BioMed Research International: Rheumatology The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Association of Immunological Cell Profiles with Specific Clinical Phenotypes of Scleroderma Disease Thu, 10 Apr 2014 08:20:37 +0000 This study aimed to search the correlation among immunological profiles and clinical phenotypes of scleroderma in well-characterized groups of scleroderma patients, comparing forty-nine scleroderma patients stratified according to specific clinical phenotypes with forty-nine healthy controls. Five immunological cell subpopulations (B, CD4+ and CD8+ T-cells, NK, and monocytes) and their respective stages of apoptosis and activation were analyzed by flow cytometry, in samples of peripheral blood mononuclear cells (PBMCs). Analyses of results were stratified according to disease stage, time since the diagnosis, and visceral damage (pulmonary fibrosis, pulmonary hypertension, and cardiac affliction) and by time of treatment with corticosteroids. An increase in the percentages of monocytes and a decrease in the B cells were mainly related to the disease progression. A general apoptosis decrease was found in all phenotypes studied, except in localized scleroderma. An increase of B and NK cells activation was found in patients diagnosed more than 10 years ago. Specific cell populations like monocytes, NK, and B cells were associated with the type of affected organ. This study shows how, in a heterogeneous disease, proper patient’s stratification according to clinical phenotypes allows finding specific cellular profiles. Our data may lead to improvements in the knowledge of prognosis factors and to aid in the analysis of future specific therapies. José Manuel López-Cacho, Soledad Gallardo, Manuel Posada, Miriam Aguerri, David Calzada, Teodoro Mayayo, María Luisa González-Rodríguez, Antonio María Rabasco, Carlos Lahoz, and Blanca Cárdaba Copyright © 2014 José Manuel López-Cacho et al. All rights reserved. IL-6, IL-8, and IL-10 Are Associated with Hyperferritinemia in Rapidly Progressive Interstitial Lung Disease with Polymyositis/Dermatomyositis Tue, 01 Apr 2014 07:57:13 +0000 Objective. Hyperferritinemia is frequently accompanied by rapidly progressive (RP) interstitial lung disease (ILD) with polymyositis (PM)/dermatomyositis (DM). To clarify the mechanism of RP-ILD with hyperferritinemia, we investigated the associations between serum ferritin levels and various cytokines in patients with PM/DM. Methods. This retrospective study included 38 patients admitted to our hospital with PM/DM. Levels of serum ferritin and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, TNF-α, IFN-α, IFN-γ, and IP-10) were measured. Disease activity was evaluated using the tool proposed by the International Myositis Assessment and Clinical Studies Group. We analyzed the associations between disease activity and levels of serum ferritin and cytokines. Results. The levels of serum ferritin, IL-8, IL-10, IL-18, and TNF-α, were significantly correlated with disease activity. In a multivariate analysis, IL-6 , IL-8 , and IL-10 significantly contributed to serum ferritin levels. The levels of serum ferritin, IL-6, IL-8, and IL-10, were higher in the RP-ILD subset than in the non-ILD subset or the chronic ILD subset. Conclusion. IL-6, IL-8, and IL-10 are significant contributors to hyperferritinemia in PM/DM. The regulation of these cytokines might offer a possible treatment strategy for RP-ILD with PM/DM. Hidenaga Kawasumi, Takahisa Gono, Yasushi Kawaguchi, Hirotaka Kaneko, Yasuhiro Katsumata, Masanori Hanaoka, Sayuri Kataoka, and Hisashi Yamanaka Copyright © 2014 Hidenaga Kawasumi et al. All rights reserved. CD20+ B Cell Depletion in Systemic Autoimmune Diseases: Common Mechanism of Inhibition or Disease-Specific Effect on Humoral Immunity? Thu, 27 Mar 2014 08:54:44 +0000 Autoimmunity remains a complex physiologic deviation, enabled and perpetuated by a variety of interplayers and pathways. Simplistic approaches, targeting either isolated end-effectors of more centrally placed interactors of these mechanisms, are continuously tried in an effort to comprehend and halt cascades with potential disabling and deleterious effects in the affected individuals. This review focuses on theoretical and clinically proved effects of rituximab-induced CD20+ B cell depletion on different systemic autoimmune diseases and extrapolates on pathogenetic mechanisms that may account for different interindividual or interdisease responses. Panagiotis Pateinakis and Athina Pyrpasopoulou Copyright © 2014 Panagiotis Pateinakis and Athina Pyrpasopoulou. All rights reserved. Imbalance between Endothelial Damage and Repair: A Gateway to Cardiovascular Disease in Systemic Lupus Erythematosus Wed, 26 Mar 2014 13:41:28 +0000 Atherosclerosis is accelerated in patients with systemic lupus erythematosus (SLE) and it leads to excessive cardiovascular complications in these patients. Despite the improved awareness of cardiovascular disease and advent of clinical diagnostics, the process of atherogenesis in most patients remains clinically silent until symptoms and signs of cardiovascular complications develop. As evidence has demonstrated that vascular damage is already occurring before clinically overt cardiovascular disease develops in lupus patients, intervention at the preclinical stage of atherogenesis would be plausible. Indeed, endothelial dysfunction, one of the earliest steps of atherogenesis, has been demonstrated to occur in lupus patients even when they are naïve for cardiovascular disease. Currently known “endothelium-toxic” factors including type 1 interferon, proinflammatory cytokines, inflammatory cells, immune complexes, costimulatory molecules, neutrophils extracellular traps, lupus-related autoantibodies, oxidative stress, and dyslipidemia, coupled with the aberrant functions of the endothelial