Sarcoidosis immunopathogenesis - a new concept of maladaptive trained immunity.

Sarcoidosis is a chronic immune disease of unknown origin for which we still lack an immunological framework unifying causal agents, host factors, and natural history of disease. Here, we discuss the initial triggers of disease, and how myeloid cells drive granuloma formation and contribute to immunopathogenesis. We highlight recent advances in our understanding of innate immune memory and propose the hypothesis that maladaptive innate immune training connects previous environmental exposure to granuloma maintenance and expansion. Lastly, we consider how this hypothesis may open novel therapeutic avenues, while corticosteroids remain the front-line treatment.

Immune thrombocytopenia and pregnancy: an exposed/nonexposed cohort study.

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

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.

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.

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.

Chronic interstitial lung disease associated with systemic lupus erythematosus: A multicentric study of 89 cases.

BACKGROUND AND OBJECTIVE: Chronic interstitial lung disease (ILD) occurs rarely with systemic lupus erythematosus (SLE) as compared with other connective tissue diseases. This multicentric retrospective study of patients with SLE-ILD from the OrphaLung and French SLE networks during 2005-2020 aimed to describe the characteristics of patients with SLE-ILD and analyse factors associated with prognosis. METHODS: We analysed data for 89 patients with SLE-ILD (82 women, 92.1%) (median age at SLE diagnosis: 35 years [interquartile range 27-47]). All patients met the 2019 EULAR/ACR criteria for the diagnosis of SLE. RESULTS: Forty two (47.2%) patients were positive for anti-ribonuclear protein antibodies and 45 (50.6%) for anti SSA/Ro antibodies. A total of 58 (65.2%) patients had another connective tissue disease: Sjögren's syndrome (n = 33, 37.1%), systemic sclerosis (n = 14, 15.7%), inflammatory myopathy (n = 6, 6.7%), or rheumatoid arthritis (n = 6, 6.7%). ILD was diagnosed along with SLE in 25 (28.1%) patients and at a median of 6 (0-14) years after the SLE diagnosis. The most frequent CT pattern was suggestive of non-specific interstitial pneumonia (n = 41, 46.0%) with or without superimposed organizing pneumonia. After a median follow-up of 86.5 [39.5-161.2] months, 18 (20.2%) patients had died and 6 (6.7%) underwent lung transplantation. The median 5-year and 10-year transplantation-free survival were 96% (92-100) and 87% (78-97). In total, 44 (49.4%) patients showed ILD progression. Cutaneous manifestations and Raynaud's phenomenon were associated with better survival. Only forced vital capacity was significantly associated with survival and ILD progression. CONCLUSION: ILD is a rare manifestation of SLE with good overall prognosis but with possible risk of ILD progression. Patients with SLE-ILD frequently have another connective tissue disease.

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.

N-Terminal pro-Brain Natriuretic Peptide is a biomarker for cardiovascular damage in systemic lupus erythematous: a cross-sectional study.

OBJECTIVES: Prediction models based on traditional risk factors underestimate cardiovascular (CV) risk in systemic lupus erythematosus (SLE). In a large sample of unselected SLE patients, we investigated cross-sectional associations of NT-proBNP with cardiovascular damage (CVD). METHODS: Serum NT-proBNP was measured in SLE patients enrolled in the MUHC Lupus Clinic registry. Serum were collected between March 2022 and April 2023 at annual research visits. The primary outcome was CVD identified on the SLICC Damage Index. Factors associated with CVD and NT-proBNP levels were determined. RESULTS: Overall, 270 SLE patients (female 91%, median age 50.7 [1st quartile- 3rd quartile : 39.6-62.1] years) were analyzed for the primary outcome. Among them, 33 (12%) had CVD. The ROC curve for NT-proBNP demonstrated strong associations with CVD (AUC 0.78, 95% CI 0.69-0.87) with a threshold of 133 pg/ml providing the best discrimination for those with/without CVD. Hypertension (OR 3.3, 95% CI 1.2-9.0), dyslipidaemia (OR 3.6, 95% CI 1.3-9.6) and NT-proBNP > 133 pg/ml (OR 7.0, 95% CI, 2.6-19.1) were associated with CVD in the multivariable logistic regression model. Increased NT-proBNP levels were associated with age (OR 4.2, 95% CI 2.2-8.3), ever smoking (OR 1.9, 95% CI 1.0-3.5), reduced eGFR (4.1, 95% CI 1.3-13.1), prior pericarditis/pleuritis (OR 2.5, 95% CI 1.4-4.5) and aPL antibodies (OR 2.6, 95% CI 1.4-4.9). CONCLUSION: NT-proBNP is a biomarker for CV damage in SLE. The novel associations of NT-proBNP levels with prior pericarditis/pleuritis and aPL antibodies suggest new avenues for research to better understand what drives CV risk in SLE.

