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ID PMID Title PublicationDate abstract
21216547 A clinical study of olfactory dysfunction in patients with Mikulicz's disease. 2011 Jun OBJECTIVE: Mikulicz's disease (MD) is differentiated from Sjögren's syndrome as an immunoglobulin G4 (IgG4) systemic disease. MD patients often report olfactory dysfunction (OD). To analyze cases of OD associated with MD, we studied clinicopathological and serological findings of MD patients. METHODS: A total of 44 MD patients (17 males and 27 females) were examined for OD. We evaluated clinicopathological and serological findings of these patients by dividing them into OD(+) and OD(-) groups. RESULTS: The mean IgG4 concentration (SD) in such cases was 950.5 (797.5)mg/dl. Of the 44 patients, 20 (45%) had OD even though no abnormalities, such as obstructive and inflammatory disease, were detected in their nasal cavities and sinuses. The two groups did not show significant differences in background characteristics, such as age, sex, IgG4 concentration, presence or absence of allergic rhinitis, and presence or absence of extrasalivary gland lesions. We found abundant IgG4-positive plasmacytes in the nasal mucosa specimens of the OD(+) group but not in that of the OD(-) group. CONCLUSIONS: Nasal mucosa in the MD patients with OD was infiltrated with IgG4-positive plasmacytes. We concluded that OD may be associated with infiltration by IgG4-positive cells.
20932862 Modeling Sjögren's syndrome with Id3 conditional knockout mice. 2011 Mar 30 The Id3 gene has been shown to play important roles in the development and function of broad tissue types including B and T cells. Id3 deficient mice develop autoimmune disease similar to human Sjögren's syndrome. Both B and T lymphocytes have been implicated to contribute to the disease phenotype in this disease model. In order to gain a better understanding of individual cell types in this disease model, we generated an Id3 conditional allele. An LckCre transgene was used to induce Id3 deletion in developing T cells. We showed that the Id3 gene was efficiently disrupted in early thymocyte development prior to T cell receptor (TCR)-mediated positive selection. Consequently, thymocyte maturation was impaired in the conditional knockout mice. These mice developed exocrinopathy starting at two months of age and subsequently exhibited high incidence of lymphocyte infiltration to salivary glands between eight and 12 months of age. This progressive feature of disease development is very similar to those observed in Id3 germline knockout mice. This study establishes a new model for investigating the relationship between T cell development and autoimmune disease. Our observation provides an experimental case that autoimmune disease may be induced by acquired mutation in developing T cells.
20824298 A case of disseminated DLE complicated by atopic dermatitis and Sjögren's syndrome: link 2011 Feb We report an unusual case of disseminated discoid lupus erythematosus (DLE) complicated by pre-existing atopic dermatitis (AD) and late-onset Sjögren's syndrome (SS). Disseminated DLE lesions were sparse on the expected sites for AD, such as the medial region of the extremities or v-neck area. The patient fulfilled the diagnostic criteria for AD and SS but not for systemic lupus erythematosus. Histopathological analysis of the crusted erythematous lesions revealed typical DLE with few FoxP3(+) cells and a moderate number of IL-17(+) cells. A quantitative sweating test showed impaired sweating of both lesional and non-lesional skin due to underlying hypohidrosis that was related to AD and SS. This finding suggests that dissemination of DLE was triggered by scratching and a Köbner phenomenon-like effect related to hypohidrotic and xerotic skin. To the best of our knowledge, this is the first reported case of disseminated DLE complicated by AD and SS.
