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.

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.

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.

Parathyroid hormone-related protein exhibits antioxidant features in osteoblastic cells through its N-terminal and osteostatin domains.

OBJECTIVES: Oxidative stress plays a major role in the onset and progression of involutional osteoporosis. However, classical antioxidants fail to restore osteoblast function. Interestingly, the bone anabolism of parathyroid hormone (PTH) has been shown to be associated with its ability to counteract oxidative stress in osteoblasts. The PTH counterpart in bone, which is the PTH-related protein (PTHrP), displays osteogenic actions through both its N-terminal PTH-like region and the C-terminal domain. METHODS: We examined and compared the antioxidant capacity of PTHrP (1-37) with the C-terminal PTHrP domain comprising the 107-111 epitope (osteostatin) in both murine osteoblastic MC3T3-E1 cells and primary human osteoblastic cells. RESULTS: We showed that both N- and C-terminal PTHrP peptides at 100 nM decreased reactive oxygen species production and forkhead box protein O activation following hydrogen peroxide (H2O2)-induced oxidation, which was related to decreased lipid oxidative damage and caspase-3 activation in these cells. This was associated with their ability to restore the deleterious effects of H2O2 on cell growth and alkaline phosphatase activity, as well as on the expression of various osteoblast differentiation genes. The addition of Rp-cyclic 3',5'-hydrogen phosphorothioate adenosine triethylammonium salt (a cyclic 3',5'-adenosine monophosphate antagonist) and calphostin C (a protein kinase C inhibitor), or a PTH type 1 receptor antagonist, abrogated the effects of N-terminal PTHrP, whereas protein phosphatase 1 (an Src kinase activity inhibitor), SU1498 (a vascular endothelial growth factor receptor 2 inhibitor), or an anti osteostatin antiserum, inhibited the effects of C-terminal PTHrP. CONCLUSION: These findings indicate that the antioxidant properties of PTHrP act through its N- and C-terminal domains and provide novel insights into the osteogenic action of PTHrP.Cite this article: S. Portal-Núñez, J. A. Ardura, D. Lozano, I. Martínez de Toda, M. De la Fuente, G. Herrero-Beaumont, R. Largo, P. Esbrit. Parathyroid hormone-related protein exhibits antioxidant features in osteoblastic cells through its N-terminal and osteostatin domains. Bone Joint Res 2018;7:58-68. DOI: 10.1302/2046-3758.71.BJR-2016-0242.R2.

Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis.

BACKGROUND AND PURPOSE: Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The JAK inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analysed the effect of tofacitinib on the lipid profile of hyperlipidaemic rabbits with chronic arthritis (CA) and on the changes in reverse cholesterol transport (RCT) during chronic inflammation. EXPERIMENTAL APPROACH: CA was induced in previously immunized rabbits, fed a high-fat diet, by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg·kg-1 ·day-1 ) for 2 weeks. Systemic and synovial inflammation and lipid content were evaluated. For in vitro studies, THP-1-derived macrophages were exposed to high lipid concentrations and then stimulated with IFNγ in the presence or absence of tofacitinib in order to study mediators of RCT. KEY RESULTS: Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it reduced the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while the JAK/STAT inhibition provoked by tofacitinib induced lipid release by increasing the levels of cellular liver X receptor α and ATP-binding cassette transporter (ABCA1) synthesis. CONCLUSIONS AND IMPLICATIONS: Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients.

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.

Selective estrogen receptor modulators (SERMs): new alternatives for osteoarthritis?

The dramatic rise in the prevalence rate of osteoarthritis (OA) after the menopause and the presence of estrogen receptors in joint tissues suggest that estrogen may help protect against the development of OA. Trials of estrogen therapy have produced inconclusive results, however, partly because of flaws in study design and partly because of the complexity of the mechanisms underlying estrogen's effects on joint tissues. Initial studies of the use of selective estrogen receptor modulators (SERMs) have reported beneficial effects in OA. These agents may exert both a direct effect upon joint cartilage and indirect effects on subchondral bone, synovium, muscle, tendons and ligaments. SERMs may be particularly beneficial for postmenopausal patients with osteoporotic OA, a phenotype defined by decreased bone density, associated with high remodeling in subchondral bone. More research is needed, though, before SERMs can become a therapeutic option for 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.

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

La artritis reumatoide (AR) es una enfermedad agresiva y progresiva, cuyo panorama ha cambiado de forma espectacular desde la irrupción de las terapias biológicas a finales de los años noventa. Las principales líneas de actuación en la actualidad se centran en un diagnóstico y tratamiento precoces, lo que ahora es posible gracias a la aparición de nuevos criterios diagnósticos orientados al diagnóstico y clasificación de las formas incipientes e indeterminadas. La instauración del tratamiento de forma precoz, individualizada y agresiva, con unos objetivos concretos de remisión o baja actividad ha mejorado notablemente los resultados conseguidos en muchos pacientes, especialmente en aquellos de peor pronóstico. Abatacept es uno de estos fármacos biotecnológicos que ha entrado a formar parte del arsenal terapéutico de primera línea para el tratamiento de la AR precoz y agresiva. Su eficacia y perfil de seguridad indican que es un fármaco muy prometedor para el tratamiento de los pacientes con AR(AU)

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(AU)

[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.

