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ID PMID Title PublicationDate abstract
25032213 Attenuation of collagen-induced arthritis in mice by salmon proteoglycan. 2014 Rheumatoid arthritis (RA) is a serious autoimmune disease caused by chronic inflammation of connective tissues. The basic principle of RA treatment is aimed to reduce joint inflammation. Our previous studies demonstrated that salmon cartilage proteoglycan (PG) suppresses excess inflammation in different mouse inflammatory diseases. In this study, we investigated the prophylactic effect of PG on the progression of RA using an experimental mouse model, collagen-induced arthritis (CIA). Clinical and histological severity of CIA was attenuated by daily oral administration of PG. In the joints of PG-administered mice, infiltration of macrophages and neutrophils and also osteoclast accumulation were limited. In comparison to nonadministered mice, anti-collagen antibodies in the sera of PG-administered mice did not alter. On the other hand, local expression of interleukin-17A (IL-17A), IL-6, IL-1 β, interferon- γ (IFN- γ), C-C chemokine ligand 2 (CCL2), C-X-C chemokine ligand 1 (CXCL1), and CXCL2 in the joints of PG-administered mice decreased. Moreover, in the response of type II collagen- (CII-) restimulation ex vivo, IL-17A and IFN- γ production by splenocytes from PG-administered mice was less than that of control mice. These data suggested that daily ingested PG attenuated CIA pathogenesis by modulating immune response of splenocytes to CII stimulation and local production inflammatory cytokines and chemokines in the joints.
24469603 Astragaloside IV possesses antiarthritic effect by preventing interleukin 1β-induced join 2014 Jun The saponin astragaloside IV (AST) is one of major active components purified from Astragalus membranaceus (Fisch) Bge, which has been used in traditional Chinese medicine to treat immune disorders including rheumatoid arthritis (RA). The effects of AST on the suppression of experimental arthritis and its possible mechanisms are unknown. We measured the paw swelling of ankle joints, splenocyte proliferation, interleukin 1β (IL-1β), tumor necrosis factor α (TNFα) and nitric oxide (NO) formation by macrophages in rat adjuvant-induced arthritis (AIA). Intraarticular injection of IL-1β to rat knee joint for inducing the edema and in vitro IL-1β-stimulated cartilage impairment were examined. The results showed that oral treatment of AST (100 mg/kg/day) suppressed the joint inflammation and inhibited IL-1β, TNFα and NO production in macrophages from AIA rats. Macrophages were one of AST targeted cells, and mediated the reduced splenocyte proliferation in AIA rats. In addition, AST reduced the swelling induced by intraarticular injection of IL-1β, and protected against IL-1β-induced damage of cartilage proteoglycan synthesis and chondrocyte proliferation. We conclude that AST possesses antiarthritic effect and prevents IL-1β-induced joint inflammation and cartilage destruction. These findings suggest that AST may be used for the treatment of RA and other inflammatory joint diseases.
25036817 Glycyrol suppresses collagen-induced arthritis by regulating autoimmune and inflammatory r 2014 Glycyrol is a natural compound extracted from Glycyrrhiza uralensis, first reported by us to be a new immunosuppressant. Here, we demonstrate its beneficial effect in collagen-induced arthritis (CIA) in mice, a model for rheumatoid arthritis (RA) in man, and we document the underlying mechanisms. Peroral administration of glycyrol significantly reduced clinical scores, alleviated cartilage and bone erosion and reduced levels of serum inflammatory cytokines. Glycyrol also decreased delayed-type hypersensitivity, improved carbon clearance and reduced acetic acid-induced capillary permeability. Furthermore, glycyrol decreased NF-κB and NFAT transcriptional activities and inhibited IL-2 expression. The therapeutic effect of glycyrol was associated with down-regulation of both autoimmune and inflammatory reactions. In addition, we demonstrated that glycyrol has minimal acute toxicity in mice. Therefore, we propose that glycyrol may hold promise for future treatment of RA.
