Therapeutic Target For Rheumatoid Arthritis Research Articles

AB0173 Active anti-VEGF immunization ameliorates collagen induced arthritis

BackgroundSynovial neoangiogenesis is a key process in rheumatoid arthritis, contributing to pannus development and maintenance1. Anti-angiogenesis treatments targeting the VEGF/VEGF-R system ameliorate arthritis in several animal models1,2. Here we report...

IL-32, a potential therapeutic target for rheumatoid arthritis?

Recently, we read with great interest the article, published in Rheumatol Int, showing that IL-32 injected into knee joints of CIA mice induced elevated scores of synovial inflammation, bone destruction, synovial expressions of IL1b, TNF-a, IL-18 and IFN-c [1]. Furthermore, synovial expressions of NK cell, chemokines (CCL2 and CXCL9) and chemokine receptors (CCR2 and CCR5) were markedly increased in IL-32-treated CIA mice [1]. These findings suggest that IL-32 may play an important role in the pathogenesis of rheumatoid arthritis (RA), and IL-32 may be a therapeutic target in RA. IL-32 is a multifunctional cytokine generated by T lymphocytes, NK cells, monocytes and epithelial cells. There are six isoforms of IL-32, including IL-32a, IL-32b, IL-32c, IL-32d, IL-32e and IL-32f [2]. It has been found that serum, peripheral blood mononuclear cells (PBMCs) of RA patients had increased levels of IL-32, respectively [3, 4]. Furthermore, IL-32 was highly expressed in RA synovial tissue [5–7], and IL-32 was correlated with the expression of IL-6, TNFa, IL-1b and IL-18 [5, 7]. Peritoneal macrophages collected from C3H/HeJ mice cultured with human IL-32 induced the synthesis of TNFa and IL-1b, as that of the chemokine macrophage inflammatory protein 2 (MIP-2) [7]. Similarly, human IL-32 stimulated the generation of prostaglandin E2 (PGE2) by human PBMC, an important mediator of cartilage and bone destruction in RA [7]. IL-32a transgenic mice found high levels of IL-32a mRNA expression in a variety of organs prominently in the knee joint and cardiac muscle and overexpressed IL-32a-induced constitutive expression of TNFa mRNA in colon and knee joints [8]. CD4? T cells transduced the hIL-32b gene, and then, these cells transferred to bovine type II collagen-immunized mice before the onset of arthritis. Shoda et al. [4] found that this group of mice developed arthritis earlier than the mock group of mice and showed significantly higher arthritis scores. Histological investigation of the joints showed severe cell infiltration in the hIL-32b group of mice [4]. Intra-articular injection of AdIL-32c (IL-32c mRNA derived from an adenoviral vector) into mouse knee joints resulted in markedly enhanced joint swelling, and histological analysis showed enhanced synovial infiltrating cells in the joints [5]. In synovial tissue, mRNA expression of TNFa, IL-1b, and IL-6 was significantly elevated in AdIL-32c-exposed joints [5]. It has also been found that AdIL-32c-transduced human FLS (fibroblast-like synoviocytes) increased CXCL8, IL-1b, CCL20, MMP1 and MMP3 mRNA expression [9]. On the contrary, silenced intracellular IL32c expression in FLS cells led to significant suppression of IL-6 and CXCL8 production [9]. FLS from RA patients stimulated with TNFa enhanced IL-32 expression, but the PKCd inhibitor rottlerin and the JNK inhibitor SP600125 suppressed TNFa-induced IL-32 expression in the cells [6]. Transfection with siRNA targeted against PKCd, JNK led to the suppression of expression of IL-32 as well [6]. Q. Xie C. Huang J. Zhong W.-W. Shen J. Li (&) School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, People’s Republic of China e-mail: lj@ahmu.edu.cn

Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential.