Determination of four homogeneous subgroups of patients with antiphospholipid syndrome: a cluster analysis based on 509 cases.

OBJECTIVE: APS is a heterogeneous disease with different phenotypes. Using an unsupervised hierarchical cluster analysis, we aimed to determine distinct homogeneous phenotypes among APS patients. METHODS: We performed an observational, retrospective study of APS patients enrolled in the French multicentre 'APS and SLE' registry who met the Sydney classification criteria. The clustering process involved an unsupervised multiple correspondence analysis followed by a hierarchical ascendant clustering analysis; it used 27 variables selected to cover a broad range of APS clinical and laboratory manifestations. RESULTS: These analyses included 509 patients, mainly women (77.8%). Mean (s.d.) age at APS diagnosis was 36.2 (14.6) years, and mean follow-up since diagnosis 10.3 (8.5) years. This hierarchical classification cluster analysis yielded four homogeneous groups of patients: cluster 1, mostly with venous thromboembolism without any associated autoimmune disease; cluster 2, older, lowest proportion of women, history of arterial events, and/or with migraines, arterial hypertension, diabetes mellitus, or dyslipidaemia; cluster 3, younger, highest proportion of women, associated SLE or other autoimmune diseases, and a history of venous thromboembolism or pregnancy morbidity; and cluster 4, mainly with a history of catastrophic antiphospholipid syndrome, aPL-associated nephropathy, and pregnancy morbidity, with frequent triple positivity and more deaths (16.7%). CONCLUSIONS: Our study applied an unsupervised clustering method to distinguish four homogeneous APS patient subgroups that were predominantly venous; arterial; associated with SLE or another autoimmune disease; and arterial microthrombotic. Heterogeneous pathophysiological mechanisms may explain these findings.

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.

Patients of 75 years and over with ANCA-associated vasculitis have a lower relapse risk than younger patients: A multicentre cohort study.

BACKGROUND: Little is known about antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in older patients. We aim to study relapse risk of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in patients diagnosed after 75 years and compare it with those of patients aged 65-75 years. METHODS: Data from AAV patients aged ≥65 years were extracted from the French Vasculitis Study Group (FVSG) database and from a call for observation to FVSG members. Cox and Fine-Gray models were used to assess relapse risk, taking death into account either as a censoring or a competing event, respectively. RESULTS: The analysis included 219 patients aged ≥75 years (median 79) and 80 patients aged 65-75 years (median 70), of those 155 had GPA (52%), 136 MPA (45%), with 95 (32%) anti-proteinase 3 positivity and 179 (61%) anti-myeloperoxidase. Patients aged ≥75 years had a lower relapse risk in multivariate analysis (cause-specific hazards ratio [CSHR] 0.54, 95% CI [0.33-0.89], p = 0.016, Cox model; subdistribution hazard ratio [SHR] 0.46, 95% CI [0.29-0.74], p = 0.001, Fine-Gray model) after taking into account vasculitis type. Patients aged ≥75 years had a lower probability of being treated for remission maintenance with a combination of glucocorticoids and immunosuppressants (vs. glucocorticoids alone, HR 0.28, 95% CI [0.11-0.68], p = 0.005) after adjusting to Five Factor Score, although relapse-free survival was significantly longer when receiving such combination (CSHR 0.40, 95% [CI 0.24-0.67], p < 0.001). CONCLUSIONS: AAV patients ≥75 years have a lower relapse risk than patients aged 65-75 years despite a lower probability of having received maintenance therapy with a combination of glucocorticoids and immunosuppressants, but they still benefit from such treatment regimen.

