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ID PMID Title PublicationDate abstract
16927387 Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabino 2007 Jan 1 Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARgamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARgamma in the mechanism of action of AjA. FLS, treated or not with a PPARgamma antagonist, were treated with AjA then stimulated with TNFalpha or IL-1alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARgamma positive (PPAR+/-) and PPARgamma null (PPAR-/-) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARgamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFalpha- and IL-1alpha-stimulated PPARgamma+/- and PPARgamma-/- MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARgamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.
18708134 Analgesic and anti-arthritic effects of Lingzhi and San Miao San supplementation in a rat 2008 Oct 30 AIM OF STUDY: In this study, we have investigated the analgesic and anti-arthritic effects of a traditional Chinese medicine (TCM) combination of Lingzhi and San Miao San (SMS) in a rat model of arthritis induced by Freund's complete adjuvant (FCA). MATERIALS AND METHODS: Sprague-Dawley rats were induced with monoarthritis by single unilateral injection of FCA into the knee joint. The TCM combination was administered to the rats daily by intraperitoneal injection (50mg/(kgday)) or via oral administration (500mg/(kgday)) for 7 days before induction of arthritis and 7 days after. Extension angle that provoked struggling behavior, and size and blood flow of the rat knees were measured to give indexes of allodynia, edema, and hyperemia, respectively. The extent of cell infiltration, tissue proliferation, and erosions of joint cartilage provided additional indexes of the arthritis condition. RESULTS: FCA injection produced significant allodynia, edema, hyperemia, immune cell infiltration, synovial tissue proliferation, and erosions of joint cartilage in the ipsilateral knees compared with the contralateral saline-injected knees. Intraperitoneal injection of the TCM combination (50mg/(kgday)) suppressed allodynia, edema, and hyperemia in the inflamed knees, and oral administration (500mg/(kgday)) suppressed edema and hyperemia. Histological examination showed that the TCM administered by either route reduced immune cell infiltration and erosion of joint cartilage. CONCLUSIONS: These findings suggest the Lingzhi and SMS formulation has analgesic and anti-inflammatory effects in arthritic rat knees, and concur to previous clinical studies that showed the TCM combination reduced pain in rheumatoid arthritis patients, and extends its possible benefit to suppression of inflammatory symptoms in these patients.
16563174 A promoter haplotype of the interleukin-18 gene is associated with juvenile idiopathic art 2006 Recently, we reported that genetic polymorphisms within the human IL18 gene were associated with disease susceptibility to adult-onset Still's disease (AOSD), which is characterized by extraordinarily high serum levels of IL-18. Because high serum IL-18 induction has also been observed in the systemic type of juvenile idiopathic arthritis (JIA), we investigated whether similar genetic skewing is present in this disease. Three haplotypes, S01, S02, and S03, composed of 13 genetic polymorphisms covering two distinct promoter regions, were determined for 33 JIA patients, including 17 with systemic JIA, 10 with polyarthritis, and 6 with oligoarthritis. Haplotypes were also analyzed for 28 AOSD patients, 164 rheumatoid arthritis (RA) patients, 102 patients with collagen diseases, and 173 healthy control subjects. The frequency of individuals carrying a diplotype configuration (a combination of two haplotypes) of S01/S01 was significantly higher in the JIA patients, including all subgroups, than in the healthy controls (P = 0.0045, Fischer exact probability test; odds ratio (OR) = 3.55, 95% confidence interval (CI) = 1.55-8.14). In patients with systemic JIA, its frequency did not differ statistically from that of normal controls. Nevertheless, it is possible that haplotype S01 is associated with the phenotype of high IL-18 production in systemic JIA because the patients carrying S01/S01 showed significantly higher serum IL-18 levels compared with patients with other diplotype configurations (P = 0.017, Mann-Whitney U test). We confirmed that the frequency of the diplotype configuration of S01/S01 was significantly higher in AOSD patients than in healthy control subjects (P = 0.011, OR = 3.45, 95% CI = 1.42-8.36). Furthermore, the RA patients were also more predisposed to have S01/S01 (P = 0.018, OR = 2.00, 95% CI = 1.14-3.50) than the healthy control subjects, whereas the patients with collagen diseases did not. In summary, the diplotype configuration of S01/S01 was associated with susceptibility to JIA as well as AOSD and RA, and linked to significantly higher IL-18 production in systemic JIA. Possession of the diplotype configuration of S01/S01 would be one of the genetic risk factors for susceptibility to arthritis in the Japanese population.