progenitor cells (EPC) which are crucial to vascular repair, likely tip the balance towards endothelial dysfunction and propensity to develop cardiovascular disease in lupus patients. In this review, altered physiology of the endothelium, factors leading to perturbed vascular repair contributed by lupus EPC and the impact of proatherogenic factors on the endothelium which potentially lead to atherosclerosis in lupus patients will be discussed. Anselm Mak and Nien Yee Kow Copyright © 2014 Anselm Mak and Nien Yee Kow. All rights reserved. The Interrelationship between Leukotriene B4 and Leukotriene-A4-Hydrolase in Collagen/Adjuvant-Induced Arthritis in Rats Thu, 20 Feb 2014 07:56:04 +0000 This study aimed to check the involvement of lipid mediator leukotriene (LT) B4 and the activity of LTA4 hydrolase (LTA4H) in the development of arthritis induced in rats by collagen and adjuvant (CIA). High-performance liquid chromatography (HPLC) and enzyme immunoassay (EIA) were used for measurements of LTB4 and LTA4H in plasma, synovial fluid (SF), soluble (SO), and solubilized membrane-bound fraction (MB) from synovial tissue (ST) and peripheral blood mononuclear cells (PBMCs) of CIA-arthritic and CIA-resistant. EIA process is simple, clean, and rapid and offered advantages over HPLC, showing that in SF and MB-PBMCs of CIA-arthritic and CIA-resistant, and in MB-ST of CIA-resistant, LTB4 and LTA4H were altered in parallel and were positively related. In the plasma and SO-ST and SO-PBMCs of CIA-arthritic and CIA-resistant, and in MB-ST of CIA-arthritic, this pattern was not found. The primordial role played by LTA4H in the biosynthesis of LTB4 was confirmed together with the existence of alternative steps that regulate LTB4 without participation of LTA4H. The involvement of compartmentalized and coupled changes of LTB4 and LTA4H in the resistance and development of arthritis in CIA model was demonstrated for the first time. Mariana Trivilin Mendes and Paulo Flavio Silveira Copyright © 2014 Mariana Trivilin Mendes and Paulo Flavio Silveira. All rights reserved. Proteoglycan Aggrecan Conducting T Cell Activation and Apoptosis in a Murine Model of Rheumatoid Arthritis Wed, 29 Jan 2014 00:00:00 +0000 Rheumatoid arthritis (RA) is a systemic autoimmune disease and its targeting of the joints indicates the presence of a candidate autoantigen(s) in synovial joints. Patients with RA show immune responses in their peripheral blood to proteoglycan (PG) aggrecan. One of the most relevant animal models of RA appears to be proteoglycan-induced arthritis (PGIA), and CD4+ T cells seem to play a crucial role in the initiation of the disease. In this review, the role of various T cell epitopes of aggrecan in the induction of autoreactive T cell activation and arthritis is discussed. We pay special attention to two critically important arthritogenic epitopes, 5/4E8 and P135H, found in the G1 and G3 domains of PG aggrecan, respectively, in the induction of autoimmune arthritis. Finally, results obtained with the recently developed PG-specific TCR transgenic mice system showed that altered T cell apoptosis, the balance of activation, and apoptosis of autoreactive T cells are critical factors in the development of autoimmunity. A. Hanyecz, K. Olasz, O. Tarjanyi, P. Nemeth, K. Mikecz, T. T. Glant, and F. Boldizsar Copyright © 2014 A. Hanyecz et al. All rights reserved. Regular Aerobic Training Combined with Range of Motion Exercises in Juvenile Idiopathic Arthritis Wed, 22 Jan 2014 17:03:49 +0000 Objective. To assess the effects of regular aerobic training combined with range of motion (ROM) exercises on aerobic capacity, quality of life, and function in children with juvenile idiopathic arthritis (JIA). Methods. Thirty patients with JIA and 20 healthy age-matched controls (mean age ± SD, 11.3 ± 2.4 versus 11.0 ± 2.3, resp.; ) were included. All patients performed aerobic walking (4 days a week for 8 weeks) and active and passive ROM exercises of involved joints. All patients completed the childhood health assessment questionnaire (CHAQ) and the child health questionnaire. ROM measurements of joints were performed by using universal goniometer. Aerobic capacity was determined by measuring peak oxygen uptake () during an incremental treadmill test. Results. Peak oxygen uptake and exercise duration were significantly lower in JIA group than in controls (32.5 ± 6.6 versus 35.9 ± 5.8 and 13.9 ± 1.9 versus 15.0 ± 2.0, resp.; for both). Eight-week combined exercise program significantly improved exercise parameters of JIA patients (baseline versus postexercise and exercise duration, 32.5 ± 6.6 to 35.3 ± 7.9 and 13.9 ± 1.9 to 16.3 ± 2.2, resp.; for both). Exercise intervention significantly improved CHAQ scores in JIA patients (0.77 ± 0.61 to 0.20 ± 0.28, ). Conclusion. We suggest that regular aerobic exercise combined with ROM exercises may be an important part of treatment in patients with JIA. Mine Doğru Apti, Özgür Kasapçopur, Murat Mengi, Gülnur Öztürk, and Gökhan Metin Copyright © 2014 Mine Doğru Apti et al. All rights reserved. Interleukin 6 and Rheumatoid Arthritis Sun, 12 Jan 2014 11:48:08 +0000 Interleukin-6 (IL-6) is a representative cytokine featuring pleiotropic activity and redundancy. A transient synthesis of IL-6 contributes to host defense against infectious agents and tissue injuries by inducing acute phase reactions and immunological and hematopoietic responses. However, uncontrolled persistent production of IL-6 may lead to the development of several immune-mediated diseases. Rheumatoid arthritis (RA) is a chronic disease with joint and systemic inflammation resulting from immunological abnormalities and it has been found that IL-6 plays a key role in the development of this disease. Clinical trials in various parts of the world of tocilizumab, a humanized anti-IL-6 receptor antibody, have