Antoine Huart

The HNF1B score is a simple tool to select patients for HNF1B gene analysis

HNF1B-related disease is an emerging condition characterized by an autosomal-dominant inheritance, a 50% rate of de novo mutations, and a highly variable phenotype (renal involvement, maturity-onset diabetes of the young type 5, pancreatic hypoplasia, and urogenital tract and liver test abnormalities). Given the current lack of pathognomonic characteristics and the wide overlap with other conditions, a genetic test is the diagnostic gold standard. However, pre-genetic screening is mandatory because genetic testing has substantial costs. Our aim was to develop a HNF1B score, based on clinical, imaging, and biological variables, as a pivotal tool for rational genetic testing. A score was created using a weighted combination of the most discriminative characteristics based on the frequency and specificity in published series. The HNF1B score is calculated upon 17 items including antenatal discovery, family history, and organ involvement (kidney, pancreas, liver, and genital tract). The performance of the score was assessed by a ROC curve analysis in a 433-individual cohort containing 56 HNF1B cases. The HNF1B score efficiently and significantly discriminated between mutated and nonmutated cases (AUC 0.78). The optimal cutoff threshold for the negative predictive value to rule out HNF1B mutations in a suspected individual was 8 (sensitivity 98.2%, specificity 41.1%, and negative predictive value over 99%). Thus, the HNF1B score is a simple and accurate tool to provide a more rational approach to select patients for HNF1B screening.

Population pharmacokinetics of rituximab with or without plasmapheresis in kidney patients with antibody-mediated disease

AIMS Both rituximab and plasmapheresis can be associated in the treatment of immune-mediated kidney diseases. The real impact of plasmapheresis on rituximab pharmacokinetics is unknown. The aim of this study was to compare rituximab pharmacokinetics between patients requiring plasmapheresis and others without plasmapheresis. METHODS The study included 20 patients receiving one or several infusions of rituximab. In 10 patients, plasmapheresis sessions were also performed (between two and six sessions per patient). Rituximab concentrations were measured in blood samples in all patients and in discarded plasma obtained by plasmapheresis using an enzyme-linked immunosorbent assay method. Data were analysed according to a population pharmacokinetic approach. RESULTS The mean percentage of rituximab removed during the first plasmapheresis session ranged between 47 and 54% when plasmapheresis was performed between 24 and 72 h after rituximab infusion. Rituximab pharmacokinetics was adequately described by a two-compartment model with first-order elimination. Plasmapheresis had a significant impact on rituximab pharmacokinetics, with an increase of rituximab clearance by a factor of 261 (95% confidence interval 146-376), i.e. from 6.64 to 1733 ml h(-1) . Plasmapheresis performed 24 h after rituximab infusion decreased the rituximab area under the curve by 26%. CONCLUSIONS Plasmapheresis removed an important amount of rituximab when performed less than 3 days after infusion. The removal of rituximab led to a significant decrease of the area under the curve. This pharmacokinetic observation should be taken into account for rituximab dosing, e.g. an additional third rituximab infusion may be recommended when three plasmapheresis sessions are performed after the first rituximab infusion.

Eculizumab and drug-induced haemolytic–uraemic syndrome

The monoclonal anti-C5 antibody eculizumab has been successfully tested in atypical haemolytic-uraemic syndrome (aHUS), with or without mutations in the regulatory proteins of the alternative pathway of the complement, and less convincingly in enterohaemorrhagic Escherichia coli-associated HUS. Here, we report a patient with mitomycin-C-induced HUS unresponsive to plasma exchanges. Eculizumab infusion was followed by a dramatic improvement of haematological parameters and renal function, suggesting a role of complement blockade in the management of refractory, drug-related HUS.

Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2)

Objective To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs). Methods Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group. Results Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2–4) vs 5 (5–5) administrations. Conclusion AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions. Trial registration number NCT01731561; Results.

Tocilizumab added to conventional therapy reverses both the cytokine profile and CD8+Granzyme+ T‐cells/NK cells expansion in refractory hemophagocytic lymphohistiocytosis