Clinical and experimental evidence suggest that interleukin-17A (IL-17A; also known as IL-17) is an attractive therapeutic target in rheumatoid arthritis (RA). Rheumatoid synovial tissue produces IL-17A, which causes cartilage and bone degradation in synovial and bone explants. Overexpression of IL-17A induces synovial inflammation and joint destruction in animal RA models. These effects are attenuated in IL-17A-deficient animals and by agents that block IL-17A. Serum IL-17A levels and, to a greater extent, synovial fluid IL-17A levels are elevated in many patients with RA. In some RA cohorts, higher IL-17A levels have been associated with a more severe clinical course. Several IL-17A blockers, including the anti-IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. Of these, secukinumab is the most advanced with respect to clinical evaluation in RA, with phase III trials ongoing in patients on background methotrexate who had inadequate responses to previous tumor necrosis factor blocker therapy.

Specific targeting of PI 3-kinase p110δ for the treatment of rheumatoid arthritis (P5177)

Abstract The p110δ isoform of PI3K is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which PI3K mediates inflammation are poorly understood. Here we describe a novel highly selective p110δ small molecule inhibitor, G-286, that allowed dissecting the contribution specifically of p110δ to cellular pathways that are implicated in arthritis disease pathogenesis in human and mice. Using G-286, we demonstrate that p110δ regulates B cell- but not myeloid-cell dependent inflammatory arthritis in mice. G-286 blocks B cell receptor dependent proliferation and reduces autoantibody levels in collagen-induced arthritis abrogating disease. However, G-286 does not significantly inhibit FcγR-mediated inflammatory cytokine production in murine macrophages. Accordingly, selective p110δ inhibition did not significantly affect disease progression in FcγR- and myeloid cell-dependent autoantibody-induced arthritis. Importantly, we provide evidence that human and mice diverge in their relative dependency on p110δ to regulate FcγR responses. In addition to B cells and myeloid cells, T cells and osteoclasts contribute to rheumatoid arthritis pathogenesis. Utilizing G-286, we dissect the relative impact of p110δ inhibition on human and mouse T cell and osteoclast function. These results provide new insight in the role of p110δ in arthritis disease processes and offer a compelling rationale for targeting p110δ for the treatment of human rheumatoid arthritis.

Fucosylation is a hallmark of inflammatory macrophages and a novel therapeutic target in rheumatoid arthritis (P5137)

Abstract Inflammatory macrophages (MΦ) play an important role in rheumatoid arthritis (RA). Fucosylation is a regulator of inflammation and we have observed a highly positive correlation between Fucosyltransferases (Fut)1 or Fut3 and Tnfα (p=0.0001) in RA synovial tissues. In sorted cells from human RA synovial fluid, Fut1 and Fut3 was highly expressed in M1 inflammatory MΦ (CD68+CD80+), but not in M2 MΦ (CD68+CD80-), synovial fibroblasts, Th1, Th17, and other T cells (p<0.01, n=5). Fucosylation inhibitor, 2-Deoxy-D-galactose (2-D-gal), precluded the differentiation of M1 MΦ derived by GM-CSF from mouse bone marrow or human PBMC monocytes, strongly indicating the indispensable role of fucosylation in M1 MΦ differentiation. Additionally, phalloidin staining showed 2-D-gal disrupted MΦ actin, suggesting a potential effect of fucosylation in antigen processing and presentation. Indeed, 2-D-gal treatment of fully differentiated M1 MΦ for 2 days dramatically reduced their uptake, processing and presentation of GFP-Eα (from I-Edα) and FITC-CII antigens in a dose dependent manner (p<0.01). In vivo, 2-D-gal dramatically blocked the bovine CII-induced arthritis in DBA/1J mice (scores 9.5±1.7 vs 0.5± 0.3, p<0.01) with reduced inflammatory MΦ in draining LN (1.3±0.3% vs 0.5±0.1%, p<0.05), decreased TNF-α (130 vs 39 pg/ml, p<0.05), and anti-CII in the serum. Our study indicated that M1 MΦ differentiation and function is orchestrated by fucosylation, which is a novel therapeutic target in RA.

