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Objectives To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Methods We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomized into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day and IVMP 1.0 g/day. The primary outcome was all-cause mortality, and the secondary outcomes were composite all-cause mortality and kidney failure, severe relapse and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine–Gray subdistribution hazard model were used. Results In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively. Conclusion IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA. [ABSTRACT FROM AUTHOR]

Objectives SLE is a systemic autoimmune disease characterized by heterogeneous manifestations and severity, with frequent lung involvement. Among pulmonary function tests, the measure of the diffusing capacity of the lungs for carbon monoxide (DLCO) is a noninvasive and sensitive tool assessing pulmonary microcirculation. Asymptomatic and isolated DLCO alteration has frequently been reported in SLE, but its clinical relevance has not been established. Methods This retrospective study focused on 232 SLE patients fulfilling the 2019 EULAR/ACR classification criteria for SLE. Data were collected from the patient's medical record, including demographic, clinical and immunological characteristics, while DLCO was measured when performing pulmonary function tests as part of routine patient follow-up. Results At the end of follow-up, DLCO alteration (<70% of predicted value) was measured at least once in 154 patients (66.4%), and was associated with a history of smoking as well as interstitial lung disease, but was also associated with renal and neurological involvement. History of smoking, detection of anti-nucleosome autoantibodies and clinical lymphadenopathy at diagnosis were independent predictors of DLCO alteration, while early cutaneous involvement with photosensitivity was a protective factor. DLCO alteration, at baseline or any time during follow-up, was predictive of admission in intensive care unit and/or of all-cause death, both mainly due to severe disease flares and premature cardiovascular complications. Conclusion This study suggests a link between DLCO alteration and disease damage, potentially related to SLE vasculopathy, and a prognostic value of DLCO on death or intensive care unit admission in SLE. [ABSTRACT FROM AUTHOR]

Objective This study aimed to establish prediction models for respiratory-related mortality in microscopic polyangiitis (MPA) complicated by interstitial lung disease (ILD) using clinical characteristics. Methods We enrolled patients with MPA with ILD between May 2005 and June 2021 in a multicentre cohort of Japanese patients with MPA (REVEAL cohort). We evaluated the demographic, clinical, laboratory, radiological findings, treatments and the presence of honeycombing 1 cm above the diaphragm using chest high-resolution CT (HRCT) on admission. We explored the risk factors predictive of respiratory-related mortality. Results Of 115 patients, 26 cases died of respiratory-related diseases during a median follow-up of 3.8 years. Eighteen patients (69%) died due to respiratory infection, three (12%) had diffuse alveolar haemorrhage, and five (19%) had exacerbation of ILD. In univariate analysis, older age, lower percent forced vital capacity (%FVC), lower percent diffusing capacity of carbon monoxide (%DLCO), and the presence of honeycombing in the right lower lobe were identified as risk factors. Additionally, in multivariate analysis adjusted for age and treatment, %FVC, %DLCO and the presence of honeycombing in the right lower lobe were independently associated with respiratory-related mortality. We created prediction models based on the values of %FVC, %DLCO and presence of honeycombing on chest HRCT (termed "MPF model"). The 5-year respiratory-related death-free rate was significantly different between patients with MPA with ILD stratified by the number of risk factors based on the MPF model. Conclusions Our study indicates that the MPF model may help predict respiratory-related death in patients with MPA with ILD. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the long-term impact of immunosuppressive therapeutic agents on antibody response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with autoimmune rheumatic diseases (AIRD) in order to propose a strategy for annual vaccination. Methods This prospective multicentre cohort study evaluated the humoral response to second and third BNT162b2 and/or mRNA-1273 vaccines in 382 Japanese AIRD patients classified into 12 different medication groups and in 326 healthy controls (HCs). The third vaccination was administered six months after the second vaccination. Antibody titres were measured using the Elecsys Anti-SARS-CoV-2 S assay. Results The seroconversion rate and antibody titres were lower in AIRD patients than in HCs 3–6 weeks after the second vaccination and 3–6 weeks after the third vaccination. Seroconversion rates were <90% after the third vaccination in patients receiving mycophenolate mofetil and rituximab. Antibody levels after the third vaccination were significantly lower in the groups prescribed TNF inhibitor with or without methotrexate, abatacept and rituximab or cyclophosphamide than those of HCs in a multivariate analysis adjusting for age, sex, and glucocorticoid dosage. The third vaccination induced an adequate humoral response in patients treated with sulfasalazine, bucillamine, methotrexate monotherapy, iguratimod, interleukin-6 inhibitors or calcineurin inhibitors including tacrolimus. Conclusions Repeated vaccinations in many immunosuppressed patients produced antibody responses similar to those observed in HCs. In contrast, annual vaccination in patients receiving TNF inhibitors, abatacept, mycophenolate mofetil and rituximab may require caution. [ABSTRACT FROM AUTHOR]

Objectives To determine the effect of antimalarial agents (AMA) and different doses and pharmaceutical forms of belimumab on preventing renal flares in patients with SLE treated for extra-renal disease. Methods We pooled data from the BLISS-52, BLISS-76, BLISS-SC and BLISS-Northeast Asia trials of belimumab (n  = 3225), that included patients with active SLE yet no severe ongoing nephritis. Participants were allocated to receive intravenous belimumab 1 mg/kg, intravenous belimumab 10 mg/kg, subcutaneous belimumab 200 mg, or placebo in addition to standard therapy. We estimated hazards of renal flare development throughout the study follow-up (52–76 weeks) using Cox regression analysis. Results In total, 192 patients developed a renal flare after a median of 197 days. Compared with placebo, the risk of renal flares was lower among patients receiving intravenous belimumab 10 mg/kg (HR: 0.62; 95% CI: 0.41, 0.92; P  = 0.018) and intravenous belimumab 1 mg/kg (HR: 0.42; 95% CI: 0.22, 0.79; P  = 0.007), while no significant association was found for subcutaneous belimumab 200 mg. AMA use yielded a lower hazard of renal flares (HR: 0.66; 95% CI: 0.55, 0.78; P  < 0.001). The protection conferred was enhanced when belimumab and AMA were co-administered; the lowest flare rate was observed for the combination intravenous belimumab 1 mg/kg and AMA (18.5 cases per 1000 person-years). Conclusions The protection conferred from belimumab against renal flare development in patients treated for extra-renal SLE appears enhanced when belimumab was administered along with AMA. The prominent effect of low-dose belimumab warrants investigation of the efficacy of intermediate belimumab doses. Clinical trial identification BLISS-52: NCT00424476; BLISS-76: NCT00410384; BLISS-SC: NCT01484496; BLISS-NEA: NCT01345253. [ABSTRACT FROM AUTHOR]

Objectives Active RA has been associated with an increased risk of both cardiovascular and peripheral vascular disease. We aimed to compare cerebrovascular changes in patients with and without RA, both with and without a neuropathologic diagnosis of neurodegenerative disease. Methods Patients with RA (n  = 32) who died and underwent autopsy between 1994 and 2021 were matched to non-RA controls (n  = 32) on age, sex and level of neurodegenerative proteinopathy. Routine neuropathologic examination was performed at the time of autopsy. Cerebrovascular disease severity was evaluated using modified Kalaria and Strozyk scales. Clinical dementia diagnoses were manually collected from patients' medical records. Results Prior to death, 15 (47%) RA patients and 14 (44%) controls were diagnosed with dementia; 9 patients in each group (60% and 64%, respectively) had Alzheimer's disease. The prevalence of cerebral amyloid angiopathy, microinfarcts, infarcts or strokes was found to be similar between groups. Patients with RA were more likely to have more severe vascular changes in the basal ganglia by Kalaria scale (P  = 0.04), but not in other brain areas. There were no significant differences in the presence of large infarcts, lacunar infarcts or leukoencephalopathy by Strozyk scale. Among patients with RA and no clinical diagnosis of dementia, the majority had mild–moderate cerebrovascular abnormalities, and a subset of patients had Alzheimer's disease neuropathologic changes. Conclusion In this small series of autopsies, patients with and without RA had largely similar cerebrovascular pathology when controlling for neurodegenerative proteinopathies, although patients with RA exhibited more pronounced cerebrovascular disease in the basal ganglia. [ABSTRACT FROM AUTHOR]

The article presents a study which analysed predictors in a global sample of patients with idiopathic inflammatory myopathies (IIMs) using data from the second COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. Topics include patients included in the study, patient-reported flares following COVID-19 infection among IIM patients, and factors that were found to significantly increase the risk of flares in univariate analysis.