To the Editor, Hemophagocytic lymphohistiocytosis (HLH) is a lifethreatening syndrome characterized by severe systemic inflammation and uncontrolled activation of natural killer (NK) and cytotoxic CD8+ T-cells, which both contribute to organ damage. In patients with HLH, overproduction of Th1 [interferon gamma (IFN-γ), interleukin 2 (IL-2), IL-6, IL-12 and tumour necrosis factor alpha (TNF-α)] cytokines contrasts with low levels of Th2 cytokines (IL-4) [1]. Overproduction of IL-10 is observed during the acute phase of the disease, as expected during IFN-γ overproduction [2]. Diagnostic criteria of HLH were developed in the HLH-2004 protocol and include an increased soluble CD25 (sCD25) [3]. The association of high levels of IFN-γ and IL-10 with normal or moderately elevated levels of IL-6 differentiates HLH from infection [4]. Besides primary/familial HLH mainly observed in childhood, most secondary forms occur in the setting of infection, malignancy or rheumatologic disorders. Corticosteroids, cyclosporine, etoposide or TNF-α can reverse HLH in most patients with underlying systemic disease or cancer [5]. To date, no firm consensus treatment emerged, and the treatment of refractory HLH remains challenging. In 2013, a 59-year-old patient was referred to our intensive care unit (ICU) for acute renal and respiratory failure and features of HLH including hemophagocytosis in bone-marrow aspirate, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, anaemia and low platelet count, a slightly enlarged spleen, and a dramatic increase of sCD25. Two months before his admission, he developed autoimmune manifestations characterized by arthritis, myositis, lung interstitial disease, acral cutaneous sclerosis and dry syndrome. Immunological tests showed low complement C3, C4, CH50 components, type III cryoglobulin, polyclonal hypergammaglobulinemia, positive Coombs’ test, high levels of anti-SSA, anti-SSB, anti-PMScl, anti-double strand DNA and anti-citrullinated peptides antibodies. He had been receiving corticosteroids for 2months (0.5–1mg/kg/day) without any improvement of the autoimmunity-related organ disorders. At admission in the ICU, diagnosis of HLH was retained. Abnormal liver tests, acute renal failure requiring dialysis and a moderate encephalopathy were observed.

Plasma exchanges for the treatment of severe systemic necrotizing vasculitides in clinical daily practice: Data from the French Vasculitis Study Group

The use of plasma exchanges (PLEX) in systemic necrotizing vasculitides (SNV) still need to be codified. To describe indications, efficacy and safety of PLEX for the treatment of SNV, we conducted a multicenter retrospective study on patients with ANCA-associated vasculitis (AAV) or non-viral polyarteritis nodosa (PAN) treated with PLEX. One hundred and fifty-two patients were included: GPA (n = 87), MPA (n = 56), EGPA (n = 4) and PAN (n = 5). PLEX were used for rapidly progressive glomerulonephritis (RPGN) in 126 cases (86%), alveolar hemorrhage in 64 cases (42%), and severe mononeuritis multiplex in 23 cases (15%). In patients with RPGN, there was a significant improvement in renal function compared to baseline value (P < 0.0001), the plateau being reached at month 3 after PLEX initiation, and estimated glomerular filtration rate improved especially as the number of PLEX increased. In patients with alveolar hemorrhage, mechanical ventilation was discontinued in all patients after a median time of 15 days. Patients treated for mononeuritis multiplex showed improvement of severe motor weakness. After a median follow of 22 months, 18 deaths (12%) were recorded, mainly in patients with RPGN and within the first 6 months. Incidence of end-stage renal disease and/or death was similar between groups of different baseline renal function, but was increased in MPO-ANCA compared to PR3-ANCA. Adverse events attributable to PLEX were recorded in 63%. No death occurred during PLEX. This large series describes indications, efficacy and safety of PLEX in daily practice. Randomized controlled studies are ongoing to define optimal indications, PLEX regimen and concomitant medications.

IgA-mediated anti-glomerular basement membrane disease: an uncommon mechanism of Goodpasture's syndrome.

Goodpastures (GP) disease is usually mediated by IgG autoantibodies. We describe a case of IgA-mediated GP, in a patient presenting with isolated rapidly progressive glomerulonephritis. The diagnosis was established on kidney biopsy, since routine enzyme-linked immunosorbent assay (ELISA) targeted at IgG circulating autoantibodies failed to detect the nephritogenic antibodies. Immunofluorescence microscopy showed intense linear deposition of IgA along the glomerular capillary walls. An elevated titre (1:80) of circulating IgA anti-glomerular basement membrane (GBM) antibodies was retrospectively demonstrated by indirect fluorescence. Despite immunosuppressive regimen, the disease progressed to end-stage renal failure (ESRF). Transplantation was not associated with recurrence in the kidney graft. We reviewed the 11 previously reported cases of IgA-mediated GP.

