A subgroup of lupus patients with nephritis, innate T cell activation and low vitamin D is identified by the enhancement of circulating MHC class I-related chain A.

The major histocompatibility complex (MHC) class I-related chain A (MICA) is induced upon stress, and labels malfunctioning cells for their recognition by cytotoxic lymphocytes. Alterations in this recognition and also abnormal natural killer (NK) functions have been found in systemic lupus erythematosus (SLE). MICA can be shed from cells, subsequently acting as a soluble decoy receptor (sMICA). Our purpose was to study circulating sMICA levels in relationship with the activation of innate pathways in PBMC in a cohort of lupus patients. NK cells were characterized by flow cytometry. Gene expression of Toll-like receptors (TLR), interferon (IFN)-I sensitive genes and MICA were separately analyzed in monocytes, T cells and B cells. Serum sMICA was measured with enzyme-linked immunosorbent assay (ELISA). In our cohort, NK cell counts dropped in relationship with disease activity. sMICA showed an inverse trend with NK cell counts, as well as a significant association with activity indices, but not with complement decrease. Levels of sMICA associated to proteinuria and active nephritis. A multivariate regression model revealed anti-nuclear antibody (ANA) titres, the up-regulation of TLR-4 in T cells and lower vitamin D as predictors of sMICA enhancement. Interestingly, vitamin D showed an inverse association with proteinuria and a strong correlation with T cell MICA mRNA levels. According to our data, circulating sMICA identifies a subgroup of lupus patients with low vitamin D, innate activation of T cells and nephritis. We propose that lymphocyte shedding could account for the enhancement of sMICA and reflect an immune evasion mechanism driving disease activation in lupus.

Chondrocyte enlargement is a marker of osteoarthritis severity.

OBJECTIVE: We aimed to assess whether an increase in chondrocyte size might be a feature of the articular cartilage (AC) hypertrophic-like phenotype both in experimental and in human osteoarthritis (OA). The anatomical location of these enlarged cells in the cartilage layers was also evaluated. METHODS: Experimental OA was carried out in female rabbits alone or in combination with osteoporosis (OPOA). The rabbits were subjected to destabilization knee surgery to develop OA. Osteoporosis was induced with ovariectomy and methylprednisolone administration. Human OA samples obtained from knee replacement surgery were also studied. Cartilage lesions and chondrocyte size were assessed in AC sections. Immunostaining of type-X collagen and metalloproteinase-13 were used as markers of the AC hypertrophic transformation. Both the cell size and the gene expression of type-X collagen were further analyzed in primary murine chondrocyte cultures. RESULTS: Compared to healthy AC, chondrocyte size was increased both in experimental and in human OA, in correlation with the severity of cartilage damage. No differences in chondrocyte size were found between deeper or more superficial regions of AC. In cell cultures, accretion of hypertrophic markers and cell enlargement were found to occur synchronized. CONCLUSIONS: We observed an enhancement in the mean size of chondrocytes at the OA cartilage, which showed correlation with cartilage damage, both in human and in experimental OA. The enlarged chondrocytes were homogeneously distributed throughout the AC. Our results suggest that chondrocyte size could be a reliable measure of disease progression, of potential use in the histopathological assessment of OA cartilage.

Meniscal degeneration in human knee osteoarthritis: in situ hybridization and immunohistochemistry study.

OBJECTIVE: Meniscus injury is one of the causes of secondary osteoarthritis (OA). However, the role of meniscus is still unclear. Human meniscal distribution of cells and cartilage oligomeric matrix protein (COMP) and their changes in advanced OA were analyzed. PATIENTS AND METHODS: Thirty-one medial menisci from patients with knee OA that underwent a total knee arthroplasty were studied. Normal meniscal tissue was obtained from partial arthroscopic meniscectomy. Meniscal samples were processed for histology, immunohistochemistry and in situ hybridization, for cell assessment including density, active divisions, apoptosis, COMP distribution and proteoglycan content. RESULTS: Osteoarthritic menisci demonstrated areas of cell depletion and significant decrease in COMP immunostaining. Actively dividing cells were only found in the meniscectomy group, but not in the osteoarthritic group. Proteoglycan staining was less prominent in menisci from the osteoarthritis group. CONCLUSIONS: Our results show a decreased cell population, with low COMP and altered matrix organization in osteoarthritis menisci that suggest an altered meniscal scaffold and potential impairment of meniscal function. These meniscal changes may be associated with the development of knee osteoarthritis.