22331111 Comparative study of ophthalmological and serological manifestations and the therapeutic r 2011 Nov INTRODUCTION: Scleritis is a rare, progressive and serious disease, the signs of which are inflammation and edema of episcleral and scleral tissues and is greatly associated with systemic rheumatoid diseases. PURPOSE: To perform a prospective and comparative study between ophthalmologic manifestations, serologic findings and therapeutic response of patients with isolated scleritis and scleritis associated with systemic rheumatoid disease. METHODS: Thirty-two outpatients with non-infectious scleritis were studied, from March 2006 to March 2008. The treatment was corticoid eye drops associated with anti-inflammatory agents, followed by systemic corticoids and immunosuppressive drugs if necessary, was considered successful after six months without scleritis recurrence. RESULTS: Fourteen of 32 patients had scleritis associated with systemic rheumatoid disease, of which nine had rheumatoid arthritis, two systemic lupus erythematosus, one Crohn's disease, one Behçet's disease and one gout. There were no difference in relation to involvement and ocular complications, there was predominance of nodular anterior scleritis and scleral thinning was the most frequent complication. The scleritis associated with systemic rheumatoid disease group had 64.3% of autoantibodies, versus 27.8% among those with isolated scleritis and this difference was statistically significant. In the isolated scleritis group 16.7% used anti-inflammatory, 33.3% corticosteroids, 27.8% corticosteroids with one immunosuppressive drug, 5.5% two immunosuppressive drugs, 16.7% corticosteroids with two immunosuppressive drugs and 33.3% pulse of immunosuppressive drugs, there was remission in 88.9%. In the scleritis associated with systemic rheumatoid disease group 7.1% used anti-inflammatory, 7.1% corticosteroids, 50% corticosteroids with one immunosuppressive drug, 7.1% two immunosuppressive drugs and 22.2% pulse of immunosuppressive drugs, 100% had treatment success. CONCLUSION: Prevalence of unilateral nodular scleritis was noted in both groups and higher rates of all the parameters tested were noted in the scleritis associated with systemic rheumatoid disease group. There were no differences between the groups with respect to the use of immunosuppressive drugs and therapeutic response, which was fully satisfactory in the scleritis associated with systemic rheumatoid disease group and satisfactory in the isolated scleritis group.
21062675 Reversion of resistance to immunosuppressive agents in three patients with psoriatic arthr 2011 Jan Secondary resistance may be a major problem in the management of autoimmune diseases. P-glycoprotein (P-gp) over-function has been described as a mechanism of drug resistance in autoimmune patients. P-gp function can in vitro be inhibited by cyclosporine A (CSA) and verapamil; moreover, P-gp reduction by CSA in systemic lupus erythematosus and rheumatoid arthritis has been demonstrated. Here, P-gp function before and after CSA administration in three psoriatic arthritis (PsA) patients, who developed a resistance to MTX/SSA, has been evaluated. P-gp function on patient cells was analyzed by measuring the changes in rhodamine-123 (Rh-123) fluorescence after verapamil incubation. CSA treatment resulted in good clinical outcome that was related with a significant P-gp function reduction at CD3+ and CD8+ levels. In addition to its immunosuppressive activity, CSA results may also be related to MTX/SSA effect restoration through P-gp inhibition. This is the first time that CSA has been demonstrated as being able to revert MTX/SSA resistance in PsA.
22899318 JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decre 2012 Nov OBJECTIVE: The mechanistic link between Janus kinase (JAK) signaling and structural damage to arthritic joints in rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate how selective inhibition of JAK with tofacitinib (CP-690,550) affects osteoclast-mediated bone resorption in a rat adjuvant-induced arthritis (AIA) model, as well as human T lymphocyte RANKL production and human osteoclast differentiation and function. METHODS: Hind paw edema, inflammatory cell infiltration, and osteoclast-mediated bone resorption in rat AIA were assessed using plethysmography, histopathologic analysis, and immunohistochemistry; plasma and hind paw tissue levels of cytokines and chemokines (including RANKL) were also assessed. In vitro RANKL production by activated human T lymphocytes was evaluated by immunoassay, while human osteoclast differentiation and function were assessed via quantitative tartrate-resistant acid phosphatase staining and degradation of human bone collagen, respectively. RESULTS: Edema, inflammation, and osteoclast-mediated bone resorption in rats with AIA were dramatically reduced after 7 days of treatment with the JAK inhibitor, which correlated with reduced numbers of CD68/ED-1+, CD3+, and RANKL+ cells in the paws; interleukin-6 (transcript and protein) levels were rapidly reduced in paw tissue within 4 hours of the first dose, whereas it took 4-7 days of therapy for RANKL levels to decrease. Tofacitinib did not impact human osteoclast differentiation or function, but did decrease human T lymphocyte RANKL production in a concentration-dependent manner. CONCLUSION: These results suggest that the JAK inhibitor tofacitinib suppresses osteoclast-mediated structural damage to arthritic joints, and this effect is secondary to decreased RANKL production.
