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• W2517266988 abstract "Better understanding of the pathophysiology of large vessel vasculitis (LVV) and associated conditions that may overlap will aid in developing safer therapies. In this issue, two studies address disease associations with vasculitis. Kilic et al. review 52 patients with Takayasu's arteritis (TA) for an association with inflammatory bowel disease (IBD). They report that three patients (5.8%) had IBD preceding TA. Anti-saccharomyces antibody (ASCA) and anti-neutrophil cytoplasmic antibody (ANCA) tests were not useful for predicting the association between TA and IBD. They also suggest, that TA should be ruled out in IBD patients on immunosuppression who have persistent constitutional symptoms, hypertension and raised inflammatory markers. In another study, Ungprasert et al. investigate the association between giant cell arteritis (GCA) and risk of peripheral arterial disease (PAD). In this systematic review and meta-analysis of four observational cohort studies, they observed the pooled risk ratio of PAD in patients with GCA is 1.88, compared to controls, indicating a statistically significant increase in the risk of PAD in GCA patients. Here, we discuss emerging therapies in LVV. Long-term treatment with high-dose glucocorticoids (GC) has been the gold standard for management of GCA and vasculitis in general. However, there is a paradigm shift in our approach to this treatment with increasing knowledge of adverse effects with chronic GC requirement. Inflammatory joint conditions have been the forerunner of innovative GC-free therapies in disease management. Awareness of associations with frequently encountered conditions may improve earlier detection of LVV. LVV may be classified as either: primary: secondary: The pathogenesis of GCA has been extensively studied; however, the etiology and physiologic mechanisms underlying this condition remain elusive. In this editorial we discuss GCA as a model to review the pathogenesis of LVV syndrome. There are three stages of disease progression (Fig. 1). GCs remain the mainstay of treatment in LVV, and may be required at high doses for a prolonged duration, often years, resulting in high cumulative GC doses with up to 85% of GCA and PMR patients treated with chronic GC therapy experiencing adverse effects. Common side effects are steroid-induced osteoporosis and fragility fractures, hypertension, cataracts, metabolic and cardiovascular complications, weight gain and neuropsychiatric abnormalities. Steroids can significantly worsen pre-existing co-morbidities, and increase potential for infection. Furthermore, despite GC therapy, 40–50% of patients experience disease activity relapse. Three patterns of response to chronic GC therapy are observed in LVV patients: responsive, relapsing or refractory disease. Disease activity response in GCA related to Th cell predominance has been reported by Deng et al.6 with the Th-17 pathway being GC responsive, and Th-1 pathway GC resistant. Methotrexate has been tried in refractory LVV, and also as a steroid-sparing agent. A meta-analysis showed modest efficacy of methotrexate in GCA as adjunctive therapy lowering the risk of relapse and reduced exposure to GC with reduction in cumulative dose.7 Jover et al.8 reported similar findings, from a randomized, double-blind, placebo-controlled trial. However, Spiera et al.9 showed no significant benefit with added methotrexate. Leflunomide has shown promise as a steroid-sparing agent in LVV. A case series by Adizei et al.10 of leflunomide use in difficult to treat GCA showed that 22 out of 23 patients had either a complete or partial response resulting in lower doses of GC. Leflunomide was well tolerated apart from mild diarrhea. Another case series by Diamantopoulos et al.11 with 11 refractory GCA patients showed good results with leflunomide. There was 12.4 mg/dL (CI 95% 0.7–25.5, P = 0.06) reduction in C-reactive protein, with 6.6 mg (CI 95% 2.8–10.3, P < 0.01) reduction in the cumulative prednisolone dose. Twelve patients with difficult to treat PMR were included in this case series with similar outcome. Dasgupta and Panayi15 demonstrated high serum levels of IL-6 in patients with GCA and PMR, with levels elevated in some patients even in the presence of normal acute phase reactants. The role of IL-6 blockade in LVV has been investigated since then with promising results. Tocilizumab (TCZ) a humanized monoclonal antibody against the IL-6 receptor (IL-6R) has been evaluated in LVV. A single center, Phase 2 randomized controlled trial by Villiger et al.16 with 30 newly diagnosed or relapsing GCA patients showed efficacy of TCZ for induction and maintenance of remission. Patients were randomized (2 : 1) to receive TCZ 8 mg/kg intravenously (IV) every 4 weeks for 52 weeks; or placebo IV every 4 weeks for 52 weeks, all given in combination with prednisone starting at 1 mg/kg/day and tapered to 0 mg according to a standard reduction scheme defined in the study protocol. The primary outcome was the proportion of patients who achieved complete remission of disease at a prednisolone dose of 0.1 mg/kg/day at week 12. At 12 weeks 17 from 20 patients on TCZ and four from 10 