Multidimensional tracking of phenotypes and organ involvement in a complete nationwide systemic sclerosis cohort.

OBJECTIVE: SSc is a severe, heterogeneous multi-organ disease where population-based estimates on phenotypic spectrum, overall disease burden and societal impact are largely missing. Here the objective was to provide the first-ever complete national-level data on phenotype and major organ afflictions in SSc. METHODS: A stepwise strategy was applied to find and characterize every SSc patient resident in Norway from 2000 to 2012. First we identified every case in the country registered with an International Classification of Diseases, Tenth Revision code for SSc (M34). Next we manually reviewed all cases coded as M34 to determine whether they met the 1980 ACR and/or 2013 ACR/EULAR classification criteria for SSc and could be included in the Norwegian SSc cohort (Nor-SSc). Finally, all disease features from SSc onset to study end were reviewed. RESULTS: The Nor-SSc cohort included 815 SSc patients. The mean age at diagnosis was 53 years, with 84% females and 77% limited cutaneous SSc. The estimated incidence increased from 4 per million in 2000 to 13 per million in 2012. We identified high cumulative frequencies of internal organ involvement, coexistence of multiple organ afflictions across disease subsets and autoantibody status and stable frequencies of pulmonary arterial hypertension across haemodynamic definitions, but indications of referral-related differences in pulmonary hypertension detection rates across the study area. CONCLUSION: This nationwide cohort study provides new, unbiased evidence for a high disease burden in SSc patients of Caucasian descent and indicates the existence of hurdles preventing equality of assessment across the SSc population.

Tracking Impact of Interstitial Lung Disease in Systemic Sclerosis in a Complete Nationwide Cohort.

Rationale: Interstitial lung disease (ILD) represents a major challenge in systemic sclerosis (SSc), but there are no precise, population-based data on its overall impact, limiting opportunities for screening and management strategies.Objectives: Evaluate impact of ILD in a unique, nationwide, population-based SSc cohort.Methods: ILD was assessed prospectively in the Norwegian SSc (Nor-SSc) cohort, including all 815 patients with SSc resident in the country from 2000 to 2012. Lung high-resolution computed tomography (HRCT) scans were available for fibrosis quantification at baseline (n = 650, 80%) and follow-up. Pulmonary function tests were assessed at baseline (n = 703, 86%) and follow-up. Vital status and standardized mortality ratios (SMRs) were estimated at study end (2018) in the 630 incident Nor-SSc cases and 15 individually matched control subjects. Cumulative survival rates were computed.Measurements and Main Results: At baseline, 50% of the subjects with SSc (n = 324) had ILD by HRCT and 46% displayed pulmonary function declines consistent with ILD progression. Mortality correlated with extent of lung fibrosis as SMR increased from 2.2 with no fibrosis to 8.0 with greater than 25% fibrosis. SMR was inversely related to baseline FVC% and increased at all FVC levels below 100%. In patients with normal-range baseline FVC (80-100%), the 5- and 10-year survival rates correlated with presence or absence of lung fibrosis, being 83% and 80%, respectively, with no fibrosis and 69% and 56%, respectively, with lung fibrosis (P = 0.03).Conclusions: The mere presence of ILD at baseline appears to affect outcome in SSc, suggesting that all patients with SSc should undergo a baseline pulmonary function test and lung HRCT screening to diagnose ILD early and tailor further management.

Calprotectin (S100A8/A9) should preferably be measured in EDTA-plasma; results from a longitudinal study of patients with rheumatoid arthritis.

Calprotectin (S100A8/A9), a protein expressed in neutrophils and monocytes/macrophages in circulation and inflamed tissue, is associated with measures of disease activity in rheumatoid arthritis (RA) patients both when measured in ethylenediaminetetraacetic acid (EDTA)-plasma and in serum. We wanted to explore if EDTA-plasma or serum should be preferred for calprotectin as a marker of disease activity. Calprotectin was analysed in EDTA-plasma and serum by enzyme-linked immunosorbent assay (ELISA) at baseline in 141 RA patients, starting biologic disease-modifying anti-rheumatic drugs (bDMARDs), and after three months. Differences between plasma and serum levels of calprotectin were assessed by Wilcoxon signed rank test. Variability was assessed by quartile coefficient of dispersion. Spearman's test explored correlations between calprotectin in plasma and serum and between calprotectin (plasma or serum) and clinical/ultrasound (US) measures of disease activity. Bland Altman plots were used for method comparisons. Conventional inflammatory markers were evaluated for comparison. Calprotectin had similar variability when measured in plasma and serum, but there was a significant difference in concentrations between plasma and serum (p < .001). The correlation coefficients at baseline between calprotectin measured in plasma/serum and measures of disease activity were rs = 0.62/0.46 for sum power Doppler score (PD), rs = 0.60/0.48 for assessor's global visual analogue scale (VAS), rs = 0.59/0.43 for sum grey scale (GS) score and rs = 0.47/0.37 for swollen joint count of 32, all p < .001. Similar differences were found after three months. Calprotectin measured in plasma showed the strongest associations with assessments of disease activity, and EDTA-plasma should preferably be used when evaluating disease activity in RA patients.

