Specific Follicular Helper T Cell Signature in Takayasu Arteritis.

OBJECTIVE: Our aim was to compare transcriptome and phenotype profiles of CD4+ T cells and CD19+ B cells in patients with Takayasu arteritis (TAK), patients with giant cell arteritis (GCA), and healthy donors. METHODS: Gene expression analyses, flow cytometry immunophenotyping, T cell receptor (TCR) gene sequencing, and functional assessments of cells from peripheral blood and arterial lesions from TAK patients, GCA patients, and healthy donors were performed. RESULTS: Among the most significantly dysregulated genes in CD4+ T cells of TAK patients compared to GCA patients (n = 720 genes) and in CD4+ T cells of TAK patients compared to healthy donors (n = 1,447 genes), we identified a follicular helper T (Tfh) cell signature, which included CXCR5, CCR6, and CCL20 genes, that was transcriptionally up-regulated in TAK patients. Phenotypically, there was an increase in CD4+CXCR5+CCR6+CXCR3- Tfh17 cells in TAK patients that was associated with a significant enrichment of CD19+ B cell activation. Functionally, Tfh cells helped B cells to proliferate, differentiate into memory cells, and secrete IgG antibodies. Maturation of B cells was inhibited by JAK inhibitors. Locally, in areas of arterial inflammation, we found a higher proportion of tertiary lymphoid structures comprised CD4+, CXCR5+, programmed death 1+, and CD20+ cells in TAK patients compared to GCA patients. CD4+CXCR5+ T cells in the aortas of TAK patients had an oligoclonal α/ß TCR repertoire. CONCLUSION: We established the presence of a specific Tfh cell signature in both circulating and aorta-infiltrating CD4+ T cells from TAK patients. The cooperation of Tfh cells and B cells might be critical in the occurrence of vascular inflammation in patients with TAK.

mTOR pathway activation in large vessel vasculitis.

BACKGROUND: Mammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown. METHODS: We evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV. RESULTS: Proliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV. The vascular endothelium of proliferating aorta vessels from patients with LVV showed indications of activation of the mTORC1 pathway (S6RP phosphorylation). In cultured vascular endothelial cells, sera from patients with LVV stimulated mTORC1 through the phosphorylation of S6RP. mTORC1 activation was found also in Th1 and Th17 cells both systemically and in inflamed vessels. Patients with LVV exhibited a diminished S6RP phosphorylation in Tregs. Inhibition of mTORC1 pathway with rapamycin, increase Tregs and decrease effector CD4+IFNγ+, CD4+IL17+ and CD4+IL21+ T cells in patients with LVV. CONCLUSIONS: We provided evidence that mTORC1 pathway has a central role in driving T cell inflammation and vascular lesions in LVV. Targeting mTORC pathway may represent a new therapeutic option in patients with LVV.

[Aortitis and surgery]. / Prise en charge chirurgicale des maladies inflammatoires de l'aorte.

Non-infectious aortitis are usually due to giant cell arteritis (temporal arteritis), Takayasu and Behçet's diseases. Aortitis should be suspected in the presence of aortic wall thickening or of aneurysm or occlusion of the aorta and its branches in the absence of characteristic cardiovascular risk factors. Surgery is required in case of severe damage. But the quiescence of the inflammatory disease must be obtained before endovascular or surgical treatment to prevent complications such as anastomotic false aneurysm or stent thrombosis, especially common in this disease. The frequency of aortic aneurysms (in particular of ascending aorta) in giant cell arteritis encourages its systematic screening, as well as regular monitoring of the entire aorta during the follow-up. Behçet's and Takayasu diseases require the greatest control of inflammation and the knowledge of some surgical tricks to avoid the risk of recurrence. The literature review shows that endovascular treatment could reduce perioperative morbidity but did not allow reducing long-term complications.

Takayasu Arteritis and Pregnancy.

