Publications by authors named "Mathilde de Menthon"

26 Publications

  • Page 1 of 1

Severe ulcerative gastrointestinal toxicity following ibrutinib therapy: two case studies.

Leuk Lymphoma 2020 Nov 12:1-4. Epub 2020 Nov 12.

Assistance Publique - Hôpitaux de Paris, Department of Internal Medicine and Clinical Immunology, Bicetre Hospital, Le Kremlin Bicêtre, France.

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http://dx.doi.org/10.1080/10428194.2020.1845333DOI Listing
November 2020

Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French Histiocytosis Group and systematic literature review.

Br J Haematol 2020 06 19;189(5):869-878. Epub 2020 Mar 19.

Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Centre National de Référence des Histiocytoses, Hôpital Saint-Louis, Paris, France.

Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete picture of the efficacy and safety of 2CdA (2-chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a-LCH) patients who received single-agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3-4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose <50 mg/m . Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re-treated patients, five went into CR, two in PR, and one died. Single-agent 2CdA is effective in reactivated a-LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine).
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http://dx.doi.org/10.1111/bjh.16449DOI Listing
June 2020

Usual interstitial pneumonia in ANCA-associated vasculitis: A poor prognostic factor.

J Autoimmun 2020 01 27;106:102338. Epub 2019 Sep 27.

Department of Internal Medicine and Clinical Immunology, CHU Dijon Bourgogne, Dijon, France.

Background: Progressive fibrosing interstitial lung disease (ILD) is rarely associated with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). This study focused on the outcomes of ILD patients with associated AAV (AAV-ILD).

Methods: AAV-ILD (cases: microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) with ILD) were compared to AAV patients without ILD (controls). ILD was defined as a usual interstitial pneumonia (UIP) or non-specific interstitial pneumonia (NSIP) pattern. Two controls were matched to each case for age (>or ≤65 years), ANCA status (PR3-or MPO-positive) and creatininemia (≥or <150 μmol/L).

Results: Sixty-two cases (89% MPO-ANCA+) were included. Median age at AAV diagnosis was 66 years. ILD (63% UIP), was diagnosed before (52%) or simultaneously (39%) with AAV. Cases versus 124 controls less frequently had systemic vasculitis symptoms. One-, 3- and 5-year overall survival rates, respectively, were: 96.7%, 80% and 66% for cases versus 93.5%, 89.6% and 83.8% for controls (p = 0.008). Multivariate analyses retained age >65 years (hazard ratio (HR) 4.54; p < 0.001), alveolar haemorrhage (HR 2.25; p = 0.019) and UIP (HR 2.73; p = 0.002), but not immunosuppressant use, as factors independently associated with shorter survival.

Conclusion: For AAV-ILD patients, only UIP was associated with poorer prognosis. Immunosuppressants did not improve the AAV-ILD prognosis. But in analogy to idiopathic pulmonary fibrosis, anti-fibrosing agents might be useful and should be assessed in AAV-ILD patients with a UIP pattern.
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http://dx.doi.org/10.1016/j.jaut.2019.102338DOI Listing
January 2020

F-FDG PET/CT of sarcoidosis with extensive cutaneous and subcutaneous nodules: the snow leopard sign.

Eur J Nucl Med Mol Imaging 2019 Aug 24;46(9):1980-1981. Epub 2019 May 24.

Department of Biophysics and Nuclear Medicine, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1007/s00259-019-04353-0DOI Listing
August 2019

Cold agglutinin disease as a new immune-related adverse event associated with anti-PD-L1s and its treatment with rituximab.

Eur J Cancer 2019 03 7;110:21-23. Epub 2019 Feb 7.

APHP, Service de Médecine Interne Immunologie Clinique, Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2019.01.009DOI Listing
March 2019

Methemoglobinemia as a biomarker of dapsone-induced mania severity.

J Affect Disord 2019 07 25;254:122-123. Epub 2018 Dec 25.

Service Hospitalo-Universitaire de Psychiatrie de Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin Bicêtre, F-94275, France; INSERM UMR-1178, CESP, "Depression and Antidepressants" team, Faculté de Médecine Paris-Sud, Université Paris Sud, France.

Background: The underlying mechanism involved in dapsone-induced mania remains unknown.

Methods: We report the case of a 54-year-old man with a dapsone-induced mania.