24219159 Innate immunity in systemic sclerosis pathogenesis. 2014 Mar The innate immune system is a critical part of the response to pathogens and overall immunity. Compared with the adaptive immune response, these innate responses are not antigen-specific and recognize patterns in bacteria, viruses and fungi. Chief among these are TLRs (Toll-like receptors). TLRs are PRRs (pattern recognition receptors) that are germ-line-encoded and are also able to recognize endogenous molecules that are released upon cell damage or stress and have been demonstrated to have a key role in numerous autoimmune diseases, including RA (rheumatoid arthritis) and SSc (systemic sclerosis). SSc is an autoimmune disorder in which vascular injury occurs and there is a chronic low-grade inflammation followed by excessive ECM (extracellular matrix) deposition and ultimately fibrosis. The fibrosis ultimately leads to organ dysfunction and death. The preceding vascular damage and activation of the innate immune system leads to mobilization of the innate lymphoid cells and the up-regulation of multiple genes and pro-fibrotic cytokines. These locally released cytokines activate resident fibroblasts to differentiate into myofibroblasts. The aim of the present review is to explore the role of the innate immune system in SSc and TLRs and how these interact with stromal cells to produce fibrosis. Targeting the innate immune system or specific components of the TLR signalling cascade may be a novel therapeutic option in what is an incurable disease.
24574220 Involvement of peripheral and spinal tumor necrosis factor α in spinal cord hyperexcitabi 2014 Mar OBJECTIVE: Tumor necrosis factor α (TNFα) is produced not only in peripheral tissues, but also in the spinal cord. The purpose of this study was to address the potential of peripheral and spinal TNFα to induce and maintain spinal hyperexcitability, which is a hallmark of pain states in the joints during rheumatoid arthritis and osteoarthritis. METHODS: In vivo recordings of the responses of spinal cord neurons to nociceptive knee input under normal conditions and in the presence of experimental knee joint inflammation were obtained in anesthetized rats. TNFα, etanercept, or antibodies to TNF receptors were applied to either the knee joint or the spinal cord surface. RESULTS: Injection of TNFα into the knee joint cavity increased the responses of spinal cord neurons to mechanical joint stimulation, and injection of etanercept into the knee joint reduced the inflammation-evoked spinal activity. These spinal effects closely mirrored the induction and reduction of peripheral sensitization. Responses to joint stimulation were also enhanced by spinal application of TNFα, and spinal application of either etanercept or anti-TNF receptor type I significantly attenuated the generation of inflammation-evoked spinal hyperexcitability, which is characterized by widespread pain sensitization beyond the inflamed joint. Spinally applied etanercept did not reduce established hyperexcitability in the acute kaolin/carrageenan model. In antigen-induced arthritis, etanercept decreased spinal responses on day 1, but not on day 3. CONCLUSION: While peripheral TNFα increases spinal responses to joint stimulation, spinal TNFα supports the generation of the full pattern of spinal hyperexcitability. However, established spinal hyperexcitability may be maintained by downstream mechanisms that are independent of spinal TNFα.
24223832 Systemic delivery of small interfering RNA targeting the interleukin-2/15 receptor β chai 2013 The role of interleukin (IL)-15 in the pathogenesis of rheumatoid arthritis (RA) is well established; however, systemic knockdown of IL-15 receptor (IL-15R) for reduction in inflammation at local sites has not been demonstrated. In this study, the therapeutic effect of intravenously administered siRNA targeting the β chain of IL-15R which is shared by the receptor for IL-2 was examined in rats with adjuvant-induced arthritis (AA). Polyethylenimine (PEI)-complexed siRNA nanoparticles could easily accumulate in arthritic paws of AA rats. In the paws, the nanoparticles were avidly taken up by macrophages and to a lesser extent by T cells. Weekly administered IL-2/15Rβ siRNA polyplexes were capable of decreasing disease progression in AA rats, with striking inhibition of clinical, radiologic, and histologic features of RA. The observed therapeutic effect was associated with reduced expression of proinflammatory mediators in the inflamed joints. Thus, this study provides evidence that IL-2/15Rβ could be targeted for the treatment of RA.
