Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus.

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.

Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis.

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells at baseline showed more severe disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.

Polyarteritis Nodosa: Old Disease, New Etiologies.

Polyarteritis nodosa (PAN), also known as panarteritis nodosa, represents a form of necrotizing vasculitis that predominantly affects medium-sized vessels, although it is not restricted to them and can also involve smaller vessels. The clinical presentation is heterogeneous and characterized by a significant number of patients exhibiting general symptoms, including asthenia, fever, and unintended weight loss. Although PAN can involve virtually any organ, it preferentially affects the skin, nervous system, and the gastrointestinal tract. Orchitis is a rare but specific manifestation of PAN. The absence of granulomas, glomerulonephritis, and anti-neutrophil cytoplasmic antibodies serves to distinguish PAN from other types of vasculitis. Major complications consist of hemorrhagic and thrombotic events occurring in mesenteric, cardiac, cerebral, and renal systems. Historically, PAN was frequently linked to hepatitis B virus (HBV) infection, but this association has dramatically changed in recent years due to declining HBV prevalence. Current epidemiological research often identifies a connection between PAN and genetic syndromes as well as neoplasia. This article provides a comprehensive review of PAN, specifically focusing on the progression of its clinical manifestations over time.

Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease with currently no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in 'At-Risk' populations prior to clinical disease onset is crucial to establishing effective prevention strategies. Here, we applied mass cytometry to deeply characterize the immunophenotypes in blood from At-Risk individuals identified through the presence of serum antibodies to citrullinated protein antigens (ACPA) and/or first-degree relative (FDR) status (n=52), as compared to established RA (n=67), and healthy controls (n=48). We identified significant cell expansions in At-Risk individuals compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5 low naïve B cell population was expanded in ACPA-positive FDRs. Further, we developed an "RA immunophenotype score" classification method based on the degree of enrichment of cell states relevant to established RA patients. This score significantly distinguished At-Risk individuals from controls. In all, we systematically identified activated lymphocyte phenotypes in At-Risk individuals, along with immunophenotypic differences among both ACPA+ and ACPA-FDR At-Risk subpopulations. Our classification model provides a promising approach for understanding RA pathogenesis with the goal to further improve prevention strategies and identify novel therapeutic targets.

Measurement of circulating CD21-CD27- B lymphocytes in SLE patients is associated with disease activity independently of conventional serological biomarkers.

Determining disease activity in systemic lupus erythematosus (SLE) patients is challenging and limited by the lack of reliable biomarkers. Abnormally activated B cells play a key role in the pathogenesis of SLE, but their measure in clinical practice is currently not recommended. Here, we studied peripheral B cells to identify a valid biomarker. We analyzed peripheral B cells in a discovery cohort of 30 SLE patients compared to 30 healthy controls (HC) using mass cytometry and unsupervised clustering analysis. The relevant B cell populations were subsequently studied by flow cytometry in a validation cohort of 63 SLE patients, 28 autoimmune diseases controls and 39 HC. Our data show an increased frequency of B cell populations with activated phenotype in SLE compared to healthy and autoimmune diseases controls. These cells uniformly lacked the expression of CD21 and CD27. Measurement of CD21-CD27- B cells in the blood identified patients with active disease and their frequency correlated with disease severity. Interestingly, we did not observe an increase in the frequency of CD21-CD27- B cells in patients with clinically inactive disease but with elevated conventional biomarkers (anti-dsDNA and complement levels). Accordingly, measurement of CD21-CD27- B cells represents a robust and easily accessible biomarker to assess the activity of the disease in SLE patients.

