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The Sarcoidosis Diagnostic Score (SDS) has been established to quantitate the clinical features consistent with sarcoidosis in a monocentric study.We aimed to confirm the diagnostic value of SDS in a large, multicontinental study and to assess the utility of SDS in differentiating sarcoidosis from alternative diagnosis including infectious and non-infectious granulomatous diseases.We included patients with biopsy-confirmed sarcoidosis at nine centers across the world. Patients without sarcoidosis seen at the same sites served as control patients. Using a modified World Association of Sarcoidosis and Other Granulomatous Disorders organ assessment instrument, we scored all patients for presence of granuloma on biopsy, highly probable symptoms, and least probable symptoms for each area. Two sarcoidosis scores were generated: SDS Biopsy (with biopsy) and SDS Clinical (without biopsy). SDS Clinical and Biopsy were calculated for all patients. We calculated and compared the Area Under Curve (AUC) for SDS Clinical and Biopsy according to different diagnosis scenarios.A total of 1041 patients with sarcoidosis and 1035 without sarcoidosis were included. SDS Clinical (AUC=0.888, 95%CI: 0.874-0.902) and SDS Biopsy (AUC=0.979, 95%CI: 0.973-0.985) according to AUC were good to excellent for differentiating sarcoidosis from alternative diagnosis. SDS Clinical was less discriminatory in male (p=0.01) and in "high tuberculosis prevalence" centers (p0.001). However, SDS Clinical (AUC=0.684, 95%CI: 0.602-0.766) and SDS Biopsy (AUC=0.754, 95%CI: 0.673-0.835) were not sufficiently discriminative for non-infectious granulomatous diseases, but both SDS could differentiate sarcoidosis from infectious granulomatous diseases. Algorithms were proposed for the SDS Clinical and SDS Biopsy to assist the clinician in the diagnostic process, and proposed cut-off values for the SDS Clinical and SDS Biopsy allowing the diagnosis of sarcoidosis to be safely confirmed or rejected in most cases except non-infectious granulomatous disease.This multicontinental study confirms that both SDS Clinical and SDS Biopsy have good to excellent performance to discriminate sarcoidosis from alternative diagnoses. Differences in the AUC were seen for "high tuberculosis prevalence" versus "low tuberculosis prevalence" centers and males versus females. Both SDSs had good discriminatory function for infectious granulomatous disease but failed in case of non-infectious granulomatous disease such as berylliosis.

International audience; Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.

Extrapulmonary sarcoidosis occurs in 30-50% of cases of sarcoidosis, most often in association with pulmonary involvement, and virtually any organ can be involved. Its incidence depends according to the organs considered, clinical phenotype, and history of sarcoidosis, but also on epidemiological factors like age, sex, geographic ancestry, and socio-professional factors. The presentation, symptomatology, organ dysfunction, severity, and lethal risk vary from and to patient even at the level of the same organ. The presentation may be specific or not, and its occurrence is at variable times in the history of sarcoidosis from initial to delayed. There are schematically two types of presentation, one when pulmonary sarcoidosis is first discovered, the problem is then to detect extrapulmonary localizations and to assess their link with sarcoidosis, while the other presentation is when extrapulmonary manifestations are indicative of the disease with the need to promptly make the diagnosis of sarcoidosis. To improve diagnosis accuracy, extrapulmonary manifestations need to be known and a medical strategy is warranted to avoid both under- and over-diagnosis. An accurate estimation of impairment and risk linked to extrapulmonary sarcoidosis is essential to offer the best treatment. Most frequent extrapulmonary localizations are skin lesions, arthritis, uveitis, peripheral lymphadenopathy, and hepatic involvement. Potentially severe involvement may stem from the heart, nervous system, kidney, eye and larynx. There is a lack of randomized trials to support recommendations which are often derived from what is known for lung sarcoidosis and from the natural history of the disease at the level of the respective organ. The treatment needs to be holistic and personalized, taking into account not only extrapulmonary localizations but also lung involvement, parasarcoidosis syndrome if any, symptoms, quality of life, medical history, drugs contra-indications, and potential adverse events and patient preferences. The treatment is based on the use of anti-sarcoidosis drugs, on treatments related to organ dysfunction and supportive treatments. Multidisciplinary discussions and referral to sarcoidosis centers of excellence may be helpful for difficult diagnosis and treatment decisions.

To describe the current knowledge on indications for sarcoidosis treatment.Despite the lack of evidence-based recommendations, the sarcoidosis community has adopted the concept of starting systemic anti-inflammatory treatment because of potential danger (risk of severe dysfunction on major organs or death) or unacceptable impaired quality of life (QoL). On the contrary, while QoL and functionality are patients' priorities, few studies have evaluated treatment effect on patient-reported outcomes. The awareness of long-term corticosteroids toxicities and consequences on QoL and the emergence of novel drugs have changed therapeutic management. Second-line therapy, mainly methotrexate and azathioprine, are indicated for corticosteroids sparing or corticosteroids-resistant sarcoidosis. TNF-α inhibitors are a useful third-line therapy in chronic refractory disease. In addition to organ-targeted treatment, efforts should also be taken for treating nonorgan-specific symptoms, such as physical training for fatigue, and various disease complications.Clinicians should offer a tailored treatment for each patient and ensure a holistic multidisciplinary approach, including pharmacological and nonpharmacological interventions. Patient-centered communication is critical to drive shared decisions, in particular for the tricky situation of isolated impaired QoL as the unique therapeutic indication. Once treatment is decided, clinicians should define a clear therapeutic plan, including goals and instruments to assess response.

