Marc Lambert

Azathioprine or Methotrexate Maintenance for ANCA-Associated Vasculitis

BACKGROUND Current standard therapy for Wegeners 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. METHODS In this prospective, open-label, multicenter trial, we randomly assigned patients with Wegeners 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. RESULTS 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. CONCLUSIONS 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 Wegeners granulomatosis and microscopic polyangiitis after initial remission. (ClinicalTrials.gov number, NCT00349674.)

Retrospective Analysis of Surgery Versus Endovascular Intervention in Takayasu Arteritis: A Multicenter Experience

Background— With recent advances in endovascular treatment, percutaneous endoluminal angioplasty has become particularly attractive for arterial lesions of Takayasu arteritis. However, data came from case reports or small series, and the long-term outcome has not been reported. The incidence of potential vascular complications after surgery or endovascular treatment is still to be determined. Methods and Results— This retrospective multicenter study analyzed the results and outcomes of 79 consecutive patients with Takayasu arteritis (median age, 39 years; interquartile range [IQR], 25–50 years; 63 women [79.7%]) who underwent 166 vascular procedures (surgery, 104 [62.7%]; endovascular repair, 62 [37.3%]) for the management of arterial complications. After a follow-up of 6.5 years (IQR, 2.2–11.5 years), 70 complications were observed, including restenosis (n=53), thrombosis (n=7), bleeding (n=6), and stroke (n=4). The overall 1-, 3-, 5-, and 10-year arterial complication–free survival rates were 78% (IQR, 69%–88%), 67% (IQR, 57%–78%), 56% (IQR, 46%–70%), and 45% (IQR, 34%–60%), respectively. Among the 104 surgical procedures, 39 (37.5%) presented a complication compared with 31 of the 62 (50%) with endovascular repair. In multivariate analysis, biological inflammation at the time of revascularization (odds ratio, 7.48; 95% confidence interval, 1.42–39.39; P=0.04) was independently associated with the occurrence of arterial complications after the vascular procedure. Patients who experienced complications had higher erythrocyte sedimentation rates (P<0.001) and C-reactive protein (P<0.001) and fibrinogen (P<0.005) serum levels compared with those without complications. Conclusions— The overall 5-year arterial complication rate was 44%. Biological inflammation increased the likelihood of complications after revascularization in patients with Takayasu arteritis.

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

OBJECTIVE Pulmonary 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. METHODS For 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. RESULTS Twenty-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. CONCLUSION Our 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.

The Systemic Capillary Leak Syndrome: A Case Series of 28 Patients From a European Registry

BACKGROUND The systemic capillary leak syndrome (SCLS) is a rare disease characterized by life-threatening attacks of capillary hyperpermeability. OBJECTIVE To describe the clinical characteristics, laboratory findings, treatments, and outcomes of patients with SCLS who were not previously reported in the literature. DESIGN Case series. SETTING Patients referred to a European multicenter SCLS registry between January 1997 and July 2010. PATIENTS 28 patients with SCLS. MEASUREMENTS Frequency, severity of attacks, and vital status were assessed every 6 months, from diagnosis to the end of the study. RESULTS 13 men and 15 women referred to the registry who were not previously reported in the literature had 252 attacks. Median age at disease onset was 49.1 years (range, 5.4 to 77.7 years), and median annual frequency of attacks was 1.23 (range, 0.13 to 21.18) per patient. Monoclonal IgG gammopathy was observed in 25 patients (89%). Preventive treatment included intravenous immunoglobulin (n = 18), terbutaline (n = 9), and aminophylline (n = 10). Eight patients died (29%); 1-year survival was 89%, and 5-year survival was 73%. Death was directly related to SCLS attacks in 6 of 8 cases (75%). In 10 patients with a prediagnosis period greater than 6 months who received preventive treatment, the annual frequency of attacks after diagnosis decreased by a median of 1.55 (range, 0.14 to 8.84) per patient. Five years after diagnosis, survival was 85% in 23 patients who had received prophylactic treatment and 20% in 5 patients who had not. LIMITATION The benefits of preventive treatment could not be precisely ascertained because of the small sample size and because most patients received several treatments. CONCLUSION Clinical experience with these 28 patients with SCLS suggests that prophylactic treatment with β(2)-agonists or intravenous immunoglobulin may reduce the frequency and severity of attacks and may improve survival. PRIMARY FUNDING SOURCE Université Pierre et Marie Curie, Paris, France.

