Mary Chester Wasko

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

BACKGROUND Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Gene therapy for rheumatic diseases

Rheumatic diseases are complex and correspondingly difficult to treat. Pharmacologic control has largely rested on the appropriation of preexisting drugs, often, as with methotrexate, as a result of chance observations made while treating other diseases or, as with gold, for reasons based on erroneous, but fortuitous, assumptions about disease mechanisms. During the last 20 years, there has been a dramatic increase in understanding of the basic biology of rheumatic diseases. As a result, it is now possible to design rational new therapeutic strategies based on knowledge, rather than to continue to rely on chance and supposition. Foremost among these new approaches are overlapping efforts to manipulate immune reactivity, cytokine function, and the behavior of inflammatory cells while maintaining the integrity of the affected tissues. The traditional pharmacologic approach to achieving these aims is to design or discover small, diffusible, biomodulatory molecules which can be delivered orally or by injection. Biology provides newer, alternative approaches, including gene therapy. Biologic therapy

Inflammation-mediated rheumatic diseases and atherosclerosis

For over 20 years, premature coronary heart disease has been recognised as a major determinant of morbidity and mortality in patients with systemic lupus erythematosus (SLE).1-4 Less appreciated is the fact that the same holds true for patients with rheumatoid arthritis (RA).5-7 These two autoimmune diseases share a propensity to target women of childbearing age and a treatment armamentarium that includes corticosteroids and other immunosuppressive agents. Despite clear distinctions in pathophysiology, the immune dysfunction unique to each disease results in a chronic inflammatory state, which may have implications for the atherogenesis seen in these young patients. As we compare and contrast potential cardiovascular risk factors in these two autoimmune diseases, we may further our understanding of why these young women are at high risk for premature atherosclerosis. Women with SLE have a high incidence of coronary heart disease.1-4 Several investigators have convincingly shown that women with SLE under the age of 45 are at substantially increased risk of ischaemic heart disease.1 4 We reported that women with SLE aged 35–44 were over 50 times more likely to have a myocardial infarction than were women of similar age from a population based sample (rate ratio = 52.43, 95% CI 21.6 to 98.5).1In contrast, women with SLE in the 45–64 year age group were only two to four times more likely to have a myocardial infarction than women without SLE of the same age. We also found a small decline in the incidence rates for myocardial infarction in women with SLE aged 45–54 compared with those having the same diagnosis aged 35–44. The reasons for this are unclear. A difference in overall survival is an unlikely explanation as mortality rates from all causes were not significantly different between women in these two age strata. A plausible …

Cardiovascular disease in autoimmune rheumatic diseases

Various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis, spondyloarthritis, vasculitis and systemic lupus erythematosus, are associated with premature atherosclerosis. However, premature atherosclerosis has not been uniformly observed in systemic sclerosis. Furthermore, although experimental models of atherosclerosis support the role of antiphospholipid antibodies in atherosclerosis, there is no clear evidence of premature atherosclerosis in antiphospholipid syndrome (APA). Ischemic events in APA are more likely to be caused by pro-thrombotic state than by enhanced atherosclerosis. Cardiovascular disease (CVD) in ARDs is caused by traditional and non-traditional risk factors. Besides other factors, inflammation and immunologic abnormalities, the quantity and quality of lipoproteins, hypertension, insulin resistance/hyperglycemia, obesity and underweight, presence of platelets bearing complement protein C4d, reduced number and function of endothelial progenitor cells, apoptosis of endothelial cells, epigenetic mechanisms, renal disease, periodontal disease, depression, hyperuricemia, hypothyroidism, sleep apnea and vitamin D deficiency may contribute to the premature CVD. Although most research has focused on systemic inflammation, vascular inflammation may play a crucial role in the premature CVD in ARDs. It may be involved in the development and destabilization of both atherosclerotic lesions and of aortic aneurysms (a known complication of ARDs). Inflammation in subintimal vascular and perivascular layers appears to frequently occur in CVD, with a higher frequency in ARD than in non-ARD patients. It is possible that this inflammation is caused by infections and/or autoimmunity, which might have consequences for treatment. Importantly, drugs targeting immunologic factors participating in the subintimal inflammation (e.g., T- and B-cells) might have a protective effect on CVD. Interestingly, vasa vasorum and cardiovascular adipose tissue may play an important role in atherogenesis. Inflammation and complement depositions in the vessel wall are likely to contribute to vascular stiffness. Based on biopsy findings, also inflammation in the myocardium and small vessels may contribute to premature CVD in ARDs (cardiac ischemia and heart failure). There is an enormous need for an improved CVD prevention in ARDs. Studies examining the effect of DMARDs/biologics on vascular inflammation and CV risk are warranted.

Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients

Cardiovascular disease (CVD) is the leading cause of death in patients with rheumatoid arthritis (RA). Disease‐modifying therapies that improve risk factors for CVD, such as dyslipidemia, are desired. This study used an electronic health record to determine if hydroxychloroquine (HCQ) use was associated with an improvement in lipid levels in an inception RA cohort.

Hydroxychloroquine and glycemia in women with rheumatoid arthritis and systemic lupus erythematosus.

Objective. To determine the relationship between current hydroxychloroquine (HCQ) use and 2 indicators of glycemic control, fasting glucose and insulin sensitivity, in nondiabetic women with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). Methods. Nondiabetic women with SLE (n = 149) or RA (n = 177) recruited between 2000 and 2005 for a cross-sectional evaluation of cardiovascular risk factors were characterized by HCQ usage status. Unadjusted and multivariately adjusted mean fasting glucose, median insulin, and insulin resistance [assessed by the homeostasis model assessment (HOMA-IR) calculation] were compared among HCQ users and nonusers for disease-specific groups. Results. More women with SLE were taking HCQ than those with RA (48% vs 18%; p < 0.0001; mean dose ~ 400 mg vs ~ 200 mg). For women with SLE or RA, after adjustment for age, waist circumference, disease duration, prednisone dosage, C-reactive protein, menopausal status, nonsteroidal antiinflammatory drugs, and disease-specific indicators, serum glucose was lower in HCQ users than in nonusers (SLE: 85.9 vs 89.3 mg/dl, p = 0.04; RA: 82.5 vs 86.6 mg/dl, p = 0.05). In women with SLE, HCQ use also was associated with lower logHOMA-IR (0.97 vs 1.12, p = 0.09); in those with RA, no differences in logHOMA-IR were seen. HCQ usage was not associated with fasting insulin levels in either patient group. Conclusion. HCQ use was associated with lower fasting glucose in women with SLE or RA and also lower logHOMA-IR in the SLE group. The use of HCQ may be beneficial for reducing cardiovascular risk by improving glycemic control in these patients.

Brief Report: Citrullination Within the Atherosclerotic Plaque: A Potential Target for the Anti–Citrullinated Protein Antibody Response in Rheumatoid Arthritis

OBJECTIVE To investigate whether citrullinated proteins within the atherosclerotic plaque can be targeted by anti-citrullinated protein antibodies (ACPAs), forming stimulatory immune complexes that propagate the progression of atherosclerosis. METHODS Protein lysates prepared from atherosclerotic segments of human aorta were assessed for the presence of citrulline-modified proteins, and specifically citrullinated fibrinogen (Cit-fibrinogen), by immunoprecipitation and/or immunoblotting followed by mass spectrometry. Immunohistochemical analysis of coronary artery plaque was performed to determine the presence of citrullinated proteins and peptidylarginine deiminase type 4 (PAD-4). Serum levels of anti-cyclic citrullinated peptide (anti-CCP), anti-citrullinated vimentin (anti-Cit-vimentin), and anti-Cit-fibrinogen antibodies were measured in 134 women with seropositive rheumatoid arthritis; these subjects had previously been characterized for the presence of subclinical atherosclerosis, by electron beam computed tomography scanning. RESULTS Western blot analysis of atherosclerotic plaque lysates demonstrated several citrullinated proteins, and the presence of Cit-fibrinogen was confirmed by immunoprecipitation and mass spectrometry. Immunohistochemical analysis showed colocalization of citrullinated proteins and PAD-4 within the coronary artery plaque. In age-adjusted regression models, antibodies targeting Cit-fibrinogen and Cit-vimentin, but not CCP-2, were associated with an increased aortic plaque burden. CONCLUSION Citrullinated proteins are prevalent within atherosclerotic plaques, and certain ACPAs are associated with the atherosclerotic burden. These observations suggest that targeting of citrullinated epitopes, specifically Cit-fibrinogen, within atherosclerotic plaques could provide a mechanism for the accelerated atherosclerosis observed in patients with RA.

