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Objective. The aim of the study was to assess the association between plethysmographically measured vasospasms during stepwise cooling and recovery, as an index for digital ischaemia, and nailfold capillaroscopic pattern (NCP) severity in patients with primary or secondary RP, including SSc. Methods. In 381 consecutive patients with suspected RP without a history of digital ulcers, NCP (assessed by widefield videocapillaroscopy), fingertip photoelectric plethysmography during cooling and recovery and clinical characteristics were analysed. NCPs were graded as follows: normal, non-specific, early and active. The mean ischaemic time was defined as the mean time of perfusion loss during cooling and recovery of five fingers. Results. In the patients with loss of perfusion during cooling and recovery, the NCP was normal in 152, non-specific in 96, early in 61 and active in 39 patients. The mean ischaemic time was positively associated with the severity of NCP, with P < 0.05 for each two- or three-grade increase and independent of underlying SSc. The difference was most pronounced during recovery. Conclusion. We demonstrate that the degree of vasospasm and ischaemia provoked by stepwise cooling and recovery are positively associated with NCP in patients with RP of different aetiologies and without a history of digital ulcers. [ABSTRACT FROM AUTHOR]

Objective. The aim of this study was to investigate the turnover of Treg cells in the SF of RA patients. Methods. Treg cells were enumerated in peripheral blood and SF of RA patients and analysed by flow cytometry for expression of the proliferation marker Ki-67 and binding of the apoptosis marker annexin V. Sorted Treg cells of RA patients were analysed for expression of anti-apoptotic regulators Bcl-2 and microRNA-21 (miR-21) by RT-PCR. Results. Treg cells displaying a memory phenotype were abundant in the SF of RA patients. SF Treg cells more frequently expressed the proliferation marker Ki-67 than conventional T cells. Only few SF Treg cells were apoptotic, as indicated by limited annexin V staining of these cells. SF Treg cells displayed high transcription levels of Bcl-2 and miR-21 in comparison with SF conventional T cells and peripheral blood Treg cells. Conclusion. Treg cells with a memory phenotype accumulate in the SF of RA patients. These Treg cells have a high proliferative activity and demonstrate little apoptosis. The latter finding could be explained by high transcription of Bcl-2 and miR-21 in SF Treg cells. [ABSTRACT FROM AUTHOR]

Objective. Increased numbers of IL-17-producing CD4+ T cells have been observed in AS. However, it is not known whether these CD4+ T cells are already present in early disease or if this is a late disease phenomenon only. Therefore we aimed to investigate whether IL-17-producing CD4+ T cells are involved in early active axial SpA, including patients without imaging abnormalities, by determining the frequency and phenotype of IL-17-producing CD4+ T cells in these patients. Methods. Flow cytometry was used to analyse cytokine production and surface marker expression of peripheral blood mononuclear cells from 31 patients suffering from early active HLA-B27-positive axial SpA fulfilling the Assessment of SpondyloArthritis International Society criteria with or without MRI abnormalities and 21 healthy controls. Results. Patients with early active axial SpA showed an increased percentage of IL-17-producing CD4+ T cells compared with healthy controls (mean 1.1% vs 0.4%, respectively; P = 0.013). The percentage of IL-17-producing CD4+ T cells was equally increased in patients with and without MRI abnormalities (1.2% vs 1.1%, respectively; P = 0.81). These IL-17-producing CD4+T cells expressed the αβT cell receptor but not the γδ T cell receptor, exhibited a memory phenotype and expressed CD161, but only sporadically expressed killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2). Conclusion. IL-17-producing CD4+ T cells are increased in patients with early active axial SpA both with and without MRI abnormalities. This finding shows that the frequency of IL-17-producing CD4+ T cells is enhanced in the early stages of disease. [ABSTRACT FROM AUTHOR]

