Prognosis of large vessel involvement in large vessel vasculitis.

OBJECTIVES: To assess prognosis factors and outcome of large vessel involvement (LVI) in large vessels vasculitis (LVV) patients. METHODS: Retrospective multicenter study of characteristics and outcomes of 417 patients with LVI including 299 Takayasu arteritis (TAK) and 118 Giant cell arteritis (GCA-LVI) were analyzed. Logistic regression analysis assessed prognosis factors in LVV patients. Outcome of LVI among TAK and GCA-LVI patients (ischemic complications, aneurysms complications, relapses and revascularization) were assessed. RESULTS: In multivariable analysis, stroke/transient ischemic attack [HR: 3.63 (1.46-9.04), p = 0.006] was independently associated with vascular complications in LVV. The 10-years aneurysm free survival was significantly lower [67% (48-93) vs 89% (84-95), p = 0.02] in GCA-LVI compare to TAK patients. The 5-years relapse free survival was significantly lower [47% (37-60) vs 69% (63-75), p < 0.001,] in GCA-LVI compare to TAK patients. The 10-years revascularization free survival was significantly lower [55% (48-64) vs 76% (59-99), p < 0.001] in TAK compare to GCA-LVI patients. After a median follow-up of 5 years, 16 (5.4%) TAK and 7 (5.9%) GCA-LVI patients died, mainly of aneurysm (26%) and ischemic complications (26%). CONCLUSION: This large nationwide cohort of LVI provided prognosis factors of vascular complications in LVV patients. TAK and GCA-LVI have different long-term outcome in term of aneurysm development, relapse and revascularization.

Autophagy promotes aortic adventitial fibrosis via the IL-6/Jak1 signaling pathway in Takayasu's arteritis.

BACKGROUND: Autophagy is a ubiquitous and evolutionarily conserved self-rescue process. Studies have shown that autophagy is involved in the pathogenesis of multiple diseases; however, whether autophagy is associated with the pathogenesis of Takayasu's arteritis (TA), a large vessel idiopathic inflammatory disease characterized by vascular fibrosis, remains unclear. Moreover, although IL-6 is believed to be a direct target for TA treatment, anti-IL-6 treatment could not block TA-associated fibrosis in some cases, which impairs the aortic function of patients and can result in death. Thus, identify the mechanisms associated with TA is extremely important. Based on the relationship between autophagy and IL-6, we investigated the role of autophagy in the vascular fibrosis of TA induced by IL-6. METHODS: Autophagy proteins (LC3 and Atg3), IL-6, and markers of fibrosis (collagen 1 and α-SMA) were detected in tissues with TA lesions via immunochemistry, immunofluorescence, and Western blot, respectively. Different stages of autophagy were analyzed by the specific inhibitors, 3-methyladenosine (early stage), hydroxychloroquine sulfate (late stage), and bafilomycin A1 (late stage). Autophagosomes were detected using electron microscopy and a viral-vector transfection assay. The fibrosis profiles induced by IL-6-dependent autophagy was assessed with an ELISA. RESULTS: The expression of autophagy, IL-6, and fibrosis markers were elevated and correlated with each other in the adventitia tissues of TA patients. Furthermore, exogenous IL-6/IL-6Rα could significantly increase autophagy and fibrosis in vitro. An autophagy inhibitor was found to significantly block both autophagy and fibrosis induced by IL-6. Finally, IL-6 was found to significantly promote autophagy-induced fibrosis through the activation of the Jak1 pathway. CONCLUSIONS: IL-6-induced autophagy plays an important role in vascular fibrosis of TA. Targeting autophagy pathways might represent a novel therapeutic option for the treatment of TA.

Takayasu arteritis: advanced understanding is leading to new horizons.