Objectives To describe the clinical and pathological features of biopsy-proven cutaneous vasculitis (CV) associated with SLE, focusing on diagnosis classification and impact on overall SLE activity. Methods Retrospective multicentric cohort study including SLE patients with biopsy-proven CV identified by (i) data from pathology departments of three university hospitals and (ii) a national call for cases. SLE was defined according to 1997 revised ACR and/or 2019 ACR/EULAR criteria. CV diagnosis was confirmed histologically and classified by using the dermatological addendum of the Chapel Hill classification. SLE activity and flare severity at the time of CV diagnosis were assessed independently of vasculitis items with the SELENA-SLEDAI and SELENA-SLEDAI Flare Index. Results Overall, 39 patients were included; 35 (90%) were female. Cutaneous manifestations included mostly palpable purpura (n  = 21; 54%) and urticarial lesions (n  = 18; 46%); lower limbs were the most common location (n  = 33; 85%). Eleven (28%) patients exhibited extracutaneous vasculitis. A higher prevalence of Sjögren's syndrome (51%) was found compared with SLE patients without CV from the French referral centre group (12%, P  < 0.0001) and the Swiss SLE Cohort (11%, P  < 0.0001). CV was mostly classified as urticarial vasculitis (n  = 14, 36%) and cryoglobulinaemia (n  = 13, 33%). Only 2 (5%) patients had no other cause than SLE to explain the CV. Sixty-one percent of patients had inactive SLE. Conclusion SLE-related vasculitis seems very rare and other causes of vasculitis should be ruled out before considering this diagnosis. Moreover, in more than half of patients, CV was not associated with another sign of active SLE. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to (i) investigate actual work participation in Belgian spondyloarthritis (SpA) patients compared with the general population, and (ii) identify determinants of work-related outcomes. Material and methods Adult SpA patients from the Ghent University Hospital based Be-GIANT cohort (fulfilling ASAS classification criteria) were cross-sectionally questioned on their socio-economic status and completed a Work Productivity and Activity Impairment questionnaire (May 2018 to May 2019). Results were compared with national and regional data on the general population using indirect standardization. Associations between clinical and job characteristics and work-related outcomes were analysed with logistic regression (having a paid job) and negative binomial hurdle models (sick leave and presenteeism, i.e. restrictions while at work). Results A total of 215/262 (82%) patients of working age (<65 y/o) had a paid job, corresponding to an age- and sex-adjusted employment ratio of 1.00 (95% CI 0.88, 1.14). Patients worked 39.6h (10.5h)/week, and 49% (95% CI 42, 56%) reported sick leave in the previous year, similar to the general population (39.7h/week, 42%). In total, 56% reported presenteeism of median (IQR) 10% (0–20%). In multivariate analysis, functional impairment (BASFI) and health-related quality of life (HRQoL, EuroQoL-VAS) were associated with each work-related outcome, while contextual factors (education, physically demanding job) were positively associated with, respectively, having a paid job and presenteeism. Clinical characteristics showed no independent association with any of these outcomes. Conclusions Evidence from this academic cohort study does not support a work participation gap between SpA patients and the general population, but confirms the role of physical function, overall HRQoL, and education or job type as risk factors for adverse work outcomes. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to evaluate the efficacy and safety of MMF in juvenile idiopathic inflammatory myopathies (JIIMs). Methods Patients diagnosed with JIIM and treated with MMF enrolled in the Juvenile Dermatomyositis Research Group (JDRG) in the UK or followed at the Giannina Gaslini Institute in Genoa, Italy, were included. The following information was collected retrospectively at MMF initiation, at 3, 6 and 12 months after treatment start, and at last follow-up visit: clinical manifestations, laboratory data, physicians' subjective assessment of disease activity, standardized outcome measures of muscle strength/endurance, cutaneous disease activity, physical function, global disease activity, cumulative damage, and ongoing treatment. Results Of the 29 patients included, 23 had juvenile DM and 6 had overlap myositis. During administration of MMF, improvement in measures of muscle strength, skin disease activity, and overall disease activity was seen, with an increase in the frequency of normal scores for Manual Muscle Test-8 from 50.0% to 83.3%, Childhood Myositis Activity Score from 53.5% to 88.9%, muscle component of DAS from 55.2% to 84.2%, skin component of DAS from 31.0% to 42.1%, visual analogue scale for skin disease activity from 25.0% to 47.4%, and visual analogue scale for overall disease activity from 7.1% to 42.1%. The number of patients with inactive disease increased from 10.3% at baseline to 68.5% at last follow-up. CS dose was significantly reduced, from 0.3 to 0.1 mg/kg/day. No relevant side effects were reported. Conclusion Our experience suggests that MMF is a valuable therapeutic option for the management of JIIM. [ABSTRACT FROM AUTHOR]

Objectives Treatments for SSc-associated interstitial lung disease (SSc-ILD) differ in attributes, i.e. mode of administration, adverse events (AEs) and efficacy. As physicians and patients may perceive treatments differently, shared decision-making can be essential for optimal treatment provision. We therefore aimed to quantify patient preferences for different treatment attributes. Methods Seven SSc-ILD attributes were identified from mixed-methods research and clinician input: mode of administration, shortness of breath, skin tightness, cough, tiredness, risk of gastrointestinal AEs (GI-AEs) and risk of serious and non-serious infections. Patients with SSc-ILD completed an online discrete choice experiment (DCE) in which they were asked to repeatedly choose between two alternatives characterized by varying severity levels of the included attributes. The data were analysed using a multinomial logit model; relative attribute importance and maximum acceptable risk measures were calculated. Results Overall, 231 patients with SSc-ILD completed the DCE. Patients preferred twice-daily oral treatments and 6–12 monthly infusions. Patients' choices were mostly influenced by the risk of GI-AEs or infections. Improvement was more important in respiratory symptoms than in skin tightness. Concerning trade-offs, patients accepted different levels of increase in GI-AE risk: +21% if it reduced the infusions' frequency; +15% if changing to an oral treatment; up to +37% if it improved breathlessness; and up to +36% if it reduced the risk of infections. Conclusions This is the first study to quantitatively elicit patients' preferences for treatment attributes in SSc-ILD. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in clinical practice. [ABSTRACT FROM AUTHOR]

Objective BILAG-2004 index is a comprehensive disease activity instrument for SLE but administrative burden and potential frequency of errors limits its use in routine practice. We aimed to develop a tool for more accurate, time-efficient scoring of BILAG-2004 index with full fidelity to the existing instrument. Methods Frequency of BILAG-2004 items was collated from a BILAG-biologics registry (BILAG-BR) dataset. Easy-BILAG prototypes were developed to address known issues affecting speed and accuracy. After expert verification, accuracy and usability of the finalized Easy-BILAG was validated against standard format BILAG-2004 in a workbook exercise of 10 case vignettes. Thirty-three professionals ranging in expertise from 14 UK centres completed the validation exercise. Results Easy-BILAG incorporates all items present in ≥5% BILAG-BR records, plus full constitutional and renal domains into a rapid single page assessment. An embedded glossary and colour-coding assists domain scoring. A second page captures rarer manifestations when needed. In the validation exercise, Easy-BILAG yielded higher median scoring accuracy (96.7%) than standard BILAG-2004 documentation (87.8%, P = 0.001), with better inter-rater agreement. Easy-BILAG was completed faster (59.5 min) than the standard format (80.0 min, P = 0.04) for 10 cases. An advantage in accuracy was observed with Easy-BILAG use among general hospital rheumatologists (91.3 vs 75.0, P = 0.02), leading to equivalent accuracy as tertiary centre rheumatologists. Clinicians rated Easy-BILAG as intuitive, convenient, and well adapted for routine practice. Conclusion Easy-BILAG facilitates more rapid and accurate scoring of BILAG-2004 across all clinical settings, which could improve patient care and biologics prescribing. Easy-BILAG should be adopted wherever BILAG-2004 assessment is required. [ABSTRACT FROM AUTHOR]

Objectives To demonstrate the significance of the time to attain lupus low disease activity state (LLDAS) after remission induction therapy in patients with severely active SLE. Methods We enrolled 79 patients starting prednisolone ≥0.4 mg/kg/day for active lupus with a BILAG 2004 index of A ≥ 1 or B ≥ 2, or for severe flare based on the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI). The time to LLDAS attainment was divided into ≤6, 6–12 and >12 months and non-LLDAS; associations between the timing of LLDAS and flares, damage accrual and ≥50% LLDAS attainment were examined. Results The mean SLEDAI was 17; median starting dose of prednisolone, 0.95 mg/kg/day; and mean observational period, 39.7 months. Six (7.6%) and 41 (51.9%) patients achieved LLDAS within 6 and 12 months. Patients with a shorter time to LLDAS achievement were more likely to spend ≥50% of the time in LLDAS and had a lower cumulative prednisolone dose; no differences were observed in damage accrual. Patients requiring longer than 12 months to achieve LLDAS had a higher prevalence of thrombocytopenia and those with non-LLDAS had lower renal function and a higher starting dose of prednisolone and steroid pulse therapy than those who achieved LLDAS within 12 months. Conclusion Achieving LLDAS within 12 months of induction therapy may be favourable in patients with severely active SLE. The low frequency of LLDAS attainment in high-risk populations highlights the need for a new strategy for SLE treatment. [ABSTRACT FROM AUTHOR]

Objective Idiopathic inflammatory myositis-associated interstitial lung disease (IIM-ILD) significantly increases morbidity and mortality. Lung ultrasound B-lines and Krebs von den Lungen-6 (KL-6) are identified as new sonographic and serum markers of ILD, respectively. The aim of our work was to assess the role of B-lines and KL-6 as markers of the severity of IIM-ILD. For this purpose, the correlation among B-lines score, serum KL-6 levels, high-resolution CT (HRCT) score, and pulmonary function tests were investigated in IIM-ILD patients. Methods Thirty-eight patients with IIM-ILD underwent chest HRCT scans, lung ultrasound and pulmonary function tests (independently performed within 1 week) examination. To assess severity and extent of ILD at HRCT, the Warrick score was used. The B-lines score denoting the extension of ILD was calculated by summing the number of B-lines on a total of 50 scanning sites. Serum KL-6 levels (U/ml) was measured by chemiluminescent enzyme immunoassay. Results A significant correlation was found between the B-lines score and serum KL-6 levels (r  = 0.43, P  < 0.01), and between the Warrick score and serum KL-6 levels (r  = 0.45, P  < 0.01). A positive correlation between B-lines score and the Warrick score (r  = 0.87, P  < 0.0001) was also confirmed. Both B-lines score and KL-6 levels inversely correlated to diffusion capacity for carbon monoxide (r  = −0.77, P  < 0.0001 and r  = −0.42, P  < 0.05, respectively) and total lung capacity (r  = −0.73, P  < 0.0001 and r  = −0.36, P  < 0.05, respectively). Moreover, B-lines correlated inversely with forced vital capacity (r  = −0.73, P  < 0.0001), forced expiratory volume in 1 s (r  = −0.69, P  < 0.0001). Conclusion B-lines score and serum KL-6 levels correlate with HRCT findings and pulmonary function tests, supporting their use as measures of IIM-ILD severity. [ABSTRACT FROM AUTHOR]

