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Patients with paroxysmal nocturnal hemoglobinuria (PNH) are susceptible to complement-mediated intravascular hemolysis and thrombosis. Factor H (FH) is the main regulator of the complement alternative pathway, which protects cells from unwanted complement-mediated damage. Although FH is not a glycosylphosphatidylinositol-linked molecule, it may play a role in PNH. We sought to determine if rare germline variants in complement factor H (CFH) affect the PNH course, screening 84 patients with PNH treated with eculizumab for rare variants in CFH, CFI, and C3 genes. We compared the allelic frequencies with populational data and a geographically-matched control group, looking for an association between presence of the variants and treatment response (transfusion independence by 6 months). Sixteen patients presented rare variants, 9 in CFH (10.7%). Germline CFH variants were more frequent among patients with PNH than among controls (P = .02) or public data (P < .001) and were more likely to be transfusion-dependent at 6 months after eculizumab initiation (P = .015). With a median follow-up of 5.8 years, 8 of 9 patients with the CFH variant received transfusions, and 2 developed thromboses. None of the patients with the CFH variant had severe aplastic anemia from eculizumab initiation until 6 months. We demonstrated for the first time that rare CFH variants are over-represented among patients with PNH and that germline genetic background may affect the response to eculizumab.

Survivors of immune-mediated thrombotic thrombocytopenic purpura (iTTP) are exposed to clinical relapses when a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13 (ADAMTS13) activity decreases during follow-up. Although preemptive rituximab usually improves ADAMTS13 activity in this context, 15% of patients experience refractoriness or intolerance to rituximab and require alternative strategies. Here, we addressed whether cyclosporine A (CSA) could improve ADAMTS13 activity and prevent clinical relapses in this context. We treated preemptively with CSA 14 iTTP patients who were unresponsive (n = 11) or intolerant (n = 3) to rituximab. All patients had a severe ADAMTS13 deficiency (activity20%) and otherwise in clinical remission. ADAMTS13 activity normalized in almost all patients (n = 13, 93%), after a median time of 2.5 months [IQR 1-6] following initiation. Median duration of CSA treatment was 17.5 months [IQR 10-34]. ADAMTS13 activity further declined to undetectable values during follow-up in five patients, but retreatment with rituximab or CSA allowed a recovery in ADAMTS13 activity in three cases. CSA could be stopped durably in two patients, while two others experienced an ADAMTS13 relapse. Severe but reversible side effects requiring cessation of the treatment occurred in two patients. CSA provides high and sustained response rates in patients who are refractory or intolerant to rituximab, with acceptable adverse events.

BackgroundThe immune form of thrombotic thrombocytopenic purpura (iTTP) and the hemolytic and uremic syndrome (HUS) are two major forms of thrombotic microangiopathy (TMA). Their treatment has been recently greatly improved. In this new era, both the prevalence and predictors of cerebral lesions occurring during the acute phase of these severe conditions remain poorly known.AimThe prevalence and predictors of cerebral lesions appearing during the acute phase of iTTP and shigatoxin-producingEscherichia coli-HUS or atypical HUS were evaluated in a prospective multicenter study.MethodsUnivariate analysis was performed to report the main differences between patients with iTTP and those with HUS or between patients with acute cerebral lesions and the others. Multivariable logistic regression analysis was used to identify the potential predictors of these lesions.ResultsAmong 73 TMA cases (mean age 46.89 ± 15.99 years (range: 21-87 years) with iTTP (n = 57) or HUS (n= 16), one third presented with acute ischemic cerebral lesions on magnetic resonance imagery (MRI); two individuals also had hemorrhagic lesions. One in ten patients had acute ischemic lesions without any neurological symptom. The neurological manifestations did not differ between iTTP and HUS. In multivariable analysis, 3 factors predicted the occurrence of acute ischemic lesions on cerebral MRI: 1) the presence of old infarcts on cerebral MRI, 2) the level of blood pulse pressure, 3) the diagnosis of iTTP.ConclusionCerebral MRI is crucial to detect both symptomatic and covert ischemic lesions at the acute phase of iTTP and HUS and helps identify patients with old infarcts, at the highest risk of neurological worsening. The diagnosis of iTTP further increases the risk of ischemic lesions but also an increased level of blood pressure that may represent a potential target to further improve the therapeutic management of these conditions.Key points-One third of patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) or the hemolytic uremic syndrome (HUS) present with acute ischemic cerebral lesions on magnetic resonance imagery (MRI);-The cerebral manifestations on MRI did not differ between iTTP and HUS;-The presence of old infarcts on cerebral MRI, the level of blood pulse pressure and a diagnosis of iTTP predict the occurrence of acute ischemic lesions on cerebral MRI.

