Pulmonary hypertension in connective tissue diseases: What every CTD specialist should know - but is afraid to ask!

Pulmonary hypertension (PH) is a possible complication of connective tissue diseases (CTDs), especially systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). It is defined by an elevation of the mean pulmonary arterial pressure above 20mmHg documented during a right heart catheterization (RHC). Due to their multiorgan involvement, CTDs can induce PH by several mechanisms, that are sometimes intricated: pulmonary vasculopathy (group 1) affecting arterioles (pulmonary arterial hypertension, PAH) and possibly venules (pulmonary veno-occlusive-like disease), left-heart disease (group 2), chronic lung disease (group 3) and/or chronic thromboembolic PH (group 4). PH suspicion is often raised by clinical manifestations (dyspnea, fatigue), echocardiographic data (increased peak tricuspid regurgitation velocity), isolated decrease in DLCO in pulmonary function tests, and/or unexplained elevation of BNP/NT-proBNP. Its formal diagnosis always requires a hemodynamic confirmation by RHC. Strategies for PH screening and RHC referral have been extensively investigated for SSc-PAH but data are lacking in other CTDs. Therapeutic management of PH depends of the underlying mechanism(s): PAH-approved therapies in group 1 PH (with possible use of immunosuppressants, especially in case of SLE or MCTD); management of an underlying left-heart disease in group 2 PH; management of an underlying chronic lung disease in group 3 PH; anticoagulation, pulmonary endartectomy, PAH-approved therapies and/or balloon pulmonary angioplasty in group 4 PH. Regular follow-up is mandatory in all CTD-PH patients.

Steroid hormones in systemic sclerosis: associations with disease characteristics and modifications during scleroderma renal crisis.

OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) and glucocorticoids (GCs) are involved in vascular remodeling and fibrosis, but have not been extensively studied in systemic sclerosis (SSc). Our aim was to investigate the RAAS and GC hormones in SSc patients. METHODS: Serum levels of renin (dosage and activity), aldosterone and its precursors (DOC, B, 18-OH-DOC, 18-OH-B), and GCs (cortisol, cortisone, 11-deoxycortisol, 18-OH-F) were assessed in 122 SSc patients and 52 healthy controls. After applying stringent inclusion criteria aimed at ensuring accurate hormone assessments (exclusion of interfering drugs, strict sampling conditions), we analyzed RAAS hormones in 61 patients, and GCs in 96 patients. Hormone levels were compared between patients and controls; and associations with disease characteristics were assessed in patients. RESULTS: Regarding RAAS hormones, SSc patients displayed significantly lower aldosterone levels (although within normal range), similar renin levels, and higher B levels than controls. Abnormal RAAS hormone levels were associated with a more severe SSc phenotype (lung and skin fibrosis, heart and pulmonary vascular involvements, inflammation). Regarding GC hormones, SSc patients had higher levels of cortisol, 11-desoxycortisol (precursor) and 18-OH-F (metabolite) but lower levels of cortisone (inactive counterpart) than controls.RAAS hormone levels were assessed in 5 SSc patients before and during scleroderma renal crisis (SRC): concentrations varied considerably between patients, but consistently included normal/increased aldosterone levels and elevated renin levels. CONCLUSION: RAAS and GC hormones are abnormally produced in SSc patients, especially in patients with severe SSc and during SRC. This could suggest a participation of these hormonal systems in SSc pathogenesis.

Atteintes coronariennes et artérite a cellules géantes : à propos de 2 cas et revue de la littérature.

INTRODUCTION: Coronaritis is a rare but serious complication of giant-cell arteritis (GCA), with an estimated prevalence of less than 1%, however difficult to establish, and of early onset. METHODS: We describe 2 cases of GCA presenting with coronaritis and present a review of the literature on this complication. RESULTS: The first patient presented with stable angina on common trunk coronaritis with ostial stenosis. Corticosteroid combined with tocilizumab from the outset resulted in improvement. Angioplasty was performed at 6months with good outcome. The second patient presented with asymptomatic tritruncular ostial coronaritis. Corticosteroid allowed clinic-biological improvement of GCA. Two years later, he presented relapse with an acute coronary syndrome, with favorable evolution after angioplasty, increase of corticosteroids and addition of tocilizumab. CONCLUSION: Patients presented were successfully treated with corticosteroids combined with tocilizumab and angioplasty of their coronary stenoses. Efficacy of tocilizumab in GCA has not been evaluated especially on coronaritis due to the rarity of this complication. Our experience and the cases reported in the literature suggest good results of angioplasty in this indication. Studies with long-term follow-up will be necessary to evaluate the risk of restenosis.

