A. Mekinian

Management of large-vessel vasculitis with FDG-PET: a systematic literature review and meta-analysis.

AbstractWe aimed to clarify the role of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the management of large-vessel vasculitis (LVV), focusing on 3 issues which are as follows: describe and determine the different FDG-PET criteria for the diagnosis of vascular inflammation, the performance of FDG-PET for the diagnosis of large-vessel inflammation in giant cell arteritis (GCA) patients, and the performance of FDG-PET to evaluate the disease inflammatory activity in Takayasu arteritis (TA) patients.MEDLINE, Cochrane Library, and EMBASE database were searched for articles that evaluated the value of FDG-PET in LVV, from January 2000 to December 2013. Inclusion criteria were American College of Rheumatology criteria for GCA or TA, definition PET positivity threshold, and >4 cases included. Sensitivity (Se) and specificity (Sp) of FDG-PET for the diagnosis of large-vessel inflammation were calculated from each included individual study, and then pooled for meta-analysis with a random-effects model.Twenty-one studies (413 patients, 299 controls) were included in the systematic review. FDG-PET showed FDG vascular uptake in 70% (288/413) of patients and 7% (22/299) of controls. Only vascular uptake equal to or higher than the liver uptake was significantly different between GCA/TA patients and controls (P < 0.001). The meta-analysis of GCA patients (4 studies, 57 patients) shows that FDG-PET has high Se and Sp for the diagnosis of large-vessel inflammation in GCA patients in comparison to controls, with a pooled Se at 90% (95% confidence interval [CI], 79%–93%) and a pooled Sp at 98% (95% CI, 94%–99%). The meta-analysis of TA patients (7 studies, 191 patients) shows that FDG-PET has a pooled Se at 87% (95% CI, 78%–93%) and Sp at 73% (95% CI, 63%–81%) for the assessment of disease activity in TA, with up to 84% Sp, with studies using National Institutes of Health criteria as the disease activity assessment scale.FDG-PET showed good performances in the diagnosis of large-vessel inflammation, with higher accuracy in GCA patients than in TA patients. Although a vascular uptake equal to or higher than the liver uptake appears to be a good criterion for the diagnosis of vascular inflammation, further studies are needed to define the threshold of significance as well as the clinical significance of the vascular uptake.

Tocilizumab in refractory Takayasu arteritis: A case series and updated literature review

BACKGROUND/PURPOSE The aim of this study is to analyze the efficacy and tolerance of tocilizumab in patients with Takayasu arteritis (TA). METHODS We retrospectively studied patients with TA (ACR and/or Ishikawas criteria): 5 French multicenter cases and 39 from the literature. Clinical, biological, radiological disease activity and treatment were analyzed before tocilizumab, during the follow-up and at the last available visit. RESULTS Forty-four patients (median age 26years [3-65];) were included in the present study: 5 patients from the 3 French university hospitals and 39 cases from the literature review. Median follow-up after initiation of tocilizumab was 15months [8-33]. Clinical and biological activities significantly decreased within 3months, similarly to steroid amount (from 15mg/day [5-75] at baseline to 10mg/day [2-30] at 6months; p<0.05) and steroid-dependence rate. Even radiological activity did not significantly decrease at 6months, significant decrease of arterial FDG uptake was noted at 6months. Median duration of tocilizumab treatment was 9months [3-180]. At the last visit, tocilizumab was continued in 17/32 patients (53%), and was discontinued in the 15 remaining cases because of the remission (n=5), relapse (n=3), persistent radiological activity (n=3), cutaneous rash (n=2), severe infection (n=1) and lacking of care welfare system (n=1). No death related to tocilizumab treatment was noted. CONCLUSION This study show the efficacy of tocilizumab in terms of clinical, biological and radiological response, as well as steroid-sparing agent. Only well-designed studies could definitely address the efficacy of tocilizumab in TA.

Efficacy of rituximab in primary Sjögren's syndrome with peripheral nervous system involvement: results from the AIR registry

Objective To evaluate rituximab (RTX) in primary Sjögrens syndrome (pSS) with peripheral nervous system (PNS) involvement. Methods Patients with pSS and PNS involvement who were included in the French AIR registry were analysed. Results 17 patients (age 60 years (44–78 years); 14 were female) were analysed. Neurological improvement was noted in 11 patients (65%) at 3 months. Rankin scale decreased from 3 (1–5) to 2 (1–5), 2 (1–5) and 2 (1–6) after 3, 6 and 9 months (p=0.02). European Sjögrens Syndrome Disease Activity Index decreased from 18 (10–44) to 11 (5–20), 11 (5–29) and 12 (5–30) after 3, 6 and 9 months (p<0.05). RTX was effective in neurological involvement in 9/10 patients with vasculitis or cryoglobulinaemia (90%) (group 1) at 3 months and in 2/7 cases (29%) without cryoglobulinaemia and vasculitis (p=0.03). Rankin and European Sjögrens Syndrome Disease Activity Index scales decreased significantly in group 1. Conclusion RTX seems effective in cryoglobulinaemia or vasculitis-related PNS involvement in pSS.

