J. Graveleau

Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients

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 physicians 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.

Vertebral Osteomyelitis: An Unusual Presentation of Bartonella henselae Infection

OBJECTIVES To report cases of cat scratch disease with vertebral osteomyelitis. METHODS We describe clinical features, diagnostic, treatment, and outcome of 2 patients with vertebral osteomyelitis due to Bartonella henselae and provide a review of the relevant literature. RESULTS A 47-year-old man was investigated for fever, splenomegaly, and cervical adenopathy. A lymphoma was suspected on the clinical picture, the laboratory tests, and the computed tomographic scan. [(18)F]-fluoro-2-deoxy-d-glucose-positron emission tomography detected splenic nodules and a hypermetabolic focus of C7 vertebral body compatible with a vertebral osteomyelitis on magnetic resonance imaging. B henselae infection was confirmed by polymerase chain reaction performed on lymph node biopsy. A 34-year-old woman was investigated for fever and right upper quadrant abdominal pain. She had consulted 2 weeks before for a unique lesion of right index and an axillar adenopathy that have improved spontaneously. A technetium bone scan performed 1 week later because of a thoracic backache demonstrated an increased uptake of the T6 vertebra. Vertebral magnetic resonance imaging was compatible with a T6 osteomyelitis. B henselae infection was confirmed by serology (seroconversion). Both patients were treated with rifampin and doxycycline and recovered within 3 months. CONCLUSIONS B henselae vertebral osteomyelitis can involve immunocompetent adults. In the case of vertebral osteomyelitis with negative blood cultures, recent history of local lymphadenopathy and cat exposure must be investigated and B henselae serology must be performed. Nevertheless, even if serology is positive, vertebral biopsy is required to rule out other pathogens or malignancy. B henselae infection can be confirmed by polymerase chain reaction performed on vertebral or lymph node biopsy.

T Cell Polarization toward TH2/TFH2 and TH17/TFH17 in Patients with IgG4-Related Disease

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder involving virtually every organ with a risk of organ dysfunction. Despite recent studies regarding B cell and T cell compartments, the disease’s pathophysiology remains poorly understood. We examined and characterized subsets of circulating lymphocytes in untreated patients with active IgG4-RD. Twenty-eight consecutive patients with biopsy-proven IgG4-RD were included in a prospective, multicentric study. Lymphocytes’ subsets were analyzed by flow cytometry, with analysis of TH1/TH2/TH17, TFH cells, and cytokine release by peripheral blood mononuclear cells. Results were compared to healthy controls and to patients with primary Sjögren’s syndrome. Patients with IgG4-RD showed an increase of circulating T regulatory, TH2, TH17, and CD4+CXCR5+PD1+ TFH cell subsets. Accordingly, increased levels of IL-10 and IL-4 were measured in IgG-RD patients. TFH increase was characterized by the specific expansion of TFH2 (CCR6−CXCR3−), and to a lesser extent of TFH17 (CCR6+CXCR3−) cells. Interestingly, CD4+CXCR5+PD1+ TFH cells normalized under treatment. IgG4-RD is characterized by a shift of circulating T cells toward a TH2/TFH2 and TH17/TFH17 polarization. This immunological imbalance might be implicated in the disease’s pathophysiology. Treatment regimens targeting such T cells warrant further evaluation.

Comparison of idiopathic (isolated) aortitis and giant cell arteritis-related aortitis. A French retrospective multicenter study of 117 patients.

OBJECTIVES The aim of the study was to compare clinical/imaging findings and outcome in patients with idiopathic (isolated aortitis, IA) and with giant cell arteritis (GCA)-related aortitis. METHODS Patients from 11 French internal medicine departments were retrospectively included. Aortitis was defined by aortic wall thickening >2mm and/or an aortic aneurysm on CT-scan, associated to inflammatory syndrome. Patients with GCA had at least 3 ACR criteria. Aortic events (aneurysm, dissection, aortic surgeries) were reported, and free of aortic events-survival were compared. RESULTS Among 191 patients with non-infectious aortitis, 73 with GCA and 44 with IA were included. Patients with IA were younger (65 vs 70 years, p=0.003) and comprised more past/current smokers (43 vs 15%, p=0.0007). Aortic aneurisms were more frequent (38% vs 20%, p=0.03), and aortic wall thickening was more pronounced in IA. During follow-up (median=34 months), subsequent development of aortic aneurysm was significantly lower in GCA when compared to IA (p=0.009). GCA patients required significantly less aortic surgery during follow-up than IA patients (p=0.02). Mean age, sex ratio, inflammatory parameters, and free of aortic aneurism survival were equivalent in patients with IA ≥ 60 years when compared to patients with GCA-related aortitis. CONCLUSIONS IA is more severe than aortitis related to GCA, with higher proportions of aortic aneurism at diagnosis and during follow-up. IA is a heterogeneous disease and its prognosis is worse in younger patients <60 years. Most patients with IA ≥ 60 years share many features with GCA-related aortitis.

Altered innate function of plasmacytoid dendritic cells restored by enzyme replacement therapy in Gaucher disease.

