We aimed to compare the efficacy of steroids alone or associated with immunosuppressive drugs for the prevention of relapse in cardiac sarcoidosis (CS).
In this monocentric multidisciplinary ...retrospective single center study, all consecutive patients with histologically proven sarcoidosis hospitalized from January 2012 to December 2016 were considered. All patients with symptomatic CS were studied. Patients received steroids or steroids plus immunosuppressive drugs (IS) for CS treatment at diagnosis. The efficacy of each treatment strategy (steroids vs steroids + IS) was assessed by the cardiac relapse rate over follow up.
326 consecutive patients with histologically proven sarcoidosis were screened. Among them, 36 (11%) had symptomatic CS (20 (55.5%) men, median age at diagnosis 48.5 22.8–76). Twenty-four patients received steroids and 12 received steroids + IS (azathioprine n = 5, methotrexate n = 5, cyclophosphamide n = 2) at CS diagnosis. Over a median follow up of 3.6 1–15.2 years, 13 (36.1%) patients suffered a cardiac relapse including reduced left ventricular ejection fraction (LVEF, n = 4), third degree heart block (n = 2), atrio-ventricular (n = 1) or ventricular (n = 1) tachycardia and sudden cardiac death (n = 1). Except for a higher frequency of black patients in patients receiving IS, CS features at diagnosis and median time to relapse did not significantly differ between patients who did or did not receive IS. Relapse rate was 45.8% in the steroids group versus 16.7% in the steroids + IS group (p = 0.048).
In cardiac sarcoidosis, the combination of steroids with immunosuppressive drugs might reduce the risk of cardiac relapse, as compared to steroids alone.
•Heart involvement is the leading cause of death in sarcoidosis•Evidence-based data regarding cardiac sarcoidosis treatment are poor•Steroids and immunosuppressive drugs may be more effective than steroids alone in preventing cardiac sarcoidosis relapse.
Langerhans cell histiocytosis (LCH) and the non-LCH neoplasm Erdheim-Chester disease (ECD) are heterogeneous neoplastic disorders marked by infiltration of pathologic macrophage-, dendritic cell–, or ...monocyte-derived cells in tissues driven by recurrent mutations activating MAPK signaling. Although recent data indicate that at least a proportion of LCH and ECD patients have detectable activating kinase mutations in circulating hematopoietic cells and bone marrow–based hematopoietic progenitors, functional evidence of the cell of origin of histiocytosis from actual patient materials has long been elusive. Here, we provide evidence for mutations in MAPK signaling intermediates in CD34+ cells from patients with ECD and LCH/ECD, including detection of shared origin of LCH and acute myelomonocytic leukemia driven by TET2-mutant CD34+ cell progenitors in one patient. We also demonstrate functional self-renewal capacity for CD34+ cells to drive the development of histiocytosis in xenotransplantation assays in vivo. These data indicate that the cell of origin of at least a proportion of patients with systemic histiocytoses resides in hematopoietic progenitor cells prior to committed monocyte/macrophage or dendritic cell differentiation and provide the first example of a patient-derived xenotransplantation model for a human histiocytic neoplasm.
•BRAFV600E mutations are detectable in hematopoietic stem and progenitors in adults with histiocytosis.•Transplantation of CD34+ cells from histiocytosis patients can give rise to genetically and phenotypically accurate xenografts.
Objective
Infective endocarditis (IE) mimics primary systemic vasculitis, and there are sporadic reports of positivity for antineutrophil cytoplasmic antibodies (ANCAs) among patients with IE. ...Because the frequency of ANCAs in IE is unknown, this study was undertaken to assess the seroprevalence of ANCAs in a large number of patients with IE.
Methods
The study was conducted in the framework of a single‐center prospective cohort study of incident IE cases. Demographic, clinical, laboratory, and microbiologic data were collected, and magnetic resonance imaging of the brain was performed at diagnosis. For those patients whose serum had been stored at diagnosis, ANCAs were assessed by indirect immunofluorescence assay in ethanol‐, formalin‐, and methanol‐fixed neutrophils. In addition, ANCA specificity for proteinase 3 (PR3) and myeloperoxidase (MPO) was assessed by enzyme‐linked immunosorbent assay. Rheumatoid factor (RF), antinuclear antibodies (ANAs), anticardiolipin antibodies (aCL), and serum Ig levels were also measured. Comparisons between groups were made using Wilcoxon's rank sum and chi‐square or Fisher's exact tests.
