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ID PMID Title PublicationDate abstract
21333822 [Gastric sarcoidosis revealed by cutaneous follicular sarcoidosis]. 2011 Feb BACKGROUND: Sarcoidosis is a disease well known to dermatologists because of the frequency of cutaneous involvement. Routine screening is performed for involvement of the lungs, lymph nodes, eyes, liver and heart. However, gastro-intestinal sarcoidosis is both rare and frequently silent, and it thus often goes undiagnosed. We report the case of a Caribbean woman whose cutaneous lesions allowed a posteriori diagnosis to be made of gastric sarcoidosis. PATIENTS AND METHODS: A 45-year-old Caribbean woman consulted for diffuse erythematous or hypochromic, squamous and follicular micropapular lesions associated with inflammatory rheumatoid arthritis. Clinical examination and laboratory data led to a diagnosis of cutaneous sarcoidosis. It was later discovered that she had presented epigastric pains a few months earlier and that she had undergone gastroscopy and gastric biopsies. Histopathology had revealed non-caseating epithelioid-cell granulomas with giant cells, but no further exams were performed. The patient was diagnosed a posteriori with cutaneous-articular and gastric sarcoidosis. DISCUSSION: In contrast with hepatic involvement, which is frequent and well-known, sarcoidosis affecting the gastro-intestinal tract is rare and poorly known. This form of the disease is frequently clinically silent and is thus probably under-reported. The stomach is the site most frequently affected. Gastric sarcoidosis is seen in some 10% of patients with systemic sarcoidosis and is symptomatic in less than 1% of cases. It is important to diagnose these forms since they may be associated with a certain degree of morbidity.
20123076 The role of HMGB1 in the pathogenesis of rheumatic disease. 2010 Jan HMGB1 is a ubiquitous nuclear protein that can be released by any damaged cell or by activated macrophages and certain other cell types. HMGB1 has been successfully therapeutically targeted in multiple preclinical models of infectious and sterile diseases including arthritis. Extracellular HMGB1 mediates inflammation via induction of cytokine and metalloproteinase production and recruitment and activation of dendritic cells needed for priming of naïve T helper type 1 lymphocytes. HMGB1 can bind endogenous molecules such as IL-1beta and nucleosomes and exogenous agents like endotoxin and microbial DNA. These complexes synergistically increase the capacity for activation of adaptive and innate immunity. HMGB1-nucleosome complexes induce autoantibody formation against double-stranded DNA and nucleosomes, which does not occur if HMGB1 is absent. These antibodies are central in the pathogenesis of systemic lupus erythematosus and patients with active disease have both increased HMGB1 and HMGB1-nucleosome levels in circulation. Furthermore, HMGB1 is strongly bipolar charged, enabling cell membrane passage and intracellular transport of complexed molecules including DNA. Rheumatoid arthritis patients have excessive extracellular HMGB1 levels in joints and serum. The HMGB1 release is caused by cytokines, activated complement and hypoxia. The most prominent HMGB1 protein and mRNA expression arthritis is present in pannus regions, where synovial tissue invades articular cartilage and bone. HMGB1 promotes the activity of proteolytic enzymes, and osteoclasts need HMGB1 for functional maturation. Neutralizing HMGB1 therapy in preclinical models of arthritis confers striking protection against structural damage. This review summarizes selected aspects of HMGB1 biology relevant for induction and propagation of some autoimmune conditions.
22491168 Calcium alginate cross-linked polymeric microbeads for oral sustained drug delivery in art 2010 Apr After the successful optimization and development of a drug entity, design of dosage form then plays an important role. Hence, research continuously keeps on searching for ways to deliver drugs over an extended period of time. With aceclofenac, a novel NSAID used in the treatment of rheumatoid arthritis, frequency of administration may cause certain GI-adverse effects. The objective of the present research work was to develop a microparticulate oral sustained release dosage form, to reduce dosing frequency, to eliminate the dose related adverse effects and to ultimately improve compliance in the pharmacotherapy of arthritis. The microbeads were prepared by an ionotropic external gelation technique, by using sodium alginate as the hydrophilic carrier and calcium chloride as the cross-linking agent. The shape and surface characteristics were determined by scanning electron microscopy (SEM). Particle size distribution was determined by an optical microscope. The physical state of the drug in the formulation was determined by differential scanning calorimetry (DSC). While increasing the concentration of sodium alginate dispersion increased flow properties, mean particle size, swelling ratio and drug entrapment efficiency. The mean particle sizes of drug-loaded microbeads were found to be in the range 596.45 ± 1.04 to 880.10 ± 0.13 μm. The drug entrapment efficiency was obtained in the range of 63.24-98.90% (w/v). The release of drug from the microbeads at pH 1.2 is negligible. Under neutral conditions, the beads will swell and the drug release depends on swelling and the erosion process resulting in an optimum level of drug released in a sustained manner which exhibits zero-order kinetics.