Introduction La sarcoidose est une granulomatose systemique d’etiologie indeterminee [1] . De nombreux cas et des series d’infections opportunistes (IO) chez des patients atteints de sarcoidose sont rapportes dans la litterature medicale [2] , [3] . Sont generalement exclues les aspergilloses cavitaires et les tuberculoses, associees respectivement a la fibrose et a des elements demographiques communs. Les agents opportunistes rapportes sont varies (Cryptococcus neoformans, JC virus, mycobacteries atypiques, Nocardia spp.) mais actuellement aucun facteur de risque d’infection opportuniste n’est decrit au cours de la sarcoidose. Patients et methodes Nous avons effectue un recueil de la litterature medicale via le moteur de recherche Medline et realise un appel a observations via le groupe sarcoidose francophone a la recherche d’associations « infection opportuniste » et « sarcoidose ». Les caracteristiques cliniques des IO ont ete comparees a une population temoin constituee de patients porteurs d’une sarcoidose sans IO issus d’une cohorte de notre service. Resultats La revue de la litterature a permis de recenser 164 cas d’infections qualifiees d’opportunistes chez des patients porteurs d’une sarcoidose. Parmi ces 164 infections, 83 etaient des cryptococcoses (51 %) et 39 etaient des leuco-encephalopathies multifocales progressives (LEMP) (24 %). Notre appel a observations a permis de recenser 50 IO chez 49 patients, incluant : 24 cryptococcoses (49 %), 12 LEMP (24 %), 7 pneumocystoses (14 %) et 7 autres infections (14 %) dont 3 mycobacterioses atypiques, 2 nocardioses et 2 infections a cytomegalovirus. Ces 49 patients avec IO ont ete compares a 135 controles porteurs d’une sarcoidose sans IO. Dans le groupe infection opportuniste, le compte lymphocytaire moyen etait de 1000/mm3 (100-2680/mm3) et 14 patients ne presentaient pas de lymphopenie (29 %). Les facteurs de risques identifies en analyse univariee etaient : le sexe masculin (OR = 4,76; IC95 % [2,12 ; 10,00]), la presence d’adenopathies peripheriques (OR = 3,45 ; [1,49 ; 8,04]), d’une hepatomegalie (OR = 8,10 ; [1,91 ; 40,41]) ou d’une splenomegalie (OR = 9,00, [1,80 ; 58,86]), la presence d’une atteinte pulmonaire de stade ≥2 (OR = 6,66 ; [2,80 ; 17,74]), d’une atteinte neurologique centrale (OR = 8,73 ; [1,98 ; 53,52]) ou d’une insuffisance renale (OR = 5,65 ; [1,33 ; 25,24]), la corticotherapie (OR = 10,26 ; [4,15 ; 29,22]) et l’utilisation du cyclophosphamide (OR = 9,42 ; [1,61 ; 98,92]) ou d’un anti-TNFα (OR = 7,68 ; [1,21 ; 83,62]). En analyse multivariee (ajustement sur l’âge et le sexe), les facteurs de risque identifies etaient l’utilisation de corticoides (OR = 10,60 ; [4,31 ; 29,57]) ou d’un anti-TNFα (OR = 13,47 ; [2,05 ; 129,43]), la presence d’une hepatomegalie (OR = 9,91 ; [2,23 ; 55,85]), une atteinte pulmonaire de stade 2 ou superieur (OR = 5,65 ; [2,34 ; 15,36]) et l’insuffisance renale (OR = 11,76 ; [2,32 ; 68,35]). La lymphopenie Conclusion Les facteurs de risque d’IO dans notre etude sont associes a la gravite de la sarcoidose et/ou a sa diffusion systemique. Il existe un facteur confondant lie a l’utilisation des immunosuppresseurs chez des patients avec une sarcoidose plus severe. Dans notre serie, 6 % des patients ont developpe une infection opportuniste sans aucun facteur de risque, suggerant neanmoins une immunosuppression propre a la sarcoidose dans ces cas.

Introduction: Sarcoidosis is a systemic granulomatous disease of unknown etiology mostly affecting lungs and lymph nodes. Previous whole-exome sequencing (WES) studies have shown that autophagy and especially Ras-related C3 botulinum toxin substrate 1 (RAC1) and mammalian target of rapamycin (mTOR) pathways were possibly implicated in sarcoidosis (Pacheco et al. Trends Immunol 2020 Accepted manuscript). Aims: The SARCFAM (familial sarcoidosis) cohort gathered families aggregating sarcoidosis cases. We hypothesized that relevant genes variants in patients with sarcoidosis and uveitis phenotype were also related to autophagy. Methods: A WES study was performed on 20 patients in 6 families out of the SARCFAM cohort compared with 10 internal controls among siblings. 2 genomic subtractions were performed to compare uveitis and sarcoidosis phenotype to sarcoidosis without uveitis phenotype and to healthy controls. Results: 4 of the 20 patients presented uveitis phenotype. In 3 different families, 38, 142 and 104 variants concerning autophagy were found and respectively 12, 40 and 34 were associated with the uveitis clinical phenotype. Most relevant genes were NOD2, UNC93B, NLRP14, UBQLNL and those related to Toll-like receptors (TLR5). All genes were shown to be related to autophagy/mTOR/RAC1 pathways. NLRP14/NOD2 polymorphisms were respectively found to be related to Behcet uveitis and Blau syndrome. These proteins are targets for various environmental antigens (viruses, mycobacteria) suggesting imbrication of genetic predisposition and environmental triggers. Conclusion: Autophagy could be a major key point in the pathophysiology of sarcoidosis and mTOR may represent an interesting target to treat sarcoidosis.