Objectives. The aim of the study was to examine the effect of bosentan on blood flow in the hand in a subset of patients who had reduced blood flow relative to healthy subjects. Additionally, the relationship between blood flow in the hands of SSc patients and the presence of digital ulcers (DUs) was assessed.Methods. SSc patients with a recent history of DUs and healthy subjects were included. Patients were classified into four subgroups: no current DUs or pitting scars, pitting scars only, new DUs or persistent DUs. The hand was categorized into three regions of interest (ROIs) and blood flow was measured by laser Doppler perfusion imaging at baseline, 4 and 12 weeks. Patients who had a reduction in blood flow of >50% relative to healthy control subjects in ROI 1 on baseline were treated with bosentan for 12 weeks.Results. Fifty-two SSc patients and 51 healthy subjects were included in the analysis. There was no significant difference in blood flow in the hand across the patient subgroups at baseline. Sixteen SSc patients had a reduction of blood flow of ≥50% vs healthy subjects and received bosentan. Bosentan significantly (P < 0.05) increased blood flow in the whole hand after 12 weeks compared with baseline.Conclusion. No relationship was found between blood flow in the hands and the presence of DUs. After 12 weeks of bosentan treatment, blood flow had increased in the SSc patients but had not normalized to that of healthy subjects.Trial registration: https://www.clinicaltrialsregister.eu/ (EudraCT number 2010-023908-27). [ABSTRACT FROM PUBLISHER]

Objective. Regulatory B cells (Bregs) constitute a subset of B cells with immunomodulatory properties. Numerical and functional alterations in the Breg compartment have been associated with autoimmunity. The aim of this study was to assess the frequency and function of Bregs in patients with ANCA-associated vasculitis (AAV).Methods. B cell subsets were determined in the peripheral blood of 48 AAV patients (12 active, 36 in remission) and 41 healthy controls (HCs) by flow cytometry. Bregs were defined within the CD19+ population as CD24hiCD38hi or CD24hiCD27+ cells. The percentage of IL-10-positive B cells in circulation was analysed by flow cytometry. Sorted CD19+ B cells were co-cultured with monocytes to evaluate their capacity to inhibit monocyte TNF-α production upon lipopolysaccharide stimulation.Results. The frequency of circulating CD19+CD24hiCD38hi cells was not different in AAV patients in remission compared with HCs, but was decreased in patients with active disease [mean in HCs 5.5% (s.d. 1.6) vs active 3.8% (s.d. 2.8), P = 0.0104]. Furthermore, the percentage of CD19+CD24hiCD27+ cells was significantly decreased in both remission and active patients when compared with HCs [HCs 15.0% (s.d. 9.3) vs remission 6.6% (s.d. 4.4) (P < 0.0001) vs active 6.4% (s.d. 6.2) (P = 0.0006)]. The frequency of IL-10-positive B cells was comparable between patients and HCs. B cells from AAV patients suppressed monocyte TNF-α production to a similar extent to cells from HCs.Conclusion. Based on immunophenotypic classification, Bregs are numerically diminished in AAV patients. However, B cell function in terms of IL-10 production and their capacity to suppress monocyte activation is not compromised in AAV patients in remission. [ABSTRACT FROM AUTHOR]

Objective. ACPAs are thought to play a pathogenic role in RA. Because of their polyclonal nature it is difficult to study characteristics of ACPAs such as cross-reactivity or affinity. This study aimed to analyse the ACPA response at clonal level.Methods. Citrullinated fibrinogen-specific B cells were isolated from blood derived from an RA patient by fluorescent automated cell sorting (FACS). Antigen specificity was verified by ELISA of culture supernatant. RNA of antigen-specific B cells was isolated and VH and VL chains were cloned and subsequently expressed as IgG1 antibodies.Results. Two human recombinant antibodies were obtained that bind to citrullinated fibrinogen peptide (cFib). Both monoclonal antibodies originate from different naive B cells, undergo extensive somatic hypermutation and bind to cFib (but not to Fib) with moderate avidity. Furthermore, they show distinct cross-reactivity patterns towards other citrullinated peptides, suggesting that both antibodies have different primary targets.Conclusion. Together these data suggest that ACPAs are formed by antigen-driven maturation, and that multiple citrullinated antigens are involved in activating the B-cell response. [ABSTRACT FROM PUBLISHER]

