Iron deficiency in pernicious anemia: Specific features of iron deficient patients and preliminary data on response to iron supplementation.

BACKGROUND & AIMS: While vitamin B12 (B12) deficiency is considered as the hallmark of pernicious anemia (PA), iron deficiency (ID) is also prevalent. Indeed, this auto immune gastritis is responsible for parietal cell atrophy and increase in gastric pH, leading to impaired iron absorption. We compared PA patients' features according to their iron status at PA diagnosis, and we assessed the iron status recovery after oral or intravenous iron supplementation. METHODS: We prospectively included patients presenting with a newly diagnosed PA in a tertiary referral hospital between November 2018 and October 2020. Iron status was assessed at PA diagnosis then regularly during a standardized follow-up. In case of ID, the decision of treatment with oral and/or intravenous iron supplementation was left to the clinician convenience. RESULTS: We included 28 patients with newly diagnosed PA. ID was observed in 21/28 (75.0%) patients: from the PA diagnosis in 13 patients, or during the follow-up in 8 patients. Iron deficient PA patients had higher plasma B12 (p = 0.04) and lower homocysteine levels (p = 0.04). Also, ID was independently associated with the 'APCA (anti-parietal cell antibodies) alone' immunological status (absence of anti-intrinsic factor antibodies) after adjustment for age, gender and B12 level (aOR 12.1 [1.1-141.8], p = 0.04). High level of APCA was associated with lower ferritin level. After 3 months of supplementation, 3/11 PA patients normalized the iron status with oral iron supplementation, versus 7/8 with intravenous iron supplementation (p = 0.02). CONCLUSION: The high frequency of iron deficiency in PA highlights the interest of regular assessment of iron status in this condition. ID was associated with a profile including APCA alone and less pronounced B12 deficiency. Intravenous iron supplementation seemed to be more efficient than an oral supplementation in these preliminary data.

Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants.

BACKGROUND: The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear. OBJECTIVE: We sought to assess a potential link between HLHa outcomes and HLH-related gene variants. METHODS: Clinical characteristics of 130 HLHa patients (age ≥ 18 years and HScore ≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. A total of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit. RESULTS: HLHa-associated diseases (ADs) were neoplasia (n = 49 [37.7%]), autoimmune/inflammatory disease (n = 33 [25.4%]), or idiopathic when no AD was identified (n = 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P = .0008; 2-3 vs 0: 29.4 [3.62-3810], P = .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P = .018; 2-3 vs 0: 13.2 [2.91-126.8], P = .0003). CONCLUSIONS: HLH-related gene variants may be key components to the severity and refractoriness of HLHa.

An immuno-lipidomic signature revealed by metabolomic and machine-learning approaches in labial salivary gland to diagnose primary Sjögren's syndrome.

Introduction: Assessing labial salivary gland exocrinopathy is a cornerstone in primary Sjögren's syndrome. Currently this relies on the histopathologic diagnosis of focal lymphocytic sialadenitis and computing a focus score by counting lym=phocyte foci. However, those lesions represent advanced stages of primary Sjögren's syndrome, although earlier recognition of primary Sjögren's syndrome and its effective treatment could prevent irreversible damage to labial salivary gland. This study aimed at finding early biomarkers of primary Sjögren's syndrome in labial salivary gland combining metabolomics and machine-learning approaches. Methods: We used a standardized targeted metabolomic approach involving high performance liquid chromatography coupled with mass spectrometry among newly diagnosed primary Sjögren's syndrome (n=40) and non- primary Sjögren's syndrome sicca (n=40) participants in a prospective cohort. A metabolic signature predictive of primary Sjögren's syndrome status was explored using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the data set into training, validation, and test sets. Results: Among 126 metabolites accurately measured, we identified a discriminant signature composed of six metabolites with robust performances (ROC-AUC = 0.86) for predicting primary Sjögren's syndrome status. This signature included the well-known immune-metabolite kynurenine and five phospholipids (LysoPC C28:0; PCaa C26:0; PCaaC30:2; PCae C30:1, and PCaeC30:2). It was split into two main components: the first including the phospholipids was related to the intensity of lymphocytic infiltrates in salivary glands, while the second represented by kynurenine was independently associated with the presence of anti-SSA antibodies in participant serum. Conclusion: Our results reveal an immuno-lipidomic signature in labial salivary gland that accurately distinguishes early primary Sjögren's syndrome from other causes of sicca symptoms.

The relevance of pacing strategies in managing symptoms of post-COVID-19 syndrome.