Recommendations for an update of the 2010 European regulatory guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis and reflections about related clinically relevant outcomes: expert consensus statement.

OBJECTIVE: The European Society on Clinical and Economic aspects of Osteoporosis and Osteoarthritis (ESCEO) organised a working group to evaluate the need for updating the current European guideline on clinical investigation of drugs used in the treatment of osteoarthritis (OA). DESIGN: Areas of potential attention were identified and the need for modifications, update or clarification was examined. Proposals were then developed based on literature reviews and through a consensus process. RESULTS: It was agreed that the current guideline overall still reflects the current knowledge in OA, although two possible modifications were identified. The first relates to the number and timing of measurements required as primary endpoints during clinical trials of symptom-relieving drugs, either drugs with rapid onset of action or slow acting drugs. The suggested modifications are intended to take into consideration the time related clinical need and expected time response to these drugs - i.e., a more early effect for the first category in addition to the maintenance of effect, a more continuous benefit over the long-term for the latter - in the timing of assessments. Secondly, values above which a benefit over placebo should be considered clinically relevant were considered. Based on literature reviews, the most consensual values were determined for primary endpoints of both symptom-relieving drugs (i.e., pain intensity on a visual analogue scale (VAS)) and disease-modifying drugs (i.e., radiographic joint-space narrowing). CONCLUSIONS: This working document might be considered by the European regulatory authorities in a future update of the guideline for the registration of drugs in OA.

O-linked N-acetylglucosamine (O-GlcNAc) protein modification is increased in the cartilage of patients with knee osteoarthritis.

OBJECTIVE: There is increasing evidence that the addition of O-linked N-acetylglucosamine (O-GlcNAc) to proteins plays an important role in cell signaling pathways. In chondrocytes, accumulation of O-GlcNAc-modified proteins induces hypertrophic differentiation. Osteoarthritis (OA) is characterized by cartilage degradation, and hypertrophic-like changes in hyaline chondrocytes. However, the mechanisms responsible for these changes have not been described. Our aim was to study whether O-GlcNAcylation and the enzymes responsible for this modification are dysregulated in the cartilage of patients with knee OA and whether interleukin-1 could induce these modifications in cultured human OA chondrocytes (HOC). DESIGN: Human cartilage was obtained from patients with knee OA and from age and sex-matched healthy donors. HOC were cultured and stimulated with the catabolic cytokine IL-1α. Global protein O-GlcNAcylation and the synthesis of the key enzymes responsible for this modification, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), were assessed by western blot. RESULTS: OA was associated with a 4-fold increase in the global O-GlcNAcylation in the cartilage. OA cartilage showed a re-distribution of the OGT and OGA isoforms, with a net increase in the presence of both enzymes, in comparison to healthy cartilage. In HOC, IL-1α stimulation rapidly increased O-GlcNAcylation and OGT and OGA synthesis. CONCLUSIONS: Our results indicate that a proinflammatory milieu could favor the accumulation of O-GlcNAcylated proteins in OA cartilage, together with the dysregulation of the enzymes responsible for this modification. The increase in O-GlcNAcylation could be responsible, at least partially, for the re-expression of hypertrophic differentiation markers that have been observed in OA.

Effects of PTH [1-34] on synoviopathy in an experimental model of osteoarthritis preceded by osteoporosis.

PURPOSE: Synoviopathy contributes to cartilage degradation in osteoarthritis (OA). Intermittent parathyroid hormone (PTH) [1-34] administration inhibits terminal differentiation of human chondrocytes and prevents cartilage damage. We aimed to determine whether PTH [1-34] could modify synovial changes in experimental OA preceded by osteoporosis (OP). METHODS: Twenty osteoporosis (OP) rabbits underwent knee surgery to induce OA. They were administered either saline vehicle or PTH for 10 weeks. Ten healthy rabbits were used as controls. Following sacrifice, synovial changes were assessed by Krenn synovitis score, immunohistochemistry for macrophages (RAM-11), B and T lymphocytes, type I collagen, parathyroid hormone 1 receptor (PTH1R), and anti-proliferating cell nuclear antigen (PCNA). Synovial mRNA levels of Col1A1, IL-1ß, cyclooxygenase 2 (COX-2), matrix-degrading metalloproteinases (MMP-9, MMP-13), and monocyte chemotactic protein-1 (MCP-1), as well as protein expression of PTH1R were also determined. Cartilage damage was analyzed by Mankin score. RESULTS: OPOA + vehicle rabbits showed an increase in synovitis score vs controls (P = 0.003), mainly due to synovial hyperplasia and fibrosis, while PTH reduced these changes (P = 0.017). Mankin and Krenn scores were well correlated in all groups (r = 0.629, P = 0.012). Immunostaining for RAM-11 and B lymphocytes was increased (P ≤ 0.05), whereas PTH1R protein levels tended to be higher in OPOA + vehicle animals vs controls. PTH did not modify RAM-11 staining or PTH1R levels; however, it restored PTH1R localization to the vicinity of synovial vessels. PTH also decreased type I collagen, MCP-1, and MMP-13 expression (P < 0.05), as well as PCNA staining compared to vehicle-treated OPOA rabbits. CONCLUSIONS: In our model of OA aggravated by previous OP, synoviopathy correlated well with cartilage damage. Intermittent PTH [1-34] administration ameliorated both hyperplasia and fibrosis.