[Hereditary angioedema and its new treatments: An update]. / Mise au point sur les angiœdèmes héréditaires et leurs nouvelles thérapeutiques.

Hereditary angioedema, with or without deficient C1 inhibitor level or function, is a rare disease characterized by recurrent attacks of noninflammatory subcutaneous and/or submucosal edema. It may be life-threatening and substantially affects quality of life. Attacks may be spontaneous or induced, in a setting of emotional stress, by infections or physical trauma, in particular. As the key mediator is bradykinin, this angioedema does not respond to the usual treatments of mast cell-mediated angioedema (antihistamines, corticosteroids, adrenaline), which is much more frequent. Therapeutic management of hereditary angioedema first consists in treating severe attacks with a selective B2 bradykinin receptor antagonist or a C1 inhibitor concentrate. The latter or an attenuated androgen (danazol) can be used for short-term prophylaxis. Therapeutic solutions conventionally proposed for long-term prophylaxis (danazol, antifibrinolytics [tranexamic acid], C1 inhibitor concentrate) vary in efficacy and/or pose problems of safety or ease of use. Kallikrein inhibitors (subcutaneous lanadelumab, oral berotralstat) recently made available as disease-modifying treatment constitute an important advance in long-term prophylaxis of hereditary angioedema attacks. The advent of these new drugs is accompanied by a new ambition for patients: optimize control of the disease and thereby minimize its impact on quality of life.

[Updated indications and contraindications in 2022 for lung transplantation in France]. / Transplantation pulmonaire en France : actualisation des indications et contre-indications en 2022.

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

[GATA2 gene mutations: 3 cases]. / Mutations du gène GATA2 : à propos de 3 cas.

INTRODUCTION: Heterozygous germline mutations of GATA2 gene (guanine-adenine-thymine-adenine binding protein 2) are hereditary mutations that can be pathogenic, sometimes occurring sporadically, responsible for a florid clinical-biological picture, sometimes serious and quickly leading to the death. CASE REPORTS: We reported two women and one man with germline mutations in the GATA2 gene. The first patient, aged 19, initially presented with monocytopenia and chronic lymphedema of the four limbs, suggestive of Emberger syndrome. The second patient, 28-years-old, presented with a disseminated atypical mycobacterium (Mycobacterium kansasii) infection, raising suspicion of an immune deficiency such as MonoMAC syndrome (deficiency syndrome of dendritic cells, monocytes, B lymphocytes and NK cells). The last patient, 30-years-old, presented with pancytopenia, leading to the diagnosis of a family form of myelodysplastic syndromes and acute myeloid leukemia characterized by a mutation of the GATA2 gene. CONCLUSIONS: Each case illustrates a typical clinical presentation of GATA2 deficiency, although the evolution of these syndromes ultimately reveals a complex, heterogeneous and intricate picture of hematological, dermatological, infectious, pulmonary, ENT or oncological symptoms. Mutations in the GATA2 gene remain a diagnostic and therapeutic challenge for the internist, and require multidisciplinary management given the florid picture that can be of interest to all specialties. The clinical spectrum of these GATA2 mutations as well as the latest management recommendations from the recent litterature and the "GATA2 club" are described in this article.

[Telomeropathies: A study of 15 cases]. / Téloméropathies de recrutement hématologique : étude de 15 cas.

INTRODUCTION: Telomeres are composed of a repeated sequence of double-stranded nucleotides TTAGGG and numerous proteins including the Shelterin complex. Their main role is to maintain the stability of the genome during cell replication through a mechanism of copying the repeted sequence by the telomerase complexe. All the diseases involving a deregulation of this complex are now grouped together under the term telomeropathies. They are difficult to diagnose and manage. Our objective was to describe the clinico-biological characteristics and treatments used, in patients affected by telomeropathies previously seen by an hematologist followed at the Lille University Hospital Center. METHODS: This is a retrospective, single-center study carried out within the department of internal medicine-clinical immunology, Reference center for rare autoimmune and systemic diseases at Lille University Hospital Center between 2005 and 2020 including all patients followed for telomeropathy. RESULTS: Probands and relatives were included. Fifteen patients were studied from 10 independant families. Sixty percent had an heterozygous TERC gene mutation. Sixty seven percent had haematological diseases including macrocytosis, anemia and/or thrombocytopenia, 20 % had a fibrotic hepatic disease, 27 % had a fibrotic pulmonary disease. Lymphocyte immunophenotyping showed a double negative T lymphocyte population with γδ TCR expression in 5 (33 %) patients. Forty-seven percent of the patients had not received any treatment. Twenty-seven percent were on androgen therapy. Twenty percent had received cyclosporine and 13 % anti-lymphocyte serum in the context of initial misdiagnosis. CONCLUSION: It is important to be aware of the complexity of telomeropathies, a differential diagnosis of immune aplastic anemia, in order to optimize management and avoid inappropriate treatments. Allografting of hematopoietic stem cells is the only potentially curative treatment. Our analysis found particularities in immunophenotyping lymphocyte not previously described to our knowledge, whose physiopathological imputability remains to be demonstrated.

