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ID PMID Title PublicationDate abstract
19216731 Genetic control of disease in an experimental model for Sjögren's syndrome. 2009 Sjögren's syndrome is an autoimmune disease with a complex etiology depending on hereditary and environmental factors. The disease is characterized by lymphocytic infiltration and inflammation in the salivary and lacrimal glands, leading to oral and ocular dryness. To understand the genetic susceptibility in Sjögren's syndrome, studies of disease phenotypes have been performed in the non-obese diabetic (NOD) mouse. By the identification of genetic regions controlling development of autoimmune exocrinopathy in the NOD mouse and by reducing one of these regions considerably, Nguyen et al. in a recent issue of Arthritis Research and Therapy propose candidate genes for development of Sjögren's syndrome.
20191499 Dehydroepiandrosterone (DHEA) substitution treatment for severe fatigue in DHEA-deficient 2010 Jan 15 OBJECTIVE: Primary Sjögren's syndrome (SS) is characterized by fatigue and low levels of serum dehydroepiandrosterone/dehydroepiandrosterone sulfate (DHEA/DHEAS). Our aim was to study whether SS patients with severe fatigue and low serum DHEAS values benefit from DHEA substitution (50 mg/day). METHODS: A multicenter, investigator-based, powered, randomized controlled clinical trial (crossover, washout design) using fatigue as the primary outcome measure was performed on patients with primary SS (n = 107) who had a general fatigue score > or =14 on the 20-item Multiple Fatigue Inventory (MFI-20), combined with age- and sex-adjusted serum DHEAS values below the mean. Fatigue was assessed using MFI-20 subscales, i.e., general fatigue, physical fatigue, mental fatigue, reduced motivation, and activity (scale 4-20), and with a visual analog scale (VAS; scale 0-100). RESULTS: In an intent-to-treat analysis, a 50-mg DHEA substitution dose and placebo similarly improved fatigue. All of the MFI-20 subscales and the fatigue VAS improved from the baseline levels as a result of treatment (P < 0.001), but with negligible differences between these 2 treatments. The mean between-treatment difference was -0.1 for general fatigue (the primary outcome measure), 0.0 for physical fatigue, 0.0 for mental fatigue, 0.0 for reduced motivation, 0.3 for reduced activity, and 2.2 for the fatigue VAS. None of these differences was statistically significant. CONCLUSION: Similar to earlier results using pharmacologic doses, substitution treatment with 50 mg of DHEA in DHEA-deficient and severely tired primary SS patients does not help against fatigue better than placebo. This may relate to the prohormone nature of DHEA and its recently described defective intracrine tissue-specific conversion to active sex steroids in SS.
18682951 Health-related quality of life in patients with common rheumatic diseases referred to a un 2009 Jan The aim of the present study was to assess the health-related quality of life (HRQoL) in patients with common rheumatic diseases referred to a rheumatology clinic and to compare it to the HRQoL of the general population. All patients with a new referral to the Department of Rheumatology of the Helsinki University Central Hospital were asked to participate in the study during the period from May 2002 to April 2003. A total of 295 patients with various rheumatic diseases were included in the analysis: 99 patients with rheumatoid arthritis (RA), 47 with arthralgia and fibromyalgia, 43 with other chronic arthritis (spondyloarthritis, psoriatic arthritis, enteropathic arthritis), 44 with osteoarthritis (OA), 22 with active reactive arthritis (ReA), 17 with systemic rheumatic diseases, 9 adults with juvenile idiopathic arthritis (JIA) and 14 with other diagnoses. HRQoL was measured by a disease specific instrument, the Stanford health assessment questionnaire (HAQ) and by a generic instrument, 15D. The mean baseline 15D score of the 295 included patients (0.822, SD 0.114) was significantly lower than of the general population (0.903, SD 0.098). Patients with OA and chronic arthritis reported the poorest HRQoL scores (both 0.810 on a 0-1 scale). In patients with RA and ReA the 15D score improved in a statistically significant and clinically important manner during the 8-month follow-up. Discomfort and symptoms caused by the disease were alleviated in a statistically significant manner in patients with RA as well as in those with arthralgia and fibromyalgia, chronic arthritis, ReA and systemic rheumatic diseases. HAQ score improved significantly in patients with RA, arthralgia and fibromyalgia, and ReA. The HRQoL of patients with common rheumatic diseases at referral to rheumatology clinic is significantly lower than the HRQoL of age-standardized general population. The most affected patients are those with OA, chronic arthritis and RA. A significant improvement in HRQoL with conventional interventions was achieved in patients with RA and ReA.