Deficient or abundant but unable to fight? Estimation of circulating FoxP3+ T regulatory cells and their counteracting FoxP3− in rheumatoid arthritis and correlation with disease activity

Aim of the workPersistent inflammation and recurring activity in rheumatoid arthritis (RA) daring a quarterback of T regulatory cells (Tregs) intrigued rheumatologists. Tregs’ most specific marker is the forkhead box P3 (FoxP3) denoting FoxP3+ cells as suppressors whereas FoxP3− as effectors. This study evaluates subset distribution of peripheral blood (PB) CD4+CD25+ Tregs according to FoxP3 expression in RA to better understand its role in pathogenesis. Patients and methodsIn our observational cross-sectional study PB Tregs from 40 RA patients and 20 age and sex matched healthy controls (HC) were characterized and quantified by flow cytometry. Disease activity was evaluated by DAS28. Patients were divided into: active RA group (ARA) and remission RA group (RRA). ResultsSignificantly higher CD4+CD25+FoxP3+ Tregs were found on comparing RRA, ARA patients and HC (mean 153.25±6.29, 136.3±3.27 and 97.25±6.25, respectively) with a statistically highly significant difference (F=553.13, p<0.001). CD4+CD25+FoxP3− increased 3-folds in RRA and 4-folds in ARA compared to HC and CD4+CD25+FoxP3+ increased 1.6-folds in RRA and 1.5-folds in ARA. Thus the ratio of FoxP3−/FoxP3+ cells is altered from 1:3 in HC to 2:3 in RRA and 1:1 in ARA. CD4+CD25+FoxP3+ had a highly significant negative correlation with disease activity score DAS28 (r=−0.86, p<0.001). ConclusionThough CD4+CD25+FoxP3+ and CD4+CD25+FoxP3− are both increased in RA, their balance is more important; abundant FoxP3− cells with effector function have the upper hand over suppressive FoxP3+ cells. This imbalance relates to RA presence and activity. Reinforcing FoxP3 expression might be a good potential therapeutic target in RA.

The Th17 Pathway as a Therapeutic Target in Rheumatoid Arthritis and Other Autoimmune and Inflammatory Disorders

Production of the pro-inflammatory cytokine interleukin (IL)-17 by Th17 cells and other cells of the immune system protects the host against bacterial and fungal infections, but also promotes the development of rheumatoid arthritis (RA) and other autoimmune and inflammatory disorders. Several biologicals targeting IL-17, the IL-17 receptor, or IL-17-related pathways are being tested in clinical trials, and might ultimately lead to better treatment for patients suffering from various IL-17-mediated disorders. In this review, we provide a clear overview of current knowledge on Th17 cell regulation and the main Th17 effector cytokines in relation to IL-17-mediated conditions, as well as on recent IL-17-related drug developments. We demonstrate that targeting the Th17 pathway is a promising treatment for rheumatoid arthritis and various other autoimmune and inflammatory diseases. However, improvements in technical developments assisting in the identification of patients suffering from IL-17-driven disease are needed to enable the application of tailor-made, personalized medicine.

Deficiency of β-arrestin1 ameliorates collagen-induced arthritis with impaired TH17 cell differentiation

Rheumatoid arthritis (RA) is an inflammatory disease in which interleukin 17 (IL-17)-producing T helper 17 (T(H)17) cells have been critically involved. We show that in patients with RA, the expression of a multifunctional regulator β-arrestin1 was significantly up-regulated in peripheral and synovial CD4(+) T cells, which correlated well with active phases of RA. In collagen-induced arthritis, deficiency of β-arrestin1 ameliorated disease with decreased T(H)17 cell differentiation, proinflammatory cytokine production, synovitis, and cartilage and bone destruction. Further mechanistic study reveals that β-arrestin1 promoted signal transducer and activator of transcription 3 (STAT3) activation required for T(H)17 cell differentiation through scaffolding the interaction of Janus kinase 1 and STAT3. These findings indicate a critical role for β-arrestin1 in the pathogenesis of collagen-induced arthritis and T(H)17 cell differentiation and suggest β-arrestin1 as a potential diagnostic biomarker and therapeutic target for RA.