BACKGROUND: Post-COVID-19 syndrome (PCS) shares many features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PCS represents a major health issue worldwide because it severely impacts patients' work activities and their quality of life. In the absence of treatment for both conditions and given the beneficial effect of pacing strategies in ME/CFS, we conducted this study to assess the effectiveness of pacing in PCS patients. METHODS: We retrospectively included patients meeting the World Health Organization definition of PCS who attended the Internal Medicine Department of Angers University Hospital, France between June 2020 and June 2022, and were followed up until December 2022. Pacing strategies were systematically proposed for all patients. Their medical records were reviewed and data related to baseline and follow-up assessments were collected. This included epidemiological characteristics, COVID-19 symptoms and associated conditions, fatigue features, perceived health status, employment activity, and the degree of pacing adherence assessed by the engagement in pacing subscale (EPS). Recovery was defined as the ability to return to work, and improvement was regarded as the reduction of the number and severity of symptoms. RESULTS: A total of 86 patients were included and followed-up for a median time of 10 [6-13] months. Recovery and improvement rates were 33.7% and 23.3%, respectively. The EPS score was the only variable significantly associated with recovery on multivariate analysis (OR 40.43 [95% CI 6.22-262.6], p < 0.001). Patients who better adhered to pacing (high EPS scores) experienced significantly higher recovery and improvement rates (60-33.3% respectively) than those with low (5.5-5.5% respectively), or moderate (4.3-17.4% respectively) scores. CONCLUSION: Our findings demonstrated that pacing is effective in the management of patients with PCS, and that high levels of adherence to pacing are associated with better outcomes.

Identifying high-risk profile in primary antiphospholipid syndrome through cluster analysis: French multicentric cohort study.

INTRODUCTION: Antiphospholipid syndrome (APS) is an autoimmune disease characterised by thrombosis (arterial, venous or small vessel) or obstetrical events and persistent antiphospholipid antibodies (aPL), according to the Sydney classification criteria. Many studies have performed cluster analyses among patients with primary APS and associated autoimmune disease, but none has focused solely on primary APS. We aimed to perform a cluster analysis among patients with primary APS and asymptomatic aPL carriers without any autoimmune disease, to assess prognostic value. METHODS: In this multicentre French cohort study, we included all patients with persistent APS antibodies (Sydney criteria) measured between January 2012 and January 2019. We excluded all patients with systemic lupus erythematosus or other systemic autoimmune diseases. We performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with baseline patient characteristics to generate clusters. RESULTS: We identified four clusters: cluster 1, comprising 'asymptomatic aPL carriers', with low risk of events during follow-up; cluster 2, the 'male thrombotic phenotype', with older patients and more venous thromboembolic events; cluster 3, the 'female obstetrical phenotype', with obstetrical and thrombotic events; and cluster 4, 'high-risk APS', which included younger patients with more frequent triple positivity, antinuclear antibodies, non-criteria manifestations and arterial events. Regarding survival analyses, asymptomatic aPL carriers relapsed less frequently than the others, but no other differences in terms of relapse rates or deaths were found between clusters. CONCLUSIONS: We identified four clusters among patients with primary APS, one of which was 'high-risk APS'. Clustering-based treatment strategies should be explored in future prospective studies.

Prognostic factors in giant cell arteritis associated aortitis with PET/CT and CT angiography at diagnosis.

BACKGROUND: Prognosis data on giant-cell arteritis (GCA)-associated aortitis are scarce and heterogeneous. The aim of this study was to compare the relapses of patients with GCA-associated aortitis according to the presence of aortitis on CT-angiography (CTA) and/or on FDG-PET/CT. METHODS: This multicenter study included GCA patients with aortitis at diagnosis; each case underwent both CTA and FDG-PET/CT at diagnosis. A centralized review of image was performed and identified patients with both CTA and FDG-PET/CT positive for aortitis (Ao-CTA+/PET+); patients with positive FDG-PET/CT but negative CTA for aortitis (Ao-CTA-/PET+), and patients solely positive on CTA. RESULTS: Eighty-two patients were included with 62 (77%) of female sex. Mean age was 67±8 years; 64 patients (78%) were in the Ao-CTA+/PET+ group; 17 (22%) in the Ao-CTA-/PET+ group and 1 had aortitis only on CTA. Overall, 51 (62%) patients had at least one relapse during follow-up: 45/64 (70%) in the Ao-CTA+/PET+ group and 5/17 (29%) in the Ao-CTA-/PET+ group (log rank, p = 0.019). In multivariate analysis, aortitis on CTA (Hazard Ratio 2.90, p = 0.03) was associated with an increased risk of relapse. CONCLUSION: Positivity of both CTA and FDG-PET/CT for GCA-related aortitis was associated with an increased risk of relapse. Aortic wall thickening on CTA was a risk factor of relapse compared with isolated aortic wall FDG uptake.

