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Effects of repeated infliximab therapy on serum lipid profile in patients with refractory rheumatoid arthritis
Abstract
Patients with rheumatoid arthritis (RA) frequently display an atherogenic lipid profile which has been linked with inflammation. Tumor necrosis factor-alpha (TNF-alpha), a pivotal pro-inflammatory cytokine in RA may be involved in the development of the disturbed lipid metabolism. We investigated whether infliximab, an anti-TNF-alpha therapy, may modify the lipid profile.
56 consecutive RA patients were treated with infliximab (3 mg/kg at weeks 0, 2, 6, 14, 22, 30). Lipid profile and CRP were assayed at baseline and before infusion at weeks 6 and 30. Baseline values were compared with those in 56 healthy volunteers.
At baseline, the concentrations of HDL-cholesterol were lower in RA patients than in the controls (1.3+/-0.4 vs. 1.5+/-0.2 mmol/L; p<0.01). The triglyceride concentrations (1.6+/-0.8 vs. 1.3+/-0.4 mmol/L, p<0.01), the ratio of total cholesterol/HDL-cholesterol (4.3+/-1.6 vs. 3.2+/-0.5, p<0.001) and LDL-cholesterol/HDL-cholesterol (2.6+/-1.2 vs. 1.7+/-0.5, p<0.001) were significantly higher in RA patients than in controls. After 6 weeks of infliximab therapy, the mean total cholesterol concentration increased by 25% (p<0.001), LDL-cholesterol by 24% (p<0.001) and HDL-cholesterol by 30% (p<0.001). The decrease in CRP levels to 30 week inversely correlated with the increase in HDL-cholesterol (r=-0.47, p=0.005).
Infliximab administration is associated with important increases in cholesterol levels in all its forms but as no significant beneficial effect on the atherogenic ratio.
... Data on patients with RA treated with infliximab were obtained from four RCTs (three full-length articles [54][55][56] and two conference abstracts [57,58]), 11 PCs (11 full-length articles [35,[59][60][61][62][63][64][65][66][67][68] and one conference abstract [69]), and five RCs (four full-length articles [38,49,51,70] and one conference abstract [19]). Data from several studies showed that treatment with infliximab resulted in significant increase in TC [54, 57-63, 65, 67, 68, 70], HDL-C [57][58][59][60][61][62][63][64][65], and TG [61,63,65,70]. ...
... Data on patients with RA treated with infliximab were obtained from four RCTs (three full-length articles [54][55][56] and two conference abstracts [57,58]), 11 PCs (11 full-length articles [35,[59][60][61][62][63][64][65][66][67][68] and one conference abstract [69]), and five RCs (four full-length articles [38,49,51,70] and one conference abstract [19]). Data from several studies showed that treatment with infliximab resulted in significant increase in TC [54, 57-63, 65, 67, 68, 70], HDL-C [57][58][59][60][61][62][63][64][65], and TG [61,63,65,70]. Results with LDL-C and atherogenic index were mixed. ...
... Results with LDL-C and atherogenic index were mixed. In three PC studies, there was significant increase in LDL-C for at least the first 12 weeks [60,61,64], whereas data from two RCTs [54,57,58] and two PC studies [65,67,68] showed no significant change. Significant improvement in atherogenic index was reported in one RCT [57,58], but significant worsening was reported in three PC studies [61,63,65], and no significant change was reported in one RCT [56] and two PC studies [59,60]. ...
IntroductionRheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients. MethodsA systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events. ResultsOf the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated. Conclusions
Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients.
... Consequently, inflammation reduction after pharmacological treatments (DMARDs, biologic therapy) may increase lipid levels (not only HDL, but also total and LDL cholesterol). Therefore, changes in lipid profiles, particularly the elevation in cholesterol and triglycerides levels that occur with treatments for severe inflammation, may not represent increased cardiovascular risk as in the usual understanding of lipid-level elevations in individuals without significant inflammation [33][34][35]. Rather, such changes in lipid levels, in part or largely, may represent a predictable response to attenuation of inflammation. Finally, in clinical practice, the current advice on the use of lipid profiles in any patient with RA is [33] to measure both total cholesterol and HDL cholesterol and to use the total cholesterol: HDL cholesterol ratio in conjunction with other established risk factors for the calculation of absolute CV risk, and [27] to treat accordingly when the absolute CV risk is high [29]. ...
... Interestingly, increases from lower than normal base line lipid concentrations have been observed with other efficacious therapies including TNF inhibitors [34,35]. Some studies, based on reduction of inflammatory response in RA, have shown decreased rates of cardiovascular events, despite the increase in lipid concentration [36,37]. ...
... Increase in total and low-density lipoprotein cholesterol levels in this study were low previous reports [22,38,39] and were associated with marked decreases in CRP [40,41]. Considering the recognised higher incidence of cardiovascular mortality in RA patients [30,34,42], traditional risk factors for cardiovascular disease, including dyslipidemia, are not necessarily predictive of events for patients with RA [43]. ...
Objective: To evaluate the rapid response to Tocilizumab (TCZ) treatment in Rheumatoid Arthritis (RA) patients, not responded to a previous biologic therapy.
Methods: We enrolled 29 patients with mild/severe RA (24 women, 5 men) according to the American College Rheumatology 2010 Criteria, who were refractory to Disease Modifying Anti-Rheumatic Drugs (DMARDs), including TNFinhibitors, anti-CD20 and anti-CTL4. They were treated with TCZ 162 mg weekly, Methotrexate (MTX) 10-15mg weekly and low dose prednisone daily (5-7, 5mg). The patients underwent clinical, laboratory, and Power Doppler Ultrasonography (PDUS) evaluation at baseline, 1, 3, 6 months. Efficacy was evaluated based on disease activity and ultrasonographic manifestations of synovitis in the examinated joints.
Results: We observed a rapid, statistically significant improvement of both clinical and laboratoristic parameters. After the initial TCZ treatment, the mean DAS 28-ESR (Erythrocyte Sedimentation Rate) decreased from 6,41 at baseline to 2,33 (p<0.05), and the efficacy has been maintained during this period of TCZ treatment. TCZ treatment decreased the synovitis of affected joints, as measured by ultrasonography. The mean grade of synovitis activity decreased in all patients receiving TCZ treatment (Δ-6,80; p<0.05). Mean plasma concentrations of total cholesterol, HDL cholesterol and triglycerides raised minimal during the follow up period (Tot cholesterol Δ+18.50, HDL Δ +5.80, triglycerides Δ+25.10), but not statistically significant. Rapid and sustained improvements in the acute phase response markers as C Reactiv Protein (CRP) were seen (CRP: Δ-4,85 p<0.05; haemoglobin Δ1.40 p<0.05). There were greater and statistically significant improvements in physical function, as showed in HAQ-DI (Δ-0,155 p<0.05), SF-36 (ISF Δ+6,60 p<0.05 – ISM Δ+16,10 p<0.05) and FACIT fatigue (Δ-11 p<0.05) from baseline, with TCZ treatment.
Conclusion: Our study confirms the rapidity and effectivness of TCZ in treating inflammation in RA patients, both with clinical evaluation and with ultrasonography. PDUS allow a more accurate evaluation of treatment response and a more complete follow-up.
... The influence of tumor necrosis factor alpha (TNF-α) inhibitors on lipid profile [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] and AI [3, 5, 7-9, 11, 13, 14, 17] in patients with rheumatologic diseases has been examined in several studies (Table 1), with inconsistent results. In some studies TNF-α inhibitors promoted an atherogenic lipid profile, while in others there was no such effect. ...
... A comparison of our results with those reported in the literature must take into account the different study designs. The 15 studies that assessed the effects of TNF-α inhibitors on lipid profile (Table 1) [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] were of shorter duration, ranging from 2 to 30 weeks in nine studies [4, 6-8, 10-12, 15, 17] and up to 52 weeks in six other studies [3,5,9,13,14,16]. Follow-up in our study was 104 weeks. ...
... We conducted our analysis on pooled data of rheumatic patients in the ASPARA cohort while most of the published studies analyzed a single disease: 12 studies of RA, one study of PsA, and one study of AS. Sample size also varied: 15-80 patients in published studies [4, 6-13, 16, 17] Our finding of a significant increase in TC levels following TNF-α inhibitor treatment (Table 3) is in line with the results of 10 of the 15 studies mentioned [3][4][5][6][7][8][9][10][11]14]. Six of the 15 studies also reported an increase in TG levels following TNF-α inhibitors [3,5,9,11,12,14], similar to our findings, while the other nine showed no significant changes in TG levels. ...
Background
The aim was to assess the influence of long-term treatment with tumor necrosis factor alpha (TNF-α) inhibitors on total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and atherogenic index (AI) in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) patients.
Methods
A retrospective cohort study was conducted on RA, PsA, and AS patients treated with TNF-α inhibitors for at least 270 days between 2001 and 2011. Levels of TC, TG, LDL, and HDL and the AI were compared with baseline values at 0–6, 6–12, 12–18, and 18–24 months. Patients were further subdivided into three groups according to their HMG CoA reductase inhibitor (statin) treatment status in order to assess their effect on the results.
Results
The records of 311 patients (152 RA, 90 PsA, and 69 AS) were reviewed. TC and TG increased following treatment with TNF-α inhibitors, from 180.85 ± 2.12 mg/dl and 116.00 ± 3.55 mg/dl at baseline to 188.12 ± 2.35 mg/dl (p = 0.02) and 132.02 ± 4.63 mg/dl at 0–6 months (p < 0.01), respectively, and to 184.88 ± 2.09 mg/dl (p = 0.02) and 129.36 ± 4.32 mg/dl at 18–24 months (p < 0.01), respectively. AI increased following treatment with TNF-α inhibitors, from –0.032 ± 0.017 at baseline to 0.004 ± 0.019 at 18–24 months (p < 0.01). LDL decreased significantly in patients who were treated with statins before and during the entire study period, from 119.97 ± 2.86 mg/dl at baseline to 104.02 ± 3.57 mg/dl at 18–24 months (p < 0.01), in contrast to an increase in LDL values in patients who did not receive statins during the study.
Conclusions
TNF-α inhibitor treatment was associated with a significant increase in TC and TG levels and the AI. Adding statins to the treatment was associated with a significant decrease in LDL levels.
... At the end of the selection procedure, 33 full-text articles met the eligibility criteria and were considered for this paper (Figure 1). Of the 33 studies, the vast majority concerned anti-TNF users, usually infliximab, adalimumab, and etanercept [11,14151617181920212223242526272829303132, 8 studies concerned tocilizumab (including three randomized clinical trials) [21,33343536373839, and 5 studies investigated rituximab effects on lipids pattern [14,40414243 . Data on other biologicals, including abatacept , anakinra, golimumab, or certolizumab have not been addressed here due to their very limited and preliminary character. ...
... Studying 56 patients with RA receiving infliximab for 30 weeks, Allanore et al. found no changes in the atherogenic index despite a significant stable increase of HDL and TC. They also noticed no relations between response to therapy and lipid pattern modifications [15]. Similar findings have been reported by Seriolo et al. in 34 consecutive RA patients treated with various TNF blockers (n = 16 for etanercept, n = 14 for infliximab, and n = 4 for adalimumab) for 24 weeks [26]. ...
... The apparent heterogeneity of these results may be due to several factors. Firstly, it mostly concerns small-group studies enrolling RA patients from diverse countries with a distinctive health care system and lifestyle habits, including physical activity (biking for the Dutch population) [11, 23– 25, 31, 32] and alimentation (fish-reach diet in Northern Europe, Mediterranean diet in the Southern Europe) [14, 15, 17, 18, 20, 26, 28]. Secondly, a difference between the anti-TNF agents may be present, leading to a more proatherogenic profile in the case of infliximab [11, 17], with milder effects for adalimumab and etanercept [19, 24, 32]. ...
Cardiovascular (CV) diseases are a serious concern in rheumatoid arthritis (RA), accounting for approximately one-third to one-half of all RA-related deaths. Besides the attempts to identify new risk factors, the proper management of traditional CV risk factors such as dyslipidemia should become a priority in the periodic evaluation of every RA patient. Atherogenic index has been suggested to be less susceptible to disease activity variation during large periods of time, making him more attractive to be used in CV risk prediction in this group of patients as compared to individual lipids concentrations. Nevertheless, inflammation may negatively impact HDL antiatherogenic properties, suggesting that HDL function assessment is of particular importance when predicting CV risk in these patients. A tight control of inflammation becomes therefore crucial for a successful CV risk management. The present paper debates these hypotheses focusing on the effects of therapy with biologicals on the above mentioned parameters.
... One explanation by which these effective anti-inflammatory drugs may reduce vascular risk is through modulation of lipid profiles. There are ample studies now linking suppression of inflammation (with TNF-alpha blocking agents) to alternation in lipid profiles but the data appear somewhat inconsistent (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). This systematic review and meta-analysis was undertaken to evaluate the overall effect of TNF-alpha blocking therapy on lipid profiles using appropriate statistical analyses. ...
... All included studies used data of patients initiating TNF-alpha blocking therapy for the first time and were thus TNF-alpha blocking agent-naïve at baseline. Five studies had a study population of more than 50 individuals (14,15,19,25,26). Mean follow-up duration after start of TNF-alpha blocking therapy was 10 weeks and ranged from 2 weeks to 6 months. ...
... The age of study participants ranged from 46 and 63 years and 17% of all study participants were male. Furthermore, disease duration ranged from 5 to 20 years, and DAS28 at baseline ranged from 3 to 8. In total, 13 of 15 studies (87%) reported concomitant use of corticosteroids and methotrexate among their patients (12,(14)(15)(16)(17)(18)(19)(20)(21)(23)(24)(25)(26), while 2 of 8 studies (22%) included patients who used statins (25,26). Median qual-ity score of studies (using NOS) was 5. ...
