RESUMEN
Spondyloarthropathies (SpA) are associated with increased cardiovascular risk. Among possible mechanisms is the dysfunction of serum lipoproteins in regulating cell cholesterol homeostasis. Cholesterol efflux capacity (CEC)-the atheroprotective ability of HDL (high density lipoproteins) to accept cholesterol from macrophages-might predict cardiovascular disease independently of HDL-cholesterol levels. We aimed at evaluating modifications of CEC and of the atherogenic cholesterol loading capacity (CLC) of serum lipoproteins in psoriatic arthritis (PsA) and ankylosing spondylitis (AS) following anti-rheumatic treatment. A total of 62 SpA patients (37 PsA and 25 AS) were evaluated before and after treatment with tumor necrosis factor inhibitor and/or methotrexate. CEC and CLC were measured by radioisotopic and fluorometric techniques, respectively. Endothelial function was assessed by finger plethysmography (Endopat). In the whole SpA group, total and HDL-cholesterol increased after treatment, while lipoprotein(a) decreased and CLC was unchanged. Treatment was associated with increased Scavenger Receptor class B type I (SR-BI)-mediated CEC in the AS group. SR-BI- and ABCG1-mediated CEC were negatively associated with inflammatory parameters and positively related to coffee consumption. SR-BI CEC and CLC were positively and negatively associated with endothelial function, respectively. Our pilot study suggests that anti-rheumatic treatment is associated with favorable modulation of lipoprotein quality and function in SpA, particularly in AS, in spite of the induced increase in total cholesterol levels. If confirmed in a larger population, this might represent an atheroprotective benefit beyond what is reflected by conventional serum lipid profile.
RESUMEN
BACKGROUND: Patients with autoimmune arthritis (AA) are at increased risk for impaired cardiac function and heart failure. This may be partly due to the effect of inflammation in heart function. The impact of antirheumatic drugs on cardiac dysfunction in AA remains controversial. Therefore, we aimed to examine effects of antirheumatic treatment on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in AA patients and its relationship to inflammatory markers. METHODS: We examined 115 patients with AA (64 rheumatoid arthritis (RA), 31 psoriatic arthritis and 20 ankylosis spondylitis) starting with methotrexate (MTX) monotherapy or tumor necrosis factor inhibitors (TNFi) with or without MTX co-medication. NT-proBNP (measured in serum by ECLIA from Roche Diagnostics), and other clinical and laboratory parameters were evaluated at baseline, after 6 weeks and 6 months of treatment. RESULTS: NT-proBNP levels did not change significantly after 6 weeks and 6 months of antirheumatic therapy (pbaseline-6weeks = 0.939; pbaseline-6months = 0.485), although there was a modest improvement from 6 weeks to 6 months in the MTX only treatment group (median difference = -18.2 [95% CI = -32.3 to -4.06], p = 0.013). There was no difference in the effects of MTX monotherapy and TNFi regimen on NT-proBNP levels. The changes in NT-proBNP after antirheumatic treatment positively correlated with changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Baseline NT-proBNP levels were related to baseline CRP and ESR levels, and some other established markers of disease activities in crude analyses. CONCLUSION: Circulating levels of NT-proBNP were related to established inflammatory markers at baseline, and the changes in NT-proBNP after antirheumatic treatment were positively related to these markers. Nevertheless, antirheumatic therapy did not seem to affect NT-proBNP levels compared to baseline, even though inflammatory markers significantly improved.