Accurate stratification between VEXAS syndrome and differential diagnoses by deep learning analysis of peripheral blood smears.

OBJECTIVES: VEXAS syndrome is a newly described autoinflammatory disease associated with UBA1 somatic mutations and vacuolization of myeloid precursors. This disease possesses an increasingly broad spectrum, leading to an increase in the number of suspected cases. Its diagnosis via bone-marrow aspiration and UBA1-gene sequencing is time-consuming and expensive. This study aimed at analyzing peripheral leukocytes using deep learning approaches to predict VEXAS syndrome in comparison to differential diagnoses. METHODS: We compared leukocyte images from blood smears of three groups: participants with VEXAS syndrome (identified UBA1 mutation) (VEXAS); participants with features strongly suggestive of VEXAS syndrome but without UBA1 mutation (UBA1-WT); participants with a myelodysplastic syndrome and without clinical suspicion of VEXAS syndrome (MDS). To compare images of circulating leukocytes, we applied a two-step procedure. First, we used self-supervised contrastive learning to train convolutional neural networks to translate leukocyte images into lower-dimensional encodings. Then, we employed support vector machine to predict patients' condition based on those leukocyte encodings. RESULTS: The VEXAS, UBA1-WT, and MDS groups included 3, 3, and 6 patients respectively. Analysis of 33,757 images of neutrophils and monocytes enabled us to distinguish VEXAS patients from both UBA1-WT and MDS patients, with mean ROC-AUCs ranging from 0.87 to 0.95. CONCLUSIONS: Image analysis of blood smears via deep learning accurately distinguished neutrophils and monocytes drawn from patients with VEXAS syndrome from those of patients with similar clinical and/or biological features but without UBA1 mutation. Our findings offer a promising pathway to better screening for this disease.

Efficacy and safety of anakinra in adults presenting deteriorating respiratory symptoms from COVID-19: A randomized controlled trial.

OBJECTIVE: We aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients. METHODS: In this controlled, open-label trial, we enrolled adults with COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation. RESULTS: Between 27th April and 6th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference-21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89). CONCLUSION: This trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.

Intravenous Immunoglobulins Tapering and Withdrawal in Systemic Capillary Leak Syndrome (Clarkson Disease).

BACKGROUND: The systemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a very rare condition characterized by recurrent life-threatening episodes of vascular hyperpermeability in the presence of a monoclonal gammopathy. Extended intravenous immunoglobulin (IVIG) treatment is associated with fewer recurrences and improved survival, but the optimal treatment dosage and duration remain unknown. OBJECTIVE: We aim to evaluate the safety of IVIG tapering and withdrawal in patients with SCLS. METHODS: We conducted a retrospective multicenter study including all adult patients with monoclonal gammopathy-associated SCLS from the EurêClark registry who received at least 1 course of IVIG. The primary end point was overall survival according to IVIG withdrawal. RESULTS: Fifty-nine patients of mean ± SD age 51 ± 13 years were included. Overall cumulative probabilities of 2-, 5-, 10- and 15-year survival were 100%, 85%, 72%, 44%, respectively. The IVIG was withdrawn at least once in 18 patients (31%; W+ group) and never in 41 patients (69%; W- group). Cumulative probabilities of 10-year survival in W+ versus W- groups were 50% and 83% (log rank test, P = .02), respectively. Relapse rate and the median number of relapses in the W+ versus the W- groups were 72% versus 58% (P = 0.3) and 2.5 (0.3-4) versus 1 (0-2) (P = .03), respectively. The IVIG tapering was not statistically associated with increased person-year incidence of attacks using a mixed linear model. CONCLUSIONS: The IVIG withdrawal was associated with increased mortality and higher rate of recurrence in SCLS patients. The IVIG tapering might be cautiously considered in stable SCLS patients.

Diagnostic and Therapeutic Perspectives Associated to Cobalamin-Dependent Metabolism and Transcobalamins' Synthesis in Solid Cancers.