16951943 Tumour necrosis factor alpha promoter polymorphisms and etanercept therapy in juvenile idi 2007 Feb The objective of this study was to investigate the influence of TNF-alpha promoter alleles on clinical response to etanercept therapy in JIA. TNF-alpha promoter polymorphisms at positions -163, -238, -244, -308, -376 were determined in 137 JIA patients treated with etanercept for at least 3 months. A PCR fragment of about 500 bp of the TNF gene promoter was amplified. Polymorphisms were detected by a single sequencing procedure. Patients with the genotype -308GG achieved an ACR-JRA 30 response at month 6 more frequently than patients with the genotype -308GA or AA. This was already notable at month 3 of therapy. This difference in the total patient group is attributable to the JIA subgroup with rheumatoid factor negative polyarthritis. In this subgroup, patients with the -308GG genotype achieved an ACR-JRA 30 response more frequently than those with the -308GA or AA genotype (84 vs. 33% at months three, P < 0.01, 93 vs. 67% at months six, P < 0.05). There was no influence of the -238 TNF-alpha promoter alleles on clinical response. The rare alleles at position -376 or at positions -163 and -244 were too infrequent. There is an association between TNF gene promoter polymorphisms and response to etanercept in rheumatoid factor negative polyarticular JIA.
17763416 Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive 2007 Sep OBJECTIVE: Degeneration of extracellular matrix of cartilage leads to the production of molecules capable of activating the immune system via Toll-like receptor 4 (TLR-4). The objective of this study was to investigate the involvement of TLR-4 activation in the development and progression of autoimmune destructive arthritis. METHODS: A naturally occurring TLR-4 antagonist, highly purified lipopolysaccharide (LPS) from Bartonella quintana, was first characterized using mouse macrophages and human dendritic cells (DCs). Mice with collagen-induced arthritis (CIA) and mice with spontaneous arthritis caused by interleukin-1 receptor antagonist (IL-1Ra) gene deficiency were treated with TLR-4 antagonist. The clinical score for joint inflammation, histologic characteristics of arthritis, and local expression of IL-1 in joints were evaluated after treatment. RESULTS: The TLR-4 antagonist inhibited DC maturation induced by Escherichia coli LPS and cytokine production induced by both exogenous and endogenous TLR-4 ligands, while having no effect on these parameters by itself. Treatment of CIA using TLR-4 antagonist substantially suppressed both clinical and histologic characteristics of arthritis without influencing the adaptive anti-type II collagen immunity crucial for this model. Treatment with TLR-4 antagonist strongly reduced IL-1beta expression in articular chondrocytes and synovial tissue. Furthermore, such treatment inhibited IL-1-mediated autoimmune arthritis in IL-1Ra(-/-) mice and protected the mice against cartilage and bone pathology. CONCLUSION: In the present study, we demonstrate for the first time that inhibition of TLR-4 suppresses the severity of experimental arthritis and results in lower IL-1 expression in arthritic joints. Our data suggest that TLR-4 might be a novel target in the treatment of rheumatoid arthritis.
17393436 A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same 2007 Apr OBJECTIVE: The cyclic peptide WP9QY (YCWSQYLCY) was designed to mimic the most critical tumor necrosis factor alpha (TNFalpha) recognition loop on TNF receptor I, and it prevents interactions of TNFalpha with its receptor. We undertook this study to compare the effects of the WP9QY peptide on collagen-induced arthritis (CIA) in mice with those of anti-TNFalpha monoclonal antibody. METHODS: CIA was induced by primary and secondary immunizations. Osmotic minipumps were implanted in the backs of all mice on the day of the booster injection (day 21), and vehicle, anti-TNF antibody (4 mg/kg/day), or WP9QY peptide (2 mg/kg/day or 4 mg/kg/day) was continuously infused until the mice were killed (day 40). Thereafter, clinical, radiographic, and histologic assessments were performed. RESULTS: WP9QY treatment inhibited CIA-induced increases in the arthritis score, but onset of disease was not delayed by the peptide. The inhibitory effect of WP9QY on inflammation was definitely weaker than that of anti-TNF antibody. Microfocal computed tomography analyses, however, revealed that WP9QY blocked CIA-induced bone destruction at the knee joints to the same extent as did anti-TNF antibody. In addition, WP9QY inhibited synovial pannus infiltration and reduced osteoclast number. Furthermore, inhibition of CIA-induced systemic bone loss by WP9QY was more apparent than that by anti-TNF antibody. CONCLUSION: The TNFalpha antagonist WP9QY would be a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.