[Alternatives in the treatment of rheumatoid arthritis: reasons for using abatacept]. / Disyuntivas en el tratamiento de la artritis reumatoide: razones para el uso de abatacept.

Rheumatoid arthritis (RA) is an aggressive and progressive disease in which the prognosis has improved dramatically since the arrival of biological therapies at the end of the nineties. Nowadays, the main management strategies focus on early diagnosis and treatment, which is now more feasible due to the development of new classification criteria orientated towards diagnosis and classification of early and undifferentiated disease. The implementation of early, individualized and intensive treatment, with the aim of achieving remission or a low disease activity state, has notably improved the results obtained in a great percentage of patients, especially in those with a poorer prognosis. Abatacept is one of the biotechnological agents that have become part of the first line therapeutic armamentarium for early and aggressive RA. The efficacy and safety profile of this drug are very promising for the treatment of patients with RA.

A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project.

OBJECTIVE: AMELIA (OsteoArthritis Modifying Effects of Long-term Intra-articular Adant) was designed to compare against placebo the efficacy and safety of repeated injections of hyaluronic acid (HA) and its effect on disease progression over 40 months. METHODS: A multicentre, randomised, patient and evaluator-blinded, controlled study in 306 patients fulfilling American College of Rheumatology criteria for knee osteoarthritis, radiological grades II-III (Kellgren-Lawrence) and joint space width ≥ 2 mm. Patients received four cycles of five intra-articular HA or placebo injections with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles. Osteoarthritis Research Society International (OARSI) 2004 responder criteria were used to assess efficacy. The consumption of rescue medication was a secondary outcome. Adverse events were recorded for safety purposes. RESULTS: At the 40-month visit significantly more patients responded to HA compared with placebo (OARSI 2004, p=0.004). The number of responders to HA increased through the study, whereas those to placebo did not change. Significant differences were also found in favour of HA for each individual component of the OARSI 2004. No safety problems were recorded. CONCLUSIONS: The results of AMELIA offer pioneer evidence that repeated cycles of intra-articular injections of HA not only improve knee osteoarthritis symptoms during the in-between cycle period but also exert a marked carry-over effect for at least 1 year after the last cycle. In this respect, it is not possible to establish if this carry-over effect reflects true osteoarthritis remission or just a modification of the disease's natural course. ClinicalTrials.gov number, NCT00669032.

Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis.

PURPOSE: Impairment of subchondral bone density and quality aggravates cartilage damage in osteoarthritis (OA). Accordingly, we assessed whether improving microstructure and quality at subchondral bone by the bone-forming agent parathyroid hormone (PTH) [1-34] prevent cartilage damage progression in a rabbit model of OA preceded by osteoporosis (OP). METHODS: OP was induced in 20 female rabbits. At week 7, these rabbits underwent knee surgery to induce OA and, at week 12, they started either saline vehicle (n=10) or PTH (n=10) for 10 weeks. Ten healthy animals were used as controls. At week 22, microstructure was assessed by micro-computed tomography and bone remodelling by protein expression of alkaline phosphatase (ALP), metalloproteinase-9 (MMP9), osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) at subchondral bone. Cartilage damage was evaluated using Mankin score. RESULTS: PTH reversed the decrease of bone area/tissue area, trabecular thickness, plate thickness, polar moment of inertia, ALP expression and OPG/RANKL ratio, as well as counteracted the increase of fractal dimension and MMP9 expression at subchondral bone of osteoarthritis preceded by osteoporosis (OPOA) rabbits compared to vehicle administration (P<0.05). Likewise, PTH decreased cartilage damage severity in OPOA rabbits. Good correlations were observed between subchondral bone structure or remodelling parameters, and cartilage Mankin score. CONCLUSIONS: Improvement of microstructural and remodelling parameters at subchondral bone by PTH [1-34] contributed to prevent cartilage damage progression in rabbits with early OPOA. These findings support the role of subchondral bone in OA. Further studies are warranted to establish the place of bone-forming agents as potential treatment in OA.

