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

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

Off-label use of biologics for the treatment of refractory and/or relapsing granulomatosis with polyangiitis.

OBJECTIVE: To describe the efficacy and safety of off-label use of biologics for refractory and/or relapsing granulomatosis with polyangiitis (GPA). METHODS: We conducted a French retrospective study including GPA patients who received off-label biologics for refractory and/or relapsing disease after failure of conventional immunosuppressive regimens. RESULTS: Among 26 patients included, 18 received infliximab (IFX), 2 adalimumab (ADA) and 6 abatacept (ABA). Biologics were initiated in median as 4th-line therapy (IQR 3-6) for relapsing and/or refractory disease in 23 (88%) and/or significant glucocorticoid-dependency in 8 cases (31%). At biologics initiation, median (IQR) BVAS and prednisone dose in anti- TNF-α and ABA recipients were 7 (3-8) and 2 (1-6), and 20 (13-30) mg/day and 20 (15-25) mg/day, respectively. Clinical manifestations requiring biologics were mainly pulmonary and ENT manifestations in 58% each. Anti-TNF-α and ABA were continued for a median duration of 8 months (IQR 6-13) and 11 months (IQR 6-18) respectively. Anti-TNF-α recipients showed remission, partial response and treatment failure in 10%, 30% and 60% at 6 months, and 25%, 20% and 55% at 12 months, respectively. ABA recipients showed remission, partial response and treatment failure in 17%, 33% and 50% at 6 months and 17%, 33% and 50% at 12 months. One patient treated with IFX experienced life-threatening reaction while one patient treated with ABA experienced a severe infection. CONCLUSION: This real-life study suggests that off-label use of anti-TNF-α and abatacept shows efficacy in less than 50% of refractory and/or relapsing GPA.

Diagnostics différentiels de la maladie de Castleman.

Clinicians are sometimes confronted with the diagnostic difficulties of the idiopathic form of Castleman's Disease (iMCD). As this review reports with demonstrative clinical cases, iMCD can mimic various serious systemic pathologies such as certain autoimmune diseases, Still's disease, POEMS syndrome, and malignant lymphoproliferations, sharing a very similar histology and identical symptoms. To make a diagnosis of iMCD, the clinician must eliminate all the pathologies mentioned above, but he must first think of it and evoke this diagnosis of rare disease before the first symptoms but also know how to evoke this diagnosis again even after several years of evolution of a disease like those mentioned above whose evolution is not favorable. © 2022 Published by Elsevier Masson SAS on behalf of Société nationale française de médecine interne (SNFMI).

[Challenges and potential solutions in first-line treatments for immune thrombocytopenia in adults]. / Traitements de première ligne au cours du purpura thrombopénique immunologique de l'adulte : état des lieux et perspectives.

The first line treatment of immune thrombocytopenic purpura (ITP) is well established and based on short course of corticosteroids associated with intravenous immunoglobulins (IVIg) for the most severe forms. Predniso(lo)ne is the corticosteroid agent usually given but dexamethasone appears as an alternative. Some guidelines recommend to use dexamethasone as first line when a rapid increase of platelet count is required. Dexamethasone could be used rather than IVIg for moderate to severe but non life-threatening bleeding manifestations. Other therapeutic options such as anti FcRn monoclonal antibodies or recombinant FcγR currently in development for ITP could be an option in the future. In newly diagnosed ITP, we unfortunately lack robust predictive risk factors of severity and chronic outcome. Identifying such factors could be helpful for considering the early use of some treatments which are commonly used as second or third line.

[Immune thrombocytopenia: From pathogenesis to treatment]. / Thrombopénie immunologique : de la physiopathologie aux traitements.

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to an immune peripheral destruction of platelets and an inappropriate platelet production. The pathogenesis of ITP is now better understood: it involves a humoral immune response which dependents on the stimulation of B cells by specific T cells called T follicular helper cells, leading to their differentiation into plasma cells that produce antiplatelet antibodies thus promoting the phagocytosis of platelets mainly by splenic macrophages. The deciphering of ITP pathogenesis has led to a better understanding of the inefficiency of treatments such as rituximab, although it has not provided yet the determination of biological predictive factor of response to treatments. Moreover, new therapeutic perspectives have been opened in the last few years with the development of molecules targeting Fcγ receptor signalling such as Syk inhibitor, or molecules increasing the clearance of pathogenic autoantibodies such as inhibitors of the neonatal Fc receptor (FcRn).