... So far, data regarding lipid profile alterations during treatment with infliximab are contradictory. Several studies reported that infliximab treatment is associated with an unfavorable lipid profile [46][47][48]. In contrast, others suggest that infliximab could have a reduced influence on the atherogenic lipid profile [49]. ...
... It is well established that infliximab reduces the inflammatory process by inhibiting the TNFα pathway, leading to decreased pro-inflammatory cytokines such as IL-1β and IL-6, which are correlated with lower levels of hs-PCR, known as an independent predictor of cardiovascular risk [50]. Our findings were consistent with previous studies reported [46][47][48]. ...
Background: Hyperlipidemia and inflammation are critical components in the pathophysiology of endothelial disorder, which can lead to vascular complications. Our study aimed to evaluate the effects of immunomodulatory therapy (methotrexate and infliximab) in a diet-induced hyperlipidemia rat model. Methods: Sprague-Dawley (wild type (WT), male, n = 32) rats were divided into four groups: one group fed with standard diet (SD), one group fed with high lipid diet (HLD), and two groups that received HLD and drug treatment (methotrexate (Mtx) or infliximab (Ifx)). In order to evaluate if modifications to the endothelial cells may influence the risk of vascular complications following hyperlipidemia or treatment reactivity, each group was doubled by a rats group that overexpressed beta-3 receptors on the endothelial cells (transgenic (TG-beta 3), male, n = 32). Serum lipid profile, liver enzymes, oxidative stress, and inflammation markers were determined. Histopathologic analysis of the liver and aorta was performed. Results: After 9 weeks of HLD, rats exhibited significant pathologic serum lipid profiles, elevated oxidative stress, and pro-inflammatory markers. Additionally, the aortic histopathological analysis revealed aorta media-intima thickening (p < 0.05) in the transgenic group. Methotrexate and infliximab significantly decreased inflammation and oxidative stress parameters, but presented opposing effects on lipid profiles (methotrexate decreased, whereas infliximab increased the atherosclerosis index). Drug treatment decreased the aorta media-intima thickness (p < 0.05) only in transgenic rats. Conclusions: HLD was associated with hyperlipidemia, inflammation and oxidative stress. The overexpression of beta-3 receptors on endothelial cells increased aortic thickening in response to the HLD. Methotrexate and infliximab reduced oxidative stress and inflammation in all groups, but led to favorable histopathologic vascular results only in the transgenic groups.
... After inf liximab treatment for 6 weeks, total cholesterol and HDL cholesterol both significantly increased, with no change in the atherogenic index, persisting up to 30 weeks. 17,18 In a study by Spanakis et al., a significantly decreased atherogenic index of low-density lipoprotein (LDL:HDL) ratio was seen after 6 months of therapy with infliximab. 19 Another study by Popa and associates showed increased HDL levels and reduced CRP and IL-6 levels after 2 weeks of treatment with adalimumab, possibly improving the CV risk profile of patients with RA. ...
... Anti-TNF-α and obesity Significant weight gain in both psoriasis and psoriatic arthritis patients (? gain of fat-free mass) [26][27][28] Anti-TNF-α and insulin sensitivity Improvement with treatment (in most cases) resulting from inhibition of proinflammatory cytokines 22 Anti-TNF-α and lipids Variable results; however, most studies show increased high-density lipoprotein cholesterol 17,18 Anti-TNF-α and congestive heart failure (CHF) ...
Psoriasis is associated with numerous comorbid conditions, including psoriatic arthritis, metabolic syndrome, and cardiovascular disease, which often share a similar pathogenesis and follow a progressive pattern. Biologic agents, specifically those targeting tumor necrosis factor, constitute a relatively new, effective, and safe treatment modality for this disease. Because these agents are effective in suppressing the inflammation that occurs in psoriasis, they appear to play a key, but somewhat novel, role in preventing some comorbidities. This review article attempts to elucidate this concept through the currently available literature. We evaluate the possible effects of tumor necrosis factor antagonists on the natural history of psoriasis comorbidities in an effort to shed some light on this exciting frontier.
... L'indice d'athérogénécité est donc resté constant. Chez 56 patients ayant une PR active, Allanore a observé, après six et 30 semaines de traitement avec l'infliximab, une augmentation de 25 % du taux du CT, de 24 % de LDL-C et de 30 % de HDL-C sans changement de l'indice d'athérogénécité [15]. Kiortsis a étudié le profil lipidique après six mois de traitement avec l'infliximab chez 50 patients ayant une PR active. ...
... Il y avait une augmen-tation des TG et du HDL cholestérol sans changement de l'indice d'athérogénécité. Notre étude a porté sur un petit nombre de patients qui n'ont été suivis que pendant une courte durée mais contrairement aux études précédentes [9,[13][14][15][16][17] nous n'avons pas congelé les sérums ce qui influence peut-être les résultats puisque la congélation affecte le HDL cholestérol [6]. L'effet favorable de la thérapie anti-TNF sur la morbidité cardiovasculaire n'a probablement aucun lien aux effets sur le métabolisme lipidique [18]. ...
Objectifs
Analyser les effets de la thérapie anti-TNF sur les taux sériques des lipides chez des patients atteints de polyarthrite rhumatoïde (PR).
Méthodes
Vingt-neuf patients (26 femmes et trois hommes) ayant une PR établie et recevant une thérapie anti-TNF (n = 12, adalimumab ; n = 11, infliximab ; n = 6, etanercept) ont été recrutés. Le cholestérol total, le LDL-cholestérol, le HDL-cholestérol, les triglycérides, les apolipoprotéines (Apo B et Apo A) ont été dosés au départ et après 14 semaines de traitement.
Résultats
Le DAS28 (disease activity score — signe d’évolutivité d’une maladie) était 5,19 ± 0,90 et réduit à 3,46 ± 0,97 à 16 semaines (p < 0,001). Le taux de CT était inchangé (5,65 ± 0,98 mmol/l contre 5,78 ± 1,06 mmol/l ; p = 0,43), TG (1,40 ± 0,79 mmol/l contre 1,45 ± 0,67 mmol/l ; p = 0,59), HDL-C (1,92 ± 0,49 mmol/l contre 1,97 ± 0,49 mmol/l ; p = 0,36), Apo A1 (1,92 ± 0,28 g/l contre 1,99 ± 0,29 g/l ; p = 0,06) et LDL-C (3,41 ± 0,91 mmol/l contre 3,47 ± 0,96 mmol/l ; p = 0,66), de même Apo B (1,126 ± 0,302 g/l contre 1,13 ± 0,28 g/l ; p = 0,89), l’indice d’ « athérogénicité » (3,13 ± 1,05 contre 3,09 ± 0,89 ; p = 0,69) ou le ratio Apo B/Apo A1 (0,58 ± 0,25 contre 0,56 ± 0,22 ; p = 0,33).
Conclusion
L’effet favorable de la thérapie anti-TNF sur la morbidité cardiovasculaire n’est pas lié aux effets sur le métabolisme des lipides.
... Sulphasalazine monotherapy or combination therapy with methotrexate (MTX) and prednisolone in RA patients increased the serum HDL-C and TC, however the TC/HDL-C ratio was reduced [121]. In short-term therapy (< 6 months) with anti-TNF-α, the TC/HDL-C ratio remained constant with a concomitant proportional increase in both TC and HDL-C levels [122][123][124][125]. Over time, further increases in TC and HDL-C levels shifted the balance, resulting in an increased atherogenic index. ...
Obesity can instigate and sustain a systemic low-grade inflammatory environment that can amplify autoimmune disorders and their associated comorbidities. Metabolic changes and inflammatory factors produced by the adipose tissue have been reported to aggravate autoimmunity and predispose the patient to cardiovascular disease (CVD) and metabolic comorbidities. Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are autoimmune arthritic diseases, often linked with altered body mass index (BMI). Severe joint inflammation and bone destruction have a debilitating impact on the patient's life; there is also a staggering risk of cardiovascular morbidity and mortality. Furthermore, these patients are at risk of developing metabolic symptoms, including insulin resistance resulting in type 2 diabetes mellitus (T2DM). In addition, arthritis severity, progression and response to therapy can be markedly affected by the patient's BMI. Hence, a complex integrative pathogenesis interconnects autoimmunity with metabolic and cardiovascular disorders. This review aims to shed light on the network that connects obesity with RA, PsA, systemic lupus erythematosus and Sjӧgren's syndrome. We have focused on clarifying the mechanism by which obesity affects different cell types, inflammatory factors and traditional therapies in these autoimmune disorders. We conclude that to further optimize arthritis therapy and to prevent CVD, it is imperative to uncover the intricate relation between obesity and arthritis pathology.
... For instance, there is conflicting evidence on the net effect of infliximab on lipid indices. While some studies demonstrated no changes in lipid profile, the others have shown significant rises in total cholesterol and HDL (Soubrier et al., 2008;Allanore et al., 2006;Wijbrandts et al., 2009). In stark contrast with other biologic studies, the LDL and total cholesterol levels in this study showed a decreasing trend with adalimumab therapy. ...
Tumor necrosis factor alpha (TNFα) is a multifunctional cytokine which plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). Apart from its well recognized pro-inflammatory properties, it is known to interfere with lipid metabolism and erythropoiesis.
Materials and Methods: We evaluated the effects of adalimumab on hematologic, lipid and inflammatory parameters using data from patients on adalimumab 40 mg fortnightly from 2 centers in Malaysia. Mean changes in laboratory values from baseline to Weeks 4, 12 and 24 were compared using paired T test and Wilcoxon signed-rank test.
Results: We studied 18 patients with RA who were on adalimumab 40 mg fortnightly. The inflammatory markers i.e. erythrocyte sedimentation rate and C reactive protein showed significant changes as early as at week 4 compared to baseline with p values of 0.003 and 0.005, respectively. From a baseline of high disease activity with a mean Disease Activity Score using 28 joint counts (DAS 28) of 5.3, there was a steady improvement in the disease activity and remission was achieved at week 24 with a DAS 28 of 2.4. The hemoglobin level improved at week 12 (p=0.013) and this was sustained till week 24. As opposed to previous studies, the LDL level significantly decreased at week 12 (p=0.015) and this change persisted till week 24 (p=0.001). The total cholesterol showed a similar pattern as the LDL.
Conclusions: The pharmacodynamics of adalimumab therapy in rheumatoid arthritis extend beyond the joints with favorable effects on haemoglobin and lipid profile.
... For instance, there is conflicting evidence on the net effect of infliximab on lipid indices. While some studies demonstrated no changes in lipid profile, the others have shown significant rises in total cholesterol and HDL (Soubrier et al., 2008;Allanore et al., 2006;Wijbrandts et al., 2009). In stark contrast with other biologic studies, the LDL and total cholesterol levels in this study showed a decreasing trend with adalimumab therapy. ...
Introduction: Tumor necrosis factor alpha (TNFα) is a multifunctional cytokine which plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). Apart from its well recognized pro-inflammatory properties, it is known to interfere with lipid metabolism and erythropoiesis. Materials and Methods: We evaluated the effects of adalimumab on hematologic, lipid and in-flammatory parameters using data from patients on adalimumab 40 mg fortnightly from 2 centers in Malaysia. Mean changes in laboratory values from baseline to Weeks 4, 12 and 24 were com-pared using paired T test and Wilcoxon signed-rank test. Results: We studied 18 patients with RA who were on adalimumab 40 mg fortnightly. The in-flammatory markers i.e. erythrocyte sedimentation rate and C reactive protein showed significant changes as early as at week 4 compared to baseline with p values of 0.003 and 0.005, respective-ly. From a baseline of high disease activity with a mean Disease Activity Score using 28 joint counts (DAS 28) of 5.3, there was a steady improvement in the disease activity and remission was achieved at week 24 with a DAS 28 of 2.4. The hemoglobin level improved at week 12 (p=0.013) and this was sustained till week 24. As opposed to previous studies, the LDL level sig-nificantly decreased at week 12 (p=0.015) and this change persisted till week 24 (p=0.001). The total cholesterol showed a similar pattern as the LDL. Conclusions: The pharmacodynamics of adalimumab therapy in rheumatoid arthritis extend be-yond the joints with favorable effects on haemoglobin and lipid profile.
... Some studies have shown an improvement in dyslipidemia with TNFa blockade in RA and others have shown a more atherogenic lipid profile following prolonged treatment with TNF blockers. 55,56 However, these findings must be interpreted with caution as the overall clinical impact of these changes in lipid profile on the incidence of CVD in RA is at present unclear. 50,57 Oxidized LDL-C (oxLDL) and antibodies to oxidized LDL (anti-oxLDL) are both significant risk factors for CVD in RA, wherein oxLDL levels increase with active disease. ...
Rheumatoid arthritis (RA) is associated with an approximately twofold increased risk of atherosclerotic cardiovascular disease (CVD) including myocardial infarction and stroke. The increased risk of CVD in RA is due to an interplay between traditional risk factors such as hyperlipidemia, hypertension, and smoking and disease-related variables such as the presence of rheumatoid factor and anticyclic citrullinated peptide antibodies, high erythrocyte sedimentation rate, and joint swelling. Systemic inflammation and immune mechanisms form a pathogenic link between synovitis and atherosclerosis in RA. Indeed, high levels of C-reactive protein, an inflammatory marker, predict cardiovascular mortality in RA. Furthermore, the risk of CVD is greatly diminished among patients who respond to disease modifying antirheumatic drugs and biological therapies such as tumor necrosis factor (TNF) alpha antagonists. Through adverse effects on lipid profile and blood glucose level, long-term use of high-dose glucocorticoids in RA also increases cardiovascular risk. However, through control of active disease, glucocorticoids may also indirectly attenuate cardiovascular risk. Through their lipid-lowering and immunomodulatory effects, statins may have a dual benefit in the treatment of patients with RA. However, data on cardiovascular risk reduction in RA through management of traditional risk factors remain scant. Current research efforts are directed toward elucidating the risk factors for CVD in RA and developing strategies to minimize this risk.
