Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case-noncase study in the French Pharmacovigilance Database.

BACKGROUND: Inhibitors of dipeptidyl peptidase (DPP)-IV have been suspected in the onset of bullous pemphigoid for several years now. However, comparative studies assessing the link between DPP-IV inhibitor exposure and bullous pemphigoid have not yet been performed. OBJECTIVES: To detect, from the French Pharmacovigilance Database (FPVD), a signal of risk of bullous pemphigoid during DPP-IV inhibitor exposure by comparative study. METHODS: All spontaneous reports of DPP-IV inhibitor-related bullous pemphigoid recorded in the FPVD between April 2008 and August 2014 were described. We conducted disproportionality analyses (case-noncase method) to assess the link between DPP-IV inhibitors and bullous pemphigoid, calculating reporting odds ratios (RORs). We also compared DPP-IV inhibitor-induced bullous pemphigoid reports rated per million defined daily doses dispensed during the study period. RESULTS: Among 217 331 spontaneous adverse drug reaction reports registered in the FPVD, 1297 involved DPP-IV inhibitors. Among these observations, 42 were bullous pemphigoid (vildagliptin, n = 31; sitagliptin, n = 10; saxagliptin, n = 1). The ROR for pooled DPP-IV inhibitors was 67·5 [95% confidence interval (CI) 47·1-96·9]. Disproportionality was also observed for each DPP-IV inhibitor: vildagliptin (ROR 225·3, 95% CI 148·9-340·9), sitagliptin (ROR 17·0, 95% CI 8·9-32·5) and saxagliptin (ROR 16·5, 95% CI 2·3-119·1). Analyses adjusted on dispensing data led to similar results. CONCLUSIONS: These data confirm a strong signal for an increased risk of bullous pemphigoid during DPP-IV inhibitor exposure. This adverse drug reaction is observed for each DPP-IV inhibitor, suggesting a class effect. The signal was higher with vildagliptin than with the other DPP-IV inhibitors.

Efficacy of anti-TNF alpha in severe and/or refractory Behçet's disease: Multicenter study of 124 patients.

OBJECTIVE: To report the efficacy and safety of anti-TNF agents in patients with severe and/or refractory manifestations of Behçet's disease (BD). METHODS: We performed a multicenter study of main characteristics and outcomes of anti-TNF alpha treatments [mainly infliximab (62%), and adalimumab (30%)] in 124 BD patients [48% of men; median age of 33.5 (28-40) years]. RESULTS: Overall response (i.e. complete and partial) rate was 90.4%. Clinical responses were observed in 96.3%, 88%, 70%, 77.8%, 92.3% and 66.7% of patients with severe and/or refractory ocular, mucocutaneous, joint, gastro-intestinal manifestations, central nervous system manifestations and cardiovascular manifestations, respectively. No significant difference was found with respect to the efficacy of anti-TNF used as monotherapy or in association with an immunosuppressive agent. The incidence of BD flares/patient/year was significantly lower during anti-TNF treatment (0.2 ± 0.5 vs 1.7 ± 2.4 before the use of anti-TNF, p < 0.0001). The prednisone dose was significantly reduced at 6 and 12 months (p < 0.0001). In multivariate analysis, retinal vasculitis was negatively associated with complete response to anti-TNF (OR = 0.33 [0.12-0.89]; p = 0.03). The efficacy and relapse free survival were similar regardless of the type of anti-TNF agent used. After a median follow-up of 21 [7-36] months, side effects were reported in 28% of patients, including infections (16.3%) and hypersensitivity reactions (4.1%). Serious adverse events were reported in 13% of cases. CONCLUSION: Anti-TNF alpha therapy is efficient in all severe and refractory BD manifestations. Efficacy appears to be similar regardless of the anti-TNF agent used (infliximab or adalimumab).

Imaging in Erdheim-Chester disease: classic features and new insights.

Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis. Osseous involvement is the most frequent feature with bilateral and symmetric osteosclerotic changes in long bone diaphyseal and metaphyseal regions, classically sparing epiphyses. 99mTc scintigraphy shows bilateral and symmetrical metaphysal and diaphyseal increased uptake in almost all the patients, even asymptomatic. Other classical features on CT-scan, very evocative of Erdheim-Chester disease, must be recognised: e.g. 'coated' aorta, 'hairy kidney' patterns. New imaging techniques such as MRI have led to a better description of cardiac and central nervous system involvements. Pachymeningitis and right atrium wall infiltration are new evocative images of this disease. Fluorodeoxyglucose Positron Emission Tomography in the diagnosis or prognosis assessment is still discussed. The objective of this review is to discuss the place of each imaging technique in Erdheim-Chester disease in 2013.

Genotype and phenotype relationships in 10 Pakistani unrelated patients with inherited factor VII deficiency.

Inherited factor VII (FVII) deficiency is one of the commonest rare bleeding disorders. It is characterized by a wide molecular and clinical heterogeneity and an autosomal recessive pattern of inheritance. Factor VII-deficient patients are still scarcely explored in Pakistan although rare bleeding disorders became quite common as a result of traditional consanguineous marriages. The aim of the study was to give a first insight of F7 gene mutations in Pakistani population. Ten unrelated FVII-deficient patients living in Pakistan were investigated (median FVII:C = 2%; range = 2-37%). A clinical questionnaire was filled out for each patient and direct sequencing was performed on the coding regions, intron/exon boundaries and 5' and 3' untranslated regions of the F7 gene. Nine different mutations (eight missense mutations and one located within the F7 promoter) were identified on the F7 gene. Five of them were novel (p.Cys82Tyr, p.Cys322Ser, p.Leu357Phe, p.Thr410Ala, c-57C>T, the last being predicted to alter the binding site of transcription factor HNF-4). Half of the patients had single mutations in Cys residues involved in disulfide bridges. The p.Cys82Arg mutation was the most frequent in our series. Six of seven patients with FVII:C levels below 10% were homozygous in connection with the high percentage of consanguinity in our series. In addition, we graded the 10 patients according to three previously published classifications for rare bleeding disorders. The use of the bleeding score proposed by Tosetto and co-workers in 2006 appears to well qualify the bleeding tendency in our series.

[Castleman-like presentation of systemic lupus: About a case report]. / Présentation « Castleman-like ¼ de lupus systémique : à propos d'un cas.

INTRODUCTION: Castleman disease is a rare lymphoproliferation, which may mimic systemic lupus. Conversely, systemic lupus sometimes presents like an hematological malignancy. In these cases, a "Castleman-like" histology has been exceptionally described. OBSERVATION: A 55-year-old female treated by methotrexate for systemic lupus with skin and joint involvement presented weight loss, polyadenopathy and clinical signs of lupus flare. Biology showed pancytopenia, complement activation, and positive anti-DNA antibodies. PET/CT showed hypermetabolic polyadenopathy. The lymph node biopsy showed "Castleman-like" features. Treatment with corticosteroids and azathioprine resulted in complete remission. CONCLUSION: Systemic lupus and Castleman disease may share common clinical, biological, and histological features. The presence of specific elements of systemic lupus flare and the remission obtained by low-dose corticosteroids results in considering the diagnosis of Castleman-like systemic lupus and avoiding treatment intensification.

French practical guidelines for the diagnosis and management of relapsing polychondritis.