Cryofibrinogénémie : étude monocentrique au CHU de Toulouse

PURPOSE Cryofibrinogenemia is an unknown disorder and studies dedicated to it are limited. The aim of our study was to report on the incidence, clinical manifestations and associated diseases in patients with isolated cryofibrinogenemia. METHODS This is a retrospective single-center study. Patients included in this study had a positive and isolated detection of cryofibrinogen between January 1st, 2011 and December 31st, 2012. Identification was possible through the database of the laboratory of immunology. RESULTS Two hundred and eighty-one consecutive orders of cryofibrinogenemia were identified. Seventy-three patients had a positive detection of cryofibrinogenemia. Among them, 12 had an isolated cryofibrinogenemia and sixty-one patients (84%) had concomitant cryofibrinogenemia and cryoglobulinemia. The mean age was 59±19years. Seven patients were female (58%). Cutaneous manifestations were present in half case. Peripheral nerve involvement was present in 5 cases (42%) and rheumatic manifestations in 4 patients (33%). A thrombotic event was reported in 7 patients (58%). Renal impairment was present in 7 patients. The median cryofibrinogen concentration was 254±304mg/L. Five patients had a secondary cryofibrinogenemia. The most often prescribed treatment was corticosteroids. CONCLUSION Cryofibrinogenemia is an unknown disorder. Testing for cryoglobulinemia is more frequent than for cryofibrinogenemia whereas clinical manifestations are similar. Detection of cryofibrinogen is positive in most of the cases, with an important prevalence of thrombotic events in this population. This study confirms the importance of conducting prospective studies on cryofibrinogenemia.

Acquired factor VIII haemophilia following influenza vaccination

Autoimmune diseases should present or be worsened by vaccination due to the pharmacological properties of vaccines. We report a case of acquired haemophilia mediated by anti-factor VIII antibody following a vaccination against influenza. A 72-year-old woman suffered from spontaneous bruises of the wrists at the end of October, 2009. She had been exposed for 31 years (1977–2008) to prednisone for a pulmonary sarcoidosis. She was also being treated with L-thyroxine for Hashimoto’s thyroiditis, amlodipine for essential arterial hypertension and paroxetine for depression. The patient was vaccinated against seasonal influenza (MUTAGRIP) 8 days prior to the first haemorrhagic symptom. No local complication was noted during the intramuscular injection. This was the first time she had been vaccinated with a seasonal influenza vaccine. The results of the clinical examination were normal, except the haemorrhagic syndrome. Platelet count was 320,000/μL, activated cephalin time (equivalent to activated partial thromboplastin time) was 72 s (indicator: 28 s) and prothrombine time was 100%. The amount of factor VIII was 1%, and antibody directed against factor VIII was detected at 8 Bethesda units, without any von Willebrand factor deficiency. There was no clinical or biological evidence for any haematopoietic malignancy or systemic disease. Antinuclear antibodies were detected at the limit of significance (titre: 1/160), without any specificity (antiDNA nor anti-extractable nuclear antigens). Symptomatic treatment with activated prothrombin complex concentrates (FEIBA) was prescribed for 24 h. Due to the ineffectiveness of prednisone (1 week at 1 mg/kg/day), rituximab was introduced (375 mg/m/week, 4 infusions), which resulted in clinical and biological remission: 3 weeks after the last infusion of rituximab, factor VIII and its auto-antibody were 8% and 4 Bethesda units respectively; 4 months after the last infusion, these values were 48% and not detectable, respectively. According to World Health Organization–Uppsala Monitoring Centre criteria [1], the score of causality assessment was considered to be “possible”. Acquired haemophilia is a very rare disorder due to an anti-factor VIII antibody: its incidence is estimated to range from 0.2 to 1.9/million/year [2]. An underlying cause is present in approximately half of cases: solid tumours, haematopoietic malignancies, auto-immune diseases, pregnancy and post-partum, infections, drugs (penicillins, sulfa antibiotics, phenytoin, chloramphenicol, methyldopa, interferon-α, fludarabine, levodopa, clopidogrel) [3–5]. None of the drugs taken by our patient were known to induce acquired haemophilia. To the best of our knowledge, no post-vaccination-acquired haemophilia has G. Moulis :G. Pugnet Service de Medecine Interne, Centre Hospitalier Universitaire de Toulouse, Universite de Toulouse, Toulouse, France

Pretransplant urinary proteome analysis does not predict development of chronic kidney disease after liver transplantation

Chronic kidney disease (CKD) is a common complication after liver transplantation. Kidney biopsies cannot be easily performed before liver transplantation to predict patients at high risk for CKD. The aim of our study was to determine whether pre‐, peri‐ and post‐transplant factors, as well as peptides present in preliver transplant urine samples were associated with loss in kidney function at 6 months post‐transplantation using proteome analysis.