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Abstract Background There is no international consensus on an optimal ultrasound score for monitoring of rheumatoid arthritis (RA) on patient-level yet. Our aim was to reassess the US7 score for the identification of the most frequently pathologic and responsive joint/tendon regions, to optimize it and contribute to an international consensus. Furthermore, we aimed to evaluate the impact of disease duration on the performance of the score. Methods RA patients were assessed at baseline and after 3 and 6 months of starting/changing DMARD therapy by the US7 score in greyscale (GS) and power Doppler (PD). The frequency of pathologic joint/tendon regions and their responsiveness to therapy were analyzed by Friedman test and Cochrane-Q test respectively, including the comparison of palmar vs. dorsal regions (chi-square test). The responsiveness of different reduced scores and the amount of information retained from the original US7 score were assessed by standardized response means (SRM)/linear regression. Analyses were also performed separately for early and established RA. Results A total of 435 patients (N = 138 early RA) were included (56.5 (SD 13.1) years old, 8.2 (9.1) years disease duration, 80% female). The dorsal wrist, palmar MCP2, extensor digitorum communis (EDC) and carpi ulnaris (ECU) tendons were most frequently affected by GS/PD synovitis/tenosynovitis (wrist: 45%/43%; MCP2: 35%/28%; EDC: 30%/11% and ECU: 25%/11%) and significantly changed within 6 months of therapy (all p ≤0.003 by GS/PD). The dorsal vs. palmar side of the wrist by GS/PD (p

Abstract Background Fluorescence optical imaging (FOI) enables visualisation of inflammation in both hands in rheumatoid arthritis (RA). Objective To investigate the usefulness of FOI in treatment monitoring under anti-TNFα therapy with certolizumab pegol (CZP) in patients with RA in comparison to clinical and laboratory outcome parameters. Methods CZP-naïve patients with RA were eligible for this open-label study with an observational period of 52 weeks. Disease activity was monitored by the clinical score DAS28, tender/swollen joint count (TJC-28/SJC-28) and laboratory outcomes for systemic inflammation (CRP and ESR). FOI results were analysed in three different phases (P1-3) and PrimaVistaMode (PVM) by the FOI activity score (FOIAS). Results Twenty-eight RA patients (median age 52.5 years, 26 females, thirteen with a history of other biologic therapy) were included. DAS28 (CRP) decreased from moderate disease activity at baseline (median 4.6, IQR 1.8) to low disease activity at week (w)52 (median 2.7, IQR 2.1; p

Abstract Objectives To investigate the frequency of subclinical skin inflammation in both hands by fluorescence optical imaging (FOI) in patients with psoriasis/psoriatic arthritis (Pso/PsA) vs. rheumatoid arthritis (RA) and healthy individuals, and to correlate these findings with cardiovascular (CV) risk factors. Patients and methods The FOI scans were analyzed retrospectively to detect clinically invisible skin enhancement (0–3 scale) in both hands without relationship to underlying joints or blood vessels. We further characterized the FOI patterns and sorted the scans into groups based on the assumed diagnosis (Pso/PsA, RA, and healthy controls), which was compared with the physician’s diagnosis. Furthermore, the associations between CV risk factors and imaging findings were investigated by regression analyses. Results We included FOI scans of patients with Pso/PsA (n = 80), RA (n = 78), and healthy controls (n = 25). Subclinical skin enhancement on the back of their hands was more common in Pso/PsA (72.5%) than in RA patients (20.5%) and healthy individuals (28.0%) (p

