Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) is a rare type of anti-neutrophil cytoplasm antibody-associated vasculitis. Nevertheless, eosinophilic granulomatosis ...with polyangiitis stands apart because it has features of vasculitis and eosinophilic disorders that require targeted therapies somewhat different from those used for other anti-neutrophil cytoplasm antibody-associated vasculitides. Considerable advances have been made in understanding the underlying pathophysiology of eosinophilic granulomatosis with polyangiitis that have highlighted the key role of eosinophils and opened new therapeutic opportunities. Its conventional treatment relies mainly on agents that decrease inflammation: corticosteroids and immunosuppressant adjunction for severe manifestations. New therapeutic approaches are needed for refractory disease, relapses and issues associated with corticosteroid dependence, especially for asthma manifestations. Drugs under evaluation mostly target eosinophils and B cells. Results of low-evidence-based trials suggested possible efficacies of biologicals: B-cell-blocking rituximab and anti-immunoglobulin E omalizumab. Recently, the first large-scale randomised controlled trial on eosinophilic granulomatosis with polyangiitis proved the efficacy of anti-interleukin-5 mepolizumab. That finding opens a new era in eosinophilic granulomatosis with polyangiitis management, with mepolizumab approval but also in future drug evaluations and trial designs for eosinophilic granulomatosis with polyangiitis. Additional studies are needed to determine which patients would benefit most from targeted therapies and achieve personalised treatment for patients with eosinophilic granulomatosis with polyangiitis. Herein, we review eosinophilic granulomatosis with polyangiitis characteristics and provide an overview of established and novel pharmacological agents.
Rituximab, an anti-B-cell biological therapy, has been investigated in several clinical trials on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs).
In this paper, the ...clinical trials and open-label studies on rituximab efficacy and safety in treating AAVs are reviewed.
Rituximab achieved high remission-induction and sustained-maintenance rates for patients with these severe diseases, thereby challenging the cornerstone treatment of corticosteroids and cyclophosphamide followed by azathioprine. Rituximab should be used as first-line therapy with corticosteroids to induce remission of severe AAVs, especially in situations in which cyclophosphamide may be problematic (relapse after cyclophosphamide, women of childbearing age, risk of malignancy). Cyclophosphamide indications are likely to be restricted in the future. Whenever possible, rituximab should be preferred to azathioprine to maintain remission. The current maintenance regimen has been extended to at least 18 months but its optimal duration remains unknown and recent data suggest the possibility to extend treatment to 4 years. Future challenges include defining the best dose regimen: at present, different schedules are used as alternatives to those recognized as standards by health authorities. In addition, it remains to identify which patients will benefit the most from long-term retreatment: potentially those with relapsing disease or anti-proteinase-3 ANCA-positivity.
Updates for the treatment of EGPA Raffray, Loïc; Guillevin, Loïc
La Presse médicale (1983),
10/2020, Volume:
49, Issue:
3
Journal Article
Peer reviewed
Open access
Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–Strauss syndrome) is the least frequent antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). Major advances of our ...knowledge on its pathophysiology have revealed features of both AAV and eosinophilic disorders. The development of targeted biotherapies for both diseases opened new possibilities for EGPA management. In this review, we highlight the rationale underlying the routine treatment strategy, which relies mainly on corticosteroids, with immunosuppressant adjunction for severe disease. However, novel therapies are still needed for refractory/relapsing disease and to alleviate the corticosteroid-dependence of asthma and chronic rhinosinusitis. At present, the most promising biotherapies target either eosinophil biology, like mepolizumab, an anti-interleukin-5, or the B-cell compartment, with rituximab. Recent clinical data on new treatment options are discussed and therapeutic strategies are proposed.
Red eye and joint pain Richier, Quentin; Dubernet, Arthur; Raffray, Loïc
European journal of internal medicine,
August 2023, 2023-Aug, 2023-08-00, 20230801, Volume:
114
Journal Article
The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and ...pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis.