Introduction Pulmonary fibrosing sarcoidosis is associated with increased mortality. This study was aimed to explore the prognosis value of a panel of parameters for predicting mortality. Methods This retrospective study included 216 patients with confirmed stage 4 pulmonary sarcoidosis. Stage 4 diagnosis date served as baseline. The following information was systematically present at baseline: epidemiological characteristics; treatments; pulmonary function; composite physiologic index (CPI); systolic pulmonary artery pressure at echocardiography; pulmonary fibrosis extent, main pulmonary artery/ascending aorta diameters ratio (MPAD/AAD) and MPAD/body surface area (BSA) measured and calculated using computed tomography, Walsh's algorithm based on CPI, lung fibrosis extent and MPAD/AAD ratio, and modified Walsh's algorithm with MPAD/BSA replacing MPAD/AAD allowed to estimate good or bad prognosis profiles. The primary outcome of the study was all cause mortality and lung transplantation. The value of baseline parameters was tested as predictors of mortality using univariate and multivariate analyses. Results Median follow-up was 105 months. There were 41 deaths and 5 transplantations. At multivariate analysis, survival was independently predicted by several parameters including CPI, lung fibrosis extent, pulmonary hypertension at echography or MPAD/BSA ratio, Walsh's algorithm, and geographic origin. The modified Walsh's algorithm was most highly predictive. Conclusion Survival was best predicted by geographic origin, lung fibrosis extent, PH at echography or MPAD/BSA ratio, as well as by various scores among them the modified Walsh's algorithm had very high predictive value thanks to MPAD/BSA ratio which accurately predicted mortality.

Patients with interstitial lung disease have been considered at high risk of complications of COVID-19 because of their underlying lung disease and use of immunosuppressive agents.1 However, data on COVID-19 in patients with sarcoidosis are scarce.2–4 Several reasons for an increased risk of severe forms of COVID-19 among sarcoidosis patients have been hypothesised: the involvement of the lung in almost 90% of patients with COVID-19, some of whom have reduced pulmonary function and comorbidities such as diabetes or hypertension, which are largely associated with the use of glucocorticosteroids for treating sarcoidosis; and the use of immunosuppressive agents in a subset of these patients.5 Recently, Gyorfi et al 6 described the case of a patient with sarcoidosis who experienced a symptomatic SARS-CoV-2 infection with spontaneous clinical improvement, and a virological relapse after steroids treatment. This case illustrated the fact that immunosuppression with glucocorticoids may induce relapse of COVID-19 in patients with sarcoidosis. However, we lack data on the outcomes of patients with sarcoidosis affected by COVID-19. We retrospectively collected data for all patients with sarcoidosis and SARS-CoV-2 infection seen among 15 French centres between 1 March and 20 May 2020. The inclusion criteria were a sarcoidosis diagnosis based on the American Thoracic Society/European Respiratory Society/World Association for Sarcoidosis and other granulomatous diseases …

Purpose of review Sarcoidosis remains a mysterious disease that presents many challenges both in pathogenetic understanding and in the management of patients. This review presents experimental models for sarcoidosis developed since 2016 and discusses their strengths and weaknesses and how they have contributed to the understanding and therapeutic approaches in this disease. In addition, future directions are proposed to overcome the limitations of current models. Recent findings New cellular models using infectious antigen as trigger, and transgenic models in mice have recently been developed to study signaling pathways potentially implicated in the pathogenesis of sarcoidosis. Summary No model fully reproduces sarcoidosis, but most of them generate data supporting key concepts and some open up therapeutic perspectives, like mTOR inhibition or IL-1β blocking. However, there are still many limitations to these models, largely related to the complexity of sarcoidosis, which might be overcome with new technologies, such as mathematical modeling.

Sarcoidosis is a systemic, granulomatous, and noninfectious disease of unknown etiology. The clinical heterogeneity of the disease (targeted tissue(s), course of the disease, and therapy response) supports the idea that a multiplicity of trigger antigens may be involved. The pathogenesis of sarcoidosis is not yet completely understood, although in recent years, considerable efforts were put to develop novel experimental research models of sarcoidosis. In particular, sarcoidosis patient cells were used within in vitro 3D models to study their characteristics compared to control patients. Likewise, a series of transgenic mouse models were developed to highlight the role of particular signaling pathways in granuloma formation and persistence. The purpose of this review is to put in perspective the contributions of the most recent models in the understanding of sarcoidosis.

Few studies have examined the effects of air pollution in diffuse interstitial lung disease and they have focused on small numbers of patients. Most data are available in idiopathic pulmonary fibrosis and studies suggest that the level of exposure to pollutants may influence the development of acute exacerbations (ozone and NO2), their incidence (NO2), decline in respiratory function (PM10) and death (PM10 and PM2.5). Several studies show an increase in the incidence of rheumatoid arthritis in people living near busy roads. In systemic scleroderma, hypersensitivity pneumonitis and sarcoidosis although negative effects of pollution have been reported the data are insufficient to be conclusive. Nevertheless, the observed effects of air pollution are consistent with those described for other chronic respiratory diseases. Exposure to pollution induces oxidative stress, chronic inflammation and shortening of telomeres, which are all mechanisms described in fibrogenesis. New epidemiological studies are needed with individual measurements of exposure to outdoor and indoor pollution, as well as fundamental studies to clarify the effect of pollution on fibrogenesis.