25484009 Attenuation of collagen induced arthritis by Centella asiatica methanol fraction via modul 2014 Dec OBJECTIVE: To investigate the anti-inflammatory, antioxidant and anti-arthritic effects of Centella asiatica methanolfraction (CaME) on collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. METHODS: Arthritis was induced in female wistar rats by immunization with porcine type II collagen. The CIA rats were treated orally with CaME (50, 150, and 250 mg/kg/day) for 15 d (beginning on day 21 of the experimental period). The clinical, histological, biochemical, and immunological parameters were assessed. RESULTS: CaME treatment (150 and 250 mg/kg) significantly attenuated the severity of CIA and reduced the synovial inflammation, cartilage erosion, and bone erosion as evident from both histological and radiographic data. The escalated plasma levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-12 alongwith nitric oxide in CIA rats decreased significantly on CaME treatment. The serum levels of type-II collagen antibody were significantly lower in rats of CaME (150 and 250 mg/kg) treated group than those in the arthritic group. Furthermore, by inhibiting the above mediators, CaME also contributed towards the reversal of the disturbed antioxidant levels and peroxidative damage. CONCLUSION: Our results clearly indicate that oral administration of CaME suppresses joint inflammation, cytokine expression as well as antioxidant imbalance, thereby contributing to an amelioration of arthritis severity in CIA rats.
23618803 Diagnosis and surgical treatment of progressive pseudorheumatoid dysplasia in an adult wit 2013 Dec Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal-recessive disorder. The polyarthritis of PPD has been detailed before. However, the spinal disorder and surgical treatment been rarely mentioned. A 44-year-old patient who has been misdiagnosed as juvenile rheumatoid arthritis (JRA) and given unilateral total hip replacement yet, suffers mainly from severe spinal disorder this time. The platyspondyly, Scheuermann-like lesions of the spine and JRA-like features of the peripheral joints were found on radiographic films, combining negative inflammatory and rheumatoid factors, which most suggested the diagnosis of PPD. As the homozygous nucleotide deletion was found in WISP3 gene, diagnosis of PPD was definite. Neurological examination and further imaging examination indicated severe compression of thoracic and lumbar spinal cord which might lead to his conspicuous spinal disorder. Decompressive laminectomy, posterior fusion and fixation were performed. And an excellent clinical outcome was achieved 1 year after the decompression and fusion: leg pain and hypoesthesia resolved and osseous fusion performed. This is the first reported decompression in the adult spine of PPD. Surgical treatment could receive satisfactory result in PPD, however, it is a palliative therapy which has less help to prevent the development of this disease. Early diagnosis and rehabilitation interventions remain the most important. Clinical, radiographic and genetic features in PPD are crucial in the differential diagnosis.
25132679 Regulation of cytokine polarization and T cell recruitment to inflamed paws in mouse colla 2014 Nov OBJECTIVE: The chemokine receptor CXCR6 is highly expressed on lymphocytes isolated from the synovium of patients with rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis, suggesting that CXCR6 regulates immune cell activation or infiltration into arthritic joints. This study was undertaken to examine the role of CXCR6 in T cell activation and arthritis development. METHODS: A collagen-induced arthritis model was used to examine arthritis development in wild-type and CXCR6(-/-) mice. CXCR6 expression, lymphocyte accumulation, and intracellular cytokine production were examined by flow cytometry. Collagen-specific antibodies were measured in the serum. Collagen-specific recall responses were examined in vitro via proliferation and cytokine release assays. T cell homing to inflamed joints was examined using competitive adoptive transfer of dye-labeled lymphocytes from wild-type and CXCR6(-/-) mice. RESULTS: The numbers of CXCR6+ T cells were increased in the paws and draining lymph nodes of arthritic mice. The incidence of arthritis, disease severity, extent of T cell accumulation, and levels of collagen-specific IgG2a antibodies were significantly reduced in CXCR6(-/-) mice compared to wild-type mice. T cells from wild-type mice exhibited Th1 (interferon-γ [IFNγ]) polarization in the inguinal lymph nodes following immunization. At disease peak, this shifted to a Th17 (interleukin-17A [IL-17A]) response in the popliteal lymph nodes. T cells in CXCR6(-/-) mice exhibited impaired cytokine polarization, resulting in a decreased frequency and number of IL-17A- and IFNγ-producing cells. Recruitment of activated CXCR6(-/-) mouse T cells to the inflamed paws was impaired compared to recruitment of wild-type mouse T cells. CONCLUSION: These experiments demonstrate that CXCR6 plays important roles in the pathogenesis of arthritis through its effects on both T cell cytokine polarization and homing of T cells to inflamed joints.