An experimental study of COMP (cartilage oligomeric matrix protein) in the rabbit menisci.

INTRODUCTION: Secondary knee osteoarthritis (OA) is currently associated with meniscal injuries, but the pathogenesis is unclear. We analyzed the distribution of cells and cartilage oligomeric matrix protein (COMP) and its changes in the early stages of degeneration in meniscus. METHOD: Ten New Zealand rabbits underwent anterior cruciate ligament (ACL)-transection of the right knee-joint. Left knee-joints were used as controls. The animals were killed at 4 and 12 weeks. Gross injuries in meniscus and articular cartilage were scored. Meniscal tissues were immunostained with a specific antibody against COMP, with Ki-67, using TUNEL-assay and alcian blue stain. The number of cells was counted. RESULTS: At 4 weeks post-ACL-transection, 2/5 of the operated knees showed articular damages and medial menisci tears. Menisci showed a weak increase of cells, higher in cells under division and an increase of apoptosis, COMP and proteoglycans. At 12 weeks, 5/5 of the medial menisci and 2/5 of lateral menisci presented tears, and osteoarthritic changes were seen in the cartilage of all the operated knees. Meniscal cells reverted to normal number, while active cell division decreased below normal, apoptotic events were still high, COMP remained elevated, and glycosaminoglycans were even more elevated. CONCLUSION: Extracellular matrix changes and altered cell distribution occur early in the degenerative meniscus. There is a close relationship between changes in the articular cartilage and the menisci at the onset of secondary OA.

EULAR evidence-based recommendations for the diagnosis of knee osteoarthritis.

OBJECTIVE: To develop evidence-based recommendations for the diagnosis of knee osteoarthritis (OA). METHODS: The multidisciplinary guideline development group, representing 12 European countries, generated 10 key propositions regarding diagnosis using a Delphi consensus approach. For each recommendation, research evidence was searched systematically. Whenever possible, the sensitivity, specificity and likelihood ratio were calculated for individual diagnostic indicators and a diagnostic ladder was developed using Bayes' method. Secondary analyses were undertaken to test directly the recommendations using multiple predictive models in two populations from the UK and the Netherlands. Strength of recommendation was assessed by the EULAR visual analogue scale. RESULTS: Recommendations covered the definition of knee OA and its risk factors, subsets, typical symptoms and signs, the use of imaging and laboratory tests and differential diagnosis. Three symptoms (persistent knee pain, limited morning stiffness and reduced function) and three signs (crepitus, restricted movement and bony enlargement) appeared to be the most useful. Assuming a 12.5% background prevalence of knee OA in adults aged > or =45 years, the estimated probability of having radiographic knee OA increased with increasing number of positive features, to 99% when all six symptoms and signs were present. The performance of the recommendations in the study populations varied according to the definition of knee OA, background risk and number of tests applied. CONCLUSION: 10 key recommendations for diagnosis of knee OA were developed using both research evidence and expert consensus. Although there is no agreed reference standard, thorough clinical assessment alone can provide a confident rule-in diagnosis.

Improvement of experimental accelerated atherosclerosis by chondroitin sulphate.

The rheumatic diseases have been associated with accelerated atherosclerosis. Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by persistent synovial inflammation which leads to disability and structural changes in joints. Epidemiological studies have demonstrated an increased cardiovascular mortality in patients with RA. In these patients, atherosclerotic plaque occurs earlier, and it has a faster evolution than in general population. Atherosclerosis (AT) is also an inflammatory disease partly mediated by cytokines, many of them involved on chronic synovitis. Our group has developed a rabbit experimental model of AT aggravated by chronic arthritis to study inflammatory mechanisms involved on the progression of vascular lesions and their response to drugs. A preliminary study using this model suggests a beneficial effect of chondroitin sulphate (CS), a drug recommended for the treatment of osteoarthritis, in controlling AT lesions. Yet clinical trials should be conducted with this compound to address the same hypothesis in human studies.