20490802 Clinical efficacy of the SmartPlug™ in the treatment of primary Sjogren's syndrome with 2011 Dec To evaluate the efficacy of a thermo-sensitive punctum plug, (SmartPlug™) in Primary Sjogren's Syndrome (pSS) patients with dry eyes, whose symptoms persist despite preservative-free artificial tear treatment. In this study, 22 Primary Sjögren's Syndrome (pSS), as defined by American-European Consensus Group Classification Criteria. All patients being followed up by Ege University Departments of Rheumatology and Ophthalmology. The patients had positive Schirmer test results (<5 mm without anesthesia). SmartPlug™ (Medennium, Irvine, California, USA) was inserted into the inferior lacrimal canaliculi of both eyes. Visual acuity measurements, Schirmer I test measurements, lissamine green staining scores, and tear-film breakup times (BUT) were noted before plug insertion and at the 1st, 6th, and 12th months following the procedure. Minimum follow-up period was 6 months for 19 patients and 12 months for 16 patients. Significant improvements were seen in the Schirmer I test scores (before insertion: 1.98 ± 2.67; 1st month: 5.68 ± 6.69; 6th month: 5.35 ± 5.38; 12th month 6.43 ± 5.14 P = 0.006), tear-film BUT in seconds (before insertion: 4.64 ± 3.7; 1st month: 5.80 ± 2.36; 6th month: 7.53 ± 2.92; 12th month 7.50 ± 2.52, P < 0.0001), respectively. Thermodynamic punctum plug insertion only in inferior canaliculus is a simple, effective, and comfortable option for treatment of severe aqueous tear deficiency that cannot be controlled using preservative-free tears.
19250228 The MRI view of synovitis and tenosynovitis in inflammatory arthritis: implications for di 2009 Feb MRI scanning is the current gold standard modality for imaging synovitis and tenosynovitis in patients with inflammatory arthritis. Inflamed synovial membrane within the joints and investing tendon sheaths appears thickened on T1-weighted sequences and enhances postcontrast. On T2-weighted sequences, synovitis and synovial effusions typically show a high signal. Studies have shown correlations between the degree of inflammation and vascularity of synovium obtained at biopsy and postcontrast enhancement on matching dynamic MRI scans. Scoring systems have been devised that are based on quantifying synovial membrane thickening and signal intensity on static postcontrast scans and have been validated in multireader settings. Moderate to high reliability has been demonstrated with trained readers and quantification of synovitis in this way is being used increasingly as an outcome measure in clinical trials to assess response to therapy. MRI-observed synovitis is almost invariable in those with active rheumatoid arthritis, but recent studies have also demonstrated its presence in patients in clinical remission, emphasizing the sensitivity of this technique and the importance of subclinical joint inflammation. MRI-observed synovitis has been validated against other imaging modalities, including power Doppler ultrasound, and has also been investigated in normal subjects (where mild enhancement can rarely occur). Studies over 1-2 years have suggested that MRI synovial membrane volume and postcontrast enhancement on dynamic imaging can predict the development of erosions. In the long term, an overall score of inflammation incorporating synovitis, tenosynovitis, and bone edema may be a more useful MRI predictor of aggressive erosive disease.
