Vincent Sobanski

Survival and Prognostic Factors in Systemic Sclerosis-Associated Pulmonary Hypertension A Systematic Review and Meta-Analysis

OBJECTIVEnPulmonary hypertension (PH) is a frequent and life-limiting complication of systemic sclerosis (SSc). However, data on survival rates and their evolution over time, as well as prognostic factors in SSc complicated by PH, are still conflicting. The aim of this study was to conduct a systematic review and meta-analysis of cohort studies to assess pooled survival and prognostic factors for survival in patients with SSc-associated PH.nnnMETHODSnFor this systematic review and meta-analysis, we searched the Medline and EMBase databases (January 1960 to January 2012). All cohort studies in which survival and/or prognostic factors for SSc-associated PH were reported were included in the analysis. We calculated the pooled survival rates and analyzed their evolution over time and identified prognostic factors for survival.nnnRESULTSnTwenty-two studies were included, representing a total of 2,244 patients with SSc-associated PH. The pooled 1-, 2-, and 3-year survival rates were 81% (95% confidence interval [95% CI] 79-84%), 64% (95% CI 59-69%), and 52% (95% CI 47-58%), respectively. Meta-regression did not reveal a significant change in survival over time, while baseline hemodynamic measures of PH severity were significantly correlated with survival. In patients with SSc complicated by pulmonary arterial hypertension (PAH), age, male sex, diffusing capacity for carbon monoxide (DLCO), pericardial effusion, and the parameters classically associated with the severity of idiopathic PAH, including the 6-minute walk distance, mean pulmonary artery pressure, cardiac index, and right atrial pressure, were significant prognostic factors. DLCO and pericardial effusion were the only prognostic factors in patients with interstitial lung disease-related PH.nnnCONCLUSIONnOur meta-analysis revealed a poor pooled 3-year survival rate of 52% in patients with SSc-associated PH. Baseline hemodynamic measures of PAH severity, but not the period of time during which patients were included in the studies, correlated significantly with survival in patients with SSc-associated PAH. All of the prognostic factors typically observed in idiopathic PAH, including the 6-minute walk distance and right atrial pressure, were also prognostic factors in SSc-associated PAH.

Prevalence of Anti–RNA Polymerase III Antibodies in Systemic Sclerosis: New Data From a French Cohort and a Systematic Review and Meta‐Analysis

Studies assessing the prevalence of anti–RNA polymerase III (anti–RNAP III) antibodies in systemic sclerosis (SSc) have yielded a wide range of results. The aim of the present study was to describe a new SSc cohort tested for presence of anti–RNAP III and perform a systematic review and meta‐analysis to assess the prevalence of anti–RNAP III in patients worldwide and the potential factors of variability.

Characteristics and Survival of Anti–U1 RNP Antibody–Positive Patients With Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs). This study aimed to investigate the clinical and hemodynamic characteristics and survival of anti–U1 RNP–positive patients with CTD‐associated PAH, with a focus on systemic sclerosis (SSc)–associated PAH.

Characteristics and survival of patients with anti-U1RNP antibodies in connective tissue disease associated pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs). This study aimed to investigate the clinical and hemodynamic characteristics and survival of anti–U1 RNP–positive patients with CTD‐associated PAH, with a focus on systemic sclerosis (SSc)–associated PAH.

Effect of in vitro and in vivo anakinra on cytokines production in Schnitzler syndrome.

IL-1 receptor antagonist anakinra is usually highly efficient in Schnitzler syndrome (SS), a rare inflammatory condition associating urticaria, fever, and IgM monoclonal gammopathy. In this study, we aimed to assess lipopolysaccharide (LPS)-induced production of inflammatory cytokines by peripheral blood mononuclear cells (PBMCs) before and after 1 month of anakinra in patients with SS. LPS-induced production of IL-1β, IL-6 and TNFα was assessed by enzyme-linked immunosorbent assay with and without anakinra in vitro, and before and after 1 month (in vivo condition) of treatment in 2 patients with SS. Spontaneous production of IL-1β, IL-6 and TNF-α by PBMCs was similar in the patients and the healthy controls and was almost undetectable. Stimulation with LPS caused a higher release of cytokines from the patients than from the healthy controls. Before in vivo anakinra start, in vitro adjunction of anakinra reduced the high LPS-induced production of IL-1β and TNFα in both patients and of IL-6 in one patient. After 1 month of treatment with anakinra, while the patients had dramatically improved, there was also a marked reduction in LPS-induced cytokines production, which was almost normalized in one patient. This study shows an abnormal LPS-induced inflammatory cytokines production in SS, which can be decreased or even normalized by in vitro and in vivo anakinra.

Current Approaches to the Treatment of Systemic-Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH).