21305506 Nicotine-induced differential modulation of autoimmune arthritis in the Lewis rat involves 2011 Apr OBJECTIVE: Rheumatoid arthritis (RA) is a debilitating autoimmune disease, and smoking is an important environmental factor in a subset of RA patients. A role of the cholinergic antiinflammatory pathway in autoimmune inflammation is increasingly being realized. Nicotine is a major component of cigarette smoke, and it stimulates the α7 nicotinic acetylcholine receptors. Therefore, defining the mechanisms underlying the immunomodulatory effects of nicotine on arthritis is of high relevance. The purpose of this study was to address this issue using the rat adjuvant-induced arthritis (AIA) model of human RA. METHODS: Lewis rats were immunized subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra for disease induction. Rats were treated with nicotine intraperitoneally either before (pretreatment) or after (posttreatment) the onset of AIA. Control rats received the vehicle (buffer) in place of nicotine. The severity of arthritis was assessed and graded. The draining lymph node cells were tested for T cell proliferative and cytokine responses against the disease-related antigen mycobacterial heat-shock protein 65. The sera were tested for anti-cyclic citrullinated peptide (anti-CCP) antibodies and anti-mycobacterial Hsp65 antibodies. RESULTS: Nicotine pretreatment aggravated the arthritis, whereas nicotine posttreatment suppressed the disease. This altered severity of AIA directly correlated with the levels of the anti-CCP antibodies, of the Th1/Th17 cytokines, and of the corresponding dendritic cell-derived cytokines. The majority of these effects on cellular responses could be replicated in vitro. CONCLUSION: Nicotine-induced modulation of AIA involves specific alterations in the disease-related cellular and humoral immune responses in AIA. These results are of significance in advancing our understanding of the pathogenesis of RA.
21982514 Human epidermal growth factor receptor bispecific ligand trap RB200: abrogation of collage 2011 INTRODUCTION: Rheumatoid arthritis (RA) is a chronic disease associated with inflammation and destruction of bone and cartilage. Although inhibition of TNFα is widely used to treat RA, a significant number of patients do not respond to TNFα blockade, and therefore there is a compelling need to continue to identify alternative therapeutic strategies for treating chronic inflammatory diseases such as RA. The anti-epidermal growth factor (anti-EGF) receptor antibody trastuzumab has revolutionised the treatment of patients with EGF receptor-positive breast cancer. Expression of EGF ligands and receptors (known as HER) has also been documented in RA. The highly unique compound RB200 is a bispecific ligand trap that is composed of full-length extracellular domains of HER1 and HER3 EGF receptors. Because of its pan-HER specificity, RB200 inhibits responses mediated by HER1, HER2 and HER3 in vitro and in vivo. The objective of this study was to assess the effect of RB200 combined with TNF blockade in a murine collagen-induced arthritis (CIA) model of RA. METHODS: Arthritic mice were treated with RB200 alone or in combination with the TNF receptor fusion protein etanercept. We performed immunohistochemistry to assess CD31 and in vivo fluorescent imaging using anti-E-selectin antibody labelled with fluorescent dye to elucidate the effect of RB200 on the vasculature in CIA. RESULTS: RB200 significantly abrogated CIA by reducing paw swelling and clinical scores. Importantly, low-dose RB200 combined with a suboptimal dose of etanercept led to complete abrogation of arthritis. Moreover, the combination of RB200 with etanercept abrogated the intensity of the E-selectin-targeted signal to the level seen in control animals not immunised to CIA. CONCLUSIONS: The human pan-EGF receptor bispecific ligand trap RB200, when combined with low-dose etanercept, abrogates CIA, suggesting that inhibition of events downstream of EGF receptor activation, in combination with TNFα inhibitors, may hold promise as a future therapy for patients with RA.
