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Primary antiphospholipid syndrome (PAPS) is a life-threatening clotting disorder mediated by pathogenic autoantibodies. Here we dissect the origin of self-reactive B cells in human PAPS using peripheral blood and bone marrow of patients with triple-positive PAPS via combined single-cell RNA sequencing, B cell receptors (BCR) repertoire profiling, CITEseq analysis and single cell immortalization. We find that antiphospholipid (aPL)-specific B cells are present in the naive compartment, polyreactive, and derived from the natural repertoire. Furthermore, B cells with aPL specificities are not eliminated in patients with PAPS, persist until the memory and long-lived plasma cell stages, likely after defective germinal center selection, while becoming less polyreactive. Lastly, compared with the non-PAPS cells, PAPS B cells exhibit distinct IFN and APRIL signature as well as dysregulated mTORC1 and MYC pathways. Our findings may thus elucidate the survival mechanisms of these autoreactive B cells and suggest potential therapeutic targets for the treatment of PAPS. Primary antiphospholipid syndrome (PAPS) is a clotting disorder attributed to autoreactive antibodies produced by B cells. Here the authors show, using single cell omics and B cell repertoire data, that autoreactive B cells originate from the natural B cell repertoire and escape germinal center selection to persist in PAPS patient via potential dysregulation of mTORC1 and MYC pathways.

Background The risk of severe COVID-19 and its determinants remain largely unknown in patients with autoimmune and inflammatory rheumatic diseases. The objective of this study was to assess the prevalence of COVID-19 infection in patients followed for rare autoimmune diseases as well as the predictors of COVID-19 and disease flare-ups. Methods Cross-sectional phone survey from April 9, 2020, to July 2, 2020, during which patients with autoimmune diseases followed at the National Reference Center for Rare Autoimmune diseases of Strasbourg were systematically contacted by phone and sent a prescription for a SARS-CoV-2 serology. Results One thousand two hundred thirty-two patients were contacted. One thousand fifty-five patients with a confirmed diagnosis of systemic autoimmune disease were included (4 unreachable, 4 moves abroad, 5 deaths before pandemic, 50 without consent, and 114 without autoimmune disease). Among them, 469 (44.5%) patients were tested for SARS-CoV-2 serology. Thirty-nine patients (7.9%) had SARS-CoV-2 infection (either through chest CT-scan [n = 5], RT-PCR on nasopharyngeal swab [n = 14], or serology [n = 31]) among the 496 who underwent at least one of those 3 diagnosis modalities. Of the 39 proven cases, 33 had clinical manifestations (6 asymptomatic patients were diagnosed through systematic serology testing), 31 were managed by home care, 3 were hospitalized due to a need for oxygenation, two required admission to an intensive care unit, and one died. Among patients with confirmed SARS-CoV-2 infection, reported flares were more frequent than in uninfected patients (26.3% [10/38] vs. 7.0% [32/457], p < 0.0001). Preventive sick leave had no significant impact on the prevalence of SARS-CoV-2 infection (5.8% [3/53]) compared to work continuation (7.6% [30/397], p = 0.64). Overall, the seroprevalence of SARS-CoV-2 was 6.6% (31/469) which was numerically lower to the Grand-Est general population estimated to be 9.0%. Conclusions This systematic survey of more than 1000 patients with rare systemic autoimmune diseases reports a low prevalence of proven SARS-CoV-2 infection and very rare severe infections, probably related to good compliance with prophylactic measures in these patients.

From a 1-year survival of less than 50% before the discovery of glucocorticoids to over 90% at 10 years in most dedicated centres, the spectrum of SLE has profoundly evolved. Despite this improvement, several major challenges currently remain. The aim of this review is to analyse what are, according to us, the 10 most important contemporary challenges in the management of SLE. Among those are the need to treat to target to favour disease remission (or low disease activity), limit the use of glucocorticoids, derive more comprehensive tools for the evaluation of disease activity, develop more effective drugs (yielding successful trials), dissect the heterogeneity of the disease both at the molecular and genetic levels, identify relevant biomarkers for individualised treatment, manage fertility and pregnancy, tackle comorbidities such as cardiovascular risk, the prevention of infections and osteoporosis, improve the network of care (from the patients’ perspective), and favour a holistic approach (integrating fatigue, adherence to treatment, physical activity). Altogether, these 10 contemporary challenges in SLE may be considered as a roadmap for those involved in the daily care of patients with SLE, as well as for researchers who may wish to contribute to an improved management of this rare and complex disease.