... 16 While some studies have reported significant increases in HDL levels after 2-24 weeks of anti-TNF therapy, 7 23 24 others of varying duration have found only a transient increase in HDL, 16 an initial increase followed by a significant decrease in HDL, 25 or no change. 14 26 In addition, statistically significant increases in LDL levels at weeks 14 23 and 30 27 have also been observed, although most report no significant change in LDL levels following anti-TNF therapy. 7 14 16 The current analysis of 1081 patients in the GO-FORWARD and GO-BEFORE trials is the largest prospective study of the effects of anti-TNF treatment on levels of lipids and inflammatory markers in patients with RA. ...
The objective of this study was to assess the effect of golimumab on carotid ultrasound measures and cardiovascular serious adverse events (SAEs) in patients with inflammatory arthritides.
An exploratory carotid artery ultrasound substudy was performed in the GO-BEFORE study of methotrexate (MTX)-naive rheumatoid arthritis patients, with ultrasounds performed at weeks 0, 24, and 52 to measure common carotid artery intima-media thickness, distensibility coefficient, interadventitial diameter, and plaque count. Cardiovascular SAEs reported over 2 years of follow-up were assessed in 5 golimumab phase 3 clinical trials of patients with rheumatoid arthritis (GO-BEFORE, GO-FORWARD, and GO-AFTER), psoriatic arthritis (GO-REVEAL), and ankylosing spondylitis (GO-RAISE). In GO-BEFORE and GO-FORWARD, patients received placebo + MTX, golimumab 50 mg + MTX, or golimumab 100 mg +/- MTX at baseline and every 4 weeks; in the other 3 trials, patients received placebo or golimumab 50 or 100 mg.
The carotid ultrasound substudy showed inconsistent changes in common carotid artery intima-media thickness in the golimumab + MTX groups over time, and there was large variability in the measurements. Increases in interadventitial diameter were observed in the golimumab 100 mg + placebo group, but not in the golimumab + MTX groups. There were no significant differences in the distensibility coefficient and plaque count between the golimumab and placebo groups. Very few patients overall experienced a cardiovascular SAE, and the incidence of cardiovascular SAEs was not statistically different between the golimumab and placebo groups.
The results of the carotid ultrasound substudy were inconclusive, and no increase or decrease in cardiovascular SAEs was observed following 2 years of treatment with golimumab with or without MTX.
... One study has revealed an improvement in the lipid pattern, 19 and another a progression toward an atherogenic profile; 20 in still others, no significant effect on the atherogenic index was reported. [21][22][23][24][25] In a recent meta-analysis, significant change after TNF-alpha blockade was found. 26 In another meta-analysis, Daïen et al noted increased HDL and total cholesterol levels after long-term TNF-alpha blockade treatment, but no change in LDL levels ...
Systemic inflammation plays an important role in the increased cardiac risk observed in rheumatoid arthritis (RA). Effective control of inflammation and disease activity may be of benefit in reducing cardiovascular risk in RA patients.
Our study was conducted in patients with active RA to investigate the effects of 24-week abatacept treatment on aortic stiffness measured by pulse wave velocity (PWV).
The study included 21 patients, of whom 17 were females, with a mean age of 65.2±13.7 years. Ten patients had positive rheumatoid factors, 16 positive anti-citrullinated protein antibodies, and 19 presented an erosive form of RA. Sixteen patients were nonresponders to anti-tumor necrosis factor-alpha treatments. After 6 months of abatacept treatment, there was a significant increase in PWV levels (9.8±2.9 versus 8.5±3.9 m/second; P=0.02). A nonsignificant increase in total cholesterol and low-density lipoprotein cholesterol was observed. There was also a significant increase in high-density lipoprotein cholesterol levels, which led to a nonsignificant decrease in atherogenic index. The improvement in disease activity was significant, and there was a decrease of systemic inflammatory parameters, but without reaching statistical significancy. Changes in PWV were significantly correlated with changes in Disease Activity Score on 28 joints based on erythrocyte sedimentation rate (r=0.46; P=0.035) and in high-density lipoprotein cholesterol (r=-0.38; P=0.046). No correlation was observed with changes in C-reactive protein and in other parameters of lipid profile or in steroid dose.
The worsening of aortic stiffness found after 6 months of abatacept therapy might be due to an insufficient decrease in systemic inflammation.
... Serological tests are important to investigate the levels of fatty acids (saturated, monounsaturated and polyunsaturated fats, triglycerides, and cholesterol (HDL, LDL and VLDL) for effective verification of the results, but in this case these tests were not conducted. In contrast, other authors have attributed these changes to the inflammatory process and antirheumatic drugs [22][23]. ...
Rheumatoid arthritis is a systemic inflammatory disease of unknown
causes and a new methods to identify it in early stages are needed. The
main purpose of this work is the biochemical differentiation of sera
between normal and RA patients, through the establishment of a
statistical method that can be appropriately used for serological
analysis. The human sera from 39 healthy donors and 39 rheumatics donors
were collected and analyzed by Fourier Transform Infrared Spectroscopy.
The results show significant spectral variations with p<0.05 in
regions corresponding to protein, lipids and immunoglobulins. The
technique of latex particles, coated with human IgG and monoclonal
anti-CRP by indirect agglutination known as FR and CRP, was performed to
confirm possible false-negative results within the groups, facilitating
the statistical interpretation and validation of the technique.
... 16 While some studies have reported significant increases in HDL levels after 2-24 weeks of anti-TNF therapy, 7 23 24 others of varying duration have found only a transient increase in HDL, 16 an initial increase followed by a significant decrease in HDL, 25 or no change. 14 26 In addition, statistically significant increases in LDL levels at weeks 14 23 and 30 27 have also been observed, although most report no significant change in LDL levels following anti-TNF therapy. 7 14 16 The current analysis of 1081 patients in the GO-FORWARD and GO-BEFORE trials is the largest prospective study of the effects of anti-TNF treatment on levels of lipids and inflammatory markers in patients with RA. ...
Objectives
To assess the effect of golimumab, with or without methotrexate (MTX), on serum lipids and inflammatory markers of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) in two phase 3, randomised, placebo-controlled trials (GO-BEFORE and GO-FORWARD).
Methods
Patients in GO-BEFORE (n=637, MTX-naïve) and GO-FORWARD (n=444, MTX-inadequate response) were randomised to placebo+MTX, golimumab 100 mg+placebo, golimumab 50 mg+MTX, or golimumab 100 mg+MTX. Subcutaneous injections (placebo and golimumab) were given every 4 weeks. Patients with an insufficient response entered early escape at week 16 (GO-FORWARD) or 28 (GO-BEFORE). All placebo+MTX patients in GO-FORWARD crossed over to golimumab 50 mg+MTX at week 24. Changes from baseline to weeks 14 (GO-FORWARD) or 24 (GO-BEFORE), and 52 in serum lipid levels and inflammatory markers were assessed.
Results
At week 14 in the GO-FORWARD trial, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) increased in golimumab+MTX patients versus MTX-only patients (16.00 vs 2.00 (p<0.001); 3.00 vs 0.00 (p<0.05); 8.00 vs 4.00 (p<0.001); respectively); favourable changes in LDL subfractions were only observed in golimumab-treated patients. At week 24 in GO-BEFORE, TC and LDL increased, and LDL subfractions improved in the MTX-only and golimumab+MTX groups. Inflammatory markers of CVD risk improved significantly with golimumab+MTX versus placebo+MTX in both studies and were generally maintained through week 52. Atherogenic indices were generally stable.
Conclusions
While TC and LDL levels increased mildly in RA patients receiving golimumab+MTX, atherogenic indices generally remained stable, favourable changes in LDL subfractions were observed, and inflammatory markers improved.
... Longterm infliximab treatment has also been demonstrated to improve insulin sensitivity (grade C evidence) [59]. For lipid regulation, infliximab therapy has been shown to increase total cholesterol, LDL, and HDL levels without altering the atherogenic ratio (grade B evidence) [60]. [62]. ...
Introduction
Traditional clinical trials in psoriasis exclude a significant proportion of patients with complex disease and comorbidities. A consensus panel of 14 experts in the field of psoriasis was formed to conduct a Delphi method exercise to identify difficult-to-treat psoriasis clinical scenarios and to rank treatment approaches.
Methods
The exercise consisted of both survey questionnaires and a live meeting to review and discuss current data (as of 2009, when the exercise was conducted) and arrive at a consensus for optimal treatment options. Seventy difficult treatment scenarios were identified, and the top 24 were selected for discussion at the live meeting.
Results
Six of the 24 discussed case scenarios are presented in this article (another five are presented in Part 2): (1) psoriasis with human papilloma virus-induced cervical or anogenital dysplasia; (2) concomitant psoriasis and systemic lupus erythematosus; (3) severe psoriatic nail disease causing functional or emotional impairment; (4) psoriasis therapies that potentially reduce cardiovascular morbidity and mortality; (5) older patients (≥65 years of age) with psoriasis; and (6) severe scalp psoriasis that is unresponsive to topical therapy.
Conclusion
The Delphi exercise resulted in guidelines for practicing physicians to utilize when confronted with challenging patients with psoriasis.
... A small to modest increase in total cholesterol in CAPS patients who received rilonacept may also potentially result from a treatment-related decrease in inflammation because cholesterol is reduced as part of the acutephase response; 1,20 other anticytokine agents have also been reported to increase cholesterol in patients with chronic inflammatory diseases. [21][22][23][24] Some patients who received rilonacept developed detectable antirilonacept antibodies consistent with the recognized potential for immunogenicity associated with protein therapeutics. 25 However, the clinical significance of these antibodies is uncertain, because no evident effect was seen on the efficacy of rilonacept or on safety parameters. ...
Cryopyrin-associated periodic syndromes (CAPS) are rare, inherited autoinflammatory disorders associated with considerable hardship to patients. The interleukin-1 inhibitor rilonacept has been shown to be well-tolerated and effective in preventing CAPS symptoms in 2 pivotal studies.
In this study, the long-term effects of rilonacept for improvement in CAPS symptoms and its safety and tolerability were evaluated during extended treatment.
Patients with CAPS entered a 72-week open-label extension (OLE) following 2 sequential placebo-controlled Phase III studies (n = 44), or entered directly into the OLE (n = 57). Adults received weekly subcutaneous rilonacept 160 mg, and pediatric patients received subcutaneous rilonacept 2.2 mg/kg, up to 160 mg/week. Safety was evaluated in all patients, and efficacy was evaluated using a validated composite key symptom score in 56 patients.
After rilonacept treatment for 72 to 96 weeks mean key symptom score at OLE Week 72 was reduced from 2.6 to 0, and the mean number of multisymptom flare days was reduced from 7.3 (34.8% of days) at baseline to 0.6 (2.9% of days) at end point. Elevated levels of inflammatory markers (eg, high sensitivity-C reactive protein and serum amyloid A, were normalized. Adverse events were generally mild to moderate, the most common being injection site reactions and upper respiratory tract infections. The incidence of these events was similar to or lower than the rate reported in the pivotal studies.
Long-term treatment with rilonacept of up to 96 weeks resulted in improvements in clinical signs and symptoms of CAPS and normalized biomarkers of inflammation. Rilonacept exhibited a generally favorable safety and tolerability profile in adult and pediatric patients with CAPS throughout the extended treatment period. ClinicalTrials.gov identifier: NCT 00288704.
... One study did not fi nd any link between the response to treatment and changes in lipid levels. 39 Six studies reported an association between ΔDAS and/ or variation in the erythrocyte sedimentation rate and C reactive protein and HDL-cholesterol levels. 22 32-35 43 A decrease of one point in the DAS28 increased the HDL-cholesterol level by 0.045 mmol/l. ...
Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Lipid changes related to inflammation have been described in RA. Tumour necrosis factor α (TNFα) inhibitor (TNFi) treatment is effective in controlling inflammation and decreasing the number of cardiovascular events.
To assess the change in lipid levels with TNFi treatment in patients with RA by systematic review and meta-analysis.
A Medline search was performed for articles published up to March 2011. Reports describing values for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), atherogenic index (AI) and apolipoprotein B/A (apoB/A) collected before and after TNFi initiation were included. Data were analysed according to short-, mid- and long-term treatment. Statistical analysis of pre-post data was performed by comprehensive meta-analysis. A random effects model was used when there was evidence of heterogeneity.
The search retrieved 32 articles, of which 13 prospective before/after studies were analysed. Long-term TNFi treatment was associated with increased levels of HDL (+0.27 mmol/l, p<0.0001) and TC (+0.27 mmol/l, p=0.03), whereas LDL levels and AI remained unchanged. After long-term treatment, TG levels increased (+0.28 mmol/l, p<0.001) and apoB/A decreased (-0.3, p<0.0001).
The presumed cardioprotective effects of TNFi in RA do not seem to be explained by quantitative lipid changes since long-term treatment has no effect on LDL levels or on AI. Increased HDL levels could have some beneficial effects, but this needs to be confirmed by prospective studies with long-term follow-up.
... This is especially important given the increased cardiovascular risk associated with RA, and therefore further investigation into this risk factor is suggested. The anti-TNF-a biologic agent, infliximab, has also been found to elevate the lipid profile [34]. However, no increase in cardiovascular events was noted in any of the short-term tocilizumab studies [22,23,26]. ...
To assess the risk of adverse events (AEs) in patients with RA treated with tocilizumab, an IL-6 receptor antibody, in published randomized controlled trials (RCTs).
