Hennie G. Raterman

Endothelial Dysfunction, Inflammation, and Apoptosis in Diabetes Mellitus

Endothelial dysfunction is regarded as an important factor in the pathogenesis of vascular disease in obesity-related type 2 diabetes. The imbalance in repair and injury (hyperglycemia, hypertension, dyslipidemia) results in microvascular changes, including apoptosis of microvascular cells, ultimately leading to diabetes related complications. This review summarizes the mechanisms by which the interplay between endothelial dysfunction, inflammation, and apoptosis may cause (micro)vascular damage in patients with diabetes mellitus.

(Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis

IntroductionBoth cardiovascular disease and osteoporosis are important causes of morbidity and mortality in the elderly. The co-occurrence of cardiovascular disease and osteoporosis prompted us to review the evidence of an association between cardiovascular (CV) disease and osteoporosis and potential shared common pathophysiological mechanisms.MethodsA systematic literature search (Medline, Pubmed and Embase) was conducted to identify all clinical studies that investigated the association between cardiovascular disease and osteoporosis. Relevant studies were screened for quality according to guidelines as proposed by the Dutch Cochrane Centre and evidence was summarized.ResultsSeventy studies were included in this review. Due to a large heterogeneity in study population, design and outcome measures a formal meta-analysis was not possible. Six of the highest ranked studies (mean n = 2,000) showed that individuals with prevalent subclinical CV disease had higher risk for increased bone loss and fractures during follow-up compared to persons without CV disease (range of reported risk: hazard ratio (HR) 1.5; odds ratio (OR) 2.3 to 3.0). The largest study (n = 31,936) reported a more than four times higher risk in women and more than six times higher risk in men. There is moderate evidence that individuals with low bone mass had higher CV mortality rates and incident CV events than subjects with normal bone mass (risk rates 1.2 to 1.4). Although the shared common pathophysiological mechanisms are not fully elucidated, the most important factors that might explain this association appear to be, besides age, estrogen deficiency and inflammation.ConclusionsThe current evidence indicates that individuals with prevalent subclinical CV disease are at increased risk for bone loss and subsequent fractures. Presently no firm conclusions can be drawn as to what extent low bone mineral density might be associated with increased cardiovascular risk.

A non-inferiority trial of an attenuated combination strategy (‘COBRA-light’) compared to the original COBRA strategy: clinical results after 26 weeks

Background Early, intensive treatment of rheumatoid arthritis (RA) with the combination of (initially high dose) prednisolone, methotrexate and sulfasalazine (COBRA therapy) considerably lowers disease activity and suppresses radiological progression, but is infrequently prescribed in daily practice. Attenuating the COBRA regimen might lessen concerns about side effects, but the efficacy of such strategies is unknown. Objective To compare the ‘COBRA-light’ strategy with only two drugs, comprising a lower dose of prednisolone (starting at 30 mg/day, tapered to 7.5 mg/day in 9 weeks) and methotrexate (escalated to 25 mg/week in 9 weeks) to COBRA therapy (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks, methotrexate 7.5 mg/week and sulfasalazine 2 g/day). Method An open, randomised controlled, non-inferiority trial in 164 patients with early active RA, all treated according to a treat to target strategy. Results At baseline patients had moderately active disease: mean (SD) 44-joint disease activity score (DAS44) 4.13 (0.81) for COBRA and 3.95 (0.9) for COBRA-light. After 6 months, DAS44 significantly decreased in both groups (–2.50 (1.21) for COBRA and –2.18 (1.10) for COBRA-light). The adjusted difference in DAS44 improvement between the groups, 0.21 (95% CI –0.11 to 0.53), was smaller than the predefined clinically relevant difference of 0.5. Minimal disease activity (DAS44 <1.6) was reached in almost half of patients in both groups (49% and 41% in COBRA and COBRA-light, respectively). Conclusions At 6 months COBRA-light therapy is most likely non-inferior to COBRA therapy. Clinical Trial Registration Number 55552928.

HDL protein composition alters from proatherogenic into less atherogenic and proinflammatory in rheumatoid arthritis patients responding to rituximab.