Endovascular stenting for chronic femoro-iliac venous obstructive disease: Clinical efficacy and short-term outcomes.

PURPOSE: To report the clinical efficacy and mid-term outcomes of endovascular treatment in patients with chronic, symptomatic, post-thrombotic femoro-iliac venous obstruction. MATERIALS AND METHODS: Forty-two patients with post-thrombotic syndrome (PTS) presenting with femoro-iliac venous obstructive lesions treated in our institution by endovascular approach between March 2012 and October 2017 were retrospectively included. There were 27 women and 15 men with a mean age of 47.3±17 (SD) years (range: 22-86 years). Procedure included first venous recanalization, then pre-dilatation and self-expandable metallic stenting of the narrowed or occluded iliac and/or femoral veins. Severity of PTS and quality of life were assessed at baseline and 3 months after the intervention respectively, using Villalta score and Chronic Venous Insufficiency Questionnaire (CIVIQ-20) scale. Imaging follow-up evaluation of stent patency was based on the results of duplex Doppler ultrasound and computed tomography. RESULTS: Immediate technical success was achieved in 41/42 (97.6%) patients, without any major complications. Primary patency, primary assisted patency and secondary patency at the end of the median imaging follow-up of 18.1 months (IQR, 9.7-34.4) were achieved in 29/42 (66.7%) patients, 33/42 (78.6%) patients and 37/42 (88.1%) patients, respectively. Median Villalta and CIVIQ-20 scores decreased from 14 (IQR, 10-19) and 57 (IQR, 39-72) at baseline, respectively, to 5 (IQR, 2-9) and 30 (IQR, 24-50) 3 months after the procedure, respectively (P<0.0001), showing significant decrease in the severity of PTS and improvement in the quality of life. The multiple linear regression model showed that both baseline Villalta and CIVIQ-20 scores ([95% CI: -7.80-3.79; P<0.0001] and [95% CI: 0.07-0.20; P<0.0001], respectively), age (95% CI: 0.04-0.19; P=0.002) and stenting expanse (95% CI: 0.97-5.65; P=0.006) were independent variables related to Villalta gain. Baseline Villalta (95% CI: 0.89-2.23; P<0.0001) was the single independent variable related to CIVIQ-20 gain. CONCLUSION: This study confirms the high clinical efficacy and favorable mid-term outcomes of endovascular stenting in patients with chronic symptomatic femoro-iliac venous obstructive lesions.

[Immunosuppressive therapy and fertility preservation: Indications and methods]. / Traitements immunosuppresseurs et préservation de la fertilité : indications et modalités pratiques.

Fertility preservation is routinely performed in cancerology but less systematically used in the field of immune diseases, even though the use of gonadotoxic treatments in young patients may be required and even though the disease itself can alter fertility. This review aimed to clarify the indications and methods of fertility preservation in this context. Cyclophosphamide is the only immunosuppressive drug requiring fertility preservation in women. In men, fertility preservation should be proposed before treatment with cyclophosphamide, methotrexate, mycophenolate mofetil or mTOR inhibitors. Other factors inherent to the disease or the patient may alter fertility. Thus, screening for infertility and fertility preservation have to be implemented as much as possible to increase the chances of successful procreation in patients with immune disease. For women, the choice between the different preservation methods depends on the patient's age, disease activity, the time available before the start of treatment, the possibility of future pregnancy and the woman's and even couple's wishes. Before puberty, the only accepted method is cryopreservation of ovarian tissue. After puberty, the first-line method is the cryopreservation of mature oocytes. If the treatment has to be started in an emergency, if ovarian hyperstimulation/oocyte retrieval is contraindicated or if the patient refuses this option, cryopreservation of ovarian tissue or GnRH agonists could be proposed. For men, the accepted method is sperm cryopreservation. For prepubertal boys, the cryopreservation of spermatogonia after testicular biopsy is still experimental.

[From pathogenesis of giant cell arteritis to new therapeutic targets]. / De la physiopathologie de l'artérite à cellules géantes aux nouvelles cibles thérapeutiques.