[Impact of disease on daily activities, emotions and quality of life of patients with hereditary angioedema]. / Impact de l'angiœdème héréditaire sur les activités de la vie quotidienne, la sphère émotionnelle et la qualité de vie des patients.

INTRODUCTION: Hereditary angioedema (HAE) is characterized by recurrent attacks of swelling of various locations and severity. An impaired quality of life of patients with HAE has been reported by several studies. We aimed at examining the overall impact of the disease in patients followed for type I HAE, particularly its impact on daily life activities, emotions and quality of life. METHODS: A questionnaire was distributed to patients consulting for type I HAE, collecting demographics, disease characteristics, impact on professional life, Hospital Anxiety and Depression score (HAD), SF-36 score and the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR). RESULTS: The 33 patients included reported an average of 5.17 attacks over the last year. Stress was the main trigger A long-term treatment was reported by 58% of patients, 72% received specific treatment in the event of a serious attack. Sick days were reported by 33% of patients during their studies, and by 34% during work. One patient suffered from depressive symptoms and ten from anxious symptoms, according to the HAD score. The areas most impacted on the SF-36 score were general health and vitality. The mean score for MACTAR was low. CONCLUSION: HAE still has a significant impact on the daily and emotional lives of patients, despite the availability of prophylactic and crisis treatments.

[Acquired angioedema due to C1-inhibitor deficiency: CREAK recommendations for diagnosis and treatment]. / Angiœdèmes par déficit acquis en C1-inhibiteur : recommandations du CREAK pour le diagnostic et la prise en charge.

Acquired angioedema with C1-inhibitor deficiency is a rare and peculiar entity belonging to the spectrum of bradykinin angioedemas. It usually occurs in subjects over 60 years old, and is mostly associated with a B-cell lymphoid hemopathy or a monoclonal gammopathy. The diagnosis relies on at least one angioedema episode, lasting more than 24 h, and on the decrease of functional C1-inhibitor. Low C1q is observed in 90% of patients, and an anti C1-inhibitor antibody is found in 50% of patients. The treatment of severe attacks relies on icatibant or C1-inhibitor perfusions. Long term prophylaxis in patients with frequent attacks requires treatment of the associated hemopathy if so. In case of idiopathic angioedema, tranexamic acid and danazol may be used, provided that there is-no thrombophilia; as well as rituximab as second-line treatment. Inhibitors of kallikrein still need to be evaluated in this therapeutic indication.

Raising rare disease awareness using red flags, role play simulation and patient educators: results of a novel educational workshop on Raynaud phenomenon and systemic sclerosis.

BACKGROUND: As lack of awareness of rare diseases (RDs) among healthcare professionals results in delayed diagnoses, there is a need for a more efficient approach to RD training during academic education. We designed an experimental workshop that used role-play simulation with patient educators and focused on teaching "red flags" that should raise the suspicion of an RD when faced with a patient with frequently encountered symptoms. Our objective was to report our experience, and to assess the improvement in learners' knowledge and the satisfaction levels of the participants. RESULTS: The workshop consisted of 2 simulated consultations that both started with the same frequent symptom (Raynaud phenomenon, RP) but led to different diagnoses: a frequent condition (idiopathic RP) and an RD (systemic sclerosis, SSc). In the second simulated consultation, the role of the patient was played by a patient educator with SSc. By juxtaposing 2 seemingly similar situations, the training particularly highlighted the elements that help differentiate SSc from idiopathic RP. When answering a clinical case exam about RP and SSc, students that had participated in the workshop had a higher mean mark than those who had not (14 ± 3.7 vs 9.6 ± 5.5 points out of 20, p = 0.001). Participants mostly felt "very satisfied" with this training (94%), and "more comfortable" about managing idiopathic RP and SSc (100%). They considered the workshop "not very stressful" and "very formative" (both 71%). When asked about the strengths of this training, they mentioned the benefits of being put in an immersive situation, allowing a better acquisition of practical skills and a more interactive exchange with teachers, as well as the confrontation with a real patient, leading to a better retention of semiological findings and associating a relational component with this experience. CONCLUSIONS: Through the use of innovative educational methods, such as role-play simulation and patient educators, and by focusing on teaching "red flags", our workshop successfully improved RP and SSc learning in a way that satisfied students. By modifying the workshop's scenarios, its template can readily be applied to other clinical situations, making it an interesting tool to teach other RDs.