A systematic literature search was conducted using the Cochrane library, PUBMED and EMBASE for all RCTs (of the use of tocilizumab for RA) until September 2009. Fixed effect meta-analyses were conducted to compare the incidence of AEs after treatment with tocilizumab 8 and 4 mg/kg in combination with MTX, and 8 mg/kg tocilizumab monotherapy, with controls. Pooled summary odds ratios (ORs) were calculated using the Mantel-Haenszel method.
Six trials were analysed (four trials included 8 mg/kg tocilizumab and MTX combination therapy, three of which also assessed the 4 mg/kg dose). Three studies assessed tocilizumab monotherapy at 8 mg/kg. Pooled ORs revealed statistical significance for an increased risk of AEs in the 8 mg/kg combination group compared with controls (OR = 1.53; 95% CI 1.26, 1.86). The risk of infection was significantly higher in the 8 mg/kg combination group compared with controls (OR = 1.30; 95% CI 1.07, 1.58). No increased incidence of malignancy, tuberculosis reactivation or hepatitis was seen.
Tocilizumab in combination with MTX as a treatment for RA is associated with a small but significantly increased risk of AEs, which is comparable with that of other biologics. Vigilance for untoward effects is, therefore, imperative in any patient treated with these immuno-suppressive agents.
... Interestingly, increases from lower than normal baseline lipid concentrations, have been observed with other efficacious therapies, including TNF inhibitors [61][62][63][64] . Studies in which the inflammatory response in RA was reduced, as with TNF inhibitors, have shown decreased rates of cardiovascular events, despite the increase in lipid concentrations [65][66][67][68][69] . ...
Rheumatoid Arthritis is a chronic systemic inflammatory disease characterized by joint pain, stiffness and swelling, with progressive destruction of small joints of the hands and feet. Methotrexate remains the most commonly used therapy and has been the recommended standard against which new drugs should be evaluated and, to date, there is limited evidence that monotherapy with other treatments is superior to MTX. The introduction of biologic agents, such as TNFα-antagonists, represented an advance in the treatment of RA. However, there are still patients with no or inadequate response, patients in whom responsiveness to treatment is lost over time, and patients in whom safety issues may develop. Thus, patients may benefit from treatment with newer biologic agents with a different mechanism of action. Tocilizumab is an IL-6 receptor inhibitor which shows significant (and rapid) clinical efficacy in the treatment of Rheumatoid Arthritis patients, as assessed by ACR responses and DAS remission rates, with an acceptable safety profile.
... Within a couple weeks of starting Infliximab treatment, HDL levels may increase in the short term [39]. Long-term studies with Infliximab have shown that HDL levels decreased [40], or did not change HDL levels at all [41,42]. Inflammation itself affects lipid levels. ...
Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population. Patients have reduced life expectancy and the leading cause of death is cardiovascular disease (CVD), with patients experiencing at least a 2-fold increased risk of myocardial infarction. RA is recognized as an independent risk factor for CVD. Inflammation is a key contributor to the pathogenesis of atherosclerosis and cardiovascular events. As a common catalyst of both diseases, inflammation is the likely cause of increased prevalence of CVD in the RA population. Abating disease-related inflammation in RA may be an effective strategy in reducing CVD risk. Several other therapies used to modify cardiovascular risk factors in the general population such as statins and angiotensin-converting enzyme inhibitors are under investigation in patients with RA. This review discusses the parallels in the pathology of RA and atherosclerosis and discusses current therapies for RA and how they affect cardiovascular risk.
... VLDM has minimal effect on LDL-C and at most leads to a marginal increase in HDL-C [35]. This is a markedly different lipid response from that observed for other potential anti-inflammatory agents including TNF-inhibitors (infliximab, enteracept) and IL-6 inhibitors (tocilizumab) that are more potent inhibitors of CRP than LDM, but also lead to substantive lipid abnormalities [36][37][38]. Thus, VLDM would test the inflammatory hypothesis of atherothrombosis without major confounding effects on lipid levels, platelet function, or other indices of hemostasis and thrombosis. ...
While inflammation is a crucial component of atherothrombosis and patients with elevated inflammatory biomarkers such as high sensitivity C-reactive protein (hsCRP) are at increased vascular risk, it remains unknown whether inhibition of inflammation per se will lower vascular event rates. The recently completed JUPITER (N Engl J Med 2008, 359, 2195) trial demonstrates that statins reduce myocardial infarction, stroke, and all-cause mortality among healthy individuals with low cholesterol and elevated hsCRP. However, a direct test of the inflammatory hypothesis of atherothrombosis requires an agent that inhibits inflammation without impacting other components of the atherothrombotic process, and has an acceptable safety profile for a trial setting. On this basis, the cardiovascular inflammation reduction trial (CIRT) proposes to allocate 7000 stable coronary artery disease patients with persistent elevations of hsCRP to placebo or very-low-dose-methotrexate (VLDM, 10 mg weekly), a proven anti-inflammatory regimen that reduces TNFalpha, IL-6, and CRP levels and is in wide use among rheumatoid arthritis patients. If successful, CIRT would both confirm the inflammatory hypothesis of atherothrombosis and open novel approaches to the treatment and prevention of cardiovascular disorders.
... In a Swedish registry cohort [52], treatment with TNF inhibitors was associated with a lower incidence of first MI in patients with RA. Anti-TNF treatment in RA patients increases HDL-cholesterol levels [53], insulin sensitivity [54] and reduces carotid IMT [55] and MI [56]. Recently, macrophage migration inhibitory factor (MIF) has emerged as a potential link between RA, SLE and atherosclerosis development (for review, see [57]). ...
The increased burden of cardiovascular disease in patients with rheumatoid arthritis and systemic lupus erythematosus has recently become the focus of intense investigation. Proatherogenic risk factors and dysregulated inflammation are the main culprits, leading to enhanced atherosclerosis in subgroups of patients with inflammatory diseases. Common molecular pathways shared by atherosclerosis and inflammatory disease may be involved. In this review we map the key determinants of the increased incidence of cardiovascular disease in patients with inflammatory diseases at each step of the atherogenesis.
Objective: Inflammation plays important role in atherosclerotic cardiovascular diseases (CVDs), but the interaction between the inflammation and lipid profile is largely unrevealed in humans. Patients with rheumatoid arthritis (RA) suffer from a higher risk of CVDs. Decreased total cholesterol (TC) and high-density lipoprotein (HDL) were prevalent in patients with RA. Anti-tumor necrosis factor (TNF) therapies relieve disease activity and decrease CVDs risk in RA, but their comprehensive effects on the lipid profile are unclear. This study aims to investigate the changes in blood lipid profile along time in the patients with RA accepting anti-TNF therapies by meta-analysis.
Methods: The MEDLINE, the Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for eligible literature. Data of lipids were classified into short-, mid-, and long-term according to treatment duration. Meta-analyses were performed to compare the lipid levels before and after treatments.
Results: A total of 44 records and 3,935 patients were included in the meta-analyses. Anti-TNF therapies were associated with significant increase in TC [mean difference (MD): +0.14, +0.23, and +0.26 mmol/l, respectively] and HDL (MD): +0.11, +0.12, and +0.11 mmol/l, respectively) in the short-, mid-, and long-term; anti-TNF therapies were associated with increased low-density lipoprotein (LDL) (MD: +0.06 mmol/l) and apolipoprotein A1 (ApoA1) (MD: +0.07 g/l) in the short-term, but not in the mid-term and long-term; triglyceride (TG) and apolipoprotein B (ApoB) do not change significantly in all the periods; proatherosclerotic indexes (TC/HDL, ApoB/ApoA1, and LDL/HDL) tend to decrease in the short- and mid-term, but return to baseline in the long-term after TNF inhibition.
Conclusion: Anti-TNF therapies were related to a long-term raised HDL level, which, together with evidence of improved HDL function, may contribute partially to the decreased CVDs risk by TNF inhibition.
Objectives
Rheumatoid arthritis (RA) is a debilitating disease, but patient management and treatment have been revolutionized since the advent of bDMARDs. However, about one third of RA patients do not respond to specific bDMARD treatment without clear identified reasons. Different bDMARDs must be tried until the right drug is found. Here, we sought to identify a predictive protein signature to stratify patient responsiveness to rituximab (RTX) among patients with an insufficient response to a first anti-TNFα treatment.Methods
Serum samples were collected at baseline before RTX initiation. A proteomics study comparing responders and nonresponders was conducted to identify and select potential predictive biomarkers whose concentration was measured by quantitative assays. Logistic regression was performed to determine the best biomarker combination to predict good or nonresponse to RTX (EULAR criteria after 6 months’ treatment).ResultsEleven biomarkers potentially discriminating between responders and nonresponders were selected following discovery proteomics. Quantitative immunoassays and univariate statistical analysis showed that fetuin-A and thyroxine binding globulin (TBG) presented a good capacity to discriminate between patient groups. A logistic regression analysis revealed that the combination of fetuin-A plus TBG could accurately predict a patient’s responsiveness to RTX with an AUC of 0.86, sensitivity of 80%, and a specificity of 79%.Conclusion
In RA patients for whom a first anti-TNFα treatment has failed, the serum abundance of fetuin-A and TBG before initiating RTX treatment is an indicator for their response status at 6 months. ClinicalTrials.gov identifier: NCT01000441.Key Points• Proteomic analysis revealed 11 putative predictive biomarkers to discriminate rituximab responder vs. nonresponder RA patients.• Fetuin-A and TBG are significantly differentially expressed at baseline in rituximab responder vs. nonresponder RA patients.• Algorithm combining fetuin-A and TBG accurately predicts response to rituximab in RA patients with insufficient response to TNFi.
The prevention of cardiovascular disease (CVD) is of major concern when considering patients with inflammatory rheumatic disease. Biological therapeutic agents have improved the quality of life of patients, but their side effects are a concern. Since tumour necrosis factor-inhibitors have been approved for clinical usage, their effects on lipid levels have been analysed in a number of studies of both short and long duration. These studies show a consistent trend towards increased levels of total cholesterol and high-density lipoprotein cholesterol, as well as an increase in the levels of triglycerides. However, the results of the lipid ratios are more inconsistent. Whether changes in the lipid profile are beneficial or, on the contrary, carry risk of CVD is still unclear. Treatment with interleukin 6 receptor inhibitor has been observed to increase lipid levels and manufacturers recommend that lipid abnormalities should be monitored during treatment. In this article, published data on the effects of biological therapy on lipids and lipid levels are reviewed and discussed in relation to duration of therapy and CVD prevention, mainly in rheumatoid arthritis.
Patients with rheumatoid arthritis (RA) have a high mortality rate than the general population with cardiovascular disease resulting from accelerated atherosclerosis being the most common cause of death. Plasma lipoprotein levels are an important determinant of atherosclerosis, the major cause of coronary artery disease (CAD) and stroke. The study group consisted of 10 patients (27-78 years) with RA. The reference group was made up of 13 healthy subjects (22-52 years). The aim of the present study was to investigate lipid, lipoprotein, ox-LDL concentrations and lipid and lipoprotein ratios in RA patients and compared to healthy subjects. The serum levels of lipids and apoAI, apoB, and oxidized-LDL (ox-LDL) were determined. Lipid and lipoprotein profiles were obtained in serum after 14-hour overnight fasting. Lipids and lipoproteins (apoA, apoB) were determined on Hitachi 902 analyzer. LDL-cholesterol (LDL-C) was calculated according to the Friedewald formula. Non-HDL-cholesterol (non-HDL-C) was calculated as total cholesterol (TC) minus HDL-C. Ox-LDL concentration was made using the ELISA method from BioMedica, Vien, Austria. The obtained results in RA patients show that those had significantly increased TG, TC, LDL-C, non-HDL-C, apoB, ox-LDL concentrations and TG/HDL-C, TC/HDL-C, LDL-C/HDL-C ratios, and decreased HDL-C level and apoAI/apoB, HDL-C/apoAI ratios as compared to the reference group. Conclusion. Disturbances in lipid and lipoprotein profiles and high ox-LDL level suggest that RA patients have a high risk of arteriosclerosis. However, future studies are required.
Aim:
To evaluate tocilizumab (TLZ) effects on blood lipids composition and severity of carotid arteries (CA) atherosclerosis in rheumatoid arthritis (RA) patients after 24 week TLZ treatment.
Material and methods:
Before and 24 weeks after TLZ treatment 43 RA patients (33 women and 10 men) were examined by DAS 28 index, for blood serum concentration of cholesterol, triglycerides (TG), LPHD and LPLD cholesterol. The drug was injected intravenously in drops in a dose 8 mg/kg each 4 weeks.
Results:
A 24 week TLZ treatment produced satisfactory and good anti-inflammatory effects in RA patients. Hypoalphalipoproteinemia incidence and atherogenicity index (AI) reduced 3 and 5 times, respectively (p < 0.05). Elevated levels of cholesterol, TG, LDPL cholesterol occurred with the same frequency before and after TLZ treatment. Cholesterol rose by 11.6%, LPHD cholesterol--by 48.9%, TG lowered by 7%, Al--by 31.9% (p < 0.05). LDLP cholesterol decreased Blood lipids composition shifts were associated with marked reduction in the disease activity: decreased concentration of C-reactive protein, IgM rheumatoid factor, DAS28 index, improvement of the patient functional status. Maximal thickness of the intima-media complex of CA increased by 8.2%. Atherosclerotic plaques were revealed before and after treatment in 17 (41.4%) patients from 41, in 5 (12.2%) patients the plaques arose after 6 months and in 5 (12.2%) patients the number of plaques increased.
Conclusion:
Because of both positive and negative effects of IL-6 receptor inhibitors on blood lipids, combined treatment of RA must include statins for correction of dyslipidemia.