Asunto(s)
Antirreumáticos/administración & dosificación , Artritis , Enfermedades Autoinmunes , Metotrexato/administración & dosificación , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Adulto , Artritis/sangre , Artritis/tratamiento farmacológico , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/tratamiento farmacológico , Biomarcadores/sangre , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Sindecano-1/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Metotrexato/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The complement system is involved in pathogenesis of cardiovascular disease, and might play a role in accelerated atherogenesis in spondylarthropathies (SpA). Hence, we examined complement activation in SpA, and its relationship to antirheumatic treatment, inflammatory and cardiovascular markers. METHODS: From PSARA, a prospective observational study, we examined 51 SpA patients (31 psoriatic arthritis (PsA), and 20 ankylosing spondylitis (AS)), starting tumor necrosis factor (TNF) inhibitor alone (n = 25), combined with methotrexate (MTX) (n = 10), or MTX monotherapy (n = 16). Complement activation was determined by the soluble terminal complement complex (sC5b-9), inflammation by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and endothelial function by finger plethysmography (Endopat) at baseline, after 6 weeks and 6 months of treatment. RESULTS: SpA patients had sC5b-9 levels at (PsA) or above (AS) the upper limit of the estimated reference range. Median sC5b-9 levels decreased significantly from baseline to 6 weeks, with no significant difference between the AS and PsA group. Notably, a significant reduction in sC5b-9 was observed after administration of TNF inhibitor ± MTX, whereas no significant changes were observed in patients treated with MTX alone. Between 6 weeks and 6 months, sC5b-9 remained stable across all subgroups. Reduction in sC5b-9 was independently related to decreased ESR and CRP, and to increased high density cholesterol and total cholesterol. Reduction in sC5b-9 from baseline to 6 weeks was associated with improved EF in age and gender adjusted analyses. CONCLUSION: TNF-inhibition, but not MTX monotherapy, led to rapid and sustained reduction of complement activation in SpA. Thus, the observed decrease in cardiovascular morbidity in patients treated with TNF-inhibitors might be partly due to its beneficial effect on complement. TRIAL REGISTRATION: Clinical Trials (NCT00902005), retrospectively registered on the 14th of May 2009.
Asunto(s)
Activación de Complemento/efectos de los fármacos , Espondiloartropatías/inmunología , Inhibidores del Factor de Necrosis Tumoral/farmacología , Adulto , Complejo de Ataque a Membrana del Sistema Complemento/inmunología , Femenino , Humanos , Masculino , Metotrexato/administración & dosificación , Metotrexato/farmacología , Metotrexato/uso terapéutico , Persona de Mediana Edad , Espondiloartropatías/sangre , Espondiloartropatías/tratamiento farmacológico , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/uso terapéuticoRESUMEN
OBJECTIVES: The reason for increased cardiovascular risk in inflammatory arthritis (IA) is unclear. Interestingly, selenium-deficiency is suspected to contribute to the development of cardiovascular disease (CVD) in the general population. Although the reference range of serum selenium (s-selenium) is 50-120⯵g/L, there are indications that levels up to 85⯵g/L might not be sufficient for optimal cardioprotection. Our aim was to examine s-selenium levels in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), to evaluate the effect of anti-rheumatic treatment on s-selenium levels, and to assess relationships between s-selenium levels and clinical and laboratory parameters including markers of disease activity and CVD risk. METHODS: We examined 64 patients with RA, 40 with PsA and 26 with AS starting with methotrexate (MTX) monotherapy or anti-tumor necrosis factor therapy (anti-TNF) with or without methotrexate (anti-TNF⯱â¯MTX) due to active disease. S-selenium, inflammatory biomarkers, endothelial function (EF) and other variables were examined at baseline and after 6 weeks and 6 months of treatment. RESULTS: In the total IA group, s-selenium increased within 6 weeks of anti-rheumatic treatment, and thereafter the levels remained stable until the end of the 6 months follow-up period. There were no significant differences in s-selenium changes between the three diagnostic groups and between the two treatment regimens. Changes in s-selenium were negatively related to changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), but there were no significant relationships to any other of the examined risk parameters for CVD including EF. CONCLUSION: IA patients had s-selenium within the reference range, but below the level that might be necessary for optimal CVD protection. Anti-rheumatic treatment had a relatively rapid and sustained effect on s-selenium levels. The increase in s-selenium was related to reduction in inflammatory activity. In theory, anti-rheumatic drugs might improve s-selenium levels through inhibition of pro-inflammatory processes or through other mechanisms. Although we have not revealed any significant relationships between s-selenium and CVD risk parameters, the role of suboptimal s-selenium levels in pathogenesis of premature CVD in IA cannot be ruled out.