Angioedema associated with thrombolysis for ischemic stroke: analysis of a case-control study.

BACKGROUND: Bradykinin-mediated angioedema (AE) is a complication associated with thrombolysis for acute ischemic stroke. Risk factors are unknown and management is discussed. OBJECTIVES: To clarify risk factors associated with bradykinin-mediated AE after thrombolysis for acute ischemic stroke. METHODS: In a case-control study conducted at a French reference centre for bradykinin angiœdema, patients with thrombolysis for acute ischemic stroke and a diagnosis of bradykinin-mediated angiœdema, were compared to controls treated with thrombolysis treatment without angiœdema. RESULTS: Fifty-three thrombolysis-related AE were matched to 106 control subjects. The sites of attacks following thrombolysis for ischemic stroke mainly included tongue (34/53, 64%) and lips (26/53, 49%). The upper airways were involved in 37 (70%) cases. Three patients required mechanical ventilation. Patients with bradykinin-mediated angiœdema were more frequently women [33 (62%) vs. 44 (42%); P = 0.01], had higher frequency of prior ischemic stroke [12 (23%) vs. 9 (8%); P = 0.01], hypertension [46 (87%) vs. 70 (66%); P = 0.005], were more frequently treated with angiotensin-converting enzyme inhibitor [37 (70%) vs. 28 (26%); P < 0.001] and were more frequently hospitalized in intensive care medicine [ICU; 11 (21%) vs. 5 (5%); P = 0.004]. In multivariate analysis, factors associated with thrombolysis-related AE were female sex [odds ratio (OR), 3.04; 95% confident interval (CI), 1.32-7.01; P = 0.009] and treatment with angiotensin-converting enzyme inhibitors [(OR), 6.08; 95% (CI), 2.17-17.07; P < 0.001]. CONCLUSIONS: This case-control study points out angiotensin-converting enzyme inhibitors and female sex as risk factors of bradykinin AE associated with thrombolysis for ischemic stroke.

Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature.

BACKGROUND: Data on survival and prognosis factors in incident cohorts are scarce in systemic sclerosis (SStc). To describe survival, standardized mortality ratio (SMR), and prognosis factors in systemic sclerosis (SSc), we analyzed a multicenter French cohort of incident patients and performed a systematic review of the literature and meta-analysis. METHODS: A multicenter, French cohort study was conducted between January 1, 2000, and December 31, 2013. Patients were followed-up until July 1, 2016. A systematic review of the literature was carried out in MEDLINE and EMBASE up to July 2017. Meta-analysis was performed using all available data on SMR and hazard ratios of prognosis factors. RESULTS: A total of 625 patients (493 females, 446 lcSSc) were included. During the study period, 104 deaths (16.6%) were recorded and 133 patients were lost to follow-up. Overall survival rates at 1, 3, 5, and 10 years from diagnosis were 98.0%, 92.5%, 85.9%, and 71.7% respectively in the French cohort. Overall SMR was 5.73 (95% CI 4.68-6.94). Age at diagnosis > 60 years, diffuse cutaneous SSc, scleroderma renal crisis, dyspnea, 6-min walking distance (6MWD), forced vital capacity < 70%, diffusing capacity of the lungs for carbon monoxide < 70%, pulmonary hypertension (PH), telangiectasia, valvular disease, malignancy, anemia, and CRP > 8 mg/l were associated with a poorer survival after adjustment. Eighteen studies (11,719 patients) were included in the SMR meta-analysis and 36 studies (26,187 patients) in the prognosis factor analysis. Pooled SMR was 3.45 (95%CI 3.03-3.94). Age at disease onset, male sex, African origin, diffuse cutaneous SSc, anti-Scl70 antibodies, cardiac and renal involvement, interstitial lung disease, PH, and malignancy were significantly associated with a worse prognosis. Anti-centromere antibodies were associated with a better survival. CONCLUSIONS: Overall, our study highlights a high mortality rate in SSc patients and confirms previously described prognosis factors related to skin extension and organ involvement while identifying additional prognosis factors such as autoantibody status, telangiectasia, 6MWD, and valvular disease.

