Surgery in rare bleeding disorders: the prospective MARACHI study.

Background: Despite the wide use of bleeding scores and the reliability of clotting factor level measurement, bleeding risk stratification before surgery remains challenging in patients with rare inherited bleeding disorders. Objectives: This multicenter observational prospective study assessed in patients with rare coagulation factor deficiency, the perioperative hemostatic management choices by hemostasis experts and the bleeding outcomes after surgery. Methods: One hundred seventy-eight patients with low coagulation activity level (factor [F] II, FV, combined FV-FVIII, FVII, FX, or FXI <50%) underwent 207 surgical procedures. The bleeding outcome, Tosetto's bleeding score, and perioperative hemostatic protocols were collected. Results: Among the 81 procedures performed in patients with severe factor deficiency (level ≤10%), 27 were done without factor replacement (including 6 in patients at high bleeding risk), without any bleeding event. Factor replacement therapy was used mainly for orthopedic procedures. In patients with mild deficiency, 100/126 surgical procedures were carried out without perioperative hemostatic treatment. In patients with FVII or FXI deficiency, factor replacement therapy was in function of the procedure, bleeding risk, and to a lesser extent previous bleeding history. Tranexamic acid was used in almost half of the procedures, particularly in case of surgery in tissues with high fibrinolytic activity (76.8%). Conclusions: The current perioperative hemostatic management of patients with rare bleeding disorders appears to be adapted. Among the 207 procedures, only 6 were associated with excessive bleeding. Our findings suggest that rather than the bleeding score, factor level and surgery type are the most relevant criteria for perioperative factor replacement therapy.

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.

Presentation and Real-World Management of Giant Cell Arteritis (Artemis Study).

Background: Few studies of daily practice for patients with giant cell arteritis (GCA) are available. This French study aimed to describe the characteristics and management of GCA in a real-life setting. Methods: Cross-sectional, non-interventional, multicenter study of patients ≥50 years old who consulted hospital-based specialists for GCA and were under treatment. Patient characteristics and journey, diagnostic methods and treatments were collected. Descriptive analyses were performed. Results: In total, 306 patients (67% females, mean age 74 ± 8 years old) were recruited by 69 physicians (internists: 85%, rheumatologists: 15%); 13% of patients had newly diagnosed GCA (diagnosis-to-visit interval <6 weeks). Overall median disease duration was 13 months (interquartile range 5-26). Most patients were referred by general practitioners (56%), then ophthalmologists (10%) and neurologists (7%). Most common comorbidities were hypertension (46%), psychiatric disorders (10%), dyslipidemia (12%), diabetes (9%), and osteoporosis (6%). Initial GCA presentations included cranial symptoms (89%), constitutional symptoms (74%), polymyalgia rheumatica (48%), and/or other extra-cranial manifestations (35%). Overall, 85, 31, 26, and 30% of patients underwent temporal artery biopsy, high-resolution temporal artery Doppler ultrasonography, 18FDG-PET, and aortic angio-CT, respectively. All patients received glucocorticoids, which were ongoing for 89%; 29% also received adjunct medication(s) (methotrexate: 19%, tocilizumab: 15%). A total of 40% had relapse(s); the median time to the first relapse was 10 months. Also, 37% had comorbidity(ies) related to or aggravated by glucocorticoids therapy. Conclusion: This large observational study provides insight into current medical practices for GCA. More than one third of patients had comorbidities related to glucocorticoid therapy for a median disease duration of 13 months. Methotrexate and tocilizumab were the most common adjunct medications.

DADA2 diagnosed in adulthood versus childhood: A comparative study on 306 patients including a systematic literature review and 12 French cases.

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease usually presenting before the age of 10 years. Non-specific clinical features or late-onset presentation may delay its diagnosis until adulthood. OBJECTIVE: To determine whether DADA2 diagnosed in adulthood is associated with specific characteristics compared to DADA2 diagnosed in childhood. METHODS: We pooled a cohort of 12 adult DADA2 patients followed in France with cases identified through a systematic literature review. For each patient, we determined the type of clinical presentation and assessed six key organ involvements. RESULTS: A total of 306 cases were included. Among the 283 patients with available data regarding age at diagnosis, 140 were diagnosed during adulthood and 143 during childhood. The vascular presentation of DADA2 was more frequent in the adult diagnosis group (77.9% vs. 62.9%, p < 0.01), whereas the hematological presentation (bone marrow failure) prevailed in the pediatric diagnosis group (10.0% vs. 20.3% p = 0.02). In patients with vasculopathy, severe skin manifestations developed in 35% and 10% of the adult and pediatric diagnosis groups, respectively. Conversely, fewer strokes occurred in the adult group presenting with systemic vasculopathy (54% vs. 81%). Symptomatic humoral immune deficiency (HID) was rarely a clinical presentation in itself (5% and 2.8%) but accompanied other phenotypes of DADA2, especially the hematological phenotype in the adult group (33% vs. 4%). CONCLUSION: DADA2 diagnosed in adulthood presents more often with a vascular phenotype and less often with bone marrow failure than DADA2 diagnosed in childhood. Adults diagnosed with DADA2 vasculopathy display more severe skin involvement but fewer strokes.