19180475 Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase-positive dendritic cells i 2009 Feb OBJECTIVE: We have demonstrated previously that dendritic cells (DCs) modified with immunosuppressive cytokines, and exosomes derived from DCs can suppress the onset of murine collagen-induced arthritis (CIA) and reduce the severity of established arthritis. Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme that is important for immune regulation and tolerance maintenance. DCs expressing functional IDO can inhibit T cells by depleting them of essential tryptophan and/or by producing toxic metabolites, as well as by generating Treg cells. This study was undertaken to examine the immunosuppressive effects of bone marrow (BM)-derived DCs genetically modified to express IDO, and of exosomes derived from IDO-positive DCs. METHODS: BM-derived DCs were adenovirally transduced with IDO or CTLA-4Ig (an inducer of IDO), and the resulting DCs and exosomes were tested for their immunosuppressive ability in the CIA and delayed-type hypersensitivity (DTH) murine models. RESULTS: Both DCs and exosomes derived from DCs overexpressing IDO had an antiinflammatory effect in CIA and DTH murine models. The suppressive effects were partially dependent on B7 costimulatory molecules. In addition, gene transfer of CTLA-4Ig to DCs resulted in induction of IDO in the DCs and in exosomes able to reduce inflammation in an IDO-dependent manner. CONCLUSION: These results demonstrate that both IDO-expressing DCs and DC-derived exosomes are immunosuppressive and antiinflammatory, and are able to reverse established arthritis. Therefore, exosomes from IDO-positive DCs may represent a novel therapy for rheumatoid arthritis.
19565504 Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate dise 2009 Jul OBJECTIVE: To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent-onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures. METHODS: Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second-line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG-U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance-weighted discrimination normalization. RESULTS: Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor beta-inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets. CONCLUSION: Gene expression signatures in PBMCs from patients with recent-onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.
19765818 The treatment of established murine collagen-induced arthritis with a TNFR1-selective anta 2009 Dec Blocking the binding of TNF-alpha to TNF receptor subtype-1 (TNFR1) is an important strategy for the treatment of rheumatoid arthritis (RA). We recently succeeded in developing a TNFR1-selective antagonistic TNF mutant, R1antTNF. Here, we report the anti-inflammatory effects of R1antTNF in a murine collagen-induced arthritis model. To improve the in vivo stability of R1antTNF, we first engineered PEG (polyethylene glycol)-modified R1antTNF (PEG-R1antTNF). In prophylactic protocols, PEG-R1antTNF clearly improved the incidence, and the clinical score of arthritis due to its long plasma half-life. Although, the effect of PEG-R1antTNF on the incidence and production of IL1-beta was less than that of the existing TNF-blocking drug Etanercept, its effect on severity was almost as marked as Etanercept. Interestingly, in therapeutic protocols, PEG-R1antTNF showed greater therapeutic effect than Etanercept. These data suggest that the anti-inflammatory effects of PEG-R1antTNF depend on the stage of arthritis. Recently, there has been much concern over the reactivation of viral infection caused by TNF blockade. Unlike Etanercept, PEG-R1antTNF did not reactivate viral infection. Together, these results indicate that selective inhibition of TNF/TNFR1 could be effective in treating RA and that PEG-R1antTNF could serve as a promising anti-inflammatory drug for this purpose.
20164680 TGF-beta-treated antigen presenting cells suppress collagen- induced arthritis through the 2010 Mar 31 Collagen-induced arthritis (CIA) is mediated by self-reactive CD4(+) T cells that produce inflammatory cytokines. TGF-beta(2)-treated tolerogenic antigen-presenting cells (Tol-APCs) are known to induce tolerance in various autoimmune diseases. In this study, we investigated whether collagen-specific Tol-APCs could induce suppression of CIA. We observed that Tol-APCs could suppress the development and severity of CIA and delay the onset of CIA. Treatment of Tol-APCs reduced the number of IFN-gamma- and IL-17-producing CD4(+) T cells and increased IL-4- and IL-5-producing CD4(+) T cells upon collagen antigen stimulation in vitro. The suppression of CIA conferred by Tol-APCs correlated with their ability to selectively induce IL-10 production. We also observed that treatment of Tol-APCs inhibited not only cellular immune responses but also humoral immune responses in the process of CIA. Our results suggest that in vitro-generated Tol-APCs have potential therapeutic value for the treatment of rheumatoid arthritis as well as other autoimmune diseases.
