Jonathan London

Rituximab for induction and maintenance therapy in granulomatosis with polyangiitis (Wegener's). Results of a single-center cohort study on 66 patients

The aim of this study was to evaluate the efficacy and safety of rituximab (RTX) associated with glucocorticoid treatment based on disease severity, as a remission induction treatment for granulomatosis with polyangiitis (GPA) (Wegeners) and to analyze the results of long-term maintenance therapy with low doses of RTX in a routine time-based protocol. This single-center retrospective study used standardized data collection from all GPA patients receiving RTX between 2002 and 2013. The remission induction regimen consisted of RTX and glucocorticoids, adapted according to disease severity. Once remission was achieved, patients received RTX maintenance treatment (500xa0mg every 6 months) for 18 months. Sixty-six GPA patients received RTX for remission induction. After six months, a response had been achieved in 78.8% of these patients, with a moderate oral prednisone regimen (mean dose at baseline, 32.8xa0±xa023.4xa0mg/day). Subglottic stenosis increased the risk of treatment failure (ORxa0=xa031.2, Pxa0=xa00.0104). RTX maintenance treatment was continued for 18 months in 92% of the GPA patients, who were followed for 34.2xa0±xa026.2 months (mean total cumulative RTX dose of 4.6xa0±xa01.7xa0g). The relapse rate was 11.2/100 patient-years. The relapses occur a mean of 13.5xa0±xa014.7 months after the last RTX infusion. Twenty-one severe adverse events were recorded; 13.6% patients had severe infections. We conclude that in this single-center cohort, RTX associated with glucocorticoid treatment adapted for disease severity appeared to induce remission effectively in GPA patients. Maintenance treatment with low doses of RTX in a routine time-based protocol was safe and associated with low rates of relapse on treatment.

Implication of B lymphocytes in the pathogenesis of ANCA-associated vasculitides

ANCA-associated vasculitis (AAV) is a subgroup of vasculitides characterized by the detection of anti-neutrophil cytoplasm antibodies (ANCA). Until recently, the pathogenesis of AAV mainly involved neutrophils, T cells, and ANCA. Importantly, data were recently published supporting B-cell implication in this setting. Thus, the identification of activated B lymphocytes in granulomatous lesions and the efficacy of B-cell depletion using rituximab in the treatment of patients with AAV changed our mind. However, the impact of B lymphocytes on disease activity and its specific role in the pathogenesis of AAV remains unclear, at least in part as the consequence of the limited number of patients investigated and the restricted number of studies investigating B-cell subsets. Perturbations of B-cell homeostasis have been identified in AAV with increased expression of CD38 and decreased expression of CD5 in active phase, contrasting with increased expression of CD25 and CD86 in remission state. Although decreased secretion of interleukin (IL)-10 has also been reported during disease flares, these data remain controversial and the cytokines secretion profile of B-cells needs to be further investigated. Herein, we summarize recent advances in the understanding of the implications of B-cells in the field of AAV and propose new fields of investigation for a better understanding of B lymphocytes in the pathogenesis of AAV.

Sarcoidosis Occurring After Lymphoma: Report of 14 Patients and Review of the Literature

AbstractSarcoidosis is a granulomatous disease that most frequently affects the lungs with pulmonary infiltrates and/or bilateral hilar and mediastinal lymphadenopathy. An association of sarcoidosis and lymphoproliferative disease has previously been reported as the sarcoidosis-lymphoma syndrome. Although this syndrome is characterized by sarcoidosis preceding lymphoma, very few cases of sarcoidosis following lymphoma have been reported. We describe the clinical, biological, and radiological characteristics and outcome of 39 patients presenting with sarcoidosis following lymphoproliferative disease, including 14 previously unreported cases and 25 additional patients, after performing a literature review. Hodgkin lymphoma and non-Hodgkin lymphoma were equally represented. The median delay between lymphoma and sarcoidosis was 18 months. Only 16 patients (41%) required treatment. Sarcoidosis was of mild intensity or self-healing in most cases, and overall clinical response to sarcoidosis was excellent with complete clinical response in 91% of patients. Sarcoidosis was identified after a follow-up computerized tomography scan (CT-scan) or 18fluorodeoxyglucose-positron emission tomography/computerized tomography (18FDG-PET/CT) evaluation in 18/34 patients (53%). Sarcoidosis is therefore a differential diagnosis to consider when lymphoma relapse is suspected on a CT-scan or 18FDG-PET/CT, emphasizing the necessity to rely on histological confirmation of lymphoma relapse.

High prevalence of infectious events in thrombotic thrombocytopenic purpura and genetic relationship with toll-like receptor 9 polymorphisms: experience of the French Thrombotic Microangiopathies Reference Center

Infectious events have been reported as major environmental triggers of thrombotic thrombocytopenic purpura (TTP). We detail here the potential association between infections and TTP.

Scleroderma Peripheral B Lymphocytes Secrete Interleukin-6 and Transforming Growth Factor β and Activate Fibroblasts: IL-6 AND TNFβ SECRETION BY SSc PERIPHERAL B LYMPHOCYTES

To study the role of B lymphocytes in systemic sclerosis (SSc).

Scleroderma peripheral B lymphocytes secrete interleukin-6 and TGF-β and activate fibroblasts.

To study the role of B lymphocytes in systemic sclerosis (SSc).