Few studies have examined dyslipidemia in patients with rheumatoid arthritis (RA), especially in Japanese cohorts. The aims of this study were to investigate the lipid profiles of RA patients, to assess the relationships between lipid profiles and RA activity and treatment, and to elucidate the effects of HMG-CoA reductase inhibitors (statins) in Japanese patients with RA. A multicenter observational study was conducted in 488 patients with RA. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels, and RA activity as assessed by disease activity score 28 (DAS28), and treatment for RA were analyzed retrospectively. In statin-treated patients, drug efficacy was also analyzed. The prevalence of hyper LDL-C, hyper TG, and hypo HDL-C were 29.3, 24.2, and 10.2 %, respectively, and the overall prevalence of dyslipidemia was 56.5 %. The level of HDL-C was inversely correlated with DAS28. Patients treated with low-dose glucocorticoids showed significantly higher levels of HDL-C and lower TC/HDL-C ratios compared with patients not receiving glucocorticoid treatment. Conversely, patients treated with biologic agents showed significantly higher levels of LDL-C, lower levels of HDL-C, and higher TC/HDL-C ratios. Atorvastatin significantly improved lipid profiles after a few months of treatment. The prevalence of dyslipidemia in Japanese patients with RA is higher than that in the non-RA population. Our result suggests that controlling RA disease activity might improve lipid profiles and eventually lower cardiovascular risk. Low-dose atorvastatin was effective for treatment of dyslipidemia in RA patients but had no apparent effect on RA disease activity.
Background:
Some studies showed an anti-atherogenic effect of TNF-α blockers on lipid profile, but these data have been challenged.
Objective:
To perform a meta-analysis on lipid profile changes induced by TNF-α blocker treatment.
Methods:
Prospective studies on rheumatic patients receiving TNF-α blockers and providing before-and-after treatment values of triglycerides (TGs), total cholesterol (TC), HDL-cholesterol (HDLc), LDL-cholesterol (LDLc), and atherogenic index (AI) were included. Standardized mean differences (SMD) in lipid profile were analyzed at short-term (2-12 weeks), middle-term (13-24 weeks), and long-term (25-52 weeks) assessments.
Results:
Thirty articles (1707 patients) were included. TNF-α blockers determined an increase in TC at short-term, middle-term, and long-term assessments (SMD: 0.20 mmol/L [95% CI: 0.04, 0.35]; SMD: 0.27 mmol/L [95% CI: 0.08, 0.46]; SMD: 0.22 mmol/L [95% CI: 0.01, 0.43]). HDLc increased only at the short-term assessment (SMD: 0.19 mmol/L [95% CI: 0.10, 0.28]), and TGs achieved a significant increase at the long-term assessment (SMD: 0.19 mmol/L [95% CI: 0.04, 0.34]). LDLc and AI were not affected by TNF-α blocker treatment.
Conclusions:
Slight but significant increases in TC occurred without any significant change in LDLc and AI. Changes in HDLc and TGs were not consistent among the different time point assessments. These quantitative changes in lipid profile do not seem to be able to explain cardiovascular risk improvement reported in patients receiving TNF-α blockers. Further studies on other mechanisms are needed to address this issue.
L’objectif était d’évaluer l’intérêt de l’électrocardiogramme (ECG) systématique, comme outil de détection des anomalies cardiaques au cours des spondylarthropathies (SPA) et de la polyarthrite rhumatoïde (PR).
Méthodes
Des malades consécutifs atteints de SPA, PR ou maladies articulaires dégénératives (considérés comme témoins) hospitalisés sur une période de six mois et indemnes d’évènement cardiovasculaire ont été inclus. Un ECG – 12 dérivations – était réalisé et interprété par un cardiologue en insu du diagnostic.
Résultats
Au total, 108 patients avec SPA (durée moyenne 11 ± dix ans), 106 malades avec PR (durée moyenne 12 ± neuf ans) et 74 témoins ont été inclus. Ceux-ci étaient asymptomatiques sur le plan cardiaque et sans antécédent cardiovasculaire. Les populations étaient homogènes, concernant la présence des facteurs de risque cardiovasculaire, hormis pour le diabète, plus fréquent dans les groupes PR et témoin. Les proportions d’extrasystoles, de blocs auriculoventriculaires (2,8 % dans le groupe SPA ; 1,9 % dans le groupe PR ; 2,7 % chez les témoins), de bloc de branche gauche complet ou incomplet (respectivement : 0,9 % ; 0,9 % ; 2,7 %), de bloc de branche droit complet ou de bloc de branche gauche (respectivement : 0,9 % ; 4,7 % ; 4,1 %) et d’anomalie évocatrice d’ischémie myocardique (10,2 % ; 19,8 % ; 17,6 %) étaient similaires chez les patients atteints de PR ou de SPA par comparaison à la population témoin.
Conclusion
Chez les patients sans antécédent cardiovasculaire, asymptomatiques, la réalisation d’un ECG systématique ne permet pas de mettre en évidence le risque accru de complications cardiaques spécifiques liées à ces pathologies, chez les patients atteints de SPA et PR.
Dyslipidaemia is commonly observed in patients with active rheumatoid arthritis (RA), with lower total cholesterol levels as well as lower levels of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) reported in these patients than in individuals without RA. This pattern is mirrored in sepsis and other inflammatory states, suggesting systemic inflammation has the general effect of lowering circulating lipid levels. In line with such observations, suppressing inflammation with DMARDs, biologic therapies and small-molecule Janus kinase inhibitors seems to elevate levels of lipid fractions in RA, albeit in a variable manner dependent presumably upon the mechanism of action of the different agents. In addition, limited epidemiological data in patients with RA suggest increased cardiovascular disease (CVD) risk at relatively low cholesterol levels, a pattern contrasting with that observed in the population without RA. Our understanding of the potential mechanisms behind these inflammation-associated lipid changes remains suboptimal and requires further study. In clinical terms, however, use of the total cholesterol to HDL-C ratio as the lipid component of CVD risk scoring in patients with RA would seem appropriate given that these lipid parameters generally change in parallel with inflammation and suppression of inflammation. Whether alternative lipid or lipoprotein measures (or simple markers of inflammation) could improve stratification of CVD risk in RA beyond the established risk factors requires future investigation.
Actinic keratoses (AK) are the most common premalignant pathology seen in dermatological practice and represent a burgeoning burden upon health services. Increasingly recognized is the damage to surrounding, perilesional skin, forming the premise for field-directed therapy. Ingenol mebutate gel is a novel agent for field-directed treatment of AK, requiring only 2 or 3 days of application. Following an overview of existing treatment modalities, the authors review recent trials and safety data pertaining to the use of ingenol mebutate gel and discuss its role in the treatment of AK.
Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents.
Committee members developed and refined a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline.
It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease.
Tocilizumab, humanized monoclonal antibody to sIL-6R, is a promising new agent for the treatment of rheumatoid ar-thritis. Safety data from randomized controlled trials (RCT) to date have been overall reassuring with no evidence of in-creased opportunistic infections or malignancies, and some signals for elevated liver function tests and changed lipid profiles. The true implications of these signals in RCTs must be addressed in larger numbers of RA patients with longer term exposure before firm conclusions are reached.
To determine the association of use of tumor necrosis factor-α (TNF-α) inhibitors with differences in lipid levels in patients with rheumatoid arthritis (RA).
We studied 807 patients with incident RA to compare differences in lipid levels in TNF-α inhibitor users versus nonusers, with adjustment for relevant covariables.
TNF-α inhibitor use was not associated with differences in levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), triglycerides, LDL:HDL, or TC:HDL compared to nonusers.
Use of TNF-α inhibitor was not associated with differences in lipid levels in patients with RA.
In addition to a high prevalence of the metabolic syndrome and a significant under-diagnosis of vascular risk factors (VRFs), the effect of chronic inflammation also represents the cornerstone of the raised cardiovascular (CV) risk in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Moreover, the finding that among current anti-inflammatory treatments, the use of tumor necrosis factor (TNF)-α blockers is associated with optimal rheumatologic and CV outcomes further supports the impact of inflammation on the CV risk. However, up-to-date treatment guidelines suggest that TNF-α blockers should be used only after the failure of traditional disease-modifying antirheumatic drugs (DMARDs). Early predictors of the therapeutic efficacy of traditional DMARDs are needed to identify candidates for TNF-α blocker treatment. Furthermore, whether the CV risk should be taken into account while choosing antirheumatic treatments is an emerging issue to be addressed. Common educational programs for specialists and general practitioners and appropriate CV prevention programs, taking into consideration traditional VRFs as well as the inflammatory status, should be planned to prevent ischemic events and to achieve optimal inflammation control in rheumatic patients.
Treatment with tumor necrosis factor alpha (TNF-α) inhibitors may have favourable effects on the lipid profile. This is the first study to assess the impact of etanercept on the lipid profile in patients with moderate-to-severe plaque psoriasis. To investigate the effect of etanercept on the lipid profile after 24 weeks of treatment in patients with moderate-to-severe plaque psoriasis. We conducted a retrospective cohort study reviewing the medical records of 45 consecutive patients who were treated for psoriasis with etanercept between June 2006 and September 2009. Demographic and clinical data were collected. Levels of total cholesterol, LDL-C, HDL-C, triglycerides, fasting glucose and C-reactive protein were recorded at the start of etanercept and at week 24. Levels of total cholesterol, LDL-C and triglycerides increased after 24 weeks of treatment with etanercept, with mean differences of 7.1 mg/dL (p=0.505), 2.0 mg/dL (p=0.718) and 2.8 mg/dL (p=0.180), respectively. HDL-C decreased, with a mean difference of -1.4 mg/dL (p=0.995). None of these changes were statistically significant. We found no favourable changes on the lipid profile after 24 weeks of treatment with etanercept in responding patients with chronic plaque psoriasis.
The fundamental role of the inflammatory activation in the pathophysiology of atherosclerosis is now widely established. Different strategies for positive modulation of these processes have been proposed, but the clinical results have been contradictory and sometimes, due to safety issues, a specific therapeutic approach has been withdrawn before reaching the final acceptation of the regulatory agencies. The reasons for these negative conclusions can be multiple and not always completely clarified. In addition it is frequently difficult to separate the metabolic or cardiovascular effects of these approaches (i.e., hypocholesterolemic, hypoglycemic, hypotensive) from the real anti-inflammatory effects. The present review discusses the effects of different anti-inflammatory strategies developed in the last decade for the treatment of atherosclerosis, and consequently for the prevention of cardiovascular events. The complexity of the inflammatory network, well represented by the presence and the action of a plethora of cells and molecules, suggests a word of caution in the evaluation of the clinical results about significant improvements of the atherosclerotic burden: only randomized controlled trials with cardiovascular hard end points can give the final answer.
Systemic autoimmune diseases may be progressive and lead to organ system dysfunction and premature death. Current treatment paradigms are usually predominantly based on the administration of immunosuppressive and/or immunomodulatory drug therapy. Such therapy can stabilize systemic manifestations of connective tissue disease (CTD) and may put the disease into remission, and many of these agents are commonly used to treat CTD-associated interstitial lung disease (ILD). Although these agents have largely revolutionized the treatment of the systemic autoimmune diseases, adverse reactions, which can be serious and life threatening, to the various immunosuppressive agents used in the treatment of CTD can occur. Treating physicians must be aware of mechanisms of action of various immunosuppressive agents and be able to recognize the potential adverse reactions that may occur with therapy as well as potentially harmful effects on fetal development. Appropriate monitoring may prevent or limit toxicity from these agents, and knowledge of drug-drug interactions is essential when these agents are prescribed.
Atherosclerosis plays a key role in cardiovascular disease in patients with rheumatoid arthritis (RA). Although therapy with TNF-alpha antagonists has resulted in dramatic improvement in the prognosis of RA, its effects on circulatory lipids are unclear. We conducted a systematic review of the literature to summarize the available evidence on lipid profile modification in patients with RA treated with TNF-alpha antagonists, with extensive searches in PubMed, the Cochrane Collaboration database (Central), and SCOPUS. Twenty-four observational studies met the inclusion criteria; 12 included only patients with RA treated with infliximab and three, patients with RA treated with adalimumab. The other nine included a mix of patients with various rheumatic diseases, or receiving one of several TNF-alpha antagonists. Eleven studies found a statistically significant increase in total cholesterol (TC) and high-density lipoprotein (HDL); six of 20 found significant increases in triglycerides (TG). Four of 13 studies found a statistical increase in low-density lipoprotein. No major changes were observed for ApoB/ApoA1 ratios. A small trend to increased TC was observed in patients receiving TNF-alpha antagonists, mostly due to an increase in HDL. There was a small trend to increased TG, and no changes in ApoB/ApoA1 ratio. The clinical impact of these findings is unclear, and further studies are needed to clarify the role of these lipid changes on cardiovascular morbidity in RA.
To assess the usefulness of routine electrocardiography for heart disease screening in patients with spondyloarthropathy (SpA) or rheumatoid arthritis (RA).
We included consecutive patients with SpA or RA or with degenerative joint disease (control group) admitted over a 6-month period and free of cardiovascular events. A 12-lead electrocardiogram (ECG) was obtained and was interpreted by a cardiologist who was unaware of the diagnosis.
We included 108 patients with SpA (mean duration, 11+/-10 years), 106 with RA (mean duration, 12+/-9 years), and 74 with degenerative joint disease (controls). No patient had cardiovascular symptoms or a prior history of cardiovascular disease. The only difference in cardiovascular risk factors across the three populations was a higher prevalence of diabetes in the RA and control groups. We found no differences between the SpA or RA groups and the control group regarding the rates of the following ECG findings: premature beats, atrioventricular block (2.8% in the SpA group, 1.9% in the RA group, and 2.7% in the control group), complete or incomplete left bundle branch block (0.9%, 0.9%, and 2.7%, respectively), complete right bundle branch bloc or left bundle branch block (0.9%, 4.7%, and 4.1%, respectively); and abnormalities suggesting myocardial ischemia (10.2%, 19.8%, and 17.6%, respectively).