OBJECTIVE: To assess the relationship between Takayasu arteritis (TAK) and pregnancy outcome. METHODS: This study included 240 pregnancies in 96 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK and/or the 1994 Chapel Hill Consensus Conference nomenclature/criteria for vasculitis. We analyzed obstetric and maternal outcomes in women who were pregnant before and/or at the same time as or after TAK diagnosis. We assessed factors associated with complicated pregnancy. RESULTS: One hundred forty-two pregnancies occurred in 52 patients before TAK diagnosis (median age at pregnancy 26 years [interquartile range 23-30 years]), and 98 pregnancies occurred in 52 patients concomitant with or after TAK diagnosis (median age at pregnancy 28 years [interquartile range 26-31 years]). Pregnancies concomitant with or after TAK diagnosis had a 13-fold higher rate of obstetric complications compared to pregnancies before TAK diagnosis (odds ratio 13 [95% confidence interval 5-33], P < 0.0001). TAK was associated with a 40% frequency of obstetric complications, including preeclampsia/eclampsia (24 pregnancies [24%]), premature delivery (8 pregnancies [8%]), and intrauterine fetal growth restriction or death (5 pregnancies [5%]). Maternal complications of TAK occurred during 39% of pregnancies and included mainly new-onset or worsening hypertension (26 pregnancies [27%]). In multivariate analysis, smoking (odds ratio 6.15 [95% confidence interval 1.31-28.8]) and disease activity of TAK (a National Institutes of Health score of >1) (odds ratio 28.7 [95% confidence interval 7.89-104.7]) were independently associated with obstetric and maternal complications. CONCLUSION: TAK negatively affects pregnancy outcomes. Disease activity increases the risk of obstetric and maternal complications, mainly due to arterial hypertension.

Indications to open surgical repair of the thoracic aorta in the "endovascular" era.

Endovascular techniques have deeply modified the indications to open surgical repair in nearly all the vascular tree and especially in areas where the invasiveness of open surgery is real like the thoracic aorta. However their anatomical and technological limits on one hand and uncertainty on their long term results on the other hand still leave a large place for open surgery. Also, immediate as well as late results of open surgery have continued their progress during the endovascular era, rendering it competitive in trained centers for fit selected patients.

Th1 and Th17 cytokines drive inflammation in Takayasu arteritis.

OBJECTIVE: Takayasu arteritis (TAK) is a large-vessel vasculitis that induces damage to the aorta and its branches. Glucocorticoids remain the gold standard of therapy for TAK. The nature of the T cells driving vascular inflammation and the effects of glucocorticoids on the systemic components of TAK are not understood. The aim of this study was to analyze T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta in patients with TAK. METHODS: T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta were analyzed using Luminex analysis, flow cytometry, and immunohistochemical analysis. The study included 41 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK (17 patients with active TAK and 24 patients with disease in remission), 30 patients with giant cell arteritis and 39 patients with Behçet's disease (disease controls), and 20 age- and sex-matched healthy control subjects. RESULTS: We observed a marked increase in the expression of Th1 and Th17 cells, which correlated with TAK disease activity. The addition of serum from patients with active TAK to sorted CD4+ T cells from healthy donors in culture medium induced significant production of interferon-γ (IFNγ) and interleukin-17A (IL-17A). We demonstrated the presence of IFNγ-, IL-6-, and IL-17A-producing T cells in vascular inflammatory infiltrates in patients with TAK. Corticosteroid therapy was associated with decreased levels of circulating Th1 cytokines in corticosteroid-treated patients with TAK compared with steroid-free patients with TAK (for IL-2, mean ± SD 5,079 ± 5,300 versus 7,359 ± 3,197 pg/ml; for IFNγ, 2,592 ± 3,072 versus 8,393 ± 3,392 pg/ml; for tumor necrosis factor α, 847 ± 724 versus 1,491 ± 392 pg/ml). However, glucocorticoids had essentially no effect on the frequency of Th17 cytokines (IL-1 receptor, IL-17, and IL-23). CONCLUSION: The Th17 and Th1 pathways contribute to the systemic and vascular manifestations of TAK. Glucocorticoid treatment suppresses Th1 cytokines but spares Th17 cytokines in patients with TAK.

[Fibromuscular dysplasia]. / Dysplasie fibromusculaire.