18701557 Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: 2009 Aug BACKGROUND: Mikulicz's disease (MD) has been considered as one manifestation of Sjögren's syndrome (SS). Recently, it has also been considered as an IgG(4)-related disorder. OBJECTIVE: To determine the differences between IgG(4)-related disorders including MD and SS. METHODS: A study was undertaken to investigate patients with MD and IgG(4)-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG(4)-positive multiorgan lymphoproliferative syndrome (IgG(4)+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG(4) (>135 mg/dl) and infiltration of IgG(4)(+) plasma cells in the tissue (IgG(4)+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG(4)+MOLPS and 31 patients with typical SS were compared. RESULTS: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG(4)+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG(2), IgG(4) and IgE levels were significantly increased in IgG(4)+MOLPS. Histological specimens from patients with IgG(4)+MOLPS revealed marked IgG(4)+ plasma cell infiltration. Many patients with IgG(4)+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG(4)+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG(4)+MOLPS treated with glucocorticoids showed marked clinical improvement. CONCLUSION: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG(4)+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG(4)+MOLPS.
20888090 [Acquired Gitelman syndrome associated with Sjögren's syndrome and scleroderma]. 2011 Aug Tubulopathy can complicate autoimmune diseases. It is usually a distal tubular acidosis, but Fanconi syndrome or Bartter syndrome has been exceptionally reported. We report a case of acquired Gitelman syndrome in a 32-year-old male who also presented diffuse scleroderma autoimmune thyroiditis, and Sjögren's syndrome. Only three cases of Sjögren syndrome associated with Gitelman syndrome have been previously reported in literature. The absence of other cases in the family and absence of mutation SLC12A3 emphasise the relation between autoimmune disease and this tubulopathy.
20532788 [Novel approach for the early detection of inflammatory rheumatic diseases in the populati 2010 Oct Current evidence-based guidelines for patients with rheumatoid arthritis (RA) emphasize the need for early diagnosis and treatment with disease-modifying antirheumatic drugs. However, these recommendations have not been implemented universally in Germany. This prompted the German Cooperative Rheumatology Group Rhine-Ruhr to devise a screening programme for inflammatory rheumatic diseases (IRD) using a specially equipped bus, which was sent on a 5-week tour of a series on local towns. Visitors were asked to fill out a questionnaire (RheumaCheck) and to undergo a blood test for rheumatoid factor and anti-mutated citrullinated vimentin antibodies. In the case of positive test results or on request due to symptoms, visitors could undergo targeted examination on the bus by a rheumatologist. Of the 2691 people who visited the bus (73% females, average age 62 years), 1330 consulted the rheumatologist. IRD was suspected in 319 attendees and confirmed in 104 of 172 screening participants, who went on to attend a rheumatological practice. RA was diagnosed in a total of 54 cases (2.1% of all visitors).
21205510 [Peripheral neuropathy caused by leflunomide. A case reported with a brief review]. 2010 Sep BACKGROUND: Leflunomide (LEF) is an immunomodulator derived from isoxazole It is an approved drug in the rheumatoid arthritis (RA). The peripheral neuropathy (PN) is a recognized side effect of some medications. CLINICAL CASE: A 48 years old woman with diabetes type 2 (DM2) and RA; with serum negative rheumatoid factor. She got nonsteroidal anti-inflammatories drugs, corticosteroid, methotrexate, sulfasalazine and chloroquine. Despite this, she was clinically within the functional class III and data of osteopenia. The treatment was switched to LEF, chloroquine and prednisone. After four months, she began with dysesthesia in the left cubital area, paresthesias in her right knee; and then in a progressive pattern others paresthesias, hyporeflexia and a decrease in the muscular strength. She was treated with cholestyramine, but her neuropathy did not improve. Severe segmental demyelination polyneuropathy and retrograde axonal degeneration with predominance of the thoracic members over the pelvic members was reported in the electroneurophysiological and electromyography studies. CONCLUSIONS: It is advisable to perform electrophysiological studies in patients' with DM2 before they get treatment with LEF.