25146875 An update on the management of hepatitis C virus-related arthritis. 2014 Oct INTRODUCTION: Hepatitis C virus (HCV)-related arthritis is an uncommon disease belonging to the autoimmune disorders due to the chronic stimulus exerted by the virus on the immune system. It shows two clinical subsets: a symmetrical polyarthritis resembling rheumatoid arthritis but less aggressive and an intermittent mono-oligoarthritis involving the lower limbs. AREAS COVERED: We extensively review the current literature using the largest electronic databases (MEDLINE, EMBASE and COCHRANE) with regard to HCV-related arthritis (HCVrA) and studies focusing on the co-existence of HCV and other kinds of arthritides. EXPERT OPINION: The therapeutic approach to HCVrA remains largely empirical, because few studies have been published on this topic. Mainstream treatment based on the administration of hydroxychloroquine and low doses of corticosteroid is still largely preferred. Cyclosporine represents a useful alternative due to its antiviral properties. Anti-TNF agents are safe, but their hypothetic use appears excessive for a mild disorder such as HCVrA. IFN-α (and more recently pegylated IFN-α) when administered as a component of the combined (IFN-α + ribavirin) anti-HCV therapy can promote the appearance or the worsening of several autoimmune HCV-related disorders, including arthritis. New and forthcoming antiviral molecules will be used in the near future for a revolutionary IFN-free treatment.
25041942 A metabonomic study of adjuvant-induced arthritis in rats using ultra-performance liquid c 2014 Oct Rheumatoid arthritis (RA) is a chronic systemic inflammatory and autoimmune disease accompanied by the destruction and deformities of joints. Adjuvant-induced arthritis (AIA) is one of the excellent animal models of RA used to understand disease pathogenesis and screen potential drugs. In this paper, a urinary metabonomics method based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) has been established to investigate the disease progression of AIA and find potential biomarkers of secondary inflammation in AIA rats. 24 potential biomarkers were identified, including xanthurenic acid, kynurenic acid, 4-pyridoxic acid, and phenylalanine, which revealed that tryptophan metabolism, phenylalanine metabolism, gut microbiota metabolism and energy metabolism were disturbed in AIA rats. These potential biomarkers and their corresponding pathways are helpful to further understand the mechanisms of AIA and pathogenesis of RA. This study demonstrates that metabonomics based on UPLC-Q-TOF-MS is a powerful methodology to analyze the underlying disease pathogenesis.