Fibromuscular dysplasia is a segmentary, non-atherosclerotic, non-inflammatory vascular disease that may result in stenosis, occlusion, aneurysms or dissection of medium arteries. Renal involvement is the most frequent location, described in 60-100% of patients. Renal stenosis can be asymptomatic or complicated with arterial hypertension or less frequently with renal insufficiency. Carotid and vertebral involvements are less frequent (10-35%). Surgical management of fibromuscular dysplasia is now less common because of the better efficacy of percutaneous transluminal angioplasty. Thus, histologic characteristics are no longer relevant prognostic criteria. Clinical features and outcome vary according to angiographic presentation (focal or multifocal disease), with an increased recovery rate of hypertension with focal lesions. In the presence of renal fibromuscular dysplasia, only symptomatic patients are revascularized (recent or resistant hypertension) or patients with asymmetric renal size or impaired renal function. Transluminal angioplasty is the first-line treatment except for patients with complex lesions or stenosis associated with aneurysm.

Restoration of intestinal continuity after colectomy for non-occlusive ischemic colitis.

BACKGROUND: Non-occlusive ischemic colitis (IC) is a rare and life-threatening abdominal disease associated with high rates of postoperative mortality. When surgery is performed, in patients with IC, either a Hartmann's procedure (HP) or a total colectomy and ileostomy is required. The possibility of restoration of intestinal continuity in surviving patients is an important issue. The aim of the present study was to report the outcome of surgically managed IC patients and to identify predictive factors for restoration of intestinal continuity and to assess the results of this procedure. METHODS: Between January 1997 and May 2011, 96 IC patients underwent total colectomy and 68 underwent left colectomy. IC was spontaneous in 62 patients and occurred after prior surgery in 102. Eighty patients died during the postoperative period and nine died during the follow-up from an unrelated disease. Fifteen patients were lost to follow-up. The remaining 60 surviving patients were our study population. RESULTS: There were 44 men and 16 women with a mean age of 67 years ± 12 SD. Restoration of bowel continuity was performed in 24 patients (40%). There were no predictive factors for restoration of intestinal continuity in terms of sex, age, IC etiology, and the extent of colon resection at primary surgery. The median interval between first surgery and restoration of bowel continuity was 7.9 months (range 0.2-35 months). There were no postoperative deaths and the overall morbidity rate was 45% (11/24). No patients developed anastomotic leak or underwent unplanned reoperation. CONCLUSIONS: Reversal of HP after IC is feasible in 40% of surviving patients with acceptable mortality and morbidity rates. This restoration of intestinal continuity should therefore be discussed for every surviving IC patient.

Immunosuppressants reduce venous thrombosis relapse in Behçet's disease.

OBJECTIVE: To investigate and describe the long-term outcome of venous thrombosis in patients with Behçet's disease (BD). METHODS: In a retrospective cohort of 807 BD patients, a reported 296 patients (36.7%) (73.3% male, median age 30 years [interquartile range 24-36 years]) met the international classification criteria for BD and had venous thrombosis. We assessed factors associated with thrombosis relapse and mortality. RESULTS: There were a total of 586 venous thrombosis events, including 560 cases of deep thrombosis and 26 cases of superficial thrombosis. Deep venous thrombosis events included 323 cases of limb thrombosis (55.1%), 77 cases of cerebral venous thrombosis (13.1%), 57 cases of pulmonary embolism (9.7%), 63 cases of vena cava lesions (10.7%), 14 cases of Budd-Chiari syndrome (2.4%), and 13 cases of cervical vein thrombosis (2.2%). One hundred of 296 patients (33.8%) experienced at least 1 venous thrombosis relapse. The mortality rate was 6.4% (19 of 296 patients) after a median followup of 4.75 years (interquartile range 2-7 years). In univariate analysis, death was associated with cardiac involvement (P = 0.026) and Budd-Chiari syndrome (P = 0.004). In multivariate analysis, the use of immunosuppressive agents was found to prevent relapse of venous thrombosis (hazard ratio 0.27 [95% confidence interval 0.14-0.52], P = 0.00021), and there was a trend toward prevention of relapse with the use of glucocorticoids (hazard ratio 0.62 [95% confidence interval 0.40-0.97], P = 0.058). CONCLUSION: Immunosuppressive agents significantly reduce venous thrombosis relapse in BD.