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Psoriásica/sangre , Artritis Psoriásica/tratamiento farmacológico , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/uso terapéutico , Espondilitis Anquilosante/sangre , Espondilitis Anquilosante/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Selenio , Factor de Necrosis Tumoral alfa/sangre , Adulto JovenRESUMEN
BACKGROUND: Pentraxin 3 is proposed to be a marker of inflammation and cardiovascular risk, but its role in inflammatory rheumatic diseases (IRDs) is still uncertain. Therefore, we wanted to examine if anti-rheumatic treatment reduced serum PTX3 (s-PTX3) levels in IRDs, and if s-PTX3 levels were related to other markers of inflammation and to endothelial function (EF). METHODS: We examined s-PTX3, EF and established inflammatory biomarkers in 114 IRD patients from the PSARA study before and after 6 weeks and 6 months of treatment with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNF) therapy with or without MTX co-medication. RESULTS: s-PTX3 levels in all IRD diagnoses were above the upper limit of the reference range. In contrast to established inflammatory markers, in particular CRP and ESR, s-PTX3 levels did not change significantly after 6 weeks and 6 months of anti-rheumatic therapy. There was no difference in change in s-PTX3 levels from baseline to 6 weeks and 6 months between MTX monotherapy and anti-TNF regimens. CRP, ESR and EF were not related to changes in s-PTX3 neither in crude nor adjusted analyses. CONCLUSION: IRD patients have increased s-PTX3 levels, which, in contrast to other inflammatory markers, do not seem to improve within 6 months of therapy with MTX and/or anti-TNF. Thus, s-PTX3 might reflect a persisting immune process, even a causal factor of inflammation, not inhibited by the standard anti-rheumatic treatment. Furthermore, even though s-PTX3 is thought to be a strong predictor of cardiovascular prognosis, it was not related to EF.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Psoriásica/sangre , Artritis Reumatoide/sangre , Proteína C-Reactiva/metabolismo , Metotrexato/uso terapéutico , Componente Amiloide P Sérico/metabolismo , Espondilitis Anquilosante/sangre , Adulto , Anciano , Artritis Psoriásica/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Biomarcadores/sangre , Quimioterapia Combinada , Femenino , Humanos , Inflamación/sangre , Masculino , Persona de Mediana Edad , Espondilitis Anquilosante/tratamiento farmacológico , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND: Inflammatory arthritis (IA), including rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA), leads to increased cardiovascular disease occurrence probably due to atherosclerosis. One of the first stages in atherogenesis is endothelial dysfunction (ED). Therefore, we aimed to compare endothelial function (EF) in patients with IA, and to examine the effects of methotrexate (MTX) monotherapy and antitumor necrosis factor (anti-TNF) treatment with or without MTX comedication (anti-TNF ± MTX) on EF. METHODS: From the PSARA observational study, all patients with RA (n = 64), PsA (n = 29), and AS (n = 20) were evaluated for EF. In patients with ED at baseline (n = 40), we evaluated changes in the Reactive Hyperemic Index (RHI) after 6 weeks and 6 months of antirheumatic therapy. RESULTS: In IA patients with ED, RHI significantly improved after 6 weeks (p < 0.001) and 6 months (p < 0.001) of treatment, independent of changes in disease activity parameters. After 6 months, RHI had improved more in the MTX group than in the anti-TNF ± MTX group, and the difference remained statistically significant after adjustments for potential confounders. Among patients with active RA, AS, and PsA, those with AS appeared to have the worst endothelial function, although they were the youngest. CONCLUSION: Treatment with MTX and anti-TNF ± MTX was associated with a relatively fast improvement of EF in IA patients with ED, independent of change in disease activity. Therefore, modes of action other than the anti-inflammatory effect may contribute to the EF improvement. After 6 months, the EF improvement was more pronounced in the MTX group than in the anti-TNF ± MTX group. TRIAL REGISTRATION: Clinicaltrials, NCT00902005 . Registered on 13 May 2009.