Cardiovascular Risk in Rheumatoid Arthritis: Comparing TNF-α Blockade with Nonbiologic DMARDs

Background

Elevated tumor necrosis factor (TNF)-α likely contributes to the excess cardiovascular risk observed in rheumatoid arthritis. We compared the cardiovascular risk in rheumatoid arthritis patients starting a TNF-α blocking agent versus a nonbiologic disease-modifying antirheumatic drug (nbDMARD).

Methods

Subjects with rheumatoid arthritis participating in several different US insurance programs between 1998 and 2007 who received methotrexate were eligible. Those who added a TNF-α blocking agent were compared with subjects who added a nbDMARD in Cox regression models stratified by propensity score decile and adjusted for oral glucocorticoid dosage. We examined the composite cardiovascular end point of myocardial infarction, stroke, or coronary re-vascularization after 6 months.

Results

We compared 8656 new users of a nbDMARD with 11,587 new users of a TNF-α blocking agent with similar baseline covariates. Incidence rates per 100 person-years for the composite cardiovascular end point were 3.05 (95% confidence interval [CI], 2.54-3.65) for nbDMARDs and 2.52 (95% CI, 2.12-2.98) for TNF-α blocking agents. The hazard ratio (HR) for the TNF-α blocking agent compared with nbDMARD carrying the first exposure forward was 0.80 (95%, CI 0.62-1.04), while the HR for the as-treated analysis was 0.71 (95% CI, 0.52-0.97). The potential cardiovascular benefit of TNF-α blocking agents was strongest among individuals ≥65 years of age (HR 0.52; 95% CI, 0.34 -0.77; P for interaction = 0.075).

Conclusion

Among subjects with rheumatoid arthritis, TNF-α blocking agents may be associated with a reduced risk of cardiovascular events compared with an nbDMARD. Randomized controlled clinical trials should be considered to test this hypothesis.     

The Effect of Oral Administration of Silymarin on Serum Levels of Tumor Necrosis Factor-α and Interleukin-1ß in Patients with Rheumatoid Arthritis

Background: Rheumatoid Arthritis (RA) is a systemic chronic autoimmune disease. Several inflammatory agents play key roles in RA pathogenesis, among which tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) are of great importance. Silymarin is a potent anti-oxidant extracted from Silybummarianum L. seeds. Objective: To study the effect of silymarin on serum levels of TNF-α and IL-1β in patients with RA. Methods: Patients with stable RA received 140 mg of silymarin, 3 times a day, for 3 months. Serum samples were collected before and after the treatment. Both TNF-α and IL-1β serum levels were measured by ELISA. Results: 42 patients (14.3% male, and 85.7% female, with a mean age of 47.59±12.8 years old) completed the treatment course. There was no significant difference in the overall mean concentration of either TNF-α (p=0.14) or IL-1β (p=0.27) in all 42 patients after the treatment with silymarin. Conclusion: The addition of silymarin to the treatment regimen of patients with stable RA has no significant effect on the serum levels of TNF-α and IL-1β, however, this study needs further evaluation with a larger sample size.     

Infections in Patients With Rheumatoid Arthritis Undergoing Anti-TNFα Drug Therapy

Infections are more frequent in patients with rheumatoid arthritis (RA). The capacity of the anti-TNF drugs (infliximab, etanercept, and adalimumab) to increase the risk of infections has been a motive of discussion during the past years. Only in two of the trials that have allowed the marketing of the infliximab and adalimumab more serious infections were observed. TB was not observed in the trials. Nevertheless, later they have been published not controlled studies that show infections and TB in patients with RA that receive anti-TNFα drugs. The disagreement between the trials and the not controlled studies has been the motive of the accomplishment of metaanalysis which study the frequency of infections in patients with RA that receive anti-TNFα drugs. The three metaanalysis published show an increase of the risk of infections in patients with AR in treatment with infliximab and with adalimumab, specially when they administer high doses. This risk does not seem to increase with etanercept, probably due to the fact that doses superior to the recommended ones have not been used in the analyzed trials. Increased risk of infections was not detected in the trials, but the metaanalysis increases the statistical power and allow demonstrating increased risk of infections. A causal relation exists between the administration of anti-TNFα and the development of infections, fulfilling all the criteria of causality.     