[New ultra rapid test for detection of bacteria]. / Nouveau test ultrarapide pour la détection de bactéries.

INTRODUCTION: Bacteriological testing is aimed to reduce the risk of transmission of infections. However, the detection of Bacteria by culture requires from 18hours to 14 days and may produce erroneous results for fastidious species. The goal of this work was to design and validate a new tool for bacterial testing. METHODS: The test is based on the fast real-time PCR (frt PCR). The DNA extracted from samples containing internal controls are introduced into four tubes containing primers and probes for the frt PCR. The cycling program consists in 1×at 95°C for 10min and 45×(15s at 95°C, 8s) at 52°C and 10s at 72°C. RESULTS: The frt PCR detects 0,01 CFU/µl of Bacteria and identifies eight Genera without interferences from the environment or from fungi and with no need for melting curve analysis or additional sequencing. DISCUSSION: The frt PCR detects and quantifies Bacteria identifying and assessing the load of Staphylococci, Streptococci, Haemophilus, Pseudomonas, Enterobacteria, Acinetobacter, Propionibacteriacae and Corynebacteria. CONCLUSION: Cultures require at least 24hours but the new frt PCR reduces the time to 90minutes. Larger series of samples are necessary to confirm the usefulness of this new test for routine bacterial sterility controls.

[Evolution of the treatment of chronic post-traumatic aneurysms of the descending thoracic aorta: 30 years experience]. / Evolution du traitement des anévrismes post-traumatiques chroniques de l'aorte thoracique descendante: une expérience personnelle de 30 ans.

The authors present the early and late results of a series of 40 patients treated for chronic post-traumatic aneurysms of the descending thoracic aorta from 1975 to 2005. With the exception of a patient who died of an intra-pleural rupture before surgery, the patients were treated by aortotomy and prosthetic graft (N=17), aortotomy and direct suture (N=17) or endoprosthesis (N=5). The use of distal aortic perfusion in 22 patients enabled 17 direct sutures (77.3%) thanks to extensive mobilisation of the aortic arch. Endoprostheses have been used since 1997 in high surgical risk patients with severe comorbid conditions. There were no deaths, one transient paraparesia after simple aortic clamping, one reoperation for a haemothorax and four cases of dysphonia due to paralysis of the recurrent laryngeal nerve. Thirty-five patients (90%) were followed up for an average of 119.7 +/- 16.4 months. There were no clinical complications and the late morphological results were good in all cases with the exception of one type 1 endoprosthetic leak. The treatment of chronic post-traumatic aneurysms of the descending thoracic aorta gives excellent early and late results, justifying wide operative indications. The wish to avoid use of a prosthesis in young patients with a long life expectancy should give preference to conventional surgical techniques which, providing distal aortic perfusion is employed, allow direct suture of three quarters of cases. Endovascular treatment is reserved only for "poor surgical risks".

[Intramuscular vascular malformations as a differential diagnosis of focal myositis]. / Les malformations vasculaires à développement intramusculaire: un diagnostic différentiel rare de myosite focale.

INTRODUCTION: Focal myositis constitutes an original and rare pathological entity, characterized by a localized inflammation within skeletal muscle, presenting as a soft tissue painful tumefaction. Diagnosis requires histological confirmation because of its non-specific clinical feature and the numerous differential diagnoses. EXEGESIS: We report a 27 year-old man who presented with suggestive symptoms of focal myositis. MR imaging and echography were compatible with this diagnosis but also demonstrated the existence of a vascular component within the tumefaction. The diagnosis of a benign vascular malformation with intramuscular development was made by a surgically guided biopsy. CONCLUSION: Vascular malformations are histologically heterogeneous with extremely variable clinical expressions. When they develop within skeletal muscle, they may mimic focal myositis. Hence, their diagnosis has to be evoked before performing muscle biopsy, because of the potential hemorrhagic risk.

Percutaneous transluminal angioplasty in severe diabetic foot ischemia: outcomes and prognostic factors.