Results: The maximum of manic symptoms was correlated with the maximum of methemoglobinemia and mania decreased concomitantly with the methemoglobinemia level.

Limitations: This is a single case.

Conclusions: This case shows that dapsone-induced mania severity is correlated with methemoglobinemia level, leading for the first time to the hypothesis of a physiopathological mechanism by which dapsone could induce mania.
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http://dx.doi.org/10.1016/j.jad.2018.12.123DOI Listing
July 2019

Clinical Spectrum, Quality of Life, BRAF Mutation Status and Treatment of Skin Involvement in Adult Langerhans Cell Histiocytosis.

Acta Derm Venereol 2017 Jul;97(7):838-842

Assistance Publique- Hôpitaux de Paris, Département de Dermatologie, Hôpital Saint-Louis, Paris, France.

Langerhans cell histiocytosis is a rare histiocytic disorder for which skin involvement and management are poorly described in adults. The aim of this retrospective monocentric study in a national reference centre is to describe the clinical characteristics, quality of life, BRAF mutation status and outcomes of skin involvement in adult patients with Langerhans cell histiocytosis. Twenty-five patients (14 females, mean age 47 years) were included, with a median follow-up of 33 months (range 4-420 months). Patients experienced poor dermatological quality of life despite low body surface involvement. BRAFV600 mutations were detected in 8 of the 18 patients analysed (45%). Eight patients had an associated malignancy. Several treatment options were used and consisted of surgery, topical steroids and carmustine, thalidomide, methotrexate, vinblastine and steroids and cladribine. This study highlights the need to evaluate quality of life and to screen for associated malignancy in adult patients with Langerhans cell histiocytosis.
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http://dx.doi.org/10.2340/00015555-2674DOI Listing
July 2017

[Adult Langerhans cell histiocytosis].

Presse Med 2017 Jan 2;46(1):55-69. Epub 2016 Nov 2.

Université Paris-Diderot, Sorbonne Paris Cité, Inserm UMR 1153 CRESS, équipe de recherche en biostatistiques et épidémiologie clinique, 75010 Paris, France; Assistance publique-Hôpitaux de Paris, hôpital Saint-Louis, centre national de référence de l'histiocytose langerhansienne, service de pneumologie, 75010 Paris, France.

Langerhans cell histiocytosis (LCH) is a rare disease affecting both genders and can occur at any age. It often evolves through successive flares, and its severity varies from benign forms that don't require treatment to life threatening disease. Some patients have important functional impairment with psychological and social consequences and prolonged disability. LCH may affect only one organ, with uni- or multifocal involvement or be multisystem disease involving multiple organs. The organs most frequently involved are bones, lung, skin and the endocrinal system. Pulmonary LCH is strongly related to smoking. Some patients have mixed histocytosis combining LCH and other histiocytic disorders. The diagnosis relies on the histological study of tissues samples, and shows tissue infiltration with large cell with pale cytoplasm and reniform nucleus, staining for CD1a and Langerin (CD207) on immunohistochemistry. The BRAF mutation is observed in tissue samples in approximately half of patients and the activation of the RAS-RAF-MEK-ERK pathway has been shown to be constantly activated in LCH lesions, regardless the BRAF status. These findings represent an important forward step in the understanding of the physiopathology of the disease. Treatment must be adapted to the severity of the disease and goes from conservative observation to systemic chemotherapy. Therapies targeting the RAS-RAF-MEK-ERK pathway are promising treatments for progressive disease.
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http://dx.doi.org/10.1016/j.lpm.2016.09.015DOI Listing
January 2017

Neutrophilic Dermatoses in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A French Multicenter Study of 17 Cases and Literature Review.

Medicine (Baltimore) 2016 Mar;95(11):e2957

From the Department of Internal Medicine, Caen University Hospital, Caen (HDB, NMS, BB, AA); Department of Internal Medicine, Brest University Hospital (CDM); Department of Internal Medicine, Nantes University Hospital (AN); Department of Internal Medicine, Assistance Publique Hôpitaux de Paris, Saint-Louis Hospital, Paris, France (MDM); Department of Rheumatology, Assistance Publique Hôpitaux de Paris, Bichat University Hospital, Paris, France (OM); Department of Internal Medicine, Lille University Hospital, France (DL); Mount Sinai Hospital, University Health Network, and University of Toronto, Toronto, Ontario, Canada (CP); and Department of Internal Medicine, Assistancec Publique Hôpitaux de Paris, Cochin Hospital, Paris, France (LG, XP).