Results
Among 109 patients with IE, 18% had cytoplasmic ANCAs (cANCA) and/or perinuclear ANCAs (pANCA) and 8% had PR3‐ANCAs or MPO‐ANCAs, some with very high titers. Positivity for both cANCA or pANCA and PR3‐ANCAs or MPO‐ANCAs was found in 6% of patients, and RF, ANAs, and aCL were detected in 35%, 16%, and 23% of samples, respectively. No consistent clinical pattern of IE was observed in the anti‐PR3/anti‐MPO–positive IE patients, whereas positivity for cANCA/pANCA was associated with younger age (P = 0.022), more frequent occurrence of echocardiographic vegetations (P = 0.043), and above‐normal serum IgG levels (P = 0.017).
Conclusion
ANCAs, including PR3‐ and MPO‐ANCAs, occur in a substantial proportion of patients with IE. The link between cANCA/pANCA and specific features of IE requires further study.
To analyze the impact of chronic kidney disease (CKD) on major clinical outcome in SLE by using a nationwide database.
Characteristics of all admitted SLE patients experiencing CKD (eGFR ...<60 mL/min/1.73 m2) in France from 2009 to 2015 were analyzed through the French medico- administrative database. Factors associated with CKD and major clinical outcomes such as end-stage renal disease (ESRD), cardiovascular event (CVE), septic shock and death were assessed. We used a multivariate Cox proportional hazard model and subdistribution hazard models to analyze survival without major clinical events according to the presence of CKD.
From 2009 to 2015, 26,320 SLE patients were hospitalized in France. Among them, 6439 (86.5% women; mean age 45.7 16.5 years old) had a baseline stay in 2009 during which CKD was reported in 428 (6.7%) cases. Multivariate analysis showed that lupus nephritis (OR 6.6 5.2–8.4), high blood pressure (OR 3.5 2.8–4.5), septic shock (OR 3.2 1.7–6.0) and past cardiovascular history (OR 1.4 1.0–2.0) were associated with CKD status. From 2009 to 2015, ESRD, CVE, septic shock, and death occurred in 4.0%, 14.4%, 6.3% and 9.6% of the 6439 SLE patients. CKD at baseline was independently and strongly associated with the occurrence of ESRD (sdHR 15.9 11.6–21.9), CVE (sdHR 1.7 1.4–2.2), septic shock (sdHR 2.1 1.5–2.8) and death (HR 1.7 1.3–2.2) during the follow up.
CKD is a major risk factor for overall morbidity and mortality in SLE patients, highlighting the need for early pre-CKD lupus nephritis diagnosis and treatment.
•Nationwide database analysis of major outcomes in SLE was performed.•CKD is a major risk factor for overall morbidity and mortality in SLE.•Early pre-CKD lupus nephritis diagnosis and treatment is mandatory.
Current standard therapy for Wegener's granulomatosis and microscopic polyangiitis combines corticosteroids and cyclophosphamide to induce remission, followed by a less toxic immunosuppressant such ...as azathioprine or methotrexate for maintenance therapy. However, azathioprine and methotrexate have not been compared with regard to safety and efficacy.
In this prospective, open-label, multicenter trial, we randomly assigned patients with Wegener's granulomatosis or microscopic polyangiitis who entered remission with intravenous cyclophosphamide and corticosteroids to receive oral azathioprine (at a dose of 2.0 mg per kilogram of body weight per day) or methotrexate (at a dose of 0.3 mg per kilogram per week, progressively increased to 25 mg per week) for 12 months. The primary end point was an adverse event requiring discontinuation of the study drug or causing death; the sample size was calculated on the basis of the primary hypothesis that methotrexate would be less toxic than azathioprine. The secondary end points were severe adverse events and relapse.