Survival after COVID-19-associated organ failure among inpatients with systemic lupus erythematosus in France: a nationwide study.

OBJECTIVE: We analysed the incidence of, the specific outcomes and factors associated with COVID-19-associated organ failure (AOF) in patients with systemic lupus erythematosus (SLE) in France. METHODS: We performed a cohort study using the French national medical/administrative hospital database for the January 2011-November 2020 period. Each patient with SLE diagnosed in a French hospital with a COVID-19-AOF until November 2020 was randomly matched with five non-SLE patients with COVID-19-AOF. We performed an exact matching procedure taking age ±2 years, gender and comorbidities as matching variables. COVID-19-AOF was defined as the combination of at least one code of COVID-19 diagnosis with one code referring to an organ failure diagnosis. RESULTS: From March to November 2020, 127 380 hospital stays in France matched the definition of COVID-19-AOF, out of which 196 corresponded with patients diagnosed with SLE. Based on the presence of comorbidities, we matched 908 non-SLE patients with COVID-19-AOF with 190 SLE patients with COVID-19-AOF. On day 30, 43 in-hospital deaths (22.6%) occurred in SLE patients with COVID-19-AOF vs 198 (21.8%) in matched non-SLE patients with COVID-19-AOF: HR 0.98 (0.71-1.34). Seventy-five patients in the SLE COVID-19-AOF group and 299 in the matched control group were followed up from day 30 to day 90. During this period, 19 in-hospital deaths occurred in the SLE group (25.3%) vs 46 (15.4%) in the matched control group; the HR associated with death occurring after COVID-19-AOF among patients with SLE was 1.83 (1.05-3.20). CONCLUSIONS: COVID-19-AOF is associated with a poor late-onset prognosis among patients with SLE.

Clonal haematopoiesis of indeterminate potential and cardiovascular events in systemic lupus erythematosus (HEMATOPLUS study).

OBJECTIVE: The detection of somatic mutations among the genes of myeloid cells in asymptomatic patients-defining clonal haematopoiesis of indeterminate potential (CHIP)-is associated with a predisposition to cardiovascular events (CVEs) in the general population. We aimed to determine whether CHIP was associated with CVEs in SLE patients. METHODS: The study is an ancillary study of the randomized, double-blind, placebo-controlled, multicentre PLUS trial conducted from June 2007 through August 2010 at 37 centres in France, involving 573 SLE patients. The search for somatic mutations by high-throughput sequencing of 53 genes involved in clonal haematopoiesis was performed on genomic DNA collected at PLUS inclusion. CHIP prevalence was assessed in SLE and in a retrospective cohort of 479 patients free of haematological malignancy. The primary outcome was an incident CVE in SLE. RESULTS: Screening for CHIP was performed in 438 SLE patients [38 (29-47) years, 91.8% female]. Overall, 63 somatic mutations were identified in 47 patients, defining a CHIP prevalence of 10.7% in SLE. Most SLE patients (78.7%) carried a single mutation. Most variants (62.5%) were located in the DNMT3A gene. CHIP frequency was related to age and to age at SLE diagnosis, and was associated with a lower frequency of aPLs. CHIP occurred >20 years earlier (P < 0.00001) in SLE than in controls. The detection of CHIP at inclusion was not found to be associated with occurrence of CVEs during follow-up [HR = 0.42 (0.06-3.21), P = 0.406]. CONCLUSION: The prevalence of CHIP is relatively high in SLE for a given age, but was not found to be associated with incident CVEs. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05146414.

Efficacy and safety of TNF-α antagonists and tocilizumab in Takayasu arteritis: multicentre retrospective study of 209 patients.