proved its efficacy and tolerable safety either as monotherapy or in combination with disease-modifying antirheumatic drugs. As a result, it is currently used as a first-line biologic for the treatment of moderate-to-severe RA in more than 100 countries. Clarification of the mechanism(s) through which tocilizumab exerts its effect on RA and of the reason(s) why IL-6 is continuously produced in RA can be expected to lead to the best use of this agent for RA patients and aid in investigations into the pathogenesis of RA. Yuji Yoshida and Toshio Tanaka Copyright © 2014 Yuji Yoshida and Toshio Tanaka. All rights reserved. Statins Do Not Influence Long-Term Rituximab Clinical Efficiency in Rheumatoid Arthritis Patients Wed, 08 Jan 2014 13:06:48 +0000 Objective. This longitudinal study aims to determine if statins inhibit the response to rituximab in rheumatoid arthritis (RA) patients. Methods. 41 patients initiating rituximab were included; 17 patients were exposed to the combination of statins and rituximab. The total cholesterol, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were assessed. The clinical response was evaluated using Disease Activity Score (DAS28) and European League against Rheumatism (EULAR) response at 6 and 18 months. Results. A tendency of increasing in DAS28 was observed in statin-exposed group but the correlation was very weak (at 18 months: , ). The statin-exposed status was negatively and very weakly correlated with EULAR response at 6 months (, ) and 18 months (, ). There was a negative correlation between statin-exposed status and inflammatory markers values (ESR and CRP); however, the correlation was very weak. The use of statin did not influence the cardiovascular risk measured by modified Systematic Coronary Risk Evaluation (mSCORE). Conclusions. Long-term significant inhibitory effects of statins on rituximab treatment in RA have not been proved using clinical response scores or biologic markers. Diana Mazilu, Tania Gudu, Ruxandra Ionescu, and Daniela Opris Copyright © 2014 Diana Mazilu et al. All rights reserved. Serum Levels of Three Angiogenic Factors in Systemic Lupus Erythematosus and Their Clinical Significance Mon, 06 Jan 2014 14:06:05 +0000 Our research investigates the serum levels of three angiogenic factors in the AF family, namely, placenta growth factor (PlGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF), in 54 patients with SLE (SLE group) and 28 healthy controls (normal control) through ELISA measurement. And their interrelationships were also systematically analyzed. The SLE patients were then divided into active SLE group and inactive SLE group according to the SLEDAI score. The results show that serum levels of PlGF, bFGF, and VEGF in all SLE group and active SLE group were higher than those in normal controls. Serum levels of PlGF and bFGF in inactive SLE group were higher than those in normal controls. The level of PlGF was positively correlated with VEGF in SLE patients and positive correlation is also shown in bFGF with VEGF. The levels of PlGF and VEGF in SLE patients were positively correlated with both ESR and SLEDAI score. Thus a tentative conclusion can be drawn that the serum levels of the angiogenic factors, for example, PlGF, bFGF, and VEGF, may be relevant in the pathogenesis of SLE, and the concentrations of PlGF and VEGF seem to be the markers of SLE activity. Ling Zhou, Guoyuan Lu, Lei Shen, Linfeng Wang, and Mingjun Wang Copyright © 2014 Ling Zhou et al. All rights reserved. Intensity-Dependent Effect of Treadmill Running on Knee Articular Cartilage in a Rat Model Tue, 31 Dec 2013 17:53:20 +0000 Objective. To understand the changes of femoral cartilage in response to treadmill running with different intensities in the hope of differentiating “moderate” and “strenuous” running in a rat model. Method. A total of 24 male Wistar rats were randomly assigned into groups of sedentary (SED), low-intensity running (LIR), medium-intensity running (MIR), and high-intensity running (HIR). Rats in LIR, MIR, and HIR groups underwent 8 weeks’ treadmill running programs. After sacrificed, femoral condyles were collected to take histomorphometric analysis and immunohistochemistry for collagen II. Results. Gross and histological observation showed osteoarthritic changes in group HIR. In comparison to SED group, there was significant increase in cartilage thickness, number of chondrocytes, and GAG content in groups LIR and MIR. Conversely, decrease in cartilage thickness, chondrocyte number, and GAG content was found in rats of HIR group, without significant difference though. In addition, in comparison to SED group, HIR group exhibited disorganization of collagen fibril and significantly lower content of collagen type II. Conclusion. An intensity-dependent effect was suggested on the articular cartilage. Our results also demonstrated that running with low-to-medium intensity applied in the present study should be regarded as “moderate” running, whereas high-intensity running as “strenuous” running. Guo-Xin Ni, Sheng-Yao Liu, Lei Lei, Zhe Li, Yue-Zhu Zhou, and Li-Qiong Zhan Copyright © 2013 Guo-Xin Ni et al. All rights reserved. Rare Variants in the TREX1 Gene and Susceptibility to Autoimmune Diseases Wed, 09 Oct 2013 09:59:50 +0000 TREX1 (DNase III) is an exonuclease involved in response to oxidative stress and apoptosis. Heterozygous mutations in TREX1 were previously observed in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). We performed a mutational analysis of the TREX1 gene on three autoimmune diseases: SLE (210 patients) and SS (58 patients), to confirm a TREX1 involvement in the Italian population, and systemic sclerosis (SSc, 150 patients) because it shares similarities with SLE (presence of antinuclear antibodies and connective tissue damage). We observed 7 variations; two of these are novel