Multiple problems may be encountered during the diagnosis of sarcoidosis: at first diagnose sarcoidosis in an appropriate clinical setting, secondly, identify any manifestation to be linked to sarcoidosis at diagnosis work-up and during evolution; thirdly, recognize "danger" in sarcoidosis and parasarcoidosis syndromes, and finally, diagnose sarcoidosis recovery. Diagnosis is often delayed as presentation may be diverse, non-specific, or atypical. Diagnosis of sarcoidosis is based on three criteria: a compatible presentation; evidence of non-caseating granulomas and exclusion of any alternative diagnosis. However, even when all criteria are fulfilled, the probability of sarcoidosis diagnosis varies from definite to only possible depending upon the presence of more or less characteristic radio-clinical and histopathological findings and on the epidemiological context. Bilateral hilar lymphadenopathy and/or diffuse lung micronodules mainly along lymphatics are the most frequent highly suggestive findings. Evidence of granulomas relies on superficial biopsies of clinically suspected lesion when present or most often by bronchial endoscopy. The diagnosis of sarcoidosis may be difficult in absence of thoracic or skin manifestations and may require the benefit of hindsight before being definitive. Differential diagnoses, mainly tuberculosis, must be considered. The diagnosis of events during evolution relies on serial clinical, pulmonary function, radiographic evaluation and on extrapulmonary manifestations work-up, including electrocardiogram and blood biology. Affected organs need to be related to sarcoidosis using an appropriate diagnostic assessment instrument. To declare the recovery of sarcoidosis, all manifestations must have disappeared spontaneously or after 3-5 years post-treatment without relapse.

Sarcoidosis is a systemic granulomatous disease that can reduce life expectancy mainly due to pulmonary fibrosis resulting from granulomatous inflammation The lack of vascularization within pulmonary granulomas suggests that macrophages localized in the center of these structures are hypoxic. Hypoxia signaling pathways are known to be pro-inflammatory and pro-fibrotic in various pathological conditions. Recent data suggest an involvement of the transcription factor hypoxia-inducible factor (HIF) in the pathogenesis of sarcoidosis. This could represent a new research approach for the understanding and therapeutic management of sarcoidosis.

International audience; Background: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a reliable technique providing high diagnostic yield in mediastinal lymphadenopathy. However, mediastinoscopy is sometimes necessary to eliminate false-negative results. Elastography is a recent technique that can be combined with EBUS to evaluate the elasticity and consequently the nature of a tissue. The primary objective was to evaluate the diagnostic performance of EBUS-TBNA combined with elastography for the assessment of mediastinal lymph nodes.Methods: Single-center, prospective study in patients with mediastinal lymphadenopathy. EBUS-TBNA combined with elastography was performed in each patient. Several elastographic parameters were studied: colorimetric score, average elasticity, elasticity ratio, percentage of hard areas. The final diagnosis was that obtained by TBNA cytology, histology of a surgical biopsy, when performed, or follow-up CT and PET-CT at 6 months.Results: Overall, 110 lymph nodes were examined in 87 patients: 44 were malignant according to TBNA. These nodes had significantly higher elasticity ratio, percentage of hard areas and colorimetric score and significantly lower average elasticity compared to benign nodes (P

Resume La sarcoidose est une granulomatose de cause inconnue avec une atteinte pulmonaire quasi-constante et une evolution difficile a predire. Le diagnostic est retenu dans un triple contexte devant un tableau clinico-radiologique le plus souvent evocateur, la mise en evidence de granulomes typiques sans necrose caseeuse par des biopsies de lesions superficielles, per-endoscopiques bronchiques ou encore ganglionnaires mediastinales sous controle echoendoscopique et l’exclusion des autres causes de granulomatose pouvant donner un meme tableau. La corticotherapie constitue le traitement de premiere ligne en cas d’indication therapeutique, situation rencontree chez la moitie des patients. Les traitements de deuxieme et de troisieme ligne sont respectivement les agents cytotoxiques et les biomedicaments anti-TNF-α. Les formes pulmonaires severes — fibrose sarcoidienne, hypertension pulmonaire, stenoses bronchiques et greffe aspergillaire — sont les premieres causes de morbi-mortalite. Les enjeux dans l’atteinte pulmonaire sont de ne pas meconnaitre un diagnostic alternatif, de savoir quand et comment traiter les patients et de cibler au mieux ceux a risque de developper des formes severes.

