Marie-Elise Truchetet

Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis

BackgroundTargeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab).MethodsA systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R©, package meta.ResultsOverall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 % (95 % CI, 65–79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18–30 %). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56–66 %) for ipilimumab 3 mg/kg and 79 % (95 % CI, 69–89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 % of patients.The median time of onset of irAEs was about 10 weeks (IQR, 6–12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients.ConclusionThe price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions.

Role of extracellular vesicles in autoimmune diseases

Extracellular vesicles (EVs) consist of exosomes released upon fusion of multivesicular bodies with the cell plasma membrane and microparticles shed directly from the cell membrane of many cell types. EVs can mediate cell-cell communication and are involved in many processes including inflammation, immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. Accumulating evidence reveals that EVs act in the establishment, maintenance and modulation of autoimmune processes among several others involved in cancer and cardiovascular complications. EVs could also present biomedical applications, as disease biomarkers and therapeutic targets or agents for drug delivery.

Gut metagenome and spondyloarthritis

Joint Bone Spine - In Press.Proof corrected by the author Available online since mardi 25 juin 2013

Atacicept as an investigated therapy for rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is a chronic, painful and debilitating autoimmune disease. Although the outcome for patients with RA has improved markedly in the past decades, adequate disease control cannot be achieved in a substantial proportion of patients. Since RA is a syndrome with different biological subsets, new drugs with a novel mechanism of action may represent a valuable addition to the current armamentarium. Areas covered: This review focuses on the pharmacodynamics and pharmacokinetics of atacicept. Furthermore, the article both summarises and comments on the drug’s efficacy and safety profile in RA patients. Expert opinion: Atacicept is designed to neutralise B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand, two cytokines involving B-cell function and survival. Two recent Phase II studies have demonstrated that atacicept was not effective in RA patients with an inadequate response to methotrexate or TNF antagonists. However, atacicept displayed significant biological activity, including reduction of Ig and rheumatoid factor levels. Adverse events were slightly more frequent among patients treated with atacicept compared with placebo. In contrast to patients with systemic lupus erythematosus, RA patients receiving atacicept did not show an increased susceptibility to infections. In view of its important impact on immunoglobulin-secreting cells, this drug might be a rational therapy for hematological diseases.

Switching from originator infliximab to biosimilar CT-P13 in real-life: the weight of patient acceptance

OBJECTIVEnTo explore acceptance and retention rate of biosimilar CT-P13 after switching from originator infliximab (OI) in patients with various rheumatic diseases.nnnMETHODSnPatients with stable rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA) under OI were proposed to switch to CT-P13 at the same regimen. A prospective cohort of infliximab-naïve patients beginning CT-P13 and a retrospective cohort of patients treated with OI were used as controls. The primary outcome was to evaluate the retention rate of CT-P13. Secondary outcomes were the switch acceptance rate, reasons of failure and safety.nnnRESULTSnSwitch was proposed to 100 patients and accepted by 89 of them (63 AS, 12 PsA and 14 RA). After a median follow-up of 33 weeks, 72% of patients were still treated with CT-P13. This retention rate was significantly lower than the one found in our retrospective and prospective control cohorts: 88% and 90% respectively (P-value=0.0002). Within patients who asked to be reswitched to OI, 13/25 (52%) presented clinical disease activity, one developed serum sickness and 11 (44%) presented no objective activity. A subanalysis excluding these 11 patients abrogated difference in retention rates between the 3 cohorts (P-value=0.453). After reswitching to OI, patients without objective disease activity claimed to recover original efficacy.nnnCONCLUSIONSnRetention rate was lower after switching from OI to CT-P13 compared to our control cohorts. However, this difference faded after excluding patients without objective clinical activity, suggesting a reluctance of patients to the switch and a negative perception of the biosimilar.