Cobalamin or vitamin B12 (B12) is a cofactor for methionine synthase and methylmalonyl-CoA mutase, two enzymes implicated in key pathways for cell proliferation: methylation, purine synthesis, succinylation and ATP production. Ensuring these functions in cancer cells therefore requires important cobalamin needs and its uptake through the transcobalamin II receptor (TCII-R). Thus, both the TCII-R and the cobalamin-dependent metabolic pathways constitute promising therapeutic targets to inhibit cancer development. However, the link between cobalamin and solid cancers is not limited to cellular metabolism, as it also involves the circulating transcobalamins I and II (TCI or haptocorrin and TCII) carrier proteins, encoded by TCN1 and TCN2, respectively. In this respect, elevations of B12, TCI and TCII concentrations in plasma are associated with cancer onset and relapse, and with the presence of metastases and worse prognosis. In addition, TCN1 and TCN2 overexpressions are associated with chemoresistance and a proliferative phenotype, respectively. Here we review the involvement of cobalamin and transcobalamins in cancer diagnosis and prognosis, and as potential therapeutic targets. We further detail the relationship between cobalamin-dependent metabolic pathways in cancer cells and the transcobalamins' abundancies in plasma and tumors, to ultimately hypothesize screening and therapeutic strategies linking these aspects.

Distinction between clonal and paraclonal cutaneous involvements in VEXAS syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) syndrome is an inflammatory disorder with hematological and systemic features. A recent study demonstrated that the dermal infiltrate in neutrophilic dermatosis from VEXAS patients is derived from the pathological UBA1-mutated myeloid clone. Neutrophilic dermatosis is, however, only one of the various skin involvements observed in VEXAS syndrome. We analyzed 10 formalin-fixed paraffin-embedded skin biopsies from genetically confirmed VEXAS syndrome. UBA1 mutation was found in the biopsies related to neutrophilic dermatitis but in none of the other histological patterns (leukocytoclastic vasculitis and septal panniculitis). This could lead to a distinction between clonal and paraclonal cutaneous involvements in VEXAS syndrome, which could in turn improve therapeutic outcomes.

A Tear Metabolomic Profile Showing Increased Ornithine Decarboxylase Activity and Spermine Synthesis in Thyroid-Associated Orbitopathy.

About half of patients with Graves' disease develop an orbitopathy related to an inflammatory expansion of the periorbital adipose tissue and muscles. We used a targeted metabolomic approach measuring 188 metabolites by mass spectrometry to compare the metabolic composition of tears in patients with active (n = 21) versus inactive (n = 24) thyroid-associated orbitopathy. Among the 44 metabolites accurately measured, 8 showed a significant alteration of their concentrations between the two groups. Two short-chain acylcarnitines, propionylcarnitine and butyrylcarnitine, and spermine showed increased concentrations in the tears of patients with active orbitopathy, whereas ornithine, glycine, serine, citrulline and histidine showed decreased concentrations in this group. In addition, the ratio putrescine/ornithine, representing the activity of ornithine decarboxylase, was significantly increased in patients with active compared to inactive orbitopathy (p = 0.0011, fold change 3.75). The specificity of this candidate biomarker was maintained when compared to a control group with unclassified dry eye disease. Our results suggest that the stimulation of ornithine decarboxylase by TSH receptor autoantibodies in orbital fibroblasts could lead to increased synthesis of spermine, through the increased activity of ornithine decarboxylase, that may contribute to periorbital expansion in Graves' ophthalmopathy.

Non-criteria manifestations in primary antiphospholipid syndrome: a French multicenter retrospective cohort study.