Distal lung diseases, such as pulmonary fibrosis or acute lung injury, are commonly associated with local alveolar hypoxia that may be deleterious through the stimulation of alveolar epithelial cell (AEC) apoptosis. In various murine models of alveolar injury, administration of allogenic human mesenchymal stem cells (hMSCs) exerts an overall protective paracrine effect, limiting lung inflammation and fibrosis. However, the precise mechanisms on lung cells themselves remain poorly understood. Here, we investigated whether hMSC-conditioned medium (hMSC-CM) would protect AECs from hypoxia-induced apoptosis and explored the mechanisms involved in this cytoprotective effect. Exposure of rat primary AECs to hypoxia (1.5% O2for 24 h) resulted in hypoxia-inducible factor (HIF)-1α protein stabilization, partly dependent on reactive oxygen species (ROS) accumulation, and in a twofold increase in AEC apoptosis that was prevented by the HIF inhibitor 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl-indazole and the antioxidant drug N-acetyl cysteine. Incubation of AECs with hMSC-CM significantly reduced hypoxia-induced apoptosis. hMSC-CM decreased HIF-1α protein expression, as well as ROS accumulation through an increase in antioxidant enzyme activities. Expression of Bnip3 and CHOP, two proapoptotic targets of HIF-1α and ROS pathways, respectively, was suppressed by hMSC-CM, while Bcl-2 expression was restored. The paracrine protective effect of hMSC was partly dependent on keratinocyte growth factor and hepatocyte growth factor secretion, preventing ROS and HIF-1α accumulation.

To study how demographic differences impact disease manifestation of sarcoidosis using the WASOG tool in a large multicentric study.Clinical data regarding 1445 patients with sarcoidosis from 14 clinical sites in 10 countries were prospectively reviewed from Feb 1, 2020 to Sep 30, 2020. Organ involvement was evaluated for the whole group and for subgroups differentiated by sex, race, and age.The median age of the patients at diagnosis was 46 years old; 60.8% of the patients were female. The most commonly involved organ was lung (96%), followed by skin (24%) and eye (22%). Black patients had more multiple organ involvement than White patients (OR = 3.227, 95% CI: 2.243-4.643) and females had more multiple organ involvement than males (OR = 1.238, 95% CI: 1.083-1.415). Black patients had more frequent involvement of neurologic, skin, eye, extra thoracic lymph node, liver and spleen than White and Asian patients. Women were more likely to have eye (OR = 1.522, 95%CI: 1.259-1.838) or skin involvement (OR = 1.369, 95%CI: 1.152-1.628). Men were more likely to have cardiac involvement (OR = 1.326, 95%CI: 1.096-1.605). A total of 262 (18.1%) patients did not receive systemic treatment for sarcoidosis. Therapy was more common in Black patients than in other races.The initial presentation and treatment of sarcoidosis was related to sex, race, and age. Black and female individuals are found to have multiple organ involvement more frequently. Age at diagnosis45, Black patients and multiple organ involvement were independent predictors of treatment.

Introduction La sarcoidose est une maladie systemique d’etiologie inconnue, caracterisee par la formation de granulomes epithelioides sans necrose. Bien qu’une guerison spontanee soit frequente, pres de la moitie des patients necessiteront un traitement prolonge par corticoides, et 10 % progresseront sous traitement immunosuppresseur (Lancet ;2014 ;383 :1155-67). Une forte reponse aux inhibiteurs de JAK dans des formes de sarcoidoses chroniques multiviscerales resistantes aux immunosuppresseurs suggere l’implication de la voie JAK/STAT dans la pathogenie de la sarcoidose. L’objectif de notre etude etait d’etudier l’expression des membres de la voie JAK/STAT dans le granulome sarcoidien. Methodes L’expression des membres de la voie JAK/STAT a ete etudiee par immunohistochimie sur 60 biopsies (realisees entre 1999 et 2015), confirmant le diagnostic de sarcoidose, issues de 5 organes : poumon (n = 11), glandes salivaires (n = 12), foie (n = 10), peau (n = 14) et ganglions (n = 13). Pour chaque organe, nous avons evalue la positivite de l’immunomarquage, le type cellulaire marque au sein du granulome et la localisation cellulaire du marquage. Parallelement les caracteristiques cliniques des patients etaient recueillies retrospectivement. Resultats L’etude des formes phosphorylees (actives) des kinases JAK (P-JAK) montre une expression majoritaire de P-JAK2 dans la population lymphocytaire de la couronne peri-granulomateuse. Les formes phosphorylees des facteurs de transcription STAT (P-STAT-1/-3/-5) sont presentes dans les populations de macrophages et de cellules epithelioides au niveau du follicule central du granulome. Ces resultats sont observes dans toutes les biopsies d’organes etudies avec des degres de representativite variables, a l’exception du foie ou seule P-JAK2 est detectee. La correlation de ces donnees immunohistochimiques avec les donnees cliniques est en cours. Conclusion Les formes actives de plusieurs membres de la voie JAK/STAT sont exprimees dans les granulomes sarcoidiens presents dans differents organes. La variabilite d’expression au sein des populations cellulaires du granulome et selon le tissu d’origine suggere une implication de la voie JAK/STAT dans l’evolution de la pathogenie de la sarcoidose.

Most cases of sarcoidosis are mild and self-limited, with a spontaneous cure. However, in some patients, this disease may also be life-threatening, particularly when severe manifestations induce vital organ dysfunction. Sarcoidosis may also severely impair the quality of life through diverse, persistent disabling symptoms. To date, there is no curative treatment for sarcoidosis, but only anti-inflammatory drugs limiting the pathologic impact of sarcoidosis in reducing enhanced immunity reactions, granulomatous formation, and their consequences. Current anti-inflammatory treatments for sarcoidosis include corticosteroids as the first-line treatment; disease-modifying antisarcoid drugs, mainly immunosuppressive and immunomodulatory drugs, as second-line treatment; and finally tumor necrosis factor (TNF) inhibitors, as third-line treatment. Corticosteroids are most effective; they give rapid results, sometimes with serious, incremental adverse effects. A second-line treatment, mainly low-dose methotrexate and azathioprine, is indicated in case of corticosteroid resistance, intolerance, or contraindication or more often as a corticosteroid-sparing agent when a prolonged treatment of more than 10 mg/d equivalent prednisone is expected. TNF inhibitors are considered in severe refractory sarcoidosis. Infliximab has been proven effective. Usually, treatment for sarcoidosis lasts up to 1 year or longer. The usual drug regimen is made of an induction and then a maintenance protocol before a step-by-step decrease and eventual withdrawal. Contraindications may exist. Each therapeutic decision must follow a rigorous diagnostic evaluation to determine the disease impact, its outcome (progression or not), and its response to treatment in the long run. Pharmacogenetics is still in its infancy, but could help develop a more personalized therapy. Non anti-inflammatory treatments, such as implantable cardiac devices, are also useful, particularly for some organs. In the end, persistent disabling symptoms are very frequent and call for an accurate diagnosis, which may be difficult to treat.

