Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Clinical characteristics and outcomes of Respiratory Syncytial Virus-associated ARF in immunocompetent patients: a seven-year experience at a tertiary hospital in France.

BACKGROUND: Respiratory syncytial virus (RSV) is widely recognized as a cause of acute respiratory failure in infants and immunocompromised patients. However, RSV can also contribute to acute respiratory failure in adults, particularly among the elderly population. The objective of this study was to analyze the clinical characteristics and outcomes of immunocompetent adults hospitalized for RSV infection. METHODS: This retrospective study included all immunocompetent adult patients consecutively admitted to a tertiary care hospital with RSV-related acute respiratory failure over a seven-year period (2016 - 2023). Diagnosis of RSV infection was made through nasal swabs or pulmonary samples, with multiplex reverse transcription polymerase chain reaction (RT-PCR). Patients were eligible for inclusion if they required supplemental oxygen therapy for at least 48hours. RESULTS: One hundred and four patients met the inclusion criteria. Median age [IQR] was 77 years [67 - 85]. Ninety-seven patients had at least one comorbidity (97/104, 93%). At the time of RSV diagnosis, 67 patients (67/104, 64%) experienced acute decompensation of a pre-existing chronic comorbidity. Antibiotics were started in 80% (77/104) of patients; however, only 16 patients had a confirmed diagnosis of bacterial superinfection. Twenty-six patients needed ventilatory support (26/104, 25%) and 21 were admitted to the intensive care unit (21/104, 20%). The median duration of oxygen therapy [IQR] was 6 days [3 - 9], while the median hospital length of stay [IQR] was 11 days [6 - 15]. The overall mortality rate within one month of hospital admission was 13% (14/104). The sole variables associated with one-month mortality were age and maximum oxygen flow during hospitalisation. CONCLUSION: RSV-associated acute respiratory failure affected elderly individuals with multiple comorbidities and was associated with prolonged hospitalization and a high mortality rate.

Limb arteries involvement assessed by FDG/PET CT at diagnosis of giant cell arteritis and risk of relapse: An observational study.

INTRODUCTION: Steroids and anti-IL6 biotherapy are highly effective in obtaining remission in patients with giant cell arteritis (GCA) but the risk of relapses remains high. We aimed to identify predictors of relapse in GCA. METHODS: All consecutive patients admitted with a new diagnosis of GCA - according to the 2022 American College of Rheumatology/EULAR (ACR/EULAR) classification criteria - between May 2011 and May 2022 were eligible for this study. The primary outcome was the GCA relapse rate over the 36-months follow up. Factors associated with the primary outcome and time to first relapse were analyzed. RESULTS: One hundred and eight patients (74 [69-81] years, 64.8% women) with a new diagnosis of GCA were studied. GCA was biopsy-proven in 65 (60.2%) cases. Ninety-eight (90.7%) FDG/PET CT scans performed at diagnosis were available for review. All patients received steroids given for 21.0 [18.0-28.5] months, associated with methotrexate (n=1, 0.9%) or tocilizumab (n=2, 1.9%). During a median follow-up of 27.5 [11.4-35.0] months, relapse occurred in 40 (37%) patients. Multivariable Cox regression model, including general signs, gender, aortic wall thickness, FDG uptake in arterial wall and IV steroid pulse as covariates, showed that both general signs (HR 2.0 [1.0-4.0, P<0.05) and FDG uptake in limb arteries (HR 2.7 [1.3-5.5], P<0.01) at diagnosis were associated with GCA relapse. CONCLUSION: FDG uptake in limb arteries at diagnosis is a predictor of relapse in newly diagnosed GCA.

PD-L1- and IL-4-expressing basophils promote pathogenic accumulation of T follicular helper cells in lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis.

Risk factors for severe hearing loss in Susac syndrome: A national cohort study.