25514237 Crossreactive autoantibodies directed against cutaneous and joint antigens are present in 2014 BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease of unknown origin, characterized by erosions and new bone formation. Diagnosis of PsA is mainly clinical and there are no biomarkers available. Moreover in PsA autoantibodies have not been described so far. Indeed an autoimmune origin has been suggested but never proven. Aim of the study was to investigate the possible presence of autoantibodies typically associated with PsA. METHODS: We used pooled IgG immunoglobulins derived from 30 patients with PsA to screen a random peptide library in order to identify disease relevant autoantigen peptides. RESULTS: Among the selected peptides, one was recognised by nearly all the patients' sera. The identified peptide (PsA peptide: TNRRGRGSPGAL) shows sequence similarities with skin autoantigens, such as fibrillin 3, a constituent of actin microfibrils, desmocollin 3, a constituent of the desmosomes and keratin 78, a component of epithelial cytoskeleton. Interestingly the PsA peptide shares homology with the nebulin-related anchoring protein (N-RAP), a protein localized in the enthesis (point of insertion of a tendon or ligament to the bone), which represents the first affected site during early PsA. Antibodies affinity purified against the PsA peptide recognize fibrillin, desmocollin, keratin and N-RAP. Moreover antibodies directed against the PsA peptide are detectable in 85% of PsA patients. Such antibodies are not present in healthy donors and are present in 13/100 patients with seroposive rheumatoid arthritis (RA). In seronegative RA these antibodies are detectable only in 3/100 patients. CONCLUSIONS: Our results indicate that PsA is characterized by the presence of serum autoantibodies crossreacting with an epitope shared by skin and joint antigens.
25467403 [Presence of riziform bodies in a patient with juvenile idiopathic arthritis: case report 2014 Oct 23 Riziform bodies are structures formed by fibrin and cells that can be found in the synovial fluid or attached to the synovium, and have this denomination due to its rice grain-like appearance. They have already been described in several diseases such as tuberculous arthritis, rheumatoid arthritis, and rarely in juvenile idiopathic arthritis (JIA). This is the case of a boy with a 4-month course of chronic monoarthritis of the left knee, with family history of sarcoidosis in which diagnostic investigation showed the presence of these riziform bodies in the synovial biopsy. Diagnostic investigation ruled out sarcoidosis, tuberculosis and malignancies, establishing the diagnosis of JIA. Our objective was to describe what we believe is the 9th case reported on the presence of riziform bodies in JIA, which are probably underdiagnosed, and should be considered mainly in cases of severe arthritis of difficult medical treatment.
24455774 Scopoletin suppresses IL-6 production from fibroblast-like synoviocytes of adjuvant arthri 2013 Dec Scopoletin, a coumarin compound naturally occurring in many medicinal plants, has previously been demonstrated to ameliorate synovial inflammation and destruction of cartilage and bone in adjuvant arthritis (AA) rats. As interleukin (IL)-6 is critically involved in the initiation and development of rheumatoid arthritis (RA), the present study was performed to investigate the effect of scopoletin on IL-6 production from fibroblast-like synoviocytes (FLS) to get insight into its anti-RA mechanisms. FLS were isolated from synovial membrane tissues of AA rats, and stimulated with IL-1β (10 ng/mL). Scopoletin, at concentrations of 15, 30, and 60 μM, was shown to only moderately inhibit FLS proliferation, but dramatically reduce IL-6 production at both mRNA and protein levels. It also inhibited the phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), protein kinase C (PKC) and cAMP response element binding protein (CREB). These findings suggest that scopoletin exerts anti-RA action probably through suppressing IL-6 production from FLS via MAPK/PKC/CREB pathways.
22978269 7,3'-dimethoxy hesperetin inhibits inflammation by inducing synovial apoptosis in rats wit 2013 Feb Rheumatoid arthritis (RA) is an autoimmune disease characterized by pronounced inflammation and excessive synovial hyperplasia within affected joint. We previously reported 7, 3'-dimethoxy hesperetin (DMHP) as a highly anti-inflammatory active derivative of hesperidin showed apparent pro-apoptotic effect in vitro on fibroblast-like synoviocytes of rats with adjuvant arthritis (AA), an animal model of RA. Here, we investigated the therapeutic effects of DMHP on inflammation and synovial apoptosis in rats with AA in vivo. Paw swelling, arthritis index, TNF-α and IL-1β serum levels were measured to evaluate the effect of DMHP on inflammation in AA rats. DNA ladder detection and TUNEL assay were used to investigate the pro-apoptotic effect of DMHP on synovial apoptosis in vivo. Bcl-2, Bax mRNA and protein expressions in synovium were determined by real-time Q-PCR and western blot, respectively. We found DMHP inhibited secondary hind paw swelling and arthritis index, and decreased TNF-α and IL-1β serum levels in AA rats. Typical DNA ladder formation was found in DNA extraction of synovium from DMHP treated groups. The number of apoptotic synovial cells was elevated with DMHP treatment in TUNEL assay. DMHP markedly decreased Bcl-2 expression whereas increased Bax expression in synovium of AA rats at both transcription and protein levels. Moreover, DMHP treatment on AA rats significantly decreased the protein ratio of Bcl-2/Bax in synovium. In conclusion, DMHP has an apparent therapeutic effect on inflammation in rats with AA. Mechanisms of this effect are partly related to induction of synovial apoptosis through modulation of Bcl-2 and Bax expression.
