Systemic sclerosis (SSc) has the highest cause-specific mortality of all the connective tissue diseases, and the aetiology of this complex and heterogeneous condition remains an enigma. Current disease-modifying therapies for SSc predominantly target inflammatory and vascular pathways but have variable and unpredictable clinical efficacy, and none is curative. Moreover, many of these therapies possess undesirable safety profiles and have no appreciable effect on long-term mortality. This Review describes the most promising of the existing therapeutic targets for SSc and places them in the context of our evolving understanding of the pathophysiology of this disease. As well as taking an in-depth look at the immune, inflammatory, vascular and fibrotic pathways implicated in the pathogenesis of SSc, this Review discusses emerging treatment targets and therapeutic strategies. The article concludes with an overview of important unanswered questions in SSc research that might inform the design of future studies of treatments aimed at modifying the course of this disease.

Emerging targets of disease-modifying therapy for systemic sclerosis

CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse

Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature

Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology, manifesting in patients as tissue fibrosis, endothelial dysfunction, and inflammation. The disease is characterized by a...

https://journals.sagepub.com/doi/pdf/10.5301/jsrd.5000258

Contribution of Interleukin-6 to the Pathogenesis of Systemic Sclerosis:

Systemic sclerosis (SSc) is a connective tissue disease with a significant morbidity and reduced survival of patients. Effective treatment and clinical control of the disease remain challenging. In particular, the development of pulmonary and cardiac fibrosis and pulmonary hypertension are severe complications responsible for excessive mortality. Currently available treatment strategies only alleviate symptoms and slow disease progression. Here, we investigated the therapeutic potential of ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor used in B cell malignancies, to alter B cell pathology in SSc in an in vitro model of autoimmunity. PBMCs and sorted B cells of 24 patients with SSc were used for functional testing after stimulation with hypomethylated DNA fragments (CpG) to induce an innate immune response. The effects of ibrutinib on cytokine production, autoantibody release, and activation of the transcription factor NFκB were evaluated. Ibrutinib was able to reduce the production of the profibrotic hallmark cytokines IL-6 and TNF-α mainly from the effector B cell population in patients with SSc. Importantly, small doses of ibrutinib (0.1 μM) preserved the production of immunoregulatory IL-10 while effectively inhibiting hyperactivated, profibrotic effector B cells. In a flow cytometry analysis of phosphorylated NFκB, an important transcription factor in the induction of innate immune responses in B cells, significantly less activation was observed with ibrutinib treatment. Our data could pave the avenue for a clinical application of ibrutinib for patients with SSc as a novel treatment option for the underlying pathogenetic immune imbalance contributing to disease onset and progression.

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Inhibition of effector B cells by ibrutinib in systemic sclerosis.

Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naive subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-β (TGF-β) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.

Role of B cells in the pathogenesis of systemic sclerosis.

Debriefing is a phase of synthesis and reflection that immediately follows a real-life or simulated situation. It is an essential educational step that forces the learners to reflect upon the thought processes that underlie their actions. Debriefing encourages a personal and collective reflection in order to remodel erroneous mental schemas and rectify actions done in context. Debriefing cannot be improvised; it requires a sound structure and regular practice in order to be truly effective. The debriefer must be considerate, choose appropriate learning objectives and dedicate ample time to the learners. Debriefing is focused on learning acquired in context-in other words, on the actions that were performed within a real-life or simulated clinical practice situation-and immediately follows the situation. After an initial phase of emotional release, the debriefer will help learners analyse their actions to identify their underlying rationale (contextualization), extract the overarching principles related to the lived situation in order to modify the rationale if needed (decontextualization) and assist the transfer of learning to real life (in the case of simulation) and to similar situations (recontextualization). A final summary of learning achieved during the training session concludes the debriefing. Debriefing is useful in any learning situation, including in internal medicine. Even if simulation is still underused in internal medicine, post-event debriefing can be implanted in our clinical services. Indeed, training our students and shaping them into healthcare professionals rest in no small part on hospital rotations where the intern is confronted with real-patient situations that are suitable to learning. Some in-hospital clinical encounters can be actively transformed into learning opportunities thanks to post-event debriefing, but can also passively morph into bad daily practice if no supporting action is implemented. Debriefing can thus provide an opportunity to develop non-technical skills in critical situations, or doctor-patient communication skills, within a team or between colleagues. These competencies are the hallmark of well-trained interns and are indispensable for the proper functioning of a care team. We will not develop the emotional and psychological management of debriefing in this article. We hope we will helpfully introduce as many of our colleagues as possible to the art of debriefing in most circumstances.