The neutrophil protein S100A12 is associated with a comprehensive ultrasonographic synovitis score in a longitudinal study of patients with rheumatoid arthritis treated with adalimumab.

BACKGROUND: The calcium-binding protein S100A12 correlates with measures of disease activity in patients with rheumatoid arthritis (RA). The protein reflects neutrophil activation and the present objective was to explore in a pilot study the associations between S100A12 and other inflammatory markers, clinical assessments as well as degree of synovitis detected by a comprehensive ultrasonography (US) examination in RA patients during biologic treatment. METHODS: Twenty patients with RA were examined clinically and by use of US as well as laboratory markers S100A12, calprotectin, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) before starting adalimumab, with follow-up after 1, 3, 6 and 12 months. Ultrasonographic B-mode (BM) and power Doppler (PD) assessments of 78 joints, 36 tendons/tendon groups and 2 bursas were performed, and sum US scores calculated. Wilcoxon signed rank test assessed treatment response and Spearman rank correlation test was used to calculate correlations. RESULTS: The concentrations of S100A12 decreased after 3 months (p < 0.01) and significant correlations were found between S100A12 and the other laboratory markers during follow-up (0.50-0.62, p < 0.05). Of the clinical assessments, S100A12 had highest correlations with the assessor's global VAS (0.46-0.85, p < 0.05). Compared with CRP and ESR, S100A12 showed higher correlations with the sum US scores (both BM and PD), with median (range) correlation coefficients of 0.55 (0.35-0.78 (NS-p < 0.001)) for sum BM scores and 0.45 (0.27-0.75 (NS-p < 0.001)) for sum PD scores. CONCLUSIONS: The S100A12 protein was significantly associated with other inflammatory markers, clinical assessments as well as sum US scores, indicating that S100A12 is a potential marker of inflammation in RA patients.

Effect of dietary interventions on nutritional status in patients with rheumatoid arthritis and spondyloarthritis - A systematic review and meta-analysis.

BACKGROUND & AIM: Patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) have an increased risk of developing altered body composition, such as low muscle mass, and an increased risk of developing cardiovascular diseases (CVD). Thus, investigating how to improve body composition and CVD risk factors is a relevant topic to improve management of RA and SpA. The aim of this study was to identify dietary interventions that can improve body composition, as well as reduce CVD risk factors in RA and SpA. METHODS: We searched the databases Medline, Embase and Cochrane. Duplicates were removed using Endnote and records were screened through Rayyan. The primary outcomes were muscle mass (kg) and fat mass (kg). Secondary outcomes were body weight (kg), body mass index (BMI: kg/m2), waist circumference (cm) and lipid profile (total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, mmol/L). RESULTS: A total of 4965 articles were identified, and 17 articles were included in this review, of which 15 were suitable for meta-analysis. We found a reduction in TC and LDL-C, (Mean difference, [95%CI]: -0.36, [-0.63, -0.10], I2 = 43%, and -0.20, [-0.35, -0.05], I2 = 0% respectively). Otherwise, no other significant effect was seen in either primary or secondary outcomes. The evidence was graded as moderate for TC and low for LDL-C. CONCLUSION: Dietary interventions might reduce the levels of blood lipids, and consequently, the risk of cardiovascular diseases. However, body composition did not change significantly after a 2-4 month dietary intervention. Both short intervention period and lack of reliable methods to assess body composition are possible explanations for this finding. Further studies of longer duration are needed.

CD64 as a potential biomarker in septic arthritis.

BACKGROUND: Traditional inflammatory markers are generally unhelpful in discerning septic arthritis from inflammatory joint disease due to their lack of specificity. We wished to explore the discriminatory power of the novel inflammatory marker, Fc-gamma-receptor type 1, CD64, in patients presenting with acute arthritis. METHODS: Patients were recruited prospectively in the time period June 2009 to December 2011. Thirty-six patients presenting with an acute flare of chronic rheumatic arthritis, 31 with crystal-induced arthritis and 23 with septic arthritis were included. Traditional inflammatory markers, CD64 and procalcitonin (PCT) were measured and their diagnostic abilities were compared. RESULTS: CD64 and PCT both demonstrated a specificity of 98%, but poor sensitivities of 59% and 52%, respectively. White blood cell count (WBC), and erythrocyte sedimentation rate (ESR) did not have significant discriminatory power, while C-reactive protein (CRP) proved to have the best diagnostic accuracy as measured by area under the ROC curve (AUC 0.92, 95% confidence-interval 0.87-0.98). Subgroup analysis excluding patients with septic arthritis without concurrent bacteremia, and likewise exclusion of the patients with septic arthritis caused by coagulase negative staphylococci, both improved the diagnostic accuracy of CD64 and PCT, but not of WBC and CRP. CONCLUSIONS: CD64 and PCT are highly specific for infectious disease, but they predominantly measure bacteremia. Their use in hospital practice has yet to be defined, and especially so in localized infections.