OBJECTIVE: To assess the safety and the efficacy of TNF-α antagonists and tocilizumab in patients with Takayasu arteritis (TAK). METHODS: A total of 209 patients with TAK [median age 29 years (interquartile range 7-62)], 186 (89%) females] were included. They received either TNF-α antagonists [n = 132 (63%) with 172 lines; infliximab (n = 109), adalimumab (n = 45), golimumab (n = 8), certolizumab (n = 6) and etanercept (n = 5)] or tocilizumab [n = 77 (37%) with 121 lines; i.v. and s.c. in 95 and 26 cases, respectively]. RESULTS: A complete response at 6 months was evidenced in 101/152 (66%) patients on TNF-α antagonists and 75/107 (70%) patients on tocilizumab. Age ≥30 years [odds ratio 2.09 (95% CI 1.09, 3.99)] was associated with complete response, whereas vascular signs [OR 0.26 (95% CI 0.1, 0.65)], baseline prednisone ≥20 mg/day [OR 0.51 (95% CI 0.28, 0.93)] were negatively associated with the complete response to TNF-α antagonists or tocilizumab. During a median follow-up of 36 months, 103 relapses were noted. Supra-aortic branches and thoracic aorta involvement [HR 2.44 (95% CI 1.06, 5.65) and 3.66 (1.18, 11.4), respectively] and systemic signs at baseline [HR 2.01 (95% CI 1.30, 3.11)] were significantly associated with relapse. The cumulative incidence of treatment discontinuation and relapse were similar in TNF-α antagonists and tocilizumab. Fifty-eight (20%) adverse effects occurred on biologic targeted therapies [37 (21%) on TNF-α antagonists and 21 (17%) on tocilizumab (P = 0.4), respectively]. CONCLUSION: This large multicentre study shows high efficacy of biologic targeted treatments in refractory TAK. Efficacy, relapse and drug retention rate were equivalent with TNF-α antagonists and tocilizumab.

Brain magnetic resonance imaging lesion load at diagnosis, severity at onset and outcomes in Susac syndrome: A prospective cohort study.

BACKGROUND: Susac syndrome (SuS) is a rare occlusive microvessel disease of the brain, retina and inner ear. We aimed to determine whether brain lesion load at the acute phase predicts poor outcomes in SuS. METHODS: A prospective national cohort study was conducted from December 2012 to December 2019 in 20 centres in France. Patients included at the principal investigator's center with available brain magnetic resonance imaging (MRI) at diagnosis were analyzed. MRI was reviewed by an experienced neuroradiologist blinded to clinical status. The size, topography and number of hyperintense lesions on diffusion-weighted imaging (DWI-HL) were analyzed at diagnosis and during follow-up. Outcomes involved descriptive characteristics of patients at onset and last follow-up. RESULTS: Twenty-three patients (38.1 [18.8-56.5] years, 16 females) were prospectively studied. The triad (i.e., brain, eye and ear involvement) was complete at onset in 17 patients. Brain MRI was performed 1.1 (0.1-3.4) months after the first symptom. All patients had DWI-HL at the acute phase. Patients were separated into two groups according to the number of DWI-HL on first MRI: a first group of patients (n=15) displaying low brain lesion load (<50 DWI-HL per patient) and a second group of patients (n=8) displaying high brain lesion load (≥100 DWI-HL). The median follow-up was 57.9 (9.7-98) months. Clinical features, treatment, relapse rate, time to disappearance of DWI-HL, disabilities and professional outcome did not differ according to brain lesion load. CONCLUSION: Brain lesion load assessed by DWI at the acute phase is not associated with risks of disability in SuS.

Epidemiology of interstitial lung disease in systemic lupus erythematosus in France: A nation-wide population-based study over 10 years.