Gender can influence incidence and clinical course of autoimmune diseases (ADs). Antiphospholipid syndrome (APS) is a rare AD characterised by thromboses and/or pregnancy morbidities and antiphospholipid antibodies (aPL) positivity. Our aim is to conduct a gender-oriented analysis of primary thrombotic APS (t-APS).Consecutive patients diagnosed with primary t-APS, followed from 1967 to 2019 in four European Centres, were enrolled.The cohort included 296 women and 137 men. Median age at onset [31 (24-46) vs. 41 (29-53) years, p0.001] was lower in females. In women, venous thromboses were more frequent while, among males, arterial events prevailed. During follow-up, 14% of patients suffered at least two relapses and this occurred especially among males (22% vs. 10%, p=0.001). No gender differences were found in the aPL profile (33% single, 24% double and 43% triple aPL positivity). Most patients had concomitant risk factors (RFs) for thrombosis: established cardiovascular RFs were represented especially among men while estrogenic exposure was the main RF in women.Women presented mostly with venous thromboses at a younger age, while men with arterial events, later in life and suffered more recurrent events. This different frequency of arterial and venous thromboses could be attributed mainly to the presence of additional RFs rather than to biological gender-specific issues. However, some RFs are exclusive or more represented in one gender rather than the other, so assessing the link of causality between gender and manifestations of t-APS remains difficult.

Background: Takayasu arteritis (TA) is a large vessel vasculitis that may complicate with cerebrovascular ischemic events. The objective was to describe clinical and vascular features of TA patients with cerebrovascular ischemic events and to identify risk factors for these events. Methods: We analyzed the prevalence and type of stroke/transient ischemic attack (TIA), factors associated with cerebrovascular ischemic events, and stroke-free survival in a large cohort fulfilling the American College of Rheumatology or Ishikawa criteria of TA. Results: Among 320 patients with TA (median age at diagnosis, 36 [25–47] years; 261 [86%] women), 63 (20%) had a stroke (n=41; 65%) or TIA (n=22; 35%). Ischemic event localized in the carotid territory for 55 (87%) patients and the vertebral artery territory in 8 (13%) patients. Multiple stenosis were observed in 33 (52%) patients with a median number of stenosis of 2 (minimum, 0 to maximum, 11), and aneurysms were observed in 10 (16%) patients. A history of stroke or TIA before TA diagnosis (hazard ratio [HR], 4.50 [2.45–8.17]; P P =0.05), myocardial infarction history (HR, 0.21 [0.05–0.89]; P =0.039), thoracic aorta involvement (HR, 2.05 [1.30–3.75]; P =0.023), time from first symptoms to diagnosis >1 year (HR, 2.22 [1.30–3.80]; P =0.005), and aspirin treatment (HR, 1.82 [1.04–3.19]; P =0.035) were associated with cerebrovascular ischemic event. In multivariate analysis, time from first symptoms to TA diagnosis >1 year (HR, 2.16 [1.27–3.70]; P =0.007) was independently associated with cerebrovascular ischemic events in patients with TA. The HR for cerebrovascular ischemic event in patients who already experienced a stroke/TIA was 5.11 (2.91–8.99; P Conclusions: Carotid stroke/TIA is frequent in TA. We identified factors associated with cerebrovascular ischemic events.

Thrombin generation assay (TGA) is a useful tool to evaluate the initiation, propagation and inhibition of coagulation. TGA is a global test that is used to assess hemorrhagic risk in hemophilia patients, but it can also be used to study hypercoagulable states. The interest of TGA is to screen for cardiovascular risk, which is regularly associated with autoimmune disease (AID) such as antiphospholipid syndrome. Indeed, TGA has been used to evaluate hypercoagulability in patients with antiphospholipid syndrome treated with rivaroxaban versus warfarin. In other AIDs without thrombotic events, TGA measurement is elevated, mainly in rheumatoid arthritis (RA), systemic lupus erythematosus and Behcet's disease. These findings in RA are correlated with the inflammatory activity of the disease. In systemic lupus erythematosus and Behcet's disease, TGA appears to reflect disease activity. In conclusion, TGA remains relatively under used in the clinical evaluation of AID, but it could play a greater role in the evaluation of certain potentially thrombogenic treatments in AID. Finally, TGA helps measuring AID activity, due to the clearlink between coagulation and inflammation, despite some limitations of interpretation mainly due to a lack of standardization.