25452092 [Metacarpophalangeal joint arthroscopy]. 2014 Dec OBJECTIVE: Pain reduction in the affected metacarpophalangeal joint (MP joint) by synovectomy, loose body extraction and resection of intraarticular scars. INDICATIONS: Synovitis in rheumatoid arthritis (RA) not responding to antirheumatic treatment, primary and secondary degenerative arthritis, osteochondral lesions, loose bodies, foreign bodies, capsular contracture, septic arthritis, posttraumatic arthralgia (old collateral ligament injury), intraarticular fractures. CONTRAINDICATIONS: Established biomechanical changes in RA such as ulnar deviation and palmar subluxation with extensor tendon luxation of the MP joint. Advanced radiologic changes in degenerative arthritis. Joint instability in posttraumatic conditions. Fresh skin lesion near portals. SURGICAL TECHNIQUE: Longitudinal traction of the affected finger in a Chinese finger trap. The joint is filled with Ringer solution. Placement of a radial and ulnar dorsal portal at joint space level, through the extensor hood, at the dorsal border of the collateral ligaments. Diagnostic arthroscopy. In case of insufficient visibility (i.e., bulky synovitis in RA) "blind" shaving in the dorsal recess at first. Completion of synovectomy under sight. If necessary additional ablation of synovial tissue by a radiofrequency (RF) electrosurgical system. Use of arthroscope (1.9 mm) with a 30° angle of vision and shaver (aggressive cutter; 2.0 mm). Low-suction drain, soft padded dressing. POSTOPERATIVE MANAGEMENT: Immediate postoperative mobilization for the full range of finger movement. RESULTS: In 106 MP joint arthroscopies from 2009-2011, very high patient satisfaction was achieved. Best results were obtained in RA, even in advanced radiologic changes (Larsen stages 1-3). Only in Larsen stage 4 results were rated lower. In early stages of degenerative arthritis (Kellgren-Lawrence 0-2), patient satisfaction was also very high, however decreased rapidly with increasing degree of radiologic changes. The results in posttraumatic cases are promising.
24375529 Toll-like receptors: Role in inflammation and therapeutic potential. 2014 May Inflammation is an essential process in response to injury and infection. However, under certain circumstances dis-regulation of this process can lead to pathologies such as rheumatoid arthritis, atherosclerosis, lupus, and is a contributory factor in the progression of many cancers. The Toll-like family of receptors (TLRs) has major roles in the initiation of the inflammatory response and as such has attracted much focus for their potential as therapeutic targets. Here we review the role of TLRs in the inflammatory response and associated disease and examine how this important family of molecules might be targeted for therapeutic benefit.