SLAMF Receptor Expression Identifies an Immune Signature That Characterizes Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology, linked to alterations in both the innate and the adaptive immune system. Due to the heterogeneity of the clinical presentation, the diagnosis of SLE remains complicated and is often made years after the first symptoms manifest, delaying treatment, and worsening the prognosis. Several studies have shown that signaling lymphocytic activation molecule family (SLAMF) receptors are aberrantly expressed and dysfunctional in SLE immune cells, contributing to the altered cellular function observed in these patients. The aim of this study was to determine whether altered co-/expression of SLAMF receptors on peripheral blood mononuclear cells (PBMC) identifies SLE characteristic cell populations. To this end, single cell mass cytometry and bioinformatic analysis were exploited to compare SLE patients to healthy and autoimmune diseases controls. First, the expression of each SLAMF receptor on all PBMC populations was investigated. We observed that SLAMF1+ B cells (referred to as SLEB1) were increased in SLE compared to controls. Furthermore, the frequency of SLAMF4+ monocytes and SLAMF4+ NK were inversely correlated with disease activity, whereas the frequency SLAMF1+ CD4+ TDEM cells were directly correlated with disease activity. Consensus clustering analysis identified two cell clusters that presented significantly increased frequency in SLE compared to controls: switch memory B cells expressing SLAMF1, SLAMF3, SLAMF5, SLAMF6 (referred to as SLESMB) and circulating T follicular helper cells expressing the same SLAMF receptors (referred to as SLEcTFH). Finally, the robustness of the identified cell populations as biomarkers for SLE was evaluated through ROC curve analysis. The combined measurement of SLEcTFH and SLEB1 or SLESMB cells identified SLE patients in 90% of cases. In conclusion, this study identified an immune signature for SLE based on the expression of SLAMF receptors on PBMC, further highlighting the involvement of SLAMF receptors in the pathogenesis of SLE.

Restoration of NK Cell Cytotoxic Function With Elotuzumab and Daratumumab Promotes Elimination of Circulating Plasma Cells in Patients With SLE.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by multiple cellular and molecular dysfunctions of the innate and adaptive immunity. Cytotoxic function of NK cells is compromised in patients with SLE. Herein, we characterized the phenotypic alterations of SLE NK cells in a comprehensive manner to further delineate the mechanisms underlying the cytotoxic dysfunction of SLE NK cells and identify novel potential therapeutic targets. Therefore, we examined PBMC from SLE patients and matched healthy controls by single-cell mass cytometry to assess the phenotype of NK cells. In addition, we evaluated the cell function of NK cells (degranulation and cytokine production) and the killing of B cell subpopulations in a B cell-NK cell in vitro co-culture model. We found that SLE NK cells expressed higher levels of CD38 and were not able to adequately upregulate SLAMF1 and SLAMF7 following activation. In addition, ligation of SLAMF7 with elotuzumab or of CD38 with daratumumab on SLE NK cells enhanced degranulation of both healthy and SLE NK cells and primed them to kill circulating plasma cells in an in vitro co-culture system. Overall, our data indicated that dysregulated expression of CD38, SLAMF1 and SLAMF7 on SLE NK cells is associated with an altered interplay between SLE NK cells and plasma cells, thus suggesting their contribution to the accumulation of (auto)antibody producing cells. Accordingly, targeting SLAMF7 and CD38 may represent novel therapeutic approaches in SLE by enhancing NK cell function and promoting elimination of circulating plasma cell.

[Biologics and systemic lupus erythematosous : new insights and perspectives]. / Biologiques et lupus érythémateux systémique : nouveautés et perspectives.

Systemic lupus erythematosus is a complex autoimmune disease that remains challenging to treat. Recent advances in the understanding of the pathogenesis of SLE pave the way for the evaluation of biologic medicine. The most promising therapeutic targets in SLE are those that interfere with B cells count or normal function, interferon inhibitors, JAK inhibitors and biologicals that alter the cytokines imbalance that characterizes SLE. Recent phase 3 clinical trials have evaluated the role of belimumab in lupus nephritis and the usefulness of anifrolumab in the treatment of moderate to severe SLE. Many more trials are currently underway and may improve the level of care of patients with SLE in the near future.

Le lupus érythémateux systémique (LES) est une maladie autoimmune complexe, dont le traitement reste un challenge. Les progrès récents sur les connaissances de l'immunopathologie du LES ont permis d'évaluer la place de nouveaux traitements biologiques dans des études cliniques. Celles-ci concernent les anticorps monoclonaux antilymphocytes B, les inhibiteurs de l'interféron et des Janus kinases, ou encore les traitements par administration de cytokines, comme l'interleukine 2. Des études de phase 3 récentes ont évalué la place du bélimumab dans le traitement de la néphrite lupique et l'utilité du blocage de l'interféron par l'anifrolumab dans le traitement du LES modéré à sévère. Plusieurs études cliniques en cours pourraient révolutionner la prise en charge des patients atteints d'un LES dans les années à venir.

Multisystem inflammatory syndrome with refractory cardiogenic shock due to acute myocarditis and mononeuritis multiplex after SARS-CoV-2 infection in an adult.

