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Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins and defects in B cell maturation leading to an increased susceptibility to infections. Some patients develop complications such as autoimmune diseases, enteropathy, and lymphoproliferation, resulting in higher morbidity and mortality. Follicular helper T (Tfh) cells are specialized in helping B cell differentiation into Ig-producing cells. Three subsets have been described, namely non B-cell helper Tfh1 and the two B-helper cell subsets Tfh2 and Tfh17. We determined that circulating Tfh cells were elevated in CVID patients and skewed toward a Tfh1 profile. Interestingly, elevated levels of Tfh1 cells were significant only in patients harboring non-infectious complications regardless of the type of complication and inversely correlated with switched memory B cells. Moreover, CXCR3 + cells are increased in splenic CVID germinal centers. Our observations suggest that the altered balance in Tfh subsets in CVID is linked to a more severe disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Intravenous immunoglobulin (IVIG) IQYMUNE® is a highly purified 10% IVIG that was assessed using the new stringent definition of response described in the revised guideline on the clinical investigation of IVIG. The efficacy and the safety of IQYMUNE® were investigated in adult patients with chronic primary immune thrombocytopenia (ITP)., Methods: In this phase III multinational, multicentre, prospective, uncontrolled, open-label, single-arm study, adult patients with a baseline platelet count < 30 × 10 9 /L were treated with IVIG 10% at a dose of 2 g/kg body weight administered over 2 consecutive days. The primary endpoint was Response over the study period and was defined according to the recent and most stringent European Medicines Agency guidelines (platelet count ≥ 30 × 10 9 /L and a ≥ 2-fold increase from baseline, no new bleeding, and no concomitant treatment with drugs that affect platelet count and/or induce bleeding cessation)., Results: Thirty-eight patients were enrolled; 73 infusions were administered (38 on Day 1 and 35 on Day 2). Response was reached by 24 patients corresponding to 63.2% of patients in the full analysis set (95% CI: 46.0; 78.2) and 68.6% of patients in the per-protocol set (95% CI: 50.7; 83.1). The median time to Response was 1 day. The median duration of Response was 13.5 days. Reasons for non-response were failure to reach the required platelet count (n = 12), a new bleeding event (n = 1), and forbidden medication use (n = 1). Among the 23 patients with a baseline platelet count ≤ 20 × 10 9 /L, 19 patients (82.6%) achieved a platelet count ≥ 50 × 10 9 /L at least once before Day 5 (previous European Medicines Agency definition of response). Treatment was well tolerated even in patients with a high flow rate (≥ 6 mL/kg/h in 40% of patients). Headache (34.2%), pyrexia (15.8%), and creatinine renal clearance decrease, including one case of decrease in glomerular filtration rate (10.5%) were the most frequently reported drug-related adverse events., Conclusions: Administration of IQYMUNE® for 2 consecutive days at a dose of 2 g/kg was safe and efficacious. These results support the treatment of adult patients with chronic ITP with IQYMUNE®., (Copyright 2018, Rodeghiero et al.)

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., Competing Interests: Competing interests: BT has received consulting and speaking fees (Roche, LFB, Grifols, GSK). MH has received personal fees from Roche. AK has received personal fees and non-financial support from Roche. XP has received speaking fees and honoraria (Pfizer, LFB, Roche) and a research grant (Pfizer)., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Whipple's disease usually presents as chronic joint pain followed by digestive manifestations. However, many different presentations have been described in the literature. We report here the first proven case of muscular vasculitis related to Whipple's disease, associated with an expansion of circulating activated γδ T lymphocytes.

Objective: To describe the characteristics of patients suffering from secondary immunodeficiencies (SID) associated with hematological malignancies (HM), who started immunoglobulin replacement therapy (IgRT), physicians' expectations regarding IgRT, and IgRT modalities., Methods: Non-interventional, prospective French cross-sectional study., Results: The analysis included 231 patients (66 ± 12 years old) suffering from multiple myeloma (MM) (N = 64), chronic lymphoid leukemia (CLL) (N = 84), aggressive non-Hodgkin B-cell lymphoma (aNHL) (N = 32), indolent NHL (N = 39), acute leukemia (N = 6), and Hodgkin disease (N = 6). Of the HM, 47% were currently treated, 42% were relapsing or refractory, 23% of patients had received an autologous hematopoietic stem-cell transplant, and 1% had received an allograft. Serum immunoglobulin trough levels in 195 individuals were less than 5 g/L in 68.7% of cases. Most patients had a history of recurrent infections. Immunoglobulin dose was about 400 mg/kg/mo. Half of patients started with subcutaneous infusion. When starting IgRT, physicians mainly expected to prevent severe and moderate infections. They also anticipated improvement in quality of life and survival which is beyond evidence-based medicine., Conclusion: NHL is a frequent condition motivating IgRT besides well-recognized indications. Physicians mainly based the decision of starting IgRT on hypogammaglobulinemia and recurrence of infections but, irrespective of current recommendations, were also prepared to start IgRT prophylactically even in the absence of a history of infections., (© 2018 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Azathioprine is widely used in internal medicine and frequently implicated in occurrence of adverse events. Among these adverse events the bone marrow suppression, a dose-related one, is the most serious because of is potential morbidity and mortality. Severe myelosuppression, associated with abnormal AZA metabolism, is linked to the thiopurine methyltransferase (TPMT) genetic polymorphism that results in a high variability of its activity with 89% of patients with a normal activity, 11% with an intermediate activity, and 0.3% with very low activity leading to a very high risk of bonne marrow suppression. TPMT status can be assessed prior to AZA treatment by measuring enzyme activity or genotyping techniques to identify patients for which the standard dose is not advisable. Furthermore, azathioprine metabolites monitoring is helpful for the follow up of patients, especially in therapeutic failure, to distinguish non-compliant patients from under-dosed, "shunters" or resistant patients., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Nonadherence to treatment is a major cause of lupus flares. Hydroxychloroquine (HCQ), a major medication in systemic lupus erythematosus, has a long half-life and can be quantified by high-performance liquid chromatography. This international study evaluated nonadherence in 305 lupus patients with flares using drug levels (HCQ <200 ng/ml or undetectable desethylchloroquine), and self-administered questionnaires (MASRI <80% or MMAS-8 <6). Drug levels defined 18.4% of the patients as severely nonadherent. In multivariate analyses, younger age, nonuse of steroids, higher body mass index, and unemployment were associated with nonadherence by drug level. Questionnaires classified 39.9% of patients as nonadherent. Correlations between adherence measured by questionnaires, drug level, and physician assessment were moderate. Both methods probably measured two different patterns of nonadherence: self-administered questionnaires mostly captured relatively infrequently missed tablets, while drug levels identified severe nonadherence (i.e., interruption or erratic tablet intake). The frequency with which physicians miss nonadherence, together with underreporting by patients, suggests that therapeutic drug monitoring is useful in this setting. (Trial registration: ClinicalTrials.gov: NCT01509989.)., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient's life quality index (LQI)., Methods: This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunodeficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%., Results: Thirty patients entered the study; 28 completed the two periods. IgRT exposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump., Conclusions: Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician's armamentarium which is preferred by some patients and is cost-effective. CLINICALTRIALS., Gov Identifier: NCT02180763 CLINICAL IMPLICATIONS: Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician's armamentarium.