PURPOSE To describe the posterior ophthalmic manifestations of catastrophic antiphospholipid syndrome. METHODS Retrospective case series of patients presenting with catastrophic antiphospholipid syndrome and posterior segment ocular manifestations. The main outcomes were the type of posterior segment manifestations at catastrophic antiphospholipid syndrome diagnosis, specifically retinal vascular occlusion, vasculitis, or choroidopathy, and the final best-corrected visual acuity. RESULTS This study included 23 patients (11 cases treated by the authors and 12 published case reports); 21 (91%) of them female. Their median age at diagnosis was 28 years (range, 16-79 years). Ophthalmologic manifestations were usually bilateral (n = 19, 83%) and involved vascular occlusive retinopathy (n = 17, 74%), choroidopathy (n = 11, 48%), or retinal vasculitis (n = 1, 4%). Final best-corrected visual acuity was not significantly worse than the best-corrected visual acuity at diagnosis (P = 0.16). Retinal vascular occlusions were associated with poorer final visual acuity than choroidopathy (P = 0.002). After a median follow-up of 14 months (range, 2-132 months), nearly half the patients (n = 11, 48%) had permanent vision loss including best-corrected visual acuity of

ImportanceCatastrophic antiphospholipid syndrome (CAPS) is a severe, rare complication of antiphospholipid syndrome (APS), but cutaneous involvement has not yet been adequately described.ObjectiveTo describe cutaneous involvement during CAPS, its clinical and pathological features, and outcomes.Design, Setting, and ParticipantsThis cohort study was a retrospective analysis of patients included in the French multicenter APS/systemic lupus erythematosus register (ClinicalTrials.gov: NCT02782039) by December 2020. All patients meeting the revised international classification criteria for CAPS were included, and patients with cutaneous manifestations were analyzed more specifically.Main Outcomes and MeasuresClinical and pathological data as well as course and outcome in patients with cutaneous involvement during CAPS were collected and compared with those in the register without cutaneous involvement.ResultsAmong 120 patients with at least 1 CAPS episode, the 65 (54%) with skin involvement (43 [66%] women; median [range] age, 31 [12-69] years) were analyzed. Catastrophic antiphospholipid syndrome was the first APS manifestation for 21 of 60 (35%) patients with available data. The main lesions were recent-onset or newly worsened livedo racemosa (n = 29, 45%), necrotic and/or ulcerated lesions (n = 27, 42%), subungual splinter hemorrhages (n = 19, 29%), apparent distal inflammatory edema (reddened and warm hands, feet, or face) (n = 15, 23%), and/or vascular purpura (n = 9, 14%). Sixteen biopsies performed during CAPS episodes were reviewed and showed microthrombi of dermal capillaries in 15 patients (94%). These lesions healed without sequelae in slightly more than 90% (58 of 64) of patients. Patients with cutaneous involvement showed a trend toward more frequent histologically proven CAPS (37% vs 24%, P = .16) than those without such involvement, while mortality did not differ significantly between the groups (respectively, 5% vs 9%, P = .47).Conclusions and RelevanceIn this cohort study, half the patients with CAPS showed cutaneous involvement, with a wide spectrum of clinical presentations, including distal inflammatory edema. Skin biopsies confirmed the diagnosis in all but 1 biopsied patient.

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.