BACKGROUND: From this retrospective study, we aimed to (1) describe the prevalence and characteristics of non-criteria features in primary antiphospholipid syndrome (p-APS) and (2) determine their prognostic value. METHODS: This retrospective French multicenter cohort study included all patients diagnosed with p-APS (Sydney criteria) between January 2012 and January 2019. We used Kaplan-Meier and adjusted Cox proportional hazards models to compare the incidence of relapse in p-APS with and without non-criteria manifestations. RESULTS: One hundred and seventy-nine patients with p-APS were included during the study time, with a median age of 52.50 years [39.0; 65.25] and mainly women (n = 112; 62.6%). Among them, forty-three patients (24.0%) presented at least one non-criteria manifestation during the follow-up: autoimmune cytopenias (n = 17; 39.5%), Libman Sachs endocarditis (n = 5; 11.6%), APS nephropathy (n = 4; 9.3%), livedo reticularis (n = 8; 18.6%), and neurological manifestations (n = 12; 27.9%). In comparison to p-APS without any non-criteria manifestations (n = 136), p-APS with non-criteria features had more arterial thrombosis (n = 24; 55.8% vs n = 48; 35.3%; p = 0.027) and more frequent pre-eclampsia (n = 6; 14.3% vs n = 4; 3.1%; p = 0.02). The prevalence of triple positivity was significantly increased in patients with non-criteria features (n = 20; 47.6% vs n = 25; 19.8%; p = 0.001). Patients with p-APS and non-criteria manifestations (n = 43) received significantly more additional therapies combined with vitamin K antagonists and/or antiaggregants. Catastrophic APS (CAPS) tended to be more frequent in p-APS with non-criteria features (n = 2; 5.1% vs none; p = 0.074). The p-APS with non-criteria manifestations had significantly increased rates of relapse (n = 20; 58.8% vs 33; 33.7%; p = 0.018) in bivariate analysis, but in survival analyses, the hazard ratio (HR) of relapse was not significantly different between the two groups (HR at 1.34 [0.67; 2.68]; p = 0.40). CONCLUSIONS: The presence of non-criteria features is important to consider, as they are associated with particular clinical and laboratory profiles, increased risk of relapse, and need for additional therapies. Prospective studies are necessary to better stratify the prognosis and the management of p-APS.

Clinical phenotype and cytokine profile of adult IgA vasculitis with joint involvement.

OBJECTIVE: Joint involvement can be observed during the course of adult IgA vasculitis (IgAV). However, clinical picture, prognosis, or pathophysiological data associated with this condition have been overlooked. We aimed to describe the clinical characteristics and outcome of IgAV patients with joint involvement and look to a specific cytokine profile. METHODS: We analyzed clinical and biological data from a nationwide study that included adult IgAV patients. Presentation and outcomes of patients with or without joint involvement were compared at baseline and during follow-up. Plasma cytokine measurements of IgAV patients included in a prospective study were also analyzed using multiplex assays. RESULTS: Among 260 patients, 62% had joint involvement. Among them, rheumatological manifestations included arthralgia (100%) or arthritis (16%), mostly involving the knees and ankles. In multivariate analysis, patients with joint involvement, compared to those without, were younger (p = 0.002; OR 0.87; 95% CI 0.80-0.95) and showed more frequent gastrointestinal tract involvement (p = 0.012; OR = 2.08; 95% CI 1.18-3.67). However, no difference in terms of clinical response, relapse, end-stage renal disease, or death was observed between groups. Among 13 cytokines measured, plasma interleukin (IL)-1ß level was higher in patients with joint involvement compared to those without (mean ± SEM IL-1ß, 3.5 ± 1.2 vs. 0.47 ± 0.1 pg/ml; p = 0.024) or healthy controls (vs. 1.2 ± 0.5 pg/ml; p = 0.076). CONCLUSION: Joint involvement is frequent in adult IgAV and is associated with more frequent gastrointestinal involvement. Increased plasma IL-1ß levels raise the question of targeting this cytokine in patients with chronic and/or refractory joint involvement. Key Points • Joint involvement in adult IgAV is a frequent manifestation. • Joint involvement is associated with more frequent gastrointestinal manifestations. • Interleukin-1ß (IL-1ß) might orchestrate joint inflammation in adult IgAV. • IL-1ß might be a therapeutic target in patients with chronic and/or refractory joint involvement.

Discordant Predictions of Extraglandular Involvement in Primary Sjögren's Syndrome According to the Anti-SSA/Ro60 Antibodies Detection Assay in a Cohort Study.

Electrophoresis-derived techniques for anti-SSA/Ro60 KDa (anti-SSA) antibodies detection have been progressively replaced by methods using non-native antigens. We aimed to compare the patients' phenotypes and the occurrence of extraglandular manifestations in primary Sjögren's syndrome according to the method used to detect anti-SSA antibodies. Sera from patients with a diagnosis of pSS according to ACR/EULAR 2016 criteria between 2008 and 2017 were tested for anti-SSA antibodies using methods with non-native antigens (magnetic bead multiplex assay; line immunoassays) and one with native antigens (counterimmunoelectrophoresis (CIE)). The population was split into three groups according to anti-SSA antibodies status: absence (SSA-), presence in any method except for CIE (SSA+CIE-), and presence in CIE (SSA+CIE+). The patients in the SSA+CIE+ group (n = 70, 42.7%) were ten years younger and presented more immunological activity compared with both the SSA- (n = 80, 48.8%) and SSA+CIE- groups (n = 14, 8.5%). The SSA- and SSA+CIE- groups were poorly distinct. The presence of anti-SSA antibodies solely in CIE was significantly associated with the occurrence of extraglandular manifestations of pSS (HR = 4.45 (2.35-8.42)). Contrary to CIE, methods using non-native antigens to detect anti-SSA antibodies were unable to predict the occurrence of systemic expression of pSS.

