Treatment of ankylosing spondylitis and extra-articular manifestations in everyday rheumatology practice

The SpAs are a group of overlapping, chronic, inflammatory rheumatic diseases including AS, a chronic inflammatory disease primarily affecting the SI joints. In addition to inflammatory back pain, AS patients are also more likely to experience extra-articular manifestations belonging to the SpA concept which can affect the eyes, the gastrointestinal tract and the skin and other related inflammatory conditions. This review focuses on current progress in treatment options in SpA with special emphasis on extra-articular features. TNF inhibition has demonstrated effectiveness in the treatment of AS symptoms and all currently available anti-TNF agents appear to have similar efficacy. However, the efficacy of anti-TNF agents varies in the treatment of extra-articular manifestations and comorbidities. Analyses of trials of anti-TNF agents in patients with AS have revealed significant reductions in the incidence of flares of uveitis and IBD with infliximab and adalimumab (uveitis only) treatment but not with etanercept. All three anti-TNF agents (infliximab, adalimumab, etanercept) have demonstrated efficacy in psoriasis (not associated with AS). When evaluating as to which agent to use in the treatment of AS, an important consideration is the overall well-being of the patient. This should include any additional inflammatory burden that manifests in other parts of the body, which may currently be subclinical. Based on current evidence, among TNF inhibitors, the monoclonal antibodies (infliximab and adalimumab) are more appropriate than etanercept if extra-articular manifestations or comorbid conditions are present or suspected. To date, infliximab appears to be the best studied agent with a wide spectrum of proven efficacy

MAIT cells come to the rescue in cancer immunotherapy?

Recent progress in immunobiology has led to the observation that, among cells classically categorized as the typical representatives of the adaptive immune system, i.e., T cells, some possess the phenotype of innate cells. Invariant T cells are characterized by T cell receptors recognizing a limited range of non-peptide antigens, presented only in the context of particular molecules. Mucosal-associated invariant T cells (MAIT cells) are an example of such unconventional cells. In humans, they constitute between 1% and 8% of the peripheral blood T lymphocytes and are further enriched in mucosal tissues, mesenteric lymph nodes, and liver, where they can account for even 40% of all the T cells. MAIT cells recognize antigens in the context of major histocompatibility complex class I-related protein (MR1). Upon activation, they instantly release pro-inflammatory cytokines and mediate cytolytic function towards bacterially infected cells. As such, they have been a rapidly evolving research topic not only in the field of infectious diseases but also in the context of many chronic inflammatory diseases and, more recently, in immuno-oncology. Novel findings suggest that MAIT cells function could also be modulated by endogenous ligands and drugs, making them an attractive target for therapeutic approaches. In this review, we summarize the current understanding of MAIT cell biology, their role in health and disease and discuss their future potential in cancer immunotherapy. This is discussed through the prism of knowledge and experiences with invariant natural killer T cells (iNKT)—another prominent unconventional T cell subset that shares many features with MAIT cells

An optimized method for isolating and expanding invariant natural killer T cells from mouse spleen

The ability to rapidly secrete cytokines upon stimulation is a functional characteristic of the invariant natural killer T (iNKT) cell lineage. iNKT cells are therefore characterized as an innate T cell population capable of activating and steering adaptive immune responses. The development of improved techniques for the culture and expansion of murine iNKT cells facilitates the study of iNKT cell biology in in vitro and in vivo model systems. Here we describe an optimized procedure for the isolation and expansion of murine splenic iNKT cells. Spleens from C57Bl/6 mice are removed, dissected and strained and the resulting cellular suspension is layered over density gradient media. Following centrifugation, splenic mononuclear cells (MNCs) are collected and CD5-positive (CD5(+)) lymphocytes are enriched for using magnetic beads. iNKT cells within the CD5(+) fraction are subsequently stained with alpha GalCer-loaded CD1d tetramer and purified by fluorescence activated cell sorting (FACS). FACS sorted iNKT cells are then initially cultured in vitro using a combination of recombinant murine cytokines and plate-bound T cell receptor (TCR) stimuli before being expanded in the presence of murine recombinant IL-7. Using this technique, approximately 10(8) iNKT cells can be generated within 18-20 days of culture, after which they can be used for functional assays in vitro, or for in vivo transfer experiments in mice

Progress in spondylarthritis. Immunopathogenesis of spondyloarthritis: which cells drive disease?