20732647 Pharmacotherapy: concepts of pathogenesis and emerging treatments. Novel targets in bone a 2010 Aug The spectrum of arthritis ranges from erosive (e.g., rheumatoid arthritis) to ossifying disease with formation of new bone (e.g., ankylosing spondylitis and osteoarthritis). The molecular basis for these different patterns of arthritis had long been unclear. In the last few years, however, characterisation of catabolic and anabolic molecular pathways in different forms of arthritis led to a better understanding of joint remodelling and revealed novel therapeutic targets. Recent findings show that catabolic and anabolic molecular pathways govern bone and cartilage remodelling in healthy and arthritic joints. The predominance of catabolic molecular pathways (e.g., receptor activator of nuclear factor-kappaB ligand (RANKL)/RANK and cathepsin K) causes erosive disease whereas anabolic signalling (e.g., Wnt and fibroblast growth factor (FGF)18) favours the formation of new bone including bony spurs and subchondral sclerosis. Other pathways may have a dual function in arthritis (e.g., hedgehog) leading to either catabolic or anabolic joint remodelling dependent on other factors. Key mediators within these signalling pathways may serve as novel targets for treating pathological remodelling of bone and cartilage in arthritis. Molecular pathways govern remodelling processes of bone and cartilage in arthritic joints. Future therapies will likely target the pathologic activity of these molecular pathways to specifically block either catabolic or anabolic joint remodelling in arthritis.
18984038 Differences in the injury/sprouting response of splenic noradrenergic nerves in Lewis rats 2009 Feb Sympathetic nerves in the spleen undergo an injury and sprouting response with development of adjuvant-induced arthritis (AA), a model of rheumatoid arthritis (RA). The objective of the present study was to determine whether this injury and sprouting response is disease-specific or occurs in a non-specific manner similar to injury and sprouting responses following sympathectomy with specific neurotoxins. Changes in noradrenergic (NA) innervation in spleens from Lewis rats 28 days following adjuvant treatment to induce arthritis and/or local 6-hydroxydopamine (6-OHDA) treatment to destroy NA nerves were examined using immunocytochemistry for tyrosine hydroxylase (TH). We observed significant increases in sympathetic innervation of hilar regions, sites of nerve entry into the spleen, and a striking decline in innervation of splenic regions distant to the hilus in arthritic compared to non-arthritic rats. While increased hilar and decreased distal NA innervation in arthritic rats was strikingly similar to that of non-arthritic 6-OHDA-treated rats, there were differences in splenic compartments innervated by sympathetic nerves between these groups. In 6-OHDA-treated rats, NA nerves re-innervated splenic compartments normally innervated by sympathetic nerves. In arthritic rats, sympathetic nerves returned to normally innervated splenic compartments, but also abundantly innervated red pulp. These findings suggest that splenic sympathetic nerves undergo a disease-associated injury/sprouting response with disease development that alters the normal pattern and distribution of NA innervation. The altered sympathetic innervation pattern is likely to change NA signaling to immune cell targets, which could exert long-term regulatory influences on initiation, maintenance, and resolution of immune responses that impact disease pathology.
20080669 Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administrati 2010 Feb 2 The beneficial effects of probiotics have been described in many diseases, but the mechanism by which they modulate the immune system is poorly understood. In this study, we identified a mixture of probiotics that up-regulates CD4(+)Foxp3(+) regulatory T cells (Tregs). Administration of the probiotics mixture induced both T-cell and B-cell hyporesponsiveness and down-regulated T helper (Th) 1, Th2, and Th17 cytokines without apoptosis induction. It also induced generation of CD4(+)Foxp3(+) Tregs from the CD4(+)CD25(-) population and increased the suppressor activity of naturally occurring CD4(+)CD25(+) Tregs. Conversion of T cells into Foxp3(+) Tregs is directly mediated by regulatory dendritic cells (rDCs) that express high levels of IL-10, TGF-beta, COX-2, and indoleamine 2,3-dioxygenase. Administration of probiotics had therapeutical effects in experimental inflammatory bowel disease, atopic dermatitis, and rheumatoid arthritis. The therapeutical effect of the probiotics is associated with enrichment of CD4(+)Foxp3(+) Tregs in the inflamed regions. Collectively, the administration of probiotics that enhance the generation of rDCs and Tregs represents an applicable treatment of inflammatory immune disorders.