[Reliability and validity of a workbook for assessment of professional competencies of internal medicine residents]. / Évaluation multicentrique de la reproductibilité et de la validité d'un carnet d'évaluation des compétences professionnelles des internes de médecine interne.

INTRODUCTION: Though several assessment tools for resident professional skills based on workplace direct observation have been validated, they remain scarcely used in France. The objective of this study was to evaluate the reliability and the validity of a workbook including several assessment forms for different components of the professional competency. METHODS: Three assessment forms have been tested over a period of 6 months in a multicentric study including 12 French internal medicine departments: the French version of the mini-CEX, an interpersonal skills assessment form (OD_CR) and the multisource feedback form (E_360). Reliability has been assess using the intra-class correlation coefficient (ICC) and the Cronbach alpha coefficient. Arguments for validity have been provided looking at the ability of the forms to detect an increase in the scores over time and according to the level of experience of the resident. RESULTS: Twenty-five residents have been included. The Cronbach alpha was of 0.90 (n=70) with the mini-CEX, 0.89 with the OD_CR (n=62) and 0.77 with the E_360 (n=86). ICC showed a wide variation according to the items of the mini-CEX and the OD-CR probably due to the poor number of observations performed by residents. The scores of most of the items of these two forms increased between M1 and M6. The scores of the E_360 were high: 7.3±0.8 to 8.3±2.4 (maximum 9) and did not vary according to the level of experience. CONCLUSION: This study suggest that it would be difficult to ensure a sufficient reliability for professional skills assessment using these tools given our available current human and material resources. However, these assessment forms could be added to the resident portfolio as supports for the debriefing in order to document their progression during their formation.

[Exploring illness perceptions of lupus patients for a motivational environment in therapeutic education]. / Exploration des dimensions de la personne lupique pour un environnement motivationnel en éducation thérapeutique du patient.

PURPOSE: Therapeutic education (TE) intends to help patients with systemic lupus erythematosus to better understand their disease and to improve their quality of life. The objective of this study was to assess illness perceptions of the person to provide a motivational environment for TE. METHODS: Systemic lupus erythematosus patients followed in the department of internal medicine in Lille university hospital responded to a questionnaire assessing five dimensions of the person as proposed by Giordan: the cognitive (knowledge), perceptual (fatigue and pain), affective (anxious and depressive symptoms), infra-cognitive (intimate reasoning) and metacognitive (worldview) dimensions. The quality of life was also evaluated. RESULTS: One hundred and twenty-four patients (114 women (92%); mean age 44.3±14.3 years) responded to the questionnaire. Regarding the cognitive dimension: quantity of information at the time of diagnosis was considered insufficient for 57 patients (46%). The median adherence evaluated by a scale had a median 97mm [88-100]. Regarding the perceptual dimension: pain was assessed at 59mm [44-78] and fatigue at 66mm [50-79] at visual scales. Regarding the affective dimension: prevalence of anxiety symptoms was 67% (83/124) and 28% (35/124) for depressive symptoms. Regarding the infra-cognitive dimension 78 patients (63%) had an external control place. Concerning the metacognitive dimension, systemic lupus erythematosus had repercussions on professional and family life. The quality of life was impacted. CONCLUSION: Multiple dimensions of systemic lupus erythematosus patient have to be considered for an optimal motivational environment for the practice of TE.

Combined pulmonary fibrosis and emphysema in systemic sclerosis: A syndrome associated with heavy morbidity and mortality.

BACKGROUND: The syndrome of combined pulmonary fibrosis and emphysema (CPFE) primarily due to tobacco smoking has been reported in connective tissue disease, but little is known about its characteristics in systemic sclerosis (SSc). METHODS: In this retrospective multi-center case-control study, we identified 36 SSc patients with CPFE, and compared them with 72 SSc controls with interstitial lung disease (ILD) without emphysema. RESULTS: Rate of CPFE in SSc patients with CT scan was 3.6%, and 7.6% among SSc patients with ILD. CPFE-SSc patients were more likely to be male (75 % vs 18%, p < 0.0001), smokers (83 % vs 33%, p < 0.0001), and to have limited cutaneous SSc (53 % vs 24% p < 0.01) than ILD-SSc controls. No specific autoantibody was significantly associated with CPFE. At diagnosis, CPFE-SSc patients had a greater decrease in carbon monoxide diffusing capacity (DLCO 39 ± 13 % vs 51 ± 12% of predicted value, p < 0.0001) when compared to SSc-ILD controls, whereas lung volumes (total lung capacity and forced vital capacity) were similar. During follow-up, CPFE-SSc patients more frequently developed precapillary pulmonary hypertension (PH) (44 % vs 11%, p < 10-4), experienced more frequent unscheduled hospitalizations (50 % vs 25%, p < 0.01), and had decreased survival (p < 0.02 by Kaplan-Meier survival analysis) as compared to ILD-SSc controls. CONCLUSIONS: The CPFE syndrome is a distinct pulmonary manifestation in SSc, with higher morbidity and mortality. Early diagnosis of CPFE by chest CT in SSc patients (especially smokers) may result in earlier smoking cessation, screening for PH, and appropriate management.

Efficacy of anti-TNF alpha in severe and refractory major vessel involvement of Behcet's disease: A multicenter observational study of 18 patients.

OBJECTIVE: To describe the outcome and tolerance in patients treated with anti-TNFα in severe and refractory major vessel disease in Behçet's disease (BD). METHODS: A multicenter study evaluating 18 refractory BD patients with major vessel involvement [pulmonary artery (n = 4), aorta (n = 4) or peripheral artery aneurysm (n = 1) and/or pulmonary artery (n = 7), inferior vena cava (n = 5), or intra-cardiac (n = 3) thrombosis or Budd Chiari Syndrome (n = 2)] treated with anti-TNFα agents. RESULTS: Vascular remission was achieved in 16 (89%) patients. The 9 months risk of relapse was significantly higher with conventional immunosuppressants used prior anti-TNFα agents as compared to anti-TNFα therapy [OR = 8.7 (1.42-62.6), p = 0.03]. The median daily dose of corticosteroids significantly decreased at 12 months. Side effects included infection (n = 4) and pulmonary edema (n = 1). CONCLUSION: TNFα-antagonists are safe and might be associated with a decreased risk of relapse at 9 months compared to conventional immunosuppressants in BD patients with major vessels disease.

Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome.

Purpose The purpose of this study was to evaluate the safety of antithrombotic treatments prescribed during pregnancy in patients with antiphospholipid syndrome (APS). Methods This international, multicenter study included two cohorts of patients: a retrospective French cohort and a prospective US cohort (PROMISSE study). Inclusion criteria were (1) APS (Sydney criteria), (2) live pregnancy at 12 weeks of gestation (WG) with (3) follow-up data until six weeks post-partum. According to APS standard of care, patients were treated with aspirin and/or low-molecular weight heparin (LMWH) at prophylactic (pure obstetric APS) or therapeutic doses (history of thrombosis). Major bleeding was defined as abnormal blood loss during the pregnancy and/or post-partum period requiring intervention for hemostasis or transfusion, or during the peripartum period greater than 500 mL and/or requiring surgery or transfusion. Other bleeding events were classified as minor. Results Two hundred and sixty-four pregnancies (87 prospectively collected) in 204 patients were included (46% with history of thrombosis, 23% with associated systemic lupus). During pregnancy, treatment included LMWH ( n = 253; 96%) or low-dose aspirin ( n = 223; 84%), and 215 (81%) patients received both therapies. The live birth rate was 89% and 82% in the retrospective and prospective cohorts, respectively. Adverse pregnancy outcomes occurred in 28% of the retrospective cohort and in 40% of the prospective cohort. No maternal death was observed in either cohort. A combined total of 45 hemorrhagic events (25%) occurred in the retrospective cohort, but major bleeding was reported in only six pregnancies (3%). Neither heparin nor aspirin alone nor combined therapy increased the risk of hemorrhage. We also did not observe an increased rate of bleeding in the case of a short interval between last LMWH (less than 24 hours) or aspirin (less than five days) doses and delivery. Only emergency Caesarean section was significantly associated with an increased risk of bleeding (odds ratio (OR) 5.03 (1.41-17.96); p=.016). In the prospective cohort, only one minor bleeding event was reported (vaginal bleeding). Conclusion Our findings support the safety of antithrombotic therapy with aspirin and/or LMWH during pregnancy in high-risk women with APS, and highlight the need for better treatments to improve pregnancy outcomes in APS. PROMISSE Study ClinicalTrials.gov identifier: NCT00198068.

Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.