19604441 Chronic arthritis directly induces quantitative and qualitative bone disturbances leading 2009 May OBJECTIVES: Rheumatoid arthritis (RA) is associated with an increased risk of fragility fractures. In RA patients, the direct effect of inflammation on bone is difficult to study because their skeleton is also affected by medication with corticosteroids and other drugs as well as aging and menopause, which contribute to bone fragility. This study used an animal model of chronic arthritis to evaluate the direct impact of chronic inflammation on biomechanical properties and structure of bone. METHODS: In the SKG mouse chronic arthritis model three point bending tests were performed on femoral bones and compression tests on vertebral bodies. Collagen structure was analysed using second-harmonic generation (SHG) imaging with a two-photon microscope, ultramorphology by scanning electron microscopy (SEM) coupled with energy dispersive x-ray spectroscopy (EDS) and bone density using water pycnometer. RESULTS: Arthritic bones had poor biomechanical quality compared to control bones. SHG, SEM and pycnometry disclosed variable signs of impaired collagen organization, poor trabecular architecture and low bone density. CONCLUSION: Present data demonstrate for the first time that chronic inflammation per se, without confounding influence of drugs and aging, leads to impairment of bone biomechanics in terms of stiffness, ductility and ultimate strength (fracture).
20490959 Prednisolone-loaded PLGA microspheres. in vitro characterization and in vivo application i 2010 Jun This study aimed at preparation of a sustained-release steroidal treatment for chronic inflammatory conditions, such as rheumatoid arthritis. To achieve such a goal, biodegradable poly-lactide-co-glycolide prednisolone-loaded microspheres were prepared using o/w emulsion solvent evaporation method. Formulation parameters were adjusted so as to optimize the microsphere characteristics. The prepared microspheres exhibited smooth and intact surfaces, with average size range not exceeding 65 microm. The encapsulation efficiency percent of most microsphere formulations fell within the range of 25-68%. Drug release from these microspheres took place over 4 weeks, with near-to-zero-order patterns. Two successful formulations were chosen for the treatment of unilateral arthritis, induced in mice using Freund's complete adjuvant (FCA). Inflammatory signs of adjuvant arthritis included severe swelling of the FCA-injected limbs, in addition to many histopathological lesions. These included inflammatory cell infiltration, synovial hyperplasia, cartilage, and bone erosion. Parenteral administration of the selected formulae dramatically reduced the swelling of the FCA-injected limbs. In addition, histological examination revealed that the microsphere treatment protocol efficiently protected cartilages and bones of mice, injected with FCA initial and booster doses, from erosion. These results could not be achieved by a single prednisolone dose of 5 mg/kg.
20931654 Monoclonal anti-CD8 therapy induces disease amelioration in the K/BxN mouse model of spont 2010 Oct OBJECTIVE: CD8+ T cells are part of the T cell pool infiltrating the synovium in rheumatoid arthritis (RA). However, their role in the pathogenesis of RA has not been fully delineated. Using the K/BxN mouse model of spontaneous chronic arthritis, which shares many similarities with RA, we studied the potential of CD8+ T cell depletion with monoclonal antibodies (mAb) to stop and reverse the progression of experimental arthritis. METHODS: CD8+ T cells from the blood and articular infiltrate of K/BxN mice were characterized for cell surface phenotypic markers and for cytokine production. Additionally, mice were treated with specific anti-CD8 mAb (YTS105 and YTS169.4), with and without thymectomy. RESULTS: CD8+ T cells from the peripheral blood and joints of K/BxN mice were mainly CD69+ and CD62L-CD27+ T cells expressing proinflammatory cytokines (interferon-γ [IFNγ], tumor necrosis factor α [TNFα], interleukin-17a [IL-17A], and IL-4), and granzyme B. In mice receiving anti-CD8 mAb, the arthritis score improved 5 days after treatment. Recovery of the CD8+ T cells was associated with a new increase in the arthritis score after 20 days. In thymectomized and anti-CD8 mAb-treated mice, the arthritis score improved permanently. Histologic analysis showed an absence of inflammatory infiltrate in the anti-CD8 mAb-treated mice. In anti-CD8 mAb-treated mice, the serologic levels of TNFα, IFNγ, IL-6, and IL-5 normalized. The levels of the disease-related anti-glucose-6-phosphate isomerase antibodies did not change. CONCLUSION: These results indicate that synovial activated effector CD8+ T cells locally synthesize proinflammatory cytokines (IFNγ, TNFα, IL-17, IL-6) and granzyme B in the arthritic joint, thus playing a pivotal role in maintaining chronic synovitis in the K/BxN mouse model of arthritis.
