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Objectives To explore mortality and causes of death among Norwegian patients with RA, PsA and axial spondyloarthritis (axSpA) compared with the general population by conducting a nationwide registry-based cohort study. Methods Patients with RA, PsA and axSpA were identified from the Norwegian Patient Registry based on ICD-10 codes between 2008 and 2017. Using age as the time variable, all-cause and cause-specific mortality were estimated between 2010 and 2017 with the Kaplan–Meier estimator and the cumulative incidence competing risk method, respectively. Sex-, education level-, health region- and age group-adjusted hazard ratios (HRs) for mortality were estimated using Cox regression models. Results We identified 36 095 RA, 18 700 PsA and 16 524 axSpA patients (70%, 53% and 45% women, respectively). RA and axSpA were associated with increased all-cause mortality (HR 1.45 [95% CI: 1.41, 1.48] and HR 1.38 [95% CI: 1.28, 1.38], respectively). Women but not men with PsA had a slightly increased mortality rate (HR 1.10 [95% CI: 1.00, 1.21] among women and 1.02 [95% CI: 0.93, 1.11] among men). For all patient groups as well as for the general population, the three leading causes of death were cardiovascular diseases, neoplasms and respiratory diseases. RA patients had increased mortality from all of these causes, while axSpA patients had increased mortality from cardiovascular and respiratory diseases. Conclusion Even in the era of modern treatments for IJDs, patients with RA and axSpA still have shortened life expectancy. Our findings warrant further attention to the prevention and management of comorbidities.

Background: It is recommended to heat and humidity CO2 in laparoscopic surgery to prevent postoperative pain and hypothermia but information about its effects on hemodynamic and respiratory parameters is limited. We aimed to investigate the effects of standard and heated-humidified CO2 on hemodynamic and respiratory parameters, body temperature and pain in healthy patients. Methods: One hundred patients who underwent total laparoscopic hysterectomy for benign pathology were divided into two groups: Group CD (cold-dry) patients were administered standard CO2, while Group HH (heated-humidified) patients were administered 95% humidified insufflation at 37 degrees C. Hemodynamic and respiratory parameters, body temperature, pain score and blood count parameters were recorded. Results: A total of 96 patients were included in the study, taken from the 100 patients. Group HH (n:47) had only higher systolic blood pressure at 75, mean blood pressure at 50 and 55 and a lower heart rate between 15 and 45 min (p:0.049, 0.037, 0.013 respectively). Pain score, morphine consumption, end-tidal CO2 and arterial blood gas values were not different between the groups, with only body temperature from 40 min and minimum value being significantly higher (at a difference of 0.86-1.04 degrees C) in Group HH. Postoperative leukocyte, neutrophil and NLR (neutrophil-leukocyte ratio) were found to be higher in this group (p < 0.05). Conclusion: It has been found that both standard and heated-humidified CO2 do not constitute a problem in terms of hemodynamic and respiratory parameters in healthy patients. The heated-humidified CO2 group had only a higher core body temperature and inflammatory response. (C) 2021 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V.

Primary care physicians can play a crucial role by recognising Sjogren's syndrome (SS) in the early stages identifying those patients with the greatest probability of being diagnosed with SS. SS has a very specific epidemiological profile at presentation (female aged 3050 years), which may aid an early diagnosis. Although the disease may be expressed in many guises, there are three predominant clinical presentations that should be considered as key clues to increased clinical suspicion (multiple symptoms of dryness, asthenia-polyalgia syndrome and systemic organ-specific manifestations). The physical examination may provide important clues to systemic involvement (parotid gland enlargement, skin lesions suggestive of purpura or annular erythema, respiratory crackles, arthritis, neurological sensory or motor deficits). Simple laboratory studies may be very useful in reinforcing the clinical suspicion of SS, and the triad of cytopenia, raised erythrocyte sedimentation rate and high serum gamma globulin levels is a very specific "biological" pattern suggesting SS. A solid clinical suspicion of SS requires both the patient reporting sicca symptoms and objective evidence that these symptoms are associated with dysfunction of the lachrymal and salivary glands. Ultrasonography of the parotid glands, a non-invasive method, may be a major advance in the diagnostic approach to SS in primary care. Primary care physicians must be considered essential members of the multidisciplinary team in charge of the follow-up of SS patients, due to their key role in the continuum of patient care and their cross-sectional knowledge of common diseases that frequently coexist in patients with SS.

Objectives: To compare the effect of treat-to-target-based escalations in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics on clinical disease activity and magnetic resonance imaging (MRI) inflammation in a rheumatoid arthritis (RA) cohort in clinical remission. Method: One-hundred patients with established RA, Disease Activity Score based on 28-joint count–C-reactive protein (DAS28-CRP)

Key messages Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Abstract Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1–2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

INTRODUCTION: Fatigue is one of the most important symptoms reported by patients with systemic lupus erythematosus (SLE) and a key concept of interest in SLE clinical trials. Despite this, fatigue remains poorly understood and sub-optimally measured by existing patient-reported outcome (PRO) instruments and scales. Here, we psychometrically evaluated the measurement properties of three PRO scales that purport to measure fatigue, using data from two SLE clinical trials. METHODS: Data were pooled from two completed phase 3 SLE trials: EMBODY1 (NCT01262365) and EMBODY2 (NCT01261793). FACIT-F, SF-36 Vitality and LupusQoL Fatigue data were selected for post hoc Rasch Measurement Theory psychometric analysis in two stages: (1) scale-to-sample targeting, thresholds for item response options, item fit statistics, and reliability; and (2) proposal and evaluation of pooled fatigue items based on the best-performing items. Responsiveness analyses on group-level (two effect size [ES] calculations and relative efficiency) and individual level (within person statistically significant difference), were conducted to compare original scales and pooled item sets. RESULTS: Scale-to-sample targeting was good for FACIT-F, but suboptimal for SF-36 Vitality and LupusQoL Fatigue. Thresholds for item response options were ordered for all three scales. Item misfit was found in all three scales (FACIT-F 10/13; SF-36 Vitality 4/4; LupusQoL Fatigue 1/4). Reliability statistics were good for FACIT-F (0.93) and LupusQoL Fatigue (0.80) but low for SF-36 Vitality (0.53). The pooled fatigue items improved some psychometric properties despite persisting misfit issues (2/10) and were more sensitive in detecting change at week 24 compared with un-pooled data (ES 0.41 vs. 0.26-0.25). CONCLUSIONS: FACIT-F, SF-36 Vitality, and LupusQoL Fatigue were found to have important limitations in the EMBODY1 and EMBODY2 SLE clinical trials. Findings from pooled fatigue items support the need for further research to improve conceptual underpinnings of fatigue PROs and make them fit for purpose for drug development. ispartof: RHEUMATOLOGY AND THERAPY vol:8 issue:3 pages:1287-1301 ispartof: location:England status: published

Objectives We wanted to estimate the magnitude of the risk from all-cause, cause-specific and sex-specific mortality in patients with SLE and relative risks compared with matched controls and to evaluate the influence of exposure to medication on risk of mortality in SLE. Methods We conducted a population-based cohort study using the Clinical Practice Research Datalink, Hospital Episode Statistics and national death certificates (from 1987 to 2012). Each SLE patient (n = 4343) was matched with up to six controls (n = 21 780) by age and sex. Cox proportional hazards models were used to estimate overall and cause-specific mortality rate ratios. Results Patients with SLE had a 1.8-fold increased mortality rate for all-cause mortality compared with age- and sex-matched subjects [adjusted hazard ratio (HR) = 1.80, 95% CI: 1.57, 2.08]. The HR was highest in patients aged 18–39 years (adjusted HR = 4.87, 95% CI: 1.93, 12.3). Mortality rates were not significantly different between male and female patients. Cumulative glucocorticoid use raised the mortality rate, whereas the HR was reduced by 45% with cumulative low-dose HCQ use. Patients with SLE had increased cause-specific mortality rates for cardiovascular disease, infections, non-infectious respiratory disease and for death attributable to accidents or suicide, whereas the mortality rate for cancer was reduced in comparison to controls. Conclusion British patients with SLE had a 1.8-fold increased mortality rate compared with the general population. Glucocorticoid use and being diagnosed at a younger age were associated with an increased risk of mortality. HCQ use significantly reduced the mortality rate, but this association was found only in the lowest cumulative dosage exposure group.