BACKGROUND Gaucher disease (GD) is caused by an autosomal-recessive deficiency of β-glucocerebrosidase leading to an accumulation of glucosylceramide in monocytes/macrophage lineage. We analyzed immune cells and especially the function of dendritic cells to evaluate the potential impact of glucosylceramide accumulation in these cells and its possible role in infections and malignancies usually described in this pathology. These analyses were performed for each patient without and under enzyme replacement therapy. METHODS Seven GD patients were studied and compared with healthy volunteers. Immune cells (B cells, T cells, NK, dendritic cells), were analyzed by flow cytometry directly on whole blood. Cytokine production by blood dendritic cells was assessed after stimulation by toll-like receptor ligands. Cytokines in sera were measured using a multiplex assay. RESULTS GD patients displayed decreased numbers of NK cells, γδ2 T cells and increased frequency of memory CD4(+)CD45RO(+) T cells, when compared to healthy controls. Numbers of dendritic cells (myeloid (mDC) and plasmacytoid (pDC) dendritic cells) were also decreased. We demonstrated that pDC from GD patients exhibited a decrease in IFNα production after TLR9 stimulation compared to controls. Importantly, enzyme replacement therapy restored pDC function. Finally, we observed an increase of IL-8 and IL-18 in GD patient sera, which were reduced under enzyme replacement therapy. CONCLUSIONS Our data confirm that patients with GD exhibit altered numbers of innate and T lymphocytes and show for the first time that pDC from GD patients exhibit altered responsiveness to TLR9. These alterations could contribute to a decreased response to pathogens and could favor the development of malignancies.

Venous thromboembolism related to warm autoimmune hemolytic anemia: A case–control study

BACKGROUND The risk of venous thromboembolism (VTE) during warm autoimmune hemolytic anemia (wAIHA) is apparent in several published series. Unlike proximate disorders (autoimmune thrombocytopenia, non-immune hemolytic diseases) little is known about the presentation and risk factors for VTE in this setting. OBJECTIVE To determine the frequency, presentation and risk factors for VTE associated with wAIHA. METHODS We performed a single center retrospective study of adult patients (>18years) followed for wAIHA between 2009 and 2013. VTE risk factors were systematically assessed. The characteristics of patients with or without VTE were compared. VTE presentation and precipitating factors were analyzed. The Padua VTE risk score was calculated in each case. RESULTS Forty patients were included. wAIHA was idiopathic in 24 patients (60%). Twelve patients (30%) had Evans syndrome. Mean lowest hemoglobin level was 6.6g/dl [3.7-11.5]. Eight patients (20%) presented VTE after the appearance of wAIHA, at a mean age of 52.5years. All patients had pulmonary embolus, associated with a deep venous thrombosis in 4 cases. At the time of VTE 7/8 patients had frank hemolysis (median hemoglobin level: 7g/dL) and 6/8 were outpatients with a low Padua VTE risk score. The frequency of usual VTE risk factor was similar in cases and controls. By contrast, lowest hemoglobin level was significantly lower in patients that experienced VTE (5.3 vs 7.2g/dL, p=0.016). During the first episode of wAIHA, patients with concurrent VTE had a more pronounced anemia (5.3 vs 7.4g/dL, p=0.026). At the time of VTE, anemia was more severe when no other precipitating factor was present (6 vs 8.9g.dL, p=0.04). CONCLUSION In our cohort, 20% of patients with wAIHA presented VTE. The vast majority of VTE occurred during severe hemolytic flares and were not attributable to usual VTE risk factors. VTE prophylaxis is advisable in any patient admitted for wAIHA, irrespective of Padua VTE risk score. Prophylaxis also seems reasonable for outpatients with marked hemolysis.

Juvenile Temporal Vasculitis: A Rare Case in a Middle-Aged Woman

BACKGROUND Classic giant cell arteritis affects older adults who are aged >50 years. Temporal arteritis is uncommon in young adults but juvenile temporal vasculitis (JTV) is the most frequent form found in young people. Clinical presentation is usually poor, with localized temporal inflammatory changes without consistent systemic manifestations. Generally, the patients have a benign clinical course, without ophthalmic or ischemic manifestations. In these rare JTVs, excision of the involved section of temporal artery is often curative and corticosteroid therapy is not required. METHOD The present study reports a case of JTV in a middle-aged woman. RESULTS A 44-year-old woman complained of violent temporal headache, with a slight inflammatory syndrome. She had no vascular systemic manifestation and no cause of secondary vasculitis. Doppler ultrasonography suggested a localized inflammatory arteritis. Temporal biopsy was performed. Histologic findings were compatible with JTV (nongranulomatous panarteritis with mononuclear cells and eosinophils). All the symptoms disappeared after excision. One year later, she remains well and reports neither systemic manifestation nor recurrence. CONCLUSION Vasculitis of the temporal arteries in young people is uncommon and JTV is rare in middle-aged people. It is necessary to search for systemic or secondary vasculitis. In contrast to giant cell arteritis, steroids are not required.

Two cases of anakinra-induced neutropenia during auto-inflammatory diseases: Drug reintroduction can be successful

La Presse Medicale - In Press.Proof corrected by the author Available online since mardi 21 janvier 2014

Manifestations cutanées associées aux gammapathies monoclonales

Whatever their aetiology, monoclonal gammopathies can be associated to several clinical features. Mechanisms are various and sometimes unknown. Skin is frequently involved and may represent a challenging diagnosis. Indeed, skin manifestations are either the presenting features and isolated, or at the background of a systemic syndrome. Our objective was to review the various skin manifestations that have been associated with monoclonal gammopathies.

Thrombin generation in patients with acquired haemophilia and clinical bleeding risk.

Leiden, Department of Vascular Medicine, Academic Medical Center, Amsterdam, Department of Haematology, University Medical Center Groningen, Groningen, Department of Haematology, University of Maastricht, Maastricht, and Department of Clinical Epidemiology and Medical Technology Assessment, University Hospital Maastricht, Maastricht, The Netherlands. E-mail: s.middeldorp@amc.uva.nl