20702773 Anti-inflammatory and antiosteoclastogenesis properties of endogenous melanocortin recepto 2010 Dec The development of biological therapies has improved management of rheumatoid arthritis. However, costs and unresponsiveness to therapy in a sizeable proportion of patients limit their use, making it imperative to identify new targets for drug development programs. Here we investigated the melanocortin-receptor type 3 (MC(3)) pathway. Gene-deficient mice were subjected to a model of serum-transfer-induced arthritis and joints analyzed for gene expression (cytokines, MCs) and morphology. Pharmacological analyses were also conducted in this model. Osteoclastogenesis was studied from bone marrow cells. Mc(3)(-/-) mice displayed an exacerbated inflammatory arthritis, associated with prominent bone erosion and higher articular expression of Rankl. Osteoclastogenesis studied from Mc(3)(-/-) bone marrow cells revealed a higher degree of responsiveness to Rankl, linked to prolonged NF-κB activation compared to wild types. Up-regulation of a discrete set of inflammatory genes, including Il-1β, Il-6, and Nos2, was measured in Mc(3)(-/-) mice, and a marked up-regulation of joint Mc(3) accompanied arthritis resolution in wild-type mice. Administration of an MC(3) agonist, D[Trp8]-γ-MSH, attenuated disease incidence and severity in wild-type but not Mc(3)(-/-) mice. Overall, these findings identify MC(3)-mediated signaling as a beneficial pathway in experimental arthritis; hence this receptor is a novel target for the development of therapeutics for arthritis.
20637063 Rare incidence of methotrexate-specific lesions in liver biopsy of patients with arthritis 2010 INTRODUCTION: The present study objective was to evaluate the incidence of methotrexate (MTX)-specific liver lesions from the analysis of a liver biopsy of inflammatory arthritis patients with elevated liver enzymes. METHODS: A case-control study was performed with 1,571 arthritis patients on long-term low-dose MTX therapy. Results of liver biopsy were analyzed in 41 patients with elevated liver enzymes. The expression of autoimmune markers was also assessed. This population was compared with 41 disease control subjects obtained from the same database, also on MTX but without elevated liver enzymes, matched for age, sex and rheumatic disease. RESULTS: Compared with the disease controls, patients with liver biopsy showed lower disease duration and lower MTX exposure, weekly and cumulative doses, reflecting shorter treatment duration due to liver abnormalities. Liver biopsies showed 17 autoimmune hepatitis-like (AIH-like) lesions, 13 nonalcoholic steatohepatitis-like lesions, seven limited liver lesions, and two primary biliary cirrhoses. However, MTX-specific lesions with dystrophic nuclei in hepatocytes were seen in only two cases. Liver biopsy lesions were associated with autoimmune markers (P = 0.007); notably, AIH-like lesions were associated with rheumatoid arthritis and with the presence of the HLA-DR shared epitope. CONCLUSIONS: MTX-specific liver lesions are rarely observed in arthritis patients under long-term MTX therapy and elevated liver enzymes.
20537152 The inhibitory effect against collagen-induced arthritis by Schistosoma japonicum infectio 2010 Jun 10 BACKGROUND: A long-term existing schistosome infection can aid in maintaining immuno-homeostasis, thus providing protection against various types of autoimmune diseases to the infected host. Such benefits have often been associated with acute or egg stage infection and with the egg-induced Th2 response. However, since schistosome infection undergoes different stages, each associated with a specific induction of Th responses, the requirements for the ability of the different stages of schistosome infection to protect against autoimmune disease has not been elucidated. The present study was designed to study whether different stages of schistosome infection offer unique protection in collagen-induced arthritis and its mechanisms. RESULTS: Arthritis susceptible strain DBA/1 male mice were infected with Schistosoma japonicum for either 2 weeks resulting in early stage infection or for 7 weeks resulting in acute or egg stage infection. Following Schistosoma japonicum infection, collagen II was administered to induce collagen-induced arthritis, an animal model for human rheumatoid arthritis. Infection by Schistosoma japonicum significantly reduced the severity and the incidence of experimental autoimmune collagen-induced arthritis. However, this beneficial effect can only be provided by a pre-established acute stage of infection but not by a pre-established early stage of the infection. The protection against collagen-induced arthritis correlated with reduced levels of anti-collagen II IgG, especially the subclass of IgG2a. Moreover, in protected mice increased levels of IL-4 were present at the time of collagen II injection together with sustained higher IL-4 levels during the course of arthritis development. In contrast, in unprotected mice minimal levels of IL-4 were present at the initial stage of collagen II challenge together with lack of IL-4 induction following Schistosoma japonicum infection. CONCLUSION: The protective effect against collagen-induced arthritis provided by Schistosoma japonicum infection is infection stage-dependent. Furthermore, the ability of schistosomiasis to negatively regulate the onset of collagen-induced arthritis is associated with a dominant as well as long-lasting Th2 response at the initiation and development of autoimmune joint and systemic inflammation.