18495731 Combined blockade of granulocyte-macrophage colony stimulating factor and interleukin 17 p 2009 May OBJECTIVE: A pathogenic role for granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)17 in rheumatoid arthritis (RA) has been suggested. In previously published work, the therapeutic potentials of GM-CSF and IL17 blockade in arthritis have been described. In the present study, the simultaneous blockade of both pathways in a mouse model for chronic arthritis was investigated to identify whether this double blockade provides a superior therapeutic efficacy. METHODS: A chronic relapsing arthritis was induced in C57Bl/6 wild type (WT) and C57Bl/6 genetically deficient for IL17 receptor (IL17R knockout (KO)) mice by intra-articular injection of Streptococcal cell wall (SCW) fragments into knees on days 0, 7, 14 and 21. Treatments (intraperitoneal) were given weekly starting on day 14. Animals were analysed for inflammation, joint damage and a range of inflammatory mediators. RESULTS: Joint swelling and cartilage damage were significantly reduced in the IL17R KO mice and in WT mice receiving anti-GM-CSF neutralising mAb 22E9 compared to isotype control antibodies. The therapeutic effect was significantly more pronounced in mice where IL17 and GM-CSF pathways were inhibited (eg, IL17R KO mice treated with 22E9 mAb). Tumour necrosis factor (TNF)alpha blockade had essentially no effect. CONCLUSION: Our data further support the therapeutic potentials of GM-CSF and IL17 blockade in a RA model that is no longer responsive to an established TNFalpha antagonist, moreover, our results suggest that concomitant inhibition of both pathways may provide the basis for a highly effective treatment of chronic RA in patients that are resistant to treatment by TNFalpha inhibitors.
18253928 Active immunization with IL-1 displayed on virus-like particles protects from autoimmune a 2008 Mar IL-1 is an important mediator of inflammation and a major cause of tissue damage in rheumatoid arthritis (RA). Therapeutic administration of recombinant IL-1 receptor antagonist (IL-1Ra) is efficacious in reducing clinical symptoms of disease, but suffers from several drawbacks, including the need for frequent administrations of large amounts. Here, we show that immunization of mice with either IL-1alpha or IL-1beta chemically cross-linked to virus-like particles (VLP) of the bacteriophage Qbeta elicited a rapid and long-lasting autoantibody response. The induced Ab efficiently neutralized the binding of the respective IL-1 molecules to their receptors in vitro and their pro-inflammatory activities in vivo. In the collagen-induced arthritis model, both vaccines strongly protected mice from inflammation and degradation of bone and cartilage. Moreover, immunization with either vaccine showed superior efficacy than daily administrations of high amounts of IL-1Ra. In the T and B cell-independent collagen Ab transfer model, immunization with the IL-1beta vaccine strongly protected from arthritis, whereas immunization with the IL-1alpha vaccine had no effect. Our results suggest that active immunization with IL-1alpha, and especially IL-1beta conjugated to Qbeta VLP, might become an efficacious and cost-effective new treatment option for RA and other systemic IL-1-dependent inflammatory disorders.
16574227 Somatic mutations and activation-induced cytidine deaminase (AID) expression in establishe 2007 Jan Epstein-Barr virus (EBV) transforms human peripheral B cells into lymphoblastoid cell lines (LCLs), allowing the production of specific antibody-secreting cell lines. We and others have previously found that in contrast to peripheral blood B cells, EBV-transformed lymphoblastoid cell lines express the activation-induced cytidine deaminase (AID) gene. The opposite is true for the germinal center-specific BCL6 gene: it is expressed in adult peripheral blood B cells and is no longer expressed in LCLs. The present work extends our findings and shows that whereas AID expression is rapidly induced following EBV infection, BCL6 expression is gradually down-regulated and is fully extinguished in already established LCLs. The question of whether AID activation induces the process of somatic hypermutation (SHM) was investigated in adult-derived LCLs. It was found that the VH gene from the rheumatoid factor-producing RF LCL (derived from a rheumatoid arthritis patient), accumulated somatic point mutations in culture. Overall, nine unique mutations have accumulated in the rearranged VH gene since the generation of the RF cell line. Four additional intraclonal mutations were found among 10 cellular clones of the RF cells. One out of the four was in CDR1 and could be correlated with loss of antigen-binding activity in three out of the 10 clones. Altogether, these 13 mutations were preferentially targeted to the DGYW motifs and showed preference for CG nucleotides, indicating that they were AID-mediated. By contrast, mutations were not detected among 3700-4000 nucleotides each of the Vlambda, Cmu and GAPDH genes derived from the same RF cell cultures and the cellular clones. Our results thus show that AID may generate point mutations in the rearranged Ig VH during in vitro cell culture of adult-LCLs and that these mutations may be responsible, at least in part, for the known instability and occasional loss of antigen-binding activity of antibody-secreting LCLs.