Abstract Background Digital ulcers (DU) present a challenging complication in systemic sclerosis (SSc). The aim of this study was to combine clinical characteristics and imaging methods to a composite score for the prediction of DU in SSc patients. Methods Seventy-nine SSc patients received clinical examination, their patient history was taken and nailfold capillaroscopy (NC), colour Doppler ultrasonography (CDUS) and fluorescence optical imaging (FOI) of the hands were performed at baseline. Newly developed DU over a period of approximately 12 months were registered. We used criteria with area under the curve (AUC) of at least 0.6 in regard to the development of these new DU to create the score (CIP-DUS, clinical features, imaging, patient history—digital ulcer score). Results Twenty-nine percent of all SSc patients developed new DU during follow-up (48.1% diffuse, 18.4% limited SSc). Based on the cross-validated (cv) AUC, a weight (cvAUC > 0.6 and ≤ 0.65: 1; cvAUC > 0.65 and ≤ 0.7: 2; cvAUC > 0.7: 3) was assigned to each selected parameter. The performance of the final CIP-DUS was assessed with and without the CDUS/FOI component. For the scleroderma patterns in NC, three points were appointed to late, two to active and one point to early capillaroscopy pattern according to Cutolo et al. The CIP-DUS including the CDUS and FOI parameters resulted in a good diagnostic performance (AUC after cross-validation: 0.83, 95%CI 0.74 to 0.92) and was well calibrated (chi-square = 12.3, p = 0.58). The cut-off associated with the maximum of sensitivity and specificity was estimated at ≥ 10 points resulting in a sensitivity of 100% and specificity of 74% for new DU during follow-up. Excluding CDUS and FOI parameters leads to a non-statistically significant lower performance (AUC after cross-validation: 0.81, 95%CI 0.72 to 0.91). However, including CDUS and FOI resulted in a better classification of patients in respect to the outcome new DU in follow-up due to significantly better reclassification performance (NRI = 62.1, p = 0.001) and discrimination improvement (IDI = 9.7, p = 0.01). Conclusion A new score was introduced with the aim to predict digital ulcers. If applied correctly and with the new imaging techniques proposed, all patients at risk of digital ulcers throughout 12 months could be identified.

Abstract Objective Systemic sclerosis (SSc) can lead to ischemic complications such as digital ulcers (DUs). The aim of the study was to find predictors of DUs by clinical and new imaging methods. Patients and methods All 79 SSc patients included in the study received a clinical, colour Doppler ultrasound (CDUS), fluorescence optical imaging (FOI) and capillaroscopy examination at baseline, and their capacity to predict new DU development was analysed in 76 patients at 12 months follow-up. Results Twenty-two of 76 patients (28.9%) developed new ulcers during follow-up (diffuse SSc 48.1%; limited SSc 18.4%). Receiver operating characteristic (ROC) curve analysis revealed an area under the curve of 0.7576 for DU development, with a specificity of 87% and a sensitivity of 54.6% (p = 0.0003, OR = 8.1 [95%CI 2.5–25.6]) at a cut-off of ≥ 21 points (ACR/EULAR classification criteria for SSc). Capillaroscopy and CDUS had high sensitivity (100% and 95.5%) but low specificity (28.9% and 22.2%) for ulcer occurrence when used alone, but better specificity (46.3%) when combined (OR = 18.1 [95%CI 2.3–144.4]; p = 0.0004). Using FOI, fingers with pathologic staining had a higher risk for new ulcer development in the same finger (p = 0.0153). General future DU (i.e. DU also in other fingers) was associated with a missing FOI signal in the right digit III at baseline (p = 0.048). Conclusion New imaging modalities can predict digital ulcer development in SSc patients with high sensitivity for capillaroscopy and CDUS and enhanced specificity when combined. A missing signal of FOI in the right digit III at baseline was associated with general future DU.

Objective. The main objective of this study was to evaluate the 7-joint ultrasound (US7) score by detailed joint region analysis of an arthritis patient cohort. Methods. The US7 score examines the clinically most affected wrist, MCP and PIP II, III, MTP II, and V joints for synovitis, tenosynovitis/paratenonitis, and erosions. Forty-five patients with rheumatoid arthritis (RA) (84.4%) and spondyloarthritis with polyarticular peripheral arthritis (PsA 13.3%; AS 2.2%) with a median disease duration of 6.5 yrs (range 7.5 mths–47.6 yrs) were included and examined at baseline and 3, 6, and 12 months after starting or changing therapy (DMARD/biologic). In this study, detailed US7 score joint region analysis was firstly performed. Results. The joint region analysis performed at baseline disclosed synovitis in 95.6% of affected wrists in the dorsal aspect by greyscale (GS) US where Grade 2 (moderate) was most often (48.9%) detected. Palmar wrist regions presented Grade 1 (minor) capsule elevation in 40% and Grade 2 (moderate synovitis) in 37.8%. Tenosynovitis of the extensor carpi ulnaris (ECU) tendon was found in 40%, with PD activity in 6.6%. Most of the erosions in MCP II were detected in the radial (68.9%), followed by the dorsal (48.9%) and palmar (44.4%) aspects. In MTP V, erosions were seen in 75.6% from lateral. Conclusions. Synovitis in GSUS was more often detected in the wrist in the dorsal than in the palmar aspect. ECU tendon involvement was frequent. Most erosions were found in the lateral scan of MTP V and the medial (radial) scan of MCP II.