19266262 Intra-articular treatment of inflammatory arthritis with microsphere formulations of metho 2009 Aug INTRODUCTION: Methotrexate (MTX) encapsulated microspheres release MTX in the joint in a slow, controlled manner following intra-articular injection in healthy rabbits. The objective of this study was to determine the pharmacokinetics of MTX and to evaluate the efficacy following intra-articular treatment of MTX-loaded microspheres in an antigen-induced inflammatory arthritis rabbit model. METHODS: Arthritis was induced in both knee joints of rabbits using ovalbumin. Rabbits were intra-articularly treated with MTX solution or MTX microspheres and plasma concentrations of MTX were determined in the first 8 h following intra-articular treatment. Rabbits were killed 14 days following treatment and histological analysis of rabbit joints was conducted to determine efficacy. RESULTS: Arthritis was successfully induced in the joints of rabbits with the observation of histopathological features resembling rheumatoid arthritis. No significant differences were detected between MTX solution and MTX microspheres treated groups compared to phosphate buffered saline (control) animals. CONCLUSIONS: MTX microspheres effectively delivered the drug to the intra-articular space. However, a high degree of inter-animal variability, the severity of the disease induced and insufficient length of the observation period were suggested to be possible causes for the lack of therapeutic responses to MTX-loaded microspheres treatment.
19333927 Microanatomic studies to define predictive factors for the topography of periarticular ero 2009 Apr OBJECTIVE: The microanatomic basis for formation of erosions in inflammatory arthritis is incompletely understood but is thought to be related to bare areas and the associated cartilage-synovium junction. The purpose of this study was to test the hypothesis that erosion-prone sites are associated with microdamage in macroscopically normal joints. METHODS: Histologic evaluation of erosion-prone sites was performed on 20 collateral ligaments (CLs) from the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of 5 normal cadavers. In addition, the MCP joints (n = 17) and PIP joints (n = 3) of 20 patients with rheumatoid arthritis (RA) were assessed by computed tomography (CT) to ascertain whether the topography of erosion formation in patients with RA corresponded to the cadaveric findings. RESULTS: Absence of a bare area was noted in cadaveric tissue at the periligamentous erosion-prone regions, especially in the distal MCP joints and both distal and proximal PIP joints. Nevertheless, these sites exhibited soft-tissue pathologic features and bony microdamage/cyst formation. Other significant findings included the presence of pannus without inflammatory changes in the regions in which a bare area was absent, and the replacement of bare area regions with fibrovascular synovial tissue in joints without inflammatory changes. The sites of cadaveric tissue microdamage corresponded to CT-determined erosion formation in the MCP and PIP joints of patients with RA, in whom erosions adjacent to the CLs were more common than dorsal or volar erosions. CONCLUSION: Periarticular erosion formation may not necessarily depend on the presence of a bare area and has a propensity to occur adjacent to ligaments in which bone microdamage is common. These findings suggest that periligamentous locations prone to microdamage may critically influence the topography of erosion formation in inflammatory arthritis.