OBJECTIVES: To evaluate the outcomes of severe ischemic diabetic foot ulcers for which percutaneous transluminal angioplasty (PTA) was considered as the first-line vascular procedure. Factors associated with successful PTA were sought. RESEARCH DESIGN AND METHODS: In 32 consecutive diabetic patients with foot ulcers and severe limb ischemia, PTA was performed if feasible; if not, primary bypass grafting was done when feasible. All patients were followed until healing or for at least one year. Patients with worsening ulcers after PTA underwent bypass grafting. Clinical and angiographic factors influencing outcomes after PTA were sought by univariate and multivariate analysis. RESULTS: PTA was done in 25 of the 32 (78%) patients, and considered clinically successful in 13 (52%). After 1 year, the healing rate was 70% and the limb salvage rate 90%. Successful PTA was significantly associated with a higher post-PTA transcutaneous oxygen pressure (P = 0.03) and presence of at least one patent pedal vessel (P = 0.03) in the univariate analysis; only a patent pedal vessel was significant in the multivariate analysis. CONCLUSION: Primary PTA in diabetic patients with severe ischemic foot ulcers provides similar outcomes to usual results obtained in severe ischemia in absence of diabetes. The presence of one patent pedal vessel on arteriography before PTA is the best prognostic factor.

[Treatment for carotid stenosis: surgery, the reference]. / Traitement d'une sténose carotide: chirurgie, la référence.

THE CONTROVERSY: The indications for carotid revascularisation are clearly codified, but the surgical treatment is debatable. The angioplasty initially proposed for non-atheromatous stenosis or for high surgical risk patients is used by some as first-line therapy, although no benefit/risk ratio in its favour has been demonstrated. ARE THERE ANY BENEFITS WITH SURGICAL TREATMENT?: The efficacy of surgery in the treatment of atheromatous carotid stenosis has been demonstrated. The interest of angioplasty The advantages expected with carotid angioplasty are the absence of cervical incision and cervical nerve lesions, together with a reduction in the duration of hospitalisation and costs. Nevertheless, there are risks inherent to the femoral puncture and endovascular propagation from the femoral to the carotid artery. Till now, the published studies have not concluded in the superiority or equivalence of angioplasty versus surgery. FOR CERTAIN SUB-GROUPS: It has not been demonstrated but it is possible that a sub-group of high-risk patients could benefit from carotid angioplasty. There are no arguments for recommending angioplasty in the treatment of carotid re-stenosis following endarterectomy or for post-radiation stenosis. ANTI-EMBOLIC TREATMENT SHOULD BE FORESEEN: Carotid angioplasty is associated with embolus, the frequency of which is 8-fold greater than that observed after endarterectomy. The systematic use of cerebral protection is therefore recommended. TODAY: The treatment of reference of carotid stenosis remains endarterectomy conducted by vascular surgeons.

[Aortic dissections: recent endovascular therapeutic advances and current indications]. / Dissections aortiques: apports thérapeutiques endovasculaires récents et indications actuelles.

Dissection is one of the most serious diseases of the aorta if only because of its potential for rupture, but also for other complications which may be fatal. Replacement with a prosthesis remains the treatment of reference as an emergency for proximal dissection and as an elective procedure for selected cases of distal dissection with complications. Despite steady progress in ancillary management (distal perfusion, circulatory arrest, cardiac, neurological and visceral protection) the operation remains a very invasive procedure. Aortic endoprostheses represent the therapeutic innovation of the decade for the treatment of aortic aneurysms and their use could be extended to dissections, at least for the most distal forms and to patients at very high surgical risk.

Outcome of severe diabetic foot ulcers after standardised management in a specialised unit.

OBJECTIVE: The primary objective was to evaluate the efficacy in terms of limb salvage and healing time of standardised multidisciplinary management for high-grade diabetic foot ulcers. The secondary objective was to retrospectively identify the factors that influenced time to healing. STUDY DESIGN AND METHODS: Over a 2-year period, 157 patients with diabetic foot ulcers were managed in our specialised unit using a standard treatment strategy; 118 were followed until healing or for at least 7 months (range, 7-29) after hospital discharge and form the basis for this study. Predetermined criteria were used to diagnose and manage the lesions. The number of major amputations and the time to healing were the main outcome measures. Univariable and multivariable analyses were done retrospectively to look for factors associated with time to healing. RESULTS: The limb salvage rate was 97.5% and the healing rate was 50% after 10 months and 70% after 16 months. Factors significantly associated with healing time were arterial disease without bypass surgery (p<0.001) and renal replacement therapy (p<0.05). Osteomyelitis, as managed in this study, did not increase the healing time (p > 0.6). CONCLUSION: In high-grade diabetic foot ulcers, standardised conservative management with second-line bone-sparing surgery, if needed, yields an acceptable limb salvage rate. With combined medical and surgical treatment, osteomyelitis is not a poor prognosis factor.