Immune thrombocytopenia (ITP) is an acquired antibody-mediated disease, for which splenectomy remains a curative treatment. We analyzed histology and phenotypes of ITP-splenectomy specimens from 41 adult patients, with different previous ITP-specific treatments, including B-cell-depleting rituximab (RTX) or not, in an attempt to predict splenectomy success or failure on the basis of day 56 postoperative platelet counts. RTX-naive ITP-spleen samples, compared with those from a 20-patient control trauma cohort, contained the following nonspecific, ITP-evocative, white-pulp lesions: follicular helper T-cell (programmed death-1 and inducible T-cell COStimulator) expansion in reactive follicles (P=0.01 and 0.03, respectively) and regulatory T-cell (FOXP3) expansion in the T-cell zone (P=0.049). On comparing ITP-splenectomy samples that would be successful with those that would be failures, only marginal zone hyperplasia differed (P=0.017). Indeed, 13/21 (61.9%) successful splenectomy samples exhibited marginal zone hyperplasia, as opposed to 1/9 (11.1%) failed splenectomy specimens. RTX impact on ITP-splenectomy samples was characterized by white-pulp (P=0.03) and marginal zone atrophies (P=0.01), and periarteriolar T-cell-zone hyperplasia (P<0.0001). The results of this novel comparative study of the histologic patterns of 41 ITP patients' evocative splenic lesions enabled clear description of different ITP morphologies and phenotypes, as a function of prior treatment and splenectomy success or failure.