Relapsing polychondritis is a rare systemic disease. It usually begins in middle-aged individuals. This diagnosis is mainly suggested in the presence of chondritis, i.e. inflammatory flares on the cartilage, in particular of the ears, nose or respiratory tract, and more rarely in the presence of other manifestations. The formal diagnosis of relapsing polychondritis cannot be established with certainty before the onset of chondritis, which can sometimes occur several years after the first signs. No laboratory test is specific of relapsing polychondritis, the diagnosis is usually based on clinical evidence and the elimination of differential diagnoses. Relapsing polychondritis is a long-lasting and often unpredictable disease, evolving in the form of relapses interspersed with periods of remission that can be very prolonged. Its management is not codified and depends on the nature of the patient's symptoms and association or not with myelodysplasia/vacuoles, E1 enzyme, X linked, autoinflammatory, somatic (VEXAS). Some minor forms can be treated with non-steroidal anti-inflammatory drugs, or a short course of corticosteroids with possibly a background treatment of colchicine. However, the treatment strategy is often based on the lowest possible dosage of corticosteroids combined with background treatment with conventional immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil, rarely cyclophosphamide) or targeted therapies. Specific strategies are required if relapsing polychondritis is associated with myelodysplasia/VEXAS. Forms limited to the cartilage of the nose or ears have a good prognosis. Involvement of the cartilage of the respiratory tract, cardiovascular involvement, and association with myelodysplasia/VEXAS (more frequent in men over 50years of age) are detrimental to the prognosis of the disease.

Statin-induced lupus: a case/non-case study in a nationwide pharmacovigilance database.

Statin use has been advocated to prevent atheromatous complications in lupus patients and may be widely prescribed for these patients in future. Statin-induced lupus has also been described, though the risk is not confirmed. The goal of this study was to detect a safety signal regarding statin-induced lupus. We conducted a case/non-case study in the French PharmacoVigilance Database from January 2000 until December 2010. Cases were drug-induced lupus reports. Non-cases were all reports of other adverse drug reactions (ADRs). Exposure to statins at the time of ADR was screened in each report. Among 235,147 ADR reports, 232 were drug-induced lupus. Exposure to statins was present in 17 (7.3%) cases and in 10,601 (4.7%) non-cases. Reporting odds ratio (ROR) for statin exposure associated with lupus erythematosus was 1.67 (95% confidence interval 1.02-2.74). The ROR was > 1 for each statin but fluvastatin. This pharmacoepidemiological study suggests a link between statin exposure and lupus induction. The benefit-to-risk ratio of statin therapy in lupus patients should be evaluated through randomized controlled trials.

New insights into the epidemiology of immune thrombocytopenia in adult patients: Impact for clinical practice / [Actualités de l'épidémiologie du purpura thrombopénique immunologique de l'adulte : Impact pour la pratique clinique].

New insights into immune thrombocytopenia (ITP) epidemiology in adult patients highlight three main outcomes of morbidity and mortality: bleeding, infection and thrombosis. This review depicts current evidence about incidence and risk factors of bleeding, infection and thrombosis as well as predictors of chronicity, and shows how this assessment impacts the choice of ITP second-line treatment at the individual-level basis.

[TAFRO syndrome and cutaneous necrotizing vasculitis]. / Syndrome TAFRO et vascularite nécrosante cutanée : une association inédite.

INTRODUCTION: TAFRO syndrome is a systemic inflammatory syndrome in the spectrum of Castleman's disease, associating thrombocytopenia, anasarca, fever, renal failure and/or reticulin myelofibrosis and organomegaly. Its association with necrotizing cutaneous vasculitis has not yet been reported. CASE REPORT: A 69-year-old woman presented with weight loss, fever, anasarca, organomegaly, lymphadenopathy, anuria and extensive necrotic livedo occurring after acute diarrhea. Biology showed anemia, thrombocytopenia, renal failure, hypergammaglobulinemia, a circulating B-lymphocyte clone, hypoparathyroidism and autoimmune hypothyroidism. The skin biopsy showed small vessel vasculitis with fibrinoid necrosis. Methylprednisolone infusions associated with tocilizumab were ineffective and the patient became anuric. Rituximab and plasma exchanges associated to corticosteroids allowed remission for 2 months. Combination of rituximab, cyclophosphamide and dexamethasone resulted in a prolonged remission. CONCLUSION: We report here the first case of severe cutaneous necrotizing vasculitis in a patient suffering from TAFRO syndrome. The possible resistance to tocilizumab should be known.

[Insufficient influenza vaccination coverage in giant cell arteritis. A French population-based study]. / Couverture vaccinale anti grippale insuffisante dans l'artérite à cellules géantes.