18804867 Lactobacillus casei potentiates induction of oral tolerance in experimental arthritis. 2008 Nov Probiotics have been shown to exert beneficial effects on modulation of diverse diseases. However, no information is available for the effect of probiotics in the induction of oral tolerance in autoimmune diseases. The main purpose of this study was to elucidate whether Lactobacillus casei (L. casei) affect the induction of oral tolerance in experimental rheumatoid arthritis (RA). Type II collagen (CII) alone or together with L. casei was orally administered into collagen-induced arthritis (CIA) rats, and its effects on the clinical and histopathological aspects of RA were investigated. Co-administration of L. casei with CII more effectively suppressed clinical symptoms, paw swelling, lymphocyte infiltration and destruction of cartilage tissues of experimental arthritis than the rats treated with CII alone. The enhanced therapeutic efficacy was associated with an increase in anti-inflammatory cytokines (IL-10 and TGF-beta) while decreasing pro-inflammatory cytokines (IL-1beta, IL-2, IL-6, IL-12, IL-17, IFN-gamma and TNF-alpha). Co-administration of L. casei with CII more effectively suppressed CII-reactive T cell proliferation and the levels of Th1-type IgG isotypes (IgG2a and IgG2b), while up-regulating Foxp3 expression levels and the population of Foxp3(+) CD4(+) T cells. Our study provides evidence that L. casei could potentiate antigen-specific oral tolerance and suppress Th1-type immune responses of arthritic inflammation.
17891165 Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats. 2008 Mar BACKGROUND AND PURPOSE: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. EXPERIMENTAL APPROACH: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. KEY RESULTS: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg(-1), twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1beta, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. CONCLUSIONS AND IMPLICATIONS: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.
17364077 Patient satisfaction with rheumatology practitioner clinics: can we achieve concordance by 2007 Feb INTRODUCTION: The objective of this study was to determine if patient information needs are being met and the level of patient satisfaction with rheumatology practitioners in participatory decision-making and thereby indirectly explore whether concordance was achieved. MATERIALS AND METHODS: The design was a cross-sectional postal questionnaire survey of 420 patients attending outpatient clinics at the Norfolk and Norwich University Hospital who were taking disease modifying anti-rheumatic drugs (DMARDs) or a biological treatment. The population served is ethnically homogeneous and predominantly Caucasian. RESULTS: The response rate was 76%. Most respondents (79%) had inflammatory arthritis while 66% had rheumatoid arthritis. Seventy-seven per cent of patients reported that the rationale behind commencing treatment was explained and that they were given ample opportunities to ask questions. Eighty-two per cent said they were given an appropriate amount of information. Sixty-four per cent of patients were satisfied with their level of participation in the decision-making process, although a substantial number (25%) said that information from different sources was conflicting. There was no correlation between concern about side effects and patients' perceptions of the effectiveness of medication. Females were more concerned than males about possible side effects; P =0.009, using the Mann-Whitney U test. One third of the patients altered their medication in response to whether their arthritis felt better or worse. CONCLUSION: The majority of patients were satisfied that their information needs were met and with the care provided in the practitioner clinic. Participatory decision-making was sub-optimal despite patient satisfaction with the amount of time allocated to meeting their information needs. We found that patients exercise autonomy in managing their arthritis by regulating their medications through an active decision-making process, which is informed by their previous experience of medication, and how well controlled they felt their arthritis was. Research into this decision-making process may hold the key to achieving concordance.