Long-term TNF-α Blockade in Patients with Amyloid A Amyloidosis Complicating Rheumatic Diseases

Objective

To evaluate the effectiveness and safety of anti-tumor necrosis factor therapy in patients with amyloid A amyloidosis.

Methods

Multicenter, controlled, dynamic prospective cohort study of 36 patients with amyloid A amyloidosis (94% kidney involvement) treated with anti-tumor necrosis factor agents (drug exposure of 102.97 patient-years). As an external control group, 35 propensity score-matched non-amyloid patients were chosen from the Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología registry. The end points were kidney response and progression, anti-tumor necrosis factor continuation rate, patient survival, and adverse events.

Results

At the end of follow-up, a kidney response was observed in 12 of 22 patients (54.5%) and a kidney progression was observed in 6 of 36 patients (17%). The kidney amyloidosis remained stable in 16 of 36 patients (44%). The level of acute phase reactants diminished but did not reach the normal level. The continuation rates of anti-tumor necrosis factor drugs among patients with amyloid A amyloidosis after 1, 2, 3, and 4 or more years were 80%, 80%, 61%, and 52%, respectively, comparable to controls. The 5-year cumulative survival of amyloid A amyloidosis cases was 90.6%, and the 10-year survival was 78.5%. In a multivariate Cox regression analysis, the duration of amyloidosis and the level of proteinuria at the onset of anti-tumor necrosis factor treatment were independent predictors of treatment failure, whereas the level of proteinuria was the only factor that predicts mortality. Most adverse events were similar in both groups, although the number of infections was 3 times higher in amyloid A amyloidosis cases.

Conclusion

Anti-tumor necrosis factor drugs are effective in treating amyloid A amyloidosis, although they might increase the risk of infection.     

All-cause Mortality Associated with TNF-α Inhibitors in Rheumatoid Arthritis: A Meta-Analysis of Randomized Controlled Trials

Objective

To compare mortality data obtained from randomized controlled trials for the 5 tumor necrosis factor-α (TNF-α) inhibitors used in the treatment of rheumatoid arthritis.

Methods

A systematic review of articles published up to November 2014 was performed using electronic databases. We included randomized, controlled trials, with a follow-up period of at least 24 weeks, comparing TNF-α inhibitors to placebo or disease-modifying antirheumatic drugs. The primary outcome was the occurrence of all-cause mortality.

Results

Twenty-three studies were selected. These articles included 6525 patients in the anti-TNF-α group and 3523 in the control group. The duration of patient follow-up ranged from 24 to 104 weeks. The risk of all-cause mortality in patients receiving TNF-α inhibitors was not significantly different from those receiving the comparator (odds ratio 1.32; 95% confidence interval, 0.76-2.29). Subgroup analyses with respect to the molecule used, the dose received, the use of TNF-α inhibitors as monotherapy or combination therapy, or the quality of the trial did not modify the findings.

Conclusion

This meta-analysis performed on a large number of patients and including the 5 TNF-α inhibitors currently available shows no increased risk of medium-term all-cause mortality in patients with rheumatoid arthritis.     

Serum Levels of TNF-α, TNF-αRI,TNF-αRII and IL-12 in Treated Rheumatoid Arthritis Patients