Objectives PD-1+CXCR5−CD4+T peripheral helper (Tph) cells, a recently identified T cell subset, are proven to promote B cell responses and antibody production in rheumatoid arthritis, but their role in the pathogenesis of SLE is unknown. We explored the role of Tph in lupus disease development. Methods This cohort study included 68 patients with SLE and 41 age- and sex-matched healthy individuals. The frequency of PD-1+CXCR5−CD4+T cells was analysed in peripheral blood by flow cytometry. Inducible T-cell costimulator, CD38, MHC-II, IL-21, CXCR3 and CCR6 expression were measured in Tph cells. Comparisons between the two groups were performed, and correlations between Tph cells and other parameters were investigated. Results We revealed a markedly expanded population of Tph cells (8.31 ± 5.45 vs 2.86 ± 1.31%, P < 0.0001) in the circulation of patients with SLE (n = 68), compared with healthy controls (n = 41). Tph cells were much higher in the active group than in the inactive group (14.21 ± 5.21 vs 5.49 ± 2.52%, P < 0.0001). Tph cells were significantly associated with SLEDAI score (r = 0.802), ESR (r = 0.415), IgG (r = 0.434), C3 (r = −0.543), C4 (r = −0.518) and IL-21 level (r = 0.628), and ANA titre (r = 0.272). Furthermore, Tph cells were much higher in lupus patients with arthritis, nephritis, rash, alopecia, pleuritis, pericarditis and haematological involvement. Tph cells were associated with CD138+/CD19+ plasma cells (r = 0.518). Furthermore, MHC-II, inducible T-cell costimulator, CD38, and IL-21 expression were all higher in Tph cells from SLE patients compared with healthy controls. CXCR3+CCR6−Tph (Tph1) cells were expanded in the SLE patients. Conclusion Our data show that relative number of Tph cells is correlated with disease measures in patients with SLE, suggesting an important role in lupus disease development. [ABSTRACT FROM AUTHOR]

Objectives To validate enhanced liver fibrosis (ELF) test and its components—amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA—as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort. Methods Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software. Results Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = −0.21, P = 0.0012; PIIINP, r = −0.26, P = 0.0001), TLC% (ELF score, r = −0.20, P = 0.0036; TIMP-1, r = −0.32, P < 0.0001; PIIINP, r = −0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score. Conclusion Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression. [ABSTRACT FROM AUTHOR]

Objective. To investigate the frequency and risk factors of postoperative complications in RA patients treated with abatacept (ABA). Methods. The Orencia RA registry recruited 1012 patients receiving ABA for RA in routine care. Data from patients treated with ABA who underwent surgery were reviewed to describe the frequency of postoperative complications. Characteristics of patients and surgeries with and without complications were compared to identify factors associated with complications. Results. We identified 205 (20.3%) patients who underwent 263 surgeries, including 176 (66.9%) orthopaedic surgeries. Nineteen (7.2%) surgeries, in 19 patients (9.3%), entailed complications, including 7 delayed wound healing (2.7% of surgeries) and 6 surgical site infections (2.3% of surgeries). The median time between the last infusion of ABA and surgery was 5.9 weeks (range: 0.3-12.0 weeks), with no significant difference between patients with and without complications. The median corticosteroids daily dosage was higher in the group with complications [10.0 (6.25-15.0) vs 6.0 (5.0-10.0) mg/day, P = 0.042]. In multivariate analysis, only the duration of ABA treatment was significantly associated with postoperative complications [adjusted odds ratio (aOR) = 0.94 (95% CI: 0.89, 0.99) for each month of treatment], as were orthopaedic surgeries compared with other kinds of surgery [aOR = 4.45 (95% CI: 1.01, 20.2)]. Conclusion. In RA patients treated with ABA, the rate of surgical complications was low: 7.2% and higher in case of orthopaedic procedure and a more recent initiation of ABA. The median time between surgery and the last infusion of ABA was short and did not influence the rate of postoperative complications. [ABSTRACT FROM AUTHOR]

Objectives. The aim was to investigate the effects of nicotine on neutrophil extracellular traps (NETs) formation in current and non-smokers and on a murine model of RA. Methods. We compared spontaneous and phorbol 12-myristate 13-acetate-induced NETosis between current and non-smokers by DNA release binding. Nicotine-induced NETosis from non-smokers was assessed by DNA release binding, NET-specific (myeloperoxidase (MPO)-DNA complex) ELISA and realtime fluorescence microscopy. We also used immunofluorescent staining to detect nicotinic acetylcholine receptors (nAChRs) on neutrophils and performed a functional analysis to assess the role of nAChRs in nicotine-induced NETosis. Finally, we investigated the effects of systemic nicotine exposure on arthritis severity and NETosis in the CIA mouse model. Results. Neutrophils derived from current smokers displayed elevated levels of spontaneous and phorbol 12-myristate 13-acetate-induced NETosis. Nicotine induced dose-dependent NETosis in ex vivo neutrophils from healthy non-smokers, and co-incubation with ACPA-immune complexes or TNF-α facilitated a synergistic effect on NETosis. Real-time fluorescence microscopy revealed robust formation of NET-like structures in nicotine-exposed neutrophils. Immunofluorescent staining demonstrated the presence of the α7 subunit of the nAChR on neutrophils. Stimulation of neutrophils with an α7-specific nAChR agonist induced NETosis, whereas pretreatment with an nAChR antagonist attenuated nicotine-induced NETosis. Nicotine administration to mice with CIA exacerbated inflammatory arthritis, with higher plasma levels of NET-associated MPO-DNA complex. Conclusion. We demonstrate that nicotine is a potent inducer of NETosis, which may play an important role in accelerating arthritis in the CIA model. This study generates awareness of and the mechanisms by which nicotine-containing products, including e-cigarettes, may have deleterious effects on patients with RA. [ABSTRACT FROM AUTHOR]

Objectives. The aim was to establish the prevalence and severity of faecal incontinence (FI) in SSc, its association with other intestinal manifestations and potential predictors of FI, and its impact on quality of life. Methods. A multicentre, cross-sectional study of 298 SSc subjects followed in the Canadian Scleroderma Research Group cohort was performed using validated questionnaires: Jorge-Wexner score (an FI severity scale), Bristol stool scale (a visual scale of stool consistency) and FI Quality-of-Life scale. Constipation was defined by the Rome III criteria. Associations between the Jorge-Wexner score and other clinical variables were determined using multivariate regression analyses. Results. Eighty-one (27.2%) subjects had FI, which was mild in 37 (12.4%) and moderate to severe in 44 (14.8%). Most patients had well-formed stools, 111 (38.8%) reported constipation and 38 (13.4%) had been previously treated for small intestinal bacterial overgrowth (SIBO). Variables independently associated with FI were: loose vs well-formed stools [odds ratio (OR) = 7.01, 95% CI: 2.09, 23.51)], constipation (OR = 3.64, 95% CI: 1.61, 8.27, P = 0.002), history of SIBO (OR = 2.97, 95% CI: 1.06, 8.27) and urinary incontinence (OR = 2.45, 95% CI: 1.14, 5.27). Quality of life measured with the FI Quality-of- Life scale was inversely correlated with FI severity (correlation coefficients between -0.602 and -0.702, P < 0.001). Conclusion. FI was common and often severe in SSc. Loose stools, SIBO, constipation and urinary incontinence were strongly associated with FI. Other than targeting anorectal dysfunction, concomitant treatment of clinical correlates could lead to improvement in FI and quality of life in SSc. [ABSTRACT FROM AUTHOR]

Objective. Blindness is a recognized complication of GCA; however, the frequency of and risk factors for this complication have not been firmly established. The aim of this study was to examine the incidence and determinants of blindness in patients with GCA, using a large international cohort. Methods. The analysis was conducted among subjects recruited into the Diagnosis and Classification Criteria in Vasculitis Study. The study captures consecutive patients presenting to clinic-based physicians. New-onset blindness was assessed 6 months after diagnosis by completion of the Vasculitis Damage Index. Logistic regression analysis was used to assess the association between blindness and clinical variables. Results. Of 433 patients with GCA from 26 countries, 7.9% presented with blindness in at least one eye at 6 months. Risk factors identified at baseline for blindness at 6 months were identified and included prevalent stroke [odds ratio (OR) = 4.47, 95% CI: 1.30, 15.41] and peripheral vascular disease (OR = 10.44, 95% CI: 2.94, 37.03). Conclusion. This is the largest study to date of subjects with incident GCA and confirms that blindness remains a common complication of disease and is associated with established vascular disease. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01066208. [ABSTRACT FROM AUTHOR]