Objective An atherogenic lipid profile is an established risk factor for cardiovascular (CV) diseases. Interestingly, high inflammatory states as present in rheumatoid arthritis (RA) are associated with unfavourable lipid profile. Data about effects of novel immunomodulating agents as rituximab (RTX) on lipid profile are limited. Therefore, changes in lipids in RTX treated RA patients were evaluated. Methods In 49 consecutive RTX treated RA patients, serum and EDTA plasma samples were collected at baseline, 1, 3 and 6 months. In these samples, lipid and levels were assessed to determine changes in time. Surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) MS analysis was performed in six good and six non-responding RA patients to study functional high density lipoprotein (HDL) protein composition changes in time. Results In the total group (n=49), the atherogenic index decreased from 4.3 to 3.9 (∼9%) after 6 months. Testing for effect modification revealed a difference in the effect on lipid levels between responders and non-responders upon RTX (p<0.001). ApoB to ApoA-I ratios decreased significantly (∼9%) in good responding (n=32) patients. SELDI-TOF MS analysis revealed a significant decrease in density of mass charge (m/z) marker 11743, representing a decrease in serum amyloid A, in good responding patients. Conclusion This study indicates beneficial effects on cholesterol profile upon RTX treatment along with improvement of disease activity. Proteomic analysis of the HDL particle reveals composition changes from proatherogenic to a less proatherogenic composition during 6 months RTX treatment. Whether these HDL particle alterations during immunotherapies result in a lower CV event rate remains to be established.

Rheumatoid arthritis is associated with a high prevalence of hypothyroidism that amplifies its cardiovascular risk

Objective: Rheumatoid arthritis (RA) patients have an increased risk of developing cardiovascular diseases (CVD). Other autoimmune diseases such as hypothyroidism are also associated with an enhanced risk for CVD. Our objective was to determine first, the prevalence of hypothyroid disorders in RA patients, and second, the risk of CVD in RA patients with hypothyroid abnormalities. Methods: Subjects were RA patients who participated in an ongoing prospective cohort study of cardiovascular mortality and morbidity (n = 358) in which hypothyroid abnormalities were assessed. CVD was defined as a verified medical history of coronary, cerebral or peripheral arterial disease. Results: Clinical hypothyroidism was observed in 16 of 236 female RA patients (6.8%), which is significantly higher than in the general population of The Netherlands. Subclinical hypothyroidism was detected in 6 out of 236 RA women (2.5%). In female RA patients, CVD was present in 6 out of 16 (37.5%) of all hypothyroid women. The odds ratio for CVD comparing female hypothyroid RA patients with female euthyroid RA patients was 4.1 (95% CI 1.2–14.3) after adjustment for sex, age, diabetes, smoking (ever), hypertension and statin use. Conclusions: Clinical hypothyroidism was observed three times more often in female RA patients than females in the general population. In female RA patients, clinical hypothyroidism was associated with a fourfold higher risk of CVD in comparison with euthyroid female RA patients independently of the traditional risk factors.

Pharmacological induction of interferon type I activity following treatment with rituximab determines clinical response in rheumatoid arthritis

Objective Despite the fact that rituximab depletes B cells in all treated patients with RA, not all patients show a favourable clinical response. The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab. Methods Gene expression profiling was performed on peripheral blood RNA of 13 patients with RA (test group) using Illumina HumanHT beadchip microarrays. An independent group of nine patients was used for validation using TaqMan quantitative PCR. Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score (ΔDAS28) and European League Against Rheumatism (EULAR) response criteria. Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation. Results Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab. Interestingly, only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the ΔDAS28 response. Good responders (∆DAS>1.2; n=7) exhibited a selective increase in the expression of type I IFN-response genes, whereas this activity was unchanged or hardly changed in non-responders (∆DAS<1.2; n=6) (p=0.0040 at a cut-off of 1.1-fold induction). Similar results were obtained using EULAR response criteria. These results were validated in an independent cohort of nine patients (five non-responders and four responders, p=0.0317). Conclusions A good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in patients with RA. This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab.

The metabolic syndrome is amplified in hypothyroid rheumatoid arthritis patients: a cross sectional study