A « tipical » but rare cause of neck pain Richier, Quentin; Travers, Jean-Yves; Raffray, Loïc
European journal of internal medicine,
12/2022, Volume:
106
Journal Article
Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 and its associated pathology, COVID-19, have been of particular concerns these last months due to the worldwide burden they represent. The ...number of cases requiring intensive care being the critical point in this epidemic, a better understanding of the pathophysiology leading to these severe cases is urgently needed. Tissue lesions can be caused by the pathogen or can be driven by an overwhelmed immune response. Focusing on SARS-CoV-2, we and others have observed that this virus can trigger indeed an immune response that can be dysregulated in severe patients and leading to further injury to multiple organs. The purpose of the review is to bring to light the current knowledge about SARS-CoV-2 virologic and immunologic features. Thus, we address virus biology, life cycle, tropism for many organs and how ultimately it will affect several host biological and physiological functions, notably the immune response. Given that therapeutic avenues are now highly warranted, we also discuss the immunotherapies available to manage the infection and the clinical outcomes.
Abstract
Objectives
To describe the clinical presentation, treatments and prognosis of gastrointestinal (GI) involvement in adult IgA vasculitis (IgAV).
Methods
Data from 260 adults with IgAV ...included in a French multicentre retrospective survey were analysed. Presentation and outcomes of patients with (GI+) and without (GI-) GI involvement were compared.
Results
One hundred and thirty-seven (53%) patients had GI involvement. Initial manifestations were abdominal pain in 99%, intestinal bleeding in 31%, diarrhoea in 26% and acute surgical abdomen in only 4%. Abdominal imaging revealed thickening of intestinal wall in 61%, and endoscopies revealed abnormalities in 87%, mostly mucosal ulcerations. GI+ vs GI- patients were younger (46 ± 18 vs 54 ± 18 years; P = 0.0004), had more constitutional symptoms (43% vs 23%; P = 0.0005) and joint involvement (72 vs 50%; P = 0.0002), and higher CRP levels (3.7 vs 1.9 mg/dl; P = 0.001). Clinical response and relapse rates were comparable between groups, and all causes mortality (2 vs 4%) and IgAV-related mortality (1% vs 2%) as well. GI-related deaths were due to intestinal perforation and mesenteric ischaemia.
Conclusion
GI involvement is frequent in adult IgAV. GI involvement is frequent in adult IgAV. Mortality is not uncommon but does not seem to be specifically related to GI. Immunosuppressants should not be preferred as first-line therapy for GI+ patients but may be required in case of acute surgical abdomen.
Since 2018, a dengue epidemic has been raging annually in Reunion Island, which poses the major problem of its morbidity and mortality. However, there is no consensus in the literature on factors ...associated with severity of illness. The objective of this study was to identify the factors associated with the occurrence of severe dengue (SD) according to the criteria adopted in 2009 by the World Health Organization (WHO), during the 2019 epidemic.
A total of 163 patients with RT-PCR-confirmed dengue were included in a multicenter prospective cohort study in Reunion Island between January and June 2019. Of these, 37 (23%) were classified as SD, which involves presentation dominated by at least one organ failure, and 126 (77%) classified as non-SD (of which 90 (71%) had warning signs). Confusion, dehydration, and relative hypovolemia were significantly associated with SD in bivariate analysis (p < 0.05). The factors associated with SD in multivariate analysis were a time from first symptom to hospital consultation over 2 days (OR: 2.46, CI: 1.42-4.27), a history of cardiovascular disease (OR: 2.75, 95%CI: 1.57-4.80) and being of Western European origin (OR: 17.60, CI: 4.15-74).
This study confirms that SD is a frequent cause of hospitalization during dengue epidemics in Reunion Island. It suggests that cardiovascular disease, Western European origin, and delay in diagnosis and management are risk factors associated with SD fever, and that restoration of blood volume and correction of dehydration must be performed early to be effective.
NCT01099852; clinicaltrials.gov.
Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain ...elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS+ blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4+ T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.
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•OX40L is expressed by myeloid antigen-presenting cells in patients with active SLE•OX40 signals promote the differentiation of human Th cells toward the Tfh lineage•Strong TCR signals promote the expression of Tfh molecules by human Th cells•RNP-Anti-RNP immune complexes induce monocytes to express OX40L via TLR7
Although increased activity of T follicular helper (Tfh) cells plays a pathogenic role in systemic lupus erythematosus (SLE), the mechanism has been unclear. Ueno and colleagues show that exaggerated OX40 signals promote the generation of Tfh cells in SLE.
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