In patients with SpA or RA who have no cardiovascular symptoms or history of cardiovascular disease, a routine ECG shows no increase in the cardiac abnormalities specifically associated with these joint diseases, compared to controls with degenerative joint disease.
Cardiovascular disease (CVD) is partially attributed to traditional cardiovascular risk factors, which can be identified and managed based on risk stratification algorithms (Framingham Risk Score, National Cholesterol Education Program, Systematic Cardiovascular Risk Evaluation and Reynolds Risk Score). We aimed to (a) identify the proportion of at risk patients with rheumatoid arthritis (RA) requiring statin therapy identified by conventional risk calculators, and (b) assess whether patients at risk were receiving statins.
Patients at high CVD risk (excluding patients with established CVD or diabetes) were identified from a cohort of 400 well characterised patients with RA, by applying risk calculators with or without a x1.5 multiplier in specific patient subgroups. Actual statin use versus numbers eligible for statins was also calculated.
The percentage of patients identified as being at risk ranged significantly depending on the method, from 1.6% (for 20% threshold global CVD risk) to 15.5% (for CVD and cerebrovascular morbidity and mortality) to 21.8% (for 10% global CVD risk) and 25.9% (for 5% CVD mortality), with the majority of them (58.1% to 94.8%) not receiving statins. The application of a 1.5 multiplier identified 17% to 78% more at risk patients.
Depending on the risk stratification method, 2% to 26% of patients with RA without CVD have sufficiently high risk to require statin therapy, yet most of them remain untreated. To address this issue, we would recommend annual systematic screening using the nationally applicable risk calculator, combined with regular audit of whether treatment targets have been achieved.
Few, if any, areas of medical therapeutics have witnessed such dramatic changes as those that have occurred in the therapy of rheumatoid arthritis (RA) during the past two decades. Improvements in clinical trials methodologies, the introduction of no fewer than nine biologic agents with distinct mechanisms of action, and the development of better strategies for the use of such agents have all contributed to the new age in RA therapeutics. Here, we review these developments and attempt to describe the current landscape of RA therapy in terms of available treatments, agreed-upon principles of RA management, as well as some important controversies in this field. Despite the great pace at which developments are moving, a treatment-free remission for patients with RA remains an elusive goal and unmet medical needs remain. The quest for better therapies for this potentially devastating disease is still as important as ever; research in this exciting area is ongoing, and it is reasonable to hope that, during the next decade, developments will lead to improved, rationally designed, targeted therapies for RA.
As a multifunctional cytokine, tumor necrosis factor alpha (TNF-alpha) exerts a series of biological actions in different cells, tissues, organs, and species and has been demonstrated to regulate and interfere with energy metabolism, especially lipid homeostasis. A large body of researches suggested that the effects of TNF-alpha on lipid metabolism mainly include five aspects: (1) suppresses free fatty acid (FFA) uptake and promotes lipogenesis; (2) induces lipolysis; (3) inhibits lipid-metabolism-related enzymes activity; (4) regulates cholesterol metabolism; (5) regulates other adipocyte-derived adipokines. The molecular mechanisms underlying these actions are complex and several signal transduction pathways might be involved. Regulation of metabolism-related gene expression at transcriptional and protein levels and impact on enzymes activity might be of importance. Identification and verification of these pathways might provide novel potential strategies and drug targets for dyslipidemia therapy. However, the inconsistent and even conflict conclusions on lipid profile drawn from human subjects after infliximab therapy poses the possibility that the effect of TNF-alpha on lipid metabolism might be more complicated than it appeared to be.
Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic disease, which negatively influences patients' quality of life, work productivity and longevity. Current therapies include traditional and biologic disease-modifying antirheumatic drugs (DMARDs). Although these are effective for many, a substantial proportion of patients fail to respond to these agents, suffer from loss of efficacy and/or experience unpleasant side effects, highlighting the need for alternatives.
To address how a greater proportion of RA patients may potentially achieve disease remission, we reviewed data on IL-6 as a therapeutic target.
IL-6 is an important driver of RA pathogenesis, mediating both articular and systemic effects of the disease. Tocilizumab, an inhibitor of the IL-6 receptor (IL-6R), is beneficial in treating RA in a variety of clinical contexts. Evidence to date supports the use of tocilizumab, as monotherapy or combination therapy, as an effective approach to the treatment of RA. Here, we discuss key efficacy and safety data from the recently published Phase III trials.
Subjects with rheumatoid arthritis (RA) have increased cardiovascular risk and may show atherogenic forms of dyslipidemia. The present study investigated whether patients with early RA, beyond alterations in plasma lipids, also show lower LDL size and altered LDL subclass distribution.
We identified 25 subjects with RA (47+/-8 years, body mass index (BMI) 25+/-4kg/m(2)) by the American College of Rheumatology diagnostic criteria, with a disease durations <1 year and no prior treatment against it. In patients and 22 healthy subjects matched for age and BMI (controls) we measured plasma lipids and LDL size and subclasses by gradient gel electrophoresis.
As compared to controls RA patients had higher plasma triglycerides (1.8+/-0.5 vs. 1.0+/-0.5mmol/L, p<0.0001) and lower HDL-cholesterol concentrations (1.2+/-0.2 vs. 1.4+/-0.2mmol/L, p=0.0027), while total- and LDL-cholesterol concentrations were similar. LDL particle size was lower in RA patients than controls (264+/-7 vs. 281+/-9A, p<0.0001), due to less LDL-I (31+/-6 vs. 38+/-7%, p=0.0004) and LDL-IIA (14+/-3 vs. 16+/-3%, p=0.0182), and more LDL-IIIB (7+/-1 vs. 5+/-1%), -IVA (11+/-2 vs. 8+/-2%) and -IVB particles (12+/-2 vs. 9+/-2%,) (p<0.0001 for all). Further, about 1/3 of patients showed the complete "atherogenic-lipoprotein-phenotype" (e.g. the concomitant presence of high triglycerides, low HDL-cholesterol and elevated small, dense LDL).
Beyond plasma lipids, increased levels of small, dense LDL seems to be common in drug-naïve patients with early RA. Yet, whether these findings affect the atherogenic process and the clinical endpoints in these subjects remains to be determined by future prospective studies.
The mechanism by which genes involved in cholesterol biosynthesis and import are preferentially up-regulated in response to
sterol depletion was elucidated with the cloning of sterol regulatory element binding protein-1 (SREBP-1). SREBP-1 is a transcription
factor whose entry into the nucleus is gated by sterol-regulated proteolysis. We have investigated the role of tumor necrosis
factor-α (TNF-α) as a mediator of SREBP-1 maturation in human hepatocytes. TNF-α is capable of inducing SREBP-1 maturation
in a time- and dose-dependent manner that is consistent with the kinetics of TNF-α-mediated activation of neutral sphingomyelinase
(N-SMase). Antibodies to N-SMase inhibit TNF-α-induced SREBP-1 maturation suggesting that N-SMase is a necessary component
of this signal transduction pathway. Ceramide, a product of sphingomyelin hydrolysis, is also capable of inducing SREBP-1
maturation. The mature form of SREBP-1 generated by TNF-α, sphingomyelinase or ceramide treatment translocates to the nucleus
and binds the sterol regulatory element. This promotes transcription of the gene upstream of the sterol regulatory element.
A unique finding of our studies is that ceramide stimulated SREBP-1 maturation even in the presence of cholesterol and 25-hydroxycholesterol
both of which are known suppressors of SREBP-1 maturation. Our findings indicate that ceramide-mediated maturation of SREBP-1
maturation is a novel sterol-independent mechanism by which cholesterol homeostasis may be regulated.
Lipoprotein (a), (Lp(a)), an independent atherogenic factor, was significantly increased in 93 patients with classical, seropositive rheumatoid arthritis of median disease activity. In the patients with Lp(a) concentrations above the upper reference value of 480 mg/l there was a significant correlation between Lp(a) and the concentration of orosomucoid, erythrocyte sedimentation rate, and the platelet count. The plasma concentrations of cholesterol and high density lipoprotein-cholesterol in both male and female patients were significantly lower than in controls. Apolipoprotein B and apolipoprotein AI in the patients correlated significantly with total cholesterol and high density lipoprotein-cholesterol respectively.
To determine the effect of intramuscular gold and oral hydroxychloroquine (HCQ) on the lipid profile of patients with rheumatoid arthritis (RA).
A prospective randomised clinical trial of 12 months' duration was performed in 100 RA patients. Data on clinical and laboratory parameters of disease activity, and fasting serum lipid samples was collected at baseline and at three monthly intervals over one year.
The expected second line response was seen with no significant difference in efficacy between the groups at 12 months. The HCQ group had a significant overall improvement in their lipid profile while there was a trend for lipid profiles in the gold group to worsen.
HCQ is an effective second line agent that has beneficial effects on serum lipids. This should be taken into account when choosing a disease modifying anti-rheumatic drug in patients who suffer from RA and who have significant cardiovascular risk factors.
In this issue of the Annals of the Rheumatic Diseases , Munro and colleagues1 report a comparative study of intramuscular gold and hydroxychloroquine in rheumatoid arthritis (RA). They demonstrate a beneficial effect of hydroxychloroquine on lipid profiles compared with gold and suggest that hydroxychloroquine might be considered for RA patients at adverse cardiovascular risk.
Should rheumatologists be interested in their patients’ cardiovascular and lipid status? The answer to this question is an unqualified ‘yes’. Several studies suggest that cardiovascular diseases account for about half of all deaths in RA.2 Cardiovascular deaths are more pronounced in the younger age group (<55 years), and may contribute to the substantial reduction in life expectancy, with estimates of standardised mortality ratios ranging from 1.1 to 3.3
We previously suggested that cardiovascular disease in RA may result from accelerated atherosclerosis caused by clinical or subclinical vasculitis.4 The main determinants of cardiovascular risk in the general population, however, are the concentrations of serum low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol. In men who are middle aged or over, a ratio of total to HDL cholesterol over 5 associates with increased risk of a first myocardial infarction.5 Oxidative modification of LDL may also be important and it is of interest that oxidised LDL has been noted in RA synovial biopsy specimens.6 Products of LDL oxidation may be recognised …
Rheumatoid arthritis (RA) patients experience a markedly increased frequency of cardiovascular disease. We evaluated cardiovascular risk profiles in 79 RA patients and in 39 age-matched and sex-matched osteoarthritis (OA) patients. Laboratory tests comprised ultrasensitive C-reactive protein (CRP) and fasting lipids. Insulin sensitivity (IS) was determined by the Quantitative Insulin Sensitivity Check Index (QUICKI) in all OA patients and in 39 of the RA patients. Ten RA patients were on glucocorticoids. RA patients exercised more frequently than OA patients (chi2 = 3.9, P < 0.05). Nine RA patients and one OA patient had diabetes (chi2 = 4.5, P < 0.05). The median CRP, the mean QUICKI and the mean high-density lipoprotein (HDL) cholesterol were 9 mg/l (range, 0.5-395 mg/l), 0.344 (95% confidence interval [CI], 0.332-0.355) and 1.40 mmol/l (95% CI, 1.30-1.49 mmol/l) in RA patients, respectively, as compared with 2.7 mg/l (range, 0.3-15.9 mg/l), 0.369 (95% CI, 0.356-0.383) and 1.68 mmol/l (95% CI, 1.50-1.85 mmol/l) in OA patients. Each of these differences was significant (P < 0.05). After controlling for the CRP, the QUICKI was similar in RA and OA patients (P = 0.07), while the differences in HDL cholesterol were attenuated but still significant (P = 0.03). The CRP correlated with IS, while IS was associated with high HDL cholesterol and low triglycerides in RA patients and not in OA patients. A high CRP (>/= 8 mg/l) was associated with hypertension (chi2 = 7.4, P < 0.05) in RA patients. RA glucocorticoid and nonglucocorticoid users did not differ in IS and lipids (P > 0.05). Excess cardiovascular risk in RA patients as compared with OA patients includes the presence of decreased IS and HDL cholesterol in RA patients. The latter is only partially attributable to the acute phase response. The CRP, IS, HDL cholesterol, triglycerides and hypertension are inter-related in RA patients, whereas none of these relationships were found in OA patients.
Patients with rheumatoid arthritis (RA) experience excess cardiovascular disease (CVD). We investigated the effects of disease-modifying antirheumatic drugs (DMARD) and dietary intervention on CVD risk in inflammatory arthritis. Twenty-two patients (17 women; 15 with RA and seven with spondyloarthropathy) who were insulin resistant (n = 20), as determined by the Homeostasis Model Assessment, and/or were dyslipidemic (n = 11) were identified. During the third month after initiation of DMARD therapy, body weight, C-reactive protein (CRP), insulin resistance, and lipids were re-evaluated. Results are expressed as median (interquartile range). DMARD therapy together with dietary intervention was associated with weight loss of 4 kg (0-6.5 kg), a decrease in CRP of 14% (6-36%; P < 0.006), and a reduction in insulin resistance of 36% (26-61%; P < 0.006). Diet compliers (n = 15) experienced decreases of 10% (0-20%) and 3% (0-9%) in total and low-density lipoprotein cholesterol, respectively, as compared with increases of 9% (6-20%; P < 0.05) and 3% (0-9%; P < 0.05) in diet noncompliers. Patients on methotrexate (n = 14) experienced a reduction in CRP of 27 mg/l (6-83 mg/l), as compared with a decrease of 10 mg/l (3.4-13 mg/l; P = 0.04) in patients not on methotrexate. Improved cardiovascular risk with DMARD therapy includes a reduction in insulin resistance. Methotrexate use in RA may improve CVD risk through a marked suppression of the acute phase response. Dietary intervention prevented the increase in total and low-density lipoprotein cholesterol upon acute phase response suppression.