Summary Introduction The COVID-19 pandemic is associated with a high incidence of venous thromboembolism questioning the utility of a systematic screening for deep venous thrombosis (DVT) in hospitalised patients. Methods In this prospective bicentric controlled study, 4-point ultrasound using a pocket device was used to screen for DVT, in patients with SARS-CoV-2 infection and controls admitted for acute medical illness not related to COVID-19 hospitalised in general ward, in order to assess the utility of a routine screening and to estimate the prevalence of VTE among those patients. Results Between April and May 2020, 135 patients were screened, 69 in the COVID+ group and 66 in the control one. There was no significant difference in the rate of proximal DVT between the two groups (2.2% vs. 1.5%; P = 0.52), despite the high rate of PE diagnosed among COVID-19 infected patients (10.1% vs. 1.5%, P = 0.063). No isolated DVT was detected, 37.5% of PE was associated with DVT. Mortality (7.2% vs. 1.5%) was not different (P = 0.21) between COVID-19 patients and controls. Conclusion The systematic screening for proximal DVT was not found to be relevant among COVID-19 patients hospitalized in general ward despite the increase of VTE among this population. Further studies are needed to confirm the hypothesis of a local pulmonary thrombosis which may lead to new therapeutic targets.

Resume Le PTT auto-immun (PTTi) est une maladie rare presque constamment fatale en l’absence de traitement. Sa physiopathologie repose sur un deficit fonctionnel severe de la metalloprotease ADAMTS13 (activite

We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC) in 96 adults enrolled in the cohort of the National Reference Center for Thrombotic Microangiopathies network in France during 2009-2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.

Giant cell arteritis is the most common primary vasculitis of large-vessel occurring in subjects over 50 years of age. Many imaging techniques has been evaluated to improve the diagnosis of giant cell arteritis. Among these imaging techniques, ultrasound has shown good performances to detect inflammatory involvement of the temporal arteries as well as branches of the aorta. Several publications and recent EULAR recommendations have emhasized the place of this tool in the diagnosis of giant cell arteritis., L’artérite à cellules géantes est la plus fréquente des vascularites primitives des artères de gros calibre survenant chez les sujets de plus de 50 ans. Plusieurs examens d’imagerie ont été évalués dans le but d’affiner le diagnostic de l’artérite à cellules géantes. Parmi ces techniques, l’écho-doppler a montré de bonnes performances pour dépister une atteinte inflammatoire des artères temporales ainsi que des branches de l’aorte. Plusieurs publications et les récentes recommandations de l’EULAR ont réaffirmé la place de cette technique dans le diagnostic d’artérite à cellules géantes.

Introduction Antiphospholipid syndrome (APS) is associated with greater atherothrombotic risk and endothelial dysfunction, suggesting that endothelial glycocalyx is impaired in this disease. Objectives The aim was to investigate the endothelial glycocalyx and the relationship between glycocalyx markers, endothelial dysfunction parameters and atherosclerotic markers in APS. Methods A total of 15 primary arterial APS patients and healthy controls were included in the study. Glycocalyx was assessed in both groups by sublingual sidestream dark field imaging and syndecan-1 plasma level. Endothelial function was evaluated by brachial artery flow-mediated dilatation (FMD) and early atherosclerosis by carotid intima media thickness (IMT). Thrombotic profile was also performed by measuring the plasma level of the tissue factor (TF). Results APS patients had significantly increased syndecan-1 plasma level 38.6 ± 5.0 pg/ml vs. 19.1 ± 3.5 pg/ml; p Conclusions This preliminary study supports, for the first time, that in APS patients endothelial glycocalyx is impaired, which could lead to thrombosis, endothelial dysfunction and early atherosclerosis.

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.

International audience; Le syndrome de chevauchement polyarthrite rhumatoïde (PR)/sclérodermie systémique (ScS) est une association rare et peu étudiée. Elle concerne 5 % des patients atteints de ScS. Seules des études ouvertes ayant évalué les biomédicaments (bDMARDs) ont rapporté des résultats encourageants, notamment sur l’atteinte articulaire. La prise en charge de ces patients n’est donc pas codifiée. L’objectif était d’analyser en conditions réelles la stratégie thérapeutique et la réponse aux bDMARDS, avec un focus sur l’atteinte articulaire

AIMS: The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment. METHODS AND RESULTS: Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient's opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm. CONCLUSIONS: For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Gemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA). Methods This study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016. Results Twelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4–44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2–22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0–10) before treatment vs 0 (range 0–1) after one injection, P 2 respectively in the eculizumab group and in the control group. Conclusions These results suggest that eculizumab is efficient on haemolysis and reduces transfusion requirement in G-TMA. Moreover, eculizumab may improve renal function recovery.