BACKGROUND: Nonreversible hearing loss (HL) is the main sequelae of Susac syndrome (SuS). We aimed to identify risk factors for HL in SuS. METHODS: The CARESS study is a prospective national cohort study that started in December 2011, including all consecutive patients with SuS referred to the French reference center. The CARESS study was designed with a follow-up including fundoscopy, audiometry, and brain magnetic resonance imaging at 1, 3, 6, and 12 months after diagnosis and then annually for 5 years. The primary outcome was the occurrence at last follow-up of severe HL defined as the loss of 70 dB in at least one ear on audiometry or the need for hearing aids. RESULTS: Thirty-six patients (female 66.7%, median age 37.5 [range 24.5-42.5] years) included in the clinical study were analyzed for the primary outcome. Thirty-three patients (91.7%) had cochleovestibular involvement at SuS diagnosis including HL >20 dB in at least one ear in 25 cases. At diagnosis, 32 (88.9%), 11 (30.6%), and 7 (19.4%) patients had received steroids, intravenous immunoglobulin, and/or immunosuppressive (IS) drugs, respectively. After a median follow-up of 51.8 [range 29.2-77.6] months, 19 patients (52.8%) experienced severe HL that occurred a median of 13 [range 1.5-29.5] months after diagnosis. Multivariable analysis showed that the odds of severe HL were lower in patients who received IS drugs at diagnosis (OR 0.15, 95% CI 0.01-1.07, p = 0.058). CONCLUSIONS: Severe HL in SuS is associated with the absence of IS drugs given at diagnosis. Our findings support the systematic use of IS drugs in SuS.

Clinical presentation, course, and prognosis of patients with mixed connective tissue disease: A multicenter retrospective cohort.

OBJECTIVES: The objective of this study is to better characterize the features and outcomes of a large population of patients with mixed connective tissue disease (MCTD). METHODS: We performed an observational retrospective multicenter cohort study in France. Patients who fulfilled at least one diagnostic criterion set for MCTD and none of the criteria for other differentiated CTD (dCTD) were included. RESULTS: Three hundred and thirty patients (88% females, median [interquartile range] age of 35 years [26-45]) were included. The diagnostic criteria of Sharp or Kasukawa were met by 97.3% and 93.3% of patients, respectively. None met other classification criteria without fulfilling Sharp or Kasukawa criteria. After a median follow-up of 8 (3-14) years, 149 (45.2%) patients achieved remission, 92 (27.9%) had interstitial lung disease, 25 (7.6%) had pulmonary hypertension, and 18 (5.6%) died. Eighty-five (25.8%) patients progressed to a dCTD, mainly systemic sclerosis (15.8%) or systemic lupus erythematosus (10.6%). Median duration between diagnosis and progression to a dCTD was 5 (2-11) years. The presence at MCTD diagnosis of an abnormal pattern on nailfold capillaroscopy (odds ratio [OR] = 2.44, 95% confidence interval [95%CI] [1.11-5.58]) and parotid swelling (OR = 3.86, 95%CI [1.31-11.4]) were statistically associated with progression to a dCTD. Patients who did not progress to a dCTD were more likely to achieve remission at the last follow-up (51.8% vs. 25.9%). CONCLUSIONS: This study shows that MCTD is a distinct entity that can be classified using either Kasukawa or Sharp criteria, and that only 25.8% of patients progress to a dCTD during follow-up.

High incidence of immune-mediated inflammatory diseases in sepsis survivors: A nationwide exposed-nonexposed epidemiological study.

OBJECTIVE: Sepsis is characterized by an excessive release of inflammatory cytokines. Cytokine dysregulation is pivotal to the pathophysiology of immune-mediated inflammatory diseases (IMIDs). We aimed to analyze the incidence of IMIDs in patients who survived sepsis. METHODS: We performed a matched-cohort study using the National Medico-Administrative Hospital database in order to analyze the association between sepsis and incident IMIDs in 2020 in France. Sepsis was defined by the combination of at least one infection diagnosis code and one organ failure code. Patients with a first sepsis diagnosed in 2020 were randomly matched with patients admitted during the same period for acute myocardial infarction (AMI) with an exact matching procedure using age, gender, and comorbidities as matching variables. The main outcome was an IMID diagnosis in a 9-month follow-up period starting the first day of hospitalization for sepsis or AMI. RESULTS: In France, the incidence rate of IMIDs after a sepsis in 2020-analyzed in 62,257 patients-was of 7956 (95% confidence interval [95% CI] 7392-8520) per 100,000 patient-years. As compared to the AMI population, we observed an increased risk for IMIDs of 2.80 (hazard ratio [HR]; 95% CI [2.22-3.54]) starting from day 16 after admission in the sepsis population. The risk of IMIDs onset in sepsis survivors depended on the type of IMIDs and was higher for immune thrombocytopenia (5.51 [1.97-15.4]), autoimmune hemolytic anemia (HR 4.83 [1.45-16.1]), and antineutrophil cytoplasmic antibody-associated vasculitis (4.66 [2.05-10.6]). Association between sepsis and IMIDs onset appeared well balanced across pathogen categories. CONCLUSION: Our study shows a high incidence of IMIDs among sepsis survivors.