Pulmonary arterial hypertension (PAH) is a severe condition causing significant morbidity and mortality in patients with systemic sclerosis (SSc). Despite the use of specific treatments, SSc-PAH survival remains poorer than in idiopathic PAH (IPAH). Recent therapeutic advances in PAH show a lower magnitude of response in SSc-PAH and a higher risk of adverse events, as compared to IPAH. The multifaceted underlying mechanisms and the multisystem nature of SSc probably explain part of the worse outcomes in SSc-PAH compared to IPAH. This review describes the current management of SSc-PAH with an emphasis on the impact of the different organ involvements in the prognosis and treatment response. An earlier detection of PAH and a better characterization of the clinical phenotypes of SSc-PAH are warranted in clinical practice and future trials. Determinants of prognosis, surrogate markers of clinical improvement or worsening, and relevance of the common endpoints used in clinical trials should be evaluated in this specific population. A multidisciplinary approach in expert referral centers is mandatory for SSc-PAH management.

Persistent triple antiphospholipid antibody positivity as a strong risk factor of first thrombosis, in a long-term follow-up study of patients without history of thrombosis or obstetrical morbidity.

Introduction The long-term risk of first thrombosis and benefit of prophylaxis in antiphospholipid antibody (aPL) carriers without history of thrombosis or obstetrical morbidity is poorly known. This study aimed to evaluate the long-term rate and risk factors associated with a first thrombosis in those patients. Patients and methods After a prior study ended in December 2005 and was already published, we extended the follow-up period of our cohort of aPL carriers. Results Ninety-eight of the 103 patients of the previous study were included. The annual first thrombosis rate was 2.3% per patient-year during a median of 13 years (6–17). None of the baseline characteristics was predictive of risk of first thrombosis, but persistent aPL over time were associated with an increased risk. The stronger association was found in triple aPL-positive carriers: OR 3.38 (95% CI: 1.24–9.22). Of note, conversely to our previous findings, no benefit of aspirin prophylaxis was observed. Conclusion The risk of first thrombosis in aPL carriers without history of thrombosis or obstetrical morbidity was significant, persisted linearly over time and was associated with persistent aPL. This risk was especially increased in triple aPL-positive carriers, in whom a close follow-up seems to be necessary. Nevertheless, the benefit of aspirin prophylaxis remained unclear.

Role of B cells in the pathogenesis of systemic sclerosis

Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naïve subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-β (TGF-β) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.

Pulmonary Arterial Hypertension Associated With Systemic Lupus Erythematosus: Results From the French Pulmonary Hypertension Registry

Background Pulmonary arterial hypertension (PAH) is a rare complication of systemic lupus erythematosus (SLE). Methods We identified all patients with SLE and PAH (SLE‐PAH) who were enrolled in the French Pulmonary Hypertension Registry with a diagnosis confirmed by right heart catheterization (RHC). A control group of 101 patients with SLE without known PAH was selected from SLE expert centers participating in the Pulmonary Hypertension Registry. Survival was estimated by the Kaplan‐Meier method. Hazard ratios associated with potential predictors of death were estimated using Cox proportional hazard models. Results Of the 69 patients with SLE‐PAH identified in the French Pulmonary Hypertension Registry, 51 were included in the study. They did not differ from the control group regarding age, sex, or duration of SLE at the time of the analysis but had a higher frequency of anti‐SSA and anti‐SSB antibodies. The delay between SLE diagnosis and PAH diagnosis was 4.9 years (range, 2.8‐12.9) years. The 3‐ and 5‐year overall survival rates were 89.4% (95% CI, 76.2%‐96.5%) and 83.9% (95% CI, 68.8%‐92.1%), respectively. The survival rate was significantly better in patients with anti‐U1‐RNP antibodies (P = .04). Conclusions Patients with SLE‐PAH have an overall 5‐year survival rate of 83.9% after the PAH diagnosis. Anti‐SSA/SSB antibodies may be a risk factor for PAH, and the presence of anti‐U1‐RNP antibodies appears to be a protective factor regarding survival.

Relevance of Partitioning DLCO to Detect Pulmonary Hypertension in Systemic Sclerosis

We investigated whether partitioning DLCO into membrane conductance for CO (DmCO) and pulmonary capillary blood volume (Vcap) was helpful in suspecting precapillary pulmonary (arterial) hypertension (P(A)H) in systemic sclerosis (SSc) patients with or without interstitial lung disease (ILD). We included 63 SSc patients with isolated PAH (n=6), isolated ILD (n=19), association of both (n=12) or without PAH and ILD (n=26). Partitioning of DLCO was performed by the combined DLNO/DLCO method. DLCO, DmCO and Vcap were equally reduced in patients with isolated PAH and patients with isolated ILD but Vcap/alveolar volume (VA) ratio was significantly lower in the isolated PAH group. In patients without ILD, DLCO, DmCO, Vcap and Vcap/VA ratio were reduced in patients with isolated PAH when compared to patients without PAH and both Vcap/VA and DLCO had the highest AUC to detect PAH. In patients with ILD, Vcap had the highest AUC and performed better than DLCO to detect PH in this subgroup. In conclusion, Vcap/VA was lower in PAH than in ILD in SSC whereas DLCO was not different. Vcap/VA ratio and DLCO had similar high performance to detect PAH in patients without ILD. Vcap had better AUC than DLCO, DmCO and FVC/DLCO ratio to detect PH in SSC patients with ILD. These results suggest that partitioning of DLCO might be of interest to detect P(A)H in SSC patients with or without ILD.