Background: Rheumatoid arthritis (RA) is a chronic multisystem autoimmune disease common in all races and ethnics. Cytokines and cytokines receptors play an important role in RA pathogenesis and clinical presentation. Objective: To investigate the serum levels of TNF-α, TNF-α RI, TNF-α RII and IL-12 in RA patients and healthy control group. Methods: In this study 43 patients fulfilling the revised criteria of American College of Rheumatology (ACR) for RA and 13 healthy cases as a control group were selected for TNF-α, TNF-αRI, TNF-αRII and IL-12 serum level analysis. The patients' age was 42.2 ± 22 and the age of healthy group was 40.1 ± 19.2 years (p=0.1). The pa-tients had an active disease with at least six swollen and ten tender joints. Minimum ESR was 28 mm at first hours of the morning. Early morning stiffness in patients lasted longer than 45 minutes. Results: Our study showed that IL-12 serum level of the pa-tients (91.69 ± 43.07 ρg/ml) and control (61.79 ± 40.08 ρg/ml) group was significantly different (p<0.001). The serum level of TNF-αRI was 2.36 ± 0.77 ng/ml in the patient and 1.73 ± 0.37 ng/ml in the control group (p<0.01). TNF-αRII serum concentration in patients was 8.89 ± 2.3 ng/ml, while that of control group was 7.06±1.30 ng/ml (p=0.03). The serum level of TNF-α in patients was 32.90 ± 19.27 ρg/ml and that of the control group was 24.27± 8.28 ρg/ml (p=0.08) with no significant difference between the two. Conclusions: It is concluded that IL-12, TNF-αRI and TNF- αRII serum con-centrations are more important and better predictive factors than TNF-α in RA course and in the active forms of the disease.     

Why do Patients with Rheumatoid Arthritis use Alternative Treatments?

The aim of this study was to analyse the characteristics of patients with rheumatoid arthritis (RA) who make use of alternative or complementary medicine (CM). Two hundred and sixty-two randomly chosen patients with RA filled out self-assessment health status and pain questionnaires. Differences between the group of patients making use of both CM and conventional treatment (n = 52) and the group of patients who relied only on conventional treatment prescribed by their rheumatologists (n = 210) were explored with respect to demographic characteristics, duration of RA, levels of physical, psychological and social functioning, and pain-coping behaviour. We found that female patients used CM more often than did male patients, and those who used CM were younger than those who did not. There were no differences with respect to duration of RA, physical, psychological or social functioning or pain coping; however, the perceived impact of RA on several domains of life was higher in patients who used CM than in those who did not. Nevertheless, the patient groups did not differ in terms of medical consumption, except that those who used CM visited medical specialists for RA-related complaints less than those who relied only on conventional treatments. We concluded that the higher impact of RA, in the absence of worse disease, perceived by users of CM in several domains of life, especially psychosocial functioning, could be the reason they use CM. This suggests that CM cannot be substituted by additional conventional treatment prescribed by the rheumatologist, but rather by psychosocial intervention. Received: 10 June 2000 / Accepted: 25 October 2000     

Distribution of Double-Negative (CD4−CD8−, DN) T Subsets in Blood and Synovial Fluid from Patients with Rheumatoid Arthritis

Double-negative (CD4⁻CD8⁻) T (DNT) cells have been postulated to be potentially autoreactive. However, the role of DNT cells in rheumatoid arthritis (RA) has received limited attention. We investigated the distribution of DNT subsets in peripheral blood (PB) and synovial fluid (SF) from patients with active RA to determine whether these cells have relevance to RA. Two-colour flow cytometric analysis was performed to detect DNT cells in PB from 35 RA patients, 26 healthy controls and in SF aspirated from 19 inflamed rheumatoid joints. The subsets of DNT cells, i.e those expressing T cell receptor αβ (αβDNT) or γδ (γδDNT) were simultaneously examined. Our results showed that DNT cells constituted a very minor subset of PB lymphocytes. When expressed as a percentage of total lymphocytes, αβDNT levels in normal individuals ranged from 0.27 to 2.08% ( average 0.76%), while those of γδDNT ranged from 1.02 to 11.42% (average 3.23%). Compared with normal individuals, RA patients had a similar distribution of αβDNT cells in both PB and SF. However, RA patients had significantly lower levels of γδDNT cells in PB than control subjects (1.38 ± 1.08% vs 3.23 ± 2.12%, p<0.05), while the levels of γδDNT cells in SF of RA patients were higher than those in PB from RA patients and normal controls. The difference between PB and SF in RA was statistically significant (3.90 ± 1.88% vs 1.38 ± 1.08%, p;<0.05). A higher level of γδDNT in SF than their paired PB was consistently noted from nine available paired samples. Our findings suggest that γδDNT cells, but not αβDNT cells, are probably relevant to RA. The lower percentage of circulating γδDNT cells might have resulted from migration from the circulation into the synovium, suggesting a role for γδDNT cells in the pathogenesis of rheumatoid synovitis. Received: 30 June 1998 / Accepted: 4 January 1999     