The treatment effect of intramuscular stimulation on carpal tunnel syndrome: A blinded randomized trial on 75 patients.

BACKGROUND: Carpal tunnel syndrome (CTS) is a disorder with a prevalence of about 5.8% for females and 0.6% for males. This study aims to determine whether intramuscular stimulation (IMS) to the pronator teres muscle subsequently reduces the severity of clinical parameters and the diameter of the median nerve. METHODS: Seventy-five individuals with a cross-sectional diameter of the median nerve of more than 2 mm were included in this randomized clinical trial. Thirty-seven individuals received IMS to the pronator teres muscle with a depth of up to 45-50 mm. The 38 individuals in the control group received an acupuncture needle at Li11 with a depth of 4-5 mm. Both groups had 7 treatments within 7 weeks. The primary outcome was the cross-section of the median nerve in the carpal tunnel. Additionally, Phalen's test, Tinel's sign, VAS for pain intensity, and pincer grip strength were measured. RESULTS: Both IMS subjects and controls showed significant reductions in the cross-section of the median nerve from baseline to follow-up (p < 0.001 and p = 0.002 respectively). The IMS group had the largest change, but the difference in change between the groups was not significant (p = 0.39). On all clinical tests, IMS subjects showed significant improvement from baseline compared with the control group (largest p = 0.002). CONCLUSION: In this study we found that IMS to the pronator teres muscle significantly improved all clinical variables measured, compared with the group receiving acupuncture. Furthermore, the cross-section of the median nerve reduced over time for both groups. IMS may be a low-risk alternative while patients are waiting for surgery. TRIAL REGISTRATION: Clinicaltrials. gov Identifier: NCT01102868. Retrospectively registered: March 29th, 2010.

Safety and efficacy of faecal microbiota transplantation by Anaerobic Cultivated Human Intestinal Microbiome (ACHIM) in patients with systemic sclerosis: study protocol for the randomised controlled phase II ReSScue trial.

INTRODUCTION: In the multisystem inflammatory disorder systemic sclerosis (SSc), gastrointestinal tract (GIT) affliction is highly prevalent. There are no known disease modifying therapies and the negative impact is substantial. Aiming for a new therapeutic principle, and inspired by recent work showing associations between gut microbiota changes and GIT symptoms in SSc, we performed a pilot study on faecal microbiota transplantation (FMT) with the single-donor bacterial culture 'Anaerobic Cultivated Human Intestinal Microbiome (ACHIM)'. Motivated by positive pilot study signals, we designed the ReSScue trial as a phase II multicentre, placebo-controlled, randomised 20-week trial to evaluate safety and efficacy on lower GIT symptoms of FMT by ACHIM in SSc. METHODS AND ANALYSES: We aim to include 70 SSc participants with moderate to severe lower GIT symptoms, defined by the validated patient-reported University of California Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 2.0 questionnaire. The trial includes three parts. In part A1 (induction phase) lasting from week 0 to week 12, participants will be randomised 1:1 to repeat infusions of 30 mL ACHIM or placebo at week 0 and 2 by gastroduodenoscopy. In part A2, which is an 8-week subsequent maintenance phase, all study participants will receive 30 mL ACHIM at week 12 and followed until week 20 on continued blind. In part B, which will last until the last participant completes part A2, the participants will be followed through a maximum 16-week extended monitoring period, for longer-term data on safety and intervention effects. Primary endpoint is change from baseline to week 12 in UCLA GIT subscale scores of diarrhoea or bloating, depending on the worst symptom at baseline evaluated separately for each patient. Secondary endpoints are safety measures and changes in UCLA GIT scores (total, diarrhoea and bloating). ETHICS AND DISSEMINATION: This protocol was approved by the Northern Norwegian Committee for Medical Ethics. Study findings will be published. TRIAL REGISTRATION NUMBER: NCT04300426; Pre-results. PROTOCOL VERSION: V.3.1.

Evaluation of Nutritional Status and Methods to Identify Nutritional Risk in Rheumatoid Arthritis and Spondyloarthritis.

Patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) experience several nutritional challenges and are prone to develop malnutrition. This observational study aimed to perform a comprehensive nutritional assessment of outpatients diagnosed with RA and SpA, as well as to evaluate methods to identify nutritional risk. Nutritional status was investigated by anthropometric measures, body composition (DXA, dual energy X-ray absorptiometry), and handgrip strength (HGS). Nutritional risk was classified by Nutritional Risk Screening 2002 (NRS2002) and malnutrition was defined by the Global Leadership Initiative on Malnutrition (GLIM) criteria and fat-free mass index (FFMI; kg/m2, <16.7 (M), <14.6 (F)). Out of 71 included patients, 46 (66%) were abdominally obese, 28 (39%) were obese in terms of body mass index (BMI), and 33 (52%) were obese in terms of the fat mass index (FMI; kg/m2, ≥8.3 (M), ≥11.8 (F)). Malnutrition was identified according to FFMI in 12 (19%) patients, according to GLIM criteria in 5 (8%) patients, and on the basis of BMI (<18.5 kg/m2) in 1 (1%) patient. None were identified by NRS2002 to be at nutritional risk. Our study revealed high prevalence of abdominal obesity and low FFMI. Waist circumference was a good indicator of FMI. BMI, NRS2002, and HGS did not capture patients with malnutrition identified by DXA.

Calprotectin (S100A8/A9) has the strongest association with ultrasound-detected synovitis and predicts response to biologic treatment: results from a longitudinal study of patients with established rheumatoid arthritis.

BACKGROUND: Calprotectin (S100A8/A9 or MRP8/14) and S100A12 (leukocyte-derived proteins), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) are markers of inflammation and angiogenesis. Ultrasound (US) is sensitive for detection of greyscale synovitis and power Doppler (PD) vascularization. The objective of the present study was to explore the associations between calprotectin, S100A12, IL-6, VEGF, erythrocyte sedimentation rate, C-reactive protein and a comprehensive US assessment in patients with rheumatoid arthritis (RA) starting biologic disease-modifying anti-rheumatic drug (bDMARD) treatment. METHODS: A total of 141 patients with RA were assessed by US, clinical examination and biomarker levels at baseline and at 1, 2, 3, 6 and 12 months after initiation of bDMARDs. US assessment of 36 joints and 4 tendon sheaths were scored semi-quantitatively (0-3 scale). European League Against Rheumatism (EULAR) response was calculated. Statistical assessments performed to explore the associations between biomarkers and US sum scores included Spearman's rank correlation analysis as well as linear and linear mixed model regression analyses. RESULTS: Calprotectin showed the overall strongest correlations with both US sum scores (r s = 0.25-0.62) and swollen joint counts (of 32) (r s = 0.24-0.47) (p < 0.05 at all examinations). An association with US sum scores remained after we adjusted for age, sex, disease duration and all the other markers in a regression analysis at baseline. Decreased calprotectin at the first month was predictive of both EULAR response (p ≤ 0.001) and decreased sum PD scores at 3, 6 and 12 months (p ≤ 0.05). CONCLUSIONS: Calprotectin had the highest association with US synovitis and predicted treatment response. It may thus be considered as a marker for evaluating inflammation and responsiveness in patients with RA on bDMARD treatment. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12610000284066 . Registered on 8 April 2010 (retrospectively registered).

Serum Markers in Rheumatoid Arthritis: A Longitudinal Study of Patients Undergoing Infliximab Treatment.

Objective. The aim of this study was to investigate the clinical effect and serum markers in a cohort of rheumatoid arthritis patients with moderate to high disease activity, participating in an open clinical phase IV study conducted in Norway between 2001 and 2003 receiving infliximab treatment. Method. A total of 39 patients were studied, with a mean age of 54 years and 12-year disease duration. The analyses were performed using serum from patients at four assessment time points: baseline and 3, 6, and 12 months after starting treatment with infliximab. A wide variety of clinical data was collected and disease activity of 28 joints and Simple Disease Activity Index were calculated. The joint erosion was determined by X-ray imaging and the Sharp/van der Heijde score was determined. Serum analysis included multiplex immunoassays for 12 cytokines, 5 matrix metalloproteases, and 2 VEGFs. Results. The majority of the RA patients in this study had initially moderate to high disease activity and the infliximab treatment reduced the disease activity significantly and also reduced any further joint destruction and improved disease status. Most of the serum levels of cytokines and metalloproteases remained unchanged during the course of the study, and we were unable to detect changes in TNF-α in serum. Serum levels of IL-6 and VEGF-A decreased significantly after initiation of infliximab treatment. Conclusion. The serum levels of IL-6 and VEGF-A may be promising disease markers as they vary with disease progression. The clinical significance of these findings is yet to be determined and has to be confirmed in future clinical trials before being applied in the clinics.