Giant cell arteritis (GCA) is the most common vasculitis in adults. GCA is a granulomatous large-vessel vasculitis involving the aorta and its major branches in people>50 years. Glucocorticoids (GC) remain the cornerstone of GCA treatment. Prednisone is usually started at 0.7 or 1mg/kg/day depending on the occurrence of ischemic complications. Then, GC are progressively tapered and stopped after a mean duration of 18 months. GC are very efficient but relapses often occur during their tapering. Moreover, GC-related side effects are very common during this long term GC therapy. Thus, it can be assumed that GC are not the ideal treatment for GCA and that GC-sparing strategies have to be developed. The pathogenesis of GCA is not fully understood but major advances have been achieved in the recent years. If the trigger of GCA, which is suspected to be infectious, is still not identified, mechanisms triggering the granulomatous inflammation of the arterial wall and the progressive vascular remodeling leading to the occurrence of ischemic events have been better and better deciphered. Thanks to these advances in the knowledge of GCA pathogenesis, new therapeutic targets have emerged such as blockade of the activation of T cells or inhibition of the interleukin-6 (IL-6), IL-12/23 or IL-1ß pathways.

Fcγ receptor expression on splenic macrophages in adult immune thrombocytopenia.

Splenic macrophages play a key role in immune thrombocytopenia (ITP) pathogenesis by clearing opsonized platelets. Fcγ receptors (FcγR) participate in this phenomenon, but their expression on splenic macrophages and their modulation by treatment have scarcely been studied in human ITP. We aimed to compare the phenotype and function of splenic macrophages between six controls and 24 ITP patients and between ITP patients according to the treatments they received prior to splenectomy. CD86, human leucocyte antigen D-related (HLA-DR) and FcγR expression were measured by flow cytometry on splenic macrophages. The major FcγR polymorphisms were determined and splenic macrophage function was assessed by a phagocytosis assay. The expression of the activation markers CD86 and HLA-DR was higher on splenic macrophages during ITP compared to controls. While the expression of FcγR was not different between ITP and controls, the phagocytic function of splenic macrophages was reduced in ITP patients treated with intravenous immunoglobulin (IVIg) within the 2 weeks prior to splenectomy. The FCGR3A (158V/F) polymorphism, known to increase the affinity of FcγRIII to IgG, was over-represented in ITP patients. Thus, these are the first results arguing for the fact that the therapeutic use of IVIg during human chronic ITP does not modulate FcγR expression on splenic macrophages but decreases their phagocytic capabilities.

Management of giant cell arteritis: Recommendations of the French Study Group for Large Vessel Vasculitis (GEFA).

PURPOSE: Management of giant cell arteritis (GCA, Horton's disease) involves many uncertainties. This work was undertaken to establish French recommendations for GCA management. METHODS: Recommendations were developed by a multidisciplinary panel of 33 physicians, members of the French Study Group for Large Vessel Vasculitis (Groupe d'étude français des artérites des gros vaisseaux [GEFA]). The topics to be addressed, selected from proposals by group members, were assigned to subgroups to summarize the available literature and draft recommendations. Following an iterative consensus-seeking process that yielded consensus recommendations, the degree of agreement among panel members was evaluated with a 5-point Likert scale. A recommendation was approved when ≥ 80% of the voters agreed or strongly agreed. RESULTS: The 15 retained topics resulted in 31 consensus recommendations focusing on GCA nomenclature and classification, the role of temporal artery biopsy and medical imaging in the diagnosis, indications and search modalities for involvement of the aorta and its branches, the glucocorticoid regimen to prescribe, treatment of complicated GCA, indications for use of immunosuppressants or targeted biologic therapies, adjunctive treatment measures, and management of relapse and recurrence. CONCLUSIONS: The recommendations, which will be updated regularly, are intended to guide and harmonize the standards of GCA management.

[Prevention of infections in adults and adolescents with systemic lupus erythematosus: Guidelines for the clinical practice based on the literature and expert opinion]. / Prévention des infections au cours du lupus systémique chez l'adulte et l'adolescent : élaboration de recommandations pour la pratique clinique, à partir d'une analyse de la littérature et de l'avis d'experts.

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.

Impact of microbiological samples in the hospital management of community-acquired, nursing home-acquired and hospital-acquired pneumonia in older patients.

