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Background: Guidelines that detail preventive measures against Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b, and influenza are published annually in France to decrease the risk of severe infections in immunocompromised patients. We aimed at describing adherence to these guidelines by GPs in the management of their asplenic patients in France between 2013 and 2016. Method: We conducted a multicenter retrospective study between January 2013 and December 2016 in three French hospitals: asplenic adults were identified and their GPs were questioned. A descriptive analysis was performed to identify the immunization coverage, type and length of antibiotic prophylaxis, number of infectious episodes, and education of patients. Results: 103 patients were finally included in this study: only 57% were adequately vaccinated against Streptococcus pneumoniae or Neisseria meningitidis, 74% against Haemophilus influenzae type b, and 59% against influenza. Only 24% of patients received a combination of all four vaccinations. Two-thirds of patients received prophylactic antibiotics for at least 2 years. Overall, this study found that 50% of splenectomized patients experienced at least one pulmonary or otorhinolaryngological infection, or contracted influenza. Conclusions: These data match those reported in other countries, including Australia and the United Kingdom, meaning a still insufficient coverage of preventive measures in asplenic patients. Improved medical data sharing strategies between healthcare professionals, along with educational measures to keep patients and physicians up to date in the prevention of infections after splenectomy would improve health outcomes of asplenic patients. [ABSTRACT FROM AUTHOR]

Objective. IFN α Kinoid (IFN-K) is a therapeutic vaccine composed of IFNα2b coupled to a carrier protein. In a phase I/II placebo-controlled trial, we observed that IFN-K significantly decreases the IFN gene signature in whole blood RNA samples from SLE patients. Here, we analysed extended follow-up data from IFN-K-treated patients, in order to evaluate persistence of neutralizing anti-IFNα Abs antibodies (Abs), and gene expression profiling. Methods. Serum and whole blood RNA samples were obtained in IFN-K-treated patients included in the follow-up study, in order to determine binding and neutralizing anti-IFNα Ab titres, and perform high-throughput transcriptomic studies. Results. Neutralization studies of 13 IFNα subtypes demonstrated the polyclonal nature of the Ab response induced by IFN-K. Follow-up analyses in six patients confirmed a significant correlation between neutralizing anti-IFNα Ab titres and decrease in IFN scores compared to baseline. These analyses also revealed an inhibitory effect of IFNα blockade on the expression of B cell associated transcripts. Conclusions. IFN-K induces a polyclonal anti-IFNα response that decreases IFN- and B cell-associated transcripts. Trial registration: ClinicalTrials.gov, clinicaltrials.gov, NCT01058343 [ABSTRACT FROM AUTHOR]

Objectives. The aim was to assess the immunogenicity and the impact on disease activity of pneumococcal and influenza vaccines in SLE patients. Methods. We conducted a systematic literature review and meta-analysis of studies comparing the humoral response of either pneumococcal (serotype 23F) or influenza (AH1N1, AH3N2 and B strains) vaccines between SLE patients and healthy controls, assessed by a seroconversion or a seroprotection rate 3-6 weeks after vaccination. The impact on disease activity was assessed by the comparison of the SLEDAI score before and 3-8 weeks after vaccination. Odds ratios (ORs), risk ratios and their 95% CIs were pooled using the generic inverse variance method. Results. Twenty studies were included, three for pneumococcal vaccine and 17 for influenza vaccine, gathering 1665 SLE patients and 826 healthy controls. For pneumococcal vaccination, no significant difference was observed, either for seroconversion rate between SLE patients and controls or for the SLEDAI score. For influenza vaccination, the response against AH1N1 was significantly reduced in SLE patients, with a lower rate of seroconversion (OR = 0.38; 95% CI: 0.27, 0.54; P < 0.00001, I² = 39%) and seroprotection (OR = 0.36; 95% CI: 0.28, 0.47; P < 0.00001, I² = 25%). For AH3N2, only seroprotection rate was significantly lower in SLE patients (OR = 0.26; 95% CI: 0.14, 0.50; P < 0.0001, I² = 21%). For B strain, neither seroconversion nor seroprotection rates were significantly different. Influenza vaccine did not modify the SLEDAI score. Conclusion. The immunogenicity of influenza vaccine in SLE patients depends on the viral strains. A reduced immunogenicity against influenza A is noted, while the immunogenicity against the B strain is preserved. The pneumococcal vaccine against 23F serotype has a preserved immunogenicity. These vaccines have no impact on the SLEDAI score. [ABSTRACT FROM AUTHOR]

Objective Plasmacytoid dendritic cells (PDCs) play a central role in pathogenesis of systemic lupus erythematosus (SLE) through their unique ability to produce large amounts of type I interferon (IFN) upon Toll-like receptor 7 (TLR-7) and TLR-9 triggering. PDCs express specific surface regulatory receptors involved in negative regulation of IFNα secretion. These receptors use the γ-chain of high-affinity Fc receptor (FcR) for IgE, FcɛRI. We undertook this study to test our hypothesis that IgE engagement of FcɛRI on PDCs may impact IFNα production in SLE patients. Methods Serum levels of total IgE were measured in healthy volunteers, SLE patients, and patients with IgE-dependent allergic disorders. FcɛRI expression on PDCs from SLE patients was evaluated by flow cytometry. Purified PDCs were incubated with monoclonal IgE for 24 hours, then stimulated for 18 hours with TLR agonists or immune complexes (ICs). IFNα production by PDCs was detected by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Expression of TLR-7, TLR-9, and IFN regulatory factor 7 (IRF-7) in PDCs was quantified by quantitative real-time PCR. Results We observed significantly higher IgE levels in SLE patients with quiescent disease than in those with active disease. In SLE patients, IgE levels correlated inversely with disease activity. IgE levels were not associated with the presence of antinuclear IgE. Purified PDCs treated for 24 hours with monoclonal IgE up-regulated FcɛRI expression in an IgE dose-dependent manner. IgE-treated PDCs significantly decreased IFNα secretion and down-regulated CCR7 expression upon stimulation with TLR-7 and TLR-9 ligands and ICs from lupus patients. IgE treatment down-regulated expression of TLR-9 and IRF-7. Conclusion Our results support the notion that IgE plays a protective role in SLE pathogenesis through the modulation of inflammatory response by PDCs. [ABSTRACT FROM AUTHOR]