21914168 The gene expression profile of preclinical autoimmune arthritis and its modulation by a to 2011 INTRODUCTION: Autoimmune inflammation is a characteristic feature of rheumatoid arthritis (RA) and other autoimmune diseases. In the natural course of human autoimmune diseases, it is rather difficult to pinpoint the precise timing of the initial event that triggers the cascade of pathogenic events that later culminate into clinically overt disease. Therefore, it is a challenge to examine the early preclinical events in these disorders. Animal models are an invaluable resource in this regard. Furthermore, considering the complex nature of the pathogenic immune events in arthritis, microarray analysis offers a versatile tool to define the dynamic patterns of gene expression during the disease course. METHODS: In this study, we defined the profiles of gene expression at different phases of adjuvant arthritis (AA) in Lewis rats and compared them with those of antigen mycobacterial heat shock protein 65 (Bhsp65)-tolerized syngeneic rats. Purified total RNA (100 ng) extracted from the draining lymph node cells was used to generate biotin-labeled fragment cRNA, which was then hybridized with an oligonucleotide-based DNA microarray chip. Significance analysis of microarrays was used to compare gene expression levels between the two different groups by limiting the false discovery rate to < 5%. Some of the data were further analyzed using a fold change ≥2.0 as the cutoff. The gene expression of select genes was validated by quantitative real-time PCR. RESULTS: Intriguingly, the most dramatic changes in gene expression in the draining lymphoid tissue ex vivo were observed at the preclinical (incubation) phase of the disease. The affected genes represented many of the known proteins that participate in the cellular immune response. Interestingly, the preclinical gene expression profile was significantly altered by a disease-modulating, antigen-based tolerogenic regimen. The changes mostly included upregulation of several genes, suggesting that immune tolerance suppressed disease by activating disease-regulating pathways. We identified a molecular signature comprising at least 12 arthritis-related genes altered by Bhsp65-induced tolerance. CONCLUSIONS: This is the first report of microarray analysis in the rat AA model. The results of this study not only advance our understanding of the early phase events in autoimmune arthritis but also help in identifying potential targets for the immunomodulation of RA.
22615046 Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune 2012 Aug Macrophage activation syndrome (MAS) belongs to secondary hemophagocytic lymphohistiocytosis (HLH) syndrome. It is usually associated with rheumatic diseases. We retrospectively reviewed our hospital's medical records of 102 HLH/MAS patients from the past 20 years. Demographics, clinical data, treatment, and outcomes were analyzed. Among 102 patients, eight patients with underlying juvenile systemic lupus erythematous (two patients), mixed connective tissue disease (one patient), primary anti-phospholipid syndrome (one patient), and systemic type juvenile rheumatoid arthritis (sJRA; four patients) with 13 episodes of MAS were studied. Clinical manifestations of MAS included fever (100 %), hepatosplenomegaly (77 %), lymphadenopathy (38 %), skin rash (62 %), and neurological involvement (31 %). Laboratory features included leukopenia (54 %), anemia (46 %), thrombocytopenia (77 %), jaundice (27 %), hypofibrinogenemia (40 %), decreased erythrocyte sedimentation rate (67 %), and elevated liver enzymes (77 %), lactate dehydrogenase (100 %), ferritin (88 %), triglycerides (91 %), C-reactive protein (85 %), plasma D-dimer (50 %), and hemophagocytosis in bone marrow (83 %). The Epstein-Barr virus and adenovirus infection triggered MAS in two patients with sJRA. Methylprednisolone pulse therapy was effective in two out of three patients, and high-dose intravenous immunoglobulin (IVIG) was effective in two out of six patients. Patients with sJRA responded well to corticosteroids and cyclosporine. Complications included opportunistic infection with Pneumocystis jiroveci, multiple organ failure, and intensive care unit myopathy. The mortality rate was one out of eight (12.5 %). Our results showed that MAS could be fatal and complicate various pediatric autoimmune diseases. It generally has a good response to corticosteroids and IVIG. Prompt recognition and timely treatment can result in good outcomes.