Animal models of autoimmunity and human genetic association studies indicate that the dysregulation of B-cell receptor (BCR) signaling is an important driver of autoimmunity. We previously showed that in circulating B cells from primary Sjögren’s syndrome (pSS) patients with high systemic disease activity, protein expression of the BCR signaling molecule Bruton’s tyrosine kinase (BTK) was increased and correlated with T-cell infiltration in the target organ. We hypothesized that these alterations could be driven by increased B-cell activating factor (BAFF) levels in pSS. Here, we investigated whether altered BCR signaling was already present at diagnosis and distinguished pSS from non-SS sicca patients. Using (phospho-)flow cytometry, we quantified the phosphorylation of BCR signaling molecules, and investigated BTK and BAFF receptor (BAFFR) expression in circulating B cell subsets in an inception cohort of non-SS sicca and pSS patients, as well as healthy controls (HCs). We found that both BTK protein levels and BCR signaling activity were comparable among groups. Interestingly, BAFFR expression was significantly downregulated in pSS, but not in non-SS sicca patients, compared with HCs, and correlated with pSS-associated alterations in B cell subsets. These data indicate reduced BAFFR expression as a possible sign of early B cell involvement and a diagnostic marker for pSS.

Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity.MethodsUsing a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies.ResultsPHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients’ risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy.ConclusionsPHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.

Background Skeletal muscle can be directly affected by systemic sclerosis (SSc); however, a significant burden of SSc-associated myopathy is undetected because clinical parameters such as weakness and creatine kinase (CK) are unreliable biomarkers of muscle involvement. This study presents qualitative and quantitative magnetic resonance imaging (MRI) findings that quantify the prevalence of myopathy and evaluate any association between skeletal and cardiac muscle involvement in SSc. Methods Thirty-two patients with SSc who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria underwent skeletal muscle MRI in addition to cardiac MRI. Skeletal muscles were independently assessed by two musculoskeletal radiologists for evidence of oedema, fatty infiltration and atrophy. Skeletal muscle T2 mapping times and percentage fat fraction were calculated. Linear regression analysis was used to evaluate the clinical and myocardial associations with skeletal muscle oedema and fatty infiltration. Cardiac MRI was performed using post gadolinium contrast imaging and parametric mapping techniques to assess focal and diffuse myocardial fibrosis. Results Thirteen participants (40.6%) had MRI evidence of skeletal muscle oedema. Five (15.6%) participants had fatty infiltration. There was no association between skeletal muscle oedema and muscle strength, creatine kinase, inflammatory markers or fibroinflammatory myocardial disease. Patients with skeletal muscle oedema had higher T2-mapping times; there was a significant association between subjective assessments of muscle oedema and T2-mapping time (coef 2.46, p = 0.02) and percentage fat fraction (coef 3.41, p = 0.02). Diffuse myocardial fibrosis was a near-universal finding, and one third of patients had focal myocardial fibrosis. There was no association between skeletal myopathy detected by MRI and burden of myocardial disease. Conclusions MRI is a sensitive measure of muscle oedema and systematic assessment of SSc patients using MRI shows that myopathy is highly prevalent, even in patients without symptoms or other signs of muscle involvement. Similarly, cardiac fibrosis is highly prevalent but occurs independently of skeletal muscle changes. These results indicate that novel quantitative MRI techniques may be useful for assessing sub-clinical skeletal muscle disease in SSc.

BackgroundTo address the reactivity and affinity against histidyl-transfer RNA synthetase (HisRS) autoantigen of anti-Jo1 autoantibodies from serum and bronchoalveolar lavage fluid (BALF) in patients with idiopathic inflammatory myopathies/anti-synthetase syndrome (IIM/ASSD). To investigate the associations between the reactivity profile and clinical data over time.MethodsSamples and clinical data were obtained from (i) 25 anti-Jo1+patients (19 sera with 16 longitudinal samples and 6 BALF/matching sera at diagnosis), (ii) 29 anti-Jo1−patients (25 sera and 4 BALF/matching sera at diagnosis), and (iii) 27 age/gender-matched healthy controls (24 sera and 3 BALF/matching sera). Reactivity towards HisRS full-length (HisRS-FL), three HisRS domains (WHEP, antigen binding domain (ABD), and catalytic domain (CD)), and the HisRS splice variant (SV) was tested. Anti-Jo1 IgG reactivity was evaluated by ELISA and western blot using IgG purified from serum by affinity chromatography. In paired serum-BALF, anti-Jo1 IgG and IgA reactivity was analyzed by ELISA. Autoantibody affinity was measured by surface plasmon resonance using IgG purified from sera. Correlations between autoantibody reactivity and clinical data were evaluated at diagnosis and longitudinally.ResultsAnti-Jo1 IgG from serum and BALF bound HisRS-FL, WHEP, and SV with high reactivity at the time of diagnosis and recognized both conformation-dependent and conformation-independent HisRS epitopes. Anti-HisRS-FL IgG displayed high affinity early in the disease. At the time of IIM/ASSD diagnosis, the highest autoantibody levels against HisRS-FL were found in patients ever developing interstitial lung disease (ILD) and arthritis, but with less skin involvement. Moreover, the reactivity of anti-WHEP IgG in BALF correlated with poor pulmonary function.Levels of autoantibodies against HisRS-FL, HisRS domains, and HisRS splice variant generally decreased over time. With some exceptions, longitudinal anti-HisRS-FL antibody levels changed in line with ILD activity.ConclusionHigh levels and high-affinity anti-Jo1 autoantibodies towards HisRS-FL were found early in disease in sera and BALF. In combination with the correlation of anti-HisRS-FL antibody levels with ILD and ILD activity in longitudinal samples as well as of anti-WHEP IgG in BALF with poor pulmonary function, this supports the previously raised hypothesis that the lung might have a role in the immune reaction in anti-Jo1-positive patients.

Background/Aims: Specific serum markers reflecting hepatic inflammation and fibrosis are required to tailor the treatment strategies in non-alcoholic steatohepatitis (NASH). We aimed to investigate the roles of myeloperoxidase (MPO) and calprotectin in predicting the hepatic inflammation status and disease severity in NASH. Materials and Methods: A total of 48 patients with biopsy-proven NASH and 25 healthy volunteers with normal weight were prospectively enroiled Serum MPO and calprotectin levels were compared between the NASH and control groups. Hepatic MPO and calprotectin expressions were compared in terms of histologic non-alcoholic fatty liver disease activity scores (NAS) (low NAS [5]) and fibrosis stage (insignificant [F0-1]/significant [F2-4]). Results: Serum MPO and calprotectin levels were not significantly different between the NASH and control groups. In the subgroup analysis, hepatic MPG expression was significantly increased in patients with NASH with significant fibrosis than in those with insignificant fibrosis (F2-4: 7.04 +/- 3.61 vs. F0-1: 4.83 +/- 2.42, p=0.01). We found no difference between the groups with low and high NAS with regard to serum MPG and calprotectin levels and hepatic MPG and calprotectin expressions. Conclusion: This study demonstrated that hepatic MPG expression can reflect advanced fibrosis in NASH. However, when serum MPO and calprotectin levels were evaluated as potential serum markers, both did not associate with hepatic inflammation status and fibrosis stage in NASH. Therefore, our study results preclude their use as serum markers for hepatic inflammation in NASH.