Assessment of the efficacy and safety of tocilizumab in patients over 80 years old with giant cell arteritis.

OBJECTIVE: To assess the efficacy and tolerance of tocilizumab (TCZ) in giant cell arteritis (GCA) patients over 80. METHOD: GCA patients over 80 years old from the French Study Group for Large Vessel Vasculitis register who received TCZ were analyzed. RESULTS: Twenty-one GCA patients (median age 84 [81-90] years old, including nine over 85) received TCZ for the following nonexclusive reasons: glucocorticoid (GC)-sparing effect in 14, relapsing disease in 8, disease severity in 4, and/or failure of another immunosuppressant in 4. TCZ was introduced with GCs at diagnosis in 6 patients and at 8 [3-37] months after GC initiation in 15 others. After a median delay of 8 [2-21] months post-TCZ introduction, 14 (67%) patients were able to definitively stop GCs, including 6 who were GC-dependent before TCZ. At the last follow-up (median 20 [3-48] months), 11 (52%) patients had definitively stopped TCZ, and 2 additional patients had stopped but relapsed and resumed TCZ. Seven (33%) patients experienced 11 adverse events: hypercholesterolemia in 4 patients; infections, i.e., pyelonephritis, bronchitis, and fatal septic shock associated with mesenteric infarction following planned surgery (GCs were stopped for 1 year and TCZ infusions for 2 months), respectively, in 3 patients; moderate thrombocytopenia and moderate neutropenia in 2 patients; and a 5-fold increase in transaminase levels in another that improved after TCZ dose reduction. CONCLUSION: TCZ remains a valuable GC-sparing option in the oldest GCA patients with an interesting risk-benefit ratio. Mild-to-moderate adverse events were observed in one-third of patients.

Giant cell arteritis-related aortic dissection: A multicenter retrospective study.

PURPOSE: To describe characteristics and outcomes of patients with giant cell arteritis (GCA)-related aortic dissection. PATIENTS AND METHODS: We retrospectively included, through a nationwide GCA network, all patients who had an aortic dissection either revealing GCA or occurring during follow-up. RESULTS: A total of 46 patients were included in this study. Aortic dissection was inaugural and led to GCA diagnosis in 21 patients, whereas it occurred during follow-up in the 25 others, at a median of 53 [1-265] months after GCA diagnosis. Large-vessel vasculitis (LVV) was diagnosed through imaging before or at the time of aortic dissection in 31 (67%) patients. In patients who developed an aortic dissection during follow-up, the aortic event occurred 22 [1-143] months post GCA diagnosis in the patients with previous aortitis, whereas it occurred after 72 [19-265] months in patients without previously diagnosed aortitis (p = 0.005). Aortic surgery was performed in 27 (59%) patients and 23 of them survived. A total of 15 (32%) patients died following the aortic dissection, including 11 who were not operated on. In a multivariate analysis, aortic surgery was the single predictor of survival (HR: 4.3; 95% CI: 1.47- 15.7; p = 0.007). CONCLUSION: Patients with prior LVV are more prone to develop early aortic dissection and require close monitoring of aortic morphology. One third of patients died from the aortic dissection. Surgery remains the best predictive factor for survival.

Orbital non-HIV immune reconstitution inflammatory syndrome after cytapheresis.

The immune reconstitution inflammatory syndrome is a phenomenon typically described in HIV patient during the restoration of CD4 count after highly active antiretroviral therapy. Non-HIV immune reconstitution inflammatory syndrome has also been described after organ transplantation or immune recovery in neutropenic patients. We report the case of a 50-year-old man who presented to our department with left painful proptosis and ophthalmoplegia 2 days after having performed cytapheresis for a mantel cell lymphoma. Systemic work up and biopsy were performed and symptoms were relieved with intravenous steroids therapy. To our knowledge, this is the first case of orbital non-HIV immune reconstitution inflammatory syndrome described in the literature.

Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases.

OBJECTIVES: The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease. METHODS: To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data. RESULTS: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis. CONCLUSION: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

Evaluating the cost-consequence of a standardized strategy for the etiological diagnosis of uveitis (ULISSE study).

MAIN OBJECTIVE: To prospectively assess the cost-consequence of a standardized diagnostic strategy as to compared to an open one for the etiological diagnosis of uveitis. DESIGN: This was a prospective, non-inferiority, multicentre, randomized controlled trial. METHODS: We included all consecutive patients with uveitis who had visited at least one of the Departments of Ophthalmology. In the standardized group, patients had a minimal work-up regardless of the type of uveitis (including evaluation of the CBC, ESR, C-reactive protein, tuberculin skin test, syphilis serology and chest X-ray). Depending on ophthalmological findings, further investigations could be performed. In the open strategy, ophthalmologists were free to order any kind of investigation. The main outcome was the mean cost per patient of each strategy. RESULTS: 903 uveitis patients were included from January, 2010 to May, 2013. The mean cost per patient of the standardized strategy was 182.97 euros [CI 95% (173.14; 192.80)], and the mean cost per patient of the open strategy was 251.75 euros [CI 95% (229.24; 274.25)]. Therefore, the mean cost per patient of the standardized strategy was significantly lower than the mean cost per patient of the open strategy (p<0.001). There were significantly fewer visits (p<0.001), fewer radiological procedures (p<0.004) and fewer laboratory investigations (p<0.001) in the standardized group. CONCLUSION: A standardized strategy is a cost-saving approach for the etiological diagnosis of uveitis.

Clinical presentation, treatment and outcome of IgG4-related pachymeningitis: From a national case registry and literature review.

Pachymeningitis is rare, either idiopathic or secondary to inflammatory disorders, after tumoral, surgical or infectious causes have been excluded. The fibroinflammatory IgG4-related disease is one of the etiologies of pachymeningitis with only few cases reported yet. From a single referral regional center, we evaluated the frequency of IgG4-related disease as the cause of inflammatory pachymeningitis in 10% of cases. From a National case registry of IgG4-related disease the pachymeningitis frequency was 4.1%. We report eight new cases with cranial, spinal or both involvements and a literature review of 46 pathological proven cases. We observed that IgG4-related pachymeningitis is in most cases not associated to extra-neurological manifestations of the disease. Only 27% of spinal and 40% of cranial IgG4-related pachymeningitis are associated with other disease localizations. First line treatment strategies included surgery and steroids. The use of immunosuppressants or rituximab was necessary in 18% of spinal and 54% of cranial localizations. Some patients remained with sequellae and clinical and/or radiological improvement can be difficult to obtain.

A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience.

Deficiency of adenosine deaminase 2 (DADA2) is a recently described autoinflammatory disorder. Genetic analysis is required to confirm the diagnosis. We aimed to describe the identifying symptoms and genotypes of patients referred to our reference centres and to improve the indications for genetic testing. DNA from 66 patients with clinically suspected DADA2 were sequenced by Sanger or next-generation sequencing. Detailed epidemiological, clinical and biological features were collected by use of a questionnaire and were compared between patients with and without genetic confirmation of DADA2. We identified 13 patients (19.6%) carrying recessively inherited mutations in ADA2 that were predicted to be deleterious. Eight patients were compound heterozygous for mutations. Seven mutations were novel (4 missense variants, 2 predicted to affect mRNA splicing and 1 frameshift). The mean age of the 13 patients with genetic confirmation was 12.7 years at disease onset and 20.8 years at diagnosis. Phenotypic manifestations included fever (85%), vasculitis (85%) and neurological disorders (54%). Features best associated with a confirmatory genotype included fever with neurologic or cutaneous attacks (odds ratio [OR] 10.71, p = 0.003 and OR 10.9, p < 0.001), fever alone (OR 8.1, p = 0.01), and elevated C-reactive protein (CRP) level with neurologic involvement (OR 6.63, p = 0.017). Our proposed decision tree may help improve obtaining genetic confirmation of DADA2 in the context of autoinflammatory symptoms. Prerequisites for quick and low-cost Sanger analysis include one typical cutaneous or neurological sign, one marker of inflammation (fever or elevated CRP level), and recurrent or chronic attacks in adults.