24556586 Endothelial dysfunction in an ovine model of collagen-induced arthritis. 2014 BACKGROUND: Rheumatoid arthritis (RA) induces systemic inflammation, producing a range of co-morbidities including cardiovascular disease. An early vascular change is endothelial dysfunction, characterized by reduced endothelium-dependent vasodilation. The aim of this study was to assess endothelial function in isolated coronary and digital arteries using an ovine model of collagen-induced RA. METHODS: Sheep were culled following induction of arthritis, and their endothelial function was compared to that of normal sheep. Paired arterial segments were mounted in a wire myograph and dilated with endothelium-dependent vasodilators [bradykinin, serotonin, carbachol and adenosine diphosphate (ADP); linked to either Gi or Gq signalling pathways] and endothelium-independent dilators (adenosine and sodium nitroprusside) to construct cumulative concentration-response curves. RESULTS: Coronary arteries from arthritic sheep exhibited a significantly greater EC50 value for bradykinin-induced relaxation compared to non-arthritic controls (2.9 × 10(-8) M for arthritic sheep vs. 8.6 × 10(-9) M for controls). Digital arteries from arthritic sheep also exhibited a significantly greater EC50 for relaxation to ADP and a significant decrease in the carbachol maximal response. Responses to sodium nitroprusside were unchanged in both coronary and digital arteries. CONCLUSION: Sheep with RA demonstrated attenuated arterial relaxation to endothelium-dependent vasodilators. This may provide a useful model of endothelial dysfunction in chronic inflammatory conditions. The dysfunction did not appear to be associated with one specific G-protein signalling pathway.
23390569 Evaluation of a candidate anti-arthritic drug using the mouse collagen antibody induced ar 2013 The most rigorous scenario for testing a candidate rheumatoid arthritis therapeutic would be to use clinically relevant biomarkers and readouts to monitor disease development in an animal model that has a mechanism of disease that reflects the human condition. Treatment should begin when the full spectrum of arthritic processes, including bone damage, is present. We have tried to take this approach to evaluate a novel EP4 receptor antagonist (ER-886046) for its anti-arthritic potential. This work aimed not only to test a potential drug, but to also demonstrate a strategy for performing a more clinically relevant evaluation of future candidate arthritis treatments. A variety of biomarkers including: radiographic evaluation, clinical scoring, histology analysis, F4/80 macrophage immunohistochemistry, luminol bioluminescent imaging and (99m)Tc-MDP-SPECT imaging were evaluated as disease readouts in the mouse anti-collagen antibody induced arthritis model (CAIA). CAIA mice were treated either prophylactically or therapeutically with ER-886046 and the compound's efficacy was probed using the various biomarkers and compared to the reference drugs prednisolone and celecoxib. The various biomarkers effectively measured different aspects of arthritis pathology and consistently demonstrated the efficacy of ER-886046. The compound was found to be effective even when dosed therapeutically after bone damaging processes had initiated. The results presented herein demonstrate how biomarkers and a clinically relevant experimental design can be used to evaluate a candidate therapeutic. Utilization of clinically relevant biomarkers may provide a means for more translatable pre-clinical testing of candidate therapeutics and may provide information on their mechanism of action.
22532629 Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review. 2013 Feb OBJECTIVE: Data regarding cardiovascular comorbidity and cardiovascular risk factors in patients with psoriatic arthritis (PsA) are limited. To evaluate the cardiovascular risk profile, a systematic literature search was performed to provide an extensive summary of all studies available on cardiovascular risk in PsA. METHODS: Medline, EMBASE and the Cochrane library were searched from January 1966 to April 2011 for English language articles on data concerning cardiovascular diseases and cardiovascular risk factors in PsA. Review articles, case reports and studies on psoriasis alone were excluded. RESULTS: Twenty-eight articles were included in this review. Studies on all-cause mortality revealed mixed results. Available data on cardiovascular disease appeared more consistent, indicating an increased cardiovascular mortality and morbidity in PsA. Commensurate with this, surrogate markers of subclinical atherosclerosis, arterial stiffness and cardiovascular risk factors, for example hypertension, dyslipidaemia, obesity and metabolic-related factors, were more prominent in PsA compared with controls. Suppression of inflammation was linked with a favourable effect on cardiovascular surrogate markers, for example carotid intima media thickness and endothelial dysfunction, in several (un)controlled studies. CONCLUSION: Most studies point towards an increased cardiovascular risk in PsA, broadly on a par with the risk level in rheumatoid arthritis, emphasising the need for similar cardiovascular risk management in both conditions. Further studies are needed to indicate whether inflammatory suppression or modification of traditional cardiovascular risk factors, or both, will reduce cardiovascular risk.