Objective Intravenous immunoglobulin (IVIG) represents a therapeutic alternative in antineutrophil cytoplasmic antibody-associated vasculitides (AAV), but its efficacy has been evaluated in only 2 small prospective trials. The aim of this study was to evaluate the efficacy and safety of IVIG in patients with AAV. Methods We conducted a nationwide retrospective study of patients who received IVIG as immunomodulatory therapy for AAV. Results A total of 92 patients (mean age 51 years) presenting with either granulomatosis with polyangiitis (Wegener's) (68%), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (22%), or microscopic polyangiitis (10%) received at least 1 course of IVIG. Antineutrophil cytoplasmic antibodies were present in 72% during the flare that required IVIG, as determined by immunofluorescence assay. IVIG was initiated because of relapsing disease in 83% of cases. IVIG was given for a median of 6 months (range 1-156 months) and in combination with corticosteroids in 21% of the patients or with other immunosuppressive agents in 77%. Efficacy of IVIG was assessed in the entire population and in a subset of 34 patients with unmodified background therapy. Remission rates at 6 months were 56% in the entire population and 58% in the unmodified background therapy group. Refractory disease and treatment failure at 6 months were observed in 7% and 18% in the whole population and 3% and 21% in the unmodified background therapy group, respectively. Adverse events (AEs) occurred in 33%, including serious AEs in 12% and AEs leading to discontinuation of IVIG in 7%. Conclusion This large study shows the clinical benefit of IVIG as adjunctive therapy, with an acceptable tolerance profile, and thus supports its use in AAV patients with refractory or relapsing disease. [ABSTRACT FROM AUTHOR]

Objectives. Tracheobronchial stenosis (TBS) is noted in 12-23% of patients with granulomatosis with polyangiitis (GPA), and includes subglottic stenosis and bronchial stenosis. We aimed to analyse the endoscopic management of TBS in GPA and to identify factors associated with the efficacy of endoscopic interventions. Methods. We conducted a French nationwide retrospective study that included 47 patients with GPA-related TBS. Results. Compared with patients without TBS, those with TBS were younger, more frequently female and had less frequent kidney, ocular and gastrointestinal involvement and mononeuritis multiplex. Endoscopic procedures included 137 tracheal and 50 bronchial interventions, mainly endoscopic dilatation, local steroid injection and conservative laser surgery, and less frequently stenting. After the first endoscopic procedure, the cumulative incidence of endoscopic treatment failure was 49% at 1 year, 70% at 2 years and 80% at 5 years. Factors significantly associated with a higher cumulative incidence of treatment failure were a shorter time from GPA diagnosis to endoscopic procedure [hazard ratio (HR) 1.08 (95% CI 1.01, 1.14); P=0.01] and a bronchial stenosis [HR 1.96 (95% CI 1.28, 3.00); P = 0.002]. A prednisone dose ≥30mg/day at the time of the procedure was associated with a lower cumulative incidence of treatment failure [HR 0.53 (95% CI 0.31, 0.89); P = 0.02]. Conclusion. TBS represents severe and refractory manifestations with a high rate of restenosis. High-dose systemic CSs at the time of the procedure and increased time from GPA diagnosis to bronchoscopic intervention are associated with a better event-free survival. In contrast, bronchial stenoses are associated with a higher rate of restenosis than subglottic stenosis. [ABSTRACT FROM AUTHOR]

Objective We developed interferon-α-kinoid (IFN-K), a drug composed of inactivated IFNα coupled to a carrier protein, keyhole limpet hemocyanin. In human IFNα-transgenic mice, IFN-K induces polyclonal antibodies that neutralize all 13 subtypes of human IFNα. We also previously demonstrated that IFN-K slows disease progression in a mouse model of systemic lupus erythematosus (SLE). This study was undertaken to examine the safety, immunogenicity, and biologic effects of active immunization with IFN-K in patients with SLE. Methods We performed a randomized, double-blind, placebo-controlled, phase I/II dose-escalation study comparing 3 or 4 doses of 30 μg, 60 μg, 120 μg, or 240 μg of IFN-K or placebo in 28 women with mild to moderate SLE. Results IFN-K was well tolerated. Two SLE flares were reported as serious adverse events, one in the placebo group and the other in a patient who concomitantly stopped corticosteroids 2 days after the first IFN-K dose, due to mild fever not related to infection. Transcriptome analysis was used to separate patients at baseline into IFN signature-positive and -negative groups, based on the spontaneous expression of IFN-induced genes. IFN-K induced anti-IFNα antibodies in all immunized patients. Notably, significantly higher anti-IFNα titers were found in signature-positive patients than in signature-negative patients. In IFN signature-positive patients, IFN-K significantly reduced the expression of IFN-induced genes. The decrease in IFN score correlated with the anti-IFNα antibody titer. Serum complement C3 levels were significantly increased in patients with high anti-IFNα antibody titers. Conclusion These results show that IFN-K is well tolerated, immunogenic, and significantly improves disease biomarkers in SLE patients, indicating that further studies of its clinical efficacy are warranted. [ABSTRACT FROM AUTHOR]