The fibroblast as a therapeutic target in rheumatoid arthritis

Significant advances have been made in the last 5 years that have finally allowed investigators to start targeting stromal cells such as fibroblasts in inflammatory disease. Rheumatoid arthritis is a prototype inflammatory disease, in which fibroblasts maintain the persistence of inflammation in the joint underpinned by a unique pathological phenotype driven by multiple epigenetic modifications. The step changes that are enabling the development of such therapies are an improved understanding of the mechanisms by which fibroblasts mediate persistence and the discovery of new markers that identify discrete functional subsets of fibroblast cells that have potential as disease-specific therapeutic targets.

A9.1 αvβ3 Integrin Inhibition with Cilengitide Both Prevents and Treats Collagen Induced Arthritis

Background Rheumatoid arthritis (RA) is characterised by synovial inflammation and osteoclast (OC) mediated bone erosions. AlphaVbeta3 (αvβ3) integrin is highly expressed in OCs. Avβ3 blocking antibodies reduce bone resorption and mice lacking β3 are osteopetrotic. Objectives Efficacy testing of the αvβ3 inhibitor cilengitide, a synthetic Arginine-Glycine-Asparagine amino acid peptide (RGD peptide), on osteoclastogenesis and the collagen induced arthritis (CIA) model for human RA. Materials and Methods In vitro mouse bone marrow-derived cells (BMCs) were differentiated into tartrate resistant acid phosphatase positive (TRAP+) mononuclear OC precursor cells (pre-OCs) and TRAP+ multinucleated mature OCs with macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappaB ligand (RANKL). Cilengitide, was added in increasing concentrations (2 nM to 20 µM) to the culture. These osteoclastogenesis assays were performed on plates coated with RGD containing matrixes osteopontin, fibronectin and fibrinogen but also on Poly-D-lysine to assess αvβ3 independent adhesion. In vivo CIA was induced in 6–8 week old male DBA/1 mice by immunisation with bovine type II collagen at day 1, followed by boosting at day 21. For CIA prevention mice received subcutaneously (s.c.) 1.5 mg/kg cilengitide (n = 15) or placebo (n = 15), 5 days per week, 1 day prior to CIA induction until day 53. For CIA treatment, mice with arthritis were randomised and received 1.5 mg/kg (low dose, n = 19) or 75 mg/kg (high dose, n = 7) cilengitide or placebo (n = 21), until day 59. Preventive and treatment effects were evaluated by assessing paw thickness and grip strength. Results In vitro increasing concentrations of cilengitide (IC50: 250 nM) dose-dependently reduced pre-OCs on all coatings, indicating early inhibition at the pre-OC proliferation stage. OCs were reduced above 200 nM, followed by complete disappearance above 2 µM. At 200 nM an intriguing morphological difference with reduction in OC size suggested that cilengitide may disrupt spreading and fusion capacity at the early pre-OC stage. In vivo CIA prevention with cilengitide effectively reduced incidence (92.8% versus 40%) and severity of arthritis as evidenced by reduction of clinical disease activity scores. Low and high dose cilengitide effectively inhibited progression of established arthritis. Conclusions Osteoclastogenesis requires intact αvβ3 integrin function. Systemic αvβ3 integrin inhibition with cilengitide potently prevents and treats experimental CIA. Cilengitide may be a novel therapeutic target in RA.

Mitogen-Activated Protein Kinases as Therapeutic Targets for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which imbalances in pro- and anti-inflammatory cytokines promote the induction of autoimmunity, inflammation and joint destruction. Methotrexate, the standard disease-modifying anti-rheumatic drug (DMARD), has shown a gradual loss of efficacy in a significant proportion of patients, probably due to the onset of drug resistance, and thus it was hoped that the development of biologics would revolutionise RA management. Even though biologics have improved the therapy of patients refractive to DMARDs, they require parenteral administration and may leave patients open to serious infection and cancer. Therefore, attention has also been focused on inhibitors of mitogen-activated protein kinases (MAPKs), signalling enzymes that play key roles in pathogenic cytokine production, and their downstream effector pathways, in order to create safe and effective oral drugs. This article therefore provides an overview of the structure and function of MAPKs and their role in the pathogenesis of RA as context to describing the advances in the development of specific, druggable MAPK inhibitors. Their potential as therapies in the management of RA is also discussed.