16944157 Alpha-lipoic acid suppresses the development of collagen-induced arthritis and protects ag 2007 Jan OBJECTIVE: To test the ability of alpha-lipoic acid (LA) to attenuate the development of collagen-induced arthritis (CIA) in mice. METHODS: Mice were divided into three groups and treated with intraperitoneal administration of LA (10 or 100 mg/kg) or placebo. Clinical, histologic, and biochemical parameters were assessed. Human synovial fibroblasts and peripheral blood mononuclear cells were cocultured in various concentrations of LA to evaluate the effects on osteoclastogenesis. RESULTS: LA was associated with a dose-dependent reduction of CIA, as well as preventing bone erosion and destructive changes. Intracellular reactive oxygen species in lymphocytes obtained from inguinal lymph nodes, which was significantly higher in CIA than control mice, was significantly reduced in CIA by LA. The concentrations of TNF-alpha, IL-1beta, and IL-6 in the paws, and synovial NF-kappaB binding, all of which were markedly higher in CIA than control mice, were reduced by treatment with LA. In addition, LA inhibited the formation of human osteoclasts in vitro. CONCLUSION: Amelioration of joint disease by LA was associated with reduction in oxidative stress, as well as inhibition of inflammatory cytokine activation and NF-kappaB DNA binding activity. Moreover, LA inhibited bone destruction in vivo and osteoclastogenesis in vitro. Collectively, these results indicate that LA may be a new adjunctive therapy for rheumatoid arthritis.
16651620 p21Cip1 is required for the development of monocytes and their response to serum transfer- 2006 May One of the central functions of cyclin-dependent kinase inhibitors, such as p21, p27, or p16, is to prevent entry into the cell cycle. However, the question remains as to whether they have other functions in the cell. We previously demonstrated that overexpression of p21 in fibroblasts isolated from patients with rheumatoid arthritis decreases the production of pro-inflammatory molecules. Overexpression of p21 has been also shown to reduce the development of experimental arthritis in mice and rats. To explore the role of endogenous p21 in the development of arthritis, we induced arthritis in p21(-/-) mice using the K/BxN serum transfer model of arthritis. Mice deficient in p21 were more resistant to serum transfer-induced arthritis (K/BxN) than wild-type (wt) control mice. Fewer macrophages were detected in p21(-/-) as compared to wt joints following transfer of K/BxN serum. Chemotaxis assays of bone marrow-derived macrophages from p21(-/-) and wt mice revealed no difference in migration. However, there was a substantial decrease in inflammatory monocytes circulating in peripheral blood and in monocyte precursors in bone marrow of p21(-/-) mice as compared to wt mice. Adoptive transfer of wt bone marrow-derived macrophages into p21(-/-) mice restored the sensitivity to serum transfer-induced arthritis. These data suggest a novel role for p21 in regulating the development and/or differentiation of monocytic populations that are crucial for the induction of inflammatory arthritis.
18762738 Exercise therapy in juvenile idiopathic arthritis: a Cochrane Review. 2008 Sep BACKGROUND: Exercise therapy is considered an important component of the treatment of arthritis. The efficacy of exercise therapy has been reviewed in adults with rheumatoid arthritis but not in children with juvenile idiopathic arthritis (JIA). OBJECTIVES: To assess the effects of exercise therapy on functional ability, quality of life and aerobic capacity in children with JIA. METHODS: Several electronic databases were searched up to October 2007 and references were tracked. The selection criteria were randomized controlled trials (RCTs) of exercise treatment in JIA. As for data collection and analysis, potentially relevant references were evaluated and all data were extracted by two review authors working independently. RESULTS: Three out of 16 identified studies met the inclusion criteria, with a total of 212 participants. All the included studies fulfilled at least seven of 10 methodological criteria. The outcome data of the following measures were homogenous and were pooled in a meta-analysis: functional ability (N=198; weighted mean difference [WMD] -0.07, 95% CI -0.22 to 0.08), quality of life (CHQ-PhS: N=115; WMD -3.96, 95% CI -8.91 to 1.00) and aerobic capacity (N=124; WMD 0.04, 95% CI -0.11 to 0.19). The results suggest that the outcome measures all favoured the exercise therapy but none were statistically significant. None of the studies reported negative effects of the exercise therapy. CONCLUSIONS: Overall, based on ''silver-level'' evidence there was no clinically important or statistically significant evidence that exercise therapy can improve functional ability, quality of life, aerobic capacity or pain. The included and excluded studies were all consistent about the adverse effects of exercise therapy; no short-term detrimental effects of exercise therapy were found in any study. Both included and excluded studies showed that exercise does not exacerbate arthritis. Although the short-term effects look promising, the long-term effect of exercise therapy remains unclear.