21463515 Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic a 2011 Apr 4 INTRODUCTION: Folate receptor (FR)-expressing macrophages have been shown to accumulate at sites of inflammation, where they promote development of inflammatory symptoms. To target such a macrophage population, we designed and evaluated the biologic activity of EC0746, a novel folic acid conjugate of the highly potent antifolate, aminopterin. METHODS: Using a FR-positive subclone of murine macrophage-derived RAW264.7 cells and rat thioglycollate-elicited macrophages, we studied the effect of EC0746 on dihydrofolate reductase activity, cell proliferation, and cellular response towards bacterial lipopolysaccharide as well as IFNγ activation. The EC0746 anti-inflammatory activity, pharmacokinetics, and toxicity were also evaluated in normal rats or in rats with adjuvant-induced arthritis; that is, a FR-positive macrophage model that closely resembles rheumatoid arthritis in humans. RESULTS: EC0746 suppresses the proliferation of RAW264.7 cells and prevents the ability of nonproliferating rat macrophages to respond to inflammatory stimuli. In the macrophage-rich rat arthritis model, brief treatment with subcutaneously administered EC0746 is shown to mediate an FR-specific anti-inflammatory response that is more potent than either orally administered methotrexate or subcutaneously delivered etanercept. More importantly, EC0746 therapy is also shown to be ~40-fold less toxic than unmodified aminopterin, with fewer bone marrow and gastrointestinal problems. CONCLUSIONS: EC0746 is the first high FR-binding dihydrofolate reductase inhibitor that demonstrates FR-specific anti-inflammatory activities both in vitro and in vivo. Our data reveal that a relatively toxic anti-inflammatory drug, such as aminopterin, can be targeted with folic acid to inflammatory macrophages and thereby relieve inflammatory symptoms with greatly reduced toxicity.
22329453 Gaps in transitional care: what are the perceptions of adolescents, parents and providers? 2013 Jan BACKGROUND:   Several studies have investigated preferences and experiences of adolescents with different chronic conditions and their parents. Some have included the provider's perspective. Studies comparing the three perspectives on satisfaction with (transitional) care for different chronic conditions, however, are lacking. The main aim of this paper was to explore differences and similarities in perspectives between adolescents with chronic conditions, their parents and providers on transitional care. A secondary aim was to explore the extent to which such perspectives are disease-specific. METHODS:   This quantitative study included 127 adolescents with juvenile rheumatoid arthritis (JRA), neuromuscular disorder with chronic ventilation (NMD), or diabetes Type I; 166 parents; and 19 care providers. To assess the experiences and perceptions of adolescents and parents on transitional care, we used the 'Mind the Gap' instrument. The survey for providers included a checklist of shortcomings in transitional care. RESULTS:   Adolescents rate current care significantly worse than parents on opportunities to make their own decisions and be seen without parents present. Adolescents also rated providers' current social skills lower than parents. Adolescents are more satisfied than their parents about transitional care process aspects such as co-ordination and communication between providers, but both groups indicated that the care process offers most room for improvement. Providers reported other aspects such as adolescents' lack of responsibility with regard to self-care and parents' difficulties with ceding control to their children. When looking at the three disease groups - JRA, NMD, diabetes, we found only small differences. According to providers, shortcomings in the care process with respect to guidelines, protocols and co-ordination are most prevalent. CONCLUSION:   Adolescents, parents and providers all report that there is room for improvement with regard to aspects of the care delivery process in transitional care. With respect to disease-specific issues we only found small differences.
22294642 Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis 2012 Jul OBJECTIVES: Rheumatoid arthritis (RA) shares some similar clinical and pathological features with juvenile idiopathic arthritis (JIA); indeed, the strategy of investigating whether RA susceptibility loci also confer susceptibility to JIA has already proved highly successful in identifying novel JIA loci. A plethora of newly validated RA loci has been reported in the past year. Therefore, the aim of this study was to investigate these single nucleotide polymorphisms (SNP) to determine if they were also associated with JIA. METHODS: Thirty-four SNP that showed validated association with RA and had not been investigated previously in the UK JIA cohort were genotyped in JIA cases (n=1242), healthy controls (n=4281), and data were extracted for approximately 5380 UK Caucasian controls from the Wellcome Trust Case-Control Consortium 2. Genotype and allele frequencies were compared between cases with JIA and controls using PLINK. A replication cohort of 813 JIA cases and 3058 controls from the USA was available for validation of any significant findings. RESULTS: Thirteen SNP showed significant association (p<0.05) with JIA and for all but one the direction of association was the same as in RA. Of the eight loci that were tested, three showed significant association in the US cohort. CONCLUSIONS: A novel JIA susceptibility locus was identified, CD247, which represents another JIA susceptibility gene whose protein product is important in T-cell activation and signalling. The authors have also confirmed association of the PTPN2 and IL2RA genes with JIA, both reaching genome-wide significance in the combined analysis.