Aneurysms of the innominate artery: surgical treatment of 27 patients.

PURPOSE: Aneurysms of the innominate artery (AIA) are widely considered to be a rare entity. We describe our experience with AIAs in the last three decades. METHODS: From October 1973 to October 2000, we operated on 27 patients with an AIA. The underlying cause of aneurysm was Takayasu's disease in 7 patients, degenerative disease in 6 patients, syphilis in 5 patients, chronic dissection in 3 patients, trauma in 2 patients, infection in 2 patients, a postoperative complication in 1 patient, and Marfan syndrome in 1 patient. AIA was associated with an aortic aneurysm in 17 patients. Fourteen patients had no symptoms. The remaining patients had symptoms, with thromboembolic complications in 7 patients, pain without rupture in 3 patients, and a ruptured aneurysm in 3 patients. In two patients at high risk for surgery who had a small AIA with embolic complications, a cervical approach was used as a means of performing distal exclusion and crossover bypass. In the remaining 25 patients, a midline sternotomy was used. One patient with a ruptured AIA exsanguinated during sternotomy. Ten patients underwent a prosthetic replacement of the ascending aorta and/or aortic arch with a separate prosthetic branch to the innominate artery (IA). Thirteen patients underwent ascending aorta-to-IA prosthetic bypass in association with lateral suture (8 patients) or prosthetic patching (5 patients) of the aorta. One patient with an infected aneurysm was treated by means of resection of the aneurysm, proximal ligation of the IA, and transposition of the right into the left common carotid artery. Cardiopulmonary bypass with deep hypothermic circulatory arrest was used in 10 patients. RESULTS: Three perioperative deaths occurred (2 of 4 in association with emergency treatment and 1 of 23 with elective treatment). Respiratory complications requiring prolonged artificial ventilation developed in five patients. Two patients had transient worsening of preoperative neurologic deficits. Late results, with a mean follow-up of 85 months, were good. CONCLUSION: The etiology and presentation of AIAs are variable. Surgical management with current cardiovascular techniques achieves excellent results.

Carotid artery stenosis: prospective comparison of CT, three-dimensional gadolinium-enhanced MR, and conventional angiography.

PURPOSE: To prospectively compare gadolinium-enhanced magnetic resonance (MR) angiography and computed tomographic (CT) angiography with digital subtraction angiography (DSA) for use in detecting atheromatous stenosis and plaque morphology at the carotid bifurcation. MATERIALS AND METHODS: Forty-four carotid arteries (in 22 patients) were analyzed by using CT angiography, enhanced MR angiography, and DSA. CT and enhanced MR angiograms were reconstructed with maximum intensity projection and multiplanar volume reconstruction. The following four features were analyzed: degree of stenosis on the basis of North American Symptomatic Carotid Endarterectomy Trial criteria, length of stenosis, luminal surface, and presence of ulcers. RESULTS: There was significant correlation between CT angiography, enhanced MR angiography, and DSA for degree and length of stenosis. With enhanced MR angiography and CT angiography, degree of stenosis was underestimated in two of 44 cases. No case of overestimation with CT angiography was found. Severe internal carotid artery stenoses were detected with high sensitivity and specificity: 100% and 100%, respectively, with CT angiography; 93% and 100%, respectively, with enhanced MR angiography. Luminal surface irregularities were most frequently seen at CT angiography. With CT angiography and enhanced MR angiography, more ulceration was detected than with DSA. CONCLUSION: There was a significant correlation between CT angiography, enhanced MR angiography, and DSA in evaluation of carotid artery stenosis. Enhanced MR angiography or CT angiography can be used to adequately evaluate carotid stenosis.