Autoimmune thrombotic thrombocytopenic purpura associated with HHV8-related Multicentric Castleman disease.

Keywords: n nthrombotic thrombocytopenic purpura; nMulticentric Castleman disease; nhuman immunodeficiency virus; nhuman herpes virus 8; nA Disintegrin And Metalloprotease with Thrombospondin type 1 motif member 13

Adult Onset Asthma and Periocular Xanthogranuloma (AAPOX), a Rare Entity With a Strong Link to IgG4-Related Disease: An Observational Case Report Study.

AbstractAdult onset asthma and periocular xanthogranuloma (AAPOX) is a rare non-Langerhans histiocytosis characterized histopathologically by a periocular infiltration of foamy histiocytes and Touton giant cells. Benign hyperplasia with plasma cell infiltration is classically described in eyelids or lymph nodes of AAPOX patients. It is also a characteristic feature of IgG4-related disease (IgG4-RD), a new entity defined by an IgG4-bearing plasma cell infiltration of organs.To determine if AAPOX syndrome shares clinical, biological, and histopathological characteristics with IgG4-RD, we used the comprehensive clinical diagnostic criteria for IgG4-RD in a retrospective case series of three consecutive patients with histologically-proven AAPOX. Patients who were diagnosed with AAPOX at a French academic referral center for orbital inflammation between November 1996 and March 2013 were enrolled. Biopsies from ocular adnexa or other organs were systematically reexamined. For each patient, clinical and serological data, radiologic findings, and treatment were retrospectively analyzed.Two AAPOX patients fulfilled all of the diagnostic criteria for a definite IgG4-RD. One patient who lacked the serological criteria fulfilled the criteria of a probable IgG4-RD.These 3 cases of AAPOX patients fulfilled the IgG4-RD comprehensive clinical diagnostic criteria. To our knowledge, this is the first observational case report study to clearly show a strong relationship between IgG4-RD and AAPOX syndrome.

A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience

Deficiency of adenosine deaminase 2 (DADA2) is a recently described autoinflammatory disorder. Genetic analysis is required to confirm the diagnosis. We aimed to describe the identifying symptoms and genotypes of patients referred to our reference centres and to improve the indications for genetic testing. DNA from 66 patients with clinically suspected DADA2 were sequenced by Sanger or next-generation sequencing. Detailed epidemiological, clinical and biological features were collected by use of a questionnaire and were compared between patients with and without genetic confirmation of DADA2. We identified 13 patients (19.6%) carrying recessively inherited mutations in ADA2 that were predicted to be deleterious. Eight patients were compound heterozygous for mutations. Seven mutations were novel (4 missense variants, 2 predicted to affect mRNA splicing and 1 frameshift). The mean age of the 13 patients with genetic confirmation was 12.7 years at disease onset and 20.8 years at diagnosis. Phenotypic manifestations included fever (85%), vasculitis (85%) and neurological disorders (54%). Features best associated with a confirmatory genotype included fever with neurologic or cutaneous attacks (odds ratio [OR] 10.71, pu2009=u20090.003 and OR 10.9, pu2009<u20090.001), fever alone (OR 8.1, pu2009=u20090.01), and elevated C-reactive protein (CRP) level with neurologic involvement (OR 6.63, pu2009=u20090.017). Our proposed decision tree may help improve obtaining genetic confirmation of DADA2 in the context of autoinflammatory symptoms. Prerequisites for quick and low-cost Sanger analysis include one typical cutaneous or neurological sign, one marker of inflammation (fever or elevated CRP level), and recurrent or chronic attacks in adults.

Clinical and pathological significance of cutaneous manifestations in ANCA-associated vasculitides

OBJECTIVESnCutaneous manifestations (CM) in ANCA-associated vasculitides (AAV) are frequent, but data on clinical significance and clinical-pathological correlations are lacking.nnnMETHODSnWe conducted a multicenter, retrospective study including 1553 AAV patients. Clinical, biological and pathological features have been analyzed, and tissue samples from 46 biopsies were reviewed in a blind manner.nnnRESULTSnCM were more frequent in EGPA (53.0%) and MPA (51.9%) than in GPA (36.7%). Lesions more frequently associated with GPA were oral ulcers (4.6% vs. 2.5% in EGPA and 0.3% in MPA), while pyoderma gangrenosum and palpebral xanthoma were specific to GPA. Lesions associated with MPA were segmentary edema (19.5% vs. 12.7% in EGPA and 4.3% in GPA) and livedo (12.4% vs. 0.5% and 2.6%, respectively), whereas those associated with EGPA were urticarial lesions (11.5% vs. 1.9% in GPA and 3.5% in MPA) and nodules (12,2% vs. 8.9% in GPA and 4.7% in MPA). In GPA, CM patients had more frequent vasculitis than granulomatous phenotype, and poorer relapse-free and overall survival. Pathological analysis showed vasculitis and/or granulomatous infiltrates in 87.5% of GPA, in 61.1% of EGPA and in all MPA. Vasculitis was more frequently observed in purpura and nodules, while granulomas were differently located and organized within vessels or interstitium according to the type of lesions.nnnCONCLUSIONnEach AAV seemed to be associated with a peculiar pattern of cutaneous lesions. CM are associated with poorer prognosis in GPA. Clinical-pathological correlations showed no specific feature of each AAV, whereas granulomatous infiltrates differ according to the type of lesions.