Although outcomes in Takayasu arteritis (TAK) are improving, diagnosis is typically delayed and significant arterial injury accrues. While wider use of non-invasive imaging is impacting this, the onus remains with clinicians to consider a diagnosis of TAK earlier. Meanwhile, morbidity and mortality in TAK remains increased. Herein we review the current situation, outline recent advances and summarize remaining challenges. Understanding of disease pathogenesis remains poor. However, recent genetic data and identification of pathogenic cytokines may facilitate the search for biomarkers capable of distinguishing active and inactive disease, inflammatory and non-inflammatory arterial remodelling. Imaging is critical for TAK, and each modality has important strengths and limitations. Dependence upon CS therapy remains too high. However, the impact of combination immunosuppressive therapy is now recognized, biologic therapies are increasingly available and new agents offer promise. Multicentre clinical trials are now required, and these will depend upon development of defined clinical and imaging end-points.

Pathophysiology of large vessel vasculitis and utility of interleukin-6 inhibition therapy.

Takayasu arteritis (TAK) and giant cell arteritis (GCA) affect mainly large- and medium-sized arteries. In refractory cases, vascular remodeling progresses and leads to serious outcomes. Studies have demonstrated that cytokines such as interleukin (IL)-6 play crucial roles in the pathophysiology of TAK and GCA. Recently, randomized controlled trials on IL-6 inhibition therapy using tocilizumab (TCZ) were performed, and significant effects were exhibited. The purposes of conventional treatments have been to improve symptoms and decrease the levels of inflammatory markers. Arterial changes have been considered as damages. However, after TCZ came into practical use, establishment of treat to target is desired to prevent vascular remodeling. In contrast, a combination therapy of glucocorticoids (GCs) and TCZ notably increases the risk of infections. When TCZ is used, careful attention must be paid to possible infections, and dose of GC should be tapered as much as possible. Future tasks are to establish indication and dosage of TCZ, indication for discontinuation of TCZ due to remission, efficacy of TCZ monotherapy, and protocols of TCZ for pediatric cases.

The critical role of IL-6 in the pathogenesis of Takayasu arteritis.

OBJECTIVES: To investigate T cell subsets and immune cytokine profiles in untreated Takayasu arteritis (TAK) patients and the underlying immunopathological mechanism. METHODS: We enrolled 50 untreated TAK patients and 40 age-matched controls (20 healthy controls, 20 untreated SLE patients). Enzyme-linked immunosorbent assays (ELISAs) were used to define cytokine profiles in all patients, and flow cytometry was performed for 9 TAK patients and 12 healthy controls. Hematoxylin and eosin (Handamp;E) staining and immunohistochemistry (IHC) were performed in aortic tissues of 9 TAK and 9 atherosclerosis patients; clinical data were also collected. RESULTS: Circulating CD4(+) T cells were more frequent in TAK patients (p<0.05). Frequencies of Th1, Th2, and Th17 cells were higher, whereas Treg cells were reduced in TAK. Significantly higher levels of IL-6 and lower levels of IFN-γ, IL-4, and IL-17 were detected in TAK patients (p<0.05). By H & E staining, thickened vascular walls with proliferation of collagen fibre were observed in most patients. Inflammatory sites with infiltrating macrophages, lymphocytes, and neutrophils were located in adventitia. IHC revealed T cells (mainly CD4(+) T cells) in vascular lesions. Additionally, IL-6 was positive throughout the vascular wall in most specimens, whereas IFN-γ, IL-12, and IL-17 were detected in inflammatory sites of active patients. IL-6 levels were positively related to ESR, CRP, and Kerr scores (p<0.05). CONCLUSIONS: Significantly increased levels of IL-6 were detected in peripheral blood and aortic tissues of untreated patients. IL-6 might be a sensitive biomarker to assess disease activity and could be critical in the immunopathogenesis of TAK.

A case of 37 year long Behçet disease resembling Takayasu arteritis: An autopsy report.