Incidence, risk factors and treatment of central nervous system immune reconstitution inflammatory syndrome in non-HIV patients with tuberculous meningitis: a multicentre observational study.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) affecting the central nervous system (CNS) is associated with poor outcomes. AIMS: To report on risk factors for CNS-IRIS following tuberculous meningitis (TBM) in HIV-negative patients. METHODS: In this retrospective multicentre study, all HIV-negative adult patients admitted between 2003 and 2021 with microbiologically proven TBM were included. The primary outcome measure was IRIS onset over follow-up. Characteristics of patients who developed IRIS were described. Factors associated with IRIS were identified using a multivariable logistic regression procedure. RESULTS: Fifty-six patients (33.0 (27.0-44.3) years, 39 (69.6%) men) with microbiologically proven TBM were studied. All patients received antituberculosis treatment and 48 (n = 48/56; 85.7%) steroids at TBM diagnosis. During a median follow-up of 18.0 (12.0-27.3) months, IRIS occurred in 28 (n = 28/56, 50.0%) patients, at a median time of 2.0 (1.0-3.0) months after antituberculosis treatment was started. IRIS involved the CNS in all but one case. Imaging revealed new (n = 23/28, 82.1%) and/or worsening (n = 21/28; 75.0%) of previously recognised lesions. Multivariable analysis showed that meningeal enhancement on brain magnetic resonance imaging (MRI) (odds ratio (OR): 15.3; 95% confidence interval (CI): (1.19-1193.5)) at TBM diagnosis and high blood albumin level (OR: 1.21; 95% CI: (1.02-1.60)) were associated with the occurrence of CNS-IRIS during follow-up. CONCLUSION: CNS-IRIS following TBM in non-HIV patients appears frequent and severe. Meningeal enhancement on brain MRI at tuberculosis diagnosis is a risk factor for CNS-IRIS.

Heart and systemic sclerosis-findings from a national cohort study.

OBJECTIVES: Heart involvement is one of the leading causes of death in systemic sclerosis (SSc). The prevalence of SSc-related cardiac involvement is poorly known. Our objective was to investigate the prevalence and prognosis burden of different heart diseases in a nationwide cohort of patients with SSc. METHODS: We used data from a multicentric prospective study using the French SSc national database. Focusing on SSc-related cardiac involvement, we aimed to determine its incidence and risk factors. RESULTS: Over the 3528 patients with SSc 312 (10.9%) had SSc-related cardiac involvement at baseline. They tended to have a diffuse SSc subtype more frequently, more severe clinical features, and presented more cardiovascular risk factors. From the 1646 patients available for follow-up analysis, SSc-related cardiac involvement was associated with an increased risk of death. There was no significant difference in overall survival between SSc-related cardiac involvement, ischaemic heart disease or pulmonary arterial hypertension. Regarding survival analysis, 98 patients developed SSc-related cardiac involvement at five years (5-year event rate: 11.15%). Regarding reduced LVEF < 50% and left ventricular diastolic dysfunction, the 5-year event rate was 2.49% and 5.84% respectively. Pericarditis cumulative incidence at five years was 3%. Diffuse SSc subtype was a risk factor for SSc-related cardiac involvement and pericarditis. Female sex was associated with less left ventricular diastolic dysfunction incidence. CONCLUSIONS: Our results describe the incidence and prognostic burden of SSc-related cardiac involvement at a large scale, with gender and diffuse SSc subtype as risk factors. Further analyses should assess the potential impact of treatment on these various cardiac outcomes.