Chondroitin sulfate improves synovitis in rabbits with chronic antigen-induced arthritis.

OBJECTIVE: Our aim was to explore the effect of chondroitin sulfate (CS), a natural glycosaminoglycan with attributed anti-inflammatory properties, on synovitis in a rabbit model of chronic arthritis with intense systemic inflammation bolstered by endothelial lesion and atherosclerotic diet. METHODS: Chronic arthritis was induced by intraarticular injections of ovalbumin in immunized rabbits. Systemic inflammation was boosted in these rabbits by receiving a hyperlipidemic diet after producing an endothelial lesion in the femoral arteries. A group of these rabbits were treated with CS (100mg/kg/day). At sacrifice, synovial membranes were isolated, and cyclooxygenase-2 (COX-2) and chemokine (C-C motif) ligand 2 (CCL2) mRNA, as well as protein expression were assayed by quantitative real-time polymerase chain reaction (RT-PCR) and western blot studies. Histological synovial examination was also carried out employing the histopathological synovitis score (Krenn scale). RESULTS: CS diminished both gene expression and protein synthesis of COX-2 and CCL2, and the histopathological score of the synovial membrane, when compared to untreated rabbits. In fact, CS partially prevented the intimal layer proliferation and the inflammatory cell infiltration in the synovial membrane, which was observed in non-treated animals. CONCLUSION: CS reduced the inflammatory response of the synovial membrane, as well as decreased the synovial histopathological lesions in our animal model. Further studies are warranted to demonstrate whether CS might be beneficial in the treatment of inflammatory arthritis.

Glucosamine sulphate in the treatment of knee osteoarthritis: cost-effectiveness comparison with paracetamol.

INTRODUCTION: The aim of this study was to explore the cost-effectiveness of glucosamine sulphate (GS) compared with paracetamol and placebo (PBO) in the treatment of knee osteoarthritis. For this purpose, a 6-month time horizon and a health care perspective was used. MATERIAL AND METHODS: The cost and effectiveness data were derived from Western Ontario and McMaster Universities Osteoarthritis Index data of the Glucosamine Unum In Die (once-a-day) Efficacy trial study by Herrero-Beaumont et al. Clinical effectiveness was converted into utility scores to allow for the computation of cost per quality-adjusted life year (QALY) For the three treatment arms Incremental Cost-Effectiveness Ratio were calculated and statistical uncertainty was explored using a bootstrap simulation. RESULTS: In terms of mean utility score at baseline, 3 and 6 months, no statistically significant difference was observed between the three groups. When considering the mean utility score changes from baseline to 3 and 6 months, no difference was observed in the first case but there was a statistically significant difference from baseline to 6 months with a p-value of 0.047. When comparing GS with paracetamol, the mean baseline incremental cost-effectiveness ratio (ICER) was dominant and the mean ICER after bootstrapping was -1376 euro/QALY indicating dominance (with 79% probability). When comparing GS with PBO, the mean baseline and after bootstrapping ICER were 3617.47 and 4285 euro/QALY, respectively. CONCLUSION: The results of the present cost-effectiveness analysis suggested that GS is a highly cost-effective therapy alternative compared with paracetamol and PBO to treat patients diagnosed with primary knee OA.

Genetic variation in the nuclear factor kappaB pathway in relation to susceptibility to rheumatoid arthritis.

OBJECTIVE: To examine genetic association between rheumatoid arthritis (RA) and known polymorphisms in core genes of the nuclear factor (NF)kappaB pathway, the major intracellular pathway in RA pathogenesis. METHODS: Discovery and replication sample sets of Spanish patients with RA and controls were studied. A total of 181 single nucleotide polymorphisms (SNPs) uniformly spaced along the genomic sequences of 17 core genes of the NFkappaB pathway (REL, RELA, RELB, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBIE, IKBKA, IKBKB, IKBKE, IKBKAP, KBRAS1, KBRAS2, MAP3K1, MAP3K14, TAX1BP1) were studied by mass spectrometry analysis complemented with 5'-nuclease fluorescence assays in the discovery set, 458 patients with RA and 657 controls. SNPs showing nominal significant differences were further investigated in the replication set of 1189 patients with RA and 1092 controls. RESULTS: No clear reproducible association was found, although 12 SNPs in IKBKB, IKBKE and REL genes showed significant association in the discovery set. Interestingly, two of the SNPs in the IKBKE gene, weakly associated in the discovery phase, showed a trend to significant association in the replication phase. Pooling both sample sets together, the association with these two SNPs was significant. CONCLUSION: We did not find any major effect among the explored members of the NFkappaB pathway in RA susceptibility. However, it is possible that variation in the IKBKE gene could have a small effect that requires replication in additional studies.