19568828 Imatinib mesylate inhibited rat adjuvant arthritis and PDGF-dependent growth of synovial f 2009 Overgrowth of the synovium plays an important role in the pathogenesis of rheumatoid arthritis (RA). Platelet-derived growth factor (PDGF) is one of the most potent mitogenic factors of synovial cells, and imatinib mesylate (imatinib) is a specific inhibitor of the PDGF receptor tyrosine kinase. The aim of this study was to elucidate the anti-rheumatic activity of imatinib. The in vivo effects of imatinib were assessed by evaluating the sequential manifestation of adjuvant-induced arthritis in rats using paw volume and clinical scores. Imatinib was found to inhibit rat adjuvant-induced arthritis, but the inhibitory effects were incomplete. To confirm the mechanism of anti-rheumatic-activity of imatinib, we assessed the in vitro effects of imatinib on the proliferation of RA synovial fibroblast-like cells (RASFs) using a MTT assay. Intracellular signaling of PDGF was evaluated by Western blot analysis. Platelet-derived growth factor was found to induce a significant proliferation of RASFs, while imatinib inhibited PDGF-induced proliferation of RASF. Imatinib also inhibited PDGF-induced phosphorylation of the PDGF receptor and Akt, whereas constitutive activated extracellular signal-regulated kinase was not inhibited by imatinib. In contrast, imatinib did not inhibit transforming growth factor beta- and basic fibroblast growth factor-induced proliferation of RASF. Oral administration of imatinib ameliorated adjuvant-induced arthritis in rats, and it inhibited PDGF-induced RASF proliferation through disruption of the PDGF-R to Akt kinase signaling pathway. Because imatinib cannot inhibit the non-PDGF-dependent proliferation of RASFs, the anti-rheumatic effect of imatinib may be incomplete. The development of inhibitors of RASF proliferation may lead to the successful treatment of RA.
19405003 Development and validation of a composite disease activity score for juvenile idiopathic a 2009 May 15 OBJECTIVE: To develop and validate a composite disease activity score for juvenile idiopathic arthritis (JIA), the Juvenile Arthritis Disease Activity Score (JADAS). METHODS: The JADAS includes 4 measures: physician global assessment of disease activity, parent/patient global assessment of well-being, active joint count, and erythrocyte sedimentation rate. These variables are part of the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, and Pedi 70 criteria for improvement. Validation analyses were conducted on >4,500 patients and included assessment of construct validity, discriminant validity, and responsiveness to change. Three versions of the JADAS were tested based on 71-joint (range 0-101), 27-joint (range 0-57), or 10-joint (range 0-40) counts. Statistical performances of the JADAS were compared with those of 2 rheumatoid arthritis composite scores, the Disease Activity Score in 28 joints (DAS28) and the Clinical Disease Activity Index (CDAI). RESULTS: The JADAS demonstrated good construct validity, yielding strong correlations with JIA activity measures not included in the score and moderate correlations with the Childhood Health Assessment Questionnaire. Correlations obtained for the 3 JADAS versions were comparable, but superior to those yielded by the DAS28 and CDAI. The area under the curve of the JADAS predicted long-term disease outcome, measured as radiographic progression over 3 years. In 2 clinical trials, the JADAS discriminated well between ACR Pedi 30, Pedi 50, and Pedi 70 response and revealed strong responsiveness to clinical change. CONCLUSION: The JADAS was found to be a valid instrument for assessment of disease activity in JIA and is potentially applicable in standard clinical care, observational studies, and clinical trials.
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.