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.

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.

The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: Data from a European multicenter retrospective study.

In European multicenter study, we aimed to describe the real-life hydroxychloroquine use in APS patients during pregnancy and determine its benefit in refractory obstetrical APS. We analyzed the outcome of pregnancies treated by hydroxychloroquine in patients with APS or asymptomatic antiphospholipid (aPL) antibodies carriers. Thirty patients with APS with 35 pregnancies treated by hydroxychloroquine were analyzed. Comparing the outcome of pregnancies treated by the addition of hydroxychloroquine to previous pregnancies under the conventional treatment, pregnancy losses decreased from 81% to 19% (p<0.05), without differences in the associated treatments. The univariate analysis showed that the previous intrauterine deaths and higher hydroxychloroquine amount (400mg per day) were the factors associated with pregnancy outcome. Considering 14 patients with previous refractory obstetrical APS (n=5 with obstetrical and thrombotic primary APS and n=9 with purely obstetrical APS), all with previous pregnancy losses under treatment (aspirin with LMWH in 11 cases and LMWH in 3 cases), the addition of hydroxychloroquine resulted in live born babies in 11/14 (78%) cases (p<0.05). Our study shows the benefit of hydroxychloroquine addition in patients with refractory obstetrical APS and raises the need of prospective studies to confirm our preliminary study.

Autoimmune diseases in HIV-infected patients: 52 cases and literature review

OBJECTIVES 1) To describe autoimmune diseases (AD) in HIV-infected people; and 2) to perform a literature review concerning this issue. DESIGN 52 HIV-infected patients that presented an AD in 14 medical departments in Paris and Ile-de-France area were retrospectively included in this study. RESULTS The ADs were vasculitis (11), immune cytopenias (8), rheumatic diseases (8), lupus (7), sarcoidosis (7), thyroid diseases (6), hepatic diseases (5), and antiphospholipid syndrome (4). Four patients presented 2 ADs. In 5 patients the AD preceded HIV infection, in 14 HIV infection was diagnosed at the same time as the AD and 34 were HIV-infected when they developed an AD. 40 ADs (80%) occurred in patients with a CD4 T lymphocyte count of more than 200/mm(3). Cases of autoimmune hemolytic anemia occurred only in patients severely immunodepressed. In five patients (a vasculitis case, a sarcoidosis case, three thyroid disease cases) the AD presented as a form of immune restoration inflammatory syndrome (IRIS). Some ADs allowed HIV-infection diagnosis at a stage of moderate immune deficiency (vasculitis, antiphospholipid syndrome, immune thrombocytopenia). 37 patients received immunosuppressant treatments with good tolerance. These results confirm in a large series of patients previous data concerning autoimmune diseases occurrence in HIV-infected people. CONCLUSION In the HAART era, when HIV-infected people are treated more and more early, autoimmune diseases can occur, mainly at the phase of immunological recovery. HIV infection should not limit immunosuppressant treatment use.

Functional study of TNF-α promoter polymorphisms : literature review and meta-analysis

The functional consequences of TNF-α promoter SNPs are still controversial and, to date, the functional consequences of TNF-α haplotype combinations in healthy subjects have not been assessed. In order to assess functional consequences of each TNF-α polymorphism and of their haplotype combination, TNF-α expression and secretion by LPS-stimulated monocytes from 50 healthy subjects were assessed. Monocytes were isolated and cultured for four hours, after 100  ng/mL LPS stimulation. mRNA expression was quantified using the real-time polymerase chain reaction, and TNF-α levels were measured by enzyme-linked immunosorbent assay. Each subject was genotyped for TNF-α -857 C/T, -238 G/A, -308 G/A polymorphisms. In order to confirm definitively the functional consequences of these TNF-α polymorphisms, we then performed a systematic review of the literature for TNF-α SNPs, and then a meta-analysis of the functional studies of the TNF-α -308 G/A SNP. No association between TNF-α mRNA or protein level expression, and TNF-α -238G/A, -308G/A, -857C/T polymorphisms, studied either independently or in haplotype combinations, was revealed. Using a meta-analysis for the TNF-α -308 G/A polymorphism, we confirmed the absence of any association between TNF-α mRNA and protein levels, and TNF-α -308 G/A genotypes. This study and meta-analysis of the literature confirmed the absence of any functional consequences of the TNF-α -308G/A promoter polymorphism, either alone, or in various haplotype combinations in healthy subjects.

