression models were performed to identify variables associated with BMD.Results: Data from 1066 patients with iRMD were analysed. GC doses of <5 mg prednisone equivalent per day, cumulative dose and duration of GC therapy were not associated with negative effects on BMD. Dosages of ≥5 mg/day lost their negative association with BMD after adjustment for confounders. When subanalysing patients with exactly 5 mg/day, no negative effect was seen. For patients with rheumatoid arthritis (RA), GC doses of >7.5 mg/day showed a negative association with BMD overall, but this effect seemed to be specific only to patients with moderate or high disease activity (Disease Activity Score 28-C reactive protein >3.2).Conclusions: GCs of ≤5 mg/day did not seem to be associated with a reduction of BMD in patients with iRMD and current or prior exposure to GC. This is most likely due to the dampening of inflammation by GC, which exerts a mitigating effect on the risk of OP. In RA, current GC doses of >7.5 mg/day were negatively associated with BMD, but only in patients with moderate to high disease activity.Trial Registration Number: NCT02719314. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc).Methods: 601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5-4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed.Results: During 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05).Conclusions: The present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA. [ABSTRACT FROM AUTHOR]

Objectives To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. Methods Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. Results 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; -24.0±5.2% vs -7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs -7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. Conclusions The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc. [ABSTRACT FROM AUTHOR]

Objective To estimate the changes in direct and indirect costs induced by patients with rheumatoid arthritis (RA) in German rheumatology, between 2002 and 2011. To examine the impact of functional status on various cost domains. To compare the direct costs incurred by patients at working age (18-64 years) to patients at an age of retirement (≥65 years). Methods We analysed data from the National Database of the German Collaborative Arthritis Centres with about 3400 patients each year. Costs were calculated using fixed prices as well as annually updated cost factors. Indirect costs were calculated using the human capital as well as the friction cost approaches. Results There was a considerable increase in direct costs: from €4914 to €8206 in patients aged 18-64, and from €4100 to €6221 in those aged ≥65, attributable to increasing prescription of biologic agents (18-64 years from 5.6% to 31.2%, ≥65 years from 2.8% to 19.2%). This was accompanied by decreasing inpatient treatment expenses and indirect costs due to sick leave and work disability. The total growth of cost, on average, was €2437-2981 for patients at working age, and €2121 for patients at retirement age. Conclusions The increase in treatment costs for RA over the last decade was associated with lower hospitalisation rates, better functional status and a lower incidence of work disability, offsetting a large proportion of risen drug costs. Since the rise in drug costs has manifested a plateau from 2009 onwards, no relevant further increase in total costs for patients with RA treated in German rheumatology is expected. [ABSTRACT FROM AUTHOR]

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology--a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-- conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field. [ABSTRACT FROM AUTHOR]

Objective To establish an expert consensus on which criteria are the most appropriate in clinical practice to refer patients with systemic sclerosis (SSc) for right heart catheterisation (RHC) when pulmonary hypertension (PH) is suspected. Methods A three stage internet based Delphi consensus exercise involving worldwide PH experts was designed. In the first stage, a comprehensive list of domains and items combining evidence based indications and expert opinions were obtained. In the second and third stages, experts were asked to rate each item selected in the list. After each of stages 2 and 3, the number of items and criteria were reduced according to a cluster analysis. Results A literature search and the opinions of 47 experts participating in Delphi stage 1 provided a list of seven domains containing 142 criteria. After stages 2 and 3, these domains and tools were reduced to three domains containing eight tools: clinical ( progressive dyspnoea over the past 3 months, unexplained dyspnoea, worsening of WHO dyspnoea functional class, any finding on physical examination suggestive of elevated right heart pressures and any sign of right heart failure), echocardiography (systolic pulmonary artery pressure >45 mm Hg and right ventricle dilation) and pulmonary function tests (diffusion lung capacity for carbon monoxide <50% without pulmonary fibrosis). Conclusions Among experts in pulmonary arterial hypertension-SSc, a core set of criteria for clinical practice to refer SSc patients for RHC has been defined by Delphi consensus methods. Although these indications are recommended by this expert group to be used as an interim tool, it will be necessary to formally validate the present tools in further studies. [ABSTRACT FROM AUTHOR]

Objective To compare the performance of the preliminary American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria with the 28-joint count Disease Activity Score (DAS28) remission in unselected 'real-life' patients. Methods Remission was calculated according to the DAS28 and to both versions of the ACR/EULAR criteria (Boolean or Simplified Disease Activity Index (SDAI)- based) for 6864 patients with rheumatoid arthritis (RA) who were enrolled in the national database of the German Collaborative Arthritis Centres between 2007 and 2009. Logistic regression analyses identified factors that were responsible for patients in DAS28 remission to miss the new criteria. In addition, the functional status of patients who fulfilled the different remission criteria was compared with that of an age- and sex-matched population sample. Results Of all patients, 28% were in DAS28, 7% in Boolean and 11% in SDAI remission. Of those in DAS28 remission, 21.0% were also in Boolean and 34% also in SDAI remission. Higher scores for pain and fatigue, the presence of degenerative spine disease, longer disease duration and male gender were significantly associated with missing the new criteria despite being in DAS28 remission. Compared with age- and sex-matched samples from the general population, patients in DAS28 remission had a similar functional ability while patients in remission according to the new criteria had better functional scores. Conclusions Patients fulfilling the new remission criteria tend to be not only free from active RA, but also from other disabling diseases. If these criteria are applied in clinical practice to guide treatment decisions, the impact of comorbidity should be taken into account. [ABSTRACT FROM AUTHOR]