21419242 Effects of relaxin and estrogens on bone remodeling markers, receptor activator of NF-kB l 2011 Jun 1 Rheumatoid arthritis (RA) is characterized by joint inflammation and bone destruction. The receptor activator of nuclear factor-kappa B ligand (RANKL)-osteoprotegerin (OPG) system is important for maintaining the balance between bone resorption and formation. Both serum RANKL/OPG protein and synovial tissue RANKL/OPG mRNA ratios are elevated in patients with RA. Studies indicate that hormones of pregnancy, estrogens and relaxin, administered in combination, reduce circulating (TNF)-α and joint inflammation in a rat adjuvant-induced arthritis (AIA) model of RA. The purpose of this study was to investigate whether relaxin (RLX), alone or in combination with estrogens, regulates the bone remodeling markers RANKL and OPG in vivo and in vitro. Results show that in AIA rats, treatment with relaxin, estradiol valerate (EV) or EV in combination with relaxin had no effect on circulating RANKL. However, EV increased systemic OPG and combined treatment with EV and relaxin further increased circulating OPG in comparison to EV alone. Importantly, the RANKL/OPG protein ratio was lower in rats treated with EV or EV+RLX when compared to arthritic controls. Relaxin in combination with EV decreased local RANKL transcripts, increased OPG mRNA and decreased the RANKL/OPG mRNA ratio in joints of arthritic rats when compared to controls. RLX family peptide receptor 1 (RXFP1) gene expression in joints of AIA rats increased in response to EV and EV+RLX. In parathyroid hormone-pretreated murine UMR 106-01 osteoblast cells, 17-β-estradiol (E) and E+RLX increased RXFP1 transcripts, while RLX reduced RANKL mRNA and protein expression. However, in vitamin D-treated primary rat osteoblast cells E+RLX increased OPG protein and reduced the RANKL/OPG protein ratio. These results suggest that modulation of the RANKL-OPG system by estrogens and RLX may contribute to their antiarthritic effects on bone during pregnancy.
21745460 Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 i 2011 Oct 1 Nonsteroidal anti-inflammatory drugs (NSAIDs) are now understood to fall into one of two agent classes in clinical use. Traditional NSAIDs inhibit both cyclooxygenases-1 and 2 (COX-1, 2), which act as key enzymes catalyzing the same reaction in the production of prostaglandins (PGs), while the second class of NSAIDs selectively inhibit COX-2. Inhibition of the inducible COX-2 isoform is believed to be responsible for the therapeutic effects of NSAIDs, such as anti-inflammatory, analgesic, and antipyretic effects, while COX-1 inhibition results in side-effects on the gastrointestinal (GI) system. In the present study, however, we changed this notion that inhibiting only COX-1 causes adverse effects. We discovered FK881, a specific COX-1 inhibitor which exhibits a 650-fold ratio for human whole blood COX-1/COX-2 and rats in vivo. In rats, FK881 dose dependently inhibited carrageenan-induced paw edema (ED30: 22 mg/kg; diclofenac ED30: 3.6 mg/kg, rofecoxib ED30: 26 mg/kg) and paw swelling associated with adjuvant arthritis (ED50: 17 mg/kg; diclofenac ED50: 1.4 mg/kg, rofecoxib ED50: 1.8 mg/kg). Further, FK881 dose dependently inhibited acetic acid-induced writhing in mice (ED50: 19 mg/kg; diclofenac ED50: 14 mg/kg, rofecoxib ED50: >100mg/kg) and adjuvant arthritis hyperalgesia in rats (ED50: 1.8 mg/kg; diclofenac ED50: 1.0mg/kg, rofecoxib ED50: 0.8mg/kg). However, unlike traditional NSAIDs, GI tolerability was improved, although the antipyretic effect of FK881 was weak (NOEL: >320 mg/kg; diclofenac NOEL: <1mg/kg, rofecoxib NOEL: 100 mg/kg). These results suggest that FK881 may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis.