nonsynonymous variants (p.Glu198Lys and p.Met232Val). They were detected in one SS and in one SSc patient, respectively, and in none of the 200 healthy controls typed in this study and of the 1712 published controls. In silico analysis predicts a possibly damaging role on protein function for both variants. The other 5 variations are synonymous and only one of them is novel (p.Pro48Pro). This study contributes to the demonstration that TREX1 is involved in autoimmune diseases and proposes that the spectrum of involved autoimmune diseases can be broader and includes SSc. We do not confirm a role of TREX1 variants in SLE. Nadia Barizzone, Sara Monti, Simona Mellone, Michela Godi, Maurizio Marchini, Raffaella Scorza, Maria G. Danieli, and Sandra D'Alfonso Copyright © 2013 Nadia Barizzone et al. All rights reserved. Behcet’s Disease: Systemic and Ocular Manifestations Thu, 03 Oct 2013 17:43:39 +0000 Aim. The aim of this study was to evaluate if patients with Behcet’s disease who have ocular involvement have a more severe form of this disease as compared to patients with Behcet’s disease alone. Methods. A total of 99 patients were included in the study. 76 patients were used as part of the examined group, and 23 patients formed a control group. Results. The following are the results of examined and control groups, respectively: recurrent oral aphthous ulcers 89.5%, 95.7%; genital ulcers 61.8%, 97.0%; articular involvement 72.4%, 65.2%; vasculitis 81.6%, 60.9%; positive pathergy test 25.0%, 47.8%. Higher frequency of genital ulcerations was noted in control group (). More than two major criteria were met in 100% of the cases. HLA B51 was present in 78.9% of the cases in the examined group and 43.5% of the cases in control group; thus there is significant difference between them (). Visual acuity >0.5 occurred in 76% (examined group). Most frequent ocular manifestations in the examined group were retinal periphlebitis 81.6%, periphlebitis and periarteritis 65%, and serofibrinous uveitis 63.2%. Macular edema as a complication was present in 63.2%. The majority of patients (55.3%) were treated with combined therapy consisting of cyclosporine A and systemic corticosteroids. In 38.2% of patients, laser photocoagulation was used on retinal periphery. Jelena Paovic, Predrag Paovic, and Vojislav Sredovic Copyright © 2013 Jelena Paovic et al. All rights reserved. The Effects of Pterostilbene on Neutrophil Activity in Experimental Model of Arthritis Mon, 30 Sep 2013 08:12:19 +0000 It has been demonstrated that pterostilbene inhibits reactive oxygen species production in neutrophils in vitro. However, little is known about its effects on neutrophils during inflammation in vivo. In this study, the effect of pterostilbene on neutrophil activity was investigated in experimental arthritis model. Lewis rats were injected by a single intradermal injection of heat-killed Mycobacterium butyricum in Freund’s adjuvant to develop arthritis. Another group of arthritic animals received pterostilbene 30 mg/kg, daily, p.o. The number and activity of neutrophils in blood were measured on a weekly basis during the whole experiment. Moreover, the total radical trapping potential in plasma was measured at the end of the experiment. In the pterostilbene treated arthritic group, the treatment significantly lowered the number of neutrophils in blood on days 14 and 21 without significant downregulation of neutrophil oxidative burst. Pterostilbene nonsignificantly increased total radical trapping potential in arthritic animals. These results indicate that the promising effects of pterostilbene on reactive oxygen species operate by different mechanisms in vitro and in the animal model of inflammation. In conclusion, the positive effects of pterostilbene in the model of arthritis may be attributed to regulation of neutrophil number. Tomas Perecko, Katarina Drabikova, Antonin Lojek, Milan Ciz, Silvester Ponist, Katarina Bauerova, Radomir Nosal, Juraj Harmatha, and Viera Jancinova Copyright © 2013 Tomas Perecko et al. All rights reserved. Cancer Morbidity in Rheumatoid Arthritis: Role of Estrogen Metabolites Tue, 17 Sep 2013 18:16:39 +0000 Estrogen metabolites have been implicated in rheumatoid arthritis (RA) and cancer, although the mechanism remains unestablished. Some estrogen metabolites, which are used for the assessment of cancer risk, play an important role in RA. The pathways by which malignancies associated with RA remain elusive. Possible mechanism involves enzymatic or nonenzymatic oxidation of estrogen into catecholestrogen metabolites through semiquinone and quinone redox cycle to produce free radicals that can cause DNA modifications. Modifications of DNA alter its immunogenicity and trigger various immune responses leading to elevated levels of cancer and RA antibodies. However, the role of different estrogen metabolites as a mediator of immune response cannot be ruled out in various immune-related diseases. Wahid Ali Khan and Mohd Wajid Ali Khan Copyright © 2013 Wahid Ali Khan and Mohd Wajid Ali Khan. All rights reserved. Leflunomide as a Corticosteroid-Sparing Agent in Giant Cell Arteritis and Polymyalgia Rheumatica: A Case Series Wed, 11 Sep 2013 08:48:14 +0000 Objectives. Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) affect individuals older than 50 years of age and corticosteroids are the mainstay of treatment. The aim of our study was to explore the role of leflunomide as a corticosteroid-sparing agent in GCA and PMR patients. Methods. Patients with difficult-to-treat GCA and PMR were retrospectively identified in the period from 2010 to 2013. The doses of corticosteroids and CRP values were noted before, after three months, and at the end of the treatment with leflunomide (for patients continuing treatment, censoring date was January 1, 2013). Results. Twenty-three patients were identified (12 with PMR and 11 with GCA). A reduction of 6 mg/dL (CI 95% –10.9–34.2, ) in CRP and 3.7 mg (CI 95% 0.5–7.0, ) in prednisolone dose was observed in the PMR group. In GCA patients, the reduction was 12.4 mg/dL (CI 95% 0.7–25.5, ) in CRP and 6.6 mg (CI 95% 2.8–10.3, ) in prednisolone dose. Conclusion. Leflunomide seems to be effective as a corticosteroid-sparing agent in patients with difficult-to-treat GCA and PMR. Randomized controlled trials are warranted in order to confirm the usefulness of leflunomide in the therapy of GCA/PMR. Andreas P. Diamantopoulos, Helene Hetland, and Geirmund Myklebust Copyright © 2013 Andreas P. Diamantopoulos et al. All rights reserved. Serum Proteome Analysis in Patients with Rheumatoid Arthritis Receiving Therapy with Tocilizumab: An Anti-Interleukin-6 Receptor Antibody Thu, 22 Aug 2013 12:38:33 +0000 Rheumatoid arthritis (RA) is a chronic inflammatory disorder of the synovial membrane that results in the destruction of bone and cartilage in affected joints. Tocilizumab is a biological agent and an anti-interleukin-6 (IL-6) receptor monoclonal antibody that blocks IL-6-mediated inflammatory processes in RA patients. In order to identify novel disease-related proteins and candidate biomarkers, we analyzed the changes in the serum proteome profiles of patients with RA who were treated with tocilizumab. Serum samples were collected from the RA patients before and after tocilizumab treatment. Following immunodepletion of major proteins, the proteins were digested and labeled with isobaric tag, iTRAQ reagent. The proteins were identified and quantified using liquid chromatography-tandem mass spectrometry. Among a total of 311 proteins identified, seven were decreased and 16 were increased by tocilizumab treatment. Although some of the proteins are known to be related to RA, several are currently unknown with respect to their relationship to RA and may be involved in the development of this disease. This study is the first to perform a comparative serum proteomic analysis of RA patients treated with tocilizumab. Our results may contribute to the identification of novel disease-related proteins and enhance the understanding of the pathogenesis of RA. Mitsuaki Yanagida, Mikiko Kawasaki, Maki Fujishiro, Masako Miura, Keigo Ikeda, Kazuhisa Nozawa, Hiroshi Kaneko, Shinji Morimoto, Yoshinari Takasaki, Hideoki Ogawa, Kenji Takamori, and Iwao Sekigawa Copyright © 2013 Mitsuaki Yanagida et al. All rights reserved. Topical Application of Ketoprofen Improves Gait Disturbance in Rat Models of Acute Inflammation Wed, 07 Aug 2013 11:50:15 +0000 Arthritis is a disabling health problem and commonly develops in the late stages of life; the condition is typically accompanied by chronic pain. For the assessment of pain severity and therapeutic effects of analgesic drugs, we recently developed a gait analysis system, which provides an index of pain severity based on walking stride disturbance. Using this system, we evaluated the therapeutic effect of topical nonsteroidal anti-inflammatory drugs (NSAIDs) in rat models of acute inflammation. We found that the gait analysis system is more sensitive than conventional evaluation methods, such as measurement of swelling or analgesia, which indicated the superiority of our system for drug screening. The approach also indicated that ketoprofen is superior to other NSAIDs for providing pain relief because of its higher skin permeability. To the best of our knowledge, this is the first report demonstrating the effectiveness of topical NSAIDs in experimental animal models of acute inflammation. Yosuke Amagai, Akane Tanaka, Akira Matsuda, Kumiko Oida, Kyungsook Jung, Sho Nishikawa, Hyosun Jang, Saori Ishizaka, and Hiroshi Matsuda Copyright © 2013 Yosuke Amagai et al. All rights reserved. In Systemic Sclerosis, Anxiety and Depression Assessed by Hospital Anxiety Depression Scale Are Independently Associated with Disability and Psychological Factors Mon, 29 Jul 2013 16:18:04 +0000 Background. Anxious and depressive symptoms are frequent in Systemic Sclerosis (SSc). Our objective is to assess their prevalence and association with district and global disability and psychological variables. Methods. 119 SSc patients were assessed by Hospital Anxiety Depression Scale (HADS). Clinical depression and anxiety were defined for HADS score cutoff ≥8. Patients were assessed for psychological symptoms (RSES, COPE-NIV), hand (HAMIS, CHFDS, fist closure, and hand opening) and face disability (MHISS, mouth opening), global disability, and fatigue (HAQ, FACIT). Results. Both depression and anxiety in SSc are 36%. Depressive patients with comorbid anxiety have higher HADS-D score than patients with depression only (). HADS-A and -D are positively correlated with global disability, hands and mouth disability, fatigue, self-esteem and avoidance coping strategy, and, only HADS-A, also with social support (). By multiple regression, HADS-D is independently associated with FACIT-F (), RSES (), and MHISS total score (), together explaining 50% of variance. HADS-A is independently associated with RSES (), COPE-NIV SA (), COPE-NIV SS (), FACIT-F (), and MHISS mouth opening (), explaining 41% of variance. Conclusions. In SSc depression and anxiety correlate to local and global disabilities and psychological characteristics. Depressive patients with comorbid anxiety have higher level of depressive symptoms. Angela Del Rosso, Svetlana Mikhaylova, Marco Baccini, Ilaria Lupi, Marco Matucci Cerinic, and Susanna Maddali Bongi Copyright © 2013 Angela Del Rosso et al. All rights reserved. IL-17 in the Rheumatologist’s Line of Sight Thu, 25 Jul 2013 13:19:26 +0000 Over the past decades, the identification of several new cytokines, including interleukin (IL)-17 and IL-23, and of new T helper cell subsets, including Th17 cells, has changed the vision of