Background: Monoclonal gammopathy-associated systemic capillary-leak syndrome, also known as Clarkson disease, is a rare condition characterized by recurrent life-threatening episodes of capillary hyperpermeability in the context of a monoclonal gammopathy. This study was conducted to better describe the clinical characteristics, natural history, and long-term outcome of monoclonal gammopathy-associated systemic capillary-leak syndrome., Methods: We conducted a cohort analysis of all patients included in the European Clarkson disease (EurêClark) registry between January 1997 and March 2016. From diagnosis to last follow-up, studied outcomes (eg, the frequency and severity of attacks, death, and evolution toward multiple myeloma) and the type of preventive treatments administered were monitored every 6 months., Results: Sixty-nine patients (M/F sex ratio 1:1; mean ± SD age at disease onset 52 ± 12 years) were included in the study. All patients had monoclonal gammopathy of immunoglobulin G type, with kappa light chains in 47 (68%). Median (interquartile range) follow-up duration was 5.1 (2.5-9.7) years. Twenty-four patients (35%) died after 3.3 (0.9-8) years. Fifty-seven (86%) patients received at least one preventive treatment, including intravenous immunoglobulins (IVIg) n = 48 (73.8%), theophylline n = 22 (33.8%), terbutaline n = 22 (33.8%), and thalidomide n = 5 (7.7%). In the 65 patients with follow-up, 5- and 10-year survival rates were 78% (n = 35) and 69% (n = 17), respectively. Multivariate analysis found preventive treatment with IVIg (hazard ratio 0.27; 95% confidence interval, 0.10-0.70; P = .007) and terbutaline (hazard ratio 0.35; 95% confidence interval, 0.13-0.96; P = .041) to be independent predictors of mortality., Conclusions: We describe the largest cohort to date of patients with well-defined monoclonal gammopathy-associated systemic capillary-leak syndrome. Preventive treatment with IVIg was the strongest factor associated with survival, suggesting the use of IVIg as the first line in prevention therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To demonstrate the bioequivalence between 2 intravenous immunoglobulin (IVIG) preparations, TEGELINE ® and ClairYg ® , a ready-to-use 5% IVIG, in primary immunodeficiency (PID). Secondary objectives were to assess the efficacy, safety and pharmacokinetics of ClairYg ® ., Methods: Twenty-two adult PID patients receiving stable doses of TEGELINE ® (5% lyophilized IVIG) were switched to ClairYg ® for 6 months. ClairYg ® was administered under the same conditions as TEGELINE ® , either every 3 or 4 weeks. The primary endpoint was mean average total IgG trough level at steady state with ClairYg ® versus TEGELINE ® . Clinical efficacy was also assessed in terms of infections and associated events., Results: Bioequivalence was established with a mean average total IgG trough level at steady state being 8.05g/L with TEGELINE ® and 9.17g/L with ClairYg ® (i.e. geometric mean for the difference between ClairYg ® and TEGELINE ® was 1.136; [90% CI: 1.092-1.181] P<0.001), within the pre-specified margin to establish bioequivalence (0.80-1.25). Total IgG trough levels remained clinically adequate (>4-6g/L) throughout the study. No patient was hospitalized for infection or had serious bacterial infections while receiving ClairYg ® . The median annualized infections rate per patient was similar for both products: 4.35 [0; 21.8] for TEGELINE ® and 4.30 [0; 15.1] for ClairYg ® . Infections were less common with higher IgG trough levels (>8.16g/L). ClairYg ® showed good safety, in particular good hepatic and renal tolerance, and did not induce hemolysis. ClairYg ® pharmacokinetics profile was comparable to that of TEGELINE ® ., Conclusion: ClairYg ® is safe and effective in the treatment of adult PID., (Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Introduction: The Bentall procedure is a cardiac surgery involving graft replacement of the aortic valve, aortic root and ascending aorta. Graft infection after Bentall's procedure (BGI) is infrequent but severe, and often difficult to diagnose and treat., Patients and Methods: A retrospective cohort study was performed using the Bordeaux endocarditis database of adult patients admitted to the Bordeaux University Medical Hospital for BGI between 2008 and 2014. Published case reports were identified in the literature., Results: We identified 10 BGI patients in the database and 13 in the literature. The majority of infections were late-onset (20/23) and occurred as a result of gram positive cocci bacterial infection (16/22). Detailed diagnoses of the described BGI were determined using echocardiography, computed tomography (CT) and positron emission tomography/CT (PET/CT). Labeled-leukocyte scintigraphy was not reported in any case. Prolonged antibiotic therapy and surgery were found to be the treatment of choice for BGI; however it was not always possible to perform a surgical intervention. Clinical relapses occurred even with a negative PET/CT, while PET/CT consistently positive for BGI occurred in the absence of clinical relapse. This suggests that the use of PET/CT for follow-up is questionable., Conclusion: Diagnosis of BGI is difficult, due to the combination of clinical, biological, and radiological observations obtained through transesophageal echocardiography and CT. PET/CT is an alternative method to diagnosis BGI, but its impact on clinical management remains unclear. Current data suggests that if surgical replacement of the prosthesis is not possible, patients should be treated with prolonged antibiotic therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Safety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization., Objectives: To assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France., Methods: Systematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11-25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barré syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008-2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations., Results: With a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41-0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results., Conclusion: Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Both intravenous and subcutaneous immunoglobulins are therapeutic modalities approved in various conditions, including primary and secondary immune deficiencies and autoimmune disorders. To date, immunoglobulins have more often been considered as a safe medication, with minor adverse effects such as hypertension, fever and chills, nausea, myalgia or headache. However, with the wider use of immunoglobulins in the treatment of autoimmune diseases, severe side effects have also been reported to occur in immunoglobulin-treated patients, especially anaphylaxis, aseptic meningitis, acute renal impairment, thrombotic events as well as haematological manifestations. This paper reviews all the potential adverse events related to immunoglobulin therapy and establishes a comprehensive guideline for the management of these events., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Immune thrombocytopenic purpura (ITP) is a disease characterized by antibody-mediated platelet destruction. The T- and B-cell subsets have been extensively studied in primary ITP, but the NK cell compartment has been less thoroughly explored. We investigated the NK cell receptor repertoire and the functionality of NK cells in the peripheral blood and spleen in patients with primary ITP. An immunophenotypic analysis of peripheral blood lymphocytes from patients revealed that the numbers of CD19 + B lymphocytes, CD4 + and CD8 + T lymphocytes and CD3 - CD56 + NK cells were within the normal range. No major alteration to the expression of distinct inhibitory or activating NK cell receptors was observed. The functionality of NK cells, as evaluated by their ability to degranulate in conditions of natural cytotoxicity or antibody-dependent cell cytotoxicity (ADCC), was preserved in these patients. By contrast, these stimuli induced lower levels of IFNγ production by the NK cells of ITP patients than by those of healthy controls. We then compared the splenic NK cell functions of ITP patients with those of cadaveric heart-beating donors (CHBD) as controls. The splenic NK cells of ITP patients tended to be less efficient in natural cytotoxicity conditions and more efficient in ADCC conditions than control splenic NK cells. Finally, we found that infusions of intravenous immunoglobulin led to the inhibition of NK cell activation through the modulation of the interface between target cells and NK cells., (Copyright © 2015. Published by Elsevier Inc.)

Objective: Romiplostim has maintained long-term platelet counts in patients with immune thrombocytopenia (ITP) for up to 5 yr in clinical studies. This prospective observational study aimed to describe romiplostim utilisation and outcomes in European clinical practice., Methods: Adults with primary ITP who received romiplostim in routine care were eligible., Results: Three-hundred and forty patients were eligible for analysis, of whom 299 (88%) completed the 2-yr observation period. The median age was 62 yr, with 43% of patients aged ≥65 yr, and two-thirds of patients initiated romiplostim before splenectomy. The median average weekly dose of romiplostim was 2.8 μg/kg. The median baseline platelet count was 20 × 10 9 /L, which increased after 2 wk of romiplostim treatment and remained >50 × 10 9 /L thereafter. After romiplostim initiation, there was a decrease in rates of grade ≥3 bleeding events (from 12 to 2 per 100 patient-years) and ITP-related hospitalisations (from 87 to 33 per 100 patient-years). The rate of thrombotic events was 2 per 100 patient-years, and bone marrow fibrosis occurred in two patients., Conclusions: Romiplostim dosing, effectiveness and safety in an unselected real-world ITP population seemed comparable with that observed in clinical studies., (© 2016 Amgen Inc. European Journal of Haematology. Published by John Wiley & Sons Ltd.)