Effect of Yinxieling decoction on PASI,TNF-α and IL-8 in patients with psoriasis vulgaris

Objective:To study the effect of Yinxieling decoction on PASI,TNF-α and IL-8 in patients with psoriasis vulgaris.Methods:A total of 120 cases of psoriasis vulgaris were divided into 4 groups according to syndrome differentiation of TCM and randomized controlled method:wind heat syndrome group(group A).blood stasis syndrome group(group B) blood dryness syndrome group(group C)nd control group(group D)(n=30 per group).Patients in observation groups were treated with Yinxieling decoction,while patients in control group were treated by placebo for 8 weeks.Levels of TNT-α and IL-8 were determined before treatment.4 and 8 weeks after treatment.psoriasis area and severity index score was also performed before and after treatment.Results:psoriasis area and severity index score and serum level of TNF-α,IL-8 were significantly decreased in all groups.The decrease in three observation groups was more significant(P0.05 or P0.01),and the decrease in wind heat syndrome group was the most significant(P0.01).psoriasis area and severity index was positively correlated with TNF-α and IT.-8,respectively(P0.05).Conclusions:Yinxieling decoction has therapeutical effect on psoriasis vulgaris via regulating TNF-α and IL-8.     

Effect of TNF-α inhibition on urinary albumin excretion in experimental diabetic rats

The objective is to assess the effect of TNF-α inhibition on urinary albumin excretion in experimental diabetic rats. Male Wistar rats, 8-week-old, were categorized into four groups, which were the control (n = 9), diabetes (n = 9), infliximab-treated diabetes (n = 10), and FR167653-treated diabetes (n = 9) groups. Diabetes was induced by intraperitoneal injection of STZ (40 mg/kg). Thereafter, infliximab was injected intraperitoneally once a month (5.5 mg/kg) and FR167653 was administered orally by mixing with the rat chow (0.08%). The effects of infliximab and FR167653 on urinary albumin excretion were observed for 12 weeks. Body weight, blood sugar, 24-h urinary TNF-α, and 24-h urinary albumin/creatinine ratio (Ualb/Ucr) levels were determined at 1, 4, 8, and 12 weeks after the STZ-injection. Treatment of rats with STZ caused a significant loss of body weight, as well as polyuria and hyperglycemia within 1 week, while the urinary excretions of albumin and TNF-α were increased. Neither infliximab nor FR167653 affected body weight or blood sugar levels, whereas both decreased urinary albumin excretion, together with a modest decrease in the urinary excretion of TNF-α. These results suggest a role of TNF-α in the pathogenesis of diabetic nephropathy and show that TNF-α inhibition is a potential therapeutic strategy.     

High Ascitic Fluid Leptin Levels in Patients with Decompensated Liver Cirrhosis and Sterile Ascites: Relationship with TNF-α Levels