A 19-year-old woman with a history of recurrent aphthous stomatitis and genital ulceration was diagnosed with Behçet disease. She was treated with steroids and immunosuppressive agents for more than 30 years, but multiple complications manifested including ileocecal ulcer, aortic valve regurgitation, renal failure, ischemic enterocolitis, and arteriosclerotic obliterans until her death at the age of 56 from pneumonia. An autopsy examination demonstrated an entirely calcified aorta and major aortic branches. The ascending aorta was dilatated 55 mm in diameter and branches were all stenosed. Microscopically, the aortic arch and its branches showed collagenous fibrosis of the outer media and adventitia, whereas coronary and abdominal aortic branches showed conventional atherosclerosis. Although the ante-mortem diagnosis was angio-Behçet disease, its pathophysiology along with her clinical history, morphology of the lead pipe-like aorta, predominant destruction of the outer arteries, and a human leukocyte antigen (HLA) haplotype of B39 were all suggestive of Takayasu arteritis. Thus, this case implies that HLA-B39 may be associated with the pathogenesis of arteritis like Takayasu arteritis, even if the primary disease is Behçet disease.

Late diagnosis of Takayasu's arteritis with repeated attacks of heart failure and uncontrolled hypertension due to abdominal aortic thrombosis: case report and review of the literature.

Takayasu's arteritis (TA) is a chronic, idiopathic, inflammatory disease affecting the aorta and its branches. To date, only one case involving abdominal aortic thrombosis due to TA has been reported. After bilateral artificial subclavian-iliac bypass, a case of abdominal aortic thrombosis due to TA received a delayed diagnosis in a 44-year-old Chinese male who experienced recurrent episodes of heart failure and uncontrolled hypertension with claudication of two extremities. Abdominal color Doppler sonography and computed tomography aortography (CTA) showed occlusion of the abdominal aorta and bilateral renal artery stenosis. After vascular bypass and during 1 year follow-up, his cardiac function improved and blood pressure was well controlled, with reduced serum creatinine. Postoperative CTA still showed abdominal aortic thrombosis resulting in arterial occlusion extending from the left renal artery initial segment level to the bilateral common iliac artery and the bifurcation of the renal artery, except for the vascular bypass. Abdominal aortic thrombosis due to TA is very rare and potentially life threatening, probably becoming an atherosclerosis risk factor. Doppler sonography and CTA results are important for diagnosis. Artificial vascular bypass can be used for TA in debilitated patients with diffuse aortic disease.

Environmental Triggers for Vasculitis.

Systemic vasculitides are autoimmune diseases characterized by vascular inflammation. Most types of vasculitis are thought to result from antigen exposure in genetically susceptible individuals, suggesting a likely role for environmental triggers in these conditions. Seasonal and geographic variations in incidence provide insight into the potential role of environmental exposures in these diseases. Many data support infectious triggers in some vasculitides, whereas other studies have identified noninfectious triggers, such as airborne pollutants, silica, smoking, and heavy metals. We review the known and suspected environmental triggers in giant cell arteritis, Takayasu arteritis, polyarteritis nodosa, Kawasaki disease, and antineutrophil cytoplasmic antibody-associated vasculitis.

Is aorto-arteritis a manifestation of primary antiphospholipid antibody syndrome?

A 23 year old female presented with dyspnea on exertion and absent pulses in the left upper limb. She had prior history of two first trimester abortions and pre-eclampsia with premature delivery. A Doppler examination had revealed left subclavian and axillary artery thrombosis for which she had been given warfarin six months previously. She was admitted and investigated. Patient had low positive aCL IgG antibody, positive antibeta2gp1 antibody, negative lupus anticoagulant and negative ANA. Patient had cardiomegaly and her echocardiography showed severe aortic regurgitation, moderate mitral regurgitation and moderate pulmonary artery hypertension with poor ejection fraction with normal aortic root. A diagnosis of primary antiphospholipid antibody syndrome with valvular involvement with dilated cardiomyopathy was entertained. A CT angiogram of the aorta revealed narrowing and irregularity of the aorta and its multiple branches suggestive of type III Takayasu's arteritis. Temporal relationship suggests development of aorto-arteritis secondary to APS but simultaneous presence of both these disorders in this patient cannot be ruled out.

[Asymptomatic Takayasu's arteritis: an incidental diagnosis]. / Arterite asintomatica di Takayasu: una diagnosi occasionale.