patients in the placebo group achieved complete remission (85% vs. 40%; risk difference 45%, 95% CI 11-79; P = 0.0301). At 52 weeks, 17 in the TCZ group and two in placebo group were relapse-free (85% vs. 20%, risk difference 65%, 95% CI 36–94; P = 0.0010). Evans et al.17 reported on a case series of eight patients with positron emission tomography with 18fluorodeoxyglucose (18FDG-PET) – computed tomography (CT) positive refractory LVV; all the patients had a complete response with 6–12 infusions of TCZ 8 mg/kg/month. Five patients had relapse after stopping TCZ with one patient showing revascularization on ultrasound (US) after TCZ infusion (Fig. 3). GiACTA, a large randomized clinical trial (RCT) is assessing subcutaneous TCZ 162 mg either weekly or every second week with a 6-month prednisolone taper in 250 patients with newly diagnosed or relapsed/refractory GCA.18 The trial has completed recruitment, initial results are promising but detailed results are awaited. SIRRESTA, a RCT on evaluating the efficacy of sirukumab, also a human monoclonal antibody against the IL-6R in patients with new or refractory/relapsed GCA, is underway and presently recruiting. The Phase 2 results with sirukumab are encouraging (ClinicalTrials.gov Identifier: NCT02531633).19 A retrospective study of 44 patients with refractory TA showed efficacy of TCZ with clinical, biological and radiological response, as well as steroid-sparing efficacy being the parameters for response.20 Goel et al.21 report on 10 patients with ‘difficult to treat’ TA, in whom TCZ was effective as a steroid-sparing option for rapid control of refractory disease, without benefit sustained after withdrawal. The TENOR study in 20 patients with GC treatment-naïve PMR showed that TCZ as monotherapy was efficacious in inducing remission and reducing GC requirement.22 A trial with gevokizumab (anti-IL-1β humanized monoclonal antibody) in GCA was terminated as it failed to achieve its primary target in Behcet's uveitis.23 There is a paucity of data on anakinra, a recombinant version of the IL-1 receptor antagonist (IL1-RA) in GCA. A case series of three patients with refractory GCA showed improvement with anakinra in their inflammation biomarkers and/or in their symptoms, as well as a disappearance of arterial inflammation in PET/CT for two patients.24 Abatacept, a fusion protein composed of the Fc region of IgG1 fused to the extracellular domain of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is approved for treatment of rheumatoid arthritis. A multi-center, randomized, double-blind, placebo-controlled, withdrawal design trial (AGATA) has examined the efficacy and safety of treatment with abatacept combined with prednisone in patients with GCA. In GCA patients the addition of abatacept to a standard treatment regimen with prednisone reduced the risk of relapse of vasculitis and was not associated with a higher rate of toxicity compared with prednisone alone.25 Current evidence suggests that B cells do not play a significant role in the pathogenesis of LVV or PMR. B cells are not predominant in inflamed temporal arteries of GCA patients or detected in the affected joints of PMR patients.26, 27 However, this view is being challenged with reports that serum B cell activating factor (BAFF) is increased in these conditions and that BAFF shows a robust correlation with disease activity in both GCA and PMR.28 B-cell targeted therapy is achieved with rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20. Rituximab is under investigation as a therapeutic agent in IgG4-related disease.29 A significant fraction of thoracic lymphoplasmacytic aortitis cases, about 40% of inflammatory abdominal aortic aneurysms/abdominal periaortitis cases, and a portion of retroperitoneal fibrosis cases, are considered related to IgG4-related systemic disease.30 The pathogenesis of LVV is complex and not well understood. While anti-TNF strategies have transformed the management of inflammatory joint conditions, similar strategies in LVV have been disappointing despite elevated TNF levels in temple artery explants from GCA patients.31 With increasing knowledge of the biology of inflammation there is a large pool of biologic molecules which are emerging as potential targets in the management of LVV. Presently, selective blockade of IL-6 mediated pathways holds greatest promise and results from GiACTA are eagerly awaited. Other targets being actively pursued in rheumatologic diseases include adhesion molecules, small signalling molecules, transcription factors and the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. The net is now widely cast to identify specific molecular targets and pathways that will enlighten researchers and clinicians to the molecular basis of LVV and address the unmet need for better therapeutic options, improved biomarkers and prognostic indicators of disease severity, extent and critical outcomes." @default.
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• W2517266988 title "Emerging therapies in large vessel vasculitis" @default.
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• W2517266988 doi "https://doi.org/10.1111/1756-185x.12963" @default.
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