immunological processes. The IL-17/Th17 pathway plays a critical role during the development of inflammation and autoimmunity, and targeting this pathway has become an attractive strategy for a number of diseases. This review aims to describe the effects of IL-17 in the joint and its roles in the development of autoimmune and inflammatory arthritis. Furthermore, biotherapies targeting directly or indirectly IL-17 in inflammatory rheumatisms will be developed. Marie-Elise Truchetet, M. Djavad Mossalayi, and Katia Boniface Copyright © 2013 Marie-Elise Truchetet et al. All rights reserved. From the Mediterranean to the Sea of Japan: The Transcontinental Odyssey of Autoinflammatory Diseases Tue, 23 Jul 2013 09:04:30 +0000 Autoinflammatory diseases are comprehensively caused by aberrant production of proinflammatory cytokines and are revealed by cyclically and spontaneously occurring inflammatory events. Over the last decade, there has been a revolution in the understanding of periodic fever syndromes, cryopyrinopathies, and skin disorders with pyogenic, granulomatous, or dystrophic features, which have been recognized across different countries spanning from the Mediterranean basin to the Japanese archipelago. Many children and adults with autoinflammatory diseases continue to elude diagnosis, and the diagnostic delay of many years puts these patients at risk of long-term severe complications, such as amyloidosis. Any hint of suspicion of autoinflammatory disease thus needs to be highlighted in various medical specialties, and this review examines their frequencies around the world, trying to match them with geographic location, ethnic and genetic data, in an attempt to realize a geoepidemiologic map for most of these conditions. Donato Rigante, Bruno Frediani, Mauro Galeazzi, and Luca Cantarini Copyright © 2013 Donato Rigante et al. All rights reserved. Pain Coping Strategies for Children with Arthritis Wed, 17 Jul 2013 11:02:33 +0000 Objective. To present information on pain management strategies for children with juvenile idiopathic arthritis (JIA). Methods. The second author developed a manual to present pain management strategies to children. The use of the manual was pilot-tested with a group of children with JIA. Telephone interviews were used to gather information on implementation of pain management strategies. Results. Children were able to implement the pain management strategies. Children reported a reduction in daily pain experiences related to JIA when using the pain management strategies. Conclusions. The pain management strategies were successful as an adjunctive intervention for short-term pain management. Pain symptoms related to JIA can severely limit children's participation in daily activities. Further study on how children use pain management strategies to improve their involvement in daily activities will provide useful clinical information. Kim J. Rosenzweig and Laura Nabors Copyright © 2013 Kim J. Rosenzweig and Laura Nabors. All rights reserved. Evaluation of Kinesiophobia and Its Correlations with Pain and Fatigue in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type Sun, 14 Jul 2013 16:26:54 +0000 Ehlers-Danlos syndrome hypermobility type a. k. a. joint hypermobility syndrome (JHS/EDS-HT) is a hereditary musculoskeletal disorder associating generalized joint hypermobility with chronic pain. Anecdotal reports suggest a prominent role for kinesiophobia in disease manifestations, but no study has systematically addressed this point. Objective. To investigate the impact of kinesiophobia and its relationship with pain, fatigue, and quality of life in JHS/EDS-HT. Design. Cross-sectional study. Subjects/Patients. 42 patients (40 female and 2 male) with JHS/EDS-HT diagnosis following standardized diagnostic criteria were selected. Methods. Disease features were analyzed by means of specific questionnaires and scales evaluating kinesiophobia, pain, fatigue, and quality of life. The relationships among variables were investigated using the Spearman bivariate analysis. Results. Kinesiophobia resulted predominantly in the patients’ sample. The values of kinesiophobia did not correlate with intensity of pain, quality of life, and (or) the single component of fatigue. A strong correlation was discovered between kinesiophobia and general severity of fatigue. Conclusions. In JHS/EDS-HT, the onset of pain-avoiding strategies is related to the presence of pain but not to its intensity. The clear-cut correlation between kinesiophobia and severity of fatigue suggests a direct link between musculoskeletal pain and fatigue. In JHS/EDS-HT, the underlying mechanism is likely to be facilitated by primary disease characteristics, including hypotonia. Claudia Celletti, Marco Castori, Giuseppe La Torre, and Filippo Camerota Copyright © 2013 Claudia Celletti et al. All rights reserved. Biological Activities of Phosphocitrate: A Potential Meniscal Protective Agent Thu, 11 Jul 2013 09:52:11 +0000 Phosphocitrate (PC) inhibited meniscal calcification and the development of calcium crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the mechanisms remain elusive. This study sought to examine the biological activities of PC in the absence of calcium crystals and test the hypothesis that PC is potentially a meniscal protective agent. We found that PC downregulated the expression of many genes classified in cell proliferation, ossification, prostaglandin metabolic process, and wound healing, including bloom syndrome RecQ helicase-like, cell division cycle 7 homolog, cell division cycle 25 homolog C, ankylosis progressive homolog, prostaglandin-endoperoxide synthases-1/cyclooxygenase-1, and plasminogen activator urokinase receptor. In contrast, PC stimulated the expression of many genes classified in fibroblast growth factor receptor signaling pathway, collagen fibril