Pathogenetic insights from the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities. Cytokine inhibitors have definitively proven a critical role for tumour necrosis factor α and interleukin 6 in disease pathogenesis and possibly also for granulocyte-macrophage colony-stimulating factor. More recently, clinical trials with Janus kinase (JAK) inhibitors have shown that cytokine receptors that signal through the JAK/STAT signalling pathway are important for disease, informing the pathogenetic function of additional cytokines (such as the interferons). Finally, successful use of costimulatory blockade and B-cell depletion in the clinic has revealed that the adaptive immune response and the downstream events initiated by these cells participate directly in synovial inflammation. Taken together, it becomes apparent that understanding the effects of specific immune interventions can elucidate definitive molecular or cellular nodes that are essential to maintain complex inflammatory networks that subserve diseases like rheumatoid arthritis

Secukinumab: a new treatment option for psoriatic arthritis

Introduction: Psoriatic arthritis (PsA) is an immune-mediated chronic inflammatory arthropathy associated with impaired physical function and reduced quality of life. Biologic therapies that target tumor necrosis factor (anti-TNF) have significantly improved clinical outcomes. Partial, non- and transient responses remain common comprising significant unmet clinical need. New therapies with novel modes of action are urgently required. Objectives: The interleukin (IL)-17 pathway has recently been attributed a critical role in the pathogenesis of spondyloarthritides. Herein, we review data from clinical studies with secukinumab, a novel fully human IgG1κ anti-IL-17A monoclonal antibody (mAb), in patients with active PsA. Results: Across two pivotal phase 3 studies, secukinumab provided significant and sustained reductions in the signs and symptoms of PsA, inhibition of radiographic progression, and improved patient-reported outcomes and measures of quality of life. The primary efficacy endpoint, a ≥20% improvement from baseline according to the American College of Rheumatology 20 (ACR20) response at Week 24, was significantly higher in patients treated with secukinumab compared with placebo, with improvements sustained through at least 52 weeks. Clinical benefits were seen with secukinumab regardless of concomitant methotrexate treatment and in patients who were either anti-TNF-naïve or who were inadequate responders to anti-TNF therapy. Secukinumab was well-tolerated, with a safety profile consistent with that previously reported in psoriasis trials. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and headache. Conclusion: Secukinumab offers an effective new addition to the available treatment options for PsA. Regulatory submissions have been filed worldwide, with the first approvals recently obtained in Japan and Europe. Future studies are required to define the optimal timing and strategic use of this novel treatment modality

Editorial: choosing new targets for rheumatoid arthritis therapeutics: too interesting to fail?

No abstract available

Parallel spinors and holonomy groups

In this paper we complete the classification of spin manifolds admitting parallel spinors, in terms of the Riemannian holonomy groups. More precisely, we show that on a given n-dimensional Riemannian manifold, spin structures with parallel spinors are in one to one correspondence with lifts to Spin_n of the Riemannian holonomy group, with fixed points on the spin representation space. In particular, we obtain the first examples of compact manifolds with two different spin structures carrying parallel spinors.Comment: 10 pages, LaTeX2

Rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid arthritis

MicroRNA-155—at the critical interface of innate and adaptive immunity in arthritis

MicroRNAs (miRNAs) are small non-coding RNAs that fine-tune the cell response to a changing environment by modulating the cell transcriptome. MiR-155 is a multifunctional miRNA enriched in cells of the immune system and is indispensable for the immune response. However, when deregulated, miR-155 contributes to the development of chronic inflammation, autoimmunity, cancer and fibrosis. Herein, we review the evidence for the pathogenic role of miR-155 in driving aberrant activation of the immune system in Rheumatoid Arthritis, and its potential as a disease biomarker and therapeutic target

Castleman disease and lymphocytic interstitial pneumonia: a complex diagnostic and management challenge

No abstract available

How to find the holonomy algebra of a Lorentzian manifold

Manifolds with exceptional holonomy play an important role in string theory, supergravity and M-theory. It is explained how one can find the holonomy algebra of an arbitrary Riemannian or Lorentzian manifold. Using the de~Rham and Wu decompositions, this problem is reduced to the case of locally indecomposable manifolds. In the case of locally indecomposable Riemannian manifolds, it is known that the holonomy algebra can be found from the analysis of special geometric structures on the manifold. If the holonomy algebra $\mathfrak{g}\subset\mathfrak{so}(1,n-1)$ of a locally indecomposable Lorentzian manifold $(M,g)$ of dimension $n$ is different from $\mathfrak{so}(1,n-1)$, then it is contained in the similitude algebra $\mathfrak{sim}(n-2)$. There are 4 types of such holonomy algebras. Criterion how to find the type of $\mathfrak{g}$ are given, and special geometric structures corresponding to each type are described. To each $\mathfrak{g}$ there is a canonically associated subalgebra $\mathfrak{h}\subset\mathfrak{so}(n-2)$. An algorithm how to find $\mathfrak{h}$ is provided.Comment: 15 pages; the final versio

Crossing of the w=-1 barrier in viscous modified gravity

We consider a modified form of gravity in which the action contains a power alpha of the scalar curvature. It is shown how the presence of a bulk viscosity in a spatially flat universe may drive the cosmic fluid into the phantom region (w<-1) and thus into a Big Rip singularity, even if it lies in the quintessence region (w>-1) in the non-viscous case. The condition for this to occur is that the bulk viscosity contains the power (2 alpha-1) of the scalar expansion. Two specific examples are discussed in detail. The present paper is a generalization of the recent investigation dealing with barrier crossing in Einstein's gravity: I. Brevik and O. Gorbunova, Gen. Relativ. Grav. 37 (2005) 2039.Comment: 12 pages, latex, no figure

Leukotrienes, mast cells, and T cells

No abstract available