Objective. Skin fibrosis is the predominant feature of SSc and arises from excessive extracellular matrix deposition. Glycosaminoglycans are macromolecules of the extracellular matrix, which facilitate Na+accumulation in the skin. We used 23Na-MRI to quantify Na+in skin. We hypothesized that skin Na+ might accumulate in SSc and might be a biomarker for skin fibrosis. Methods. In this observational case-control study, skin Na+was determined by 23Na-MRI using a Na+volume coil in 12 patients with diffuse cutaneous SSc and in 21 control subjects. We assessed skin fibrosis by the modified Rodnan skin score prior to 23Na-MRI and on follow-up 12 months later. Results. 23Na-MRI demonstrated increased Na+ in the fibrotic skin of SSc patients compared with skin from controls [mean (S.D.): 27.2(5.6) vs 21.4(5.3) mmol/l, P < 0.01]. Na+content was higher in fibrotic than in non-fibrotic SSc skin [26.2(4.8) vs 19.2(3.4) mmol/l, P < 0.01]. Furthermore, skin Na+ amount was correlated with changes in follow-up modified Rodnan skin score (R²=0.68). Conclusions. 23Na-MRI detected increased Na+in the fibrotic SSc skin; high Na+ content was associated with progressive skin disease. Our findings provide the first evidence that 23Na-MRI might be a promising tool to assess skin Na+and thereby predict progression of skin fibrosis in SSc. [ABSTRACT FROM AUTHOR]

Objective. The aim was to explore the agreement between 1.0 T MRI and conventional radiography (CR) to detect progression of hand OA over 5 years and the associations between structural progression and incident joint tenderness. Methods. Paired radiographs and paired MRIs of the second-fifth IP joints of the dominant hand from 69 hand OA patients were read for osteophytes, joint space narrowing and erosions. Patients with two or more joints demonstrating progression of any structural feature(s) were classified as progressors per imaging modality. Agreement between methods to detect progressors was evaluated with κ and κintraclass correlation coefficients. At the joint level, the associations between methods to detect progression were explored with generalized estimating equations. Likewise, we analysed the associations between progression per imaging modality and incident pain. Results. MRI (58.0%) and CR (62.3%) detected similar numbers of progressors. The agreement between methods to detect progressors was good (κ = 0.61). We found good agreement between methods regarding the number of progressive joints (intraclass correlation coefficient = 0.61, 95% CI: 0.43, 0.76). At the joint level, MRI progression was associated with radiographic progression (P<0.001). Incident joint tenderness was more common in joints with progression by MRI and CR, but statistically significance was not reached. Conclusion. Both 1.0 T MRI and CR detect a similar amount of progression over 5 years in patients with hand OA, although not in exactly the same joints. As CR assesses more joints for a lower cost, CR should be the imaging modality of choice rather than 1.0 T MRI in observational studies with a long period of follow-up. [ABSTRACT FROM AUTHOR]

Objectives. To identify predictors of organ damage and specifically the relationship between prolonged disease remission or low disease activity and damage accrual in a longitudinal cohort of SLE patients. Methods. Data were prospectively assessed including the occurrence of minor/major flares. Once a year remission and Lupus Low Disease Activity State (LLDAS) were determined retrospectively. A prediction model for damage accrual during follow-up was constructed with backward logistic regression analyses. Secondly, odds ratios (ORs) for damage accrual (SLICC damage index increase of ≥ 1 during follow-up) were calculated for patients with or without prolonged remission during 5 years, and with or without LLDAS in ≥ 50% of observations. Results. Data from 183 patients with a median follow-up duration of 5.0 years were analysed. The most significant predictors for damage accrual were: occurrence of ≥ 1 major flare, mean daily prednisone dose during follow-up and nephrological manifestations at baseline. Prolonged remission was present in 32.5% (38/117) and LLDAS in ≥ 50% of observations in 64.5% (118/183) of patients. Both the presence of prolonged remission during 5 years and LLDAS in ≥ 50% of observations were associated with a reduced risk of damage accrual (OR = 0.20, 95% CI: 0.07, 0.53, P = 0.001 and OR = 0.52, 95% CI: 0.28, 0.99, P = 0.046, respectively). Conclusion. This cohort study shows that prolonged remission and LLDAS were associated with an improved outcome, as determined by yearly assessments. In order to improve the outcome in SLE patients, future studies should investigate whether these targets can be reached actively with therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective. Data on the relationship between disc degeneration (DD) and fragility fractures in men are limited. The aim of this study was to prospectively analyse the risk of vertebral and non-vertebral fractures in men with thoracolumbar DD according to the severity of its radiological signs: disc space narrowing (DSN), osteophytes and endplate sclerosis. Methods. Men >50 years of age (n = 765) had lateral spine radiographs and DXA and were monitored prospectively. We analysed the risk of incident vertebral (7.5 years) and non-vertebral fractures (10 years) in men according to the severity of DD. Results. After adjustment for age and weight, BMD increased with increasing total DSN score, endplate sclerosis and osteophytosis. Over 7.5 years, 28 incident vertebral fractures occurred in 27 men. After adjustment for age, BMI, spine BMD, prior fractures and abdominal aortic calcifications, the vertebral fracture risk was 3-fold higher in the upper DSN quartile vs men without DSN. After adjustment for the same confounders, vertebral fracture risk was also nearly 3-fold higher in the upper DSN quartile vs the three lower quartiles combined. Over 10 years, 61 men sustained non-vertebral fragility fractures. After adjustment for age, BMI, hip BMD, abdominal aortic calcifications and prior falls and fractures, the non-vertebral fracture risk decreased with increasing DSN score. The risk of non-vertebral fracture was half as high in men above the median total DSN score vs men below the median. Conclusion. In older men, severe DD is associated with higher BMD. Multilevel severe DSN is associated with higher vertebral fracture risk and lower non-vertebral fracture risk. [ABSTRACT FROM AUTHOR]

Objective. IL-18 is a pro-inflammatory cytokine of the IL-1 family that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of IL-18 have been described in the serum of adult-onset Still's disease (AOSD) patients, but only total IL-18 levels (including inactive IL-18 bound to IL-18BP) have been measured. With a specific immunoassay, we aimed to measure free IL-18 serum levels in AOSD patients and other rheumatic diseases. Methods. An ELISA was developed to measure free IL-18. Its sensitivity and specificity were tested by spiking recombinant IL-18 or IL-18BP in serum and PBS supplemented with 5% BSA. The binding affinity of IL-18 to IL-18BP was calculated by titration experiments using the ELISA and by Biacore analysis. Sera of 37 AOSD patients and 138 controls (40 healthy controls, 30 RA, 29 SLE, 21 AS and 18 PsA) were assayed for free IL-18, IL-18BP, total IL-18 and other cytokines. Correlations were performed between free IL-18 and markers of disease activity in AOSD patients. Results. Free IL-18 serum levels were significantly higher in AOSD patients (median 8.89pg/ml) than in healthy and disease controls (1.37pg/ml; P<0.01). Free IL-18 serum levels correlated with AOSD activity. The affinity of IL-18 to IL-18BP was found to be much higher than previously described, with a dissociation constant ranging from 30 to 50 pM. Conclusion. Free IL-18 levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD. [ABSTRACT FROM AUTHOR]

Objectives. Decreased phagocytosis of apoptotic cells plays an important role in the pathogenesis of SLE. This can lead to secondary necrosis and release of nuclear proteins, such as high mobility group box 1 (HMGB1). We hypothesized that increased HMGB1 levels, as present in SLE, skew macrophage differentiation towards M1-like phenotypes and thereby diminish uptake of apoptotic cells. The aim of this study was to investigate the effect of HMGB1 on macrophage polarization and on phagocytic capacity of differentiated macrophages. Methods. SLE patients with quiescent disease (SLEDAI ≼ 44) and healthy controls (HCs) were included. Monocytes and differentiated M1 and M2 macrophages were assessed for expression of M1 and M2 markers and for phagocytic capacity. HMGB1 was added during differentiation and during phagocytosis. Results. Expression of CD86 (M1) was not different, whereas CD163 (M2) was significantly lower on SLE monocytes. After differentiation, no differences regarding surface receptor expression and phagocytic capacity were observed between M1 and M2 macrophages from SLE patients and HCs. Addition of HMGB1 during M2 differentiation resulted in high IL-6 and TNF-α mRNA expression and reduced phagocytic capacity of apoptotic cells. Furthermore, adding HMGB1 to apoptotic Jurkat cells diminished phagocytosis of these cells. Conclusion. Circulating monocytes from SLE patients display an M1 -like phenotype compared with HCs, but in vitro differentiation abolishes this difference. HMGB1 skews differentiation of M2-like macrophages towards an M1-like phenotype and, subsequently, reduces phagocytosis of apoptotic cells. These data imply that the phenotype of monocytes or macrophages is determined by their environment, such as the presence of cytokines and HMGB1. [ABSTRACT FROM AUTHOR]