Primary Sjögren’s syndrome (pSS) is often considered a B cell-mediated disease, yet the precise role of B cells in the pathogenesis is not fully understood. This is exemplified by the failure of multiple clinical trials directed at B cell depletion or inhibition. To date, most prognostic markers for severe disease outcomes are autoantibodies, but the underlying mechanisms by which B cells drive diverse disease presentations in pSS likely extend beyond autoantibody production. Here we outline an expanded role of B cells in disease pathogenesis drawing on examples from animal models of SS, and from other autoimmune diseases that share similar clinical or immunological abnormalities. We focus on recent findings from the detailed analysis of pathogenic B cells in patients with pSS to propose strategies for patient stratification to improve clinical trial outcomes. We conclude that an integrated cellular, molecular and genetic analysis of patients with pSS will reveal the underlying pathogenic mechanisms and guide precision medicine.

Primary Sjögren’s syndrome (pSS) is often considered a B cell-mediated disease, yet the precise role of B cells in the pathogenesis is not fully understood. This is exemplified by the failure of multiple clinical trials directed at B cell depletion or inhibition. To date, most prognostic markers for severe disease outcomes are autoantibodies, but the underlying mechanisms by which B cells drive diverse disease presentations in pSS likely extend beyond autoantibody production. Here we outline an expanded role of B cells in disease pathogenesis drawing on examples from animal models of SS, and from other autoimmune diseases that share similar clinical or immunological abnormalities. We focus on recent findings from the detailed analysis of pathogenic B cells in patients with pSS to propose strategies for patient stratification to improve clinical trial outcomes. We conclude that an integrated cellular, molecular and genetic analysis of patients with pSS will reveal the underlying pathogenic mechanisms and guide precision medicine.

Objectives: This study aims to assess the reliability and validity of the Turkish version of the European League Against Rheumatism (EULAR) Sjögren Syndrome Patient Reported Index (ESSPRI) (TR) in patients with primary Sjögren syndrome (pSS). Materials and methods: A cross-sectional survey study design and analysis were used to assess the reliability and validity of the ESSPRI (TR) between March 2019 and July 2019. A total of 30 patients (5 males, 25 females; mean age 54.1±10.5 years; range, 18 to 75 years) diagnosed as pSS according to revised American College of Rheumatology (ACR)/EULAR classification criteria were included. ESSPRI (TR) was applied to the patients with face-to-face interviews twice: on their first visit and after an interval of 15 days. The test-retest reliability was assessed with the intraclass correlation coefficient (ICC), and the internal consistency of the multi-item subscales by calculating Cronbach alpha values. The correlations between basal and stimulated salivary flow (BSF and SSF), Oral Health Impact Profile-14 (OHIP-14) and Oral Health-Related Quality of Life-UK (OHRQOL-UK) questionnaires were evaluated to determine the construct validity. Results: The ICC value for the test/retest reliability of ESSPRI (TR) was 0.925. The internal consistency was 0.682. There were low to moderate correlations between the ESSPRI (TR) total score and BSF (-0.39), SSF (-0.50), OHIP-14 total (0.57) and OHRQOL-UK total (-0.67). Conclusion: The Turkish version of the ESSPRI was found to be clinically valid and reliable to be used in clinical evaluations and rehabilitation interventions in patients with pSS.

ObjectiveTo investigate salivary gland ultrasound (SGUS) abnormalities in relation to clinical phenotype and patient characteristics, disease activity, and disease damage in patients with primary Sjögren syndrome (pSS).MethodsConsecutive outpatients included in our REgistry of Sjögren Syndrome LongiTudinal (RESULT) cohort were selected. Patients with pSS who were included were classified according to the American College of Rheumatology/European League Against Rheumatism (EULAR) criteria and underwent full ultrasonographic examination (Hocevar score 0–48) at baseline. Total SGUS scores of ≥ 15 were considered positive. Patient characteristics, disease activity, and disease damage were compared between the different SGUS groups.ResultsIn total, 172 of 186 patients with pSS were eligible, of whom 136 (79%) were SGUS positive. Compared with patients who were SGUS negative, SGUS-positive patients had significantly longer disease duration, higher EULAR Sjögren Syndrome Disease Activity Index, higher Sjögren Syndrome Disease Damage Index, and were more likely to have a positive parotid gland biopsy, anti-SSA/SSB antibodies, and abnormal unstimulated whole saliva (UWS) and ocular staining score (OSS), and higher levels of IgG and rheumatoid factor. Regarding patient-reported outcome measurements (PROM), patients who were SGUS positive scored significantly lower on the EULAR Sjögren Syndrome Patient-Reported Index for fatigue and pain, and more often found their disease state acceptable compared with patients who were SGUS negative. SGUS total score showed significant associations with various clinical and serological variables, and with PROM. Highest associations were found for UWS (ρ = –0.551) and OSS (ρ = 0.532).ConclusionPatients who were SGUS positive show a distinct clinical phenotype in all aspects of the disease compared with patients who were SGUS negative: clinical, functional, serological, and PROM. SGUS could be a helpful tool in selecting patients for clinical trials and estimating treatment need.

There is accumulating evidence that patients with primary Sjögren's syndrome (pSS) display aberrant CD4+ T cell responses, both in the peripheral compartment and in the inflamed salivary glands. CD4+ T cell abnormalities are also critically associated with B cell hyper activation, one of the hallmarks of disease, which is linked with disease severity and evolution to lymphoma. T cell activation and the cross-talk between T and B cells are tightly regulated by the balance between co-stimulatory pathways, such as the interactions between CD80/CD86:CD28, CD40:CD40L and ICOS:ICOSL, and co-inhibitory signals, including the immunoregulatory CTLA-4 protein. Evidence from patients with pSS as well as data from animal models of the disease suggests that these pathways play a critical role in pSS pathogenesis and their targeting could be exploited for therapeutic purposes. In this review, we first summarise the evidence implicating aberrant T cell co-stimulation and co-inhibition in driving the disease before focusing on the results of recent randomised controlled trials (RCTs) with compounds able to block T cell co-stimulation and enhance T cell co-inhibition. Despite a clear biological effect on downstream B cell activation has been observed in patients treated with CTLA-4-Ig (abatacept) and with monoclonal antibodies targeting CD40 and ICOSL, the clinical efficacy of this approach has so far yielded mixed results; while the anti-CD40 monoclonal antibody iscalimab showed significant improvement in systemic disease activity compared to placebo, two large RCTs with abatacept and a phase IIa RCT with an anti-ICOSL monoclonal antibody (prezalumab) failed to reach their primary endpoints. Although the discrepancies between biological and clinical efficacy of targeting T cell co-stimulation on pSS remain unresolved, several factors including drug bioavailability and receptor occupancy, patient stratification based on T-cell related biomarkers and the choice of study outcome are likely to play an important role and form the basis for further work towards the quest for a disease-modifying biologic therapy in pSS.