Improving Human Papillomavirus-Related Cervical Cancer Screening in Patients With Systemic Lupus Erythematosus.

Women with systemic lupus erythematosus (SLE), especially when exposed to immunosuppressive drugs, are at higher risk of human papillomavirus (HPV)-related cervical cancer.1 A recent study has shown that cervical cancer screening (CCS) coverage is worryingly low in this population.2.

Impact of adherence to EULAR quality indicators on the quality of life of patients with systemic lupus erythematosus.

OBJECTIVE: Quality indicators (QIs) for systemic lupus erythematosus (SLE) management based on the 2019 update of European League Against Rheumatism (EULAR) recommendations have been recently proposed. We aimed to determine whether adherence to QIs was associated with patient reported outcome (PRO). METHODS: Adherence to a set of 18 EULAR-based QIs and correlation with PRO assessed by Lupus Impact Tracker (LIT) was tested in a cohort of 162 SLE patients. RESULTS: On average, SLE patients received 41% (33; 52.5) of recommended care. Higher adherence to monitoring-related QIs was associated with an older age, a shorter SLE disease duration and a more severe disease (i.e. Class III/IV/V nephritis). LIT demonstrated that the average impact of lupus on patients' life was of 30% (12.5;47.5). In multivariable analysis, patients of female gender (OR 0.25, 95% 0.05-0.94; p = 0.05), with lupus CNS (OR 0.33, 95%CI 0.08-1.05; p = 0.08) and skin involvements (OR 0.49, 95%CI 0.23-1.04; p = 0.07) had higher odds of experiencing a negative impact of the lupus on their life. No association were found between adherences to QIs by physicians and reported quality of life in lupus patients. CONCLUSION: Our study confirms a variable degree of clinicians' adherence to QIs for SLE and shows no clear association between QIs adherence and patient reported outcome. Adherence to QIs by physicians are not enough to impact the quality of life of patients.

Impact of BNT162b2 mRNA anti-SARS-CoV-2 vaccine on interferon-alpha production by plasmacytoid dendritic cells and autoreactive T cells in patients with systemic lupus erythematosus: The COVALUS project.

OBJECTIVE: To evaluate the specific response of SLE patients to BNT162b2 vaccination and its impact on autoimmunity defined as in vivo production of interferon-alpha (IFNα) by plasmacytoid dendritic cells (pDCs) and autoreactive immune responses. METHODS: Our prospective study included SLE patients and healthy volunteers (HV) who received 2 doses of BNT162b2 vaccine 4 weeks apart. Subjects under immunosuppressive drugs or with evidence of prior COVID-19 were excluded. IgG anti-Spike SARS-CoV-2 (anti-S) antibodies, anti-S specific-B cells, anti-S specific T cells, in vivo INF-α production by pDCs, activation marker expression by pDCs and autoreactive anti-nuclear T cells were quantified before first injection, before second injection, and 3 and 6 months after first injection. RESULTS: Vaccinated SLE patients produced significantly lower IgG antibodies and specific B cells against SARS-CoV-2 as compared to HV. In contrast, anti-S T cell response did not significantly differ between SLE patients and HV. Following vaccination, the surface expression of HLA-DR and CD86 and the in vivo production of IFNα by pDCs significantly increased in SLE patients. The boosted expression of HLA-DR on pDCs induced by BNT162b2 vaccine correlated with the overall immune responses against SARS-CoV-2 (anti-S antibodies: r = 0.27 [0.05-0.46], p = 0.02; anti-S B cells: r = 0.19 [-0.03-0.39], p = 0.09); anti-S T cells: r = 0.28 [0.05-0.47], p = 0.016). Eventually, anti-SARS-CoV-2 vaccination was associated with an overall decrease of autoreactive T cells (slope = - 0.00067, p = 0.015). CONCLUSION: BNT162b2 vaccine induces a transient in vivo activation of pDCs in SLE that contributes to the immune responses against SARS-CoV-2. Unexpectedly BNT162b2 vaccine also dampens the pool of circulating autoreactive T cells, suggesting that vaccination may have a beneficial impact on SLE disease.