Efficacy of Biological-Targeted Treatments in Takayasu Arteritis Multicenter, Retrospective Study of 49 Patients

Background— The goal of this work was to assess the safety and efficacy of biologics (ie, tumor necrosis factor-&agr; antagonists and tocilizumab) in patients with Takayasu arteritis. Methods and Results— This was a retrospective, multicenter study of the characteristics and outcomes of 49 patients with Takayasu arteritis (80% female; median age, 42 years [20–55 years] treated by tumor necrosis factor-&agr; antagonists [80%] or tocilizumab [20%]) and fulfilling American College of Rheumatology or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of patients with Takayasu arteritis were inadequately controlled with or were intolerant to conventional immunosuppressive therapy (median number, 3 [1–5]). Overall response (ie, complete and partial) to biological-targeted treatments at 6 and 12 months was 75% and 83%, respectively. There were significantly lower C-reactive protein levels at the initiation of biological-targeted treatments (22 mg/L [10–46 mg/L] versus 58 mg/L [26–76 mg/L]; P=0.006) and a trend toward fewer immunosuppressants drugs used before biologics (P=0.054) in responders (ie, complete or partial responders) relative to nonresponders to biological-targeted treatments. C-reactive protein levels and daily prednisone dose significantly decreased after 12 months of biological-targeted treatments (30 versus 6 mg/L [P<0.05] and 15 versus 7.5 mg [P<0.05] at baseline and 12 months, respectively). The 3-year relapse-free survival was 90.9% (83.5%–99%) over the biological treatment period compared with 58.7% (43.3%–79.7%; P=0.0025) with disease-modifying antirheumatic drugs. No difference in efficacy was found between tumor necrosis factor-&agr; antagonists and tocilizumab. After a median follow-up of 24 months (2–95 months), 21% of patients experienced adverse effects, with biological-targeted treatments discontinued in 6.6% of cases. Conclusion— This nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile.Background— The goal of this work was to assess the safety and efficacy of biologics (ie, tumor necrosis factor-α antagonists and tocilizumab) in patients with Takayasu arteritis. Methods and Results— This was a retrospective, multicenter study of the characteristics and outcomes of 49 patients with Takayasu arteritis (80% female; median age, 42 years [20–55 years] treated by tumor necrosis factor-α antagonists [80%] or tocilizumab [20%]) and fulfilling American College of Rheumatology or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of patients with Takayasu arteritis were inadequately controlled with or were intolerant to conventional immunosuppressive therapy (median number, 3 [1–5]). Overall response (ie, complete and partial) to biological-targeted treatments at 6 and 12 months was 75% and 83%, respectively. There were significantly lower C-reactive protein levels at the initiation of biological-targeted treatments (22 mg/L [10–46 mg/L] versus 58 mg/L [26–76 mg/L]; P =0.006) and a trend toward fewer immunosuppressants drugs used before biologics ( P =0.054) in responders (ie, complete or partial responders) relative to nonresponders to biological-targeted treatments. C-reactive protein levels and daily prednisone dose significantly decreased after 12 months of biological-targeted treatments (30 versus 6 mg/L [ P <0.05] and 15 versus 7.5 mg [ P <0.05] at baseline and 12 months, respectively). The 3-year relapse-free survival was 90.9% (83.5%–99%) over the biological treatment period compared with 58.7% (43.3%–79.7%; P =0.0025) with disease-modifying antirheumatic drugs. No difference in efficacy was found between tumor necrosis factor-α antagonists and tocilizumab. After a median follow-up of 24 months (2–95 months), 21% of patients experienced adverse effects, with biological-targeted treatments discontinued in 6.6% of cases. Conclusion— This nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile. # CLINICAL PERSPECTIVE {#article-title-34}

Prognosis Assessment of Cardiac Involvement in Systemic AL Amyloidosis by Magnetic Resonance Imaging

BACKGROUND Cardiac involvement is one of the most important prognostic factors in systemic AL amyloidosis. The aim of our study was to assess the role of cardiovascular magnetic resonance (CMR) imaging in prognosis evaluation in AL amyloidosis. METHODS We retrospectively analyzed 29 consecutive patients with AL amyloidosis who had undergone CMR. Clinical, laboratory, echocardiographic, and CMR characteristics were compared between CMR-positive (ie, with CMR signs of cardiac localization of AL amyloidosis) and CMR-negative patients. Univariate and multivariate analyses were performed to assess the prognostic value of positive CMR in comparison with other prognostic factors. RESULTS CMR was positive in 11 patients (38%). The overall survival rates for CMR-positive patients were 28%, 14%, and 14% versus 84%, 77%, and 45% at 1, 2, and 5 years, respectively, for CMR-negative patients (P=.002). Late gadolinium enhancement patterns, biventricular hypertrophy, and pericardial effusion on CMR were more frequent in nonsurvivors. Congestive heart failure, abnormal echocardiography, Eastern Cooperative Oncology Group grade >1, brain natriuretic peptide, and left ventricular ejection fraction <55% also were associated with a decreased survival. The presence of congestive heart failure was the only significant variable associated with survival on multivariate analysis. CONCLUSION We found that the presence of a positive CMR in AL amyloidosis was associated with a significantly increased risk of death, in particular of cardiac origin, but was not independent of clinical congestive heart failure.