Immunological profile in primary Sjögren syndrome: Clinical significance, prognosis and long-term evolution to other auto-immune disease

OBJECTIVE To study evolution of pSS immunological profile, impact on pSS activity and the long-term evolution of patients with atypical auto-antibodies in a bicentric cohort of patients with pSS (n=445, mean age 53.6+/-14years, mean follow-up 76.1+/-51months). RESULTS 212 patients were SSA positive and 131 were both SSA and SSB positive. During follow-up, SSA antibodies disappear in 8 patients; 2 of them exhibit new systemic complications of pSS. 68 patients had cryoglobulinemia. 52 patients had other anti-nuclear antibodies (ANA) specificities: anti-RNP (n=12), anti-centromere (n=14), anti-DNA native (n=19), anti-Scl70 (n=3), anti-JO1 (n=3), anti-Sm (n=3) and anti-histone (n=1). Fourteen patients developed ANA-associated auto-immune disease during the follow-up: 5 polymyositis (mean apparition delay 78months), 6 systemic lupus erythematosus (mean occurrence delay 77months) and 2 systemic sclerosis (mean occurrence delay 133+/-64months). Among these 14 patients, only three presented atypical-ANA at pSS diagnosis. Cryoglobulinemia and anti-SSA and SSB antibodies at diagnosis were associated with new systemic involvements. IN CONCLUSION Cryoglobulinemia and SSA/SSB positivity are associated with systemic activity after diagnosis in pSS. Although atypical ANA are found in 12% of the cases, long-term evolution to ANA associated auto-immune diseases concerned patients with active immunological profile and extra-glandular manifestations.

High-dose intravenous immunoglobulins dramatically reverse systemic capillary leak syndrome.

Objective:The objective of this study was to report the dramatic improvement of patients with systemic capillary leak syndrome obtained with high-dose intravenous immunoglobulins. Design:Systemic capillary leak syndrome is a rare and life-threatening disorder characterized by hypotension that can lead to shock, weight gain, hypoalbuminemia, and elevated hematocrit secondary to unexplained episodic capillary fluid extravasation into the interstitial space. Because its cause is unknown, systemic capillary leak syndrome treatment has remained largely supportive. Main Results:Intravenous immunoglobulins administration to a patient with refractory systemic capillary leak syndrome yielded dramatic improvement. The patient is still alive 11 yrs after systemic capillary leak syndrome diagnosis and receives intravenous immunoglobulins monthly. Later, based on that result, intravenous immunoglobulins were successfully given to two other patients during the acute phase of systemic capillary leak syndrome. Both are still alive 8 and 1.5 yrs after receiving intravenous immunoglobulins at the onset of each flare. Conclusions:Intravenous immunoglobulins were effective against systemic capillary leak syndrome symptoms in three patients, but their exact mechanism remains unknown. Their immunomodulatory effect merits further investigation.

Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: An international and collaborative meta-analysis

We performed a meta-analysis to determine whether aspirin has a significant protective effect on risk of first thrombosis among patients with antiphospholipid antibodies (aPL+). Observational and interventional studies identified from the Medline, Embase and Cochrane databases were selected if they assessed the incidence of first thrombosis in aPL+ patients treated with aspirin versus those without. Pooled effect estimates were obtained using a random-effects model. Of 1211 citation retrieved, 11 primary studies (10 observational and 1 interventional) met inclusion criteria, including a total of 1208 patients and 139 thrombotic events. The pooled odds ratio (OR) for the risk of first thrombosis in patients treated with aspirin (n=601) was 0.50 (95%CI: 0.27 to 0.93) compared to those without aspirin (n=607), with significant heterogeneity across studies (I(2)=46%, p=0.05). Subgroup analysis showed a protective effect of aspirin against arterial (OR: 0.48 [95%CI: 0.28-0.82]) but not venous (OR: 0.58 [95% CI: 0.32-1.06]) thrombosis, as well as in retrospective (OR: 0.23 [0.13-0.42]) but not prospective studies (OR: 0.91 [0.52-1.59]). Subgroup analysis according to underlying disease revealed a significant protective effect of aspirin for asymptomatic aPL+ individuals (OR: 0.50 [0.25-0.99]), for systemic lupus erythematosus (SLE) (OR: 0.55 [0.31-0.98]) and obstetrical antiphospholipid syndrome (APS) (OR: 0.25 [0.10-0.62]). This meta-analysis shows that the risk of first thrombotic event is significantly decreased by low dose aspirin among asymptomatic aPL individuals, patients with SLE or obstetrical APS. Importantly, no significant risk reduction was observed when considering only prospective studies or those with the best methodological quality.