A 22-year-old male with a typical history of pauci-symptomatic COVID-19 3 weeks earlier, confirmed by positive serology for SARS-CoV-2 (IgG), was admitted to the intensive care unit because of severe myocarditis with refractory cardiogenic shock that required extracorporeal life support. Due to a clinical presentation suggestive of Kawasaki-like disease with coronary aneurysm and severe systemic inflammation, intravenous immunoglobulins were administered in combination with tocilizumab. The initial clinical course was favourable with these treatments. However, the patient subsequently developed a severe mononeuritis multiplex leading to bilateral foot drop, which required intensive immunosuppressive therapy (corticosteroids, cyclophosphamide and rituximab). The clinical presentation meets the criteria for multisystem inflammatory syndrome associated with SARS-CoV-2, but includes very severe organ damages. Early recognition, a multidisciplinary approach and aggressive therapeutic intervention can lead to a favourable outcome.

[Management of the antiphospholipid syndrome in adults]. / Prise en charge du syndrome des ­anticorps antiphospholipides chez l'adulte.

The antiphospholipid syndrome (APS) is a complex autoimmune -disease characterized by the expression of antiphospholipid -antibodies (APL) and a variety of clinical presentation. The latest classification defines APS by the occurrence of vascular thrombosis and/or typical obstetrical morbidity together with persistently -detectable APL at least 12 weeks apart. The latest recommendation proposes a risk profile based on the type and titer of APL detected, in order to guide the intensity of prophylactic measures. Based on current knowledge, novel oral anticoagulants should not be used in APS, particularly in patients with a high-risk APL profile or arterial thrombosis. Beyond the mere aspect of anticoagulant treatment, immunomodulatory approaches to the APS such as hydroxychloroquine are under investigation.

Le syndrome des anticorps antiphospholipides (SAPL) est une maladie auto-immune caractérisée par l'expression d'anticorps antiphospholipides (APL) et des manifestations cliniques variées. Les critères de classification du SAPL stipulent l'association d'une thrombose vasculaire ou d'une morbidité obstétricale ­typique et la détection répétée d'APL à au moins 12 semaines d'intervalle. Les dernières recommandations de prise en charge du SAPL proposent d'établir un profil de risque basé sur le type et le taux des APL détectés, afin de définir l'intensité des mesures préventives. À ce jour, les anticoagulants oraux directs sont à ­éviter lors de SAPL, en particulier en cas de profil APL à haut risque ou de thrombose artérielle. Au-delà du simple aspect de l'anticoagulation, d'autres approches comme l'hydroxychloroquine sont en cours d'étude dans le SAPL.

[Autoimmune diseases in the context of pandemic COVID-19]. / Maladies autoimmunes dans le contexte de la pandémie COVID-19.

Patient suffering from autoimmune diseases (AID) typically have an increased risk of infection, which is attributed to the disease itself, but also to immunosuppressive drugs (IS) and comorbidities. During the current COVID-19 outbreak, the way to manage these diseases remains elusive. Limited data is currently available on AID and IS in the context of this new coronavirus infection. To date, there is no evidence to support an increase in complications of COVID-19 in these patients. In addition, certain drugs that are commonly used to treat AID could be part of the therapeutic arsenal used in COVID-19. The purpose of this article is to review the unique aspects of patients with AID during the COVID-19 outbreak.

Les patients atteints de maladies autoimmunes (MAI) présentent classiquement un risque accru d'infections, qui est attribué à la maladie en tant que telle, mais aussi aux traitements immunosuppresseurs (IS) et aux comorbidités. Durant l'épidémie COVID-19, l'attitude à adopter par rapport à ces maladies et à leur traitement reste incertaine. En effet, les données concernant les MAI et l'IS dans le cadre de cette nouvelle infection à coronavirus restent encore très limitées. À l'heure actuelle, il n'y a pas d'évidence indiquant une augmentation des complications sévères en lien avec le COVID-19 chez ces patients. De plus, certains médicaments utilisés pour traiter les MAI pourraient faire partie de l'arsenal thérapeutique utilisé en cas d'infection par le COVID-19. Cet article passe en revue les aspects particuliers des patients souffrant de MAI durant l'épidémie COVID-19.

ANCA-associated life-threatening systemic vasculitis after alemtuzumab treatment for multiple sclerosis.