We present the case of a 56 years-old female patient that was admitted to our Unit after an incidental observation of bilateral absence of the radial pulses, with impossibility of brachial arterial pressure measurement. The patient reported being completely asymptomatic in occasion of the episode, thus like previously and later on to it. We diagnosed the patient being affected of Takayasu arteritis and adeguate therapy had been undertaken.

Assessment of Low Bone Mineral Density in Untreated Patients with Takayasu's Arteritis.

Chronic inflammation affects bone metabolism and accelerates bone loss. This study is aimed at analyzing the prevalence of low bone mineral density (LBMD) in patients with untreated Takayasu's arteritis (TA) and risk factors. Forty untreated TA patients were enrolled, including 38 premenopausal women and 2 men before 50 years old. The control group included 60 age- and gender-matched healthy persons. Bone mineral density (BMD) of lumbar vertebrae and hip in patients with TA and the control group was measured by the dual-energy X-ray method. Serum 25OHD and ß-CTX were also measured. The lumbar BMD of TA patients (0.89 ± 0.11 g/cm2) was significantly lower than that of the healthy control (0.97 ± 0.11 g/cm2). The prevalence of LBMD at the lumbar spine (17.50%) was significantly higher than that of the control group (3.33%). However, there was no significant difference at the hip. The 25OHD of TA patients was lower than that of healthy controls, while the level of ß-CTX was higher. The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in patients with LBMD were higher than those in patients with normal BMD. According to univariate correlation analysis, there was a significant negative correlation between LDL-C and lumbar BMD. Binary logistic regression analysis showed that LDL-C was an important factor affecting the occurrence of LBMD in patients with TA (OR = 25.269, P = 0.02). Our result reveals bone loss in TA patients, which hints the relationship among inflammation, lipid metabolism, and bone metabolism.

Specific microbiome profile in Takayasu's arteritis and giant cell arteritis.

Recent studies have provided evidence of a close link between specific microbiota and inflammatory disorders. While the vessel wall microbiota has been recently described in large vessel vasculitis (LVV) and controls, the blood microbiome in these diseases has not been previously reported (LVV). We aimed to analyse the blood microbiome profile of LVV patients (Takayasu's arteritis [TAK], giant cell arteritis [GCA]) and healthy blood donors (HD). We studied the blood samples of 13 patients with TAK (20 samples), 9 patients with GCA (11 samples) and 15 HD patients. We assessed the blood microbiome profile by sequencing the 16S rDNA blood bacterial DNA. We used linear discriminant analysis (LDA) coupled with linear discriminant effect size measurement (LEfSe) to investigate the differences in the blood microbiome profile between TAK and GCA patients. An increase in the levels of Clostridia, Cytophagia and Deltaproteobacteria and a decrease in Bacilli at the class level were found in TAK patients compared with HD patients (LDA > 2, p < 0.05). Active TAK patients had significantly lower levels of Staphylococcus compared with inactive TAK patients. Samples of GCA patients had an increased abundance of Rhodococcus and an unidentified member of the Cytophagaceae family. Microbiota of TAK compared with GCA patients was found to show higher levels of Candidatus Aquiluna and Cloacibacterium (LDA > 2; p < 0.05). Differences highlighted in the blood microbiome were also associated with a shift of bacterial predicted metabolic functions in TAK in comparison with HD. Similar results were also found in patients with active versus inactive TAK. In conclusion, patients with TAK were found to present a specific blood microbiome profile in comparison with healthy donors and GCA subjects. Significant changes in the blood microbiome profiles of TAK patients were associated with specific metabolic functions.

[Problems of diagnostics and treatment strategy in patients with Takayasu' arteries].