22549786 Celastrus and its bioactive celastrol protect against bone damage in autoimmune arthritis 2012 Jun 22 Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by bone erosion and cartilage destruction in the joints. Many of the conventional antiarthritic drugs are effective in suppressing inflammation, but they do not offer protection against bone damage. Furthermore, the prolonged use of these drugs is associated with severe adverse reactions. Thus, new therapeutic agents that can control both inflammation and bone damage but with minimal side effects are sought. Celastrus is a Chinese herb that has been used for centuries in folk medicine for the treatment of various inflammatory diseases. However, its utility for protection against inflammation-induced bone damage in arthritis and the mechanisms involved therein have not been examined. We tested celastrus and its bioactive component celastrol for this attribute in the adjuvant-induced arthritis model of RA. The treatment of arthritic rats with celastrus/celastrol suppressed inflammatory arthritis and reduced bone and cartilage damage in the joints as demonstrated by histology and bone histomorphometry. The protective effects against bone damage are mediated primarily via the inhibition of defined mediators of osteoclastic bone remodeling (e.g. receptor activator of nuclear factor-κB ligand (RANKL)), the deviation of RANKL/osteoprotegerin ratio in favor of antiosteoclastic activity, and the reduction in osteoclast numbers. Furthermore, both the upstream inducers (proinflammatory cytokines) and the downstream effectors (MMP-9) of the osteoclastogenic mediators were altered. Thus, celastrus and celastrol controlled inflammation-induced bone damage by modulating the osteoimmune cross-talk. These natural products deserve further consideration and evaluation as adjuncts to conventional therapy for RA.
21730129 Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced 2011 Jul 19 Arthrogenic alphaviruses, such as Ross River virus (RRV), chikungunya, Sindbis, mayaro and o'nyong-nyong viruses circulate endemically worldwide, frequently causing outbreaks of polyarthritis. The exact mechanisms of how alphaviruses induce polyarthritis remain ill defined, although macrophages are known to play a key role. Macrophage migration inhibitory factor (MIF) is an important cytokine involved in rheumatoid arthritis pathogenesis. Here, we characterize the role of MIF in alphavirus-induced arthritides using a mouse model of RRV-induced arthritis, which has many characteristics of RRV disease in humans. RRV-infected WT mice developed severe disease associated with up-regulated MIF expression in serum and tissues, which corresponded to severe inflammation and tissue damage. MIF-deficient (MIF(-/-)) mice developed mild disease accompanied by a reduction in inflammatory infiltrates and muscle destruction in the tissues, despite having viral titers similar to WT mice. In addition, reconstitution of MIF into MIF(-/-) mice exacerbated RRV disease and treatment of mice with MIF antagonist ameliorated disease in WT mice. Collectively, these findings suggest that MIF plays a critical role in determining the clinical severity of alphavirus-induced musculoskeletal disease and may provide a target for the development of antiviral pharmaceuticals. The prospect being that early treatment with MIF-blocking pharmaceuticals may curtail the debilitating arthritis associated with alphaviral infections.