Objectives. To investigate the impact of obesity on response to the first TNF-α inhibitor (TNFI) treatment course in patients with PsA followed in routine care. Methods. We performed an observational cohort study based on the Danish and Icelandic biologics registries. Kaplan-Meier plots, Cox and logistic regression analyses were performed to study the impact of obesity (BMI ≽ 30kg/m²) on TNFI adherence and response after 6 months (according to 20/ 50/70% improvement in ACR criteria and EULAR criteria). Subanalyses studied the impact of obesity according to gender, TNFI type and nationality. Results. Among 1943 PsA patients (193 Icelandic/1750 Danish) identified in the registries, 1271 (65%) had available BMI and 408 (32%) were obese. The median follow-up-time was 1.5 years [interquartile range (IQR) 0.5-3.9]. Obese patients had higher baseline disease activity, for example, 28-joint DAS [mean 4.6 (S.D. 1.2) vs 4.4 (1.2)]; CRP [median 9mg/l (IQR 5-19) vs 7 (3-18)] and visual analogue scale-pain [66 mm (IQR 48-76) vs 60 (38-74)], compared with non-obese patients (all P<0.05). TNFI adherence was shorter in obese patients, especially among men, where the median TNFI duration was 2.5 years (95% CI 1.7, 3.2) in obese vs 5.9 (4.1, 7.7) in non-obese patients (P<0.01). A EULAR good or moderate (EGOM) response was achieved by 55% of obese vs 65% of non-obese patients after 6 months (P = 0.02). In multivariable analyses, obesity increased the risk of TNFI withdrawal [hazard ratio 1.6 (95% CI 1.3, 2.0)] and reduced odds for EGOM response [odds ratio 0.47 (95% CI 0.29, 0.72)]. The impact of obesity was significant across genders, TNFI types and nationality. Conclusion: Obesity was associated with higher disease activity and seemed to diminish response and adherence to TNFIs in PsA. [ABSTRACT FROM AUTHOR]

Objectives. To determine the change in established biomarkers of cardiovascular (CV) risk, namely, total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C), N-terminal pro-brain natriuretic peptide (NT-proBNP) and insulin resistance (IR) in patients with early RA treated with two different treat-to-target strategies. Methods. Fasting glucose, lipids, insulin and NT-proBNP were measured at baseline, weeks 26 and 78 in 79 DMARD-naTve RA patients, free of CV disease, as part of a double-blind randomized controlled trial of MTX with either infliximab (IFX) or methylprednisolone as induction therapy. Homeostasis model assessment-estimated IR (HOMA-IR) (glucose*insulin/405) was used to measure IR. Multiple imputation was employed, and linear regression analyses were adjusted for baseline values. Results. Changes in DAS44-CRP did not differ between the treatment arms at weeks 26 and 78. Mean TC/ HDL-C, HOMA-IR and NT-proBNP improved in both groups at weeks 26 and 78, although change in NT-proBNP was not statistically significant at week 78. Changes in TC/HDL-C and NT-proBNP were similar between treatment arms, but HOMA-IR values in the IFX + MTX arm were 42% lower than those treated with MTX + methylprednisolone at week 78 (P = 0.003); the difference remained significant after adjustment for baseline BMI, ACPA positivity, smoking status and intramuscular glucocorticoid use (P = 0.007). Conclusion. When implementing a treat-to-target approach, treatment of early RA was associated with improvement in TC/HDL-C, HOMA-IR and NT-proBNP, and a greater long-term improvement in HOMA-IR was seen in those treated with IFX. Trial registration: EU Clinical Trials Register, http://www.clinicaltrialsregister.eu, Eudract-2005-005013-37; ISRTCNregisrty, http://www.isrctn.com, ISRCTN48638981 [ABSTRACT FROM AUTHOR]

Objectives. Cigarette smoking is a major risk factor for RA and has been associated with increased disease severity and lower rates of disease remission. We hypothesized that inflammation and disease activity would be associated with smoking status and this would be related to levels of ACPA. Methods. RA patients from the Veterans Affairs RA registry were studied (n = 1466): 76.9% anti-CCP2 positive, 89% male, median age 63 years (interquartile range 57-72), median disease duration 8.45 years (interquartile range 2.8-18). Baseline serum samples were evaluated for levels of anti-CCP2, RF, 19 distinct ACPAs and 17 cytokines. Smoking status at baseline was recorded as current, former or never. The association of smoking status with cytokines, autoantibodies and disease activity (DAS28) was evaluated. Results. Among anti-CCP-positive RA patients, RA-associated cytokines (false-discovery rates q < 0.1%) and DAS28 (P < 0.01) were higher in current smokers compared with former or never smokers. DAS28 and cytokine levels were similar between former and never smokers. In contrast, ACPA concentrations were higher among both current and former smokers compared with never smokers, and levels of ACPA were not associated with DAS28 or cytokine levels. Conclusion. Among anti-CCP2-positive RA patients, current smoking status is associated with elevations in pro-inflammatory cytokines and increased RA disease activity. Similar levels of inflammation and disease activity among former and never smokers suggests that the detrimental effects of smoking could be ameliorated through tobacco cessation. The effect of tobacco cessation on RA disease activity should be evaluated prospectively. [ABSTRACT FROM AUTHOR]

Objective. To explore the influence of TNF inhibitor (TNFi) therapy and rituximab (RTX) upon the incidence of cancer in patients with RA and prior malignancy. Methods. The study population comprised RA subjects with a prior malignancy reported to the UK national cancer registers, recruited to the British Society for Rheumatology Biologics Register from 2001 to 2013. We compared rates of first incident malignancy in a TNFi cohort, RTX cohort and synthetic DMARDs (sDMARD) cohort. Results. We identified 425 patients with a prior malignancy from 18 000 RA patients in the study. Of these, 101 patients developed a new malignancy. The rates of incident malignancy were 33.3 events/1000 person-years (py) in the TNFi cohort, 24.7 events/1000 py in the RTX cohort and 53.8 events/1000 py in the sDMARD cohort. The age- and gender-adjusted hazard ratio was 0.55 (95% CI: 0.35, 0.86) for the TNFi cohort and 0.43 (95% CI: 0.10, 1.80) for the RTX cohort in comparison with the sDMARDs cohort. The 17.0% of patients in the sDMARDs cohort had a recurrence of the same cancer in comparison with the 12.8% and the 4.3% in the TNFi and RTX cohorts, respectively. Conclusions. Although numbers are still low, it seems that patients with RA and prior malignancy selected to receive either a TNFi or RTX in the UK do not have an increased risk of future incident malignancy. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate the impact and risk factors associated with an abnormal exercise test (ET) in systemic inflammatory rheumatic disease (SIRD) patients before commencing supervised physical exercise. Methods. A total of 235 SIRD patients were enrolled in three controlled clinical trials, including 103 RA, 42 SLE and 57 AS patients. The control group consisted of 231 healthy, sedentary subjects matched for age, gender and BMI. All performed an ET, according to Bruce's or Ellestad's protocol. Cardiovascular disease risk factors, medications, comorbidities and details of each SIRD were assessed. Results. SIRD patients had a higher percentage of abnormal ETs compared with the control group, especially exercise hypertensive behaviour, higher oxygen consumption, higher resting heart rate and heart rate at the first minute of recovery, and chronotropic incompetence (C-Inc) (P < 0.001). The disease itself was involved with higher likelihood of having an abnormal ET [Odds ratio (OR) = 12.0, 95% CI: 2.5, 56.7; P = 0.002 for SLE; OR = 13.56, 95% CI: 6.16, 29.8; P < 0.001 for RA; and OR = 4.31, 95% CI: 1.17, 15.8; P = 0.028, for AS]. Each 10-year increment of age increased the chance of having an abnormal ET by 13% (P = 0.008) in AS patients, as well as hypertension (OR = 7.14, 95% CI: 1.61, 31.6; P = 0.01). Regarding C-Inc, age played a protective role (OR = 0.88, 95% CI: 0.78, 0.99; P = 0.043) in SLE, and ASDAS-ESR was associated with a higher risk in AS (OR = 2.73, 95% CI: 0.93, 8.0; P = 0.067). Conclusion. Our results showed a higher prevalence of abnormal ETs in asymptomatic cardiovascular SIRD patients, and the disease itself was associated with a higher likelihood of having an abnormal test, emphasizing the relevance and need of performing it before starting supervised physical exercise. [ABSTRACT FROM AUTHOR]

Objective. To evaluate in patients with AS (i) the fluctuation in self-reported disease activity (BASDAI), patient global well-being [visual analogue scale (VAS)--global] and spinal pain (VAS-pain) during 2 years of follow-up on a group level and (ii) the clinical relevance of these fluctuations on a patient level. Methods. Dutch patients from the Outcome in AS International Study cohort completed patient-reported outcome measures every 2 months over 2 years. On the group level, mixed linear models were used to analyse whether the outcome measures were constant over time. On a patient level, relevant changes in scores were assessed by the frequency in which changes would exceed predefined cut-off values (>1.0 or >2.0 on a 0-10 scale) during the 2 years of follow-up using 2-, 4-, 6-, 12- or 24-month assessments. Results. Ninety patients [median age 47.3 years (s.d. 11.4), 67.8% male, symptom duration 25.2 years (s.d. 11.3)] were included. On the group level, the outcome measures remained constant over time. However, large fluctuations were found on the patient level. For example, using 2 month intervals, 92% and 69% of the patients had at least one change of > 1.0 or > 2.0, respectively, in the BASDAI during the 2 year follow-up. When prolonging the interval, the proportion of changes exceeding the cut-off decreased, indicating that information is lost. Similar results were found for the VAS-global and VAS-pain. Conclusion. Substantial fluctuations in BASDAI, VAS-global and VAS-pain were found in individuals over time. With longer intervals, fewer fluctuations were observed, indicating that relevant changes might be missed. [ABSTRACT FROM AUTHOR]