Objectives To systematically review the impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and severe adverse events (SAEs) in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) in remission or low disease activity (LDA) state. Materials and methods A meta-analysis based on a systematic review of PubMed, Embase, Cochrane, until August 2019, as well as relevant databases of international conferences, was used to evaluate the risk difference (RD) at 95% confidence interval (95% CI) of incidence density of serious infections, SAEs, malignancies, cardiovascular adverse events (CV AEs), or deaths after tapering (dose reduction or spacing) compared to continuation of targeted therapies. Results Of the 1957 studies initially identified, 13 controlled trials (9 RA and 4 SpA trials) were included in the meta-analysis. 1174 patient-years were studied in the tapering group (TG) versus 1086 in the usual care group (UC). There were 1.7/100 patient-year (p-y) serious infections in TG versus 2.6/100 p-y in UC (RD (95% CI) 0.01 (0.00 to 0.02), p = 0.13) and 7.4/100 p-y SAEs in TG versus 6.7/100 p-y in UC (RD 0.00 (− 0.02 to 0.02), p = 0.82). The risk of malignancies, CV AEs, or deaths did not differ between the tapering and the usual care groups. Subgroup analysis (RA and SpA) detected no significant differences between the two groups. Conclusion We could not show significant impact of tapering bDMARD or JAKi over continuation concerning the risk of serious infections, SAEs, malignancies, CV AEs, or deaths in RA and SpA patients in remission or LDA state.

The intestinal microbiota is believed to play a role in the pathogenesis of inflammatory bowel disease in humans and chronic inflammatory enteropathy (CIE) in dogs. While most previous studies have described the gut microbiota using sequencing methods, it is fundamental to assess the spatial distribution of the bacteria for a better understanding of their relationship with the host. The microbiota in the colonic mucosa of 22 dogs with CIE and 11 control dogs was investigated using fluorescence in situ hybridization (FISH) with a universal eubacterial probe (EUB338) and specific probes for select bacterial groups. The number of total bacteria labeled with EUB338 probe was lower within the colonic crypts of dogs with CIE compared to controls. Helicobacter spp. and Akkermansia spp. were decreased on the colonic surface and in the crypts of dogs with CIE. Dogs with CIE had increased number of Escherichia coli/Shigella spp. on the colonic surface and within the crypts compared to control dogs. In conclusion, the bacterial microbiota in the colonic mucosa differed between dogs with and without CIE, with depletion of the crypt bacteria in dogs with CIE. The crypt bacterial species that was intimately associated with the host mucosa in control dogs was composed mainly of Helicobacter spp.

Contains fulltext : 220769.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Juvenile dermatomyositis (DM) is a heterogeneous systemic immune-mediated vasculopathy. This study was undertaken to 1) identify inflammation/endothelial dysfunction-related biomarker profiles reflecting disease severity at diagnosis, and 2) establish whether such biomarker profiles could be used for predicting the response to treatment in patients with juvenile DM. METHODS: In total, 39 biomarkers related to activation of endothelial cells, endothelial dysfunction, and inflammation were measured using multiplex technology in serum samples from treatment-naive patients with juvenile DM from 2 independent cohorts (n = 30 and n = 29). Data were analyzed by unsupervised hierarchical clustering, nonparametric tests with correction for multiple comparisons, and Kaplan-Meier tests with Cox proportional hazards models for analysis of treatment duration. Myositis-specific antibodies (MSAs) were measured in the patients' serum using line blot assays. RESULTS: Severe vasculopathy in patients with juvenile DM was associated with low serum levels of intercellular adhesion molecule 1 (Spearman's rho [rs ] = 0.465, P = 0.0111) and high serum levels of endoglin (rs = -0.67, P < 0.0001). In the discovery cohort, unsupervised hierarchical clustering analysis of the biomarker profiles yielded 2 distinct patient clusters, of which the smaller cluster (cluster 1; n = 8) exhibited high serum levels of CXCL13, CCL19, galectin-9, CXCL10, tumor necrosis factor receptor type II (TNFRII), and galectin-1 (false discovery rate

To update the European League Against Rheumatism (EULAR) recommendations for the role of the nurse in the management of chronic inflammatory arthritis (CIA) using the most up to date evidence. The EULAR standardised operating procedures were followed. A task force of rheumatologists, health professionals and patients, representing 17 European countries updated the recommendations, based on a systematic literature review and expert consensus. Higher level of evidence and new insights into nursing care for patients with CIA were added to the recommendation. Level of agreement was obtained by email voting. The search identified 2609 records, of which 51 (41 papers, 10 abstracts), mostly on rheumatoid arthritis, were included. Based on consensus, the task force formulated three overarching principles and eight recommendations. One recommendation remained unchanged, six were reworded, two were merged and one was reformulated as an overarching principle. Two additional overarching principles were formulated. The overarching principles emphasise the nurse's role as part of a healthcare team, describe the importance of providing evidence-based care and endorse shared decision-making in the nursing consultation with the patient. The recommendations cover the contribution of rheumatology nursing in needs-based patient education, satisfaction with care, timely access to care, disease management, efficiency of care, psychosocial support and the promotion of self-management. The level of agreement among task force members was high (mean 9.7, range 9.6-10.0). The updated recommendations encompass three overarching principles and eight evidence-based and expert opinion-based recommendations for the role of the nurse in the management of CIA.

Objectives: Low circulating vitamin D levels are associated with an increased risk of active MRI lesions and relapses in several cohorts with relapsing remitting multiple sclerosis (RRMS). Randomized controlled supplementation trials are, however, negative on their primary endpoints, while secondary MRI endpoints suggest anti-inflammatory effects. Circulating levels of neurofilament light chain (NfL) are a biomarker of disease activity in RRMS. We explored whether 48-week high-dose vitamin D 3 supplements were associated with lower circulating NfL levels. Materials & Methods: Of N = 40 Dutch interferon beta-treated participants with RRMS of the SOLAR trial, plasma samples at baseline and 48-week follow-up were available. Of these participants, N = 24 were supplemented with 14 000 IU/d vitamin D 3 and N = 16 with placebo. Twenty-five hydroxyvitamin D 3 (25(OH)D 3) levels were measured with LC-MS/MS, and NfL levels were measured in duplicate with Simoa. Results: Serum 25(OH)D 3 levels at 48 weeks were increased in the vitamin D 3 when compared to placebo group (median level 281 [IQR 205-330] vs 72 [39-88] nmol/L; P 3 for 48 weeks was not associated with lower NfL levels. This study does not support an effect of vitamin D 3 on this biomarker of neuro-axonal injury.