Among 159 eligible patients, 126 (79%) had a remission, were randomly assigned to receive a study drug in two groups of 63 patients each, and were followed for a mean (+/-SD) period of 29+/-13 months. Adverse events occurred in 29 azathioprine recipients and 35 methotrexate recipients (P=0.29); grade 3 or 4 events occurred in 5 patients in the azathioprine group and 11 patients in the methotrexate group (P=0.11). The primary end point was reached in 7 patients who received azathioprine as compared with 12 patients who received methotrexate (P=0.21), with a corresponding hazard ratio for methotrexate of 1.65 (95% confidence interval, 0.65 to 4.18; P=0.29). There was one death in the methotrexate group. Twenty-three patients who received azathioprine and 21 patients who received methotrexate had a relapse (P=0.71); 73% of these patients had a relapse after discontinuation of the study drug.
These results do not support the primary hypothesis that methotrexate is safer than azathioprine. The two agents appear to be similar alternatives for maintenance therapy in patients with Wegener's granulomatosis and microscopic polyangiitis after initial remission. (ClinicalTrials.gov number, NCT00349674.)
Systemic necrotizing vasculitis comprises a group of diseases resembling polyarteritis nodosa and anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA): granulomatosis with polyangiitis, ...eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis. The definitive diagnosis is made in cooperation with a reference center for autoimmune diseases and rare systemic diseases or a competency center. The management goals are: to obtain remission and, in the long term, healing; to reduce the risk of relapses; to limit and reduce the sequelae linked to the disease; to limit the side effects and the sequelae linked to the treatments; to improve or at least maintain the best possible quality of life; and to maintain socio-professional integration and/or allow a rapid return to school and/or professional activity. Information and therapeutic education of the patients and those around them are an integral part of the care. All health professionals and patients should be informed of the existence of patient associations. The treatment of vasculitis is based on variable combinations of glucocorticoids and immunosuppressants, chosen and adapted according to the disease concerned, the severity and/or extent of the disease, and the underlying factors (age, kidney function, etc.). Follow-up clinical and paraclinical examinations must be carried out regularly to clarify the progression of the disease, detect and manage treatment failures and possible relapses early on, and limit sequelae and complications (early then late) related to the disease or treatment. A distinction is made between the induction therapy, lasting approximately 3-6 months and aimed at putting the disease into remission, and the maintenance treatment, lasting 12-48 months, or even longer. The role of the increase or testing positive again for ANCA as a predictor of a relapse, which has long been controversial, now seems to have greater consensus: Anti-myeloperoxidase ANCAs are less often associated with a relapse of vasculitis than anti-PR3 ANCA.
Mixed connective tissue disease (MCTD) is a rare and complex autoimmune disease that presents mixed features with other connective tissue diseases, such as systemic lupus erythematosus, systemic ...sclerosis, and myositis. It is characterized by high levels of anti–U1 small nuclear ribonucleoprotein 70k autoantibodies and a high incidence of life-threatening pulmonary involvement. The pathophysiology of MCTD is not well understood, and no specific treatment is yet available for the patients. Basophils and IgE play a role in the development of systemic lupus erythematosus and thus represent new therapeutic targets for systemic lupus erythematosus and other diseases involving basophils and IgE in their pathogenesis.
We sought to investigate the role of basophils and IgE in the pathophysiology of MCTD.
Basophil activation status and the presence of autoreactive IgE were assessed in peripheral blood of a cohort of patients with MCTD and in an MCTD-like mouse model. Basophil depletion and IgE-deficient animals were used to investigate the contribution of basophils and IgE in the lung pathology development of this mouse model.
Patients with MCTD have a peripheral basopenia and activated blood basophils overexpressing C-C chemokine receptor 3. Autoreactive IgE raised against the main MCTD autoantigen U1 small nuclear ribonucleoprotein 70k were found in nearly 80% of the patients from the cohort. Basophil activation and IgE anti–U1 small nuclear ribonucleoprotein 70k were also observed in the MCTD-like mouse model along with basophil accumulation in lymph nodes and lungs. Basophil depletion dampened lung pathology, and IgE deficiency prevented its development.
Basophils and IgE contribute to MCTD pathophysiology and represent new candidate therapeutic targets for patients with MCTD.
Objective
To evaluate the usefulness of 2‐18F‐fluoro‐2‐deoxy‐d‐glucose–positron emission tomography/computed tomography (FDG‐PET/CT) in IgG4‐related disease (IgG4‐RD) for the staging of the disease ...and the followup under treatment.