Efficacy and tolerance of infliximab in refractory Takayasu arteritis: French multicentre study

OBJECTIVE To analyse the efficacy and tolerance of infliximab in refractory Takayasu arteritis (TA). METHODS French multicentre retrospective study that included patients with TA. Clinical disease activity was defined as new vascular and/or constitutional signs. RESULTS Fifteen patients with TA [median age 41 (range 17-61) years; 13 women] were included. At initiation of infliximab therapy, 14 patients were treated with CSs [prednisone; median dose 20 (range 5-35) mg/day], MTX (n = 7) or AZA (n = 4). Infliximab was used at median 5 (range 3-5) mg/kg at a median of every 6 (range 4-8) weeks. A partial or good overall response was noted in 13 (87%) of the 15 cases, 10 (77%) of the 13 cases and 8 (73%) of the 11 cases at 3, 6 and 12 months, respectively. Clinical and biological activities significantly decreased within 3 months (from 11 at baseline to 4 patients at 12 months; P < 0.05), and similarly for CS dose [from median 20 (range 5-35) mg/day at baseline to median 6 (range 2.5-30) mg/day at 12 months; P < 0.05]. Only one patient was still steroid-dependent at 12 months (vs 8 cases before infliximab). CRP regressed from a median 30 (range 4-70) mg/l to 5 (range 0-57) mg/l and 6 (0-50) mg/l at 3 and 6 months, respectively (P < 0.05). Side effects were two infusion-related reactions, one pulmonary tuberculosis, one severe bacterial infection and EBV reactivation. CONCLUSION This study confirms the interest of infliximab in terms of clinical and biological response, as well as the steroid-sparing effect in TA.

Inferior vena cava agenesis and deep vein thrombosis: 10 patients and review of the literature

Inferior vena cava agenesis (IVCA) is a rare condition, found in almost 5% of patients under 30 years old with unprovoked deep venous thrombosis (DVT). We describe 10 consecutive patients with IVCA-associated DVT and conducted an extensive literature review to investigate the typical spectrum of IVCA-associated DVT. Among our patients (eight men and two women; mean age, 25 ± 4.5 years), DVT followed intense and unusual (major) physical activity for eight of them. DVT was bilateral in six patients and unilateral in four. Ultrasonography was unable to detect IVCA, which was visualized by computed-tomography scans for seven patients, and magnetic resonance imaging and angiography for 10. Hereditary thrombophilia screening, to detect factor V Leiden or prothrombin gene heterozygosity (G20210A mutation), was positive for only two patients. Wearing elastic stockings and taking an indefinite or long-term vitamin K antagonist were prescribed for all 10 patients and nine complied with the latter. To date, 62 patients with IVCA-associated DVT have been reported in the English literature. Analysis of them and our patients yielded a typical spectrum of IVCA-associated DVT characteristics: IVCA occurs in young adults, particularly males, and is revealed by proximal DVT following major physical exertion. All were treated with a prolonged vitamin K antagonist and advised to wear elastic stockings. No precise duration of anticoagulation has been established.

European registry of babies born to mothers with antiphospholipid syndrome

Objectives This study aimed to describe the long-term outcome and immunological status of children born to mothers with antiphospholipid syndrome, to determine the factors responsible for childhood abnormalities, and to correlate the childs immunological profile with their mothers. Methods A prospective follow-up of a European multicentre cohort was conducted. The follow-up consisted of clinical examination, growth data, neurodevelopmental milestones and antiphospholipid antibodies (APL) screening. Children were examined at 3, 9, 24 months and 5 years. Results 134 children were analysed (female sex in 65 cases, birth weight 3000±500 g, height 48±3 cm). Sixteen per cent had a preterm birth (<37 weeks; n=22), and 14% weighted less than 2500 g at birth (n=19). Neonatal complications were noted in 18 cases (13%), with five infections (4%). During the 5-year follow-up, no thrombosis or systemic lupus erythematosus (SLE) was noted. Four children displayed behavioural abnormalities, which consisted of autism, hyperactive behaviour, feeding disorder with language delay and axial hypotony with psychomotor delay. At birth lupus anticoagulant was present in four (4%), anticardiolipin antibodies (ACL) IgG in 18 (16%), anti-β2 glycoprotein-I (anti-β2GPI) IgG/M in 16 (15%) and three (3%), respectively. ACL IgG and anti-β2GPI disappeared at 6 months in nine (17%) and nine (18%), whereas APL persisted in 10% of children. ACL and anti-β2GPI IgG were correlated with the same mothers antibodies before 6 months of age (p<0.05). Conclusion Despite the presence of APL in children, thrombosis or SLE were not observed. The presence of neurodevelopmental abnormalities seems to be more important in these children, and could justify long-term follow-up.