Current concepts of etiology and pathogenesis of nonspecific aortoarteritis (Takayasu's disease) are considered. A.V. Pokrovsky and his team gained the largest experience with diagnostics and treatment of patients suffering this disease. In this paper, the authors describe results of the treatment of more than 200 patients including 118 operated for isolated reconstruction of aortic arch branches (n = 43), restoration of blood flow only in thoracoabdominal aorta and its branches (n = 63), reconstruction of both brachiocephalic arteries and thoracoabdominal aorta (n = 12). The authors present their view of diagnostics and treatment strategy in patients with lesioned brachiocephalic arteries, abdominal and thoracoabdominal aorta. The necessity of following up patients in the postoperative period is emphasized.

Familial risks between giant cell arteritis and Takayasu arteritis and other autoimmune diseases in the population of Sweden.

Giant cell arteritis (GCA, also called temporal arteritis) is a rare and Takayasu arteritis (TA) is an even rarer autoimmune disease (AID), both of which present with inflammatory vasculitis of large and medium size arteries. The risk factors are largely undefined but disease susceptibility has been associated with human leukocyte antigen locus. Population-level familial risk is not known. In the present nation-wide study we describe familial risk for GCA and for GCA and TA with any other AID based on the Swedish hospital diagnoses up to years 2012. Family relationships were obtained from the Multigeneration Register. Familial standardized incidence ratios (SIRs) were calculated for offspring whose parents or siblings were diagnosed with GCA, TA or any other AID. The number of GCA patients in the offspring generation was 4695, compared to 209 TA patients; for both, familial patients accounted for 1% of all patients. The familial risk for GCA was 2.14, 2.40 for women and non-significant for men. GCA was associated with 10 other AIDs and TA was associated with 6 other AIDs; both shared associations with polymyalgia rheumatica and rheumatoid arthritis. The results showed that family history is a risk factor for GCA. Significant familial associations of both GCA and TA with such a number of other AIDs provide evidence for polyautoimmunity among these diseases.

The relationships of serum homocysteine levels and traditional lipid indicators with disease activity and coronary artery involvement in Takayasu arteritis.

Serum homocysteine (HCY) levels have been associated with the occurrence of coronary stenosis and disease activity in large-vessel vasculitis. However, whether increases in serum HCY levels and traditional lipid indicators are associated with coronary artery involvement and disease activity in Chinese Han Takayasu arteritis (TA) patients is unknown. This study aims to investigate the clinical and laboratory features of TA by assessing their association with disease activity in TA patients, and to explore the risk factors associated with coronary artery involvement in these patients. Serum HCY levels and traditional lipid indicators were tested in one hundred ninety TA patients and one hundred fifty-four healthy controls. We analyzed the relationships of serum HCY levels and traditional lipid indicators with disease activity and analyzed the risk factors for coronary artery involvement. Twenty-one TA patients were found to have coronary artery stenosis (≥ 50%). TA patients had significantly higher levels of HCY than did healthy controls (p < 0.0001). Serum levels of HCY and low-density lipoprotein cholesterol (LDL-C); the ratios of LDL-C to high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) to HDL-C, and triglycerides (TG) to HDL-C; and the values of atherogenic index of plasma (AIP) were significantly higher in patients with active TA than in patients with inactive TA and in TA patients with coronary artery involvement than in TA patients without coronary artery involvement. By contrast, the serum levels of HDL-C were significantly lower in patients with active TA than in patients with inactive TA and in TA patients with coronary artery involvement than in TA patients without coronary artery involvement (p < 0.05). In addition, the serum levels of TC and TG were significantly higher in TA patients with coronary artery involvement than those in TA patients without coronary artery involvement. Elevated serum HCY levels increased the risk of coronary artery involvement by 1.3-fold (p = 0.011, odds ratio [OR] = 1.275, 95% confidence interval [CI]: 1.056-1.539), and the cutoff value for serum HCY was 9.55 µmol/L. Elevated serum TG levels increased the risk of coronary artery involvement by 3.5-fold (p < 0.0001, OR = 3.534, 95% CI: 1.907-6.547), and the cutoff value for serum TG was 1.215 mmol/L. The risk of coronary artery involvement was 2.5-fold higher when an elevated TG/HDL-C ratio was present (p < 0.0001, OR = 2.513, 95% CI: 1.567-4.032). This study showed that serum HCY and TG levels and the TG/HDL-C ratio are independent risk factors for coronary artery involvement in TA patients.