19054826 Bortezomib attenuates murine collagen-induced arthritis. 2009 Nov OBJECTIVES: Nuclear factor kappa B (NF-kappaB) is a major regulator of pivotal proinflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA). Bortezomib inhibits NF-kappaB activation by blocking the degradation of the NF-kappaB inhibitor, I-kappaB. In this study, the efficacy of bortezomib on murine collagen-induced arthritis (CIA) was investigated. METHODS: Thirty-five male DBA/1 mice were divided into five groups. All mice except controls were injected with type II collagen. Mice in the bortezomib-treated groups were injected intraperitoneally with 0.01, 0.1 and 1 mg/kg bortezomib twice a week for 2 weeks. Controls and mice in the untreated group were also injected intraperitoneally with phosphate-buffered saline in the same manner. Arthritis score and paw thickness were measured and histopathological assessment of joint sections was performed. The expression of proinflammatory cytokines and enzymes was evaluated by immunohistochemical staining. Joint destruction was confirmed using three-dimensional micro-computerised tomography (CT). Blood cells were counted and liver and kidney functions were monitored. RESULTS: Bortezomib significantly attenuated the severity of arthritis and histopathological findings in CIA mice. The expression of tumour necrosis factor alpha, IL-1beta, IL-6, matrix metalloproteinase 3, cyclooxygenase 2 and inducible nitric oxide synthase decreased in bortezomib-treated mice compared with untreated mice. In addition, micro-CT confirmed that bortezomib reduced joint destruction. No adverse effects in blood cells, liver or kidneys were observed with bortezomib treatment. CONCLUSIONS: These data suggest that bortezomib may play an anti-inflammatory role in the pathophysiology of RA and serve as a new therapeutic modality for RA.
19828631 The alpha-isoform of p38 MAPK specifically regulates arthritic bone loss. 2009 Nov 1 Pharmacological inhibitors have provided evidence for the key role of p38 MAPK in osteoclast differentiation and in inflammation-induced bone loss. However, these inhibitors block more than one of the four p38 isoforms, usually p38alpha and p38beta, and sometimes also other kinases such as JNK3. We show in this study that p38alpha is the main p38 isoenzyme expressed in the osteoclast precursors and in the mature osteoclasts. p38alpha as well as its downstream substrates were phosphorylated in osteoclast progenitors stimulated by TNF-alpha. Using Mx-cre-mediated conditional gene inactivation we demonstrated that mice lacking p38alpha were protected against TNF-alpha-induced bone destruction at the site of inflammation as well as against TNF-alpha-mediated systemic bone loss. The bone protection was associated to decreased osteoclast numbers in vivo as well as a decreased IL-1beta expression in the inflamed tissue and in the isolated monocytes. The phenotype was cell autonomous because, similarly to p38alpha-deficient cells, knockdown of p38alpha in monocytes resulted in a decreased osteoclast differentiation in vitro. It was not caused by major changes in RANKL-mediated ERK or JNK activation but rather associated to an increased NF-kappaB activation caused by a decrease in IkappaBalpha recovery. Thus, our data show that developing specific inhibitors of the alpha-isoenzyme of p38 would be beneficial for the treatment of inflammation-induced bone destruction as observed in rheumatoid arthritis.
20456418 Protective effect of eotaxin-2 inhibition in adjuvant-induced arthritis. 2010 Aug Eotaxin-2 is a potent chemoattractant for eosinophils, basophils and T helper type 2 (Th2) lymphocytes. The eotaxin-2/CCL24 receptor CCR3 is expressed in human brain, skin, endothelium and macrophages. The aim of the current study was to evaluate the protective effect of a monoclonal anti-eotaxin-2 antibody on the development of adjuvant-induced arthritis in rats (AIA). Adjuvant arthritis was induced in Lewis rats by intradermal injection of incomplete Freund's adjuvant +Mycobacterium tuberculosis. Rats were treated by intraperitoneal (i.p.) injection with three monoclonal antibodies against eotaxin-2 (G7, G8, D8) three times per week. Controls were treated with total mouse immunoglobulin G (IgG), methotrexate (MTX) or phosphate-buffered saline (PBS). Arthritis severity was evaluated by measuring ankle swelling, arthritic score, whole animal mobility and body weight. Sample joints were obtained for pathological evaluation and postmortem X-ray of ankle joints was performed to document erosions. Significant inhibition of arthritis was observed in rats treated with anti-eotaxin-2 antibodies compared to those treated with immunoglobulin or PBS. Inhibition was manifest in ankle diameter, arthritic score and mobility score. The antibody marked D8 showed the greatest efficacy. The effect was observed both in animals treated before the appearance of arthritis and in those where treatment was begun after development of joint inflammation. Combined treatment with D8 and MTX caused additional protection. Significant reduction of inflammation in D8-treated animals was also demonstrated in pathological and X-ray examinations. Inhibition of eotaxin-2 by monoclonal antibodies has a significant protective effect in adjuvant arthritis. These results may introduce a novel therapeutic target in rheumatoid arthritis and additional inflammatory joint disorders.