19686583 Effector mechanisms of interleukin-17 in collagen-induced arthritis in the absence of inte 2009 INTRODUCTION: Interleukin (IL)-17 is a pro-inflammatory cytokine in rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Since interferon (IFN)-gamma inhibits Th17 cell development, IFN-gamma receptor knockout (IFN-gammaR KO) mice develop CIA more readily. We took advantage of this model to analyse the mechanisms of action of IL-17 in arthritis. The role of IFN-gamma on the effector mechanisms of IL-17 in an in vitro system was also investigated. METHODS: IFN-gammaR KO mice induced for CIA were treated with anti-IL-17 or control antibody. The collagen type II (CII)-specific humoral and cellular autoimmune responses, myelopoiesis, osteoclastogenesis, and systemic cytokine production were determined. Mouse embryo fibroblasts (MEF) were stimulated with IL-17, tumor necrosis factor (TNF)-alpha and the expression of cytokines and chemokines were determined. RESULTS: A preventive anti-IL-17 antibody treatment inhibited CIA in IFNgammaR KO mice. In the joints of anti-IL-17-treated mice, neutrophil influx and bone destruction were absent. Treatment reduced the cellular autoimmune response as well as the splenic expansion of CD11b+ cells, and production of myelopoietic cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-6. IL-17 and TNF-alpha synergistically induced granulocyte chemotactic protein-2 (GCP-2), IL-6 and receptor activator of NFkappaB ligand (RANKL) in MEF. This induction was profoundly inhibited by IFN-gamma in a STAT-1 (signal transducer and activator of transcription-1)-dependent way. CONCLUSIONS: In the absence of IFN-gamma, IL-17 mediates its pro-inflammatory effects mainly through stimulatory effects on granulopoiesis, neutrophil infiltration and bone destruction. In vitro IFN-gamma profoundly inhibits the effector function of IL-17. Thus, aside from the well-known inhibition of the development of Th17 cells by IFN-gamma, this may be an additional mechanism through which IFN-gamma attenuates autoimmune diseases.
20073422 A study of intima media thickness and their cardiovascular risk factors in patients with p 2009 INTRODUCTION: Psoriatic Arthritis (PsA) is an inflammatory arthritis associated with Psoriasis. Its recognition as an inflammatory disease distinct from Rheumatoid Arthritis has put forward for consideration several questions regarding its specific CVS mortality and morbidity (9, 11, 16, 26). Carotid intima media thickness is a useful surrogate and sensitive marker to determine atherosclerosis even in its subclinical stages (6, 14, 22, 27, 32). OBJECTIVE: Prevalence of carotid intima media thickness in patients with Psoriatic arthritis is unknown in Asian population. We aim to identify the presence of subclinical atherosclerosis in patients with psoriatic arthritis and disease activity association and its predictors in a series of patients with PsA attended to the rheumatology clinic, tertiary hospitals. METHODS: A total of 63 patients with PsA who fulfilled the CASPAR criteria were recruited from UKM Medical Centre and Hospital Putrajaya. Common carotid intima media thickness (IMT) was measured in both right and left carotid artery by using high resolution B-mode ultrasound. This was a cross sectional study first done in Malaysia for PsA patients. RESULTS: The positive IMT (IMT > 1.00 mm) among PsA was observed in 10 out of 63 patients (15.9 %) regardless of background cardiovascular risk. The mean +/- SD of IMT was 0.725 +/-0.260 mm for this study. Variables significantly associated with positive IMT (p < 0.05) included age at the time of study (p = 0.005), waist circumference (p = 0.001), Hypertension (p = 0.007), Diabetes (p = 0.002) and Metabolic syndrome (p = 0.001) and not associated with gender, ethnicity, duration of PsA disease, pattern of PsA, disease activity and severity. Above all, only age had positive IMT independent predictor (p = 0.032), with OR 1.116; 95 % CI (1.010-1.234). CONCLUSIONS: There was a significant association between CVS risk and positive Intima Media Thickness in Psoriatic Arthritis patients. Otherwise, there was no association in disease activity, disease severity and DMARDS therapy with positive Intima Media Thickness in Psoriatic Arthritis patients. The study was approved by Research and Ethics Committee of the faculty of medicine, Universiti Kebangsaan Malaysia with project code FF-114-2008 and by Community Research Center (CRC) of National Institutes of Health (NIH) for the case study in Hospital Putrajaya with the project code NMRR-08-970-2125.