Effectiveness of Tocilizumab in juvenile patients with refractory Takayasu arteritis: Two case reports.

RATIONALE: Takayasu arteritis (TA) is a systemic large-vessel vasculitis which can be accompanied by the symptoms associated with vascular stenosis. PATIENT CONCERNS: We describe 2 female juveniles with TA who presented with progressive intermittent claudication. DIAGNOSIS: Contrast-enhanced computed tomography (CT) revealed the stenosis of femoral arteries and increased levels of C-reactive protein (CRP), and serum amyloid A (SAA) were noted in both patients. According to European league against rheumatism consensus criteria for the diagnosis of TA was confirmed in both patients. INTERVENTIONS: Both patients had shown resistance to glucocorticoids and treated with tocilizumab (TCZ) (subcutaneous injections, 162 mg/week). OUTCOMES: These treatments improved claudication symptoms. Follow-up imaging by enhanced CT revealed restoration of advanced stenosis of the femoral arteries in both patients. They achieved normalization of levels of the acute-phase reactants CRP and SAA. Serum levels of interleukin-6 were increased transiently after TCZ injection, but declined to within normal ranges at 12 weeks. LESSONS: Juvenile patients with TA presenting with advanced stenosis of the femoral arteries are not rare. The clinical courses of our patients suggested the beneficial effects of TCZ against the progressive vascular stenosis observed in refractory TA.

Aortitis and periaortitis: The puzzling spectrum of inflammatory aortic diseases.

Aortitis and periaortitis are inflammatory diseases of the aorta and its main branches; they differ in the extension of inflammation, which is confined to the aortic wall in aortitis, and spreads to the periaortic space in periaortitis. Aortitis is classified as non-infectious or infectious. Non-infectious aortitis represents a common feature of large-vessel vasculitides but can also be isolated or associated with other rheumatologic conditions. Periaortitis can be idiopathic or secondary to a wide array of etiologies such as drugs, infections, malignancies, and other proliferative diseases. Notably, both aortitis and periaortitis may arise in the context of IgG4-related disease, a recently characterised fibro-inflammatory systemic disease. Prompt recognition, correct diagnosis and appropriate treatment are essential in order to avoid life-threatening complications.

Progress in pediatric vasculitis.

PURPOSE OF REVIEW: To examine recent advances in the pathophysiology and therapy of pediatric vasculitis. RECENT FINDINGS: The past 2 years have been marked by significant progress in extending novel techniques to the investigation of the two most common pediatric vasculitis syndromes, Henoch-Schonlein purpura and Kawasaki disease. Study of other vasculitides, such as Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis, is impeded by the small number of pediatric patients. Nonetheless, national and international registries are beginning to provide the foundation for generation of testable hypotheses regarding pathogenesis and optimal treatment. Thus, recent data from the study of children suggest that disorders in the control of inflammation, such as those that underlie familial Mediterranean fever and other autoinflammatory diseases, may predispose to vasculitis. Improved knowledge of mechanisms of disease, in turn, should pave the way for more targeted, effective, and tolerable therapies for children with systemic vasculitis. SUMMARY: International collaboration to study rare disorders such as pediatric vasculitis are demonstrating disorders of inflammatory regulation that predispose to these diseases and may point toward new treatment approaches.

Relapsing polychondritis-associated Takayasu's arteritis.

We report a 40-year-old woman with saddle shaped-nose and bilateral deformed "cauliflower" ears who was admitted to our clinic because of arthralgia, fatigue, weakness and coldness in both arms, recurrent swelling and pain of the nose and both auricles. On physical examination, bruits were heard over both carotid arteries and blood pressure was not measurable in both upper extremities. Conventional angiography revealed total occlusion of left common carotid, right internal carotid, right subclavian, right renal and bilateral vertebral arteries. Relapsing polychondritis and associated Takayasu's arteritis were diagnosed according to Mc Adam and American College of Rheumatology (ACR) criteria, respectively.