Objective Autoreactive CD4 T cells specific for nuclear peptide antigens play an important role in tolerance breakdown during the course of systemic lupus erythematosus (SLE). However, reliable detection of these cells is limited due to their low frequency in peripheral blood. The authors assess autoreactive CD4 T cells in a representative SLE collective (n=38) by flow cytometry and study the influence of regulatory T cells (Treg) on their antigenic challenge. Methods CD4 T-cell responses were determined according to intracellular CD154 expression induced after 6-h short-term in-vitro stimulation with the SLEassociated autoantigen SmD1(83-119). To clarify the infl uence of Treg on the activation of autoreactive CD4 T cells, CD25 Treg were depleted by magnetic activated cell sorting before antigen-specific stimulation in selected experiments. Results In the presence of Treg, autoreactive CD4 T-cell responses to SmD1(83-119) were hardly observable. However, Treg removal significantly increased the frequency of detectable SmD1(83-119)-specific CD4 T cells in SLE patients but not in healthy individuals. Consequently, by depleting Treg the percentage of SmD1(83-119)-reactive SLE patients increased from 18.2% to 63.6%. This unmasked autoreactivity of CD4 T cells correlated with the disease activity as determined by the SLE disease activity index (p=0.005*, r=0.779). Conclusions These data highlight the pivotal role of the balance between autoreactive CD4 T cells and CD25 Treg in the dynamic course of human SLE. Analysing CD154 expression in combination with a depletion of CD25 Treg, as shown here, may be of further use in approaching autoantigen-specific CD4 T cells in SLE and other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Objective Vascular disease is common in mixed connective tissue disease (MCTD). The aim of the present study was to investigate, whether dysbalance of angiogenic and angiostatic factors occurs in MCTD. Methods In all, 38 patients with MCTD, and 40 patients with systemic sclerosis (SSc) for comparison, were included. Four centres contributed to this cross-sectional analysis. A total of 66 healthy volunteers were used as controls. The serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endostatin were determined by ELISA. For comparisons between controls and patients with MCTD and detection of associations of serum levels with dichotomous clinical parameters in patients with MCTD the Mann-Whitney test was used. Results Serum levels of the angiogenic factor VEGF were significantly elevated in patients with MCTD and SSc. Significantly increased levels of the angiostatic factor endostatin were also detected in MCTD, but not in SSc. No differences were observed for bFGF. Levels of VEGF were higher in patients with MCTD with pulmonary arterial hypertension (PAH), acrosclerosis and myositis. In multivariate linear regression analysis, an additive model of PAH, myositis and lymphadenopathy accounted for 79% of the variability of the VEGF levels (r=0.889). Conclusions Molecular factors modulating angiogenic responses are dysregulated in patients with MCTD and SSc with increases of VEGF in MCTD and SSc and selective upregulation of endostatin in MCTD. Furthermore, high serum levels of VEGF might characterise patients with MCTD with a more severe course of the disease with increased prevalence of PAH and myositis. [ABSTRACT FROM AUTHOR]

Background New strategies and options for the treatment of rheumatoid arthritis (RA) have evolved during the past decade. A study was undertaken to investigate to what extent this influenced daily rheumatological care and how this translates into clinical and patient-reported outcomes. Methods Data from a total of 38 723 outpatients with RA enrolled in the National Database of the German Collaborative Arthritis Centres in the years 1997–2007 were analysed. The cross-sectional annual data were compared to detect time trends. Results Between 1997 and 2007 the prescription of combinations of traditional disease-modifying antirheumatic drugs (DMARDs) increased from 8% of all patients to 23%; biological agents were prescribed to 16% of patients with RA in 2007. The mean disease activity (DAS28) fell from 4.5 to 3.4 (median 4.5–3.2). The percentage of patients with low disease activity (DAS28 <3.2) increased significantly from 23% to 49%. The proportion of patients with ≥6 swollen joints fell from 43.1% in 1997 to 8.1% in 2007 and, in those with ≥6 tender joints, from 46.3% to 15.8%. There was a large decrease in the total annual number of days of sick leave due to the rheumatic condition from 27.2 to 8.8 days per gainfully employed person. This reduction is far beyond the decline in the general population. There was also a tendency to higher participation in the work force, specifically in older patients, reflecting the trend seen in the general population. Conclusions The intensity of drug treatment in patients with RA has increased during the past 7 years. This has been accompanied by not only a decrease in disease activity but also a considerable reduction of economic losses due to sick leave and permanent work disability. [ABSTRACT FROM PUBLISHER]