BACKGROUND AND OBJECTIVE: Data regarding interstitial lung disease (ILD) in the setting of systemic lupus erythematosus (SLE) are limited. We used a nationwide database to determine the incidence and the prevalence of ILD in SLE. METHODS: Characteristics of all SLE inpatients admitted between 2011 and 2012 in France were analysed through the French medico-administrative database. Features associated with the presence of ILD were studied. Cox hazard model was used to measure the impact of ILD on survival from the first stay to 2020. The incidence of ILD in SLE was estimated by analysing the onset of ILD from 2013 to 2020 in SLE patients who had no evidence of ILD in 2013. RESULTS: Between 2011 and 2012, 10,460 SLE patients had at least one hospital stay and could be traced until 2020. Among them, 134 (1.2%) had an ILD diagnosed at baseline. The frequency of ILD in SLE was higher in patients who had an associated autoimmune disease such as Sjögren's syndrome or systemic sclerosis (29.9% vs. 5.9%, p < 0.0001). ILD was associated with an increased risk of death in SLE in the multivariable analysis (hazard ratio [95% CI] 1.992 [1.420-2.794]; p < 0.0001). Among the 31,029 SLE patients with no evidence of ILD at baseline, ILD occurred in 795 (2.6%) between 2013 and 2020. The incidence rate of ILD in SLE was 10.26 for 1000 patient-years [95% CI: 10.24-10.28]. CONCLUSION: In SLE, ILD is exceedingly rare, often associated with another systemic autoimmune disorder and appears as a major risk factor for death.

Basophils and IgE contribute to mixed connective tissue disease development.

BACKGROUND: Mixed connective tissue disease (MCTD) is a rare and complex autoimmune disease that presents mixed features with other connective tissue diseases, such as systemic lupus erythematosus, systemic sclerosis, and myositis. It is characterized by high levels of anti-U1 small nuclear ribonucleoprotein 70k autoantibodies and a high incidence of life-threatening pulmonary involvement. The pathophysiology of MCTD is not well understood, and no specific treatment is yet available for the patients. Basophils and IgE play a role in the development of systemic lupus erythematosus and thus represent new therapeutic targets for systemic lupus erythematosus and other diseases involving basophils and IgE in their pathogenesis. OBJECTIVE: We sought to investigate the role of basophils and IgE in the pathophysiology of MCTD. METHODS: Basophil activation status and the presence of autoreactive IgE were assessed in peripheral blood of a cohort of patients with MCTD and in an MCTD-like mouse model. Basophil depletion and IgE-deficient animals were used to investigate the contribution of basophils and IgE in the lung pathology development of this mouse model. RESULTS: Patients with MCTD have a peripheral basopenia and activated blood basophils overexpressing C-C chemokine receptor 3. Autoreactive IgE raised against the main MCTD autoantigen U1 small nuclear ribonucleoprotein 70k were found in nearly 80% of the patients from the cohort. Basophil activation and IgE anti-U1 small nuclear ribonucleoprotein 70k were also observed in the MCTD-like mouse model along with basophil accumulation in lymph nodes and lungs. Basophil depletion dampened lung pathology, and IgE deficiency prevented its development. CONCLUSIONS: Basophils and IgE contribute to MCTD pathophysiology and represent new candidate therapeutic targets for patients with MCTD.

Musculoskeletal Tuberculosis: New Insights on Diagnosis Strategy and Treatment.

BACKGROUND/ OBJECTIVE: Skeletal tuberculosis (TB) is rare. We aimed to report on diagnostic strategy and treatment of skeletal TB. METHODS: In this multidisciplinary single-center medical records review study, all adult patients admitted between January 2009 and December 2019 with microbiologically proven skeletal TB were included. Demographic, medical history, laboratory, imaging, pathologic findings, treatment, and follow-up data were extracted from medical records. RESULTS: Among 184 patients identified with TB, 21 (16 women, 42 years [27, 48 years]) had skeletal involvement. Skeletal TB included spondylitis (n = 11), lytic bone lesions (n = 7), sacroiliitis (n = 5), arthritis (n = 3), osteitis (n = 2), and diffuse muscle abscesses without bone lesion (n = 1). Lytic lesions involved both axial and peripheral skeleton at multiple sites in most cases. 18F-fluorodeoxyglucose positron emission tomography was performed in 13 patients and helped to detect multifocal asymptomatic lesions and to target biopsy. All patients were treated with anti-TB therapy for 7 to 18 months. Fifteen patients (71.4%) received steroids as an adjunct therapy. Eleven patients needed an orthopedic immobilization corset, and 3 patients underwent surgery. All patients clinically improved under treatment, but 2 relapsed over a median follow-up of 24 months (12-30 months). No patient died or suffered long-term disabilities. CONCLUSION: Our study emphasizes the diversity of skeletal involvement in TB. 18F-fluorodeoxyglucose positron emission tomography scanner at diagnosis is key to assess the extension of skeletal involvement and guide extraskeletal biopsy. Neurological complications might be prevented by adding corticosteroids to anti-TB therapy.