Objectives: Rheumatoid arthritis (RA) patients are at increased risk of cardiovascular disease (CVD), which is even more pronounced in hypothyroid RA patients. An unfavourable cardiovascular risk profile conferred by a higher prevalence of the metabolic syndrome (MetS) and a higher Framingham risk score might explain this amplified cardiovascular morbidity. This study compared first, MetS (features) and second, the Framingham 10-year CVD risk in RA patients with hypothyroidism compared with euthyroid RA patients. Methods: RA patients participating in the CARRÉ investigation were divided into two groups: hypothyroid and euthyroid RA patients. MetS according to the National Cholesterol Education Program Third Adult Treatment Panel criteria and the Framingham risk score was compared between hypothyroid and non-hypothyroid CVD event-free RA patients. Results: In total, 257 RA patients were included: 236 with RA (91.8%) and 21 with hypothyroid RA (8.2%), respectively. The prevalence of the MetS was significantly higher in hypothyroid RA patients (43%) compared with RA patients (20%). Moreover, female hypothyroid RA patients had a higher Framingham risk score compared with euthyroid RA patients. With RA patients as the reference category, the age and gender-adjusted prevalence odds ratio for the MetS was 3.5 (95% CI 1.3 to 9.1) in hypothyroid RA. Conclusions: Hypothyroid RA patients, particularly female patients, have a more unfavourable cardiovascular risk profile, reflected by an increased prevalence of the MetS and higher Framingham score, than euthyroid RA patients, suggesting a greater need for cardiovascular risk management in these patients to prevent future CVD events.

Improvement of Thyroid Function in Hypothyroid Patients with Rheumatoid Arthritis After 6 Months of Adalimumab Treatment: A Pilot Study

Objective. Rheumatoid arthritis (RA) is characterized by high levels of cytokines such as tumor necrosis factor (TNF). TNF appears to have an etiologic role in thyroid dysfunction, and thyroid dysfunction is a common comorbidity in RA. Anti-TNF treatment might limit thyroid dysfunction. Thus, changes in thyroid hormones were studied during TNF-blocking therapy in patients with RA. Methods. At baseline and after 6 months’ treatment with adalimumab, thyroid function [thyroid-stimulating hormone (TSH), free thyroxine (fT4), and antibodies against thyroid peroxidase (TPOabs)] were assessed in 138 consecutive adalimumab-treated patients with RA who were naive for TNF-blocking agents. Patients were categorized as hypothyroid, hyperthyroid, or euthyroid. In these groups, changes in thyroid function were determined. Results. Prevalences of hypothyroidism, hyperthyroidism, and TPOabs were 13%, 5%, and 15%, respectively. After 6 months, TPOabs decreased from 267 to 201 IU/ml (p = 0.048). In hypothyroid patients without concomitant L-thyroxine, a trend for declining levels of TSH was observed. Subgroup analysis revealed that in patients who were hypothyroid and TPOabs-positive and L-thyroxine-naive, TSH levels decreased significantly, from 12.5 (interquartile range 6.7–18.4) to 7.1 (interquartile range 4.9–13.8) mU/l (p = 0.043). Conclusion. Anti-TNF treatment improves thyroid function in hypothyroid patients with RA (especially in those who are L-thyroxine-naive and TPOabs-positive), providing further evidence that inflammatory cytokines such as TNF have a pathogenic role in thyroid dysfunction.

Improvement of Work Ability, Quality of Life, and Fatigue in Patients With Rheumatoid Arthritis Treated With Adalimumab

Objective: To assess the effect of 12-month treatment with adalimumab on work ability, quality of life, and fatigue in patients with active rheumatoid arthritis (RA). Methods: One hundred twenty-six patients with active RA started treatment with adalimumab. Primary outcome measurements were work ability, assessed by the first item of the Work Ability Index, quality of life, assessed by the Rheumatoid Arthritis Quality of Life (RAQoL) instrument, and fatigue, assessed by the Checklist Individual Strength and the Need for Recovery after work Scale. Results: All primary outcome measurements showed a significant improvement. The largest improvement for all outcome measurements was gained in the first 6 months of treatment and was sustained over the following 6 months. Conclusion: Adalimumab improves patient reported outcomes in addition to improving disease activity in established RA.

Increased cardiovascular disease in patients with inflammatory arthritis in primary care: a cross-sectional observation.

Objective. To compare the prevalence of cardiovascular disease (CVD) in patients with inflammatory arthritis and control subjects registered in primary care. Methods. Conditional logistic regression analyses were used to compare the CVD prevalence in patients and controls, aged 50–75 years. Results. Overall, the CVD prevalence was 66.1 per 1000 patients in inflammatory arthritis and 37.3 per 1000 patients in controls, resulting in an odds ratio of 1.83 (95% confidence interval 1.33–2.51). Conclusion. Inflammatory arthritis patients registered in primary care are associated with an increased cardiovascular burden, which emphasizes the need for cardiovascular risk management in the primary care setting.