When and where does rheumatoid arthritis begin

The major strides accomplished in elucidating the pathophysiology of rheumatoid arthritis (RA) have translated into therapeutic breakthroughs in clinical practice. However, currently available treatments work only for as long as they are taken. The development of curative treatments will probably require a better understanding of the earliest phases of RA and perhaps the identification of the etiological factors, which are probably numerous. These objectives are being pursued in studies of preclinical RA. The literature review presented herein indicates that the immunological conflict probably originates outside the joints, at mucous membrane sites and, more specifically, in the upper aerodigestive tract. The preclinical phase of RA can last for many years, and some patients probably never progress to arthritis. An immunological conflict develops then spins out of control, causing increases in autoantibody titers and subsequently in levels of serum markers for inflammation, before the development of the first joint symptoms. Improved knowledge of the preclinical phase, together with information from genetic markers, will allow the identification of profiles associated with susceptibility to RA and perhaps, in the future, the development of preventive strategies.

Efficacy of baricitinib in the treatment of rheumatoid arthritis

ABSTRACT Introduction: although the outcome for patients with rheumatoid arthritis (ra) has improved in the past decades, adequate disease control cannot be achieved in a substantial proportion of patients. new drugs with a novel mechanism of action, may represent a valuable addition to the current armamentarium. Areas covered: This review focuses on the pharmacodynamics and pharmacokinetics of baricitinib. Furthermore, the article summarizes and comments the drug’s efficacy and safety profile in RA patients. Expert opinion: Baricitinib is an oral targeted synthetic (ts) disease-modifying antirheumatic drug (DMARD) that mainly inhibits JAK1 and JAK2. Baricitinib monotherapy, or in combination with conventional synthetic (cs) DMARDs, has demonstrated its efficacy while having an acceptable safety profile in early active RA naive to DMARDs, and active RA with an inadequate response to csDMARDs and/or biologic (b)DMARDs. The future place of baricitinib in the management of RA patients will depend on several factors. However, baricitinib offer few advantages: oral administration, rapidity of action, efficacy in monotherapy and over adalimumab in one study and non-immunization. However, pending further safety data, current practice would be to start a bDMARD when the treatment target is not achieved with csDMARDs. Availability of additional long-term safety data may influence prescribing decisions.

IgE Inhibits Toll-like Receptor 7- and Toll-like Receptor 9-Mediated Expression of Interferon-α by Plasmacytoid Dendritic Cells in Patients With Systemic Lupus Erythematosus.

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.

Efficacy and safety of autologous haematopoietic stem cell transplantation in systemic sclerosis: A systematic review of literature

We aimed to assess the efficacy of autologous haematopoietic stem cell transplantation (HSCT) for skin sclerosis (SSc) and lung function in SSc. We performed a systematic literature review in the PubMed and Scopus databases from the earliest records to March 2016. We assessed study quality using the Cochrane tool for randomized studies, the Newcastle–Ottawa Scale for controlled cohort studies and an 18‐item quality‐appraisal checklist for case series. The primary outcome was the improvement of skin thickening using the modified Rodnan Skin Score (mRSS). The secondary outcome was efficacy on lung function, using diffusing capacity of the lungs for carbon monoxide and forced vital capacity (FVC). The safety of the procedure was evaluated. The literature search identified 431 citations. There were 38 studies involving a total of 344 patients who fulfilled our inclusion criteria. No meta‐analysis was performed due to a high heterogeneity. There was a significant improvement in mRSS in the majority of the reports (P < 0·05), and the results were sustained for up to 8 years after autologous HSCT. The randomized studies and the four cohort studies each showed a slight but statistically significant improvement in FVC at 1 or 2 years. The treatment‐related mortality calculated by pooling patients of 35 studies (336 patients with a follow‐up up to 146 months) was 8·3% after autologous HSCT and 1% in cyclophosphamide‐treated groups. Despite heterogeneity among the studies, we determined that autologous HSCT significantly improved cutaneous fibrosis and slightly improved FVC. Safety of autologous HSCT is acceptable given the severity of the disease. This systematic review was registered on PROSPERO, number CRD42016027951.

IgE inhibits TLR‐7 and ‐9 mediated expression of interferon‐alpha by plasmacytoid dendritic cells in systemic lupus patients

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.