Objective. To test the hypothesis that miR-155 regulates monocyte migratory potential via modulation of chemokine and chemokine receptor expression in RA, and thereby is associated with disease activity. Methods. The miR-155 copy-numbers in monocytes from peripheral blood (PB) of healthy (n = 22), RA (n = 24) and RA SF (n = 11) were assessed by real time-PCR using synthetic miR-155 as a quantitative standard. To evaluate the functional impact of miR-155, human monocytes were transfected with control or miR-155 mimic, and the effect on transcript levels, and production of chemokines was evaluated by Taqman low-density arrays and multiplex assays. A comparative study evaluated constitutive chemokine receptor expression in miR-155-/- and wild-type murine (CD115+ Ly6C++ Ly6G-) monocytes. Results. Compared with healthy monocytes, the miR-155 copy-number was higher in RA, peripheral blood (PB) and SF monocytes (PB P < 0.01, and SF P < 0.0001). The miR-155 copy-number in RA PB monocytes was higher in ACPA-positive compared with ACPA-negative patients (P = 0.033) and correlated (95% CI) with DAS28 (ESR), R = 0.728 (0.460, 0.874), and with tender, R = 0.631 (0.306, 0.824) and swollen, R = 0.503 (0.125, 0.753) joint counts. Enforced-expression of miR-155 in RA monocytes stimulated the production of CCL3, CCL4, CCL5 and CCL8; upregulated CCR7 expression; and downregulated CCR2. Conversely, miR155-/- monocytes showed downregulated CCR7 and upregulated CCR2 expression. Conclusion. Given the observed correlations with disease activity, these data provide strong evidence that miR-155 can contribute to RA pathogenesis by regulating chemokine production and pro-inflammatory chemokine receptor expression, thereby promoting inflammatory cell recruitment and retention in the RA synovium. [ABSTRACT FROM AUTHOR]

Objective. Co-stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4-1 BB, a disintegrin and metalloprotease-17 (ADAM17) and galectin-9 (Gal-9) in RA. Methods. Stimulated mononuclear cells from patients with chronic RA (n = 12) were co-incubated with tissue inhibitor of metalloproteinase, 4-1 BB ligand and Gal-9. Plasma samples were examined for soluble 4-1 BB (s4-1BB) in newly diagnosed, treatment-naïve patients with RA (n = 97). The 28-joint DAS with CRP (28DAS-CRP), total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2-year period. Results. RA CD4+ and CD8+ synovial T cells express high levels of 4-1 BB. The addition of TNF-α to cultured synovial mononuclear cells increased shedding of 4-1 BB. 4-1 BB ligand only increased TNF-α shedding in combination with Gal-9. RNA interference-mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4-1 BB shedding. Shedding of 4-1 BB was not influenced by Gal-9. Plasma levels of s4-1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4-1 BB were equal to those of the controls. Baseline plasma levels of s4-1BB were inversely correlated with DAS28-CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing. Conclusion. ADAM17 induces 4-1 BB shedding in RA. Gal-9 is pivotal for the function of 4-1 BB and induction of TNF-α. Furthermore, high plasma levels of s4-1BB were associated with the number of swollen joints, but also with a low DAS28-CRP after 2 years treatment in early RA. [ABSTRACT FROM AUTHOR]

Objectives. To validate the Disease Activity Score 28 using ESR (DAS28-ESR) and CRP (DAS28-CRP), the Simplified Disease Activity Index and the Clinical Disease Activity Index used in RA for SSc patients. Methods. Seventy-seven SSc patients, 40 RA patients, 20 patients with primary RP (PRP) and 28 healthy volunteers were assessed. Besides the disease activity composite indices, the European Scleroderma Study Group Activity Index (EScSG-AI), the HAQ-DI, the Cochin Hand Function Scale and the Short Form Health Survey (SF36) were evaluated. The validation procedure included the assessment for truth, discrimination and feasibility. Results. DAS28-ESR, DAS28-CRP, Simplified Disease Activity Index and Clinical Disease Activity Index showed significant correlation with EScSG-AI, HAQ-DI, Cochin Hand Function Scale and the physical component of SF36 (P < 0.001). All four indices discriminated patients with SSc from RA, PRS and healthy controls, respectively (P<0.01). With the exception of DAS28-CRP, the other three indices also discriminated between subgroups of SSc based on value of EScSG-AI (≤3 and >3) (P<0.05). All four disease activity composite indices showed a good inter- and intraobserver reliability based on repeated measures of two independent investigators (P< 0.001). Conclusion. All four disease activity composite indices were found to be valid measures for assessing arthritis in SSc. DAS28-ESR showed the best performance regarding reliability and construct validity. [ABSTRACT FROM AUTHOR]

Objective. To determine feasibility of TNF inhibitor (TNFi) dose reduction for severe AS and PsA patients. Methods. A retrospective study in a real-world setting. Criteria for dose reduction of TNFi included BASDAI <4 for ≥6 months in AS; or DAS28-ESR ≤ 3.2 for ≥6 months in PsA. TNFi dose was reduced by one-third. Patients who flared (BASDAI > 4 in AS or DAS28-ESR > 3.2 in PsA) were re-escalated to standard treatment dose. Results. Twenty-six per cent (33/125) of AS and 18% (15/83) of PsA patients fulfilled criteria and underwent TNFi dose reduction. Fifty-eight per cent (19/33) of AS and 60% (9/15) of PsA patients maintained TNFi dose reduction for mean (S.D.) of 1.0 (0.8) years. Reinstating standard dose of TNFi recaptured low disease activity in all patients who failed dose reduction within 24 weeks, with no statistically significant difference in mean BASDAI compared with those maintaining TNFi dose reduction in AS at 24 weeks [mean (S.D.) BASDAI 2.4 (1.1) vs 1.9 (1.5), respectively (P = 0.229)]; however in PsA, those who failed dose reduction had higher disease activity compared with patients maintained on TNFi dose reduction at 24 weeks [mean (S.D.) DAS28-ESR 2.7 (0.6) vs 1.3 (0.5), respectively (P ≤ 0.001)]. In PsA, a lower DAS28-ESR prior to dose reduction of TNFi was associated with more successful dose reduction. Conclusions. In a real-world setting, 60% of individuals with severe AS and PsA who achieve low disease activity can successfully reduce the dose of TNFi therapy by a third for a mean of 1 year. [ABSTRACT FROM AUTHOR]

Objective. Increased atherosclerosis in RA is not fully explained by the ordinary risk factors, but it may be related to vascular inflammation. The aim of this study was to investigate the degree of carotid artery inflammation in drug-naive patients with early RA before and after DMARD triple therapy. Methods. Fifteen non-diabetic patients with recently diagnosed RA [age 51 (16) years, 6 males] were examined before and at 2 and 4 weeks after the initiation of combination therapy with MTX, SSZ, HCQ and ≤ 10mg/day oral prednisolone. Eight healthy males aged 49(6) years were examined once as con- trols. Inflammation in the carotid artery was quantified, using [18F]fluorodeoxyglucose (18F-FDG)-PET/CT, as the maximum standardized uptake value (SUVmax) and the maximum target-to-background ratio (TBRmax). Results. Before the treatment, patients with RA had significantly higher carotid artery 18F-FDG uptake, as compared with healthy controls [TBRmax 1.78(0.07) vs 1.51 (0.08), P = 0.03]. The 4-week DMARD therapy reduced the TBRmax to the level of healthy controls [1.53(0.05), P = 0.84]. Compared with the baseline, the TBRmax decreased by 12.4(16.8)% (P = 0.01) during 4-week DMARD therapy. At baseline, the SUVmax correlated with ESR (r = 0.52, P = 0.02) and CRP (r = 0.65, P = 0.01). Change in SUVmax correlated with changes in ESR and CRP after 4 weeks of treatment, as did the changes in TBRmax and SUVmax with DAS at 12 weeks of treatment. Conclusion. 18F-FDG-PET/CT revealed that drug-naive patients with early RA show carotid artery inflammation that can be efficiently reduced by 1-month DMARD triple therapy. [ABSTRACT FROM AUTHOR]

Objective. To investigate whether subfamilies of the RA-specific autoantibodies to human citrullinated fibrinogen (AhFibA) differentially associate with the RA risk factors, HLA-DRB1 shared epitope containing alleles (SE alleles) and cigarette smoking, and thus help to predict the disease outcome. Methods. AhFibA and their anti-α36-50Cit and anti-β60-74Cit subfamilies were assayed by ELISA, at baseline, in the French ESPOIR (Etude et Suivi des Polyarthrites Indifférenciées Récentes) cohort composed of undifferentiated arthritides and RA patients of <6 months' duration. Cigarette smoking, SE alleles' presence, DAS28, HAQ and modified Sharp-van der Heijde Score data were obtained at baseline, and after follow-up. Results. After 3 years, 701 patients were classified as having RA according to the ACR/EULAR 2010 criteria. Among them, 349 (50%), 203 (29%) and 257 (37%) were AhFibA-, anti-α36-50Cit- and anti-β60-74Cit-positive, respectively. The presence and titres of AhFibA and their subfamilies similarly associated with SE alleles, irrespective of their fine specificity, without significant effect of smoking. Neither their presence nor their titre was associated with DAS28 or HAQ. The presence of at least one subfamily was associated with a faster Sharp/van der Heijde score progression, albeit without correlation with the titre. Conclusion. AhFibA and their main subfamilies are similarly associated with SE alleles without additional effect of smoking. Whatever their fine specificity was, their presence (but not their titre) similarly constituted a marker of faster joint destruction. [ABSTRACT FROM AUTHOR]