Alemtuzumab is highly effective in relapsing remitting multiple sclerosis (RRMS), but autoimmune adverse events are of concern. In contrast to rare cases of immune-mediated cutaneous vasculitis, systemic vasculitis after alemtuzumab has not yet been described. We report the case of a 29-year-old man with RRMS who developed fever, auricular chondritis, cutaneous vasculitis and life-threatening diffuse alveolar haemorrhage, 12 months after alemtuzumab. Antibodies to myeloperoxidase appeared 9 months after alemtuzumab and were extremely high at the time of vasculitis. Outcome was favourable after glucocorticoids, plasma exchanges and rituximab. Thus, alemtuzumab may induce life-threatening vasculitis in patients treated for RRMS.

[From isolated cutaneous vasculitis to systemic disease†: a diagnostic approach to purpura in the adult patient]. / De la vasculite cutanée isolée aux atteintes systémiques†: l'approche diagnostique d'un purpura chez l'adulte.

Purpura can be a clinical manifestation of various diseases. The causes of purpura are divided into two main categories: thrombocytopenia and vasculopathies. Cutaneous vasculitis belongs to the latter group. Cutaneous vasculitis should be considered a symptom rather than a medical entity. Some forms of cutaneous vasculitis are limited to the skin and are known as isolated cutaneous vasculitis, while other forms may be part of a systemic disease with a more serious prognosis. It is essential to clarify the type and severity of the disease for optimal patient care. A delay in the identification and start of treatment can be the cause of serious and potentially irreversible complications. Through this article, we will propose a step-by-step approach from diagnosis to patient care.

Le purpura peut être la manifestation d'un large spectre de pathologies. Les causes sont généralement séparées en deux groupes principaux : les thrombopénies et les vasculopathies, dont fait partie la vasculite cutanée. Elle doit être considérée comme un symptôme plutôt que comme une entité en soi. Certaines formes peuvent être limitées à la peau alors que d'autres s'inscrivent dans un tableau systémique, potentiellement de mauvais pronostic. Savoir clarifier le type et la sévérité des atteintes est important pour la prise en charge optimale du patient. Un diagnostic précis et précoce est essentiel afin d'éviter des complications sévères et potentiellement irréversibles. A travers cet article, nous proposons un algorithme de raisonnement pour porter le diagnostic étiologique d'un purpura et proposer une prise en charge adaptée.

The Fatigue Assessment Scale as a simple and reliable tool in systemic lupus erythematosus: a cross-sectional study.

BACKGROUND: The vast majority of patients with systemic lupus erythematosus (SLE) complain about fatigue. They also report fatigue as one of their most debilitating symptoms. Yet, in clinical practice, fatigue is only rarely assessed and remains poorly understood. The purpose of this study is to validate the Fatigue Assessment Scale (FAS) and assess the impact of disease activity on fatigue in SLE. METHODS: A cross-sectional single-center study of patients was included in the Swiss SLE Cohort Study. The FAS and the Short Form 36 (SF-36) were administered to SLE patients and controls with primary Sjogren's syndrome (pSS) and healthy volunteers (HV) attending our clinic. Disease activity in SLE was captured at the same time as patient-reported outcomes using the SLE Disease Activity Index score with the Safety of Estrogens in SLE National Assessment modification (SELENA-SLEDAI) and the physician's global assessment. We explored the internal consistency, reproducibility, construct validity, and convergence of the FAS, in comparison to the vitality subscale (VT) of the SF-36. We examined the association of FAS with demographics, disease type, SLE disease activity, and clinical features. RESULTS: Of the 73 SLE subjects, 89% were women and 77% were Caucasians. The median age was 43 years, and 23 (32%) patients had active SLE. Demographics in pSS and HV were similar. Within the SLE group, FAS displayed good internal consistency (Cronbach's alpha = 0.93), unidimensionality, and test-retest reliability (ICC = 0.90). FAS and VT correlated well. The total FAS was highest in active SLE and pSS and higher in non-active SLE compared to HV. CONCLUSION: The FAS is a promising tool to measure fatigue in SLE. Patients with SLE display a significantly higher level of fatigue than HV, which is even more pronounced in active disease and comparable to fatigue levels measured in pSS.

[Risk of treatment failure and therapeutic novelties in asthma]. / Allergologie-immunologie: Facteurs d'échec du traitement de l'asthme et nouveautés thérapeutiques.