A few reports suggest combination of ANCA-associated vasculitis (AAV) and neutrophilic dermatoses (ND). We aimed to describe the main characteristics of patients presenting with both AAV and ND in a French cohort and through a systematic literature review, and to discuss the possible common pathogenic process involved. We conducted a retrospective study of patients with both conditions. Patients were selected via the French Internal Medicine Society (SNFMI) and the French Vasculitis Study Group (FVSG). A literature review focusing on a combination of both conditions, concentrated only on publications with well-established diagnoses and individual detailed data. Seventeen patients diagnosed with AAV and ND were identified in this cohort. Twelve patients had granulomatosis with polyangiitis (GPA), 4 had microscopic polyangiitis (MPA) and one had eosinophilic GPA (EGPA). Eight patients, all with GPA, displayed pyoderma gangrenosum (PG). Sweet's syndrome was observed in 6 patients (4 with MPA, one with GPA and one with EGPA) and erythema elevatum diutinum in the other three (2 with GPA and 1 with MPA). The literature review identified 33 additional patients with both conditions, including 26 with GPA. Altogether, of the 50 patients (17 from our study and 33 from the literature review), 33 (66%) patients presented with PG associated with GPA in 29 cases (89%). Corticosteroids were the first-line treatment in conjunction with an immunosuppressive agent in most cases. Outcomes were good and a total of 15 patients experienced a relapse. Patients who relapsed were more likely to have ear, nose and throat manifestation than patients who did not [12/15 (80%) relapsing patients vs. 15/35 (43%) non-relapsing patients; p = 0.03)]. In our stud, the most frequent association concerned GPA and PG. ND should be considered and specifically researched within the spectrum of cutaneous manifestations observed in AAV.
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http://dx.doi.org/10.1097/MD.0000000000002957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839884PMC
March 2016

Classification and classification criteria for vasculitis: achievements, limitations and prospects.

Curr Opin Rheumatol 2015 Jan;27(1):1-9

aDepartment of Internal Medicine, Hospital Saint-Louis bECSTRA Team, Epidemiology and Biostatistics, Sorbonne Paris Cité Research Center UMR 1153, Inserm, University Paris Diderot, Paris, France.

Purpose Of Review: The classification of diseases reveals the relationships between conditions that are linked in some way. Such classification has been a challenge for vasculitis because of the heterogeneous and protean nature of the illnesses. Classification criteria are critical to homogenize patient populations with vasculitis who are included in basic and clinical research studies.

Recent Findings: The most recent advance in vasculitis classification has been the revised 2012 Chapel Hill Consensus Conference (CHCC) nomenclature of vasculitis that, although mainly focusing on nomenclature, also included classification elements. Whereas still maintaining the caliber of the predominantly involved vessels as the main categorization criterion for primary systemic vasculitis, the 2012 CHCC nomenclature introduced a new category--variable-vessel vasculitis--to include Behçet's disease and Cogan's syndrome in the vasculitis spectrum. Another important feature was the expansion of the classification to secondary vasculitis and single-organ vasculitis. Similarly, classification criteria for several vasculitis entities have been altered and new criteria published, namely for Behçet's disease and cryoglobulinemic vasculitis.

Summary: The classification of vasculitis continues to be amended to account for advances in the general understanding of the nature of vasculitis and our ability to diagnose them. The relevance of the prevailing classification system, relying on affected vessel size as the primary discriminator of vasculitis entities, is still questionable for clinical practice. Clinically sound, widely accepted classification criteria are available for most vasculitis entities, although some areas remain ill-defined: polyarteritis nodosa, microscopic polyangiitis and adult immunoglobulin A vasculitis (Henoch-Schönlein).
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http://dx.doi.org/10.1097/BOR.0000000000000134DOI Listing
January 2015

Tissue-specific microvascular endothelial cells show distinct capacity to activate NK cells: implications for the pathophysiology of granulomatosis with polyangiitis.

J Immunol 2014 Apr 5;192(7):3399-408. Epub 2014 Mar 5.