PURPOSE: To evaluate the rate of seasonal influenza vaccination coverage (IVC) in incident giant cell arteritis (GCA) patients compared with controls. METHODS: The vaccination rate was estimated from vaccine dispensation. IVC was compared between GCA and their controls using longitudinal multivariate Poisson regression. RESULTS: During the influenza campaigns from 2005-2006 to 2010-2011, the IVC rates in the GCA group and the control group ranged from 60.8 to 74.7% vs. 56.6 to 70.4%, respectively. Incident GCA influenza vaccination rate was 20% higher than controls (RR=1.20 ; IC 1.09 to 1.32, P<0.001). CONCLUSION: Although suboptimal, IVC in incident GCA was statistically better than controls.

[Development of sarcoma on a ectopic extramedullary hematopoiesis secondary to hereditary spherocytosis: Case report and literature review]. / Développement d'un sarcome sur foyer ectopique hématopoïétique secondaire à une sphérocytose héréditaire : à propos d'un cas et revue de la littérature.

INTRODUCTION: Extramedullary hematopoiesis is a complication of myeloproliferative neoplasms or of chronic hemolysis. The more frequent localizations are splenic, ganglionic or paraspinal. Rarely, extramedullary hematopoiesis is associated with solid cancer. CASE REPORT: We report an original case of sarcoma located in an extramedullary hematopoiesis mass in a 72-year-old woman suffering from hereditary spherocytosis. An asymptomatic right paravertebral mass was found in 2004; the biopsy confirmed extramedullary hematopoiesis. In 2016, the patient was hospitalized due to paravertebral pain. Computed tomography showed the extension of the right paraspinal mass to pleura and mediastinum as well as vertebral bone lysis. Positron emission tomography showed an intense hypermetabolism. The biopsy showed undifferentiated sarcoma. CONCLUSION: This case report illustrates the risk of neoplastic transformation of extramedullary hematopoiesis, and the need for a biopsy when confronted to atypical aspect.

Clinical characteristics and outcome of hospitalized patients with SARS-CoV-2 infection at Toulouse University hospital (France). Results from the Covid-clinic-Toul cohort.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread worldwide from epicenter of Wuhan, China since December 2019. The aim of our study was to describe the clinical characteristics and outcome of hospitalized patients with SARS-CoV-2 pneumonia at the Toulouse university hospital, France. PATIENTS AND METHODS: We selected the patients included from March 7, 2020 to April 20, 2020 in the retrolective Covid-clinic-Toul cohort that follows all hospitalized patients with SARS-CoV-2 infection at the Toulouse Hospital. Cases were confirmed by real-time reverse transcriptase polymerase chain reaction. We report demographics, clinical, biological and radiological features, as well as unfavorable outcome at Day 14 after admission (admission in an intensive care unit, mechanical ventilation, death). RESULTS: Among 263 hospitalized patients, the median age was 65 years and 155 (58.9%) were males. Two hundred and twenty-seven patients (86.3%) had at least one comorbidity. The median time from first symptom to hospital admission was 7.0 days (interquartile range: 4-10). On day 14 after admission, 111 patients (42.2%) had been transferred to intensive care unit (ICU), including 50 (19.0%) on Day 1; 61 (23.1%) needed mechanical ventilation and 19 patients (7.2%) had died. Patients admitted to ICU at Day 1 of admission (n=50) were more frequently men (66.0% vs 57.3%), smokers (25.0% vs 7.1%), with obesity (42.0% vs 24.7%) and had a higher mean level of C-reactive protein (median: 110.9mg/L vs 46.2mg/L). CONCLUSION: This cohort provides epidemiological data on SARS-CoV-2 in hospitalized patients in a University hospital in the South of France.

[Febrile myalgia revealing Propionibacterium acnes endocarditis]. / Myalgies fébriles révélant une endocardite infectieuse à Propionibacterium acnes.