Asthma is a chronic disease that is still frequently poorly controlled, despite recent advances in understanding its pathophysiology. Poor compliance and ineffective inhalation technique remain the main causes of treatment failure. The comorbidities associated with asthma, such as obesity and chronic rhinosinusitis, are other elements to consider in the management of patients. Biological treatments targeting inflammation mediators show encouraging results in recurrent asthma exacerbations despite optimal management. However, their benefit remains limited to certain patients, thus requiring the study of predictive biomarkers to better delineate their indication.

L'asthme est une maladie chronique encore souvent mal contrôlée, et ce, malgré les récents progrès concernant la compréhension de sa physiopathologie. Une mauvaise adhésion aux traitements et une technique d'inhalation inefficace restent les causes principales d'échecs thérapeutiques. Les comorbidités associées à l'asthme, telles que l'obésité et la rhinosinusite chronique, sont d'autres éléments à considérer dans la prise en charge des patients. Lors d'exacerbations asthmatiques récidivantes, malgré une prise en charge optimale, des traitements biologiques ciblant les promoteurs de l'inflammation montrent des résultats encourageants. Leur bénéfice reste toutefois limité à certains patients, ce qui impose à l'avenir l'étude de biomarqueurs prédictifs de réponse à ces traitements ciblés.

A severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy.

BACKGROUND: The prevalence of esophageal stenosis caused by immune checkpoint inhibitors in the context of induced immune mucositis and esophagitis is extremely rare. CASE PRESENTATION: We report the case of a patient with stage IV pulmonary adenocarcinoma treated for 6 months with nivolumab who developed bilateral sterile conjunctivitis followed by oropharyngeal mucositis and esophagitis complicated by a severe esophageal stenosis. The laryngeal margin and hypopharyngeal mucosa appeared highly inflammatory with fibrinous deposits. Esophagogastroduodenoscopy revealed mucositis with a scar-like structure immediately below the upper esophageal sphincter with nonulcerative mucosa and an inflammatory aspect of the entire esophagus. No involvement of the stomach was observed. Oropharynx biopsies displayed marked lymphocytic T cell-infiltration with several foci of monocellular necrosis in the squamous epithelium. No morphologic evidence of adenocarcinoma and no signs of mycotic, bacterial or viral infection were noted. A blood sample revealed a discrete increase in the erythrocyte sedimentation rate (ESR) with no eosinophilia or leukocytosis. Liver and kidney function panel tests were normal. A thoracoabdominal CT scan reported no evidence of disease recurrence. Despite multiple boluses of methylprednisolone and high doses of prednisone continued for several months, the patient experienced very rapid symptomatological reappearance during three steroid tapering attempts and aggravation of his esophageal stenosis to an aphagic stage, requiring a nasogastric tube. This long course of high-dose corticosteroid treatment was complicated with osteoporosis-induced fractures with several spontaneous compressions of thoracolumbar vertebrae requiring an enlarged T10 to L5 cementoplasty. Anti-IL-6 blockade therapy with tocilizumab resulted in excellent clinical response, allowing the total resolution of the immune-related adverse events (irAEs) and leading to successful steroid tapering. CONCLUSIONS: Herein, we describe the first case of a patient who developed autoimmune mucositis and esophagitis complicated by a severe refractory esophageal stenosis induced during treatment by nivolumab, which completely resolved after personalized treatment with tocilizumab, suggesting a role of IL-6 blockade in the management of severe steroid refractory esophageal stenosis and more broadly in refractory immune-related adverse events.

[Sjögren's syndrome: when to suspect and how to confirm?]. / Syndrome de Sjögren: quand le suspecter et comment le confirmer?

Sjögren's syndrome (SS) is an autoimmune disease leading to mucosal dryness. It may also involve joints, nerves, kidneys and lungs. Patients with SS are also at increased risk for lymphoma. Diagnosis of SS relies on clinical, biological, histological and radiological criteria, after exclusion of other causes. Initial work-up may be performed in general practice, by serology (antinuclear and anti-SSA/SSB antibodies, rheumatoid factor) and by measuring lacrimal and salivary flow. Antibodies may be within normal range in up to one third of patients and when present are not specific for SS. Histological proof of lymphocytic sialadenitis is precious but invasive. Major salivary glands sonography may help select candidates for labial biopsy. This article elaborates the steps to be taken in case of suspected SS, in order to facilitate early diagnosis.