16896287 Genomic progress in pediatric arthritis: recent work and future goals. 2006 Sep PURPOSE OF REVIEW: Pediatric arthritis is a heterogeneous group of chronic arthropathies that are influenced by complex genetic and perhaps environmental factors. Interacting genetic traits may one day be identified that provide the basis for predicting disease risk and other characteristics such as course, age of onset, and disease severity. The purpose of this review is to describe the recent progress towards identifying the multiple genes related to pediatric arthritis and understand how they relate to each other and to disease pathology. RECENT FINDINGS: Candidate gene studies are by far the most widely reported type of genetic studies to date for juvenile arthritis with only one genome-wide screen for juvenile rheumatoid/idiopathic arthritis published. Particular attention is paid to studies of candidate genes with potential immunological roles and those associated with other forms of autoimmunity. SUMMARY: Genomic studies may perhaps one day provide information to allow future classification systems of childhood arthritis to include molecular biomarkers as a complement to clinical observations, as well as understand how these genes or proteins relate to each other and to disease pathogenesis.
17361376 The crowned dens syndrome. Evaluation with CT imaging. 2007 Mar PURPOSE: The purpose of this study was to verify the value of computed tomography (CT) in the diagnosis of the "crowned dens" syndrome, not only in crystal deposition diseases, but also in other rheumatic or nonrheumatic conditions. MATERIALS AND METHODS: Thirty-eight patients (15 men and 23 women; mean age 55 years; age range 35-79) with neck pain were examined and divided into two groups: (1) patients already identified as rheumatic and referred for further investigation of the atlantoaxial region; (2) patients with symptoms confined to the cervical spine, with inconclusive radiographic findings. Unenhanced CT of the cervical spine (Tomoscan SR 7000 Philips, Eindhoven, Netherlands) was performed in all patients. There were 11 cases of rheumatoid arthritis (ten women and one man), two calcium pyrophosphate dihydrate crystal deposition disease (both women), one of systemic sclerosis (a woman), one of osteoarthritis (a man), one of seronegative arthritis (a man), four of neoplasm (one woman and three men) with suspected cervical involvement, one (a man) of haematological disease (lymphoma), one (a woman) of menopausal osteoporosis, ten (five men and five women) of recent or previous trauma with suspected involvement of the skull base and first cervical vertebrae and six of unknown painful cervical dysfunction (three men and three women). RESULTS: CT demonstrated calcific deposits around the dens in 12 patients (three men and nine women), in the transverse and alar ligaments, and in the anterior atlantooccipital membrane. CT revealed horseshoe- or crown-like calcification surrounding the odontoid process. In our series, other rheumatic diseases, especially rheumatoid arthritis, showed similar irregular calcifications of the atlantoaxial joint. Discussion. In calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, the spine may be the only site of involvement, generally asymptomatic. Crystals located in the transverse ligament of the atlas give rise to the crowned dens syndrome, usually in patients affected by severe degenerative lesions of the atlantoaxial joint and peripheral chondrocalcinosis. Symptoms may be absent, or a neurological compressive syndrome may develop. Symptoms tend to worsen with age. The diagnosis is not always easy, as the symptoms are similar to those of other diseases, such as meningitis, cervicobrachial pain, occipitotemporal headache, calcific tendinitis of the longus colli muscle, spondylodiscitis and retropharyngeal abscess. CONCLUSION: CT is the gold standard in identifying crowned dens syndrome, as it is able to depict the shape and site of calcification and any bone erosions. Radiography of other joints (wrist, knee, pubic symphysis) may help to ascertain whether the disease is due to calcium pyrophosphate dihydrate or hydroxyapatite crystals, and is therefore recommended for routine patient management. Magnetic resonance imaging (MRI) is indicated for the study of neurological complications.