The recent development of assays that accurately quantify neurofilament light, a neuronal cytoskeleton protein, in plasma has generated a vast literature supporting that it is a sensitive, dynamic, and robust biomarker of neuroaxonal damage. As a result, efforts are now made to introduce plasma neurofilament light into clinical routine practice, making it an easily accessible complement to its cerebrospinal fluid counterpart. An increasing literature supports the use of plasma neurofilament light in differentiating neurodegenerative diseases from their non-neurodegenerative mimics and suggests it is a valuable biomarker for the evaluation of the effect of putative disease-modifying treatments (e.g. in multiple sclerosis). More contexts of use will likely emerge over the coming years. However, to assist clinical interpretation of laboratory test values, it is crucial to establish normal reference intervals. In this study, we sought to derive reliable cut-offs by pooling quantified plasma neurofilament light in neurologically healthy participants (5-90 years) from eight cohorts. A strong relationship between age and plasma neurofilament light prompted us to define the following age-partitioned reference limits (upper 95th percentile in each age category): 5-17 years= 7 pg/mL; 18-50 years =10 pg/mL; 51-60 years=15 pg/mL; 61-70 years=20 pg/mL; 70 + years =35 pg/mL. The established reference limits across the lifespan will aid the introduction of plasma neurofilament light into clinical routine, and thereby contribute to diagnostics and disease-monitoring in neurological practice. J.S. is supported by Stohne's stiftelse, Stiftelsen för Gamla Tjänarinnor, and Demensfonden. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för GamLa Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), European Union Joint Program for Neurodegenerative Disorders (JPND2021-00694), and the UK Dementia Research Institute at UCL. K.B. is supported by the Swedish Research Council (grant 2017-00915), the ADDF (grant RDAPB-201809-2016615), the Swedish Alzheimer Foundation (grant AF-742881), Hjärnfonden, Sweden (grant FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the Avtal om Läkarutbildning och Forskning agreement (grant ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (grant JPND2019-466-236), the National Institutes of Health (grant 1R01AG068398-01), and the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495). J.G. is supported by grants from the Swedish Alzheimer fund “Alzheimerfonden” (#AF-930934), Åhlénsstiftelsen (#213036) and Stiftelsen GamLa Tjänarinnor. L.N./Betula is supported by a scholar grant from the Knut and Alice Wallenberg (KAW) Foundation. M.S.C. receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 948677), the Instituto de Salud Carlos III (PI19/00155), and from a fellowship from ‘la Caixa’ Foundation (ID 100010434) and from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847648 (LCF/BQ/PR21/11840004). RG is supported by the Italian Ministry of Health, Ricerca Corrente.

BackgroundC reactive protein (CRP) levels are suggested as serum biomarkers in the diagnosis and prognosis of psoriatic arthritis (PsA). However, increased CRP levels are found in less than 50% of PsA patients even in the presence of active disease.ObjectivesTo evaluate the role of CRP levels in interventional clinical trials in PsA patients to better understand the trial generalisability, relationship with disease activity and predictive value for treatment response and decision making.MethodsA systematic review was conducted via PubMed, Cochrane and Embase. We focused on phase III trials in PsA.ResultsEight of 22 studies applied minimum baseline CRP levels for inclusion. Baseline CRP levels were wide-ranging (0.1–238 mg/L) and lower in studies without CRP in the enrolment criteria. All 22 studies used the American College of Rheumatology (ACR20) response and other endpoints that integrated CRP levels. One of seven studies that evaluated individual ACR-score components revealed a decrease in CRP levels along with improvement of other endpoints. Subanalyses show conflicting evidence on CRP levels as predictor of disease course.ConclusionCRP levels were inconsistently used as inclusion criterion in clinical trials, often limiting generalisability of the data. The use of composite scores such as ACR20 or Disease Activity Score-28-CRP is also limited since baseline levels of CRP affects their sensitivity to change. High CRP levels may be an individual predictor for disease progression and response to treatment, but the current conflicting findings and selective patient trial inclusions, do not allow CRP to play a very prominent role in treatment decision making.

Introduction Juvenile idiopathic arthritis (JIA) is a cluster of autoimmune rheumatic diseases occurring in children 16 years of age or less. While it is well-known that pain may be experienced during inflammatory and non-inflammatory states, much remains ambiguous regarding the molecular mechanisms that may drive JIA pain. Thus, in this pilot study, we explored the variability of the serum proteomes in relation to pain severity in a cohort of JIA patients. Methods Serum samples from 15 JIA patients (male and female, 12.7 ± 2.8 years of age) were assessed using liquid chromatography/mass spectrometry (LC/MS). Correlation analyses were performed to determine the relationships among protein levels and self-reported clinical pain severity. Additionally, how the expression of pain-associated proteins related to markers of inflammation (Erythrocyte Sedimentation Rate (ESR)) or morphological properties of the central nervous system (subcortical volume and cortical thickness) implicated in JIA were also evaluated. Results 306 proteins were identified in the JIA cohort of which 14 were significantly (p, In the current preliminary study, serum proteins associated with pain severity were identified in JIA patients. Pain-associated proteins had functional roles predominantly in immune or inflammatory processes. Correlations of pain-associated proteins with ESR and altered CNS morphology were also observed with ESR and altered CNS morphology were also observed. Larger-scale as well as longitudinal studies are needed to determine if evaluation of the proteome may provide a platform for identifying novel analgesic targets in JIA. Supplementary Information The online version contains supplementary material available at 10.1186/s12969-022-00662-1.

Multiple sclerosis (MS) is the most common inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. Chronic-relapsing experimental autoimmune encephalomyelitis (crEAE) in Biozzi ABH mice is an experimental model of MS. This crEAE model is characterized by an acute phase with severe neurological disability, followed by remission of disease, relapse of neurological disease and remission that eventually results in a chronic progressive phase that mimics the secondary progressive phase (SPEAE) of MS. In both MS and SPEAE, the role of microglia is poorly defined. We used a crEAE model to characterize microglia in the different phases of crEAE phases using morphometric and RNA sequencing analyses. At the initial, acute inflammation phase, microglia acquired a pro-inflammatory phenotype. At the remission phase, expression of standard immune activation genes was decreased while expression of genes associated with lipid metabolism and tissue remodeling were increased. Chronic phase microglia partially regain inflammatory gene sets and increase expression of genes associated with proliferation. Together, the data presented here indicate that microglia obtain different features at different stages of crEAE and a particularly mixed phenotype in the chronic stage. Understanding the properties of microglia that are present at the chronic phase of EAE will help to understand the role of microglia in secondary progressive MS, to better aid the development of therapies for this phase of the disease.

BackgroundAnkylosing spondylitis (AS) impacts quality of life. We assessed patient-reported outcomes (PROs), pain, fatigue, health-related quality of life (HRQoL) and work productivity in a phase III trial of tofacitinib.MethodsAdults with AS and with inadequate response/intolerance to ≥2 non-steroidal anti-inflammatory drugs received tofacitinib 5 mg twice daily or placebo for 16 weeks. Afterwards, all received open-label tofacitinib until week 48. Change from baseline to week 48 was determined for PROs: total back pain; nocturnal spinal pain; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) overall spinal pain (Q2); Functional Assessment of Chronic Illness Therapy-Fatigue; BASDAI fatigue (Q1); AS Quality of Life (ASQoL); Short Form-36 Health Survey Version 2 (SF-36v2); EuroQoL-Five Dimension-Three Level health profile and Visual Analogue Scale; and the Work Productivity and Activity Impairment (WPAI) questionnaire. Improvements from baseline ≥minimum clinically important difference, and scores ≥normative values at week 16 were evaluated.ResultsIn 269 randomised and treated patients, at week 16, there were greater least squares mean improvements from baseline with tofacitinib 5 mg twice daily versus placebo in BASDAI overall spinal pain (–2.85 vs –1.34), BASDAI fatigue (–2.36 vs –1.08), ASQoL (–4.03 vs –2.01) and WPAI overall work impairment (–21.49 vs –7.64) (all pConclusionsIn patients with AS, treatment with tofacitinib 5 mg twice daily resulted in clinically meaningful improvements in pain, fatigue, HRQoL and work productivity versus placebo to week 16, which were sustained to week 48.Trial registration numberNCT03502616.