Correlation between arthroscopic and histopathological grading systems of articular cartilage lesions in knee osteoarthritis.

PURPOSE: Arthroscopic and particularly histopathological assessments have been used to evaluate alterations of knee cartilage in osteoarthritis (OA). The aim of this study was to examine the correlation between an arthroscopic method to grade the severity of chondropathies and the histological/histochemical grading system (HHGS) applied to the corresponding articular cartilage areas in knee OA. METHODS: The articular cartilage surface was examined by chondroscopy using the Beguin and Locker severity criteria, analysing the lesions in 72 chondroscopic areas. Afterwards, samples were obtained by dividing the cartilage surface of the medial tibiofemoral compartment of three OA knee joints into equal squares and they were evaluated histologically using the HHGS. The correlation between both grading methods was assessed using the weighted Kappa coefficient (K(w)). RESULTS: The results obtained with both scores showed good agreement (K(w): mean+/-standard deviation, 0.619+/-0.071). While the average HHGS scores of the chondral samples showed a better agreement with arthroscopic grades 0, I and II, the arthroscopic evaluation has a tendency to overestimate chondral lesions for histological grades III and IV. The intra- and inter-observer reliability of the HHGS evaluation of chondral lesions was excellent (Intraclass Correlation Coefficient: 0.909 and 0.941, respectively). CONCLUSION: In this study, we found a good quantitative correlation between established arthroscopic severity and histopathological scoring systems, particularly in less advanced lesions. Our results suggest that the arthroscopic method is a valuable tool in clinical research to score chondropathies in the medial femorotibial compartment of the OA knee, although some limitations should not be overlooked.

It Is the Time to Think About a Treat-to-Target Strategy for Knee Osteoarthritis.

Osteoarthritis (OA) is a rheumatic disease that affects the well-being of the patient, compromises physical and mental function, and affects other quality of life aspects. In the literature, several evidence-based guidelines and recommendations for the management of knee osteoarthritis (KOA) are available. These recommendations list the different therapeutic options rather than addressing a hierarchy between the treatments and defining the real target. Therefore, a question arises: are patients and physicians satisfied with the current management of KOA? Actually, the answer may be negative, thus suggesting a change in our therapeutic strategies. In this article, we address this challenge by suggesting that it is time to develop a "treat to target strategy" for KOA.

Effect of chondroitin sulphate in a rabbit model of atherosclerosis aggravated by chronic arthritis.

BACKGROUND AND PURPOSE: Among the agents employed to manage osteoarthritis, chondroitin sulphate (CS) is a natural glycosaminoglycan with an anti-inflammatory effect on joint cells. CS might also influence the inflammatory component of atherosclerosis. Our aim was to examine the effect of CS administration on vascular injury and on markers of systemic inflammation in a rabbit model of atherosclerosis aggravated by systemic inflammation provoked by chronic antigen-induced arthritis. EXPERIMENTAL APPROACH: Atherosclerosis was induced in rabbits by maintaining them on a hyperlipidaemic diet after producing an endothelial lesion in the femoral arteries. Simultaneously, chronic arthritis was induced in these animals by repeated intraarticular injections of ovalbumin in previously immunized rabbits. A group of these rabbits were treated prophylactically with CS (100 mg kg(-1)day(-1)) and when the animals were killed, serum and peripheral blood mononuclear cells (PBMC) were isolated. Furthermore, femoral arteries and thoracic aorta were used for gene expression studies and histological examination. KEY RESULTS: CS administration reduced the concentration of the proinflammatory molecules C-reactive protein and IL-6 in serum. Likewise, CS inhibited the expression of CCL2/monocyte chemoattractant protein (MCP)-1 and cyclooxygenase (COX)-2 in PBMC, and reduced the nuclear translocation of nuclear factor-kappaB. In the femoral lesion, CS also diminished the expression of CCL2 and COX-2, as well as the ratio of the intima/media thickness. Moreover, CS decreased the percentage of rabbits with atherosclerosis and chronic arthritis that developed vascular lesions in the aorta. CONCLUSIONS AND IMPLICATIONS: These findings suggest that CS treatment may to some extent impede the progression of atherosclerosis.