Characterisation of a high-risk profile for maternal thrombotic and severe haemorrhagic complications in pregnant women with antiphospholipid syndrome in France (GR2): a multicentre, prospective, observational study.

BACKGROUND: Prospective data about the risks of thrombotic and severe haemorrhagic complications during pregnancy and post partum are unavailable for women with antiphospholipid syndrome. We aimed to assess thrombotic and haemorrhagic events in a prospective cohort of pregnant women with antiphospholipid syndrome. METHODS: This multicentre, prospective, observational study was done at 76 centres in France. To be eligible for this study, women had to have diagnosis of antiphospholipid syndrome; have conceived before April 17, 2020; have an ongoing pregnancy that had reached 12 weeks of gestation; and be included in the study before 18 weeks of gestation. Exclusion criteria were active systemic lupus erythematosus nephropathy, or a multifetal pregnancy. Severe haemorrhage was defined as the need for red blood cell transfusion or maternal intensive care unit admission because of bleeding or invasive procedures, defined as interventional radiology or surgery, to control bleeding. The GR2 study is registered with ClinicalTrials.gov, NCT02450396. FINDINGS: Between May 26, 2014, and April 17, 2020, 168 pregnancies in 27 centres met the inclusion criteria for the study. 89 (53%) of 168 women had a history of thrombosis. The median term at inclusion was 8 weeks gestation. 16 (10%) of 168 women (95%CI 5-15) had a thrombotic (six [4%] women; 95% CI 1-8) or severe haemorrhagic event (12 [7%] women; 95% CI 4-12). There were no deaths during the study. The main risk factors for thrombotic events were lupus anticoagulant positivity at inclusion (six [100%] of six women with thrombosis vs 78 [51%] of 152 of those with no thrombosis; p=0·030) and placental insufficiency (four [67%] of six women vs 28 [17%] of 162 women; p=0·013). The main risk factors for severe haemorrhagic events were pre-existing maternal hypertension (four [33%] of 12 women vs 11 [7%] of 156 women; p=0·014), lupus anticoagulant positivity at inclusion (12 [100%] of 12 women vs 72 [49%] of 146 women; p<0·0001) and during antiphospholipid history (12 [100%] of 12 women vs 104 [67%] of 156 women; p=0·019), triple antiphospholipid antibody positivity (eight [67%] of 12 women vs 36 [24%] of 147 women; p=0·0040), placental insufficiency (five [42%] of 12 women vs 27 [17%] of 156 women; p=0·038), and preterm delivery at 34 weeks or earlier (five [45%] of 11 women vs 12 [8%] of 145 women; p=0·0030). INTERPRETATION: Despite treatment adhering to international recommendations, a proportion of women with antiphospholipid syndrome developed a thrombotic or severe haemorrhagic complication related to pregnancy, most frequently in the post-partum period. Lupus anticoagulant and placental insufficiency were risk factors for these life-threatening complications. These complications are difficult to prevent, but knowledge of the antenatal characteristics associated with them should increase awareness and help physicians manage these high-risk pregnancies. FUNDING: Lupus France, association des Sclérodermiques de France, association Gougerot Sjögren, Association Francophone contre la Polychondrite chronique atrophiante, AFM-Telethon, the French Society of Internal Medicine and Rheumatology, Cochin Hospital, the French Health Ministry, FOREUM, the Association Prix Veronique Roualet, and UCB.

Evolution of plasma vitamin B12 in patients with solid cancers during curative versus supportive care.

INTRODUCTION: The direction of the causal link between solid cancers and elevated plasma vitamin B12 (B12) remains uncertain. METHODS: We retrospectively included patients having two B12 measurements with a B12 initially ≥ 1000 ng/l and a solid cancer diagnosed between the measurements. Patients were included in the Curative or Supportive group according to their treatments. RESULTS: B12 changes over time differed between groups (p = 0.001): +157.4 ng/l/month in the Supportive care group versus -171.6 ng/l/month in the Curative care group. CONCLUSIONS: The decrease of plasma B12 in cases of curative care could suggest that this B12 elevation is secondary to solid cancers.