ObjectivesTo analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA).MethodsPatients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0–3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA.ResultsA total of 350 patients (89% female; median age: 42 years, IQR: 34–52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2–6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models.ConclusionFatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.

ObjectiveTo refine the spectrum of anti-Ku-associated disease, a condition that is equivocally described by current diagnostic criteria for connective tissue diseases.MethodsAmong 42 consecutive patients harbouring anti-Ku antibodies, subgroups with similar phenotypes and prognosis were delineated without an a priori diagnosis using hierarchical clustering analysis of the cumulative clinico-biological features recorded during the follow-up. Features present at baseline that most efficiently predicted the outcomes were then identified using a sensitivity–specificity sum maximisation approach.ResultsClinico-biological features were clustered into three groups. Glomerulonephritis and ILD, the two fatal complications in this cohort, were unequally distributed between the three clusters that additionally differed on six clinico-biological features.Among features present at baseline, elevated serum level of creatine kinase (CK) and anti-dsDNA antibodies were generally mutually exclusive and most efficiently predicted the cluster belonging at last follow-up. Anti-Ku patients with elevated CK had a 22-fold higher risk of ILD while anti-Ku patients with anti-dsDNA antibodies had a 13-fold higher risk of glomerulonephritisConclusion“Anti-Ku with elevated CK” syndrome and “anti-Ku with anti-dsDNA” syndrome represent two distinct entities that are important to recognise in order to best tailor patient care.

Background Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID. Methods The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed. Results Among 473 patients with CVID, 16 patients displayed neutropenia (lowest count [0–1400]*10 6 /L). Sex ratio (M/F) was 10/6. Five patients died during the follow-up (11 years) with an increased percentage of deaths compared to the whole DEFI group (31.3 vs 3.4%, P  < 0.05). Neutropenia was diagnosed for 10 patients before 22 years old. The most frequent symptoms, except infections, were autoimmune cytopenia, i.e., thrombopenia or anemia (11/16). Ten patients were affected with lymphoproliferative diseases. Two patients were in the infection only group and the others belonged to one or several other CVID groups. The median level of IgG was 2.6 g/L [0.35–4.4]. Most patients presented increased numbers of CD21 low CD38 low B cell, as already described in CVID autoimmune cytopenia group. Neutropenia was considered autoimmune in 11 cases. NGS for 52 genes of interest was performed on 8 patients. No deleterious mutations were found in LRBA , CTLA4 , and PIK3 . More than one potentially damaging variant in other genes associated with CVID were present in most patients arguing for a multigene process. Conclusion Neutropenia is generally associated with another cytopenia and presumably of autoimmune origin during CVID. In the DEFI study, neutropenia is coupled with more severe clinical outcomes. It appears as an “alarm bell” considering patients’ presentation and the high rate of deaths. Whole exome sequencing diagnosis should improve management.

ObjectivesWe aimed to describe patients with autoimmune diseases (AID) developing invasive fungal disease (IFD) and identify factors associated with short-term mortality.MethodsWe analysed cases of IFD associated with AID from the surveillance network of invasive fungal diseases (Réseau de surveillance des infections fongiques invasives, RESSIF) registry of the French national reference centre for invasive mycoses. We studied association of AID-specific treatments with 30-day mortality. We analysed total lymphocyte and CD4-T cell counts in patients with Pneumocystis jirovecii pneumonia (PCP).ResultsFrom 2012 to 2018, 549 individuals with IFD and AID were included, mainly with PCP (n=227, 41.3%), fungemia (n=167, 30.4%) and invasive aspergillosis (n=84, 15.5%). Rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) were the most frequent AID in PCP (n=55 and 25, respectively) and invasive aspergillosis (n=15 and 10, respectively), inflammatory bowel diseases (IBDs) were predominant in fungemia (n=36). At IFD diagnosis, 365 (66.5%) patients received glucocorticoids (GCs), 285 (51.9%) immunosuppressants, 42 (7.7%) tumor necrosis factor (TNF)-α blockers, 75 (13.7%) other biologics. Mortality at 30 days was 28.1% (143/508). Fungemia and high-dose GCs were independently associated with higher 30-day mortality. In PCP patients, lymphopenia <1500/mm3 was frequent (132/179, 73.7%) even if CD4+T cell count exceeded 200/mm3 in 56/78 patients (71.8%) (median 472.5/mm3, IQR 160–858).ConclusionIFD associated with AID occurs primarily in RA, AAV and IBD, especially when treated with GCs and immunosuppressants. Mortality is high, especially for patients on high-dose GCs. Lymphopenia may help identify risk of PCP, but normal CD4+T cell count does not rule out the risk. Further studies are needed to assess the individual risk factors for IFD.