Platelet δ-storage pool disease (δ-SPD) is a platelet function disorder characterized by a reduction in the number or content of dense granules. Reports on δ-SPD are mostly limited to case presentations. We aimed to retrospectively describe a series of patients with δ-SPD to better characterize the disease. We studied 16 patients with congenital or acquired δ-SPD. Lumiaggregometry, α- and δ-granules content, platelet ultrastructure, α IIb β 3 integrin, and glycoprotein Ib (GPIb) activation were assessed. Most of the patients generally demonstrate mild to moderate bleeding diathesis. Platelet aggregation studies showed moderate abnormalities with variable profiles, while all the individuals had almost complete absence of adenosine triphosphate release. Mepacrine capture, CD63 expression, and study of dense granules by electron microscopy enabled to distinguish different subtypes of δ-SPD with quantitative or qualitative defect. Surprisingly, significantly decreased GPIb expression levels after platelet activation with thrombin receptor activating peptide 50 μM were found, suggesting that GPIb-impaired mobilization may represent an additional feature of the disorder. In conclusion, δ-SPD represents a complex disorder with various clinical and biological aspects, requiring a great deal of expertise to be properly diagnosed., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Purpose: The present study was designed to assess the efficacy and safety of IGNG that is a new liquid, saccharose and maltose-free highly purified ready-to-use 5% intravenous immunoglobulin (IVIg), in primary immune thrombocytopenic patients with severe thrombocytopenia., Methods: Nineteen adults with a platelet count ≤ 25 × 10 9 /L received a single dose of IGNG (1 g/kg) on Day 1, with a second identical dose on Day 3 if needed. Patients were followed for 30 days. Primary endpoint was the response rate, defined as the proportion of patients with a platelet count ≥ 50 × 10 9 /L within 96 hours after the first IGNG dose., Results: All but one of the 17 evaluable patients for efficacy responded with an overall response rate of 94.1% (95% CI 71.3%-99.9%). Response was observed after only one infusion (1 g/kg boby weight) in 11 patients (59%) and the others required a second dose. Mean time to response was 2.2 days. Maximum platelet count was reached within 1 week after the first dose and lasted for approximately 2 weeks. Patients requiring a second dose had lower platelet counts at baseline than patients requiring a single dose. In the 19 evaluable patients for safety, IGNG demonstrated good safety, good hepatic and renal tolerance, and did not induce hemolysis. This trial was registered at the French Medical Agency (AFSSAPS) as #DI n°060735.

We herein report the case of a 52-year-old woman who consulted us because of a 2-month history of a fever, anorexia and weight loss. A physical examination was unremarkable. The blood count showed mild anemia and lymphopenia, and lactate dehydrogenase was elevated. Creatinine clearance was normal and proteinuria was undetectable. CT showed enlarged kidneys. A bone marrow biopsy was normal. PET-CT showed an intense uptake of 18 fluorodeoxyglucose in both kidneys. A kidney biopsy provided the diagnosis of intravascular large B-cell lymphoma (IVLBCL). Kidney-limited IVLBCL without an impairment in the renal function or proteinuria has not been described. We analyzed the 38 published cases of IVLBCL involving the kidney to describe the main features of this entity.

Background: Although Hizentra is indicated for immunoglobulin replacement therapy in patients with primary and secondary immunodeficiencies, phase III trials have focused on patients with primary immunodeficiencies. In this 9-month, real-life, prospective, non-interventional, longitudinal, multicenter study of patients with primary and secondary immunodeficiencies in France, treatment modalities (primary endpoint), efficacy, safety, tolerability, quality of life, and treatment satisfaction were evaluated using descriptive statistics., Results: Starting in January 2012, 117 patients were enrolled (99 adults, 18 children). Secondary immunodeficiencies were present in 48.7 % of patients. At follow-up, injections were administered every 7 days in 92.2 % of patients. Nine patients (7.8 %) were taking Hizentra every 10-14 days. The median dose of Hizentra administered was 0.1 g/kg/injection. Fifty-six patients were administered doses <0.1 g/kg/injection and 13 patients were administered doses >0.2 g/kg/injection. Mean trough IgG titers were 9.0 ± 3.3 g/L (median 8.3 g/L). The mean yearly rate of infection was 1.2 ± 1.9. Mean scores on the Short Form-36 physical and mental component summaries were 46.3 ± 10.0 and 46.6 ± 9.3, respectively. Scores on the Treatment Satisfaction Questionnaire for Medication ranged from 69.9 ± 19.9 to 88.3 ± 21.2 depending on the domain. Treatment with Hizentra was well tolerated. No single drug-related systemic reaction occurred in more than one patient and few local reactions were reported (n = 5)., Conclusions: Under real-life conditions and in a cohort that included patients with primary and secondary immunodeficiencies, treatment with Hizentra was effective and well tolerated and patients were generally satisfied with the treatment.

Refractory immune thrombocytopenia (ITP) was previously defined as lack of a minimum response to splenectomy and the requirement for long-term treatment to reduce the risk of significant bleeding events. In this multicenter study, we included 37 patients with multirefractory ITP, defined as no response to splenectomy, rituximab, romiplostim, and eltrombopag. As compared with a historical cohort of 183 ITP patients, matched on the calendar year of ITP diagnosis with a 5:1 ratio, patients with multirefractory ITP were more likely to have secondary ITP (odds ratio [OR], 4.84; 95% confidence interval [CI], 1.31-17.86; P = .018) and monoclonal gammopathy of undetermined significance (OR, 5.94; 95% CI, 1.08-32.48; P = .04). The median duration of ITP before being recognized as multirefractory was 78 months (range, 6-450). The patients showed failure of a median of 10.5 prior treatment lines for ITP (range, 6-15). At the end of follow-up (median, 84 months; range, 12-455), only 1/14 patients achieved response with immunosuppressant therapy alone. By contrast, 7/10 patients achieved response with a combination of immunosuppressant therapy and thrombopoietin-receptor agonists that lasted for a median of 15 months (range, 6-32). Throughout the course of ITP, 5/37 patients died, 3 with ITP (bleeding, n = 2; sepsis n = 1); 15 (40%) had at least 1 bacterial infection and 9 (24%) at least 1 episode of thrombosis. In conclusion, multirefractory ITP was associated with high morbidity and mortality. Combining an immunosuppressant therapy with thrombopoietin-receptor agonists may be a good strategy for management for these patients with severe disease., (© 2016 by The American Society of Hematology.)