Pregnancy outcomes in women with primary Sjögren's syndrome: an analysis of data from the multicentre, prospective, GR2 study.

BACKGROUND: Adverse pregnancy outcomes in women with primary Sjögren's syndrome have only been evaluated retrospectively using heterogeneous methods and with contradictory results. We aimed to describe adverse pregnancy, delivery, and birth outcome risks in pregnant women with primary Sjögren's syndrome compared with those of a matched general population in France, and to identify factors predictive of disease flares or adverse pregnancy outcomes. METHODS: We conducted a multicentre, prospective, cohort study in France using the GR2 (Groupe de Recherche sur la Grossesse et les Maladies Rares) registry. Women from the GR2 study were eligible if they had conceived before March, 2021, had primary Sjögren's syndrome according to the American College of Rheumatology and European Alliance of Associations for Rheumatology (EULAR) 2016 classification criteria, and had an ongoing pregnancy at 12 weeks of gestation. In women who entered in the registry with pregnancies before 18 weeks of gestation, we sought to identify factors associated with primary Sjögren's syndrome flare (≥3-point increase in EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI] score) or adverse pregnancy outcomes (fetal or neonatal death, placental insufficiency leading to a preterm delivery [<37 weeks of gestation], or small-for-gestational-age birthweight). A matched controlled study compared adverse pregnancy, delivery, and birth outcome rates between pregnant women with primary Sjögren's syndrome from the GR2 registry and matched controls from the general population included in the last French perinatal survey (Enquête Nationale Périnatale 2016). FINDINGS: 1944 pregnancies were identified in the GR2 cohort, of which 106 pregnancies in 96 women with primary Sjögren's syndrome were included in this analysis. The median age at pregnancy onset was 33 years (IQR 31-36). 87 (83%) of 105 pregnancies (with ethnicity data) were in White women, 18 (17%) were in Black women; 92 (90%) of 102 had previous systemic activity (ESSDAI score of ≥1; data missing in four pregnancies), and 48 (45%) of 106 had systemic activity at inclusion. Of 93 pregnancies included at week 18 of gestation or earlier, primary Sjögren's syndrome flares occurred in 12 (13%). No baseline parameters were associated with primary Sjögren's syndrome flare. Four twin pregnancies and one medical termination were excluded from the adverse pregnancy outcome analysis; of the remaining 88, adverse pregnancy outcomes occurred in six (7%). Among pregnancies in women with data for antiphospholipid antibodies (n=55), antiphospholipid antibody positivity was more frequent among pregnancies with adverse outcomes (two [50%] of four pregnancies) compared with those without adverse outcomes (two [4%] of 51 pregnancies; p=0·023). Anti-RNP antibody positivity was also more frequent among pregnancies with adverse outcomes than those without, although this was not statistically significant. In the matched controlled study, adverse pregnancy outcomes occurred in nine (9%) of 105 pregnancies in women with primary Sjögren's syndrome and 28 (7%) of the 420 matched control pregnancies; adverse pregnancy outcomes were not significantly associated with primary Sjögren's syndrome (odds ratio 1·31, 95% CI 0·53-2·98; p=0·52). INTERPRETATION: Pregnancies in women with primary Sjögren's syndrome had very good prognoses for mothers and fetuses, with no overall increase in adverse pregnancy outcome risk compared with the general population. Women with antiphospholipid antibodies or anti-RNP antibodies require close monitoring, because these factors might be associated with a higher risk of adverse pregnancy outcomes. FUNDING: Lupus France, Association des Sclérodermiques de France, Association Gougerot Sjögren, Association Francophone Contre la Polychondrite Chronique Atrophiante, AFM-Telethon, Société Nationale Française de Médecine Interne, Société Française de Rhumatologie, Cochin Hospital, French Health Ministry, Fondation for Research in Rheumatology, Association Prix Véronique Roualet, Union Chimique Belge.