Physical Activity Measured by the SenseWear Armband in Women With Rheumatoid Arthritis

Background Individuals with rheumatoid arthritis (RA) often are sedentary and have an increased risk of developing comorbid conditions. Women with RA are more likely to experience challenges in maintaining an active lifestyle over their life span than men with RA or people who are healthy. As the benefits of physical activity (PA) are well known, measuring PA accurately in this population is important. Objectives The purposes of this study were: (1) to characterize PA as measured with the SenseWear Armband (SWA) in women with RA and (2) to determine the measurement time frame to obtain consistent estimates of PA and daily energy expenditure (EE) in women with RA. Design This was a cross-sectional study. Methods Participants wore the SWA for 7 days. Measurements of daily total energy expenditure (TEE), physical activity energy expenditure (PAEE) during activities at or above 1 metabolic equivalent (MET) level (PAEE≥1MET), PAEE during activities at or above 2 METs (PAEE≥2METs), PAEE during activities at or above 3 METs (PAEE≥3METs), and number of steps were obtained. Results Fifty-three women participated. Complete data were obtained for 47 participants (89%). Daily usage of the SWA was 98% of the time (23:31 hours/24 hours). Means (SD) were 2,099 (340) kcal/d for TEE, 1,050 (331) kcal/d for PAEE≥1MET, 642 (309) kcal/d for PAEE≥2METs, 239 (178) kcal/d for PAEE≥3METs, and 7,260 (2,710) for number of steps. Results of intraclass correlation coefficient analyses and multiple linear regressions indicated that 2 days were needed to reliably estimate TEE; 3 days for PAEE≥1MET, PAEE≥2METs, and number of steps; and 4 days for PAEE≥3METs. Limitations The sample was composed of well-educated women with RA who had mild to moderate difficulty performing daily activities. Conclusion The SWA may be useful to quantify PA in women with RA and to monitor effectiveness of interventions aiming to increase PA levels. Minimizing the number of days necessary for data collection will reduce the individuals burden and may improve adherence in studies of PA behaviors.

C-Reactive Protein and Coronary Artery Calcium in Asymptomatic Women With Systemic Lupus Erythematosus or Rheumatoid Arthritis

Patients with systemic lupus erythematosus (SLE) and those with rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. The aims of this study were to compare the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, those with RA, and healthy controls without diabetes mellitus or history of myocardial infarction, angina pectoris, or stroke and to investigate its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. The 2 patient groups had similar prevalence and extent of CAC as well as significantly increased odds of having any CAC (odds ratio 1.87, 95% confidence interval 1.09 to 3.21) and more extensive CAC (odds ratio 4.04, 95% confidence interval 1.42 to 11.56 for CAC score >100) compared with healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule-1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC compared with controls. In conclusion, asymptomatic and nondiabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC compared with age- and race-matched healthy controls. The increased odds for CAC may in part result from higher levels of inflammation and endothelial activation in these patients.

Diabetes mellitus and insulin resistance in patients with rheumatoid arthritis: risk reduction in a chronic inflammatory disease.

To perform a systematic literature review of the potential association among molecular markers of inflammation, alterations in body composition, and insulin resistance (IR), a precursor to type 2 diabetes mellitus (DM), in rheumatoid arthritis (RA) patients. To determine the impact of tumor necrosis factor α (TNFα) as a pivotal proinflammatory cytokine in the pathophysiology of type 2 DM and RA, and the effect of antirheumatic drugs on glycemic control.