Spondyloarthritides, or SpA, form a cluster of chronic inflammatory diseases with the axial skeleton as the most typical disease localisation, although extra-articular manifestations such as intestinal inflammation may frequently occur during the course of the disease. This review summarises recent progress in our understanding of the immunopathogenesis of SpA with special emphasis on the cellular constituents considered to be responsible for the initiation and/or perpetuation of inflammation. There are several arguments favouring a role for haematopoietic cells in the pathophysiology of spondyloarthritis, including HLA-B27-associated dendritic cell disturbances, HLA-B27 misfolding properties and T helper 17 cells. In addition, recent studies have pointed toward a pivotal role for stromal cells. A major challenge, however, remains to determine how recently identified genetic associations such as interleukin-23 receptor polymorphisms may influence cellular targets in spondyloarthritis

Synthesis of C-5" and C-6"-modified α-GalCer analogues as iNKT-cell agonists

Alpha-Galactosyl Ceramide (α-GalCer) is a prototypical synthetic ligand of invariant natural killer T (iNKT) cells. Upon presentation by the MHC class I-like molecule CD1d, this glycolipid stimulates iNKT cells to secrete a vast amount of both pro-inflammatory Th1 and anti-inflammatory Th2 cytokines. Recently, we discovered that selected 6″-modified α-GalCer analogues may produce markedly Th1-biased responses due to the formation of either an additional anchor with CD1d or by establishing extra interactions with the T-cell receptor of iNKT cells. Here, we report a practical synthesis towards 6″-O-carbamate and galacturonamide analogues of α-GalCer and their evaluation as iNKT cell agonists in mice

Morbid anatomy of 'erosive osteoarthritis' of the interphalangeal finger joints : an optimised scoring system to monitor disease progression in affected joints

Objectives To develop and validate a quantitative radiographic scoring system, the Ghent University Scoring System (GUSS), with better ability to detect progression over a shorter period of time in erosive osteoarthritis (OA) of the interphalangeal (IP) finger joints compared with the existing anatomic phase scoring system. Methods Thirty IP finger joints showing erosive features at baseline or follow-up were selected from 18 patients with erosive hand OA. Posteroanterior radiographs of these joints obtained at baseline, 6 and 12 months-totalling 90 images-were used for the study. All joints were first scored according to the original anatomic phase scoring system. Erosive progression and signs of repair or remodelling were then scored by indicating the proportion of normal subchondral bone, subchondral plate and joint space on an 11-point rating scale (range 0-100 with 10 unit increases). Inter-and intrareader reproducibility was studied using intraclass correlation coefficients (ICCs). Based on the within-variance of two readers, the smallest detectable change (SDC) was calculated and allowed identification of joints with changes above the SDC as 'progressors'. Results Longitudinal inter-reader ICC scores rated well for all variables and the total score (ICC 0.86-0.93). To identify 'real' change over background noise, a change of at least 40 units on the total score (range 0-300) over 12 months (SDC 0-12: 36.0), and 50 units over 6 months (SDC 0-6: 47.6) had to be present. 60% of the 30 joints were identified as 'progressors' over 6 months compared with 33.3% with the classical anatomical scoring system, and 70% versus 56.6%, respectively, over 12 months. Conclusion GUSS, is a reliable method to score radiographic change over time in erosive IP OA and detects more progression over a shorter period of time than the classical scoring system

A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance

Background: Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for improved alternatives to classic steroids. We sought to unravel how two glucocorticoid receptor-activating compounds, dexamethasone and Compound A, influence glucocorticoid receptor levels and how this can be correlated to their gene regulatory potential. Methods: Compound A and dexamethasone were applied in a short-term and long-term treatment protocol. By quantitative PCR analysis in fibroblast-like synoviocytes (FLS) the gene regulatory potential of both compounds in the two experimental conditions was analysed. A parallel Western blot assay revealed the glucocorticoid receptor protein levels in both conditions (ex vivo). In addition, this study examined the effect of systemic administration of dexamethasone and Compound A, in concentrations effective to inhibit collagen-induced arthritis, in DBA/1 mice on glucocorticoid receptor levels (in vivo). Results: Compound A does not induce a homologous downregulation of glucocorticoid receptor in vivo and ex vivo, thereby retaining its anti-inflammatory effects after prolonged treatment in FLS. This is in sharp contrast to dexamethasone, showing a direct link between prolonged dexamethasone treatment, decreasing glucocorticoid receptor levels, and the abolishment of inflammatory gene repression in FLS. It was also observed that the acquired low receptor levels after prolonged dexamethasone treatment are still sufficient to sustain the transactivation of endogenous glucocorticoid-responsive element-driven genes in FLS, a mechanism partly held accountable for the metabolic side-effects. Conclusion: Compound A is less likely to evoke therapy resistance, as it does not lead to homologous glucocorticoid receptor downregulation, which is in contrast to classic glucocorticoids