19567252 Use of biofluorescence imaging to compare the distribution of certolizumab pegol, adalimum 2009 Aug 31 Exposure to a drug at the site of inflammation may be an important consideration for the effective treatment of inflammatory disorders such as rheumatoid arthritis (RA). The purpose of this in vivo study was to identify a methodology to enable effective quantification of antibody-type reagents in normal and inflamed tissue by investigating the distribution of the tumor necrosis factor-alpha (TNF-alpha) inhibitors, certolizumab pegol, adalimumab, and infliximab, in healthy and inflamed murine tissue using a novel non-invasive biofluorescence method. Certolizumab pegol, adalimumab, and infliximab were labeled with the low molecular weight dye alexa680. The agents were administered intravenously at a dose of 2mg/kg in naïve DBA/1 mice and in DBA/1 mice with ongoing collagen-induced arthritis. Concentrations of the TNF inhibitors in the hind paws were measured using a Xenogen IVIS200 biofluorescence imager at multiple time points up to 26h post-administration. In 2 independent experiments, the distribution of certolizumab pegol was compared with that of adalimumab and infliximab. Certolizumab pegol, adalimumab, and infliximab all distributed more effectively into inflamed tissue than non-inflamed tissue in this animal model of arthritis. However, the ratio of penetration of certolizumab pegol into inflamed arthritic paws compared with normal tissue was greater than that observed with adalimumab and infliximab. Furthermore, the duration of exposure in the inflamed versus normal tissue was more prolonged for certolizumab pegol than for both adalimumab and infliximab, and the accumulation of certolizumab pegol in diseased tissue was more responsive to the severity of inflammation when compared with adalimumab and infliximab. It is probable that these features of certolizumab pegol are conferred on the molecule by PEGylation. It is important to assess exposure to drug at the site of inflammation, because distinct structural features of certain agents may affect efficacy, tolerability, rapidity and/or sustainability of effect. The novel non-invasive biofluorescence method used in this study is an effective tool for comparing tissue penetration of therapeutic agents.
19188194 The natural soluble form of IL-18 receptor beta exacerbates collagen-induced arthritis via 2010 Jan OBJECTIVE: IL-18 is a pluripotent cytokine that has been implicated in the development of rheumatoid arthritis. A soluble form of the IL-18 receptor accessory protein (sIL-18Rbeta) with unknown function has recently been identified. This study examined the ability of sIL-18Rbeta to inhibit IL-18 biological activities and to modulate immune responses during collagen-induced arthritis (CIA). METHODS: Adenoviruses encoding sIL-18Rbeta were administered intravenously in type II collagen-immunised DBA/1 mice. Humoral responses were analysed by determining anti-bovine collagen type II (BCII) antibody levels by ELISA. Cytokine production by splenic T cells and cytokine levels in serum were measured by Luminex multi-analyte technology. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) were measured by flow cytometry. RESULTS: Intravenous delivery of Ad5.sIL-18Rbeta in collagen-immunised mice led to enhanced transgene expression in splenic antigen-presenting cells (APC). A co-culture of these sIL-18Rbeta-transduced APC with purified splenic CD3(+) T cells led to a marked inhibition of IL-18-induced IFNgamma, IL-4 and IL-17 production by CD3(+) T cells. Remarkably, systemic treatment with Ad5.sIL-18Rbeta caused an exacerbation of arthritis, and histological evaluation of knee joints showed increased cartilage and bone erosion. No significant differences were observed in anti-BCII antibodies, but the aggravation was accompanied by decreased IFNgamma (-30%) and IL-4 (-44%) and increased IL-17 (+84%) production by splenic CD3(+) T cells. In addition, reduced circulating levels of CD4(+)CD25(+)Foxp3(+) Treg and anti-inflammatory IL-10 were shown. CONCLUSION: This study identifies sIL-18Rbeta as a novel IL-18 inhibitor, which promotes CIA after intravenous overexpression by affecting Treg levels and supporting a T helper type 17 response.
20509880 Optical tomographic imaging discriminates between disease-modifying anti-rheumatic drug (D 2010 INTRODUCTION: Standard measurements used to assess murine models of rheumatoid arthritis, notably paw thickness and clinical score, do not align well with certain aspects of disease severity as assessed by histopathology. We tested the hypothesis that non-invasive optical tomographic imaging of molecular biomarkers of inflammation and bone turnover would provide a superior quantitative readout and would discriminate between a disease-modifying anti-rheumatic drug (DMARD) and a non-DMARD treatment. METHODS: Using two protease-activated near-infrared fluorescence imaging agents to detect inflammation-associated cathepsin and matrix metalloprotease activity, and a third agent to detect bone turnover, we quantified fluorescence in paws of mice with collagen antibody-induced arthritis. Fluorescence molecular tomographic (FMT) imaging results, which provided deep tissue detection and quantitative readouts in absolute picomoles of agent fluorescence per paw, were compared with paw swelling, clinical scores, a panel of plasma biomarkers, and histopathology to discriminate between steroid (prednisolone), DMARD (p38 mitogen-activated protein kinase (MAPK) inhibitor) and non-DMARD (celecoxib, cyclooxygenase-2 (COX-2) inhibitor) treatments. RESULTS: Paw thickness, clinical score, and plasma biomarkers failed to discriminate well between a p38 MAPK inhibitor and a COX-2 inhibitor. In contrast, FMT quantification using near-infrared agents to detect protease activity or bone resorption yielded a clear discrimination between the different classes of therapeutics. FMT results agreed well with inflammation scores, and both imaging and histopathology provided clearer discrimination between treatments as compared with paw swelling, clinical score, and serum biomarker readouts. CONCLUSIONS: Non-invasive optical tomographic imaging offers a unique approach to monitoring disease pathogenesis and correlates with histopathology assessment of joint inflammation and bone resorption. The specific use of optical tomography allowed accurate three-dimensional imaging, quantitation in picomoles rather than intensity or relative fluorescence, and, for the first time, showed that non-invasive imaging assessment can predict the pathologist's histology inflammation scoring and discriminate DMARD from non-DMARD activity.