Tumour necrosis factor (TNF) is known to increase the concentrations of interleukin (IL) 6 and C reactive protein (CRP) and to induce proatherogenic changes in the lipid profile and may increase the cardiovascular risk of patients with rheumatoid arthritis (RA) and other inflammatory disorders.
To assess whether anti-TNF therapy modifies the cardiovascular risk profile in patients with RA.
The lipoprotein spectrum and the inflammation markers CRP and IL6 were investigated in 33 patients with RA treated with human anti-TNF monoclonal antibodies (D2E7, adalimumab, Humira) and 13 patients with RA given placebo, before and after 2 weeks' treatment.
In the anti-TNF treated group, the mean (SD) concentrations of HDL-cholesterol were significantly higher after 2 weeks' treatment (0.86 (0.30) mmol/l v 0.98 (0.33) mmol/l, p<0.01), whereas LDL and triglyceride levels were not significantly changed. Additionally, a significant decrease in CRP (86.1 (54.4) mg/l v 35.4 (35.0) mg/l, p<0.0001), and IL6 (88.3 (60.5) pg/ml v 42.3 (40.7) pg/ml, p<0.001) concentrations was seen in this group. No changes in lipid profile, IL6, or CRP levels were seen in the placebo group.
TNF neutralisation with monoclonal anti-TNF antibodies increased HDL-cholesterol levels and decreased CRP and IL6 levels after 2 weeks. Therefore this treatment may improve the cardiovascular risk profile of patients with RA.
The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a “classification tree” schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91–94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate.
In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks.
At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.
During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.
Objective
To compare the incidence of cardiovascular (CV) events in persons with rheumatoid arthritis (RA) with that in people from the general population, adjusting for traditional CV risk factors.Methods
Two hundred thirty-six consecutive patients with RA were assessed for the 1-year occurrence of 1) CV-related hospitalizations, including myocardial infarction, stroke or other arterial occlusive events, or arterial revascularization procedures, or 2) CV deaths. Both outcomes were ascertained by medical records or death certificates. For comparison, we used CV events that occurred during an 8-year period among participants in an epidemiologic study of atherosclerosis and CV disease who were ages 25–65 years at study entry. We calculated the age- and sex-stratified incidence rate ratio (IRR) of CV events between the 2 cohorts and used Poisson regression to adjust for age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index.ResultsOf the 236 RA patients, 234 were observed for 252 patient-years, during which 15 CV events occurred. Of these, 7 incident events occurred during the 204 patient-years contributed by patients ages 25–65 years, for an incidence of 3.43 per 100 patient-years. In the comparison cohort, 4,635 community-dwelling persons were followed up for 33,881 person-years, during which 200 new events occurred, for an incidence of 0.59 per 100 person-years. The age- and sex-adjusted IRR of incident CV events associated with RA was 3.96 (95% confidence interval [95% CI] 1.86–8.43). After adjusting for CV risk factors using Poisson regression, the IRR decreased slightly, to 3.17 (95% CI 1.33–6.36).Conclusion
The increased incidence of CV events in RA patients is independent of traditional CV risk factors. This suggests that additional mechanisms are responsible for CV disease in RA. Physicians who provide care to individuals with RA should be aware of their increased risk of CV events and implement appropriate diagnostic and therapeutic measures.
Objective. To validate the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), and the World Health Organization (WHO)/International League Against Rheumatism (ILAR) response criteria for rheumatoid arthritis (RA).
Methods. EULAR response criteria were developed combining change from baseline and level of disease activity attained during followup. In a trial comparing hydroxychloroquine and sulfasalazine, we studied construct (radiographic progression), criterion (functional capacity), and discriminant validity.
Results. EULAR response criteria had good construct, criterion, and discriminant validity. ACR and WHO/ILAR criteria showed only good criterion validity.
Conclusion. EULAR response criteria showed better construct and discriminant validity than did the ACR and the WHO/ILAR response criteria for RA.
Plasma lipid levels are elevated in people with diabetes, and a direct relationship can be demonstrated between indices of diabetic control and plasma lipid levels. Many observations suggest that diabetes may be associated with enhanced cytokine production, raising the possibility that some of the metabolic abnormalities associated with diabetes may be due to or exacerbated by cytokine overproduction. Tumor necrosis factor induces a rapid increase in serum triglyceride levels caused by an increase in VLDL of normal composition. Although in vitro studies showed that TNF decreases adipose tissue lipoprotein lipase activity, recent studies with intact animals demonstrated that TNF increases serum triglyceride levels by stimulating hepatic lipid secretion, not by affecting clearance. The increase in hepatic VLDL triglyceride secretion induced by TNF is due to both the stimulation of hepatic de novo fatty acid synthesis and an increase in lipolysis. Other cytokines including IL-1, IL-6, and alpha-interferon increase hepatic de novo fatty acid synthesis. Similarly, cytokines such as IL-1 and alpha-, beta-, and gamma-interferon also increase lipolysis. Thus, a variety of cytokines acting at different receptors can affect multiple processes that can alter lipid metabolism and increase serum lipid levels. These cytokine-induced increases in serum lipoprotein levels may be a beneficial response for the host. Studies show that lipoproteins, including VLDL, bind endotoxin and can protect against the toxic effects of endotoxin. Moreover, lipoproteins bind a variety of viruses, reducing their infectivity. Lipoproteins also bind urate crystals, which reduces the inflammatory response induced by these crystals.(ABSTRACT TRUNCATED AT 250 WORDS)
Extensive data implicate cholesterol in the atherosclerotic process responsible for coronary disease. Of the atherosclerotic disease outcomes, serum cholesterol is most strongly related to coronary disease. A significant relationship of serum cholesterol to all clinical manifestations of coronary heart disease has been demonstrated in the Framingham Study, after adjusting for coexistent risk factors. Cholesterol and blood pressure exert similar influences on the occurrence of coronary heart disease. Risk of coronary heart disease associated with serum cholesterol is continuous, graded, and strong, with ideal values for cholesterol probably in the 130-190 mg/dL range. The impact of serum cholesterol diminishes with advancing age, but the predictive value of cholesterol is restored when fractionated into its atherogenic LDL and protective HDL components. The predictive value of total cholesterol in serum at all concentrations, including values less than 200 mg/dL, can be enhanced by taking HDL cholesterol into account. The total/HDL cholesterol ratio is a practical, efficient means for evaluating the joint effect of the two-way cholesterol traffic. Other cardiovascular risk factors such as blood pressure, glucose, cigarette smoking, fibrinogen, and left ventricular hypertrophy markedly influence the risk associated with measured concentrations of serum cholesterol. In correcting hypertension or diabetes, lipid values are an important consideration in determining the urgency, type, and efficacy of treatment used. In contrast to coronary mortality, rates of overall mortality show a quadratic relationship to total cholesterol in serum, with excessive mortality at concentrations greater than 160 mg/dL.
A method for estimating the cholesterol content of the serum low-density lipoprotein fraction (Sf- 0.20)is presented. The method involves measure- ments of fasting plasma total cholesterol, tri- glyceride, and high-density lipoprotein cholesterol concentrations, none of which requires the use of the preparative ultracentrifuge. Cornparison of this suggested procedure with the more direct procedure, in which the ultracentrifuge is used, yielded correlation coefficients of .94 to .99, de- pending on the patient population compared. Additional Keyph rases hyperlipoproteinemia classifi- cation #{149} determination of plasma total cholesterol, tri- glyceride, high-density lipoprotein cholesterol #{149} beta lipo proteins
Tumor necrosis factor-alpha (TNF) has been implicated in the pathogenesis of a variety of human diseases including septic shock, cachexia, graft-versus-host disease and several autoimmune diseases. Monoclonal antibodies directed against TNF provide an attractive mode of therapeutic intervention in these diseases. We have generated a murine monoclonal antibody (A2) with high affinity and specificity for recombinant and natural human TNF. To increase its therapeutic usefulness, we used genetic engineering techniques to replace the murine constant regions with human counterparts while retaining the murine antigen binding regions. The resulting mouse-human chimeric antibody should have reduced immunogenicity and improved pharmacokinetics in humans. Molecular analysis of light chain genomic clones derived from the murine hybridoma suggests that two different alleles of the same variable region gene have rearranged independently and coexist in the same hybridoma cell. The chimeric A2 antibody (cA2) exhibits better binding and neutralizing characteristics than the murine A2 which was shown to contain a mixture of two kappa light chains. The properties of cA2 suggest that it will have advantages over existing murine anti-TNF antibodies for clinical use.
The host response to infection is frequently accompanied by changes in cholesterol and triglyceride (TG) metabolism. To determine the role of cytokines in mediating these changes, we studied the effects of endotoxin (LPS), tumor necrosis factor-alpha (TNF) and interleukin-1 beta (IL-1) on cholesterol and TG metabolism in C57Bl/6 (LPS-sensitive) mice and in C3H/HeJ (LPS-resistant) mice whose macrophages do not produce TNF and IL-1 in response to LPS. Sixteen hours after administration, LPS (1 micrograms/mouse) produced a 41% increase in serum cholesterol and a 62% increase in serum TG levels in C57Bl/6 mice whereas a 100-fold higher dose of LPS did not have a significant effect in C3H/HeJ mice. LPS (1 microgram/mouse) also produced a 8.6-fold increase in hepatic cholesterol synthesis and a 2.7-fold increase in hepatic fatty acid synthesis in C57Bl/6 mice but had no effect in C3H/HeJ mice. This suggests that macrophage produced cytokines such as TNF and IL-1 may be involved in mediating these effects of LPS. Additionally, LPS also increased the activity of hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. As seen with LPS, TNF and IL-1 also increased serum cholesterol and TG levels in C57Bl/6 mice. Moreover, TNF and IL-1 produced a 2.3- and 2.1-fold increase in hepatic HMG-CoA reductase activity, respectively. Finally, pretreatment of mice with anti-TNF antibodies, but not with an IL-1 receptor antagonist, blocked the effect of LPS on serum cholesterol and TG levels, hepatic cholesterol and fatty acid synthesis, and hepatic HMG-CoA reductase activity. These results suggest that whereas both TNF and IL-1 mimic the effects of LPS on cholesterol and TG metabolism, TNF may be the in vivo mediator of these late effects of LPS in mice.
In a prospective study of up to 3 years' duration of 113 patients with early rheumatoid arthritis a disease activity score (DAS) was developed based on the clinical judgment of 6 rheumatologists. The patients were divided in groups with high and low disease activity according to explicit rules. By various statistical methods, including discriminant analysis and multiple regression analysis, a DAS could be defined. This DAS is a continuous measure consisting of the variables Ritchie articular index, number of swollen joints, erythrocyte sedimentation rate and general health measured on a visual analog scale.
To investigate the overall and the cardiovascular mortality in rheumatoid arthritis (RA) in Northern Sweden. To analyze the effect of traditional risk factors and factors associated with rheumatoid disease and its treatment on the progression of cardiovascular disease (CVD) and on mortality by all causes.
A cohort of 606 patients with seropositive RA were followed from 1979 to the end of 1994 or to the death of the patient. Standardized mortality ratio and survival curves were estimated with the population of Vasterbotten as reference. Sex, age at disease onset, treatment with corticosteroids, use of disease modifying antirheumatic drugs (DMARD) and hormone replacement therapy (HRT), hypertension, diabetes mellitus, HLA types, and cause of death were recorded from disease onset. Cox's proportional hazards regression was used to identify important predictors for death and cardiovascular event during followup.
The standardized mortality ratio in both sexes was significantly higher (1.57) for all underlying causes together, for CVD (1.46) and for ischemic heart disease (IHD) (1.54) compared to the reference population. The death rate increased over time. In multiple Cox regression analyses, male sex, higher age at disease onset, and former cardiovascular event increased the death rate. Male sex, high age at disease onset, and hypertension increased the risk of cardiovascular event. Diabetes mellitus, treatment with corticosteroids, DMARD, or HRT did not influence the risks of death or first cardiovascular event.
The overall mortality and death due to CVD and IHD were in both sexes increased in seropositive RA. Male sex and high age at disease onset predicted death and cardiovascular event. Except for hypertension, which increased the risk for cardiovascular event, neither of these traditional cardiovascular risk factors nor corticosteroid treatment influenced mortality by all causes or by cardiovascular event.
The mechanism by which genes involved in cholesterol biosynthesis and import are preferentially up-regulated in response to sterol depletion was elucidated with the cloning of sterol regulatory element binding protein-1 (SREBP-1). SREBP-1 is a transcription factor whose entry into the nucleus is gated by sterol-regulated proteolysis. We have investigated the role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of SREBP-1 maturation in human hepatocytes. TNF-alpha is capable of inducing SREBP-1 maturation in a time- and dose-dependent manner that is consistent with the kinetics of TNF-alpha-mediated activation of neutral sphingomyelinase (N-SMase). Antibodies to N-SMase inhibit TNF-alpha-induced SREBP-1 maturation suggesting that N-SMase is a necessary component of this signal transduction pathway. Ceramide, a product of sphingomyelin hydrolysis, is also capable of inducing SREBP-1 maturation. The mature form of SREBP-1 generated by TNF-alpha, sphingomyelinase or ceramide treatment translocates to the nucleus and binds the sterol regulatory element. This promotes transcription of the gene upstream of the sterol regulatory element. A unique finding of our studies is that ceramide stimulated SREBP-1 maturation even in the presence of cholesterol and 25-hydroxycholesterol both of which are known suppressors of SREBP-1 maturation. Our findings indicate that ceramide-mediated maturation of SREBP-1 maturation is a novel sterol-independent mechanism by which cholesterol homeostasis may be regulated.