Objectives. The aim of the study was to analyse the cytokine memory of T-cells derived from systemic lupus erythematosus (SLE) patients and healthy donors enriched for autoantigen-specific T-cells by in vitro stimulation with SmD183–119, a common autoantigen in SLE.Methods. Autoreactive CD3+ T-cells derived from 37 SLE patients and 14 healthy donors were enriched by repetitive ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with SmD183–119. For control, PBMCs were stimulated only with interleukin-2 (IL-2). After two rounds of antigenic stimulation, cultures were stimulated with PMA/ionomycin to probe the cytokine memory by intracellular cytokine staining. Frequencies of cytokine-expressing T-cells were analysed and, in SLE patients, compared with disease activities and autoantibody levels.Results. Comparing the cytokine memory in the cultures, SLE patients displayed higher frequencies of tumour necrosis factor-α (TNF-α)+ T-cells than healthy donors and the frequencies correlated with disease activity. Frequencies of SmD183–119-specific TNF-α+ T-cells and of memory T-cells expressing interferon-γ (IFN-γ) correlated with serum anti-dsDNA antibody levels. The frequencies of IL-10 expressing SmD183–119-specific T-cells were lower among PBMCs of SLE patients. Relatively higher frequencies of IL-10+ T-cells in SLE patients correlated with low disease activities, and low anti-dsDNA and anti-SmD183–119 antibody concentrations in culture supernatants.Conclusions. The memory of autoreactive SmD183–119-specific and unspecific stimulated peripheral Th cells for re-expression of cytokines is shifted towards more cells expressing TNF-α and less IL-10+ cells, when compared SLE patients with normal donors. This shift towards proinflammatory memory effector Th cells correlates with disease severity and humoral autoimmunity. [ABSTRACT FROM AUTHOR]

In addition to releasing proteins and mediators, cells also release membrane vesicles (exosomes and apoptotic blebs) into the extracellular environment. Apoptotic blebs contain multiple autoantigens, but few data are available concerning the protein content of exosomes. Exosomes are formed during an immune response and can directly stimulate T cells or bind to dendritic cells. The aim of this study was to identify the nature of synovial exosomes from patients with different rheumatic diseases and to examine their potential autoantigenic content, which may be involved in the induction of an autoimmune response.Synovial exosomes from patients with rheumatoid arthritis (RA), patients with reactive arthritis, and patients with osteoarthritis were purified, analyzed by electron microscopy, and labeled with immunogold to detect IgG and IgM molecules. Autoantigen content was identified by 2‐dimensional electrophoresis–immunoblotting and subsequent mass spectrometry. In order to investigate the presence of citrullinated proteins, immunoblotting with anticitrulline antibodies was performed.Citrullinated proteins were observed in all exosome preparations, in contrast to other autoantigenic proteins (e.g., BiP and heterogeneous nuclear RNP A2) that were previously observed in RA and other autoimmune diseases. These citrullinated proteins included the fibrin α‐chain fragment, fibrin β‐chain, fibrinogen β‐chain precursor, fibrinogen D fragment, and the Spα (CD5 antigen‐like protein) receptor. Purification of synovial exosomes led to the detection of citrullinated fibrinogen and citrullinated Spα associated with IgM and IgG.Synovial exosomes contain citrullinated proteins, which are known to be autoantigens in RA. Although immune mechanisms in which exosomes carry citrullinated peptides could play an important role in the induction and distribution of citrullinated proteins, there must be a specific recognition of these proteins that is unique to the RA immune system. [ABSTRACT FROM AUTHOR]

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Objectives. In SSc, diagnosis and classification is based mainly on skin sclerosis. Herein, we investigated in a large multicentre cohort, to what extent skin sclerosis reflects organ involvement and additional clinical symptoms. Methods. A total of 1200 SSc patients from the register of the German Systemic Sclerosis Network (DNSS), classified as either lcSSc or dcSSc, were analysed for their serological characteristics, clinical symptoms and organ manifestations in relation to skin involvement measured by the modified Rodnan skin score (mRSS). Results. SSc patients with different mRSS did not differ significantly in their disease duration and in most of the clinical symptoms. They showed a similar distribution of most organ manifestations such as pulmonary arterial hypertension as well as cardiac, renal and nervous system involvement. More severe skin thickening was found to be associated with pulmonary fibrosis and gastrointestinal symptoms, as well as with digital ulcers and musculoskeletal involvement. Conclusions. In patients with SSc, potentially life-threatening complications and clinical symptoms with high impact on the quality of life occur independently from the extent of skin sclerosis. The diagnosis in SSc patients with a low mRSS could be missed or they could be insufficiently treated. [ABSTRACT FROM AUTHOR]

