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.

Effect of risedronate on bone mass, remodelling and biomechanical strength in orchidectomized rats.

BACKGROUND: The ability of risedronate to prevent and/or treat orchidectomy-induced osteoporosis in male rats was studied. METHODS: Ninety-five 10-week-old male Wistar rats were sham-operated or orchidectomized. Prevention study: Sham: sham-operated rats; ORX: orchidectomized rats; ORX + RSD: orchidectomized rats, treated for 6 weeks with risedronate. Animals were sacrificed 6 weeks after surgery. Treatment study: Sham(1) and ORX(1): sham and orchidectomized rats sacrificed 3 months after orchidectomy; Sham(2), ORX(2) and ORX(2) + RSD: sham-operated, and orchidectomized rats treated with placebo or risedronate for 6 weeks starting 3 months after orchidectomy, and then sacrificed. Risedronate (0.5 mg/kg/day) and placebo (saline) were administered via oral gavage. After sacrifice, bone mineral density by DEXA, bone volume (BV/TV), osteocalcin (BGP), and serum carboxyterminal telopeptide of collagen type I (CTX) were measured. Femur low-rate torsion testing was performed. RESULTS: Orchidectomy produced an increase in bone remodelling with loss of BV/TV, without effects on torsional strength. Risedronate treatment partially prevented these effects. In the treatment study, risedronate reduced bone remodelling and restored BV/TV to levels higher than those of the sham group, improving biomechanical parameters. CONCLUSIONS: These results suggest that risedronate could be used as a prevention or treatment of male osteoporosis due to hypogonadism.

Association of HLA-DM polymorphism with the production of antiphospholipid antibodies.

OBJECTIVE: To investigate whether variation in the HLA-DM gene is important in producing a group of pathogenic autoantibodies-antiphospholipid antibodies (aPL)-on the basis that HLA class II restricted antigen presentation is involved in the production of aPL. METHODS: HLA-DMA and DMB polymorphisms were genotyped by polymerase chain reaction combined with restriction enzyme digestion in 51 white patients with primary antiphospholipid syndrome (APS), 82 with systemic lupus erythematosus (SLE) (42 with APS and 40 without APS), and 109 healthy white controls. The association with the aPL profile was examined. RESULTS: The distribution of DMA alleles in APS patients and in patients with APS associated with SLE was significantly different from that in controls by 4x2 chi(2) test with 3 degrees of freedom (p = 0.035 and 0.011, respectively), but it was not different between SLE patients without APS and controls. The allelic distribution of DMA was also different between patients with IgG class anticardiolipin antibody or those with lupus anticoagulant (LA) and controls (p = 0.012 and 0.007, respectively) and between patients with and without LA among SLE patients (p = 0.035). All these differences included the increase in DMA*0102 in the former groups. CONCLUSIONS: The results suggest that HLA-DMA*0102 or its linked gene(s) form one of the genetic risks for the production of aPL.

Respuesta de los autores a la carta de Ahumada et al sobre el artículo "Análisis farmacoeconómico del tratamiento de la artritis reumatoide resistente a metotrexato con las combinaciones de leflunomida-metotrexato o infliximab-metotrexato" / Response to the letter of M. C. Ahumada et al, on the article "Pharmacoeconomic analysis of methotrexate-resistant rheumatoid arthritis with combinations of leflunomide-methotrexate or infliximab-methotrexate"

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Análisis farmacoeconómico del tratamiento de la artritis reumatoide resistente a metotrexato con las combinaciones de leflunomida-metotrexato o infliximab-metotrexato / Pharmacoeconomic analysis of treatment of methotrexate-resistant rheumatoid arthritis with combinations of leflunomidemethotrexate or infliximab-methotrexate

Objetivo: Comparar la eficiencia de leflunomidametotrexato o infliximab-metotrexato en pacientes con artritis reumatoide resistente a metotrexato. Métodos: Modelo farmacoeconómico de minimización de costes que comparó los tratamientos, administrados con las dosis y pautas recomendadas, durante un período de 12 meses. La utilización de recursos y los costes unitarios se estimaron a partir de fuentes españolas. Se hicieron análisis de sensibilidad simples univariantes del caso básico. Resultados: Según dos ensayos clínicos disponibles, aleatorizados y controlados con placebo, las tasas de respuesta ACR20 y ACR50 (respuesta del 20 y el 50 per cent según el criterio del American College of Rheumatology), a los 6 meses, de los pacientes con artritis reumatoide refractaria al tratamiento con metotrexato en monoterapia fueron del 46,2 y el 25,4 per cent, respectivamente, con leflunomidametotrexato, y del 50,0 y el 27,0 per cent, respectivamente, con infliximab-metotrexato (2p = 0,57 y 2p = 0,82). El coste por paciente de un tratamiento anual con leflunomida-metotrexato o con infliximab-metotrexato se estima en 2.823 y 11.489 , respectivamente (coste incremental de 8.666 ). El análisis de sensibilidad confirmó la consistencia del caso básico, con costes incrementales de infliximab-metotrexato entre 7.500 y 9.500 . Para que los costes de las alternativas por paciente se igualaran, el coste de adquisición de infliximab por envase debería bajar desde los 637,59 actuales hasta un coste hipotético de 33,10. Conclusiones: El coste por paciente de 12 meses de tratamiento es mayor con la combinación de infliximab-metotrexato que con la combinación de leflunomida-metotrexato, debido al mayor coste Análisis farmacoeconómico del tratamiento de la artritis reumatoide resistente a metotrexato con las combinaciones de leflunomida-metotrexato o infliximab-metotrexato (AU)

Lipoprotein(a) oxidation and autoantibodies: a new path in atherothrombosis.