Objectives Factors associated with disease activity of axial spondyloarthritis (axSpA) and switching of biologic diseasemodifying anti-rheumatic drugs have not been clearly defned. We aimed to evaluate clinical characteristics of patients with axSpA, factors related to remission in treat to target era and predictive factors for biologic disease-modifying anti-rheumatic drug switching. Method A multicenter, observational cross-sectional study was performed between February 2019 and August 2019. We included all consecutive patients≥18 years with axSpA. Demographic and clinical variables were prospectively recorded. Clinical tools included Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI), and Maastricht Ankylosing Spondylitis Enthesitis Score (MASES). Results There were 969 patients with a mean age of 43.4±10.8 years. There were 143 patients (14.8%) with remission and 223 (23.1%) patients with low disease activity. Male sex (p=0.021), positive family history (p=0.036), and human leukocyte antigen-B27 (p=0.011) were predictors of remission by ASDAS-CRP. There were 654 patients (67.5%) who did not switch to another drug. The highest BASMI and MASES scores were calculated in patients with very high disease activity (p

Background/aim: The revised Leeds Disability Questionnaire (RLDQ) is a unique assessment tool for patients with ankylosing spondylitis (AS); its comprehensive structure includes posture and neck flexibility parameters. The aim of the study was to determine the psychometric properties of the Turkish RLDQ in patients with AS. Materials and methods: A total of 100 AS patients were enrolled in the study. In the first evaluation, patients filled out the Dougados Functional Index (DFI) and Bath Ankylosing Spondylitis Functional Index (BASFI), Stanford Health Assessment Questionnaire (HAQ) in addition to RLDQ. Then, patients were refilled the revised RLDQ in the second assessment. Results: The mean age of the patients (40 women, 60 men) was 48.3 +/- 12.6 years. The test-retest reliability and internal consistency of the RLDQ total score were excellent. ICC score and Cronbach's alpha score were calculated as 0.853 and 0.905, respectively. The SEM and MDC values calculated for the RLDQ total score were 2.74 and 7.60, respectively. RLDQ had degrees of correlation with DFI, HAQ, and BASFI of 0.814, 0.742, and 0.852, respectively. Construct validity was excellent (r > 0.50, p < 0.01). Conclusion: The Turkish version of the RLDQ was found to be valid and reliable in patients with AS. It should be emphasized that the RLDQ is a distinctive and valuable tool that focuses separately on neck, posture, or other mobility parameters in the clinical assessment of AS.

Publisher Copyright: © 2021 GA²LEN. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA(2)LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous or inducible urticaria is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Background Self-efficacy, or patients’ confidence in their ability to control disease and its consequences, was recently prioritised in EULAR recommendations for inflammatory arthritis self-management strategies. However, it remains unclear which factors influence self-efficacy in early rheumatoid arthritis (RA). Methods Data were analysed from the 2-year RCT Care in early RA (CareRA), which studied remission-induction treatment regimens for early RA. Participants completed the Arthritis Self-Efficacy Scale (ASES), Short-Form 36 (SF-36), Revised Illness Perception Questionnaire (IPQ-R), Utrecht Coping List (UCL), RAQoL and Health Assessment Questionnaire (HAQ). Depending on time to first remission (DAS28-CRP < 2.6) and persistence of remission, treatment response was defined as persistent response, secondary failure, delayed response, late response or non-response. The association between ASES scores and clinical/psychosocial factors was explored with Spearman correlation and multivariate linear mixed models. Baseline predictors of week 104 ASES were identified with exploratory linear regression followed by multiple regression of significant predictors adjusted for DAS28-CRP, HAQ, treatment arm, treatment response, cumulative CRP/SJC28 and demographic/serologic confounders. Results All 379 patients had a recent diagnosis of RA and were DMARD-naïve at study initiation. Most patients were women (69%) and RF/ACPA-positive (66%), and the mean (SD) age was 52 (13) years. For all tested outcome measures, better perceived health correlated with higher self-efficacy. While patient-reported factors (HAQ, SF-36, RAQoL, IPQ-R, pain, fatigue and patient’s global assessment) showed moderate/strong correlations with ASES scores, correlations with physician-reported factors (physician’s global assessment, SJC28), TJC28 and DAS28-CRP were weak. Only more favourable outcomes on patient-reported factors and DAS28-CRP were associated with higher ASES scores at each time point. An earlier, persistent treatment response predicted higher ASES scores at both weeks 52 and 104. Significant baseline predictors of week 104 ASES included HAQ; SF-36 mental component score, vitality, mental health and role emotional; IPQ-R illness coherence, treatment control, emotional representations and consequences; UCL Passive reacting; and the RAQoL. Conclusions Patient-reported outcomes and treatment response were early determinants of long-term self-efficacy in an early RA trial. These results provide further relevance for the window of opportunity in an early treat-to-target strategy and could help to timely identify patients who might benefit from self-management interventions. Trial registration EudraCT 2008-007225-39

BACKGROUND & AIMS: Histologic features of inflammation (histologic inflammation) are associated with clinical relapse in patients with ulcerative colitis (UC). Concentration of fecal calprotectin (FC) can be used to identify patients with mucosal inflammation. We aimed to assess the accuracy of FC measurements in identifying patients with histologic inflammation and to develop a model to predict outcomes of therapy. METHODS: We performed a post hoc analysis of data from a phase 4 trial of the efficacy of multimatrix mesalamine in patients with mild to moderate UC (the MOMENTUM trial). We obtained clinical, endoscopic, and histologic data from week 8 (n = 639) and week 52 (n = 373) of the trial. We used area under the receiver operating characteristic curves to determine the accuracy and optimal cut-off values of FC in identifying patients with different therapeutic outcomes (clinical remission, endoscopic healing, deep remission, or histologic remission) at week 8 and week 52. We performed multivariable logistic regression analyses to identify factors associated with these outcomes. RESULTS: Median FC concentrations were lower in patients who achieved outcomes of clinical remission, endoscopic healing, deep remission, or histologic remission vs patients who did not. FC concentrations identified patients with endoscopic healing and histologic remission with area under the receiver operating characteristic curve values of 0.77 and 0.76 at week 8, and 0.79 and 0.80 at week 52, respectively. The optimal FC cut-off concentrations for identification of patients with histologic remission were 75 μg/g at week 8 and 99 μg/g at week 52. In the subpopulation with an endoscopy score of 0, median FC concentrations were lower in patients with histologic remission than in patients with microscopic inflammation at week 8 (30 vs 140 μg/g; area under the receiver operating characteristic, 0.72) and week 52 (21.5 vs 134.5 μg/g; area under the receiver operating characteristic, 0.71). At both time points, the optimal FC cut-off concentration was approximately 75 μg/g. Our final prediction model for week 52 histologic remission comprised endoscopic score at week 8, FC concentration at week 8, and histologic activity at baseline and week 8. CONCLUSIONS: A post hoc analysis of data from a phase 4 trial found that, even in patients with complete endoscopic healing of UC, FC concentration can be used to discriminate patients with ongoing microscopic inflammation from patients with histologic remission. The optimal cut-off concentration of FC is between 75 and 100 μg/g. ClinicalTrials.gov no: NCT01124149. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:19 issue:11 pages:2333-2342 ispartof: location:United States status: published

Systemic lupus erythematosus (SLE) is associated with a higher risk of complications in pregnancy. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been evaluated in numerous inflammatory diseases. We evaluated the possible role of these markers in SLE pregnancies. Forty-six pregnant patients with an already established diagnosis of SLE were included in the study. Complete blood counts were obtained upon admission for delivery. Seven patients were diagnosed with a flare and managed with multiple medications, whereas rest of the patients were not on any treatment or managed with monotherapy. NLR and PLR values were also evaluated between two groups and no statistically significant difference was found (p=.44 and p=.80, respectively). This study is the first to evaluate the possible role of NLR and PLR in pregnant SLE patients in the literature. Further studies are warranted for an elaborate evaluation of NLR and PLR in lupus pregnancies.Impact Statement What is already known on this subject? Pregnancy in the setting of SLE is associated with a higher risk of complications. Active disease increases the risk of adverse outcomes further. What the results of this study add? This study is the first to evaluate NLR and PLR in pregnancies complicated by SLE. No significant association between the course of the disease in pregnancy and NLR/PLR was documented. What the implications are of these findings for clinical practice and/or further research? Further studies on the markers to predict prognosis of SLE in pregnancy are required to improve the maternal and neonatal outcomes in this exclusive group of high-risk patients.