Role of CCRL2 in the pathogenesis of mouse experimental arthritis

Event Abstract Back to Event Role of CCRL2 in the pathogenesis of mouse experimental arthritis ANNALISA DEL PRETE1, 2*, Safiye Gonzalvo-Feo2, Li Wang2, Cristina Mazzon2, Eugenio Scanziani3, Annunciata Vecchi2 and Silvano Sozzani1 1 Department of Molecular and Translational Medicine, Italy 2 Istituto Clinico Humanitas IRCCS, Italy 3 University of Milan, Dept of Veterinary Pathology, Hygiene and Public Health,, Italy Rheumatoid Arthritis (RA) is an autoimmune-mediated disease characterized by chronic inflammation and leukocyte recruitment into the inflamed joints. Chemokines and chemokine receptor activation are known to represent a major component of the effector molecules involved in the onset of RA. CCRL2 [Chemokine (CC motif) receptor-like 2], also known as L-CCR, is a seven transmembrane protein that shows a high homology degree with many members of the CC chemokine receptor family. CCRL2 possesses a non-canonical DRYLIVE motif in the second intracellular loop that makes it to resemble like a nonsignaling chemotactic receptor (e.g. D6, DARC, CCX-CKR). CCRL2 is expressed by LPS-stimulated murine macrophages, neutrophils, mast cells, dendritic cells, glial cells, astrocytes and microglia and is up-regulated in human RA synovial neutrophils. In order to elucidate the role of CCRL2 in RA, CCRL2 KO mice were tested in the model of collagen-induced arthritis. Only few CCRL2 KO mice displayed the pathological signs characteristic of arthritis with reduced leukocyte infiltration, synovial hyperplasia and joint erosions and with a significant reduction in visual scoring and paw thickness. Moreover, CCRL2 KO mice showed a marked delay (about ten days) in the onset of the disease and histological features reminiscent of recent joint damage. Conversely, the level of specific anti-collagen II IgG in the serum was similar in CCRL2 KO and control mice. The mechanisms underling the protection of CCRL2 mice in RA models are currently under investigation and will help to define whether CCRL2 may represent a new therapeutic target for RA. Acknowledgements IMI JU-BeTheCure,contract 115142-2 Keywords: CCRL2, atypical chemokine receptors, Rheumatoid arthritis, leukocyte trafficking, Neutrophils Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: DEL PRETE A, Gonzalvo-Feo S, Wang L, Mazzon C, Scanziani E, Vecchi A and Sozzani S (2013). Role of CCRL2 in the pathogenesis of mouse experimental arthritis. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00722 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. ANNALISA DEL PRETE, Department of Molecular and Translational Medicine, Brescia, Italy, annalisa.delprete@unibs.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers ANNALISA DEL PRETE Safiye Gonzalvo-Feo Li Wang Cristina Mazzon Eugenio Scanziani Annunciata Vecchi Silvano Sozzani Google ANNALISA DEL PRETE Safiye Gonzalvo-Feo Li Wang Cristina Mazzon Eugenio Scanziani Annunciata Vecchi Silvano Sozzani Google Scholar ANNALISA DEL PRETE Safiye Gonzalvo-Feo Li Wang Cristina Mazzon Eugenio Scanziani Annunciata Vecchi Silvano Sozzani PubMed ANNALISA DEL PRETE Safiye Gonzalvo-Feo Li Wang Cristina Mazzon Eugenio Scanziani Annunciata Vecchi Silvano Sozzani Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Phosphoinositide 3-kinase (PI3K) as a New Therapeutic Target for Rheumatoid Arthritis