17928969 [Development of systemic lupus erythematosus with focal proliferative lupus nephritis duri 2007 Oct 15 BACKGROUND: Treatment with tumor necrosis factor-(TNF-)alpha-blocking agents is used in a variety of autoimmune diseases. In anti-TNF-alpha therapy for rheumatoid arthritis, occasionally, the development of autoantibodies as well as lupus-like syndromes have been observed, rarely, glomerulonephritides are also induced. The authors first report the development of lupus erythematosus with renal involvement in a patient with psoriatic arthritis during therapy with the soluble TNF-alpha receptor etanercept. CASE REPORT: A 70-year-old patient with long-standing psoriatic arthritis developed pleuritis, pericarditis, as well as marked arthralgias during therapy with etanercept. Laboratory investigation showed markedly increased parameters of inflammation, antinuclear antibodies (ANA), a proteinuria of 3.2 g/day, mild impairment of renal function, as well as a nephritic urinary sediment. A subsequently performed renal biopsy was diagnostic for focal proliferative lupus nephritis. After withdrawal of etanercept and initiation of a cyclophosphamide pulse therapy in combination with oral steroids, parameters of inflammation and renal function rapidly normalized; pleuritis and pericarditis were not detectable anymore. CONCLUSION: Anti-TNF-alpha therapy in patients with psoriatic arthritis or other autoimmune diseases may lead to induction of systemic lupus with renal involvement.
18025232 A complement C3 inhibitor specifically targeted to sites of complement activation effectiv 2007 Dec 1 Collagen-induced arthritis (CIA) represents an animal model of autoimmune polyarthritis with similarities to human rheumatoid arthritis, and therapy with various systemic complement-inhibitory proteins has been investigated in this model with varying results. We investigated the use of complement receptor 2 (CR2)-Crry, a complement inhibitor with the ability to target C3 breakdown products deposited in a rheumatic joint. Following induction of CIA in DBA/1J mice, animals were treated with either PBS or CR2-Crry (every other day, every 4 days, or with a single injection). The severity of clinical disease was significantly reduced in all CR2-Crry-treated groups compared with controls. Joints from mice receiving multiple doses of CR2-Crry showed significantly decreased inflammatory cell infiltrate, cartilage damage, pannus formation, and bone damage. CR2-Crry treatment also significantly decreased production of anti-collagen IgG and the inflammatory cytokines TNF-alpha and IL-1beta. IL-10 and IL-1Ra levels were increased in CR2-Crry-treated mice. CR2-Crry localized preferentially in the joints of mice with CIA. Analysis of IgG and C3 deposition in the joints of treated animals indicated that both complement regulation and the modulation of anti-collagen Ab production contributed to the protective effects of CR2-Crry. Of interest, a previous study reported that Crry-Ig, an untargeted counterpart of CR2-Crry, had minimal effect on disease, even when administered at a sufficiently high dose to maintain chronic complement inhibition.
16881124 Inhibited apoptosis of synovial fluid lymphocytes in children with juvenile idiopathic art 2006 Aug OBJECTIVE: Inhibited apoptosis of lymphocytes present in synovial fluid (SFL) and persistently infiltrating synovial tissue may be crucial in the pathogenesis of rheumatoid arthritis (RA). Similarly, this may be the case in juvenile idiopathic arthritis (JIA). Little is known about lymphocyte apoptosis in this disease. Recently, we reported significantly enhanced apoptosis of peripheral blood lymphocytes (JIA-PBL) compared to synovial fluid (JIA-SFL) or healthy lymphocytes, with downregulation of p53 in JIA-SFL. In this study we assessed other possible molecular mechanisms of this phenomenon. METHODS: PBL from 31 children with JIA and 26 healthy children were examined. SFL obtained from 18 patients was also studied. Apoptosis was assessed by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. Expression of several apoptosis-regulating proteins was analyzed, including myeloid cell leukemia 1 (Mcl-1), cross-linked inhibitor of apoptosis (XIAP), FLICE-inhibitory protein (FLIP), or Bcl-xL inhibitors and proapoptotic p53, Bcl-w, Bak, and Bid. RESULTS: We found significant overexpression of Mcl-1 and XIAP in JIA-SFL (p < 0.001 and p < 0.02, respectively). Expression of Mcl-1 and XIAP in SFL correlated inversely with the apoptotic index (p < 0.002 and p < 0.01, respectively). FLIP expression was also distinctly higher in SFL than in JIA-PBL; however, the difference was not statistically significant (p = 0.061). No statistically significant differences were found in the expression of other proteins between SFL and PBL. CONCLUSIONS: This is the first study showing that upregulation of anti-apoptotic Mcl-1 and XIAP proteins, along with downregulation of p53 protein, is correlated with inhibition of JIA-SFL apoptosis.