Warrington, Kenneth J

Objective Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome‐wide association analysis of Takayasu arteritis. Methods Two independent cohorts of patients with Takayasu arteritis from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 patients and 1,047 controls of European ancestry. Genotyping was performed using the Omni1‐Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu arteritis. Results We identified genetic susceptibility loci for Takayasu arteritis with a genome‐wide level of significance in IL6 (rs2069837) (odds ratio [OR] 2.07, P = 6.70 × 10 −9 ), RPS9 / LILRB3 (rs11666543) (OR 1.65, P = 2.34 × 10 −8 ), and an intergenic locus on chromosome 21q22 (rs2836878) (OR 1.79, P = 3.62 × 10 −10 ). The genetic susceptibility locus in RPS9 / LILRB3 lies within the leukocyte receptor complex gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin‐like receptor gene LILRB3 ( P = 2.29 × 10 −8 ). In addition, we identified candidate susceptibility genes with suggestive levels of association ( P < 1 × 10 −5 ) with Takayasu arteritis, including PCSK5, LILRA3, PPM1G/NRBP1 , and PTK2B . Conclusion Our findings indicate novel genetic susceptibility loci for Takayasu arteritis and uncover potentially important aspects of the pathophysiology of this form of vasculitis.

Objective To assess the occurrence of acute coronary syndrome (ACS) in patients with giant cell arteritis (GCA) compared to subjects without GCA. Methods We retrospectively reviewed a population‐based incidence cohort of Olmsted County, Minnesota residents with GCA diagnosed in 1950–2009. We compared this cohort with a cohort of patients without GCA of similar age, sex, and calendar year from the same population. Results The study included 245 patients with GCA and 245 non‐GCA subjects. The mean ± SD Framingham cardiovascular risk score was 30% ± 19% in GCA patients and 34% ± 23% in non‐GCA subjects ( P = 0.096) at the incidence/index date. Diabetes mellitus was significantly less common in GCA patients than non‐GCA subjects at the index date. The mean high‐density lipoprotein was higher and triglycerides were lower, with fewer patients taking lipid‐lowering medications in the GCA cohort compared to the non‐GCA cohort at the index date. During followup, no difference between the 2 cohorts was noted in the overall rate of ACS events (hazard ratio 0.74, 95% confidence interval 0.44–1.26). Overall thrombosis in myocardial infarction scores were similar in both cohorts. Revascularization procedures were done less frequently in GCA than in non‐GCA subjects (19% versus 50%; P = 0.015). Post‐ACS hospital length of stays and complications were similar in both cohorts. Conclusion Multiple cardiovascular risk factors are less atherogenic at incidence of GCA. There is no overall increased risk of ACS in patients with GCA.

Polymyalgia rheumatica (PMR) is a common inflammatory condition that often affects people over the age of 50 years. Characteristic symptoms are shoulder and hip girdle pain and prolonged morning stiffness. Markers of inflammation are often elevated. Clinicians are often faced with the challenge of distinguishing PMR from other conditions, particularly rheumatoid arthritis and spondyloarthropathy that can mimic symptoms of PMR in older people. Additionally, there is an association between PMR and giant cell arteritis, a common large-vessel vasculitis which also affects people over the age of 50 years. Imaging of the large vessels in asymptomatic patients with PMR often reveals findings of subclinical vasculitis. Presently, there are no tests that are specific for the diagnosis of PMR and clinicians rely on a combination of history, physical examination, laboratory tests and imaging studies to make a diagnosis. A recent undertaking by the European League Against Rheumatism/American College of Rheumatology has led to the publication of provisional classification criteria of PMR. Ultrasonography, which is being increasingly used by rheumatologists, can greatly aid in the diagnosis of PMR and often shows changes of synovitis and tenosynovitis. Treatment consists of low doses of glucocorticoids which are associated with morbidity. Evaluation of newer biologic therapies targeting inflammatory cytokines is underway. Despite treatment, relapses are common.

We report a case of an abdominal aortic aneurysm (AAA) that underwent inflammatory transformation which we treated medically with corticosteroids. Medical therapy resulted in resolution of presenting symptoms and observed inflammatory changes. We review the clinical features, associated pathology, diagnostic, and therapeutic options in the management of inflammatory AAA.

Background— Giant cell arteritis is a granulomatous vasculitis of the aorta and its branches that causes blindness, stroke, and aortic aneurysm. CD4 T cells are key pathogenic regulators, instructed by vessel wall dendritic cells to differentiate into vasculitic T cells. The unique pathways driving this dendritic cell–T-cell interaction are incompletely understood, but may provide novel therapeutic targets for a disease in which the only established therapy is long-term treatment with high doses of corticosteroids. Methods and Results— Immunohistochemical and gene expression analyses of giant cell arteritis-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands, Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain in wall-infiltrating T cells indicated ongoing NOTCH pathway activation in large-vessel vasculitis. NOTCH activation did not occur in small-vessel vasculitis affecting branches of the vasa vasorum tree. We devised 2 strategies to block NOTCH pathway activation: γ-secretase inhibitor treatment, preventing nuclear translocation of the NOTCH intracellular domain, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc. In a humanized mouse model, NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phases of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses. Conclusions— Blocking NOTCH signaling depleted T cells from the vascular infiltrates, implicating NOTCH- NOTCH ligand interactions in regulating T-cell retention and survival in vessel wall inflammation. Modulating the NOTCH signaling cascade emerges as a promising new strategy for immunosuppressive therapy of large-vessel vasculitis.

The vasculitides encompass a rare subset of autoimmune diseases. Reports of the concurrent association of malignancies with some forms of vasculitis raise the possibility that patients with certain types of vasculitis may be at increased risk of cancer. Conversely, some forms of vasculitis may be a manifestation of malignancy. We review cancer risk in patients with large vessel vasculitis (giant cell arteritis and Takayasu arteritis), polyarteritis nodosa, and the circulating antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides. In addition we discuss vasculitis as a paraneoplastic phenomenon, highlighting polyarteritis nodosa in association with hairy cell leukemia and reviewing the most common vasculitic manifestation of cancer, cutaneous vasculitis.

CD28 is the quintessential costimulatory molecule expressed on CD4+ and CD8+ T cells. During chronic infections and the normal aging process, CD28 expression is lost, compromising the functional activity of T cells. CD28 loss is promoted by replicative stress, particularly in the presence of tumor necrosis factor–α, owing to an inoperative CD28 initiator element. It is currently unknown whether CD28 loss is irreversible. The present study examined cytokines for their ability to reinduce CD28 expression. CD4+CD28null T cells constitutively expressed interleukin-12 (IL-12) α and β receptors, which were functional and allowed for the up-regulation of the signal transducer and activator of transcription–4 (STAT-4)–dependent gene CD161. Costimulation of the T-cell and IL-12 receptors induced the transcription of CD28 in approximately 50% of CD4+CD28null T-cell clones and lines. IL-12 by itself did not restore CD28 expression. Up-regulation of CD28 after IL-12 exposure correlated with the reassembly of the CD28–initiator protein complex. The re-expressed CD28 was functional and restored the ability of CD4+CD28null T cells to express CD25 and CD40 ligand. Our data suggest that IL-12 may, in part, functionally rescue senescent CD4+ T cells.