Intravenous Immunoglobulins Improve Survival in Monoclonal Gammopathy-Associated Systemic Capillary-Leak Syndrome.

BACKGROUND: Monoclonal gammopathy-associated systemic capillary-leak syndrome, also known as Clarkson disease, is a rare condition characterized by recurrent life-threatening episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. This study was conducted to better describe the clinical characteristics, natural history, and long-term outcome of monoclonal gammopathy-associated systemic capillary-leak syndrome. METHODS: We conducted a cohort analysis of all patients included in the European Clarkson disease (EurêClark) registry between January 1997 and March 2016. From diagnosis to last follow-up, studied outcomes (eg, the frequency and severity of attacks, death, and evolution toward multiple myeloma) and the type of preventive treatments administered were monitored every 6 months. RESULTS: Sixty-nine patients (M/F sex ratio 1:1; mean ± SD age at disease onset 52 ± 12 years) were included in the study. All patients had monoclonal gammopathy of immunoglobulin G type, with kappa light chains in 47 (68%). Median (interquartile range) follow-up duration was 5.1 (2.5-9.7) years. Twenty-four patients (35%) died after 3.3 (0.9-8) years. Fifty-seven (86%) patients received at least one preventive treatment, including intravenous immunoglobulins (IVIg) n = 48 (73.8%), theophylline n = 22 (33.8%), terbutaline n = 22 (33.8%), and thalidomide n = 5 (7.7%). In the 65 patients with follow-up, 5- and 10-year survival rates were 78% (n = 35) and 69% (n = 17), respectively. Multivariate analysis found preventive treatment with IVIg (hazard ratio 0.27; 95% confidence interval, 0.10-0.70; P = .007) and terbutaline (hazard ratio 0.35; 95% confidence interval, 0.13-0.96; P = .041) to be independent predictors of mortality. CONCLUSIONS: We describe the largest cohort to date of patients with well-defined monoclonal gammopathy-associated systemic capillary-leak syndrome. Preventive treatment with IVIg was the strongest factor associated with survival, suggesting the use of IVIg as the first line in prevention therapy.

Rituximab for induction and maintenance treatment of ANCA-associated vasculitides: a multicentre retrospective study on 80 patients.

OBJECTIVES: Rituximab has been shown to induce remission of ANCA-associated vasculitides (AAVs). Our study was undertaken to describe AAV clinical responses to rituximab used for remission-induction and/or maintenance therapy, assess rituximab's safety profile and evaluate French clinical practices. METHODS: This retrospective study concerned AAV patients who had received one or more rituximab infusion between 2002 and January 2011 and had follow-up lasting ≥12 months. RESULTS: Eighty patients were included, most with refractory or relapsing AAV: 70 (88%) with granulomatosis with polyangiitis (GPA), 9 (11%) with microscopic polyangiitis and 1 (1%) with eosinophilic GPA. Rituximab was the first agent used to induce remission in 73 patients. The two most commonly administered regimens were an infusion of 375 mg/m(2)/week for 4 weeks (54 patients) and an infusion of 1 g every 2 weeks for a month (16 patients). Rituximab was first prescribed to maintain remission in seven patients. Respective 1-, 2-, and 3-year relapse-free survival rates after the first infusion were 80% (95% CI 72, 89), 63% (51, 77) and 52% (39, 70). Relapse-free survival was longer for patients receiving rituximab maintenance therapy (P = 0.002). Among 22 (28%) rituximab-treated patients experiencing severe adverse events, 12 (15%) had infectious complications leading to 4 (5%) deaths. Only 15 (19%) patients had received anti-pneumococcal vaccine before rituximab. CONCLUSION: Rituximab was able to induce AAV remission and seemed to maintain remission better than other agents, but caution is needed concerning its safety, especially regarding bacterial infections, in this population.

[Cholestatic hepatitis: an uncommon presentation of Churg-Strauss syndrome]. / Hépatite cholestatique: une présentation inhabituelle du syndrome de Churg et Strauss.

Churg-Strauss syndrome is a rare form of severe vasculitis characterized by severe asthma and hypereosinophilia. Liver involvement is rare. We report a case of a woman with serious cholestatic hepatitis and vasculitis, without severe asthma. Marked hypereosinophilia and liver biopsy confirmed diagnosis. Churg-Strauss syndrome must be recognized because digestive involvement is very serious and affect the prognosis of this disease.