To evaluate the efficacy, pharmacokinetics, immunogenicity, and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (cA2) (infliximab; Remicade, Centocor, Malvern, PA) given alone or in combination with low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients.
In a 26-week, double-blind, placebo-controlled, multicenter trial, 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were randomized to 1 of 7 groups of 14-15 patients each. The patients received either intravenous cA2 at 1, 3, or 10 mg/kg, with or without MTX 7.5 mg/week, or intravenous placebo plus MTX 7.5 mg/week at weeks 0, 2, 6, 10, and 14 and were followed up through week 26.
Approximately 60% of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20% Paulus criteria for response to treatment, for a median duration of 10.4 to >18.1 weeks (P < 0.001 versus placebo). Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 (median duration 2.6 weeks; P=0.126 versus placebo). However, coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic, prolonging the duration of the 20% response in >60% of patients to a median of 16.5 weeks (P < 0.001 versus placebo; P=0.006 versus no MTX) and the 50% response to 12.2 weeks (P < 0.001 versus placebo; P=0.002 versus no MTX). Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease, with a Paulus response lasting a median of 0 weeks. A 70-90% reduction in the swollen joint count, tender joint count, and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX. In general, treatment was well tolerated and stable blood levels of cA2 were achieved in all groups, except for the group receiving 1 mg/kg of cA2 alone, at which dosage antibodies to cA2 were observed in approximately 50% of the patients.
Multiple infusions of cA2 were effective and well tolerated, with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60% of patients with active RA despite therapy with low-dose MTX. When cA2 at 1 mg/kg was given with low-dose MTX, synergy was observed. The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2.
There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. In studies using genetically obese ob/ob mice, TNF-alpha receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha's promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin.
Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in vivo administration of anti-TNF-alpha Ab, using a longitudinal analysis, results in the rapid down-regulation of a spectrum of cytokines, cytokine inhibitors, and acute-phase proteins. Marked diurnal variation in the serum levels of some of these were detected. These results were consistent with the concept of a cytokine-dependent cytokine cascade, and the degree of clinical benefit noted after anti-TNF-alpha therapy is probably due to the reduction in many proinflammatory mediators apart from TNF-alpha, such as IL-6, which reached normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in acute-phase proteins occurred after serum IL-6 fell and included serum amyloid A, haptoglobin, and fibrinogen. The latter reduction could be of importance, as it is a risk factor for atherosclerosis, which is augmented in RA patients.
To investigate lipid profiles in patients with untreated active rheumatoid arthritis (RA) and to assess the relationship of the inflammatory condition of RA with lipid profiles.
Forty-two patients with RA and 42 age and sex matched healthy controls were studied. Patients with RA had not been treated with corticosteroid or disease modifying antirheumatic drugs prior to the study. Total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, apolipoprotein A1 (apo A1), apolipoprotein B (apo B), lipoprotein(a) [Lp(a)], and C-reactive protein (CRP) were measured in both groups.
The levels of apo A1 and HDL-cholesterol were significantly lower in patients than in controls (128.5 vs. 151.8 mg/dl, 41.2 vs. 54.9 mg/dl, respectively). The level of Lp(a) was significantly higher in patients than in controls (27.1 vs. 18.0 mg/dl). The ratios of apo B/apo A1, total cholesterol/HDL-cholesterol, and LDL-cholesterol/HDL-cholesterol were significantly higher in patients than in controls (0.82 vs. 0.67, 4.4 vs. 3.4, 2.8 vs. 1.9, respectively). CRP showed a significant correlation with apo A1 (r = -0.44, p<0.01) and HDL-cholesterol (r = -0.35, p<0.05).
Our study suggests that patients with untreated active RA have altered lipoprotein and apolipoprotein patterns that may possibly expose them to higher risk of atherosclerosis. The inflammatory condition of RA may affect the metabolism of HDL-cholesterol and apo A1.
In the last few years, it has been demonstrated that tumor necrosis alpha (TNF-alpha) has important effects on whole-body lipid metabolism. TNF-alpha administration has been found to produce an increase in serum cholesterol levels and increased hepatic hydro-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase activity in mice. The purpose of this study was to test whether plasma levels of the soluble forms of the TNF-alpha receptors 1 and 2 (sTNFR1, sTNFR2) are associated with lipid abnormalities. A total of 36 healthy subjects (19 males, mean age 36.2 +/- 1.9, and 17 females, mean age 34.9 +/- 1.4) were studied. Plasma sTNFR1 levels correlated with total (r = 0.43, P = 0.01) and LDL-cholesterol (r = 0.52, P = 0.002) levels, but not with total or HDL2-HDL3 subfractions of HDL-cholesterol, total plasma triglycerides, VLDL-cholesterol or VLDL-triglycerides (all r < 0.11, P = NS). Plasma sTNFR2 levels also correlated with total (r = 0.44, P = 0.009) and LDL-cholesterol (r = 0.57, P < 0.0001) levels, and negatively with HDL2-cholesterol (r = -0.37, P = 0.029). A stepwise multiple linear regression was constructed to predict total cholesterol levels, with BMI, sex, age, sTNFR1 or sTNFR2 as independent variables. Both sTNFR1 and sTNFR2 were significantly associated with total cholesterol (P = 0.031 and 0.009), contributing to 26 and 19%, respectively, of its variance. In another model in which LDL-cholesterol was substituted for total cholesterol, sTNFR1 or sTNFR2 (P = 0.0084 and 0.0005) were significantly associated with LDL-cholesterol, contributing to 39 and 32% of its variance. In summary, plasma levels of sTNFR1 and sTNFR2 circulate in proportion to total and LDL-cholesterol in healthy subjects.
To identify predictors for cardiovascular disease (CVD) and for overall survival in patients with rheumatoid arthritis (RA) followed from disease onset.
A retrospective cohort of patients with seropositive RA and disease onset between 1974 and 1978 (n = 211) was followed up at the end of 1995. Potential predictors for CVD, as measured by "the first cardiovascular event," and for overall survival were registered. The predictors were identified by extended Cox regression models.
In simple Cox regression analysis, male sex, higher age at disease onset, HLA-B27, high disease activity, corticosteroid treatment early in disease, and hypertension significantly increased risk of cardiovascular event. Higher educational level, extensive disease modifying antirheumatic drug (DMARD) treatment, and corticosteroids > or =1 yr before event decreased the risk. In multiple Cox regression analysis, male sex, high age at disease onset, hypertension, higher haptoglobin level at disease onset, and corticosteroid treatment early in disease increased risk of CVD. In a multiple model comprising only patients with CVD, corticosteroids delayed the event. A high last registered erythrocyte sedimentation rate (ESR) value before event increased CVD risk, in particular when early in disease progression. Decreased life span was predicted by higher age at disease onset, male sex, low education level, high disease activity, hypertension, and CVD. HLA-B27 was associated with decreased life span, as was early, but not extensive corticosteroid treatment. DMARD treatment was associated with decreased mortality risk, as was the presence of joint prosthesis. In multiple regression, male sex, higher age at disease onset, atlantoaxial subluxation early in disease, hypertension, and cardiovascular event increased mortality. A high last registered ESR value before event or death added to that risk.
The study emphasizes the importance of inflammation as an important risk indicator for CVD and mortality in RA. The positive impact of disease activity reducing treatment on CVD risk and survival is suggested.
Unlabelled:
Infliximab is a chimaeric monoclonal antibody to human tumour necrosis factor-alpha (TNFalpha). It binds to both soluble and transmembrane forms of TNFalpha at picomolar concentrations in vitro. Secondary to inhibition of TNFalpha, infliximab reduces serum levels of inflammatory mediators and vascular endothelial growth factor, decreases the expression of chemokines in the synovial tissue and reduces lymphocyte migration into the joints of patients with rheumatoid arthritis. In 2 multicentre randomised double-blind trials conducted over 26 and 30 weeks, infliximab plus methotrexate was significantly more effective than placebo plus methotrexate according to American College of Rheumatology response criteria in patients with active rheumatoid arthritis. A substantial response to infliximab-containing regimens was evident within 2 weeks. Extension phases of these studies indicate sustained clinical efficacy for up to 54 weeks. Of considerable importance are preliminary 1-year radiographic findings that show zero median progression of joint damage in infliximab plus methotrexate recipients compared with a 7 to 8% deterioration in placebo plus methotrexate recipients. Headache, nausea, upper respiratory tract infection and infusion-related reactions are the most commonly reported adverse events with infliximab. Serious events occurred in 4.4% of infliximab versus 1.8% of placebo recipients. In the largest clinical trial, 2 patients died from disseminated infection and 3 developed new or recurrent malignancies, although the exact relationship between infliximab and these events is unknown. To date, 2 patients with rheumatoid arthritis have developed drug-induced lupus. About 10% of patients may develop antibodies to infliximab, although the clinical significance of these is presently unknown.
Conclusion:
Infliximab represents an important advance in the treatment of rheumatoid arthritis, with tolerability concerns raised by early studies having been eased somewhat by more recent data in larger patient numbers. If preliminary results indicating that infliximab is able to arrest joint destruction in patients with rheumatoid arthritis are corroborated, the drug will likely become an integral component of future management strategies for this difficult-to-treat condition.
The aim of this study is to evaluate whether lipoprotein(a) (Lp(a)) acts as the acute phase reactant and whether changes of lipids are related to inflammation in rheumatoid arthritis (RA). Lp(a) and lipids were measured after an overnight fast, before and after 14 days use of antiinflammatory agents and correlated with laboratory findings in 21 untreated RA patients and 19 healthy controls. Nine (42.3%) of 21 RA patients and 6 (31.6%) of 19 controls had high Lp(a) levels (> 30 mg/dl) and the Lp(a) level was higher in RA patients compared with controls (27.1 +/- 5.3 vs 19.0 +/- 4.2 mg/dl) without significant difference (p > 0.05). There was no significant correlation between ESR and Lp(a) and lipids in RA patients except for HDL cholesterol (r = -0.563, p = 0.008). After antiinflammatory agent use for 14 days, change in ESR (ESRsample1-ESRsample2) was significantly and negatively correlated to changes in total and HDL cholesterols in RA patients. In conclusion, although Lp(a) tended to be higher in RA, we could not find a distinct acute phase pattern of Lp(a). But changes in total and HDL cholesterols were negatively correlated with inflammation in RA. Our data support the phenomenon that dyslipoproteinemia observed in RA is associated with inflammation.
Neutralization of tumor necrosis factor a (TNF-alpha) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known.
We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-alpha, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically.
The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P<0.001). The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone. Radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6, P<0.001). Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response.
In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.
To compare the incidence of cardiovascular (CV) events in persons with rheumatoid arthritis (RA) with that in people from the general population, adjusting for traditional CV risk factors.
Two hundred thirty-six consecutive patients with RA were assessed for the 1-year occurrence of 1) CV-related hospitalizations, including myocardial infarction, stroke or other arterial occlusive events, or arterial revascularization procedures, or 2) CV deaths. Both outcomes were ascertained by medical records or death certificates. For comparison, we used CV events that occurred during an 8-year period among participants in an epidemiologic study of atherosclerosis and CV disease who were ages 25-65 years at study entry. We calculated the age- and sex-stratified incidence rate ratio (IRR) of CV events between the 2 cohorts and used Poisson regression to adjust for age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index.
Of the 236 RA patients, 234 were observed for 252 patient-years, during which 15 CV events occurred. Of these, 7 incident events occurred during the 204 patient-years contributed by patients ages 25-65 years, for an incidence of 3.43 per 100 patient-years. In the comparison cohort, 4,635 community-dwelling persons were followed up for 33,881 person-years, during which 200 new events occurred, for an incidence of 0.59 per 100 person-years. The age- and sex-adjusted IRR of incident CV events associated with RA was 3.96 (95% confidence interval [95% CI] 1.86-8.43). After adjusting for CV risk factors using Poisson regression, the IRR decreased slightly, to 3.17 (95% CI 1.33-6.36).
The increased incidence of CV events in RA patients is independent of traditional CV risk factors. This suggests that additional mechanisms are responsible for CV disease in RA. Physicians who provide care to individuals with RA should be aware of their increased risk of CV events and implement appropriate diagnostic and therapeutic measures.
To measure the extent of atherosclerosis in patients with rheumatoid arthritis (RA) with a disease duration of considerable length, and in age and sex matched individuals.
Thirty-nine patients with RA (30 women, 9 men) with disease onset occurring between 1974 and 1978, and less than 65 years of age at the time of investigation, were enrolled together with 39 sex and age matched controls. Quantitative measurement of intima-media thickness (IMT) and semiquantitative assessment of the presence of plaque were undertaken by B-mode ultrasound of the common carotid artery (CCA-IMT) and the common femoral artery on the right-hand side. Echo Doppler cardiography was performed with an Accuson Aspen. The results were related to disease activity variables and accumulated disease activity, to lipid levels [i.e., cholesterol, high density lipoproteins, low density lipoproteins, triglycerides (TG)], to hemostatic factors [tissue plasminogen activator antigen (tPAag), plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF)], and to soluble adhesion molecules (sICAM-1 and sE-selectin).
Patients with RA had higher maximal and mean IMT values compared with controls. The difference concerning mean CCA-IMT reached statistical significance in patients with RA and correlated significantly with lipids (cholesterol, LDL, LDL/HDL ratio, TG) and tPAag. The prevalence of plaques, as well as of aortic cusp sclerosis, was higher in RA but only the difference in aortic cusp sclerosis was statistically significant. Patients with plaques had significantly higher levels of lipids (cholesterol, LDL, LDL/HDL ratio) than patients without plaques, while patients with cusp sclerosis had significantly higher cholesterol and TG levels. sICAM-1 was significantly higher both in patients with plaques and in those with aortic cusp sclerosis compared to patients without.
Our results suggest an accelerated atherosclerosis in patients with RA that is related mainly to lipid levels.