Initiation au débriefing pour les internistes : état des connaissances et mise en pratique pour transformer des situations cliniques réelles ou simulées en moments d'apprentissage

Resume Le debriefing a visee pedagogique est une phase de synthese et de reflexion qui suit immediatement une situation simulee ou vecue. Il represente une etape indispensable qui amene l'apprenant a une demarche reflexive sur le raisonnement a l'origine de ses actions. Le debriefing encourage la reflexion personnelle et collective pour remodeler les schemas de raisonnement errones et corriger les actions en contexte. Le debriefing ne s'improvise pas et une bonne structure doublee d'une pratique reguliere permet d'en tirer toute sa quintessence. Le debriefeur doit rester bienveillant, choisir les objectifs de seance et accepter de consacrer un temps important aux apprenants. Le debriefing est centre sur les apprentissages realises en contexte — c'est-a-dire toutes les actions qui viennent d'etre realisees dans une situation simulee ou reelle de pratique clinique —, et surviendra immediatement apres la situation vecue. Apres une phase de reaction, le debriefeur devra aider les apprenants a decortiquer leurs actions pour en connaitre les raisons (contextualisation). Puis, il extraira les principes generaux relatifs a la situation vecue pour modifier ces raisons le cas echeant (decontextualisation) et preparer le transfert des apprentissages realises vers la vie reelle (en cas de simulation) et vers des situations similaires (recontextualisation). Un sommaire final des apprentissages realises au cours de la seance conclura le debriefing. Le debriefing est une forme de retroaction utilisable dans tout enseignement, et notamment en medecine interne. Meme si la simulation est encore peu utilisee dans notre discipline, le debriefing post-evenement (DPE) est utilisable au sein de nos services. En effet, la formation et la professionnalisation des etudiants reposent en grande partie sur les stages hospitaliers ou l'interne sera confronte a des situations d'apprentissage sur des patients reels. Certains evenements cliniques rencontres a l'hopital peuvent etre activement transformes en opportunites pedagogiques grâce au DPE, mais peuvent parfois se muter en mauvaise pratique quotidienne si aucune action de soutien n'est realisee. Tout debriefing donne la possibilite de developper des competences non techniques dans la gestion des situations critiques (principalement : leadership, communication, synergie de groupe, sensibilite situationnelle, et gestion des ressources), ou des competences de communication dans la relation medecin-malade, au sein d'une equipe ou entre confreres. Ces competences sont le temoin d'une bonne formation des internes et sont indispensables au bon fonctionnement d'une equipe soignante. Nous ne developperons pas la prise en charge emotive et psychologique du debriefing dans cet expose. Par ce travail, nous esperons initier le plus grand nombre de nos collegues a l'art du debriefing en toutes circonstances.

Iconographies supplémentaires de l'article : Initiation au débriefing pour les internistes?: état des connaissances et mise en pratique pour transformer des situations cliniques réelles ou simulées en moments d'apprentissage

S. Sanges

Papers

Role of B cells in the pathogenesis of systemic sclerosis.

Initiation au débriefing pour les internistes : état des connaissances et mise en pratique pour transformer des situations cliniques réelles ou simulées en moments d'apprentissage

Iconographies supplémentaires de l'article : Initiation au débriefing pour les internistes?: état des connaissances et mise en pratique pour transformer des situations cliniques réelles ou simulées en moments d'apprentissage