Lipoprotein(a) (Lp(a)) is considered a vascular pathogen of outstanding importance. High plasma levels of this lipoprotein are associated with premature arterial disease; however, the mechanisms involved have not been clarified. The atherosclerotic process is increasingly regarded as a chronic inflammatory reaction in the arterial wall where oxidation-mediated endothelial injury involving modified forms of low-density lipoprotein (LDL) seems to be a key event. Autoimmune pathways are involved in the progression of atherosclerosis and humoral response to oxidatively modified LDL can be considered among these pathways. A number of factors can be encountered in the pathogenesis of the accelerated arterial disease seen in patients with antiphospholipid (Hughes) syndrome (APS) and systemic lupus erythematosus (SLE). Among these, high levels of Lp(a) have been described in both and increasing evidence indicates that patients with antiphospholipid antibodies (aPL) are under oxidative stress. Recent studies suggest that the so-called 'oxidation theory of atherosclerosis' may also be applied to Lp(a). This fact makes this lipoprotein potentially suitable as a target of the immune system and antibodies reacting against oxidatively-modified Lp(a) by malondialdehyde have been recently described in APS and SLE. It is therefore likely that an immune response to the oxidized moiety of Lp(a) might be influential in the pathogenicity of this lipoprotein and, subsequently, of atherosclerosis.

Autoantibodies against malondialdehyde-modified lipoprotein(a) in antiphospholipid syndrome.

OBJECTIVE: To demonstrate the existence of antibodies that react against malondialdehyde (MDA)-modified lipoprotein(a) (MDA-Lp[a]), a molecule that exhibits behavioral similarities to MDA-modified low-density lipoprotein (MDA-LDL), and to assess the possible relationship of these antibodies (anti-MDA-Lp[a]) to anti-MDA-LDL antibodies (anti-MDA-LDL) in the antiphospholipid syndrome (APS). METHODS: We studied 104 patients with APS (61 with primary APS and 43 with APS secondary to systemic lupus erythematosus) and 106 healthy controls. Anti-MDA-Lp(a) were measured by enzyme-linked immunosorbent assay (ELISA) using MDA-Lp(a) as antigen. Plasma levels of Lp(a) were determined. Anti-MDA-LDL, anticardiolipin antibodies (aCL), and anti-beta2-glycoprotein I antibodies (anti-beta2GPI) were also measured by ELISA. Inhibition assays were performed to determine the presence of cross-reactivity between anti-MDA-Lp(a) and anti-MDA-LDL. RESULTS: Anti-MDA-Lp(a) were detected in 38 of 104 patients (37%) but in only 6 of 106 controls (6%) (chi2 = 28, P<0.0001). Levels of anti-MDA-Lp(a) were also higher in patients than in controls (P<0.0001). Titers of these antibodies did not correlate with plasma levels of Lp(a). The presence of anti-MDA-Lp(a) was significantly associated with that of anti-MDA-LDL (chi2 = 22.09, P<0.0001). There was a strong correlation between the titers of anti-MDA-Lp(a) and anti-MDA-LDL (r = 0.59, P<0.0001), and inhibition assays showed significant cross-reactivity between the 2 populations of antibodies. Anticardiolipin antibodies and anti-beta2GPI were present in sera from 67 patients (64%) and 48 patients (46%), respectively. No correlation was found between the titer of anti-MDA-Lp(a) and titers of either aCL or anti-beta2GPI. CONCLUSION: We report for the first time the existence of autoantibodies against MDA-Lp(a). The presence of antibodies reacting not only against MDA-LDL but also against MDA-Lp(a) supports the hypothesis of a role for oxidative phenomena in the pathogenesis of APS and atherosclerosis.

Arterial disease in lupus and secondary antiphospholipid syndrome: association with anti-beta2-glycoprotein I antibodies but not with antibodies against oxidized low-density lipoprotein.

The prevalence and clinical significance of antibodies against beta2-glycoprotein I (anti-beta2GPI) and antibodies against oxidized low-density lipoprotein (anti-ox-LDL) were evaluated as potential indicators of arterial disease in patients with systemic lupus erythematosus (SLE) and SLE with secondary antiphospholipid syndrome (APS). IgG anti-beta2GPI and IgG anti-ox-LDL were measured by enzyme-linked immunosorbent assay (ELISA) in serum samples from 118 patients with SLE, including 40 with secondary APS. IgG anti-beta2GPI were positive in 17% (20/118) of SLE patients. The presence and titres of IgG anti-beta2GPI were strongly associated with a history of arterial thrombosis. Haemolytic anaemia was also significantly associated with the presence of IgG anti-beta2GPI. The prevalence of IgG anti-ox-LDL was 53% (63/118), but there was no association with arterial thrombosis. No correlation between the values of anti-ox-LDL and those of anti-beta2GPI was found. These results suggest that IgG anti-beta2GPI could be a marker for arterial thrombosis in SLE patients, while IgG anti-ox-LDL were not associated with arterial disease in this group of lupus patients.