Objectives. The aim was to assess the immunogenicity and the impact on disease activity of pneumococcal and influenza vaccines in SLE patients. Methods. We conducted a systematic literature review and meta-analysis of studies comparing the humoral response of either pneumococcal (serotype 23F) or influenza (AH1N1, AH3N2 and B strains) vaccines between SLE patients and healthy controls, assessed by a seroconversion or a seroprotection rate 3-6 weeks after vaccination. The impact on disease activity was assessed by the comparison of the SLEDAI score before and 3-8 weeks after vaccination. Odds ratios (ORs), risk ratios and their 95% CIs were pooled using the generic inverse variance method. Results. Twenty studies were included, three for pneumococcal vaccine and 17 for influenza vaccine, gathering 1665 SLE patients and 826 healthy controls. For pneumococcal vaccination, no significant difference was observed, either for seroconversion rate between SLE patients and controls or for the SLEDAI score. For influenza vaccination, the response against AH1N1 was significantly reduced in SLE patients, with a lower rate of seroconversion (OR = 0.38; 95% CI: 0.27, 0.54; P < 0.00001, I² = 39%) and seroprotection (OR = 0.36; 95% CI: 0.28, 0.47; P < 0.00001, I² = 25%). For AH3N2, only seroprotection rate was significantly lower in SLE patients (OR = 0.26; 95% CI: 0.14, 0.50; P < 0.0001, I² = 21%). For B strain, neither seroconversion nor seroprotection rates were significantly different. Influenza vaccine did not modify the SLEDAI score. Conclusion. The immunogenicity of influenza vaccine in SLE patients depends on the viral strains. A reduced immunogenicity against influenza A is noted, while the immunogenicity against the B strain is preserved. The pneumococcal vaccine against 23F serotype has a preserved immunogenicity. These vaccines have no impact on the SLEDAI score. [ABSTRACT FROM AUTHOR]

Objectives. Conflicting reports of the effect of physical activity on knee cartilage may be due to the heterogeneity of populations examined and, in particular, the underlying health of the knee joint. This study examined the influence of recreational and occupational physical activity on cartilage volume loss. Methods. A total of 250 participants with no significant musculoskeletal disease were recruited. A gender-specific median cartilage volume split was used to define people in the lowest and highest 50% of baseline cartilage volume. Baseline recreational and occupational activity was examined by questionnaire, while cartilage volume was assessed by MRI at baseline and 2.4 years later. Results. Significant interactions were demonstrable between physical activity and cartilage volume loss based on stratification of baseline cartilage volume (all P ≤ 0.03). There was a dose-response relationship between frequently performed baseline occupational activities and medial cartilage volume loss in both the low (B = 0.2% per annum, 95% CI: 0.0, 0.04% per annum) and high (B = -0.2% per annum, 95% CI: -0.4, 0.0% per annum) baseline cartilage volume groups (P = 0.001 for interaction). Individuals with low baseline cartilage volume who were active in their occupation and/or recreational activity had greater medial cartilage volume loss than their more inactive counterparts (2.4% per annum vs 1.5% per annum, P = 0.02). Conclusion. Whereas people with less baseline cartilage volume are more at risk of structural knee damage with either heavy occupational or recreational workloads or both, individuals with high baseline cartilage volume may advantageously modify their risk for knee OA by participating in more frequent occupational physical activities. [ABSTRACT FROM AUTHOR]

Objective. To investigate the prevalence of underdiagnosis and undertreatment of traditional cardiovascular risk factors in RA patients. Methods. RA patients ≤70 years of age without cardiovascular disease (CVD) or diabetes mellitus were included. Systolic blood pressure and a fasting lipid profile were measured. The 10-year CVD risk was estimated using the Dutch Cardiovascular Risk Management (CVRM) guideline and EULAR modifications of the Systemic Coronary Risk Evaluation tables. Results. A total of 327 patients were included (female gender: 68%). The mean age was 53(11) years [mean (S.D.)]. The median disease duration was 7 years (inter quartile range: 2-14 years). According to the CVRM guideline, 52% of the patients had a CVD risk ≥20% and according to the EULAR guidelines, 18% of the patients had a CVD risk ≥20%. Low-density lipoprotein cholesterol (LDL-C) >2.5 mmol/l was found in >80% of the patients with a CVD risk ≥10% as estimated by both the CVRM and EULAR guidelines, and 32-42% of the patients with a CVD risk ≥10% had a systolic blood pressure >140mmHg, depending on the risk model used. Statins were used in 6% and antihypertensives in 23-25%, and 50-86% of these patients did not reach the recommended treatment targets. Conclusion. Regardless of the adapted risk assessment model used, untreated hypertension and hypercholesterolaemia were frequently found in RA patients with increased CVD risk. Treatment of these cardiovascular risk factors deserves more attention in RA. [ABSTRACT FROM AUTHOR]

Objectives. The medical management of JIA has advanced significantly over the past 10 years. It is not known whether these changes have impacted on outcomes. The aim of this analysis was to identify and describe trends in referral times, treatment times and 1-year outcomes over a 10-year period among children with JIA enrolled in the Childhood Arthritis Prospective Study. Methods. The Childhood Arthritis Prospective Study is a prospective inception cohort of children with new-onset inflammatory arthritis. Analysis included all children recruited in 2001-11 with at least 1 year of follow-up, divided into four groups by year of diagnosis. Median referral time, baseline disease pattern (oligoarticular, polyarticular or systemic onset) and time to first definitive treatment were compared between groups. Where possible, clinical juvenile arthritis disease activity score (cJADAS) cut-offs were applied at 1 year. Results. One thousand and sixty-six children were included in the analysis. The median time from symptom onset and referral to first paediatric rheumatology appointment (22.7-24.7 and 3.4-4.7 weeks, respectively) did not vary significantly (~20% seen within 10 weeks of onset and ~50% within 4 weeks of referral). For oligoarticular and polyarticular disease, 33.8-47 and 25.4-34.9%, respectively, achieved inactive disease by 1 year, with ~30% in high disease activity at 1 year. A positive trend towards earlier definitive treatment reached significance in oligoarticular and polyarticular pattern disease. Conclusion. Children with new-onset JIA have a persistent delay in access to paediatric rheumatology care, with one-third in high disease activity at 1 year and no significant improvement over the past 10 years. Contributing factors may include service pressures and poor awareness. Further research is necessary to gain a better understanding and improve important clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective. Altered energy expenditure may contribute to the nutritional complications of RA, metabolic syndrome (MS) and rheumatoid cachexia (RC). The main aim of this study was to evaluate whether the altered resting energy expenditure (REE) and physical activity (PA)-related energy expenditure (EE) are related to the duration of RA and inflammatory activity and nutritional complications in RA. Methods. Among patients with well-characterized RA (duration, activity: DAS28 ESR), we measured REE by indirect calorimetry, and PA-EE by actimetry (SenseWear Armband). MS was defined according to the International Diabetes Federation criteria and RC from DXA body composition analysis. The relations between the characteristics and nutritional complications, and EE were analysed by linear regression. Results. Fifty-seven patients were included [73% women, age 57(10) years] with a wide range of disease duration: 3.8(3.0) years, and DAS28 ESR: 3.9(1.4). The mean REE was 1486(256) kcal/day, associated with the DAS28 ESR (β= +0.21, P = 0.02 after adjusting for gender and fat free mass). The prevalence of MS and RC was, respectively, 24 and 18%, and they were unrelated to each other. The patients with MS and/or RC had double the longstanding RA score (P < 0.05), twice the homeostasis model assessment of insulin resistance values (P = 0.052) and halved levels of PA (P<0.05 for metabolic equivalent tasks (METs) and number of steps/day). Two modifiable factors were associated with the presence of MS and/or RC: a low level of PA as METs [exp(B) = 0.03, P = 0.009] and the use of glucocorticoids [exp(B) = 4.08, P = 0.046]. Conclusion. Low levels of PA and treatment by glucocorticoids are associated with the nutritional complications of RA, suggesting the potential for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objective. To describe the presenting clinical features, treatment and outcome in children with eosinophilic granulomatosis with polyangiitis (EGPA) and to define factors that predicted mortality. Methods. A retrospective case notes review of patients fulfilling the Chapel Hill Consensus Conference definition and/or ACR criteria for EGPA seen at Great Ormond Street Hospital, London. Demographics, clinical features, histopathology, treatment and outcomes were recorded. Descriptive statistics were expressed as median and range. Fisher's exact test was used for group comparisons. The Paediatric Vasculitis Activity Score and Paediatric Vasculitis Damage Index (PVDI) were calculated. Results. Thirteen children (38% female) aged at diagnosis 14.1 (4-15.6) years were identified. The median time to diagnosis was 2 (0-7.3) years. History of asthma was documented in 76%. The most common presenting features were pulmonary (69%), skin (61 %), gastrointestinal (46%), cardiac involvement (46%), paranasal sinus abnormality (38%), arthritis/arthralgia (38%) and neurological involvement (15%). Paediatric Vasculitis Activity Score at presentation was 8/63 (2-25/63); ANCA was negative in all 10/13 patients tested. Treatment included corticosteroids in all, combined with CYC in 38% or AZA in 23%. PVDI at 12 (3-48) months follow-up was 3/72 (0-13/72). Relapses were recorded in 46%. Mortality was 15%; cardiomyopathy and PVDI scores ≥5 significantly associated with mortality risk (P = 0.012). Conclusion. EGPA in the paediatric population is a rare and potentially life-threatening vasculitis. Increased awareness is essential to secure a timely diagnosis and to promptly initiate treatment since our data emphasize a high mortality, particularly in those with cardiac involvement and significant accrued damage. [ABSTRACT FROM AUTHOR]