Methods
All patients included in the French IgG4‐RD registry who underwent ≥1 FDG‐PET/CT scan were included in the study. Clinical, biologic, pathologic, radiologic, and FDG‐PET/CT qualitative and quantitative findings were retrospectively collected and analyzed.
Results
Twenty‐one patients were included in the study and 46 FDG‐PET/CT examinations were evaluated. At either diagnosis or relapse, all evaluated patients presented abnormal 18F‐FDG uptake in typical IgG4‐RD localizations. In most cases, FDG‐PET/CT was more sensitive than conventional imaging to detect organ involvement, especially in arteries, salivary glands, and lymph nodes. In few cases (small‐sized lesions and brain or kidney contiguous lesions), false‐negative results were noted. Evaluation before and after treatment showed in most cases a good correlation of FDG‐PET/CT results with treatment response and disease activity.
Conclusion
This large retrospective study shows that FDG‐PET/CT imaging is useful for the staging of IgG4‐RD. Moreover, FDG‐PET/CT is useful to assess the response to treatment during followup.
Cardiovascular disease (CVD) is a major cause of death in systemic lupus erythematosus (SLE) patients. Although the risk for cardiovascular events in patients with SLE is significant, the absolute ...number of events per year in any given cohort remains small. Thus, CVD risks stratification in patients with SLE focuses on surrogate markers for atherosclerosis at an early stage, such as reduced elasticity of arteries. Our study was designed to determine whether arterial stiffness is increased in SLE patients at low risk for CVD and analyze the role for traditional and non-traditional CVD risk factors on arterial stiffness in SLE. Carotid-femoral pulse wave velocity (PWV) was prospectively assessed as a measure of arterial stiffness in 41 SLE patients and 35 controls (CTL). Adjustment on age or Framingham score was performed using a logistic regression model. Factors associated with PWV were identified separately in SLE patients and in controls using Pearson's correlation coefficient for univariate analysis and multiple linear regression for multivariate analysis. SLE patients and controls displayed a low 10-year risk for CVD according to Framingham score (1.8±3.6% in SLE vs 1.6±2.8% in CTL, p = 0.46). Pulse wave velocity was, however, higher in SLE patients (7.1±1.6 m/s) as compared to controls (6.3±0.8 m/s; p = 0.01, after Framingham score adjustment) and correlated with internal carotid wall thickness (p = 0.0017). In multivariable analysis, only systolic blood pressure (p = 0.0005) and cumulative dose of glucocorticoids (p = 0.01) were associated with PWV in SLE patients. Interestingly, the link between systolic blood pressure (SBP) and arterial stiffness was also confirmed in SLE patients with normal systolic blood pressure. In conclusion, arterial stiffness is increased in SLE patients despite a low risk for CVD according to Framingham score and is associated with systolic blood pressure and glucocorticoid therapy.
Hydroxychloroquine (HCQ) is an important medication for treating systemic lupus erythematosus (SLE). Its blood concentration (HCQ) varies widely between patients and is a marker and predictor of SLE ...flares. This prospective randomised, double-blind, placebo-controlled, multicentre study sought to compare standard and adjusted HCQ dosing schedules that target HCQ ≥1000 ng/ml to reduce SLE flares.
HCQ was measured in 573 patients with SLE (stable disease and SELENA-SLEDAI≤12) treated with HCQ for at least 6 months. Patients with HCQ from 100 to 750 ng/ml were randomised to one of two treatment groups: no daily dose change (group 1) or increased HCQ dose to achieve the target HCQ (group 2). The primary end point was the number of patients with flares during 7 months of follow-up.
Overall, mean HCQ was 918±451 ng/ml. Active SLE was less prevalent in patients with higher HCQ. A total of 171 patients were randomised and followed for 7 months. SLE flare rates were similar in the two groups (25% in group 1 vs 27.6% in group 2; p=0.7), but a significant spontaneous increase in HCQ in both groups between inclusion and randomisation strongly suggested improved treatment adherence. Patients at the therapeutic target throughout follow-up tended to have fewer flares than those with low HCQ (20.5% vs 35.1%, p=0.12).
Although low HCQ is associated with higher SLE activity, adapting the HCQ dose did not reduce SLE flares over a 7-month follow-up.
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