Secukinumab Provides Significant and Sustained Inhibition of Joint Structural Damage in a Phase III Study of Active Psoriatic Arthritis

In this phase III, double-blind, placebo-controlled study, 606 patients with psoriatic arthritis were randomised to intravenous (IV) secukinumab 10 mg/kg (weeks 0, 2, 4) followed by subcutaneous secukinumab 150 mg (IV→150 mg) or 75 mg (IV→75 mg), or placebo. Patients were stratified by prior anti-TNF (tumour necrosis factor) exposure (71% anti-TNF-naïve). At week 16, placebo-treated patients who had ≥20% reduction in tender and swollen joint count (responders) remained on placebo until week 24; non-responders were re-randomised to secukinumab 150 or 75 mg. The van der Heijde modified total Sharp score (mTSS) was determined at baseline, week 16/24 and week 52.In the overall population, radiographic progression was inhibited through 52 weeks; efficacy was demonstrated for both erosion and joint space narrowing scores and in patients who switched from placebo to secukinumab at week 24. Subgroup analyses showed secukinumab reduced progression at week 24, regardless of prior anti-TNF use; mean change from baseline to week 24 in mTSS in the secukinumab pooled and placebo groups was 0.05 and 0.57, respectively for anti-TNF-naïve patients and 0.16 and 0.58, respectively in anti-TNF-IR patients. Anti-TNF-naïve patients showed negligible progression through week 52. Inhibition of structural damage was observed through week 52, irrespective of concomitant methotrexate use. A high proportion of patients showed no progression (≤0.5) with secukinumab from baseline to week 24 (IV→150 mg, 82.3%; IV→75 mg, 92.3%) and from week 24 to week 52 (IV→150 mg, 85.7%; IV→75 mg, 85.8%).Secukinumab inhibited radiographic progression in patients with active psoriatic arthritis through 52 weeks of therapy

Mesenchymal Stem Cells in Systemic Sclerosis: Allogenic or Autologous Approaches for Therapeutic Use?

Systemic sclerosis (SSc) is a rare autoimmune disease, which is potentially lethal. The physiopathology of the disease is still incompletely elucidated although the role of fibroblasts, endothelial cells (ECs), immune cells. and the environment (i.e., oxidative stress) has been demonstrated. This is an intractable disease with an urgent need to provide better therapeutic options to patients. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach thanks to the number of trophic and pleiotropic properties they exert. Among these, MSCs display anti-fibrotic, angiogenic, and immunomodulatory capacities that might be of interest in the treatment of SSc by acting on different processes that are dysregulated in the disease. In the recent years, the therapeutic effectiveness of MSCs has been demonstrated in different preclinical animal models and is being investigated in phase I clinical trials. Both allogenic and autologous transplantation of MSCs isolated from bone marrow or adipose tissue is being evaluated. The rationale for using allogenic MSCs in SSc, as well as in other autoimmune diseases, is based on the possibility that autologous MSCs might be altered in these diseases. In SSc, reports from the literature are controversial. Nevertheless, the role of the oxidative environment and of the crosstalk with neighboring cells (fibroblasts and ECs) on the functional properties of MSCs has been reported. Here, we review the preclinical and clinical data reporting the interest of MSC-based treatment in SSc and question the use of autologous or allogeneic MSCs in perspective of clinical applications

Serum-Mediated Oxidative Stress from Systemic Sclerosis Patients Affects Mesenchymal Stem Cell Function