Objective. The aim was to evaluate the reliability, validity and responsiveness to change of the Gout Impact Scale (GIS), a disease-specific measure of patient-reported outcomes, in a multicentre longitudinal prospective cohort of gout patients. Methods. Subjects completed the GIS, a 24-item instrument with five scales: Concern Overall, Medication Side Effects, Unmet Treatment Need, Well-Being during Attack, and Concern Over Attack. The total GIS score was calculated by averaging the GIS scale scores. HAQ-Disability Index (HAQ-DI), Short Form (SF)-36 physical and mental component summaries (PCS and MCS) and physician and patient gout severity assessments were also completed. Reliability was assessed with Cronbach's a. Baseline GIS scores were compared in subjects with and without gout attacks in the past 3 months using Wilcoxon rank sum tests. Multivariate linear regression was used to evaluate predictors of total GIS. Pearson's correlation coefficients 0.24-0.36 were considered moderate and >0.37 considered large. The effect size for responsiveness to change was interpreted as follows: 0.20-0.49 small, 0.50-0.79 medium and >0.79 large. Results. In 147 subjects, reliability was acceptable for total GIS (0.93) and all GIS scales (0.82-0.94) except Medication Side Effects and Unmet Treatment Need. Total GIS and all scales except Medication Side Effects discriminated between subjects with and without recent gout attacks (P < 0.05). Total GIS showed moderate-to-large correlations with HAQ-DI, SF-36 PCS and MCS (0.33-0.46). Improvement in total GIS tracked with improved physician and patient severity scores. Worsening physician severity score and recent gout attack predicted worsening total GIS. Conclusion. Total GIS score is reliable, valid and responsive to change in patients with gout, and differentiates between subjects with and without recent gout attacks. [ABSTRACT FROM AUTHOR]

Objective. The aim was to evaluate the utility of the common sense model (CSM) in characterizing contributors to psychological well-being and quality of life (QoL) in patients with end-stage OA. Methods. One hundred and twenty patients [34 males, 86 females; mean (S.D.) age 65.52 (9.14) years] with end-stage OA (57.5% hip, 42.5% knee) were recruited. OA symptom severity was evaluated according to the WOMAC; coping styles were assessed with the Carver Brief COPE scale; illness perceptions were explored with the Brief Illness Perceptions Questionnaire; self-efficacy was assessed with the Arthritis Self-efficacy scale; anxiety, depression and overall distress were measured using the Hospital Anxiety and Depression Scale; and QoL was assessed using the WHO Quality of Life-short version. The CSM was used to explore the interrelationships between OA symptom severity, illness perceptions and coping strategies in patients. Results. Two structural equation models were developed, with both found to have good fit. Consistent with the CSM, the standard model indicated that self-reported OA symptom severity directly influenced illness perceptions, which in turn had direct impacts upon maladaptive coping, distress and QoL. The addition of self-efficacy to the CSM resulted in a complex interaction, with OA severity directly influencing self-efficacy and self-efficacy influencing maladaptive coping, distress and QoL. Conclusion. We found interrelationships amongst OA activity, illness perceptions, coping strategies, self-efficacy, psychological distress and QoL broadly consistent with the CSM. The CSM may help inform the approach to the psychological support that patients with end-stage OA often require. [ABSTRACT FROM AUTHOR]

Objective. Previous studies have suggested a link between inflammation and central sensitization of pain in patients with RA. We conducted a prospective cohort study to determine whether US Doppler (USD), temporal summation (TS) of pain--assessed at baseline--and the potential interaction between them could predict the treatment response in RA. Methods. Patients were recruited from Departments of Rheumatology in the Copenhagen area and from private clinics. RA patients, who were scheduled to initiate therapy with either a conventional synthetic DMARD (csDMARD; including DMARD-naïve patients) or a biologic DMARD (bDMARD) agent (including bDMARD switch), were included and examined before the start of treatment and after 4 months. During the 4 months, patients received routine care from their treating rheumatologist. Results. Multiple regression analysis was conducted, with change in DAS28 as the dependent variable. In unadjusted models, baseline USD score was significantly associated with DAS28 (β= 0.06; 95% CI: 0.02, 0.09; P < 0.001), whereas TS and their interaction were not. After adjusting for age, sex, disease duration, baseline DAS28 and whether patients initiated a csDMARD or a bDMARD, the USD score was still significantly associated with change in DAS28 (β = 0.032; 95% CI: 0.001, 0.064; P =0.046), whereas TS remained insignificant. Conclusion. USD assessed at baseline is valuable as a prognostic factor for change in disease activity in 'real-life' RA patients. We did not find evidence to suggest that TS or the interaction between USD and TS was prognostically important for this group of patients. [ABSTRACT FROM AUTHOR]

Objective. To improve knowledge of vasculopathy in SSc through the assessment of serum levels of circulating angiogenetic and endothelial dysfunction markers in patients at different stages of the disease. Methods. Sera from 224 subjects were obtained and concentrations of angiopoietin-2, chemokine (C-X-C motif) ligand (CXCL)-16 (CXCL16), E-selectin, soluble intercellular adhesion molecule-1, IL-8 (CXCL8), soluble vascular adhesion molecule-1 and VEGF were determined by a Luminex assay. Subjects included 43 healthy controls, 47 early SSc patients according to LeRoy and Medsger without other signs and symptoms of evolutive disease, 48 definitive SSc (defSSc) patients according to the 2013 ACR/EULAR criteria without skin or lung fibrosis, 51 lcSSc subjects and 35 dcSSc subjects. Results. The four groups of patients showed well-distinct clinical and laboratory characteristics, with a linear decreasing trend in forced vital capacity and diffusing capacity for carbon monoxide % predicted values from early SSc to defSSc to lcSSc and to dcSSc, and a linear increasing trend in ESR, and in the prevalence of abnormal CRP, serum gamma globulins and lung fibrosis (all P< 0.0001). Highly significant linear trends pointing to an increase in angiopoietin-2 (P< 0.0001), CXCL16 (P< 0.0001), E-selectin (P = 0.001) and soluble intercellular adhesion molecule-1 (P = 0.002) in relation to the different disease subsets were observed. Conclusion. Markers characterizing vascular activation are found to be increased in SSc patients from the earliest stages of disease when clinical and laboratory findings of advanced disease cannot yet be detected. These abnormalities progress with the appraisal of the first sclerodermatous manifestation in defSSc and further increase with the onset of fibrotic manifestations. [ABSTRACT FROM AUTHOR]

Objectives. To determine the longitudinal trends in serum levels of four myositis-associated autoantibodies: anti-Jo-1, -transcription intermediary factor 1 γ (TIF1-γ), -signal recognition particle (SRP) and -Mi-2, after B cell depletion with rituximab, and to determine the longitudinal association of these autoantibody levels with disease activity as measured by myositis core-set measures (CSMs). Methods. Treatment-resistant adult and pediatric myositis subjects (n = 200) received rituximab in the 44-week Rituximab in Myositis Trial. CSMs [muscle enzymes, manual muscle testing (MMT), physician and patient global disease activity, HAQ, and extramuscular disease activity] were evaluated monthly and anti-Jo-1 (n = 28), -TIF1-γ (n = 23), -SRP (n = 25) and -Mi-2 (n = 26) serum levels were measured using validated quantitative ELISAs. Temporal trends and the longitudinal relationship between myositis-associated auto-antibodies levels and CSM were estimated using linear mixed models. Results. Following rituximab, anti-Jo-1 levels decreased over time (P < 0.001) and strongly correlated with all CSMs (P< 0.008). Anti-TIF1-γ levels also decreased over time (P< 0.001) and were only associated with HAQ, MMT and physician and patient global disease activity. Anti-SRP levels did not change significantly over time, but were significantly associated with serum muscle enzymes. Anti-Mi-2 levels significantly decreased over time and were associated with muscle enzymes, MMT and the physician global score. Conclusion. Anti-Jo-1, anti-TIF1-γ and anti-Mi-2 levels in myositis subjects decreased after B cell depletion and were correlated with changes in disease activity, whereas anti-SRP levels were only associated with longitudinal muscle enzyme levels. The strong association of anti-Jo-1 levels with clinical outcomes suggests that anti-Jo-1 autoantibodies may be a good biomarker for disease activity. [ABSTRACT FROM AUTHOR]

Objective. To quantify peptidylarginine deiminase 2 (PAD2) in SF of RA patients and OA patients, and to determine the association between PAD2 levels, disease activity and inflammatory markers in RA. Methods. Blood and SF samples were obtained from 39 RA patients and 40 patients with OA. PAD2 content and PAD activity were measured by means of in-house assays. TNF-α, IL-1β, IL-6, IL-8, IL-10 and IL-12 were measured using flow cytometry. Results. PAD2 levels and PAD activity were higher in SF from RA than OA patients (P< 0.0001 and P = 0.03, respectively), as were all cytokine levels (P< 0.0001-0.05). SF PAD2 levels were higher among anti-CCP-positive patients than among anti-CCP-negative patients (P = 0.005). PAD2 levels in SF from RA patients correlated with disease activity, as assessed by DAS28 (P < 0.005). Moreover, SF PAD2 levels correlated with circulating CRP and anti-CCP levels (P< 0.0006), as well as with leucocyte count, IL-6, IL-8 and IL-10 levels in SF (P< 0.0001-0.02). PAD activity in SF was higher in RA patients than in OA patients, and correlated with PAD2 concentration. Conclusion. Extracellular PAD2 levels in SF correlate with disease activity in RA patients. Anti-CCP-positive RA patients have higher PAD2 levels in SF than anti-CCP-negative RA patients and OA patients. Since we could demonstrate enzymatically active PADs in SF, we propose that free, extracellular PAD is of pathogenic relevance. [ABSTRACT FROM AUTHOR]