RP physiopathology includes early endothelial cell injury, vascular dysfunction and sometimes microvascular thrombosis.1 Antiphospholipid antibodies (aPL) activate endothelial cells and platelets by complexes of beta-2 glycoprotein 1 (β2GP1) and anti-β2GP12 and could therefore contribute to the initiation of and/or aggravate SSc-related RP. aPL prevalence seems increased in patients with SSc compared with controls,3 but aPL-associated clinical features are often contradictory. SSc subtype was classified based on LeRoy and Medsger’s criteria,5 and skin involvement was assessed according to the modified Rodnan skin score (mRSS).6 Interstitial lung disease (ILD) was defined by subpleural ground-glass opacities and/or interstitial reticular pattern with or without fibrosis on high-resolution CT. Raynaud’s activity and the presence of digital ischaemia was determined using a previously published severity score: 0—no Raynaud’s; 1—Raynaud’s with/without vasodilator required; 2—Digital Pitting Scars; 3—Digital Tip Ulcerations and 4—Digital Gangrene.7 ADU was defined as a score ≥3.8 Pulmonary arterial hypertension (PAH) was defined by median pulmonary arterial pressure (mPAP) ≥25 mm Hg and pulmonary arterial wedge pressure ≤15 mm Hg, not related to lung diseases and/or chronic thromboembolism. In multivariate analysis, only mRSS remained significantly associated with ADU (OR 1.07, 95% CI 1.02 to 1.11; p=0.005) with a trend towards anti-β2GP1 positivity (OR 5.27, 95% CI 0.97 to 28.62; p=0.054) (online supplementary table 3)(online supplementary table 3). aPL, APS and past thrombotic event prevalences according to the different RP subsets are depicted in online supplementary table 4.Table 1 Patient characteristics Characteristics Patients (n=168) Age, years±SD 57.8±15 Female, n (%) 147 (87.5) Smoking, n (%)  Current or past 20 (12)  Never 136 (81)  NA 12 (7) SSc type, n (%)  Limited 69 (41)  Diffuse 99 (59) Disease duration, years±SD* 8.2±13.5 Modified Rodnan skin score (0–51), mean (Q1, Q3) 8.0 (4.0, 19.0) ADU, n (%) 48 (29)  Digital tip ulcerations, n (%) 44 (26)  Digital gangrene, n (%) 4 (3) Raynaud’s severity score (0–4), mean (Q1, Q3) 1.0 (1.0, 3.0) PAH  Suspected PAH on echocardiography, n (%) 19 (11)  sPAP (mm Hg), mean±SD 31.8±13.7  PAH on RHC, n (%) 12 (7)  mPAP (mm Hg), mean±SD 30.9±15 LVEF on echocardiography (%), mean±SD 66±9 ILD, n (%) 73 (43) FVC, % predicted ±SD 94.6±24.7 DLCO, % predicted ±SD 69.1±21.1 SSc-related autoantibodies, n (%)  Anticentromere, n (%) 76 (45)  Anti-Scl70, n (%) 60 (36) LA, n (%) 17 (10)   Overall High (>40 U/mL) aCL, n (%)   Any isotype (global) 14 (8) 6 (4)  IgG 11 (6) 6 (4)  IgM 3 (2) 0 (0) Anti-β2GP1, n (%)   Any isotype 14 (8) 10 (6)  IgG 8 (5) 6 (4)  IgM 8 (5) 4 (3) ≥1 aPL, n (%) 31 (18) 26 (15)  Triple positivity, n (%) 3 (2) 1 (1) APS, n (%) 7 (4)  Related-arterial thrombosis, n (%) 4 (2)  Related-venous thrombosis, n (%) 3 (2)  Obstetrical manifestation, n (%) 0 (0) Overall arterial thrombosis history, n (%) 5 (3) Overall venous thrombosis history, n (%) 13 (8) *Time from first non-Raynaud’s symptom. aCL, anticardiolipin; ADU, active digital ulceration; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; DLCO, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; β2GP1, beta-2 glycoprotein 1;Ig, immunoglobulin; ILD, interstitial lung disease; LA, lupus anticoagulant; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary arterial pressure;NA, not available; PAH, pulmonary arterial hypertension; Q1/Q3, quartile 1/quartile 