Objective. The presence of disease-specific autoantibodies in RA but not spondyloarthritis (SpA) suggests that B-cell tolerance is preserved in the latter condition despite chronic joint inflammation. Which factors control B-cell tolerance vs autoimmunity in chronic arthritis remains incompletely understood. As single nucleotide polymorphisms in the B-cell scaffold protein with ankyrin repeats (BANK1) gene have recently been associated with various autoantibody-positive autoimmune diseases including RA, we explored whether altered expression of BANK1 was associated with humoral autoimmunity in arthritis.Methods. Peripheral B-cell subsets and inflamed synovial tissue were obtained from active SpA and RA. Quantitative PCR was used to assess the expression of full-length BANK1 and delta2 BANK1, a splice variant lacking exon 2 that counteracts BANK1 function. B-cell subsets, autoantibody titres and clinical disease were monitored upon CIA induction in Bank1 knockout (KO) mice.Results. Whereas full-length BANK1 was not differentially expressed, the BANK1 delta2 splicing variant was decreased in naïve peripheral B cells as well as in synovial tissue of SpA compared with RA. However, no differences were observed in seropositive vs seronegative RA. Performing functional analysis in mice, we found no differences in B-cell subsets and anti-collagen antibodies upon CIA induction between Bank1 KO mice and littermate controls. Accordingly, the incidence and severity of clinical disease were not altered in Bank1 KO mice.Conclusion. This study did not reveal a major role for BANK1 in humoral autoimmunity in chronic arthritis. The decreased levels of BANK1 delta2 in SpA, however, warrant more detailed analysis of the functional consequences of an altered BANK1/BANK1 delta2 balance. [ABSTRACT FROM AUTHOR]

Objective. To study the phenotypic characteristics of and the balance between systemic IL-7 receptor (IL-7R)α+ and IL-7Rα− Tregs in primary SS (pSS) patients as compared with control subjects and to assess the functional consequences this has for (IL-7-induced) T-cell activation.Methods. The functional properties of IL-7Rα+ and IL-7Rα−(CD25+) CD4 T cells from pSS patients were tested in vitro. Expression of CD25 and FoxP3 by IL-7Rα+ and IL-7Rα−CD4 T cells from pSS patients and healthy controls (HCs) were assessed. Also, the net ex vivo T-cell cytokine production and the capacity of IL-7 to activate total CD4 T cells from pSS patients compared with HCs in vitro was tested.Results. IL-7Rα+ T cells from pSS patients strongly proliferated and their numbers were slightly reduced compared with HCs. This reduced number was caused by an increase in both anergic and suppressive IL-7Rα−CD25+ T cells expressing high levels of FoxP3, but also by increases in IL-7Rα−CD25− CD4 T cells that only moderately expressed FoxP3. This altered balance in IL-7Rα+ and IL-7Rα−CD4 T cells was accompanied by unchanged ex vivo Th1, Th2 and Th17 cytokine production of total CD4 T cells. Furthermore, the increased numbers of IL-7Rα−CD25+ T cells did not prevent specific IL-7-induced Th1 and Th17 cytokine production by IL-7Rα+ T cells.Conclusion. IL-7Rα+ cells are highly proliferating cells that respond strongly to IL-7 despite an increased number of IL-7Rα− T cells that express FoxP3 and CD25. The recent finding that IL-7 and IL-7Rα+ T cells were both found to be increased in exocrine glands of pSS patients indicates that IL-7 could contribute to glandular inflammation by activation of IL-7Rα+ responder T cells despite the increased numbers of Tregs. [ABSTRACT FROM PUBLISHER]

The article presents the study which analyzed the normal frequencies of IFN-ϒ producing (Th1) and IL-17 producing T-cells (T-17) in patients with giant cell arteritis (GCA) in stimulated whole blood samples as of May 2014.