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.

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.

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.

Inflamación sinovial en un modelo experimental de síndrome metabólico en conejo / Synovial inflammation in an experimental model of metabolic syndrome in the rabbit

Objetivo: Analizar el efecto del síndrome metabólico (SM) sobre la inflamación sinovial en un modelo experimental en conejo. Material y métodos: Se probaron tres intervenciones dietéticas diferentes para inducir un modelo experimental de SM, en 21 conejos New Zealand hembra, de 8 meses de edad: 1) alimentación con dieta enriquecida con 1% de colesterol y 3% de aceite de cacahuete y agua ad libitum; 2) alimentación con dieta normal y agua con 30% de fructosa ad libitum; 3) alimentación con dieta enriquecida con 1% de colesterol y 3% de aceite de cacahuete y agua con 30% de fructosa ad limitum. Los animales se dejaron evolucionar durante 12 semanas y se hizo un seguimiento semanal de peso, glucosa basal, colesterol HDL, triglicéridos. Tras el sacrificio, se tomaron muestras de membrana sinovial para cuantificar el infiltrado macrofágico sinovial mediante inmunohistoquímica. Resultados: La única intervención dietética con la que conseguimos inducir alteraciones asociadas al SM en los conejos fue alimentándolos con una dieta hiperlipémica. Estos animales, además de presentar hiperglucemia y dislipemia, tenían un infiltrado macrofágico sinovial mayor que el del grupo control. Conclusión: La alimentación con dieta hiperlipémica induce alteraciones típicas del SM en el conejo, acompañadas de un aumento del infiltrado macrofágico sinovial, lo que sugiere que el macrófago podría desempeñar un papel importante en el inicio y/o la progresión de la artrosis descrita que se asocia con el SM (AU)

Objetive: To analyze the effect of metabolic syndrome (MS) upon synovial inflammation in an experimental model in the rabbit. Material and methodology: Three different diets were used to induce an experimental model of MS in 21 female New Zealand rabbits (aged 8 months): 1) diet enriched with 1% cholesterol and 3% peanut oil, with water, ad libitum; 2) normal diet, with water, and 30% fructose, ad libitum; 3) diet enriched with 1% cholesterol and 3% peanut oil, with water, and 30% fructose, ad libitum. The animals were followed-up on for 12 weeks, with weekly monitoring of body weight, basal glucose, HDL-cholesterol and triglycerides. Following sacrifice, synovial membrane samples were collected to quantify the synovial macrophage infiltrate using immunohistochemical techniques. Results: The only diet to induce alterations associated with MS in the rabbits was the hyperlipidemic diet. These animals, in addition to presenting hyperglycemia and dyslipidemia, showed greater synovial macrophage infiltration than the control group. Conclusion: A hyperlipidemic diet induces alterations typical of MS in the rabbit, accompanied by an increase in synovial macrophage infiltration (AU)

Pharmacological modulation by celecoxib of cachexia associated with experimental arthritis and atherosclerosis in rabbits.

BACKGROUND AND PURPOSE: Non-steroidal anti-inflammatory drugs improve inflammatory cachexia in several conditions. Thus, we have explored inhibition of cyclooxygenase-2 (COX-2) in an experimental model of rheumatoid cachexia in rabbits. EXPERIMENTAL APPROACH: Chronic arthritis was induced in immunized rabbits by repeated intra-articular injections of ovalbumin. To increase the degree of systemic inflammation and also to induce atherosclerotic lesions, the animals were fed a hyperlipidaemic diet (2% cholesterol and 6% peanut oil) and were given an endothelial injury of the femoral artery. Rabbits were randomized to receive the COX-2 inhibitor celecoxib (10 mg·kg⁻¹ ·day⁻¹) or no treatment. After 4 weeks, sera, peripheral mononuclear cells and vessel specimens were collected. KEY RESULTS: Inhibition of COX-2 by celecoxib modulated the systemic inflammatory response and increased total cholesterol and triglyceride levels. Celecoxib also minimized weight loss and prevented serum albumin fall. At a vascular level, celecoxib reduced COX-2 protein in the femoral arterial wall, but did not modify size or the macrophage infiltration of femoral lesions nor the percentage of rabbits with spontaneous aortic plaques. CONCLUSIONS AND IMPLICATIONS: Our animal model induced a severe inflammatory cachexia, comparable to that of persistently active rheumatoid arthritis. The inhibition of COX-2 by celecoxib improves this state, suggesting that COX products play an important role in its development, without affecting the development or the progression of vascular lesions. Overall, these results suggest that celecoxib might be considered as a new therapeutic tool for the treatment of rheumatoid cachexia.

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.