ObjectivesProperties of mesenchymal stromal/stem cells (MSCs) from systemic sclerosis (SSc) patients have been reported to be altered. MSC-based therapy may therefore rely on the use of allogeneic MSCs from healthy subjects. Here, we investigated whether heterologous MSCs could exhibit altered properties following exposure to oxidative environment of SSc sera.MethodsHuman bone marrow-derived MSCs were cultured in the presence of various sera: control human serum AB (SAB), SAB with HOCl-induced AOPPs at 400 or 1,000 µmol/L (SAB400 or SAB1000, respectively), or H2O2-induced AOPPs or SSc patient serum (PS). Proliferation, apoptosis, and senescence rates of MSCs were evaluated after 3, 6, and 10 days in culture. Reactive oxygen species and nitric oxide production were quantified at 24 h. Trilineage potential of differentiation was tested after 21 days in specific culture conditions and immunosuppressive function measured in a T lymphocyte proliferative assay.ResultsIn the presence of oxidative environment of PS, MSCs retained their proliferative potential and survived for at least the first 3 days of exposure, while the number of senescent MSCs increased at day 6 and apoptosis rate at day 10. Exposure to PS enhanced the antioxidant capacity of MSCs, notably the expression of SOD2 antioxidant gene. By contrast, the osteoblastic/adipogenic potential of MSCs was increased, whereas their immunosuppressive function was slightly reduced.DiscussionAlthough some functional properties of MSCs were affected upon culture with PS, evidence from preclinical studies and the present one suggested that MSCs can adapt to the oxidative environment and exert their therapeutic effect

Use of high-plex data provides novel insights into the temporal artery processes of giant cell arteritis

ObjectiveTo identify the key coding genes underlying the biomarkers and pathways associated with giant cell arteritis (GCA), we performed an in situ spatial profiling of molecules involved in the temporal arteries of GCA patients and controls. Furthermore, we performed pharmacogenomic network analysis to identify potential treatment targets.MethodsUsing human formalin-fixed paraffin-embedded temporal artery biopsy samples (GCA, n = 9; controls, n = 7), we performed a whole transcriptome analysis using the NanoString GeoMx Digital Spatial Profiler. In total, 59 regions of interest were selected in the intima, media, adventitia, and perivascular adipose tissue (PVAT). Differentially expressed genes (DEGs) (fold-change > 2 or < −2, p-adjusted < 0.01) were compared across each layer to build a spatial and pharmacogenomic network and to explore the pathophysiological mechanisms of GCA.ResultsMost of the transcriptome (12,076 genes) was upregulated in GCA arteries, compared to control arteries. Among the screened genes, 282, 227, 40, and 5 DEGs were identified in the intima, media, adventitia, and PVAT, respectively. Genes involved in the immune process and vascular remodeling were upregulated within GCA temporal arteries but differed across the arterial layers. The immune-related functions and vascular remodeling were limited to the intima and media.ConclusionThis study is the first to perform an in situ spatial profiling characterization of the molecules involved in GCA. The pharmacogenomic network analysis identified potential target genes for approved and novel immunotherapies

Intriguing Relationships Between Cancer and Systemic Sclerosis: Role of the Immune System and Other Contributors

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder, characterized by multisystem involvement, vasculopathy, and fibrosis. An increased risk of malignancy is observed in SSc (including breast and lung cancers), and in a subgroup of patients with specific autoantibodies (i.e., anti-RNA polymerase III and related autoantibodies), SSc could be a paraneoplastic syndrome and might be directly related to an immune response against cancer. Herein, we reviewed the literature, focusing on the most recent articles, and shed light onto the potential relationship between cancer and scleroderma regarding temporal and immunological dimensions

Mechanisms of Autoantibody-Induced Pathology

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein

Immunogenicity of infectious pathogens and vaccine antigens

The concept of the immunogenicity of an antigen is frequently encountered in the context of vaccine development, an area of intense interest currently due to the emergence or re-emergence of infectious pathogens with the potential for worldwide spread. However, the theoretical notion of immunogenicity as discussed in older textbooks of immunology needs reconsideration due to advances in our understanding of immunologic responses. Immunogenicity is a property that can either be a desirable attribute, for example in the generation of an effective protective immunity against infectious pathogens or an undesirable trait, for example when it relates to novel therapeutic compounds and drugs, where an immune response needs to be prevented or inhibited. In this Forum Article, we aimed to revisit the issue of immunogenicity to discuss a series of simple questions relevant to the concept that are frequently rephrased but incompletely resolved in the immunologic literature