Introduction La sarcoidose (SA) est une affection qui peut reduire l’esperance de vie principalement en raison d’une fibrose pulmonaire induite par le granulome epithelioide, lesion histologique cardinale. Du fait du manque de vascularisation des granulomes, les macrophages constitutifs de ces structures se trouvent en hypoxie (Hx). Le but de notre etude etait de determiner les consequences de l’Hx sur les macrophages dans la perennisation de l’inflammation et le developpement de la fibrose. Methodes Quarante patients atteints de SA pulmonaire (active et inactive) et 31 temoins sains apparies (âge, sexe) ont ete inclus. Leurs monocytes sanguins ont ete cultives 10 jours pour induire leur maturation en macrophages, puis places 24 h en normoxie ou Hx (1,5 % O2). Les macrophages ont ete etudies au niveau des ARNm, de la production cytokinique, des marqueurs de surface et de l’expression et l’activite transactivatrice de HIF1α. L’effet du surnageant des macrophages sur la migration, la proliferation (Ki67) et la differenciation (αSMA) de fibroblastes pulmonaires humains (NHLF) a ete etudie. Resultats L’Hx induit la transcription et de la production de cytokines pro-inflammatoires, profibrosantes et pro-angiogeniques. Cette augmentation est plus marquee dans les formes actives de SA, notamment pour des cytokines induisant une activation des lymphocytes Th1 (TNFα, IL1b, IL18) et pour les cytokines profibrosantes PAI-1, TGFβ1, VEGF-A. L’activite transactivatrice de HIF1α induite par l’Hx est exacerbee dans les SA actives. L’Hx diminue l’expression des marqueurs de polarisation M1 (CD80, CD86) dans les 2 groupes et augmente le marqueur M2 CD163 uniquement pour les SA. La phagocytose et l’expression du recepteur scavenger CD36 sont diminuees chez les temoins en Hx, mais maintenues chez les SA. Le surnageant des macrophages exposes a l’Hx ralentit la migration des NHLF particulierement pour les SA actives, sans modifier leur proliferation. L’inhibition de la migration est inversement correlee au taux de PAI-1 et s’accompagne d’un marquage αSMA des NHLF. Conclusion L’hypoxie via HIF1α pourrait favoriser le maintien du granulome dans la sarcoidose par un effet pro-inflammatoire et l’evolution vers la fibrose par sequestration et differenciation des fibroblastes en myofibroblastes en peripherie du granulome. Travail soutenu par le Fonds de Recherche en sante respiratoire, appel d’offres 2017 emis en commun avec la Fondation du Souffle.

Introduction: The diagnosis of sarcoidosis is often delayed because of the reasons is the diverse presentation of sarcoidosis. Recently the Cincinnati team developed a Sarcoidosis Diagnostic Score(SDS) based on a modified WASOG organ assessment instrument (1). The aim of this study was to confirm the diagnostic value of SDS in a large multinational study, including patients with granulomatous lung diseases not due to sarcoidosis. Methods: This study was conducted in two sites in India (Kolkata, Noida), one in US (Cincinnati) and two in Europe (Belgrade, Greater Paris). There were 1341 cases including 567 with biopsy-confirmed sarcoidosis, 173 with other granulomatous disorders and 601 with non-granulomatous lung disorders. SDS biopsy and SDS clinical (without biopsy) scores were calculated. Positive cutpoint values were defined as ≥4 for clinical and ≥7 for SDS biopsy. Results: In the total sarcoidosis and non-sarcoid granulomatous populations, sensitivity and specificity for SDS biopsy were 100% and 28.9% and for SDS clinical 72.3% and 98.6%, respectively. Considering sarcoidosis and non-granulomatous disorders, Sensitivity and specificity in the sarcoid and non-granulomatous populations for SDS biopsy were 100% and 99.2% and for SDS clinical 73.2% and 91.7%, respectively. Conclusion: The SDS system provides a good discrimination between sarcoidosis and other non-granulomatous diseases similar to the previous report (1). For patients with non-sarcoidosis granulomatous disease, the SDS biopsy was not specific. However, patients with SDS clinical scores of ≥4 had a greater than 90% chance of being diagnosed with sarcoidosis. Higher scores were more likely to be sarcoidosis. Reference: 1) Bickett et al.Chest 2018,154(5)1052–60

Sarcoidosis. Sarcoidosis is a rare, systemic granulomatosis disease of unknown cause. In almost all cases sarcoidosis affects the lung and the lymphatic system. Diagnosis and treatment can be difficult because of highly variable clinicals and evolutions presentations. Clinician must track organ dysfunctions that may be life-threatening (pulmonary, cardiac involment) or that impact functional prognosis (neurological, ophthalmic, renal) and qualified as «dangerous». It is important also to evaluate and take care of persistent signs of discomfort, which can severely affect patients' quality of life. The treatment of sarcoidosis is not systematic, but if necessary, corticosteroids, with notable side effects are the first intention treatment. Second- and third-line treatments are immunosuppressants and TNF antagonists, respectively.Sarcoïdose. La sarcoïdose est une maladie rare, de type granulomatose systémique de cause inconnue touchant presque constamment le poumon et le système lymphatique. Le diagnostic et la prise en charge thérapeutique peuvent être difficiles du fait de la diversité de ses présentations cliniques, du retentissement et de l’évolution de la maladie. Les objectifs du clinicien sont de ne pas manquer les formes avec dysfonction d’un organe pouvant mettre en jeu le pronostic vital (atteinte pulmonaire, cardiaque) ou fonctionnel (formes neurologique, ophtalmique, rénale), qualifiées de « dangereuses » mais aussi d’évaluer et prendre en charge les signes d’inconfort persistants, qui peuvent retentir sévèrement sur la qualité de vie des patients. Le traitement de la sarcoïdose n’est pas systématique mais, si nécessaire, les corticoïdes, aux effets indésirables notables, sont à donner en première intention. Les traitements de deuxième et de troisième ligne sont respectivement les immunosuppresseurs et les anti-tumor necrosis factor alpha.

This article reviews a selection of the scientific presentations on interstitial lung disease (ILD)/diffuse parenchymal lung disease (DPLD) that were made at the 2018 European Respiratory Society (ERS) International Congress in Paris. A number of advances in the epidemiology, pathogenesis, diagnosis and treatment of these disorders were presented and discussed by clinicians and researchers. The research topics span over all four groups of ERS Assembly 12: Interstitial Lung Diseases (Group 12.01: Idiopathic interstitial pneumonias; Group 12.02: ILD/DPLD of known origin; Group 12.03: Sarcoidosis and other granulomatous ILD/DPLD; Group 12.04: Rare ILD/DPLD)., A selection of the scientific presentations on interstitial lung disease from the 2018 #ERSCongress in Paris http://ow.ly/LAbD30nmsFs

High-resolution computed tomography (HRCT) has revolutionized the diagnosis, prognosis and in some cases the prediction of therapeutic response in interstitial lung disease (ILD). HRCT represents an essential second step to a patient's clinical history, before considering any other investigation, including lung biopsy. Areas covered: This review describes the current place of HRCT in the diagnosis, prognosis and monitoring of ILD. It also lists some perspectives for the near future. Expert commentary: Since the 1980s, HRCT and its interpretation have improved, the diagnosis value of patterns, and the integration of bio-clinical elements to HRCT have been better standardized. The interobserver agreement has been investigated, allowing a better use of some limits in the interpretation of various signs. It not only takes into account one particular predominant sign, but the combination of patterns and the distribution of findings. Thanks to HRCT, the range of diagnoses and their probability are more accurately identified. The contribution of HRCT has been optimized during the multidisciplinary discussion that a difficult diagnosis calls for. HRCT quantification of the extent of diffuse lung disease becomes possible and is linked to prognosis. In the future, artificial intelligence may significantly modify the practice of radiology.

Introduction La sarcoidose est une maladie systemique d’evolution variable. Les donnees sur le traitement des formes refractaires restent peu nombreuses. Methodes Dans cette etude retrospective, multicentrique, les patients ont ete inclus si ils remplissaient les criteres suivants: sarcoidose selon les criteres de l’ATS/WASOG, et administration d’au moins une perfusion de biotherapie hors anti-TNF-alpha. Les criteres de non selection etaient les suivants: perfusion realisee pour une indication autre que la sarcoidose, donnees non suffisantes. L’evaluation de l’efficacite a ete realisee par les scores ePOST et SDAI. Les donnees de tolerance ont ete recueillies dans les dossiers medicaux. Resultats Un total de 14 patients a ete inclus, 10 femmes et 4 hommes d’âge median au diagnostic de sarcoidose 31 ans (15–53). Parmi eux, 11 patients (79 %) avaient une atteinte mediastinale ou hilaire, 9 (64 %) une atteinte pulmonaire parenchymateuse, 9 (64 %) une atteinte ophtalmologique, 8 (57 %) une atteinte du systeme nerveux central. Avant la biotherapie, tous les patients avaient ete traites par corticoides, 10 (71 %) avaient recu du methotrexate, 9 (64 %) une biotherapie anti-TNF-alpha, 6 (43 %) de l’azathioprine. Chaque patient a recu au moins une ligne de biotherapie, qui etait du tocilizumab (un anti- recepteur de l’IL6) chez 6 patients, du rituximab chez 4, et de l’ustekinumab (un anti-IL12-IL23) chez 4. De facon concomitante a la biotherapie, 12 patients recevaient des corticoides (contre-indication chez 2), 6 recevaient du methotrexate, et un de l’azathioprine. L’ePOST median avant biotherapie etait de 7 et a la derniere visite sous traitement de 3 (difference non significative p 0,05), le SDAI median avant biotherapie etait de 8,5 et a la derniere visite sous traitement de 5,0 (p 0,01). Sous tocilizumab, on observait 3 reponses partielles, 2 patients stables, et une progression. La tolerance etait globalement bonne, sans evenement indesirable grave. Un patient decidait de suspendre les injections de tocilizumab apres une perfusion. Deux patients etaient traites par inhibiteurs de JAK en raison d’un echec de tocilizumab avec une bonne efficacite. Conclusion Les biotherapies non anti-TNF-alpha constituent une option therapeutique au cours de la sarcoidose. Leur place par rapport aux antagonistes du TNF-alpha qui restent l’option de seconde ligne la plus frequente parmi les immunosuppresseurs reste a preciser.

