Immune complexes containing scleroderma-specific autoantibodies induce a profibrotic and proinflammatory phenotype in skin fibroblasts

Background: In systemic sclerosis (SSc), autoantibodies provide the most accurate tool to predict the disease subset and pattern of organ involvement. Scleroderma autoantibodies target nucleic acids or DNA/RNA-binding proteins, thus SSc immune complexes (ICs) can embed nucleic acids. Our working hypothesis envisaged that ICs containing scleroderma-specific autoantibodies might elicit proinflammatory and profibrotic effects in skin fibroblasts. Methods: Fibroblasts were isolated from skin biopsies obtained from healthy subjects and patients with diffuse cutaneous SSc (dcSSc). ICs were purified by polyethylene-glycol precipitation from sera of SSc patients bearing different autoantibodies. ICs from patients with systemic lupus erythematosus (SLE) and primary anti-phospholipid syndrome (PAPS) and from normal healthy subjects (NHS) were used as controls. After incubation with ICs, fibroblasts were evaluated for ICAM-1 expression, interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)-2, tumor growth factor (TGF)-\u3b21 and Pro-CollagenI\u3b11 secretion, collagen (col)I\u3b11, mmp-1, toll-like receptor (tlr)2, tlr3, tlr4, tlr7, tlr8, tlr9, interferon (ifn)-\u3b1, ifn-\u3b2 and endothelin-1 mRNA, and NF\u39aB, p38MAPK and SAPK-JNK activation rate. Experiments were also performed after pretreatment with DNase I/RNase and NF\u39aB/p38MAPK inhibitors. Results: The antigenic reactivity for each SSc-IC mirrored the corresponding serum autoantibody specificity, while no positivity was observed in NHS-ICs or sera. SSc-ICs but not NHS-ICs increased ICAM-1 expression, stimulated IL-6, IL-8, MMP-2, MCP-1, TGF-\u3b21 and Pro-CollagenI\u3b11 secretion, upregulated et-1, ifn-\u3b1, ifn-\u3b2, tlr2, tlr3 and tlr4, and activated NF\u39aB, p38MAPK and SAPK-JNK. tlr9 was significantly upregulated by ARA-ICs, mmp-1 was significantly induced by ACA-ICs whereas colI\u3b11 was not modulated by any SSc-ICs. SLE-ICs and PAPS-ICs significantly upregulated MMP-2 and activated NF\u39aB, p38MAPK and SAPK-JNK. SLE-ICs and PAPS-ICs did not affect colI\u3b11, mmp-1 and Pro-CollagenI\u3b11. DNase I and RNase treatment significantly reduced the upregulation of study mediators induced by SSc-ICs. Pretreatment with NF\u39aB/p38MAPK inhibitors suggested that response to anti-Th/To-ICs was preferentially mediated by p38MAPK whereas ATA-ICs, ACA-ICs and ARA-ICs engaged both mediators. In dcSSc fibroblasts, stimulation with SSc-ICs and NHS-ICs upregulated IL-6 and IL-8. Conclusions: These data provide the first demonstration of the proinflammatory and profibrotic effects of SSc-ICs on fibroblasts, suggesting the potential pathogenicity of SSc autoantibodies. These effects might be mediated by Toll-like receptors via the interaction with nucleic acid fragments embedded in SSc-ICs

In-Vivo Expansion of T Regulatory Cells by Rapamycin in a Calcineurin-Inhibitor Free GVHD Prophylaxis in Unmanipulated Haploidentical Stem Cell Transplantation (SCT)

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Relationship between the prevalence of subclinical tenosynovitis and treatment in patients with RA in clinical remission: STARTER study

Objective: This study is a sub-analysis from the patient cohort of the STARTER (Sonographic Tenosynovitis Assessment in RheumaToid arthritis patiEnts in Remission) study. The aim was to evaluate differences in ultrasound-detected joint and/or tendon involvement between patients receiving therapies based on a combination of conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs) and those who were treated with either csDMARDs or bDMARDs in monotherapy. Material and methods: Four hundred and twenty-seven consecutive patients with a diagnosis of RA were recruited between October 2013 and June 2014. They were divided into three subgroups based on their therapy at baseline: patients with bDMARD in monotherapy, patients with csDMARD in monotherapy and patients in combination therapy (csDMARD + bDMARD). At baseline, 6 months and 12 months, a clinical examination (28 joint count) and an ultrasound evaluation were performed in each patient. A score of grey-scale (GS) and power Doppler (PD) synovitis and tenosynovitis was calculated based on the OMERACT scoring systems. Results: Two hundred and fifty-six patients completed the observation period: 48 patients from the bDMARD group (18.75%), 152 patients from the csDMARD group (59.38%) and 56 patients from csDMARD + bDMARD group (21.88%). The analysis showed that GS tenosynovitis and PD tenosynovitis are better controlled in combination therapy than they are ith csDMARD alone (P=0.025 and P=0.047, respectively); for PD synovitis, there was a better response in those who were treated with the combination therapy when compared with the patients receiving csDMARD (P=0.01) or bDMARD (P=0.02) alone. Conclusions: The analysis showed a lower prevalence of subclinical inflammatory manifestations detected with ultrasound imaging in those patients treated with the combination therapy than in those in monotherapy

Case Report: Invasive Fungal Infection and Daratumumab: A Case Series and Review of Literature

Life expectancy of multiple myeloma (MM) patients has improved in last years due to the advent of anti-CD38 monoclonal antibodies in combination with immunomodulators and proteasome inhibitors. However, morbidity and mortality related to infections remain high and represent a major concern. This paper describes the “real life” risk of invasive fungal infections (IFI) in patients treated with daratumumab-based therapy and reviews the relevant literature. In a series of 75 patients we only observed three cases of fungal pneumonia. Unfortunately, the early signs and symptoms were not specific for fungal infection. Diagnostic imaging, microbiology and patient history, especially previous therapies, are critical in the decision to start antifungal treatment. Recognising the subgroup of MM patients with high risk of IFI can increase the rate of diagnosis, adequate treatment and MM-treatment recovery

CHARACTERIZATION OF OSTEOCORTICAL-PERIOSTEAL LAYERS BY HIGH-RESOLUTION SONOGRAPHY USING A DOPPLER TECHNIQUE IN PAGET'S DISEASE OF BONE

The authors characterize some aspects of Paget's disease of bone, comparing clinical and radiographic findings with sonographic features; they also demonstrate the utility of sonography and the Doppler technique for the diagnosis and follow-up of Paget's disease. Two sonographic instruments were used to study the bone profile, periosteal layer, and vascularization by high-resolution sonography and color Doppler. Thirteen patients were studied between May 2006 and May 2007. The morphology of cortical bone in Paget's disease analyzed by sonography is comparable to what can be detected by X-rays. The bone profile becomes wavy, and the loss of interface linearity ends up in a loss of echogenicity; only where the interface is still reflecting are some hyperechoic tracts visible. The periosteal layer becomes thicker and forms a fibrillar echoic band between bone and overlying muscle. Color Doppler techniques show cortical hyperflow and low-capillary resistance, suggesting the absence of arteriovenous fistulae, thus confirming data observed with other techniques. Sonographic techniques display the osteoperiosteal-layer hypervascularization, a marker of active disease, thus enabling an evaluation of disease activity, both at the diagnosis and during follow-u