Objectives. Autoantibodies against the 20S-proteasome display a broad diversity with a remarkably low frequency of individual cross-reactivity against the different subunits of the proteasome. Although their pathogenic and diagnostic significance remains obscure, an involvement in the clearance of circulating proteasomes as well as an interaction with the activity of the proteolytic complex was assumed in previous studies. Methods. To investigate the anti-proteasome response in more detail and to disclose reactivities against former neglected subunits, two-dimensional electrophoresis followed by immunoblotting was used. As a novel antigen source, the immunosubunits LMP2 (β1i) and LMP7 (β5i) were expressed as recombinant proteins and employed in ELISA. Results. The subunits Iota (α1) and Zeta (α5) of the outer rings as well as the catalytic subunit Delta (β1) and all three immunosubunits [MECL-1 (β2i), LMP2 (β1i) and LMP7 (β5i)] of the inner rings of the proteasome were identified as autoantigens for the first time. Using a panel of anti-proteasome antibody-positive sera of patients with SLE, autoimmune myositis (PM/DM) and primary Sjögrens syndrome (pSS), an autoimmune response was documented against LMP2 (β1i) and LMP7 (β5i) in all three patient groups in ELISA. Conclusions. The frequent autoimmune response against LMP2 (β1i) and LMP7 (β5i) might indicate a role of inflammatory processes in the primary induction of the anti-proteasomal immune reaction, while the diversity of the humoral response against the proteasome system supports the assumption of a specific antigen-driven process leading to these extended autoimmune reactivities. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the effectiveness and safety of adalimumab in patients with rheumatoid arthritis (RA) who previously discontinued tumour necrosis factor (TNF) antagonists for any reason in clinical practice. Methods. ReAct (Research in Active Rheumatoid Arthritis) was a large, open-label trial that enrolled adults with active RA who had previously been treated with traditional disease-modifying anti-rheumatic drugs or biological response modifiers. Patients self-administered adalimumab 40 mg subcutaneously every other week for 12 weeks and were allowed to enter an optional long-term extension phase. Measures of adalimumab effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, Disease Activity Score 28 (DAS28) and the Health Assessment Questionnaire Disability Index (HAQ DI). Results. Of 6610 patients, 899 had a history of etanercept and/or infliximab therapy; these patients experienced substantial clinical benefit from adalimumab treatment. At week 12, 60% of patients had an ACR20 and 33% had an ACR50 response; 76% had a moderate and 23% had a good EULAR response. In addition, 12% achieved a DAS28 Conclusion. In typical clinical practice, adalimumab was effective and well-tolerated in patients with RA previously treated with etanercept and/or infliximab. [ABSTRACT FROM AUTHOR]

Background: As long-term treatment with antitumour necrosis factor (TNF) drugs becomes accepted practice, the risk assessment requires an understanding of anti-TNF long-term safety. Registry safety data in rheumatoid arthritis (RA) are available, but these patients may not be monitored as closely as patients in a clinical trial. Cross-indication safety reviews of available anti-TNF agents are limited., Objective: To analyse the long-term safety of adalimumab treatment., Methods: This analysis included 23 458 patients exposed to adalimumab in 71 global clinical trials in RA, juvenile idiopathic arthritis, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis (Ps) and Crohn's disease (CD). Events per 100 patient-years were calculated using events reported after the first dose through 70 days after the last dose. Standardised incidence rates for malignancies were calculated using a National Cancer Institute database. Standardised death rates were calculated using WHO data., Results: The most frequently reported serious adverse events across indications were infections with greatest incidence in RA and CD trials. Overall malignancy rates for adalimumab-treated patients were as expected for the general population; the incidence of lymphoma was increased in patients with RA, but within the range expected in RA without anti-TNF therapy; non-melanoma skin cancer incidence was raised in RA, Ps and CD. In all indications, death rates were lower than, or equivalent to, those expected in the general population., Conclusions: Analysis of adverse events of interest through nearly 12 years of adalimumab exposure in clinical trials across indications demonstrated individual differences in rates by disease populations, no new safety signals and a safety profile consistent with known information about the anti-TNF class.