Introduction Les donnees sur l’infection a Sars-Cov-2 chez les patients atteints de sarcoidose sont rares. L’hypothese d’un risque accru de formes severes de Covid-19 dans cette population a ete soulevee, du fait de l’atteinte pulmonaire sous-jacente, des comorbidites associees a l’utilisation de corticoides, et l’utilisation d’immunosuppresseurs. Nous decrivons ici la presentation clinique et le pronostic de l’infection a Sars-Cov-2 chez des patients atteints de sarcoidose a partir d’un registre multicentrique francais. Methodes Nous avons collecte retrospectivement les donnees de tous les patients atteints de sarcoidose et d’infection a Sars-Cov-2 vus dans 15 centres francais, entre le 1er mars et le 1er septembre 2020. Les criteres d’inclusion etaient un diagnostic de sarcoidose selon les criteres ATS/ERS/WASOG, et une infection a Sars-Cov-2 definie par une RT-PCR sur ecouvillon nasopharynge ou tracheal positif ou une serologie positive. Resultats Un total de 36 patients a ete inclus. La majorite des patients (72%) etaient des hommes, avec un âge median a l’infection a Sars-Cov-2 de 54,5 ans (29–100) et une duree mediane d’evolution de la sarcoidose de 10 ans (0–50) au moment de l’infection. Plus de 95% des patients avaient une atteinte ganglionnaire intrathoracique ou une atteinte parenchymateuse pulmonaire, et 33% avaient une fibrose pulmonaire. La presentation clinique de Covid-19 etait classique, et comprenait de la fievre chez la plupart des patients (67%), malgre l’utilisation de corticoides. Vingt-cinq (69%) patients prenaient un traitement par corticoides au long cours au moment de l’infection, avec une dose quotidienne mediane de 7,7 mg (5–50). Les corticoides ont ete arretes chez 1 patient au moment de l’infection. Le methotrexate a ete plus frequemment arrete au moment de l’infection, chez 4/8 (50%) patients. Parmi les 6 patients sous anti-TNF-alpha, le traitement a ete temporairement suspendu chez tous. Cinq patients sont decedes au cours de l’infection a Sars-Cov-2: 4 d’une insuffisance respiratoire aigue et le dernier d’une hypercapnie non controlee dans un contexte d’obesite. Deux de ces patients presentaient une insuffisance renale chronique, une etait sous hemodialyse et l’autre avait presente une insuffisance renale aigue compliquant la maladie renale chronique. Un total de 13 patients (36%) a ete admis en reanimation. Conclusion Ces donnees nationales montrent que la sarcoidose n’est pas associee a un exces de formes severes d’infection a Sars-Cov-2.

Sarcoidosis is a granulomatous disease of unknown cause. This proteiform disease is characterized by an almost constant and often predominant lung involvement. The natural history of disease is difficult to predict at presentation. Diagnosis is based on a compatible clinical and radiological presentation and evidence of non-caseating granulomas. Exclusion of alternative diseases is also required according to clinical presentation. Biopsy samples of superficial lesions should be considered before other sites like per-endoscopic bronchial biopsies or endobronchial ultrasound-guided transbronchial needle aspiration. Therapeutic strategy for lung disease has to take into account the possible spontaneous resolution observed in newly diagnosed patients. Corticosteroids are the first choice when a treatment is decided, which concerns half of patients. Second and third line therapy are based respectively on immunosuppressive drugs and anti-TNFα drugs. Sarcoidosis mortality and morbidity are mainly linked to advanced pulmonary sarcoidosis - lung fibrosis, pulmonary hypertension, bronchial stenosis and chronic pulmonary aspergillosis. "Non anti-inflammatory" treatments have to be considered as well. Clinicians have an essential role in treatment indication, end-point targets and evaluation of response to treatment during follow-up and in finding the best benefice to risk balance. Progress made on pharmacogenetics may offer more personalized treatments for the patients.

Sarcoidosis is a systemic disease of unknown cause with very diverse presentation, outcome, severity and need for treatments. While some presentations may be very typical, for many patients, the presentation is nonspecific, with shared associations with other diseases at times being by far more frequent or misleading, which can be a cause of significant delay and often several consultations before a diagnosis of sarcoidosis can be confirmed. This is particularly the case when pulmonary manifestations are in the forefront. The diagnosis relies on three well-known criteria. In clinical practice, these criteria are not easily implemented, particularly by physicians without expertise in sarcoidosis, which can lead to a risk of either under- or over-diagnosis. Qualifying the presentation according to sarcoidosis diagnosis is essential. However, it is often not easy to classify the presentation as typical versus compatible or compatible versus inconsistent. Further investigations are needed before any other hypothesis is to be considered. It is important to detect events and to determine whether or not they are indicative of a flare of sarcoidosis. Eventually, treatment needs to be related to the correct indications. The evaluation of the efficacy and safety of treatments is crucial. To address such issues, we present five emblematic cases that illustrate this.