Acquired factor V inhibitor: a nation-wide study of 38 patients.

Acquired factor V inhibitor (AFVI) is an extremely rare disorder that may cause severe bleeding. To identify factors associated with bleeding risk in AFVI patients, a national, multicentre, retrospective study was made including all AFVI patients followed in 21 centres in France between 1988 and 2015. All patients had an isolated factor V (FV) deficiency <50% associated with inhibitor activity. Patients with constitutional FV deficiency and other causes of acquired coagulation FV deficiencies were excluded. The primary outcome was incident bleeding and factors associated with the primary outcome were identified. Thirty-eight (74 [36-100] years, 42·1% females) patients with AFVI were analysed. Bleeding was reported in 18 (47·4%) patients at diagnosis and in three (7·9%) during follow-up (7 [0·2-48.7] months). At diagnosis, FV was <10% in 31 (81·6%) patients. Bleeding at diagnosis was associated with a prolonged prothrombin time that strongly correlated with the AFVI level measured in plasma {r = 0·63, 95% confidence interval (CI) [0·36-0·80], P < 0·05}. Bleeding onset during follow-up was associated with a slow AFVI clearance (P < 0·001). The corresponding receiver operating characteristics curve showed that AFVI clearance was predictive of bleeding onset with an AFVI clearance of seven months with a sensitivity of 100% (95% CI: 29-100) and a specificity of 86% (95% CI: 57-98, P = 0·02). Kaplan-Meier analysis showed that AFVI clearance >7 months increased the risk of bleeding by 8 (95% CI: [0·67-97], P = 0·075). Prothrombin time at diagnosis and time for clearance of FV inhibitor during follow-up are both associated with bleeding in patients with AFVI.

Clinical phenotypes of extrapulmonary sarcoidosis: an analysis of a French, multi-ethnic, multicentre cohort.

Sarcoidosis is a rare disease of unknown cause with wide heterogeneity in clinical features and outcomes. We aimed to explore sarcoidosis phenotypes and their clinical relevance with particular attention to extrapulmonary subgroups.The Epidemiology of Sarcoidosis (EpiSarc) study is a French retrospective multicentre study. Sarcoidosis patients were identified through national hospitalisation records using appropriate codes from 11 hospital centres between 2013 and 2016 according to a standardised protocol. Medical charts were reviewed. The phenotypes of sarcoidosis were defined using a hierarchical cluster analysis.A total of 1237 patients were included (562 men and 675 women). The mean age at sarcoidosis diagnosis was 43.5±13 years. Hierarchical cluster analysis identified five distinct phenotypes according to organ involvement and disease type and symptoms: 1) erythema nodosum, joint involvement and hilar lymph nodes (n=180); 2) eye, neurological, digestive and kidney involvement (n=137); 3) pulmonary involvement with fibrosis and heart involvement (n=630); 4) lupus pernio and a high percentage of severe involvement (n=41); and 5) hepatosplenic, peripheral lymph node and bone involvement (n=249). Phenotype 1 was associated with being European/Caucasian and female and with non-manual work, phenotype 2 with being European/Caucasian, and phenotypes 3 and 5 with being non-European/Caucasian. The labour worker proportion was significantly lower in phenotype 5 than in the other phenotypes.This multicentre study confirms the existence of distinct phenotypes of sarcoidosis, with a non-random distribution of organ involvement. These phenotypes differ according to sex, geographical origin and socioprofessional category.