Dysregulated activation of immune and synovial cells and their reciprocal action play a key role in the pathogenesis of rheumatoid arthritis (RA). Various signal transduction molecules regulate cellular responses and small molecular inhibitors targeting the signal molecules, such as Janus kinase (JAK) and spleen tyrosine kinase (Syk) inhibitors, which have been developed for treating RA. Phosphoinositide 3-kinase (PI3K) is one of the signal molecules, which regulates innate and adaptive immune systems and is over-expressed in RA. PI3Ks phosphorylate phosphoinositide-4,5- bisphosphate (PI-4,5-P2) generates phosphoinositide-3,4,5- triphosphate (PI-3,4,5-P3) at the cell membrane. PI3Ks are divided into class I, II and III. Two catalytic subunits, p110γ and p110δ of PI3K, modulate cellular development, differentiation, proliferation, migration, cytokine synthesis and antibody production in both innate and adaptive immune systems. In RA synovium and synovial fibroblasts, the expression of p110γ and p110δ is increased, and their upregulation results in the abnormal activation of cellular immune responses. In preclinical animal models for RA, genetic deletion of p110γ and p110δ and selective inhibitors decrease the clinical arthritis score, synovial inflammation, cellular infiltration, bone and cartilage erosion and osteoclast activity. There is a synergistic effect for controlling arthritis by dual inhibition of PI3Kγ and PI3Kδ. Through reviewing the function of PI3K in the immune system and the effect of PI3K inhibition in preclinical arthritis animal models, we can expect the PI3K inhibition as a new therapeutic target for treatment of RA.

PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

IntroductionTargeting the CD20 antigen has been a successful therapeutic intervention in the treatment of rheumatoid arthritis (RA). However, in some patients with an inadequate response to anti-CD20 therapy, a persistence of CD20- plasmablasts is noted. The strong expression of CD319 on CD20- plasmablast and plasma cell populations in RA synovium led to the investigation of the potential of CD319 as a therapeutic target.MethodsPDL241, a novel humanized IgG1 monoclonal antibody (mAb) to CD319, was generated and examined for its ability to inhibit immunoglobulin production from plasmablasts and plasma cells generated from peripheral blood mononuclear cells (PBMC) in the presence and absence of RA synovial fibroblasts (RA-SF). The in vivo activity of PDL241 was determined in a human PBMC transfer into NOD scid IL-2 gamma chain knockout (NSG) mouse model. Finally, the ability of PDL241 to ameliorate experimental arthritis was evaluated in a collagen-induced arthritis (CIA) model in rhesus monkeys.ResultsPDL241 bound to plasmablasts and plasma cells but not naïve B cells. Consistent with the binding profile, PDL241 inhibited the production of IgM from in vitro PBMC cultures by the depletion of CD319+ plasmablasts and plasma cells but not B cells. The activity of PDL241 was dependent on an intact Fc portion of the IgG1 and mediated predominantly by natural killer cells. Inhibition of IgM production was also observed in the human PBMC transfer to NSG mouse model. Treatment of rhesus monkeys in a CIA model with PDL241 led to a significant inhibition of anti-collagen IgG and IgM antibodies. A beneficial effect on joint related parameters, including bone remodeling, histopathology, and joint swelling was also observed.ConclusionsThe activity of PDL241 in both in vitro and in vivo models highlights the potential of CD319 as a therapeutic target in RA.

MicroRNA-146a, a Good Biomarker and Potential Therapeutic Target for Rheumatoid Arthritis

<i>MicroRNA-146a</i>, a Good Biomarker and Potential Therapeutic Target for Rheumatoid Arthritis

Epidermal growth factor receptor (EGFR) as a therapeutic target in rheumatoid arthritis

The epidermal growth factor receptor (EGFR) has an important role in the hyperplastic growth of tumor. Similar to tumor growth, rheumatoid arthritis (RA) synovium is hyperplastic, invasive, and expresses EGFR and its ligands. Activation of EGFR signaling is responsible for synovial fibroblast proliferation in RA. Furthermore, in addition to its role in proliferation, EGFR and its ligands can induce cytokine production of synovial fibroblasts during the pathogenesis of RA. Agents that target EGFR have yielded promising results in animal experiments involving RA, pharmacologic modulations targeting EGFR, or its ligands may give rise to new therapeutic approaches for RA. In this review article, we will discuss the biological features of EGFR and summarize recent advances regarding the role of EGFR in the pathogenesis and treatment of RA.