organization, and extracellular structure organization, including fibroblast growth factor 7, collagen type I, alpha 1, and collagen type XI, alpha 1. Consistent with its effect on the expression of genes classified in cell proliferation, collagen fibril organization, and ossification, PC inhibited the proliferation of OA meniscal cells and meniscal cell-mediated calcification while stimulating the production of collagens. These findings indicate that PC is potentially a meniscal-protective agent and a disease-modifying drug for arthritis associated with severe meniscal degeneration. Yubo Sun, Andrea Roberts, David R. Mauerhan, Andrew R. Sun, H. James Norton, and Edward N. Hanley Jr. Copyright © 2013 Yubo Sun et al. All rights reserved. Joint Involvement in Primary Sjögren’s Syndrome: An Ultrasound “Target Area Approach to Arthritis” Mon, 08 Jul 2013 08:52:23 +0000 Objective. To characterize the ultrasound (US) pattern of joint involvement in primary Sjögren’s syndrome (pSS). Methods. Seventeen patients with pSS, 18 with secondary Sjögren’s syndrome (sSS), and 17 healthy controls underwent US examinations of various articular regions. Synovitis (synovial hypertrophy/joint effusion), power Doppler (PD) signals, and erosions were assessed. Results. In patients with pSS, synovitis was found in the metacarpophalangeal joints (MCP, 76%), wrists (76%), and knees (76%), while the proximal interphalangeal joints, elbows, and ankles were mostly unscathed. Intra-articular PD signals were occasionally detected in wrists (12%), elbows (6%), and knees (6%). Erosions were evident in the wrists of three (18%) patients with pSS, one of these also having anti-cyclic citrullinated peptide (anti-CCP) antibodies. While US synovitis does not discriminate between sSS and pSS, demonstration of bone erosions in the 2nd MCP joints showed 28.8% sensitivity and 100% specificity for diagnosing sSS; in comparison, these figures were 72.2 and 94.1% for circulating anti-CCP antibodies. Conclusions. In pSS, the pattern of joint involvement by US is polyarticular, bilateral, and symmetrical. Synovitis is the US sign most commonly found in patients with pSS, especially in MCP joints, wrists, and knees, and bone erosions also may occur. Luis M. Amezcua-Guerra, Fritz Hofmann, Angelica Vargas, Pedro Rodriguez-Henriquez, Carla Solano, Cristina Hernández-Díaz, Diana Castillo-Martinez, Lucio Ventura-Ríos, Marwin Gutiérrez, and Carlos Pineda Copyright © 2013 Luis M. Amezcua-Guerra et al. All rights reserved. A Replication Study from Chinese Supports Association between Lupus-Risk Allele in TNFSF4 and Renal Disorder Mon, 01 Jul 2013 11:25:19 +0000 A recent phenotypic association study of genetic susceptibility loci in SLE suggested that TNFSF4 gene might be useful to predict renal disorder in lupus patients. To replicate the association, two single-nucleotide polymorphisms (SNPs: rs2205960 and rs10489265) were genotyped in 814 SLE patients. Correlations between genotypes and TNFSF4 expression were determined. The stainings of TNFSF4 in renal biopsy specimens were checked by immunohistochemistry. The SNPs of TNFSF4 were associated with renal involvement in lupus patients from the Chinese population ( values for rs2205960 and rs10489265 were 0.014 and 0.005 in additive model, resp.). An association between risk genotypes and low C3 levels was also observed (). Functional prediction suggested that rs2205960 had a regulatory feature. The risk alleles seemingly correlated with lower TNFSF4 expression. Strong TNFSF4 expression was detected in lymph nodes and “apparently normal” paratumor renal biopsy but not in renal biopsies from lupus nephritis. In genome-wide expression data, TNFSF4 was also observed to be downregulated in LN in both glomeruli and tubulointerstitium from kidney biopsies. However, the associations were marginally significant. Our data firstly replicated the association of TNFSF4 with renal disorder in SLE patients in the Chinese population, which supported that TNFSF4 may act as a marker of lupus nephritis. The detailed mechanisms of its role in pathogenesis will still be further needed. Xu-jie Zhou, Fa-juan Cheng, Yuan-yuan Qi, Ming-hui Zhao, and Hong Zhang Copyright © 2013 Xu-jie Zhou et al. All rights reserved. Is Neutrophil/Lymphocyte Ratio Associated with Subclinical Inflammation and Amyloidosis in Patients with Familial Mediterranean Fever? Thu, 20 Jun 2013 08:16:10 +0000 Background. The purpose of the present study is to determine the association between neutrophil/lymphocyte ratio and both subclinical inflammation and amyloidosis in familial Mediterranean fever. Methods. Ninety-four patients with familial Mediterranean fever and 60 healthy volunteers were included in the study. Of the patients, 12 had familial Mediterranean fever related amyloidosis. The neutrophil/lymphocyte ratio of the patients was obtained from the hematology laboratory archive. Results. The neutrophil/lymphocyte ratio was significantly higher among persons with familial Mediterranean fever compared to healthy individuals (). Also, neutrophil/lymphocyte ratio was significantly higher in patients with amyloidosis than in amyloidosis-free patients (). Since NLR was evaluated in nonamyloid and amyloid stages of the same patient population (type 1 phenotype), we obtained significant statistical differences ( versus , , resp.). With the cutoff value of neutrophil/lymphocyte ratio >2.21 and AUC = 0.734 (), it was a reliable marker in predicting the development of amyloidosis. Conclusion. The neutrophil/lymphocyte ratio, an emerging marker of inflammation, is higher in patients with familial Mediterranean fever in attack-free periods. The neutrophil/lymphocyte ratio may be a useful marker in predicting the development of amyloidosis. Ali Ugur Uslu, Koksal Deveci, Serdal Korkmaz, Bahattin Aydin, Soner Senel, Enver Sancakdar, and