B-cells contribute to MS pathogenesis. The association of circulating B-cell phenotypes with combined unique active lesions (CUA) on MRI at 48 weeks follow-up was investigated in 50 interferon beta-treated MS patients. Transitional B-cell proportions were lower in participants with CUA at week 0 and 48 [p = 0.004, p = 0.002]. A decrease in circulating anti-EBNA-1 IgG levels between week 0 and 48 associated with absence of CUA [p = 0.047], but not with B-cell profiles. In a multi-factor model for CUA-risk, transitional B-cell proportions contributed independent from NK/T-cell ratio, change in anti-EBNA-1 IgG, and vitamin D supplementation. Transitional B-cells may predict treatment response in MS.

Objective To investigate the long-term outcomes of coronary artery bypass grafting surgery (CABG) in patients with rheumatoid arthritis (RA). Methods Patients with RA (n = 378) were retrospectively compared to patients without RA (n = 7560), all treated with CABG in a multicentre, population-based cohort register study in Finland. The outcomes were studied with propensity score-matching adjustment for baseline features. The median follow-up was 9.7 years. Results Diagnosis of RA was associated with an increased risk of mortality after CABG compared to patients without RA (HR 1.50; CI 1.28-1.77; p < .0001). In addition, patients with RA were in higher risk of myocardial infarction during the follow-up period (HR 1.61; CI 1.28-2.04; p < .0001). Cumulative rate of repeated revascularization after CABG was 14.4% in RA patients and 12.0% in control patients (p = .060). Duration of RA before CABG (p = .011) and preoperative corticosteroid usage in RA (p = .041) were independently associated with higher mortality after CABG. There were no differences between the study groups in 30-d mortality or in the post-operative usage of cardiovascular medications. Conclusions RA is independently associated with worse prognosis in coronary artery disease treated with CABG. Preoperative corticosteroid use and longer RA disease duration are additional risk factors for mortality. Key messages Patients with rheumatoid arthritis (RA) have impaired long-term outcomes after coronary artery bypass surgery (CABG). Glucocorticoid use before CABG and duration of RA are associated with higher mortality. Special attention should be paid in secondary prevention of cardiovascular disease in RA patients after CABG.

BackgroundPain is a core domain of psoriatic arthritis (PsA). This post hoc analysis evaluated time to pain improvement and the impact of baseline pain severity on pain response in patients with PsA receiving tofacitinib.MethodsData from two trials (NCT01877668; NCT01882439) in patients receiving tofacitinib 5 mg twice daily, placebo switching to tofacitinib 5 mg twice daily at month 3 (placebo-to-tofacitinib) or adalimumab (NCT01877668 only) were included. Improvement in pain (≥30%/≥50% decrease from baseline in Visual Analogue Scale pain score) was assessed; median time to initial (first post-baseline visit)/continued (first two consecutive post-baseline visits) pain improvement was estimated (Kaplan-Meier) for all treatment arms. A parametric model was used to determine the relationship between baseline pain severity and time to pain response in patients receiving tofacitinib.ResultsAt month 3, more patients experienced pain improvements with tofacitinib/adalimumab versus placebo. Median days (95% CI) to initial/continued pain improvements of ≥30% and ≥50%, respectively, were 55 (29–57)/60 (57–85) and 85 (57–92)/171 (90–not estimable (NE)) for tofacitinib, versus 106 (64–115)/126 (113–173) and 169 (120–189)/NE (247–NE) for placebo-to-tofacitinib. Pain improvements were also experienced more quickly for adalimumab versus placebo. Predicted time to ≥30%/≥50% pain improvement was shorter in patients with higher baseline pain versus lower baseline pain (tofacitinib arm only).ConclusionsIn patients with PsA, pain improvements were experienced by more patients, and more rapidly, with tofacitinib and adalimumab versus placebo. In those receiving tofacitinib, higher baseline pain was associated with faster pain improvements.

ObjectivesTo investigate the occurrence of sick leave (SL) and the impact of clinical and socioeconomic factors on SL in early axial spondyloarthritis (axSpA).MethodsPatients with a clinical diagnosis of axSpA from the DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR) cohort with work-related data and up to 5-year follow-up were studied. Incidence, time to first SL and potential role of baseline and time-varying clinical and socioeconomic factors (age, gender, ethnicity, education, job type, marital and parental status) were analysed. Univariable analyses, followed by collinearity and interaction tests, guided subsequent multivariable time-varying Cox survival model building.ResultsIn total, 704 axSpA patients were included (mean (SD) age 33.8 (8.6); 46% men). At baseline, 80% of patients were employed; of these, 5.7% reported being on SL. The incidence of SL among those at risk during the study period (n=620, 88%) was 0.05 (95% CI 0.03 to 0.06) per 1000 days of follow-up. Mean (SD) time to first SL was 806 (595) days (range: 175–2021 days). In multivariable models, male gender (HR 0.41 (95% CI 0.20 to 0.86)) and higher education (HR 0.48 (95% CI 0.24 to 0.95)) were associated with lower hazard of SL, while higher disease activity (HR 1.49 (95% CI 1.04 to 2.13)), older age, smoking and use of tumour necrosis factor inhibitors were associated with higher hazard of SL.ConclusionsIn this early axSpA cohort of young, working-age individuals, male gender and higher education were independently associated with a lower hazard of SL, whereas older age and higher disease activity were associated with higher hazard of SL. The findings suggest a role of socioeconomic factors in adverse work outcomes, alongside active disease.

Primary care physicians can play a crucial role by recognising Sjögren's syndrome (SS) in the early stages identifying those patients with the greatest probability of being diagnosed with SS. SS has a very specific epidemiological profile at presentation (female aged 30-50 years), which may aid an early diagnosis. Although the disease may be expressed in many guises, there are three predominant clinical presentations that should be considered as key clues to increased clinical suspicion (multiple symptoms of dryness, asthenia-polyalgia syndrome and systemic organ-specific manifestations). The physical examination may provide important clues to systemic involvement (parotid gland enlargement, skin lesions suggestive of purpura or annular erythema, respiratory crackles, arthritis, neurological sensory or motor deficits). Simple laboratory studies may be very useful in reinforcing the clinical suspicion of SS, and the triad of cytopenia, raised erythrocyte sedimentation rate and high serum gamma globulin levels is a very specific "biological" pattern suggesting SS. A solid clinical suspicion of SS requires both the patient reporting sicca symptoms and objective evidence that these symptoms are associated with dysfunction of the lachrymal and salivary glands. Ultrasonography of the parotid glands, a non-invasive method, may be a major advance in the diagnostic approach to SS in primary care. Primary care physicians must be considered essential members of the multidisciplinary team in charge of the follow-up of SS patients, due to their key role in the continuum of patient care and their cross-sectional knowledge of common diseases that frequently coexist in patients with SS.