INSERM, U1016 Hôpital Saint-Vincent de Paul, 75014 Paris, France;

The relevance of tissue specificity of microvascular endothelial cells (MECs) in the response to inflammatory stimuli and sensitivity to immune cell-mediated injury is not well defined. We hypothesized that such MEC characteristics might shape their interaction with NK cells through the use of different adhesion molecules and NK cell receptor ligands or the release of different soluble factors and render them more or less vulnerable to NK cell injury during autoimmune vasculitis, such as granulomatosis with polyangiitis (GPA). To generate a comprehensive expression profile of human MECs of renal, lung, and dermal tissue origin, we characterized, in detail, their response to inflammatory cytokines and to proteinase 3, a major autoantigen in GPA, and analyzed the effects on NK cell activation. In this study, we show that renal MECs were more susceptible than lung and dermal MECs to the effect of inflammatory signals, showing upregulation of ICAM-1 and VCAM-1 on their surface, as well as release of CCL2, soluble fractalkine, and soluble VCAM-1. Proteinase 3-stimulated renal and lung MECs triggered CD107a degranulation in control NK cell. Notably, NK cells from GPA patients expressed markers of recent in vivo activation (CD69, CD107a), degranulated more efficiently than did control NK cells in the presence of renal MECs, and induced direct killing of renal MECs in vitro. These results suggest that, upon inflammatory conditions in GPA, renal MECs may contribute to the recruitment and activation of NK cells in the target vessel wall, which may participate in the necrotizing vasculitis of the kidney during this disease.
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http://dx.doi.org/10.4049/jimmunol.1301508DOI Listing
April 2014

Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net.

Orphanet J Rare Dis 2013 May 14;8:72. Epub 2013 May 14.

Department of Medicine I, Center of Hematology an Stem Cell Transplantation, Hemostasis and Medical Oncology Internal Medicine I, Elisabethinen Hospital, Fadinger Str, 1 4010, Linz, Austria.

Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus.
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http://dx.doi.org/10.1186/1750-1172-8-72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667012PMC
May 2013

[Giant-cell arteritis and Takayasu arteritis: epidemiological, diagnostic and treatment aspects].

Presse Med 2012 Oct 31;41(10):955-65. Epub 2012 Aug 31.

Centre hospitalo-universitaire de Bordeaux, hôpital Haut-Lévêque, service de médecine interne, 33604 Pessac cedex, France.

Giant-cell arteritis (GCA) and Takayasu arteritis (TAK) are primary systemic granulomatous large-vessel vasculitides. Whether both entities represent distinct phenotypic expressions of a shared etiopathogenic process remains hypothetical. GCA more commonly affects subjects of northern European background while the clinical observation that TAK might be more common in populations of Asian or African ancestry needs to be confirmed by epidemiological studies. Distinct human leukocyte antigen class II associations were identified as genetic risk factors of GCA and TAK. The increasing incidence of GCA also suggests an environmental cause. Temporal artery biopsy is the main diagnostic test for GCA, although MRI and Doppler ultrasonography of the temporal or occipital arteries may also reveal vessel wall inflammation. MRI, CT and positron emission tomography with 18F fluodeoxyglucose have progressively replaced conventional invasive imaging modalities for study of large-vessel disease. The diagnostic accuracy of these 3 imaging modalities seems equivalent, but their value in the follow-up of GCA and TAK is less clear. According to studies based on modern imaging techniques, 70-80% of patients with newly diagnosed GCA show an involvement of the aorta and/or the major branches of the aorta. Glucocorticoids are the reference therapy for GCA. Adjunctive therapy, notably with methotrexate, appears to enhance disease control and reduce glucocorticoid exposure. IL-6 blockade has hope as a new treatment option for GCA. Principles of therapy for TAK are similar to those of GCA, except that TNFα blockers, particularly infliximab, seem to show good results in TAK and revascularization procedures are an important part of the TAK therapy.
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http://dx.doi.org/10.1016/j.lpm.2012.07.011DOI Listing
October 2012

Expression of NKG2D and CD107 in CD8(+) effector memory lymphocytes in Churg-Strauss syndrome.

Clin Exp Rheumatol 2012 Jan-Feb;30(1 Suppl 70):S57-61. Epub 2012 May 14.

Allergology and Clinical Immunology, University of Torino, Italy.

Objectives: Churg-Strauss syndrome (CSS) is a necrotising vasculitis of small vessels in which oligoclonally expanded TCR Vβ CD8+ effector memory T cells populations (TEM) may be involved in vasculitic damage. The aim of this study was to assess the functional role of CD8+ T cells in CSS patients by flow cytometry analysis of membrane expression of cytotoxic markers NKG2D and CD107a.