Inherited thrombocytopenia (IT) is a heterogeneous group of rare diseases that are often confused with immune thrombocytopenia (ITP). The objective of this study was to supply clinicobiological elements that allow a distinction to be drawn between IT and chronic ITP. We then compared 23 adult patients with IT and 9 patients with chronic ITP. Our study revealed six discriminating criteria: (i) an age of discovery <34 years: positive predictive value (PPV) = 88.2% [63.6; 98.5], (ii) a family history of thrombocytopenia: PPV = 100.0% [82.4; 100.0], (iii) a personal history of bleeding: PPV = 100% [76.8; 100.0], (iv) a mean platelet volume >11 fL: PPV = 93.3% [68.1; 99.8], (v) an excess of giant platelets on blood smear: 100.0% [76.8; 100.0], and (vi) a percentage >44% of platelets with a surface area >4 µm(2) in electron microscopy: PPV = 83.3% [58.6; 96.4]. If at least three of these criteria were combined, it was possible to distinguish IT from chronic ITP with 91.3% [72.0; 98.9] sensitivity and PPV = 100.0% [66.4; 100.0] specificity. The secondary objective of this study was to assess the prevalence of potential IT diagnosis in patients with chronic thrombocytopenia of uncertain origin. Applying our diagnostic approach to a series of 20 cases allowed us to estimate that 40% of them could be suffering from IT. Finally, our diagnostic approach may help to correctly distinguish IT from chronic ITP, particularly in the context of macrothrombocytopenia.

This prospective observational cohort study aimed to explore the clinical features of incident immune thrombocytopenia in adults and predictors of outcome, while determining if a family history of autoimmune disorder is a risk factor for immune thrombocytopenia. All adults, 18 years of age or older, recently diagnosed with immune thrombocytopenia were consecutively recruited across 21 hospital centers in France. Data were collected at diagnosis and after 12 months. Predictors of chronicity at 12 months were explored using logistic regression models. The association between family history of autoimmune disorder and the risk of developing immune thrombocytopenia was explored using a conditional logistic regression model after matching each case to 10 controls. One hundred and forty-three patients were included: 63% female, mean age 48 years old (Standard Deviation=19), and 84% presented with bleeding symptoms. Median platelet count was 10×10(9)/L. Initial treatment was required in 82% of patients. After 12 months, only 37% of patients not subject to disease-modifying interventions achieved cure. The sole possible predictor of chronicity at 12 months was a higher platelet count at baseline [Odds Ratio 1.03; 95%CI: 1.00, 1.06]. No association was found between outcome and any of the following features: age, sex, presence of either bleeding symptoms or antinuclear antibodies at diagnosis. Likewise, family history of autoimmune disorder was not associated with incident immune thrombocytopenia. Immune thrombocytopenia in adults has been shown to progress to a chronic form in the majority of patients. A lower platelet count could be indicative of a more favorable outcome., (Copyright© Ferrata Storti Foundation.)

Histologic and phenotypic analyses of splenectomy samples from 17 patients with common variable immunodeficiency (CVID) showed the following nonspecific, evocative, white-pulp lesions: white-pulp hyperplasia (WPH) with reactive follicles, giant follicles (GFs), marginal zone hyperplasia, periarteriolar T-zone hyperplasia (PATH) and/or granulomas, which enabled us to discern 2 groups: the first (n=6) composed of WPH with reactive follicles without granulomas, and the second (n=9) characterized by the presence of granulomas with or without WPH. All specimens were Epstein-Barr virus negative by in situ hybridization. Molecular analyses revealed a polyclonal immunoglobulin heavy chain gene (IGH) rearrangement (n=12). WPH-only patients were mostly female individuals and younger at CVID onset, diagnosis, and splenectomy, but their interval between the first symptom and diagnosis was longer; they had more associated infectious events, autoimmune disease, pulmonary complications, and liver regenerative nodular hyperplasia; their IgG, IgA, and IgM concentrations were also higher. Granuloma-group patients were mostly male individuals; were older at CVID onset, diagnosis, and splenectomy; had disseminated granulomatous disease, but infectious events, autoimmune disease, pulmonary complications, and liver regenerative nodular hyperplasia were less common; their immunoglobulin concentrations were lower. Histologic comparisons between the WPH-only and granuloma groups showed more intense WPH and more intense marginal zone hyperplasia and fewer GFs in the former versus more developed PATH and more common GFs in the latter. The results of this novel comparative study of the histologic patterns of 17 CVID patients' evocative splenic lesions suggested different biological and clinical profiles.

Purpose: To develop French recommendations about the management of vaccinations, the screening of cervical cancer and the prevention of pneumocystis pneumonia in systemic lupus erythematosus (SLE)., Methods: Thirty-seven experts qualified in internal medicine, rheumatology, dermatology, nephrology and pediatrics have selected recommendations from a list of proposition based on available data from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified., Results: Inactivated vaccines do not cause significant harm in SLE patients. Experts recommend that lupus patient should receive vaccinations accordingly to the recommendations and the schedules for the general public. Pneumococcal vaccination is recommended for all SLE patients. Influenza vaccination is recommended for immunosuppressed SLE patients. Live attenuated vaccines should be avoided in immunosuppressed patients. Yet, recent works suggest that they can be considered in mildly immunosuppressed patients. Experts have recommended a cervical cytology every year for immunosuppressed patients. No consensus was obtained for the prevention of pneumocystis pneumonia., Conclusion: These recommendations can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients., (Copyright © 2016 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Objective: Findings from the WEGENT trial and other short-term studies have suggested that azathioprine (AZA) or methotrexate (MTX) could effectively maintain remission of granulomatosis with polyangiitis (Wegener's) (GPA) or microscopic polyangiitis (MPA). This study was undertaken to examine whether differences in rates of relapse or adverse events would appear after discontinuation of these 2 maintenance regimens, when assessed over a longer followup period., Methods: Long-term outcomes in patients enrolled in the WEGENT trial were analyzed according to their randomized treatment group (AZA or MTX). Parameters at trial entry were evaluated as potential prognostic factors for death, relapse, or damage in multivariate models., Results: Data from 10 years of followup were available for 112 (88.8%) of the 126 original trial participants. The median followup time was 11.9 years (95% confidence interval [95% CI] 11.3-12.5 years). In patients receiving AZA and those receiving MTX, the 10-year overall survival rates were 75.1% (95% CI 64.8-86.9%) and 79.9% (95% CI 70.3-90.8%) (P = 0.56), respectively, and relapse-free survival rates were 26.3% (95% CI 17.3-40.1%) and 33.5% (95% CI 23.5-47.7%) (P = 0.29), respectively. No between-treatment differences were observed with regard to rates of relapse, adverse events, damage, survival without severe side effects, and survival without relapse and severe side effects. In analyses limited to the 97 patients with GPA, no between-treatment differences in survival rates were observed. The 10-year relapse-free survival rate was lower in patients with GPA than in patients with MPA. However, in the multivariate analysis, anti-proteinase 3 antineutrophil cytoplasmic antibody (ANCA) positivity, and not GPA, was retained as being independently associated with the relapse rate., Conclusion: The results of this long-term analysis confirm that AZA and MTX are comparable treatment options for maintaining remission of GPA or MPA. Despite achieving good overall survival with these treatments, relapse rates, adverse events, and damage remain matters of concern and further studies are needed to reduce their frequency in these ANCA-associated vasculitides., (© 2016, American College of Rheumatology.)