Objective.Long-term outcome data in adults with childhood-onset systemic lupus erythematosus (cSLE) are limited. Here, we report the effects of cSLE on education, vocation, and employment in a large cohort of adults with cSLE.Methods.Patients were seen for a single study visit comprising a structured history and physical examination. Medical records were retrieved to supplement information obtained during the study visit. Education and employment status were assessed by questionnaires. Health-related quality of life (HRQOL) was measured with the 36-Item Short Form Health Survey (SF-36).Results.One hundred six patients with cSLE (93% female, 73% White), with a median disease duration of 20 years, completed the visit and questionnaires. Almost all patients stated that cSLE had influenced their education, but the level of completed education was similar to the general Dutch population. Half of the patients had adjusted their vocational choice due to the disease. Still, 44% of patients who had finished education did not have a paid job. Of the employed patients, 61% worked part time. Disease damage was equally prevalent in patients with and without paid employment. A high percentage of patients (51%) were declared work disabled, due to disease damage. Patients who did not have paid employment were often work disabled. Both had a negative effect on HRQOL.Conclusion.The effect of cSLE on academic achievements and employment is substantial, despite patients adjusting their educational and vocational choices. To optimize participation in the community, ongoing support is necessary, not only to help patients find suitable education and vocations but also to offer guidance regarding potential adjustments during their career.

Background There is a need for additional biomarkers to assist in the diagnosis and prognosis of rheumatoid arthritis (RA). The aim of our study was to evaluate the (pre-analytical, analytical and clinical) performance of serum calprotectin as a marker of inflammation in RA. Methods The study population included 463 rheumatologic patients (including 111 RA patients and 352 controls) who for the first time consulted a rheumatologist, 20 healthy controls and 27 patients with an infectious disease. Calprotectin was measured (using four different assays) in serum or in serum and EDTA plasma (healthy controls and infectious disease group). For rheumatologic patients, results for C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) were available. Results Results for blood calprotectin were assay- and matrix-dependent, with higher values found in serum than in plasma. Serum calprotectin was higher in RA patients than in rheumatologic diseased controls and in healthy controls. Serum calprotectin was lower in RA patients than in patients with an infectious disease. Serum calprotectin was associated with disease activity (DAS score). The area under the curve (AUC) to discriminate RA from controls was 0.756 for CRP, 0.714 for ESR and 0.726–0.783 for calprotectin. Conclusions Our data document that calprotectin measurement is assay- and matrix-dependent. Serum calprotectin is associated with disease activity. Additional (prospective) studies are warranted to further evaluate the prognostic and diagnostic value of blood calprotectin measurements.

Background. Early detection of renal involvement in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is of major clinical importance to allow prompt initiation of treatment and limit renal damage. Urinary soluble cluster of differentiation 163 (usCD163) has recently been identified as a potential biomarker for active renal vasculitis. However, a significant number of patients with active renal vasculitis test negative using usCD163. We therefore studied whether soluble CD25 (sCD25), a T cell activation marker, could improve the detection of renal flares in AAV.Methods. sCD25 and sCD163 levels in serum and urine were measured by enzyme-linked immunosorbent assay in 72 patients with active renal AAV, 20 with active extrarenal disease, 62 patients in remission and 18 healthy controls. Urinary and blood CD4(+) T and CD4(+) T effector memory (TEM) cell counts were measured in 22 patients with active renal vasculitis. Receiver operating characteristics (ROC) curves were generated and recursive partitioning was used to calculate whether usCD25 and serumsoluble CD25 (ssCD25) add utility to usCD163.Results. usCD25, ssCD25 and usCD163 levels were significantly higher during active renal disease and significantly decreased after induction of remission. A combination of usCD25, usCD163 and ssCD25 outperformed all individual markers (sensitivity 84.7%, specificity 95.1%). Patients positive for sCD25 but negative for usCD163 (n = 10) had significantly higher C-reactive protein levels and significantly lower serum creatinine and proteinuria levels compared with the usCD163positive patients. usCD25 correlated positively with urinary CD4(+) T and CD4(+) TEM cell numbers, whereas ssCD25 correlated negatively with circulating CD4(+) T and CD4+ TEMcells.Conclusion. Measurement of usCD25 and ssCD25 complements usCD163 in the detection of active renal vasculitis.

ObjectivesThe main objective of this study was to determine whether the DNA methylation profile of children born to mothers with rheumatoid arthritis (RA) is different from that of children born to mothers from the general population. In addition, we aimed to determine whether any differences in methylation are associated with maternal RA disease activity or medication use during pregnancy.MethodsFor this study, genome-wide DNA methylation was measured at cytosine-phosphate-guanine (CpG) sites, using the Infinium Illumina HumanMethylation 450K BeadChip, in 80 blood samples from children (mean age=6.8 years) born to mothers with RA. As controls, blood samples from 354 children (mean age=6.0 years) from the population-based Generation R Study were used. Linear mixed models were performed to investigate differential methylation between the groups, corrected for relevant confounders.ResultsA total of 147 CpGs were differentially methylated between blood samples of children born to mothers with RA and the control blood samples. The five most significantly associated CpGs were cg06642177, cg08867893, cg06778273, cg07786668 and cg20116574. The differences in methylation were not associated with maternal RA disease activity or medication use during pregnancy.ConclusionsDNA methylation at 147 CpGs differed between children born to mothers with RA and children born to mothers from the general population. It remains unknown whether the identified associations are causal, and if so whether they are caused by the disease or treatment. More research, including replication of these results, is necessary in order to strengthen the relevance of our findings for the later-life health of children born to mothers with RA.

International audience; Background: In patients with axial spondyloarthritis (axSpA), monocytes show a pre-activated phenotype. Gut inflammation is a trigger of monocyte activation and may also affect their development in the bone marrow (BM). As gut inflammation is commonly observed in axSpA patients, we performed a detailed analysis of monocyte transcriptomes of axSpA patients in two cohorts and searched for signs of activation and developmental adaptations as putative imprints of gut inflammation. Methods: Transcriptomes of blood CD14+ monocytes of HLA-B27+ axSpA patients and healthy controls (HC) were generated by microarrays from cohort 1 and by RNA-sequencing from cohort 2. Differentially expressed genes from both analyses were subjected to gene set enrichment analysis (GSEA) and to co-expression analysis in reference transcriptomes from BM cells, blood cells and activated monocytes. As serological markers of translocation, 1,3 beta-glycan, intestinal fatty acid binding protein, and lipopolysaccharide binding protein (LBP) were determined by LAL and ELISA. Results: Transcriptome analysis identified axSpA-specific monocyte signatures showing an imprint of LPS/cytokine-activated monocytes, late granulopoietic BM cells, blood neutrophils, and G-CSF-mobilized blood cells, which suggests LPS/TNF activation and more prominent BM adaptation promoting a neutrophil-like phenotype. GSEA mapped axSpA upregulated genes to inflammatory responses and TNFα signaling and downregulated probe-sets to metabolic pathways. Among translocation markers, LBP levels were significantly increased in axSpA patients vs. HC (p < 0.001). Stratified analysis by disease activity and stage identified an “active disease signature” (BASDAI ≥ 4) with an imprint of LPS/cytokine-activated monocytes and CD16+ monocyte subsets. The “AS signature” (vs. non-radiographic axSpA) showed a reinforced neutrophil-like phenotype due to deprivation of dendritic cell transcripts. Conclusions: The neutrophil-like phenotype of axSpA monocytes points towards a biased monocytopoiesis from granulocyte-monocyte progenitors. This shift in monocytopoiesis and the LPS/cytokine imprint as well as the elevated LBP levels are indicators of systemic inflammation, which may result from bacterial translocation. The BM adaptation is most prominent in AS patients while disease activity appears to be linked to activation and trafficking of monocytes.