Methods: Immunostaining of peripheral T cells and effector memory lymphocytes (TEM) from CSS patients and controls was performed by gating CD28 and CD45RA in the CD8+NKG2D+ and CD4+NKG2D+ populations. CD107a expression was evaluated in both whole CD8+ and CD4+ and the TEM cells by gating CD62 and CD45RA following polyclonal stimulation.

Results: NKG2D expression was shifted toward the CD8+CD28- fraction of T cells in CSS patients compared to healthy controls (56.1±25.8% versus 17.2±7.3%, respectively, p=0.002). CD8+Vβ+ expanded T cells showed a significantly increased expression of NKG2D compared to the whole CD8+ T cell population (91.4±1.9% versus 79.7±3.8%, respectively, p=0.015). Moreover the CD8+ population from CSS upregulates CD107a on its surface upon polyclonal stimulation in a significantly higher proportion than healthy subjects (26.2±10.8% versus 8.2±2.9%, p=0.0031) and the majority CD8+ CD107+ cells from CSS patients showed a TEM phenotype compared to controls (64.8±4.9% vs. 19.8±2.9, respectively, p<0.001).

Conclusions: In CSS, CD8+ TEM lymphocytes show markers of cytotoxic activity, which suggests a role for these cells in vasculitic damage.
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August 2012

Therapeutic plasma exchange in systemic vasculitis: an update on indications and results.

Curr Opin Rheumatol 2012 May;24(3):261-6

Department of Internal Medicine, Hospital Saint-Louis, University Paris, Paris, France.

Purpose Of Review: Therapeutic plasma exchange has been long proposed as a potentially useful modality to treat several systemic vasculitis conditions. This review summarizes the available evidence for the effectiveness of plasma exchange in systemic vasculitis.

Recent Findings: Therapy with plasma exchange, most often combined with immunosuppressive agents, has been found effective for antiglomerular basement membrane disease, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), Henoch-Schönlein purpura, cryoglobulinemic vasculitis, hepatitis B virus-associated polyarteritis nodosa and Kawasaki disease. The most common indications are life-threatening or organ function-threatening manifestations, particularly advanced renal dysfunction and disease refractory to traditional therapy. Thus, most of the available evidence favoring plasma exchange in these circumstances is from small observational studies or expert consensus. Recent advances in findings include results strengthening the notion of a small beneficial effect on preserving renal function with adjunct plasma exchange therapy in AAV with renal failure and observational data suggesting plasma exchange as a promising effective salvage option for children with Kawasaki disease not responding to standard therapy with intravenous immunoglobulins.

Summary: Evidence from case reports and case series and a few randomized controlled trials continues to support plasma exchange as a major rescue-treatment modality for several systemic vasculitis diseases. These studies offer some guidance for use of plasma exchange in systemic vasculitis, but additional data from controlled trials are needed for more accurate assessment of the indications, practical modalities, benefits and shortcomings of this treatment approach.
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http://dx.doi.org/10.1097/BOR.0b013e3283526509DOI Listing
May 2012

Relationships of HLA-B51 or B5 genotype with Behcet's disease clinical characteristics: systematic review and meta-analyses of observational studies.

Rheumatology (Oxford) 2012 May 11;51(5):887-900. Epub 2012 Jan 11.

Department of Internal Medicine, Hospital Saint-Louis, 1 avenue Claude-Vellefaux, 75475 Paris Cedex 10, France.

Objective: To investigate comprehensively the relationships between Behçet's disease (BD) clinical features and HLA-B51 or HLA-B5 (HLA-B51/B5) status using meta-analyses.

Methods: Relevant publications were identified by a systematic literature search. Eligible studies had to provide frequencies for one or more BD characteristics according to HLA-B51/B5 status. Pooled relative risks (RRs) were calculated by random-effects meta-analysis for those BD characteristics for which five or more relevant studies were identified. Between-study variability was assessed with I(2) and Q-statistics, and modelled using meta-regression.