21778904 Treatment of ankylosing spondylitis by extracorporeal photochemotherapy given for mycosis 2011 Aug We describe a patient with cutaneous T-cell lymphoma (CTCL), in association with concurrent ankylosing spondylitis (AS), who achieved a long-lasting complete remission of both diseases after 3 cycles of extracorporeal photochemotherapy (ECP). The combination of CTCL with AS is very rare. In our patient, the CTCL was refractory to psoralen-UVA. He was unable to continue with administration of interferon α because of exacerbation of his back, anterior chest, and bilateral heel pain. The Bath AS Functional Index and Bath AS Disease Activity Index scores were determined to be 2.2 and 5.8, respectively. Extracorporeal photochemotherapy has been shown to be effective in the treatment of CTCL consisting of reinfusion of 3 to 9 × 10 leukocytes, taken from the patient by leukopheresis and treated in an extracorporeal system with 8-methoxypsoralen and UVA. There is a strong suggestion that ECP as a monotherapy can provide a significant benefit for other T-cell-mediated diseases including rheumatoid arthritis and psoriatic arthritis. This is the first report describing an effective treatment of AS in which pain, inflammatory response, Bath AS Disease Activity Index, and Bath AS Functional Index improved after initiation of ECP.
21288455 [Anti-angiogenic effects of genistein on synovium in a rat model of type II collagen-induc 2011 Feb OBJECTIVE: To explore the anti-angiogenic effects of genistein on synovium in a rat model of type II collagen-induced arthritis (CIA). METHODS: Forty SD rats were randomly divided into normal group, model group, genistein group, methotrexate (MTX) group and Gen plus MTX group with 8 rats in each group. Arthritis in rats was induced by subcutaneous injection of type II collagen combined with complete Freund's adjuvant (CFA). On the second day after the injection, 1 mL of suspension liquid of genistein (30 mg/kg body weight, once daily) and MTX (0.2 mg/kg body weight, once a week) were administered by oral gavage respectively. The rats in normal group and model group were administered with normal saline in the same volume. Synovium of knee joints and peripheral serum were collected from the CIA rats. Microvessel density in synovium (MVD) was detected by immunohistochemical method and serum vascular endothelial growth factor (VEGF) and matrix metallopeptidase (MMP)-1, 2 and 9 levels were detected by using Western blotting. RESULTS: Arthritis index score, paw volume of rats in the model group were significantly higher than those in the normal group (P<0.05), which suggested that a model of CIA induced by injection of type II collagen and CFA was successfully constructed. The arthritis index scores of rats in the treatment groups were decreased compared with the model group. The results of Western blotting showed that genistein obviously attenuate the levels of VEGF and MMP-1, 2 and 9 in serum (P<0.05). Immunohistochemical method showed that MVDs in the treatment groups were reduced as compared with the model group. CONCLUSION: The expressions of VEGF and MMP-1, 2 and 9 are related to the synovial pannus formation in CIA rats. The anti-angiogenic activity of genistein may correlate to its inhibitory effect on the expressions of VEGF and MMP-1, 2 and 9 in serum of CIA rats; genistein plus MTX are superior to single agents in treating rheumatoid arthritis.
23300516 Fas-independent T-cell apoptosis by dendritic cells controls autoimmune arthritis in MRL/l 2012 BACKGROUND: Although autoimmunity in MRL/lpr mice occurs due to a defect in Fas-mediated cell death of T cells, the role of Fas-independent apoptosis in pathogenesis has rarely been investigated. We have recently reported that receptor activator of nuclear factor (NF)-κB ligand (RANKL)-activated dendritic cells (DCs) play a key role in the pathogenesis of rheumatoid arthritis (RA) in MRL/lpr mice. We here attempted to establish a new therapeutic strategy with RANKL-activated DCs in RA by controlling apoptosis of peripheral T cells. Repeated transfer of RANKL-activated DCs into MRL/lpr mice was tested to determine whether this had a therapeutic effect on autoimmunity. METHODS AND FINDING: Cellular and molecular mechanisms of Fas-independent apoptosis of T cells induced by the DCs were investigated by in vitro and in vivo analyses. We demonstrated that repeated transfers of RANKL-activated DCs into MRL/lpr mice resulted in therapeutic effects on RA lesions and lymphoproliferation due to declines of CD4(+) T, B, and CD4(-)CD8(-) double negative (DN) T cells. We also found that the Fas-independent T-cell apoptosis was induced by a direct interaction between tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) on T cells and TRAIL on Fas-deficient DCs in MRL/lpr mice. CONCLUSION: These results strongly suggest that a novel Fas-independent apoptosis pathway in T cells maintains peripheral tolerance and thus controls autoimmunity in MRL/lpr mice.