We investigated the positivity rate, the detection rates for non-covered pathogens and the therapeutic impact of microbiological samples (MS) in community-acquired pneumonia (CAP), nursing home-acquired pneumonia (NHAP) and hospital-acquired pneumonia (HAP) in elderly hospitalised patients. Patients aged 75 years and over with pneumonia and hospitalised between 1/1/2013 and 30/6/2013 in the departments of medicine (5) and intensive care (1) of our university hospital were included. Microbiological findings, intra-hospital mortality and one-year mortality were recorded. Among the 217 patients included, there were 138 CAP, 56 NHAP and 23 HAP. MS were performed in 89.9, 91.1 and 95.6 % of CAP, NHAP and HAP, respectively. Microbiological diagnosis was made for 29, 11.8 and 27.3 % of patients for CAP, NHAP and HAP, respectively (p = 0.05). Non-covered pathogens were detected for 8 % of CAP, 2 % of NHAP and 13.6 % of HAP (p = 0.1). The antimicrobial spectrum was significantly more frequently reduced when the MS were positive (46.7 % vs. 10.8 % when MS were negative, p = 10(-7)). The MS positivity rate was significantly lower in NHAP than in CAP and HAP. MS revealed non-covered pathogens in only 2 % of NHAP. These results show the poor efficiency and weak clinical impact of MS in the management of pneumonia in hospitalised older patients and suggest that their use should be rationalised.

Is there still a place for "old therapies" in the management of immune thrombocytopenia?

New molecules such as rituximab or thrombopoietin receptor agonists (romiplostim and eltrombopag) have changed the management of immune thrombocytopenia. Therefore, old drugs which are less expensive and with a well-known benefit/risk ratio are being underused. We aim to define the place of dapsone, danazol, hydroxychloroquine and vinca-alkaloids at the era of targeted therapy in immune thrombocytopenia. With a response rate around 30% to 50%, dapsone is an interesting second-line therapy to be used just after corticosteroids. Patients with positive antinuclear antibodies can benefit from hydroxychloroquine with a 50% response rate. Because of its side effects, mostly virilization, danazol will be preferentially used in the elderly. Vinca-alkaloids could be temporarily used in patients that do not respond to intravenous immunoglobulins or to limit their use to avoid shortage periods.

[Pathogenesis of large vessel vasculitis]. / Physiopathologie des vascularites primitives des gros vaisseaux.

Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are two granulomatous vasculitis affecting large arteries that present specific epidemiological and clinical features. Their pathogenesis is not fully understood but major advances have been obtained during the last years, thus allowing the emergence of new therapeutic strategies. GCA and TA develop on a specific genetic background but share some similarities regarding the immunological pathways involved in their pathogenesis. The trigger of these diseases is not clearly identified but it is thought that an infectious agent could activate and lead to the maturation of dendritic cells that are localized in the adventitia of arteries. Then, the cells of the adaptative immune response are recruited and activated: CD4 T cells that polarize into Th1 and Th17 cells, cytotoxic CD8 T cells and Natural Killer cells. Furthermore, the T regulatory cells (Treg) are decreased both in GCA and TA. Humoral immune response seems also to be involved, especially in TA. Then, the cytokines produced by T lymphocytes (especially IL-17 and IFN-γ) trigger the recruitment and activation of monocytes and their differentiation into macrophages and multinuclear giant cells that produce IL-1ß and IL-6 that are responsible for general symptoms of GCA and TA, and cytotoxic mediators and growth factors that trigger the remodeling of the arterial wall leading to aneurysms and ischemic manifestations of GCA an TA.

[Diagnosis of an increased serum level of ferritin]. / Démarche diagnostique devant une hyperferritinémie.

The discovery of a hyperferritinemia is most of the time fortuitous. The diagnostic approach aims at looking for the responsible etiology and at verifying if an iron hepatic overload is present or not. Three diagnostic steps are proposed. The clinical elements and a few straightforward biological tests are sufficient at first to identify one of the four main causes: alcoholism, inflammatory syndrome, cytolysis, and metabolic syndrome. None of these causes is associated with a significant iron hepatic overload. If the transferring saturation coefficient is raised (>50%) a hereditary hemochromatosis should be discussed. Secondly, less common disorders will be discussed. Among these, only the chronic hematological disorders either acquired or congenital are at risk of iron hepatic overload. Thirdly, if a doubt persists in the etiologic research, and the serum ferritin level is very high or continues to rise, it is essential to verify that there is no iron hepatic overload. For that purpose, the MRI with study of the iron overload is the main test, which will guide the therapeutic attitude. Identification of more than a single etiology occurs in more than 40% of the cases.