Results: Among the 859 publications evaluated, 72 (representing 74 study populations) met eligibility criteria. Pooled RRs (95% CIs) of the association of HLA-B51/B5 with the 14 analysed clinical characteristics were male sex 1.14 (1.05, 1.23); eye involvement 1.13 (1.06, 1.21); genital ulcers 1.07 (1.01, 1.14); skin involvement 1.10 (1.03, 1.16); erythema nodosum 1.11 (0.96, 1.29); pseudofolliculitis 1.07 (0.93, 1.23); positive pathergy test 1.05 (0.94, 1.17); joint involvement 0.94 (0.86, 1.04); neurological involvement 0.95 (0.71, 1.27); gastrointestinal involvement 0.70 (0.52, 0.94); thrombophlebitis 1.17 (0.77, 1.76); vascular involvement 1.00 (0.68, 1.47); chest involvement 1.55 (0.75, 3.20) and orchiepididymitis 1.13 (0.59, 2.15). For most of the analysed outcomes, between-study heterogeneity was low or absent and most of the meta-regression models were statistically non-significant.

Conclusion: The results of these meta-analyses showed that, in BD, HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin manifestations, and a decreased prevalence of gastrointestinal involvement.
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http://dx.doi.org/10.1093/rheumatology/ker428DOI Listing
May 2012

Rituximab maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis.

J Rheumatol 2012 Jan 15;39(1):125-30. Epub 2011 Nov 15.

Department of Internal Medicine, Hôpital Cochin, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France.

Objective: To evaluate the efficacy compared to the relapse risk and tolerance of systematic rituximab (RTX) infusions as maintenance therapy for patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), who entered remission taking conventional immunosuppressants or RTX.

Methods: A retrospective study of the main clinical characteristics, outcomes, and RTX tolerance of patients who had received ≥ 2 RTX maintenance infusions in our center, regardless of induction regimen, between 2003 and 2010.

Results: We identified 28 patients [4 MPA and 24 GPA; median age 55.5 yrs (range 18-78); 17 (60%) males] who received a median of 4 (range 2-10) RTX maintenance infusions, with median followup of 38 months (range 21-97) since diagnosis or last flare. None experienced a RTX infusion-related adverse event; 15 patients (among the 21 with available data) had hypogammaglobulinemia (predominantly IgM) prior to their last RTX maintenance infusion; 3 had infectious events (1 cutaneous abscess, 1 otitis, 1 fatal H1N1 flu). Two patients suffered pulmonary relapses shortly before a planned RTX maintenance infusion (both had increased antineutrophil cytoplasmic antibody levels and 1 had CD19+ lymphocyte reconstitution).

Conclusion: Rituximab maintenance therapy was well tolerated but did not completely prevent relapses and persistent "grumbling" disease. These preliminary results remain to be confirmed by a randomized controlled trial currently in progress.
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http://dx.doi.org/10.3899/jrheum.110143DOI Listing
January 2012

Treating polyarteritis nodosa: current state of the art.

Clin Exp Rheumatol 2011 Jan-Feb;29(1 Suppl 64):S110-6. Epub 2011 May 11.

Department of Internal Medicine, Hospital Saint-Louis, University Paris 7-Paris Diderot, Paris, France.

Defining treatment guidelines for polyarteritis nodosa (PAN) is complicated by the evolving definition and classification of this vasculitis, and because clinical trials have included patients with PAN, microscopic polyangiitis or, sometimes, Churg-Strauss syndrome. Nonetheless, clinical trial data support that the 'idiopathic generalised' form of PAN benefits from a severity-adapted treatment strategy, implying that cases with life-threatening manifestations require a regimen combining high-dose glucocorticoids and cyclophosphamide, whereas a non-severe disease may be treated with glucocorticoids alone. Results of uncontrolled studies indicate that hepatitis B virus-associated PAN management should include an antiviral agent, short-term glucocorticoids and plasma exchanges. No robust scientific evidence is available to guide the treatment of the limited variant 'cutaneous PAN'. Most experts recommend a less aggressive therapy with non-steroidal anti-inflammatory drugs or other agents, such as colchicine or dapsone. PAN has become an even more uncommon disease, probably due to classification changes and, perhaps also to a genuine modification of the epidemiology of this vasculitis. Although more data are needed to resolve outstanding questions, it is unclear whether all these matters can be studied in the future in large, sufficiently powered trials.
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August 2011

Infliximab or rituximab for refractory Wegener's granulomatosis: long-term follow up. A prospective randomised multicentre study on 17 patients.

Clin Exp Rheumatol 2011 Jan-Feb;29(1 Suppl 64):S63-71. Epub 2011 May 11.

Department of Internal Medicine, Hôpital Cochin, University Paris Descartes, Paris, France.