INTRODUCTION: Propionibacterium acnes endocarditis is rare and difficult to diagnose. We report a case of Propioniacterium acnes endocarditis revealed by a lower limb fasciitis. CASE REPORT: A 54-year-old patient presented with recurrent febrile myalgia of the lower limbs, that appeared three years after an aortic surgery (aortic valve sparing reimplentation and ascending aortic prosthesis implantation). Computer tomography showed fasciitis of both legs. Positron emission tomography showed 18Fluorodeoxyglucose intake of the aortic prosthesis and in muscles of the lower limbs. Ten days after blood sample drawing, cultures showed the presence of Propionibacterium acnes. The aortic prosthesis was surgically removed, whose culture confirmed infection by Propionibacterium acnes. The diagnosis of infective endocarditis revealed by lower limb emboli was made. Evolution was favorable. CONCLUSION: In patients with vascular prostheses, Propionibacterium acnes infection must be evoked face to an atypical inflammatory process. Very prolonged blood culture incubation is needed to identify the pathogen.

[Propensity score: Interests, use and limitations. A practical guide for clinicians]. / Score de propension : intérêts, utilisation et limites. Un guide pratique pour le clinicien.

Propensity scores have been proposed in the early 1980s, and are increasingly used in epidemiology since the 2000s. They are is used to minimize the selection bias in observational studies, leading to a comparability between the exposure groups close to that observed in randomized trials. However, they have important limitations. Besides, new statistical techniques to improve the propensity score performances are more and more complex, while the build and the use of propensity score require a strict methodology to avoid bias, imprecision and non-reproducibility. This overview, designed for clinicians, is aimed at describing the advantages, techniques of use and limitations of propensity scores. A reading grid is provided in order to help interpreting studies using propensity scores.

Risk factors for bleeding, including platelet count threshold, in newly diagnosed immune thrombocytopenia adults.

Essentials Risk factors of bleeding in adult immune thrombocytopenia are not known. This multicenter study assessed risk factors of bleeding at immune thrombocytopenia onset. Platelet count thresholds associated with bleeding were < 20 × 109 L-1 and < 10 × 109 L-1 . Exposure to anticoagulants was a major risk factor of severe bleeding. SUMMARY: Background The aim of this cross-sectional study was to assess risk factors for bleeding in immune thrombocytopenia (ITP) adults, including the determination of platelet count thresholds. Methods We selected all newly diagnosed ITP adults included in the Cytopénies Auto-immunes Registre Midi-PyrénéEN (CARMEN) register and at the French referral center for autoimmune cytopenias. The frequencies of any bleeding, mucosal bleeding and severe bleeding (gastrointestinal, intracranial, or macroscopic hematuria) at ITP onset were assessed. Platelet count thresholds were assessed by the use of receiver operating characteristic curves. All potential risk factors were included in logistic regression models. Results Among the 302 patients, the frequencies of any, mucosal and severe bleeding were 57.9%, 30.1%, and 6.6%, respectively. The best discriminant threshold of platelet count for any bleeding was 20 × 109 L-1 . In multivariate analysis, factors associated with any bleeding were platelet count (< 10 × 109 L-1 versus ≥ 20 × 109 L-1 , odds ratio [OR] 48.2, 95% confidence interval [CI] 20.0-116.3; between 10 × 109 L-1 and 19 × 109 L-1 versus ≥ 20 × 109 L-1 , OR 5.2, 95% CI 2.3-11.6), female sex (OR 2.6, 95% CI 1.3-5.0), and exposure to non-steroidal anti-inflammatory drugs (NSAIDs) (OR 4.8, 95% CI 1.1-20.7). A low platelet count was also the main risk factor for mucosal bleeding. Exposure to anticoagulant drugs was associated with severe bleeding (OR 4.3, 95% CI 1.3-14.1). Conclusions Platelet counts of < 20 × 109 L-1 and < 10 × 109 L-1 were thresholds for major increased risks of any and mucosal bleeding. Platelet count, female sex and exposure to NSAIDs should be considered for assessment of the risk of any bleeding. Exposure to anticoagulant drugs was a major risk factor for severe bleeding.