Mehmet Sencan Copyright © 2013 Ali Ugur Uslu et al. All rights reserved. Treatment with Anti-Interleukin 23 Antibody Ameliorates Disease in Lupus-Prone Mice Thu, 06 Jun 2013 10:30:49 +0000 Interleukin 23 receptor expressing IL-17 producing T cells have been shown to be important in the development of murine lupus. The usefulness of IL-23 inhibition in ameliorating lupus nephritis is unknown. We hypothesized that inhibition of IL-23 will ameliorate nephritis in lupus-prone mice. To this end, we treated MRL/lpr lupus-prone mice for 6 weeks with a rat anti-IL-23p19 antibody, which resulted in delaying the onset of nephritis without affecting the production of anti-dsDNA antibodies. The effect of the treatment was hampered by the production of murine anti-rat IgG antibodies. The amelioration of murine lupus by IL-23 inhibition strengthens the rationale for targeting IL-23 in patients with systemic lupus erythematosus. Vasileios C. Kyttaris, Ourania Kampagianni, and George C. Tsokos Copyright © 2013 Vasileios C. Kyttaris et al. All rights reserved. Phosphocitrate Is Potentially a Disease-Modifying Drug for Noncrystal-Associated Osteoarthritis Thu, 21 Feb 2013 08:59:16 +0000 Phosphocitrate (PC), a calcification inhibitor, inhibits the development of crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms underlying its disease-modifying effect remain elusive. This study sought to test the hypothesis that PC has calcium crystal-independent biological activities which are, at least in part, responsible for its disease-modifying activity. We found that PC inhibited the proliferation of OA fibroblast-like synoviocytes in the absence of calcium crystals. Consistent with its effect on cell proliferation, PC downregulated the expression of numerous genes classified in cell proliferation. PC also downregulated the expression of many genes classified in angiogenesis and inflammatory response including prostaglandin-endoperoxide synthase 2, interleukin-1 receptor, type I, and chemokine (C-C motif) ligand 2. In contrast, PC upregulated the expression of many genes classified in musculoskeletal tissue development, including aggrecan, type I collagen, and insulin-like growth factor binding protein 5. These findings suggest that PC is not only a promising disease-modifying drug for crystal-associated OA but also for noncrystal-associated OA. Yubo Sun, David R. Mauerhan, Atiya M. Franklin, James Norton, Edward N. Hanley Jr., and Helen E. Gruber Copyright © 2013 Yubo Sun et al. All rights reserved. Healthcare Utilization and Costs of Systemic Lupus Erythematosus in Medicaid Wed, 05 Dec 2012 08:16:04 +0000 Objective. Healthcare utilization and costs associated with systemic lupus erythematosus (SLE) in a US Medicaid population were examined. Methods. Patients ≥ 18 years old with SLE diagnosis (ICD-9-CM 710.0x) were extracted from a large Medicaid database 2002–2009. Index date was date of the first SLE diagnosis. Patients with and without SLE were matched. All patients had a variable length of followup with a minimum of 12 months. Annualized healthcare utilization and costs associated with SLE and costs of SLE flares were assessed during the followup period. Multivariate regressions were conducted to estimate incremental healthcare utilization and costs associated with SLE. Results. A total of 14,777 SLE patients met the study criteria, and 14,262 were matched to non-SLE patients. SLE patients had significantly higher healthcare utilization per year than their matched controls. The estimated incremental annual cost associated with SLE was $10,984, with the highest increase in inpatient costs (). Cost per flare was $11,716 for severe flares, $562 for moderate flares, and $129 for mild flares. Annual total costs for patients with severe flares were $49,754. Conclusions. SLE patients had significantly higher healthcare resource utilization and costs than non-SLE patients. Patients with severe flares had the highest costs. Hong J. Kan, Xue Song, Barbara H. Johnson, Benno Bechtel, Donna O'Sullivan, and Charles T. Molta Copyright © 2013 Hong J. Kan et al. All rights reserved. Dermal Ultrastructure in Low Beighton Score Members of 17 Families with Hypermobile-Type Ehlers-Danlos Syndrome Wed, 03 Oct 2012 08:06:46 +0000 The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH. Trinh Hermanns-Lê, Marie-Annick Reginster, Claudine Piérard-Franchimont, Philippe Delvenne, Gérald E. Piérard, and Daniel Manicourt Copyright © 2012 Trinh Hermanns-Lê et al. All rights reserved. The Effect of Bradykinin B2 Receptor Polymorphisms on the Susceptibility and Severity of Osteoarthritis in a Chinese Cohort Wed, 03 Oct 2012 08:04:33 +0000 Background. The B2-bradykinin receptor (BDKRB2) has been reported to associate with onset and development of Osteoarthritis (OA); however, the role of BDKRB2 genetic polymorphisms in OA remains unknown. Method. A total of 245 patients with primary knee OA and 264 healthy volunteer were recruited. BDKRB2 gene polymorphisms, −58T/C and +9/−9 bp polymorphisms, were genotyped. Results. The genotype distributions and allele frequencies of +9/−9 bp polymorphisms significantly differed between OA and control subjects. Logistic regression analysis showed carriers with −9/−9 genotype had a significantly increased risk for knee OA compared with the +9/+9 genotype (adjusted , ). The OR for −9 allele carriage was significantly higher than +9 allele carriage (adjusted , ). The +9/−9 bp polymorphisms also determined the OA radiographic severity. The presence of −9 bp was associated with severer OA. The −58T/C polymorphisms did not affect OA risk and severity. Conclusion. The +9/−9 bp polymorphisms of BDKRB2 gene may be used as a genetic marker for the susceptibility and severity of OA. Shuo Chen, Yong Zhou, Jun Li, Le-Qun Shan, and Qing-Yu Fan Copyright © 2012 Shuo Chen et al. All rights reserved.