Objectives: To compare efficacy and tolerance of infliximab versus rituximab to treat refractory Wegener's granulomatosis (WG), and clarify their respective indications.

Methods: Patients with systemic WG refractory to, or intolerant to steroids and consecutive immunosuppressant lines, including oral cyclophosphamide, were randomly assigned to receive infliximab or rituximab and their ongoing regimen. The primary endpoint was partial (PR) or complete remission (CR) at month 12. The secondary endpoint was the occurrence of adverse events. Long-term follow-up data were subjected to post-hoc analysis.

Results: Between 2004 and 2007, 9 infliximab and 8 rituximab patients were included. At M12, we observed 2 infliximab and 4 rituximab CR, 1 infliximab and 1 rituximab PR, 5 infliximab and 2 rituximab failures and 2 deaths (NS). Post-hoc analysis was conducted after 30.6±15.4 months of follow-up. Among the 15 survivors, 2 infliximab patients and 1 rituximab patient relapsed. Among 5 infliximab non-responders, 4 were successfully switched to rituximab. During follow-up, one patient from each group died. Over the long term, 10/17 (59%) patients responded to rituximab, 1 to infliximab, 2 to other strategies and 2 died. Despite the 2 deaths, tolerance of both drugs was considered acceptable in terms of WG severity before treatment and previous treatment lines.

Conclusions: Our observations demonstrate the usefulness of infliximab and/or rituximab to obtain remission of refractory WG with a trend at M12 favouring rituximab. During long-term follow-up, rituximab was better able at obtaining and maintaining remission.
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August 2011

Excessive interleukin-15 transpresentation endows NKG2D+CD4+ T cells with innate-like capacity to lyse vascular endothelium in granulomatosis with polyangiitis (Wegener's).

Arthritis Rheum 2011 Jul;63(7):2116-26

INSERM, U986, Hôpital Saint-Vincent de Paul, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.

Objective: Granulomatosis with polyangiitis (Wegener's) (GPA) is a rare systemic vasculitis of unknown etiology. Contribution of T cell-mediated immunity is suggested by the presence of granulomatous inflammation and T cell infiltrates in different tissues. We undertook this study to determine whether CD4+ T cells aberrantly expressing the NKG2D activating receptor might participate in the pathophysiology of the disease.

Methods: We performed a detailed phenotype and functional analysis of CD4+ T cells in a cohort of 90 GPA patients (37 with localized GPA and 53 with generalized GPA) in comparison with 39 age-matched controls.

Results: We observed circulating innate-like CD4+ T cells expressing an assortment of activating natural killer (NK) cell receptors (NKG2D, 2B4, DNAX-associated molecule 1, and some killer cell Ig-like receptors) and their signaling partners. Expansions of NKG2D+CD4+ T cells greater than a critical threshold of 3% yielded 100% specificity for generalized vasculitis versus localized granulomatosis, suggesting their participation in endothelium damage. Excessive interleukin-15 (IL-15) transpresentation through increased expression of IL-15 receptor α (IL-15Rα), together with abnormal expression of major histocompatibility complex (MHC) class I chain-related A protein on monocyte/macrophages, induced abnormal expansion of NKG2D+CD4+ T cells. These cells were primed in vivo to exert direct, MHC-independent cytotoxicity toward microvascular endothelial cells expressing the cognate ligands of NK cell receptors.

Conclusion: Our results suggest that NK cell-like CD4+ T cells might be the driving force of the vasculitis in GPA, and point to IL-15 as an important mediator in the progression of GPA toward generalized vasculitis. IL-15/IL-15Rα antagonists may thus become novel therapeutic tools to decrease the pool of NK cell receptor-positive CD4+ T cells in selected GPA patients.
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http://dx.doi.org/10.1002/art.30355DOI Listing
July 2011

Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease.

Blood 2010 Nov 19;116(20):4070-6. Epub 2010 Aug 19.