L.F. da Rocha Jr, et al reply

To the Editor: We thank Xie and colleagues for their comments1 on our article2 and for applying expertise to this question of interleukin 22 (IL-22) as a possible therapeutic target in rheumatoid arthritis (RA) and as a promising candidate biomarker. Novel cytokines have emerged recently as contributing to the pathogenesis of autoimmune diseases. Knowledge about the role of IL-22 in autoimmune diseases is increasing and may reveal new therapeutic options for modulation of this cytokine. The role of IL-22 has been investigated in other inflammatory autoimmune diseases, such as psoriasis3 … Address correspondence to Dr. M.G.R. Pitta, UFPE, Centro de Ciências Biológicas, Departamento de Bioquímica, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife PE, 50670-901, Brazil., E-mail: mgrpitta{at}gmail.com

Treat to Target Strategy in Rheumatoid Arthritis: Real Benefits

Treating rheumatoid arthritis (RA) with a goal or “treat to target” strategy is a therapeutic proposal taken from cardiovascular and endocrine literature. It proposes that the therapeutic target in RA should be a state of remission, or an alternative goal could be a low disease activity. Rheumatologists should measure and register disease activity in every clinical visit and if the goal has not been reached, therapeutic adjustments should be made. Current evidence from clinical trials and a meta-analysis supports the notion that this strategy has important clinical benefits in patients with early RA when compared with routine care. It is also described that using protocolized treatment offers greater benefits. Recent data from Dutch cohorts are presented showing its successful implementation. A discussion is offered on the need of more studies in established RA.

Estrategia «treat to target» en la artritis reumatoide: beneficios reales

Treating rheumatoid arthritis (RA) with a goal or «Treat to target» strategy is a therapeutic proposal taken from cardiovascular and endocrine literature. It proposes that the therapeutic target in RA should be a state of remission, or an alternative goal could be a low disease activity. Rheumatologists should measure and register disease activity in every clinical visit and if the goal has not been reached, therapeutic adjustments should be made. Current evidence from clinical trials and a meta-analysis supports the notion that this strategy has important clinical benefits in patients with early RA when compared with routine care. It is also described that using protocolized treatment offers greater benefits. Recent data from Dutch cohorts is presented showing its successful implementation. A discussion is offered on the need of more studies in established RA.

Role of the CCL21 and CCR7 pathways in rheumatoid arthritis angiogenesis

To determine the role of CCL21 and its receptor CCR7 in the pathogenesis of rheumatoid arthritis (RA). Histologic studies were performed to compare the expression of CCR7 and CCL21 in RA synovial tissue. Next, the role of CCL21 and/or CCR7 in angiogenesis was examined using in vitro chemotaxis, tube formation, and in vivo Matrigel plug assays. Finally, the mechanism by which CCL21 mediates angiogenesis was determined by Western blot analysis and endothelial cell chemotaxis and tube formation assays. CCL21, but not CCL19, at concentrations present in the RA joint, induced human microvascular endothelial cell (HMVEC) migration that was mediated through CCR7 ligation. Suppression of the phosphatidylinositol 3-kinase pathway markedly reduced CCL21-induced HMVEC chemotaxis and tube formation; however, suppression of the ERK and JNK pathways had no effect on these processes. Neutralization of either CCL21 in RA synovial fluid or CCR7 in HMVECs significantly reduced the induction of HMVEC migration and/or tube formation by RA synovial fluid. We further demonstrated that CCL21 is angiogenic, by showing its ability to promote blood vessel growth in Matrigel plugs in vivo at concentrations that are present in RA joints. Angiogenesis is dependent on endothelial cell activation, migration, and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. This study identified a novel function of CCL21 as a mediator of RA angiogenesis, supporting CCL21/CCR7 as a therapeutic target in RA.