3; RHC, right heart catheterisation; sPAP, systolic pulmonary arterial pressure; SSc, systemic sclerosis.Table 2 Factors associated with ADU Characteristics ADU− (n=120) ADU+ (n=48) P value Adjusted OR (95% CI)* Age, years±SD 58.9±15.5 55.2±13.2 0.15 ND Female, n (%) 107 (89.2) 40 (83.3) 0.31 ND Smoking, n (%)     0.43 ND  Current or past 13 (11) 7 (15)  Never 100 (83) 36 (75)  NA 7 (6) 5 (10) SSc type, n (%)     0.80 ND  Limited 50 (42) 19 (40)  Diffuse 70 (58) 29 (60) Disease duration, years±SD† 7.3±12.7 10.4±15.1 0.19 ND Modified Rodnan skin score (0–51), mean (Q1, Q3) 6.0 (2.0, 14.5) 14.0 (8.0, 26.0) <0.001 1.06(1.02to1.11) (p=0.007) PAH  Suspected PAH on echocardiography, n (%) 13 (11) 6 (13) 0.76 ND  sPAP (mm Hg), mean±SD 31.9±14.7 31.5±10.9 0.90  PAH on RHC, n (%) 8 (7) 4 (8) 0.70  mPAP (mm Hg), mean±SD 31.8±9.6 29.6±21.8 0.73 LVEF on echocardiography (%), mean±SD 65.4±9.8 67.6±6.7 0.23 ND ILD, n (%) 47 (39) 26 (54) 0.08 ND FVC, % predicted ±SD 97.3±17.4 88.3±26.9 0.09 ND DLCO, % predicted ±SD 71±21.2 64.8±20.4 0.14 ND SSc-related autoantibodies, n (%)  Anticentromere, n (%) 60 (50) 16 (33) 0.05 0.64 (0.2 to 1.87)  Anti-Scl70, n (%) 35 (29) 25 (52) 0.006 2.55 (0.91 to 7.14) aPL, n (%)  LA 10 (8) 7 (15) 0.22 ND  aCL (overall positivity) 11 (9) 3 (6) 0.54 ND  IgG 8 (7) 2 (4) 0.57 ND  IgM 2 (2) 1 (2) 0.83 ND  Anti-β2GP1 (overall positivity) 5 (4) 9 (19) 0.002 8.71(1.31to55.43) (p=0.02)  IgG 1 (1) 7 (16) <0.001 ND  IgM 4 (4) 4 (9) 0.17 ND APS, n (%) 4 (3) 3 (6) 0.39 ND Overall arterial thrombosis history, n (%) 3 (3) 2 (4) 0.61 ND Overall venous thrombosis history, n (%) 12 (10) 1 (2) 0.08 ND *Logistic regression with adjustment for anticentromere, anti-Scl70, modified Rodnan skin score, smoking, the presence of LA and/or aCL. †Time from first non-Raynaud’s symptom. aCL, anticardiolipin; ADU, active digital ulceration; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; DLCO, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; β2GP1, beta-2 glycoprotein 1;Ig, immunoglobulin; IPD, interstitial pulmonary disease; LA, lupus anticoagulant; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary arterial pressure; NA, not available ;ND, not done; PAH, pulmonary

Background. Primary Sjögren’s syndrome (PSS) is a frequent systemic autoimmune disease. In this study, we aimed to explore the cognitive impairment and the correlations with brain MRI. Methods. Twenty-five patients (mean age 55 ± 11.8 years, 21 females) with PSS were prospectively selected and tested with a French translation of the Brief Repeatable Battery for Neuropsychological Examination. The results were compared with the scores for 25 matched patients with multiple sclerosis (MS) and 25 controls. Brain lesions were assessed by brain MRI using the Wahlund classification. Results. Fifteen of the 25 PSS patients (60%) presented with cognitive disorders versus 19/25 MS patients (76%). Five patients had dementia in the PSS group. Speed of information processing, attention, immediate and long-term memory, and executive functions were frequently impaired. The mean duration of cognitive complaints was 5.6 ± 6.1 years, and the mean duration of PSS was 15.8 ± 14.0 years. A trend towards a correlation was found between the severity of cognitive impairment and the degree of white matter lesions (WML) (P=0.03, rho = 0.43). Conclusion. Cognitive impairment—mild or dementia—exists in patients with PSS. Further MRI studies are needed to better understand the precise neural basis of cognitive impairment in PSS patients.