Introduction: Thymic epithelial tumor (TET)-associated cytopenia is rare but difficult to treat., Methods: We performed a multicenter, retrospective study of TET and associated forms of cytopenia in France. Cases were collected by the French National Reference Center for Autoimmune Cytopenia and the French National Thymic Malignancy Interest Group (Réseau Tumeurs Thymiques et Cancer) and through a call for cases by the French Society of Internal Medicine., Results: Thirty-six cases were recorded between 2002 and 2014 and followed up for a median of 38 months (interquartile range, 23-106 months). Thirty-two patients underwent surgery for TET, and 14 of the latter were in complete remission at last follow-up. Cytopenia can occur before, simultaneously, or after diagnosis of TET. The most common types of cytopenia were pure red cell aplasia (in 30% of cases) and Good syndrome (GS) (also in 30% of cases). Eleven patients displayed two or more episodes of cytopenia. Eighteen patients received steroids as their first-line treatment, leading to a complete response in nine. Other first-line treatments (cyclosporine and rituximab) were less effective but should be considered as treatment options. Infections developed in 84% of the patients with GS; this did not appear to be related to the presence or absence of immunosuppressive treatment or chemotherapy. Eight patients died during the follow-up period (two died of cytopenia and five of infections)., Conclusions: The optimal treatment for TET-associated cytopenia has not been clearly defined and the outcome does not appear to be correlated with TET progression. For GS, prophylactic immunoglobulin replacement therapy and prophylactic antibiotic therapy can be recommended., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin (IG) therapy is actually used for a broad range of diseases including primary and secondary immunodeficiency disorders, and autoimmune diseases. This therapy is available for intravenous (IV) and subcutaneous (SC) administration. The efficacy of the IG therapy has been demonstrated in numerous studies and across different diseases. Generally, IG infusions are well tolerated; however some well-known adverse reactions, ranging from mild to severe, are associated with the therapy. The most common adverse reactions including headache, nausea, myalgia, fever, chills, chest discomfort, skin and anaphylactic reactions, could arise immediately during or after the infusion. Delayed events could be more severe and include migraine headaches, aseptic meningitis, haemolysis renal impairment and thrombotic events. This paper reviews all the potential adverse events related to IG therapy and establishes a comprehensive guideline for the management of these events. Moreover it resumes the opinions and clinical experience of expert endorsers on the utilization of the treatment. Published data were classified into levels of evidence and the strength of the recommendation was given for each intervention according to the GRADE system., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In anecdotal reports, some patients with immune thrombocytopenia (ITP) maintained platelet counts after discontinuing romiplostim. Here, we examined rates of platelet response (≥50 × 10(9) /l), remission, splenectomy and adverse events in patients with primary ITP duration ≤6 months who were treated with romiplostim for ≤12 months. The starting dose of romiplostim was 1 μg/kg; concomitant and rescue treatments were permitted to maintain platelet counts. Patients with platelet counts ≥50 × 10(9) /l at the end of 12 months entered a dose taper in which the romiplostim dose was decreased as long as platelet counts were maintained. Remission (platelet count ≥50 × 10(9) /l for 24 consecutive weeks with no ITP treatments) was evaluated in patients once romiplostim was discontinued. Over the 12 months, a high response rate (>90%) was observed. Platelet response occurred quickly (median, ~2 weeks) and was observed for a cumulative median of 11 months. Remission was observed in 24 patients (32%); there were no significantly predictors of remission. Most (20/24) patients had remission start before the forced taper. No new safety signals were identified. Thus, in patients with early-stage ITP, romiplostim was well tolerated and induced rapid responses, with remission occurring in approximately one-third of patients (NCT01143038, Amgen 20080435)., (© 2015 John Wiley & Sons Ltd.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells. Somatic mutation in the phosphatidylinositol glycan class A (PIG-A), X-linked gene, is responsible for a deficiency in glycosphosphatidylinositol-anchored proteins (GPI-AP). The lack of one of the GPI-AP complement regulatory proteins (CD55, CD59) leads to hemolysis. The disease is diagnosed with hemolytic anemia, marrow failure and thrombosis. Thromboembolic complication occurs in 30% of patient after 10 years of follow-up and is the first event in one out of 10 patients. The two most common sites are hepatic and cerebral veins. These locations are correlated with high risk of death. Currently, these data are balanced with the use of a monoclonal antibody (Eculizumab), which has significantly improved the prognosis with a survival similar to general population after 36 months of follow-up. Anticoagulant treatment is recommended after a thromboembolic event but has no place in primary prophylaxis., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Persistent or chronic immune thrombocytopenias (P/C-ITP) are acquired blood disorders lasting more than 3 months or 1 year, respectively. The pathogenesis of these disorders is thought to be immunological. We hypothesized that some patients with P/C-ITP might have an intrinsic megakaryopoiesis defect. We identified a group of P/C-ITP patients with acquired isolated mild thrombocytopenia (30-100 × 10(9) /l), undetectable anti-platelet antibodies, negative autoimmune investigations and no need for treatment. We examined in vitro megakaryocyte differentiation and compared these patients' results with those of acute-ITP patients and healthy controls. No difference in proliferation, ploidy or expression of surface markers was found. In contrast, P/C-ITP patients had significantly fewer proplatelet-forming megakaryocytes. This novel observation demonstrated that some patients diagnosed with P/C-ITP have an intrinsic megakaryopoiesis defect independent of the bone-marrow environment. Further investigations are needed to dissect mechanisms underlying this impaired proplatelet formation in these patients., (© 2015 John Wiley & Sons Ltd.)