Comorbidities associated with Sjögren's syndrome : from epidemiological data to individual patterns

Contexte. Le syndrome de Gougerot-Sjögren (SGS) (syndrome sec, douleurs, et fatigue) est une connectivite dont le pronostic est lié au sur-risque de lymphome. Néanmoins, ces patients présentent un recours aux soins importants : néoplasies, pathologies cardiovasculaires, et infections. Notre expérience fait aussi état de plaintes neuro-cognitives fréquentes, entachant la qualité de vie des malades. Les données épidémiologiques concernant ces comorbidités sont hétérogènes, et proviennent de population principalement Asiatiques. L’objectif de notre travail est donc de décrire l’incidence de ces comorbidités parmi une population de patients avec SGS primaire (pSS) à partir des bases de santé PMSI (Programme de Médicalisation des Systèmes Informatiques). Nous complétons notre approche par l’étude individuelle des patients suivis au CHU de Montpellier. Résultats. Nous confirmons ainsi que les pSS présentent plus d’hémopathies lymphoïdes que les patients-contrôles. En revanche, l’incidence des cancers mammaires est inférieure. Ce résultat, associé au phénotype immunologique et histologique des cancers du sein suivis au CHU, nous font discuter le concept d’immuno-surveillance exercé par le SGS à l’encontre des cellules néoplasiques. Nos résultats montrent un sur-risque d’hospitalisation pour démence, anxiété et troubles somatoformes. Ces résultats sont étayés par les tests individuels, qui objectivent une fragilité cognitive chez tous les patients se plaignant. L’implication des interférons dans ces phénomènes reste à démontrer. Nous montrons un sur-risque d’évènements coronariens, de syndrome d’apnées du sommeil, et d’hypertension pulmonaire chez les pSS. Ceci nous engage à mieux dépister et contrôler les facteurs de risque (prises en charge pluri-disciplinaire). Enfin, le risque augmenté d’hospitalisation pour infections broncho-pulmonaires renforce l’objectif d’intensification de nos politiques vaccinales. Le lien entre mycobactérie et SGS reste à préciser. Conclusion. Notre travail propose des hypothèses physiopathologiques et des perspectives de recherche pour les comorbidités étudiées, et des axes d’amélioration de prise en charge des patients (afin d’améliorer leur qualité de vie).Background. Primary Sjögren's syndrome (pSS) (sicca syndrome, pain, and fatigue) is an autoimmune disease whom prognosis is related to lymphoma. Nevertheless, these patients are also at risk of cancers, cardiovascular diseases, and infections. Neuro-cognitive and psychiatric complaints are frequent, affecting patients’ quality of life. Epidemiological data concerning these comorbidities are heterogeneous, and mainly come from Asian populations. Objective. To describe the incidence of neoplasm, neuro-psychiatric and cardiovascular diseases, and infections in a population of hospitalized pSS through the study of French Health insurance database (PMSI). To study individual data from patients followed at the Montpellier University Hospital. Results. We confirm that pSS patients exhibit more lymphomas than control patients. However, the incidence of breast cancer is decreased. This result, associated with the immunological and histological phenotype of pSS patients with breast cancers followed in Montpellier Hospital, drives us to discuss potential immune-surveillance exerted by pSS towards neoplastic cells. Our results show an increased risk of hospitalization for dementia, anxiety and somatoform disorders. These results are supported by individual tests exhibiting cognitive frailty or impairment in all patients with complaints. The key role of interferons in these symptoms is suspected. We show an increased risk of ischemic heart diseases, sleep apnea syndrome, and pulmonary hypertension in pSS suggesting a better management of risks factors. Finally, the increased risk of hospitalization for lung infections reinforces our objective of intensifying our vaccination policies. Conclusion. Our work suggests pathophysiological hypotheses and research perspectives for the studied comorbidities, as well as proposal for a better management of these (that could impact their quality of life)

Qualité à l officine (Deux cas pratiques : éducation thérapeutique du patient et prise en charge du patient cancéreux)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF