Cyclophosphamide vs rituximab for eradicating inhibitors in acquired hemophilia A: A randomized trial in 108 patients.

BACKGROUND: Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against Factor VIII, with a high mortality risk. Treatments aim to control bleeding and eradicate antibodies by immunosuppression. International recommendations rely on registers and international expert panels. METHODS: CREHA, an open-label randomized trial, compared the efficacy and safety of cyclophosphamide and rituximab in association with steroids in patients with newly diagnosed AHA. Participants were treated with 1 mg/kg prednisone daily and randomly assigned to receive either 1.5-2 mg/kg/day cyclophosphamide orally for 6 weeks, or 375 mg/m2 rituximab once weekly for 4 weeks. The primary endpoint was complete remission over 18 months. Secondary endpoints included time to achieve complete remission, relapse occurrence, mortality, infections and bleeding, and severe adverse events. RESULTS: Recruitment was interrupted because of new treatment recommendations after 108 patients included (58 cyclophosphamide, 50 rituximab). After 18 months, 39 cyclophosphamide patients (67.2 %) and 31 rituximab patients (62.0 %) were in complete remission (OR 1.26; 95 % CI, 0.57 to 2.78). In the poor prognosis group (FVIII < 1 IU/dL, inhibitor titer > 20 BU mL-1), significantly more remissions were observed with cyclophosphamide (22 patients, 78.6 %) than with rituximab (12 patients, 48.0 %; p = 0.02). Relapse rates, deaths, severe infections, and bleeding were similar in the 2 groups. In patients with severe infection, cumulative doses of steroids were significantly higher than in patients without infection (p = 0.03). CONCLUSION: Cyclophosphamide and rituximab showed similar efficacy and safety. As first line, cyclophosphamide seems preferable, especially in poor prognosis patients, as administered orally and less expensive. FUNDING: French Ministry of Health. CLINICALTRIALS: gov number: NCT01808911.

[Interest of daratumumab in refractory AL amyloidosis in a 96-year-old patient]. / Intérêt du daratumumab dans l'amylose AL réfractaire chez une patiente de 96ans.

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+plasma cells, resulting in organ dysfunction. Cardiac involvement has a major prognostic value. Antiplasma cell chemotherapy reduces the synthesis of immunoglobulin light chains (precursors of amyloid deposits). We describe a case of AL amyloidosis in a 95-year-old patient. Our patient responded poorly to treatment with rituximab, cyclophosphamide-bortezomib-dexamethasone, and rituximab-bendamustine. Finally, the anti-CD38 antibody daratumumab was associated with the best hematologic responsiveness without significant adverse effects. In conclusion, our case suggests that daratumumab is an effective and well-tolerated alternative to chemotherapy in the treatment af AL amyloidosis in very elderly patients.

Isolated CNS Sarcoidosis Versus Systemic Sarcoidosis With CNS Involvement: A Same Disease?

Neurological involvement occurs in 5 to 15% of patients with sarcoidosis. It rarely represents the sole manifestation of the disease, a condition called isolated neurosarcoidosis. Objectives: To describe patients with definite isolated central neurosarcoidosis. To compare their characteristics to a group of systemic sarcoidosis with central neurologic involvement. Methods: Monocentric retrospective study of all patients presenting with central neurosarcoidosis (NS) over a 10 year period, subsequently divided into 2 groups: isolated neurosarcoidosis (INS) and systemic neurosarcoidosis (SNS). Results: We report 10 cases of INS and subsequently, we compared their characteristics to a group of 30 patients with SNS. INS patients exhibited brain parenchymal involvement (8/10), meningeal disease (8/10), myelitis (3/10), cranial neuropathy (3/10), neuroendocrine impairment (1/10). Cerebro-spinal fluid (CSF) analysis was conducted in 8/10 patients and showed pleocytosis in 6/8 (75%), elevated protein level in (4/8) 50%, oligoclonal intrathecal synthesis in 1/5 (20%). All patients received steroids, 7/10 (70%) required associated immunosuppressive therapy, 5 of which TNFα inhibitors. When compared to patients with SNS, INS patients were more likely to experience seizures (60% vs 23.3%); display encephalic parenchymal enhancing lesions (80% vs 39.3%) or encephalic leptomeningeal involvement (80% vs 35.7%). Serum angiotensin converting enzyme (ACE) was elevated in a third of patients with SNS but none of those with INS. Conclusion: The phenotypes of patients with INS are similar to the ones described in SNS. Serum ACE should not be regarded as a diagnostic test in patients with isolated neurosarcoidosis but could be useful in detecting subclinical extra neurologic involvement during follow up.

Descriptive study of pneumococcal vaccination in cases of inflammatory disease: Analysis of practices.

INTRODUCTION: Pneumococcal infections are frequent and potentially serious in patients with inflammatory diseases treated with immunosuppressants and/or biotherapies. This patient population considered to be at very high risk of infection is subject to national vaccination recommendations. The main objective of this study was to assess pneumococcal vaccine coverage in a day hospital (internal medicine and vascular disease) in patients treated with immunosuppressants. METHODS: An observational, descriptive, retrospective, and single-center study. We included 150 consecutive patients for 3 months (February to April 2018). We studied pneumococcal vaccination coverage and the time elapsed between the date of vaccination with the 13-valent polysaccharide conjugate vaccine (PCV13) and the start of immunosuppressive therapy. RESULTS: Among the 150 patients included in the study, vaccination coverage with PCV13 was 85% (127/150) and decreased to 46.7% (70/150) for the recommended vaccination schedule. Taking into account vaccine efficacy according to the date of initiation of the treatment, only 28.7% (43/150) of the patients in the study were able to benefit from an optimal complete vaccination schedule, i.e. 33.8% (43/127) among patients vaccinated with PCV13. CONCLUSION: Despite official recommendations, vaccination coverage against pneumococcus remains insufficient in patients under immunosuppressants and/or biotherapies. In addition to the continued training of doctors, optimizing computer prescription of vaccines in view of facilitating vaccination tracing and having vaccination carried out at the site of consultation are avenues for improvement to be considered.

[Gynecologic vasculitis revealing a giant cell arteritis: A case report and literature review]. / Vascularite des artères utérines révélant une artérite à cellules géantes : cas clinique et revue de la littérature.

INTRODUCTION: Genital vasculitis are uncommon. They may be localized or be a manifestation of a systemic vasculitis. We report a patient with a giant cell arteritis (GCA) involving uterine arteries and a literature review on genital vasculitis. CASE REPORT: A 65-year-old woman was referred to a gynecologist for a cervical intraepithelial neoplasia (CIN) associated with an ovarian mass. An unexpected diagnosis of GCA involving small to medium sized uterine arteries was made through the anatomopathological analysis while the patient was asymptomatic. Two weeks later, she presented typical cranial symptoms of giant cell arteritis (GCA). PET-scanner confirmed the diagnosis of GCA with an involvement of the ascending aorta, and the axillary and the subclavian arteries. CONCLUSION: Gynecologic vasculitis are rare and usually an asymptomatic manifestations of GCA.

[The CD40-CD40L axis: Current and future implications in clinical immunology]. / L'axe CD40-CD40L : implications actuelles et futures en immunologie clinique.

The CD40-CD40 ligand (CD40L) pathway is a backbone of communication between cells of the immune system. It makes it possible to generate a proinflammatory signal and thus participates in the pathogenesis of dysimmune diseases, transplant rejection and atherosclerosis. Because of this therapeutic target of choice, several generations of anti-CD40L monoclonal antibodies have emerged since the 1990s. The first generation of antibodies was responsible for thromboembolic toxicity for which the mechanisms are starting to be defined. New generations of antibodies were designed to overcome this toxicity and are still being developed in lupus, rheumatoid arthritis, Sjogren's syndrome or immunologic thrombocytopenia. In addition to these targeted therapies, there are data suggesting the impact of several drugs among molecules used in cardiology and clinical immunology on the level of CD40L. The objective of this review is to recall the clinical issues related to the CD40-CD40L axis and to present current or future treatments that block CD40L which would allow clinicians to diversify their options for managing dysimmune diseases.

Evolution of comorbidities in people living with HIV between 2004 and 2014: cross-sectional analyses from ANRS CO3 Aquitaine cohort.

BACKGROUND: The objective of the study was to describe the evolution of chronic non-AIDS related diseases and their risk factors, in patients living with HIV (PLHIV) in the French ANRS CO3 Aquitaine prospective cohort, observed both in 2004 and in 2014 in order to improve long-term healthcare management. METHODS: The ANRS CO3 Aquitaine cohort prospectively collects epidemiological, clinical, biological and therapeutic data on PLHIV in the French Aquitaine region. Two cross sectional analyses were performed in 2004 and 2014, to investigate the patient characteristics, HIV RNA, CD4 counts and prevalence of some common comorbidities and treatment. RESULTS: 2138 PLHIV (71% male, median age 52.2 years in 2014) were identified for inclusion in the study, including participants who were registered in the cohort with at least one hospital visit recorded in both 2004 and 2014. Significant increases in the prevalence of diagnosed chronic kidney disease (CKD), bone fractures, cardiovascular events (CVE), hypertension, diabetes and dyslipidaemia, as well as an increase in treatment or prevention for these conditions (statins, clopidogrel, aspirin) were observed. It was also reflected in the increase in the proportion of patients in the "high" or "very high" risk groups of the disease risk scores for CKD, CVE and bone fracture score. CONCLUSIONS: Between 2004 and 2014, the aging PLHIV population identified in the French ANRS CO3 Aquitaine prospective cohort experienced an overall higher prevalence of non-HIV related comorbidities, including CKD and CVD. Long-term healthcare management and long-term health outcomes could be improved for PLHIV by: careful HIV management according to current recommendations with optimal selection of antiretrovirals, and early management of comorbidities through recommended lifestyle improvements and preventative measures.

Increased risk of mortality in systemic sclerosis-associated digital ulcers: a systematic review and meta-analysis.

BACKGROUND: Survival can be threatened in certain forms of systemic sclerosis (SSc) so clear prognostic factors are needed. OBJECTIVES: The aim of this meta-analysis was to assess the association between the presence of digital ulcers (DUs) and mortality in SSc. METHODS: We performed a systematic review and meta-analysis in the Pubmed and Scopus databases from the earliest records to May 2017. Two research strategies were performed: « systemic sclerosis ¼ and « digital ulcers ¼ (strategy A); « systemic sclerosis ¼ and « mortality ¼ (strategy B). The primary outcome was the mortality associated with the presence of DUs in patients with SSc. RESULTS: The literature search identified 1473 citations. Fifty-nine studies were examined for full text. Ten articles were included for the meta-analysis. SSc patients with DUs had an increased pooled mortality risk: RR = 1.53 (IC 95%: [1.23-1.90]). CONCLUSIONS: This meta-analysis revealed a higher mortality in SSc patients with associated DUs. Having DUs may be a predictive factor of developing organ involvement such as pulmonary or cardiovascular events that could be associated with poor survival. It suggests that early screening of DUs in SSc patients is important to identify patients most at risk of poor survival.

[Retrospective analysis of anti-TIF1gamma, anti-NXP2 and anti-SAE1/2 antibodies carriers at Bordeaux university hospital from November 2014 to February 2017]. / Analyse rétrospective des patients porteurs d'anticorps anti-TIF1gamma, anti-NXP2 et anti-SAE1/2 au CHU de Bordeaux de novembre 2014 à février 2017.

INTRODUCTION: Dermatomyositis are rare autoimmune diseases. The discovery of specific antibodies such as the anti-TIF1γ, anti-SAE1/2 and anti-NXP2 antibodies has been associated with specific clinical phenotypes. The recent development of standardized kits based on immunodot method is a progress in dermatomyositis diagnosis. Here, we report the clinical characteristics of patients carrying these antibodies with or without clinical setting of dermatomyositis. METHODS: This single-center french retrospective study was conducted from November 2014 to February 2017 at Bordeaux university hospital. Patients carrying anti-TIF1γ, anti-SAE1/2 and anti-NXP2 antibodies, detected by immunodot, were included. RESULTS: Among the 58 patients included, only 10 were finally diagnosed with dermatomyositis. Some form of cancer was found in all anti-TIF1γ antibodies positive patients associated with dermatomyositis. Among the 48 anti-TIF1γ, anti-SAE1/2 and anti-NXP2 antibodies positive patients without clinical phenotype of dermatomyositis, 30 had autoimmune or inflammatory condition and 39 patients presented a significant biological autoimmunity. None of them developed dermatomyositis during the follow-up. CONCLUSION: The immunodot kit allowed the diagnosis of 10 dermatomyositis. A high number of autoantibody positive patients without dermatomyositis raises the issue of the immunodot's performances in the context of biological autoimmunity.

Efficacy and safety of autologous haematopoietic stem cell transplantation in systemic sclerosis: a systematic review of the literature.

We aimed to assess the efficacy of autologous haematopoietic stem cell transplantation (HSCT) for skin sclerosis (SSc) and lung function in SSc. We performed a systematic literature review in the PubMed and Scopus databases from the earliest records to March 2016. We assessed study quality using the Cochrane tool for randomized studies, the Newcastle-Ottawa Scale for controlled cohort studies and an 18-item quality-appraisal checklist for case series. The primary outcome was the improvement of skin thickening using the modified Rodnan Skin Score (mRSS). The secondary outcome was efficacy on lung function, using diffusing capacity of the lungs for carbon monoxide and forced vital capacity (FVC). The safety of the procedure was evaluated. The literature search identified 431 citations. There were 38 studies involving a total of 344 patients who fulfilled our inclusion criteria. No meta-analysis was performed due to a high heterogeneity. There was a significant improvement in mRSS in the majority of the reports (P < 0·05), and the results were sustained for up to 8 years after autologous HSCT. The randomized studies and the four cohort studies each showed a slight but statistically significant improvement in FVC at 1 or 2 years. The treatment-related mortality calculated by pooling patients of 35 studies (336 patients with a follow-up up to 146 months) was 8·3% after autologous HSCT and 1% in cyclophosphamide-treated groups. Despite heterogeneity among the studies, we determined that autologous HSCT significantly improved cutaneous fibrosis and slightly improved FVC. Safety of autologous HSCT is acceptable given the severity of the disease. This systematic review was registered on PROSPERO, number CRD42016027951.

[Relevance assessment of requests for antineutrophil cytoplasmic antibodies detection: Retrospective study led in Bordeaux Hospital, France]. / Évaluation de la pertinence des demandes d'anticorps anticytoplasme des polynucléaires neutrophiles : étude rétrospective menée au sein du centre hospitalier universitaire de Bordeaux.

INTRODUCTION: During year 2013, 5943 tests for antineutrophil cytoplasmic antibodies (ANCA) detection were performed in Bordeaux hospital, France. This seemed disproportionate, with regard to the low prevalence of ANCA-associated vasculitis (AAV). Our purpose was to evaluate the relevance of these requests. METHODS: Requests for detection of ANCA during 2013 were recorded, with their results. A sample of 501 requests was secondarily established. Relevance of requests was assessed independently by two reviewers. During year 2014, we developed strategies of information, in order to reduce the number of requests and increase their relevance. RESULTS: Only 17.8 % of the 5943 requests for detection of ANCA resulted in a positive test using indirect immunofluorescence (including 10.6 % of the requests with titles above 1/50). Using Luminex©, 9.7 % of the test of detection against antimyeloperoxidase or antiproteinase 3 antibodies were positive. Within the sample of 501 patients, only 28.7 % of the requests were relevant. A percentage of 40.2 of them weren't justified by a clinical affection typically associated with AAV. Exactly 15.9 of the requests were performed during systematic autoimmune screening. None of these requests could lead to the diagnosis of AAV. Combination of information procedures and use of a request form enabled a 19 % decrease of the number of requests. The percentage of requests without clinical justification also reduced from 40.2 % to 17.1 %. The reduction of the number of requests led to a 46,865 € saving. CONCLUSION: The majority of the requests for detection of ANCA was not relevant and could not lead to the diagnosis of AAV. Simple solutions enabled a partial but significant improvement of their relevance.

[Systemic lupus erythematosus and contraception: A systematic literature review]. / Lupus érythémateux systémique et contraception : revue systématique de la littérature.

OBJECTIVE: The aim of our study was to evaluate the safety of contraceptive methods use among women with systemic lupus erythematosus (SLE). METHODS: A systematic review of the literature was performed using the two databases MEDLINE and SCOPUS, in order to identify articles concerning the safety of contraceptive methods use among women with SLE, through May 2016. Information on study characteristics, objectives, population, contraception and outcomes were extracted. RESULTS: A total of 907 articles were identified and 21 were selected for the systematic review. Two randomised controlled trials found no worsening of disease activity with the use of combined oral contraceptive in women with stable or inactive SLE. Disease activity was not exacerbated with the use of progestogens-only contraceptive. There was an increased risk of thrombosis with the use of combined contraceptive, particularly in women with positive antiphospholipid antibodies and this must lead to a restriction of use in these patients. CONCLUSION: Use of oral combined hormonal contraceptives should be limited to patients with non-severe and stable disease, without thrombosis risk factors.

[Cough as the presenting feature of pulmonary AL amyloidosis: A case report]. / Amylose pulmonaire AL révélée par une toux : à propos d'une observation.

INTRODUCTION: Pulmonary lesions may be a presenting feature of AL amyloidosis. OBSERVATION: We report a 49-year-old male with AL amyloidosis secondary to a multiple myeloma with symptomatic interstitial pulmonary lesions and chronic cough as the presenting feature. CONCLUSION: Lung involvement is relatively frequent during AL amyloidosis but most of the time it remains asymptomatic. Interstitial pneumonia is the rarest condition of pulmonary amyloidosis. It is related to a large diffusion of the disease as demonstrated by the usual concurrent presence of cardiac lesions.

[Granulomatous hepatitis revealing a Mycobacterium bovis widespread infection following intravesical BCG therapy]. / Hépatite granulomateuse révélant une infection disséminée à Mycobacterium bovis après BCG-thérapie intravésicale.

INTRODUCTION: Intravesical therapy with bacillus Calmette-Guérin (BCG) has proved to be effective in the treatment of superficial bladder tumors. Side-effects include local infections and rarely disseminated BCG infection with multiple end organ complications such as granulomatous hepatitis, pneumonitis, aortitis and bone marrow involvement. CASE REPORT: We report an 83-year-old man who presented with chronic granulomatous hepatitis. This was related to intravesical BCG therapy received two years earlier for superficial bladder cancer. Aortitis, splenic infarction and hematopoietic involvement were also diagnosed. Outcome was favorable following adapted antibiotic course. CONCLUSION: This case report highlights the possibility of widespread BCG infection following intravesical treatment, and the need for vigilance in patients with a history of such a therapy even several years later.

Epidemic of complicated mumps in previously vaccinated young adults in the South-West of France.

OBJECTIVE: We report the features and diagnosis of complicated mumps in previously vaccinated young adults. PATIENTS AND METHODS: We retrospectively studied 7 cases of complicated mumps managed during 1 year at the Bordeaux University Hospital. The diagnosis was suggested by the clinical presentation and confirmed using specific RT-PCR. RESULTS: Five cases of meningitis, 1 of orchitis, and 1 of unilateral hearing impairment were identified. Each of the 7 patients had been previously vaccinated with MMR, 4 had received 2 doses of this vaccine. Blood tests revealed high rates of IgG antibodies, usually considered as sufficient for immunological protection, and every patient had at least 1 positive RT-PCR test for mumps. CONCLUSION: Outbreaks of complicated mumps may still occur despite a broad coverage of MMR vaccination. The clinical presentation suggested mumps but the final diagnosis could only be confirmed by genomic detection of the virus. Unusual viral strains with increased neurovirulence, insufficient population coverage associated with immunity decrease over time may explain outbreaks of complicated mumps. A full vaccine scheme of contact people or a third injection of vaccine for previously vaccinated people who are at risk of developing mumps are required to prevent further spreading of the disease during the outbreak.

[Hereditary hemorrhagic telangiectasia]. / Maladie de Rendu-Osler.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is a development disorder of the vasculature characterized by telangiectases and arteriovenous malformations in specific locations. Among monogenic disorders, it is one of the most common, though affected individuals are widely underdiagnosed. The most common features of this disorder, nosebleeds, and telangiectases on the lips, hands, and oral mucosa are often quite subtle. Mutations in at least five genes may result in hereditary hemorrhagic telangiectasia, but mutations in two genes (ENG and ACVRL1/ALK1) account for approximately 85% of cases. Optimal management requires understanding the specific clinical patterns of these vascular malformations, especially their locations and timing during life. Therapeutic modulation of angiogenesis may be an effective therapy.

[Large granular lymphocyte leukemia: clinical and pathogenic aspects]. / Les leucémies à grands lymphocytes granuleux : de la clinique à la physiopathologie.

Large granular lymphocyte leukemia (LGL) is a hematologic disorder characterized by a monoclonal expansion of large lymphocytes containing azurophilic granules with a T CD3(+)CD57(+) or Natural Killer (NK) CD3(-)CD56(+) phenotype. The World Health Organization (WHO) classification identifies three entities: the T LGL, the chronic lymphoproliferative disorder of NK-cells, and the aggressive NK-cell leukemia. T LGL and chronic lymphoproliferative disorder of NK-cells are indolent diseases frequently associated with cytopenias and a wide spectrum of auto-immune manifestations. Neutropenia can lead to recurrent bacterial infections, which represent an indication of initiating a treatment in most of the cases. Immunosuppressive therapies are usually used in this context. In contrast, aggressive NK-cell leukemia follows a fulminant course with a poor prognosis because patients are refractory to most of the treatments. There is now a considerable interest in the pathophysiology of the disease with the perspective of new therapeutic options.