Leptin is an adipocyte-derived hormone involved in the homeostasis of body composition. An imbalance in leptin regulation has been observed in patients with liver cirrhosis. We aimed to assess serum and ascitic leptin levels in a group of patients with decompensated liver cirrhosis and to evaluate the relationship of these levels with tumor necrosis factor alpha (TNF-alpha). We assessed both serum and ascitic fluid leptin levels in a series of 16 consecutive patients with liver cirrhosis. We calculated the body mass index (BMI) and assessed body fat (BF) of all patients by means of bioelectric impedence analysis. Leptin levels were analyzed in relationship to biochemical indexes, TNF-alpha levels, and body composition. None of the patients had spontaneous bacterial peritonitis. Both serum and ascites leptin levels were correlated with BMI and BF. On average, ascitic fluid leptin levels (13.1 +/- 10.9 ng/ml) were twice as high as serum levels (7.0 +/- 6.4 ng/ml), and the ascitic fluid/serum ratio of leptin was > 1 in all patients. Serum and ascites leptin levels were positively correlated (rS = 0.675, P = 0.009), while no correlation was observed between leptin and TNF-alpha levels, both in serum and in ascites. Serum and ascites TNF-alpha were not correlated. The ascitic fluid leptin levels of cirrhotic patients with sterile ascites are on average two times higher than circulating levels of this hormone. Noteworthily, they correlate significantly with body composition. These findings seem to suggest that in patients with decompensated liver cirrhosis, intraabdominal production of leptin may contribute to the metabolic picture.     

Effect of herbs-partition moxibustion on IL-1β and TNF-α in UC rats

AIM To observe the effect of herbs-partition moxibustion on IL-1β and TNF-c in UC rats.METHODS The animal models were created by immunological method. They were divided into 5 groups atrandom, after treated by different methods, IL-1β and TNF-α in colon tissue of UC rats were detected withimmunologic technique.RESULTS In control group, there was a little or no IL-1β positive cell in colon mucosa. Compared withthat in rats of control group, the number of IL-1 positive cell in model group was much larger, and IL-1βcells with brown granules were mainly expressed in cytoplasm of macrophage in lamina propria of colon.Compared with model group, IL-1β positive cells in mild moxibustion group markedly decreased (P < 0.05),and those in electro-acupuncture group and herbs-partition moxibustion group decreased even more markedly(P < 0.01). The difference between the last two groups is evident (P < 0.05). TNF-α positive cells are not or seldomly found in UC rats, but in model group, these cells increasedevidently, which were mainly the macrophages in lamina propria of colon. Compared with those in modelgroup, the positive cells decreased markedly in electro-acupuncture group (P<0.05), and decreased moremarkedly in mild moxibustion group and in herbs-partition moxibustion group (P<0.01). There werestatistically significant differences between herbs-partition moxibustion group and electro-acupuncture group(P<0.05).CONCLUSION The mechanism of acupuncture and moxibustion may be that inhibited macrophageactivation, reduced expression of IL-1β and TNF-a and thereby blocking their further activation and thencontrolled, the initiated inflammation and its immunity cascade reaction and resulted in restoring the normalimmunity function and benefited in healing of ulcer.     

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system

There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.     

Prognostic Factors for Sustained Remission in a “Real Life” Cohort of Rheumatoid Arthritis Patients

IntroductionRheumatoid arthritis (RA) is the most frequent chronic polyarthritis. The current goal of RA treatment is to achieve clinical remission.ObjectiveThe goal of this study was to determine the prevalence of remission in a cohort of patients from clinical practice, and to identify potentially modifiable factors associated with remission.MethodsA retrospective study was performed on a cohort of RA patients seen at the first consultation at the HUGC Rheumatology Service Dr. Negrín (HUGCDN) between first of January 2000 and thirtieth of April 2014. Sustained remission was defined as DAS28 less than 2.6 in the last two available visits in the medical history.ResultsA total of 463 patients were consecutively included, most (75%) women, with a mean age at the onset of RA of 50 years and a mean duration of the disease at follow-up of 8 years. 46% of the patients achieved sustained remission. Multiple logistic regression analyses found male sex (P = .031, OR 1.7, 95% CI 1.05–2.82), diagnosis in the first year of symptoms (P = .023, OR 1.7, 95% CI 1.07–2.69) and the initial DAS28 (P = .035) to be independent predictors for sustained remission.ConclusionsThe 46% of the patients with RA followed in the HUGC Dr. Negrín are in persistent remission, being the early diagnosis a modifiable factor predictor of remission. Thus, an objective of the Rheumatology Service should be to improve the diagnostic delay of RA in the health area.