Department of Internal Medicine, French National Referral Center for Langerhans Cell Histiocytosis, Hôpital Cochin, Université de Paris Descartes, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Erdheim-Chester disease (ECD) pathophysiology remains largely unknown. Its treatment is not codified and usually disappointing. Interferon (IFN)-α therapy lacks efficacy for some life-threatening manifestations and has a poor tolerance profile. Because interleukin (IL)-1Ra synthesis is naturally induced after stimulation by IFN-α, we hypothesized that recombinant IL-1Ra (anakinra) might have some efficacy in ECD. We treated 2 patients who had poor tolerance or contraindication to IFN-α with anakinra as a rescue therapy and measured their serum C-reactive protein, IL-1β, IL-6, and monocytic membranous IL-1α (mIL-1α) levels before, under, and after therapy. Another untreated ECD patient and 5 healthy subjects were enrolled as controls. After treatment, fever and bone pains rapidly disappeared in both patients, as well as eyelid involvement in one patient. In addition, retroperitoneal fibrosis completely or partially regressed, and C-reactive protein, IL-6, and mIL-1α levels decreased to within the normal and control range. Beside injection-site reactions, no adverse event was reported. Therefore, our results support a central role of the IL-1 network, which seemed to be overstimulated in ECD. Its specific blockade using anakinra thereby opens new pathophysiology and therapeutic perspectives in ECD.
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http://dx.doi.org/10.1182/blood-2010-04-279240DOI Listing
November 2010

Macular oedema following rituximab infusion in two patients with Wegener's granulomatosis.

Clin Exp Rheumatol 2010 Jan-Feb;28(1 Suppl 57):90-2

Université Paris Descartes, Service de Médecine Interne, Assistance Publique - Hôpitaux de Paris, France.

Rituximab, a monoclonal antibody now widely used to treat autoimmune diseases, has been reported to be effective against refractory Wegener's granulomatosis and its ophthalmic involvement. Herein, we report on 2 patients with refractory Wegener's granulomatosis and scleritis in whom cystoid macular oedema occurred several weeks after rituximab infusions. Notably, scleritis had already resolved when macular oedema was diagnosed. One patient's macular oedema was successfully treated with a subtenon injection of triamcinolone but recurred soon after she received a second cycle of rituximab as maintenance therapy. To our knowledge, to date no ophthalmic side effect has been reported after rituximab administration. The short time between each rituximab infusion and the onset of cystoid macular oedema strongly suggests a causal link.
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July 2010

HLA-B51/B5 and the risk of Behçet's disease: a systematic review and meta-analysis of case-control genetic association studies.

Arthritis Rheum 2009 Oct;61(10):1287-96

Hôpital Cochin; Université Paris-René Descartes, Assistance Publique Hôpitaux de Paris, Paris, France.

Objective: To quantify by meta-analysis the genetic effect of the HLA-B5 or HLA-B51 (HLA-B51/B5) allele on the risk of developing Behçet's disease (BD) and to look for potential effect modifiers.

Methods: Relevant studies were identified using the PubMed Medline database and manual searches of the literature. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using the random-effects model. Subgroup meta-analyses and meta-regression analyses were undertaken to investigate the effects of selected study-level parameters on the pooled OR. Heterogeneity was assessed using the I2 statistic. Pooled results were used to calculate population-attributable risks (PAR) for BD in relationship to HLA-B51/B5.

Results: A total of 4,800 patients with BD and 16,289 controls from 78 independent studies (published 1975-2007) were selected. The pooled OR of HLA-B51/B5 allele carriers to develop BD compared with noncarriers was 5.78 (95% CI 5.00-6.67), with moderate between-study heterogeneity (I2 = 61%). The subgroup analyses stratifying studies by geographic locations (Eastern Asia, Middle East/North Africa, Southern Europe, Northern/Eastern Europe) yielded consistent OR ranges (5.31-7.20), with I2 ranges of 52-70%. Univariate random-effects meta-regression indicated the percentage of male BD cases (P = 0.008) as a source of heterogeneity. The PAR within the various geographic areas were estimated at 32-52%.

Conclusion: The strength of the association between BD and HLA-B51/B5, and its consistency across populations of various ethnicities, lends further support to this allele being a primary and causal risk determinant for BD. Variations according to sex support an interaction of this allele with BD characteristics.
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http://dx.doi.org/10.1002/art.24642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867978PMC
October 2009

[Intraparenchymal hemorrhage disclosing a primary angiitis of the central nervous system].

Presse Med 2009 May 17;38(5):844-6. Epub 2009 Mar 17.

Pôle de médecine interne, Centre de référence pour les vascularites nécrosantes et la sclérodermie systémique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, et UPRES EA 4058, Université Paris Descartes, Faculté de Médecine, F-75014 Paris, France.

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http://dx.doi.org/10.1016/j.lpm.2008.09.029DOI Listing
May 2009