Background: Good syndrome (GS) is a rare condition in which thymoma is associated with hypogammaglobulinemia. It is characterized by increased susceptibility to bacterial, viral, and fungal infections, as well as autoimmunity. Most patients have no circulating B cells., Methods: The French DEFicit Immunitaire de l'adulte cohort provides detailed clinical and immunological descriptions of 690 adults with primary hypogammaglobulinemia. Comparisons between patients with GS, those with common variable immunodeficiency (CVID), and those with B(-) CVID (circulating B cells <1%) were performed., Results: Twenty-one patients had GS and 440 had CVID, including 39 B(-) CVID, with a median age at diagnosis of 60, 35, and 34 years, respectively. Invasive bacterial infections were observed in 90.5% of GS, 54% of CVID, and 72% of B(-) CVID patients. Eight patients with GS had opportunistic infections, despite normal peripheral CD4(+) T-cell numbers. Autoimmune complications were demonstrated in 76% of GS, 29% of CVID, and 26% of B(-) CVID patients. The spectrum of autoimmunity in GS was uncommon, consisting of oral lichen planus, graft-vs-host disease-like colitis, and pure red cell aplasia, different from the pattern observed in CVID patients. GS patients did not display lymphoid hyperplasia nor lymphoma, unlike those with CVID or B(-) CVID., Conclusions: GS differs notably from CVID and B(-) CVID: very late onset, no familial cases, and absence of lymphoid hyperplasia. The key observation is the very high frequency of invasive bacterial infections in GS, an issue that physicians should be aware of., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The present study describes the current clinical practice and hospital management of adults with immune thrombocytopenia (ITP) between 2009 and 2012 in France, based on the national discharge hospital database. Adult ITP patients were managed almost exclusively in public hospitals. A relatively stable number of patients, around 3200 per year, were hospitalized for ITP annually over the 4-year period, about two-thirds of whom were newly-diagnosed ITP. Re-hospitalizations tended to decrease over the study period. Intravenous immunoglobulin administration, concerning half of ITP hospitalized patients, and rituximab administration were stable over time, whereas a slight decrease of splenectomies was observed., (© 2015 John Wiley & Sons Ltd.)

Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS(+) blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4(+) T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To develop French recommendations about screening and management of cardiovascular risk factors in systemic lupus erythematosus (SLE)., Methods: Thirty-nine experts qualified in internal medicine, rheumatology and nephrology have selected recommendations from a list developed based on evidence from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified., Results: Experts recommended an annual screening of cardiovascular risk factors in SLE. Statins should be prescribed for primary prevention in SLE patients based on the level of LDL-cholesterol and the number of cardiovascular risk factors, considering SLE as an additional risk factor. For secondary prevention, experts have agreed on an LDL-cholesterol target of <0.7 g/L. Hypertension should be managed according to the 2013 European guidelines, using renin-angiotensin system blockers as first line agents in case of renal involvement. Aspirin can be prescribed in patients with high cardiovascular risk or with antiphospholipid antibodies., Conclusion: These recommendations about the screening and management of cardiovascular risk factors in SLE can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients., (Copyright © 2014 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Purpose: Hydroxyurea (HU) or hydroxycarbamide is an antimetabolite chemotherapy frequently used in the treatment of chronic myeloproliferative disorders. This treatment is usually well tolerated but a few cases of fever induced by the molecule have been reported in the literature. The aim of the study was to describe the clinical and biological characteristics of HU induced fever., Methods: We performed a cross sectional study of patients treated with HU and followed-up in an internal medicine department between 2006 and 2012. We added our cases of HU induced fever with those reported in the literature (Pubmed and Cochrane databases) since 1981., Results: We identified 38 cases of HU induced fever, including our 4 cases. The mean age was 65±10.9 years and the sex-ratio 1/2. The fever appeared after a median duration of treatment of 21 days and was usually high (40°C) but clinically well tolerated. A biological inflammatory syndrome (CRP: 131±92 mg/L) was constant and one third of the patients also presented with hepatitis or lung disease. A probabilistic antibiotic treatment was introduced for 34% of the patients. For the half of the patients, HU-reintroduction test was performed, and was positive for all the patients but one. As soon as HU was withdrawn, the fever disappeared in a median of 24 hours., Conclusion: HU induced fever is unusual. Clinical presentation is very stereotyped. When this adverse effect is suspected, an infectious disease must first be ruled out. If infection is excluded, HU has to be stopped., (Copyright © 2014 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Aim: To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis., Methods: MPA areas under the concentration-time curves between 0 and 12 h, 12 h trough concentrations and pre-dose concentrations (C0 ) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients' pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed., Results: In both autoimmune diseases, at PK assessment, median MPA C0 for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l(-1) (IQR 0.9-2.1 mg l(-1)) vs. 2.95 mg l(-1) (IQR 1.38-3.73 mg l(-1)) for SLE (P = 0.048) and 1.55 mg l(-1) (IQR 0.98-2.18 mg l(-1)) vs. 3 mg l(-1) (IQR 2.2-4.4 mg l(-1)) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C0 threshold of 2.5-3 mg l(-1) was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C0 ≥ 2.5-3 mg l(-1) at inclusion had better clinical outcomes during the 12 months following PK assessment., Conclusion: Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C0 measured approximately 12 h post-dose., (© 2014 The British Pharmacological Society.)