20187132 Adeno-associated virus type 5-mediated intraarticular administration of tumor necrosis fac 2010 Mar OBJECTIVE: RNA interference (RNAi) is a powerful tool for sequence-specific gene silencing, and interest in its application in human diseases is growing. Given the success of recent strategies for administering gene therapy in rheumatoid arthritis using recombinant vectors such as adeno-associated virus type 5 (rAAV5) for optimized intraarticular gene transfer, we undertook the present study to determine the feasibility of using rAAV5-mediated RNAi-based therapy in arthritis. METHODS: We developed rAAV5 vectors expressing short hairpin small interfering RNA (shRNA) against tumor necrosis factor alpha (TNFalpha) under H1 promoter, and carrying the enhanced green fluorescent protein (eGFP) reporter gene under cytomegalovirus promoter (rAAV5-shTNF). TNFalpha gene silencing was validated in vitro with mouse macrophages. Mice with collagen-induced arthritis were injected in the ankle and knee joints, at disease onset, with either rAAV5-shTNF or control rAAV5-eGFP vectors (5 x 10(9) particles). Arthritis severity was assessed clinically and histologically, and immunologic response was examined. Local and systemic transgene expression was monitored using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemical analysis, and enzyme-linked immunosorbent assay. RESULTS: After a single injection of rAAV5-shTNF into inflamed joints, local TNFalpha gene silencing provided rapid and long-term suppression of arthritis progression and reduced joint damage compared with that observed in control groups. Treatment with rAAV5-shTNF was associated with decreased proliferation and interferon-gamma production by antigen-stimulated T cells from draining lymph nodes, and the potency of this treatment was similar to that observed with other treatment strategies targeting TNFalpha at the protein level, either locally or systemically. CONCLUSION: Our data present the first proof-of-concept for the application of rAAV5-mediated RNAi-based gene therapy for local blockade of inflammation in experimental arthritis.
19710474 Blocking of CD27-CD70 pathway by anti-CD70 antibody ameliorates joint disease in murine co 2009 Sep 15 Rheumatoid arthritis (RA) is characterized by inflammation and cellular proliferation in the synovial lining of joints that result in cartilage and bone destruction. Although the etiology of RA is unclear, activated lymphocytes and proinflammatory molecules, in particular TNF superfamily members, have been implicated in the disease pathology. A TNF superfamily member, CD70, is found on activated lymphocytes and shown to be important in memory and effector responses of lymphocytes. CD70 is expressed at high levels on chronically activated T cells in patients with autoimmune disorders, including RA. The involvement of CD70 in the progression of RA, however, remains unknown. In this study, we report effects of targeting CD70 on disease pathogenesis by using an anti-mouse CD70 Ab in a murine model of collagen-induced arthritis (CIA). In addition to blocking CD70 binding to its receptor CD27, the anti-CD70 Ab used also engages Fc-dependent effector functions including Ab-dependent cellular cytotoxicity, phagocytosis, and complement fixation. Treatment of mice with anti-CD70 Ab both before the onset or after the established disease in CIA model resulted in marked improvements in disease severity and significant reduction in the production of autoantibodies. Histopathological analyses of the joints of mice revealed a substantial reduction of inflammation, and bone and cartilage destruction in response to the anti-CD70 Ab treatment. These results uncover a novel role for CD27-CD70 interactions in the regulation of in vivo inflammatory response leading to arthritis, and provide a molecular basis to support the rationale for anti-CD70 therapy for autoimmune and inflammatory diseases.