We conducted a prospective multicenter registry of 248 adult patients with immune thrombocytopenia (ITP) treated with rituximab to assess safety. We also assessed response and predictive factors of sustained response. In total, 173 patients received 4 infusions of 375 mg/m(2) and 72 received 2 fixed 1-g infusions 2 weeks apart. The choice of the rituximab regimen was based on the physician's preference and not patient characteristics. Overall, 38 patients showed minor intolerance to rituximab infusions; infusions had to be stopped for only 3 patients. Seven showed infection (n = 11 cases), with an incidence of 2.3 infections/100 patient-years. Three patients died of infection 12 to 14 months after rituximab infusions, but the role of rituximab was questionable. In total, 152 patients (61%) showed an overall initial response (platelet count ≥30 × 10(9)/L and ≥2 baseline value). At a median follow-up of 24 months, 96 patients (39%) showed a lasting response. On multivariate analysis, the probability of sustained response at 1 year was significantly associated with ITP duration <1 year (P = .02) and previous transient complete response to corticosteroids (P = .05). The pattern of response was similar with the 2 rituximab regimens. With its benefit/risk ratio, rituximab used off-label may remain a valid option for treating persistent or chronic ITP in adults. This trial was registered at www.clinicaltrials.gov as #NC1101295., (© 2014 by The American Society of Hematology.)

Objective: Studies have suggested that systemic lupus erythematosus (SLE) may be triggered by vaccinations. We undertook this study to investigate the relationship between vaccination and onset of SLE., Methods: This international case-control study was conducted between April 2008 and June 2012 in 36 specialist referral centers (34 in France and 2 in Quebec, Canada) and recruited patients ≤60 years old recently diagnosed as having either definite SLE (meeting ≥4 American College of Rheumatology [ACR] criteria including at least 1 immunologic criterion) or probable SLE (meeting 3 ACR criteria including at least 1 immunologic criterion). Controls were recruited from general practice settings through a closely monitored protocol and matched to patients by age, sex, region of residence, and date of recruitment. Vaccinations and other potential risk factors for SLE were assessed using a standardized telephone interview. We compared proportions of patients and controls who were vaccinated 12 and 24 months before the index date (date of first clinical symptom presented by the patient) using odds ratios (ORs) from conditional logistic regression., Results: We assessed 105 patients (89 with definite SLE and 16 with probable SLE) and 712 controls. Twenty-two of the 105 patients (21.0%) and 181 of the 712 controls (25.4%) had received at least 1 vaccination within 24 months before the index date (adjusted OR 0.9 [95% confidence interval 0.5-1.5]). The proportions of patients and controls vaccinated within the previous 12 months were also similar., Conclusion: Our study showed no association between exposure to vaccination and risk of developing SLE., (Copyright © 2014 by the American College of Rheumatology.)

Objectives: The aim of this study was to investigate whether the quadrivalent human papillomavirus (HPV) vaccine Gardasil is associated with a change in the risk of autoimmune disorders (ADs) in young female subjects., Design: Systematic case-control study of incident ADs associated with quadrivalent HPV vaccination in young women across France., Participants and Setting: A total of 113 specialised centres recruited (from December 2007 to April 2011) females aged 14-26 years with incident cases of six types of ADs: idiopathic thrombocytopenic purpura (ITP), central demyelination/multiple sclerosis (MS), Guillain-Barré syndrome, connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus and autoimmune thyroiditis. Control subjects matched to cases were recruited from general practice., Analysis: Multivariate conditional logistic regression analysis; factors included age, geographical origin, smoking, alcohol consumption, use of oral contraceptive(s) or vaccine(s) other than Gardasil received within 24 months before the index date and personal/family history of ADs., Results: Overall, 211 definite cases of ADs were matched to 875 controls. The adjusted odds ratio (OR) for any quadrivalent HPV vaccine use was 0.9 [95% confidence interval (CI) 0.5-1.5]. The individual ORs were 1.0 (95% CI 0.4-2.6) for ITP, 0.3 (95% CI 0.1-0.9) for MS, 0.8 (95% CI 0.3-2.4) for connective disorders and 1.2 (95% CI 0.4-3.6) for type 1 diabetes. No exposure to HPV vaccine was observed in cases with either Guillain-Barré syndrome or thyroiditis., Conclusions: No evidence of an increase in the risk of the studied ADs was observable following vaccination with Gardasil within the time periods studied. There was insufficient statistical power to allow conclusions to be drawn regarding individual ADs., (© 2013 The Association for the Publication of the Journal of Internal Medicine.)

Background: Symptomatic Primary Humoral Immunodeficiency Diseases (PHID) constitute a highly heterogeneous group of diseases characterized by a shared hypogammaglobulinemia, resulting in increased risk of recurrent or severe infections. Associations have been described with a variety of immunological abnormalities involving B and T-cell differentiation, T-cell activation and innate immunity. However, PHID discrimination remains based on B-lymphocyte abnormalities and other components of the immune system have not been sufficiently taken into account. We carried out unsupervised and supervised methods for classification in a cohort of 81 symptomatic PHID patients to evaluate the relative importance of 23 immunological parameters and to select relevant markers that may be useful for diagnosis and prognosis., Results: We identified five groups of patients, among which the percentage of PHID complications varied substantially. Combining the set of markers involved in PHID supported the existence of two distinct mechanisms associated with complications. Switched memory B-cell attrition and CD8+ HLA-DR + activated T-cell increase were the prominent abnormalities observed in PHID complications. Furthermore, in a subgroup of 57 patients with common variable immunodeficiency, the classification that added CD8+ HLA-DR + to the consensual EUROclass classification was better than the EUROclass model in predicting complications., Conclusion: These results highlight the importance of T-cell activation that may improve discrimination of PHID patients in specific subgroups and help to identify patients with different clinical outcomes.