Rheumatoid Arthritis: Belch JJ

Belch JJ, Hill A. · Department of Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom. · Am J Clin Nutr. · Pubmed #10617996 links to  free full text

Abstract: Diets rich in arachidonic acid (20:4n-6) lead to the formation of 2-series prostaglandins (PGs) and 4-series leukotrienes (LTs), with proinflammatory effects. Nonsteroidal antiinflammatory drugs are used in rheumatoid arthritis to inhibit cyclooxygenase (prostaglandin-endoperoxide synthase), thereby decreasing production of 2-series PGs. Lipoxygenase activity remains intact, however, allowing LT production (eg, synthesis of LTB(4), a potent inflammatory mediator) to continue. Altering the essential fatty acid (EFA) content of the diet can modify some of these effects. Ingestion of a diet rich in evening primrose oil elevates concentrations of dihomo-gamma-linolenic acid (DGLA; 20:3n-6), which results in the production of 1-series PGs, eg, PGE(1). DGLA itself cannot be converted to LTs but can form a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to LTs. Increasing DGLA intake may allow DGLA to act as a competitive inhibitor of 2-series PGs and 4-series LTs and thus suppress inflammation. The results of in vitro and animal work evaluating EFAs in inflammatory situations are encouraging, which has stimulated clinical workers to evaluate these compounds in rheumatoid arthritis. Several well-controlled, randomized clinical studies have now been completed in which various EFAs were evaluated as treatments. The results of most of these studies suggest some clinical benefit to these treatments; these data are reviewed here.

Galarraga B, Khan F, Kumar P, Pullar T, Belch JJ. · Institute of Cardiovascular Research, Vascular and Inflammatory Diseases Research Unit, University Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. · Rheumatology (Oxford). · Pubmed #18854346 No free full text.

Abstract: OBJECTIVE: RA is a chronic autoimmune inflammatory condition associated with increased cardiovascular morbidity and mortality. Endothelial dysfunction, a marker of early atherosclerotic disease, occurs in some inflammatory diseases but this relationship has not been previously explored within the microvasculature of patients with RA. We therefore assessed forearm microvascular endothelial function in patients with RA and determined its relationship to RA disease activity and inflammation. METHODS: A total of 128 RA patients with no previous history of cardiovascular disease were evaluated. Endothelium-dependent and -independent forearm skin microvascular function was measured using laser Doppler imaging after iontophoretic delivery of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. Parameters of RA disease activity and inflammation were also checked. RESULTS: There was a significant negative correlation between the level of inflammation measured by log(10)CRP and maximum vasodilatation measured by peak ACh response (r(2) = -0.209, P = 0.018, Pearson correlation test). In a multiple regression model, age (beta = -0.449, P < 0.0001) and log(10)CRP (beta = -0.193, P = 0.026) were independently negatively associated with ACh responses. When RA patients were sub-divided according to their systemic inflammatory status (CRP > 10 mg/l vs CRP </= 10 mg/l), the high CRP group showed lower vasodilator responses to ACh [P = 0.018, analysis of variance (ANOVA)] and SNP (P = 0.05, ANOVA) than the low CRP group. CONCLUSIONS: In this large cross-sectional study, we found for the first time systemic inflammation (CRP) to be independently associated with microvascular dysfunction in patients with RA. This strong correlation was independent of other conventional vascular risk factors.

Galarraga B, Ho M, Youssef HM, Hill A, McMahon H, Hall C, Ogston S, Nuki G, Belch JJ. · Vascular and Inflammatory Diseases Research Unit, University Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. · Rheumatology (Oxford). · Pubmed #18362100 links to  free full text

Abstract: OBJECTIVES: Dose-dependant gastrointestinal and cardiovascular side-effects limit the use of NSAIDs in the management of RA. The n-3 essential fatty acids (EFAs) have previously demonstrated some anti-inflammatory and NSAID-sparing properties. The objective of this study was to determine whether cod liver oil supplementation helps reduce daily NSAID requirement of patients with RA. METHODS: Dual-centre, double-blind placebo-controlled randomized study of 9 months' duration. Ninety-seven patients with RA were randomized to take either 10 g of cod liver oil containing 2.2 g of n-3 EFAs or air-filled identical placebo capsules. Documentation of NSAID daily requirement, clinical and laboratory parameters of RA disease activity and safety checks were done at 0, 4, 12, 24 and 36 weeks. At 12 weeks, patients were instructed to gradually reduce, and if possible, stop their NSAID intake. Relative reduction of daily NSAID requirement by >30% after 9 months was the primary outcome measure. RESULTS: Fifty-eight patients (60%) completed the study. Out of 49 patients 19 (39%) in the cod liver oil group and out of 48 patients 5 (10%) in the placebo group were able to reduce their daily NSAID requirement by >30% (P = 0.002, chi-squared test). No differences between the groups were observed in the clinical parameters of RA disease activity or in the side-effects observed. CONCLUSIONS: This study suggests that cod liver oil supplements containing n-3 fatty acids can be used as NSAID-sparing agents in RA patients.

McLaren M, Waring A, Galarraga B, Rudd A, Morley K, Belch JJ. · Vascular Diseases Research Unit, The Institute of Cardiovascular Research, Department of Medicine, Ninewells Hospital and Medical School, Dundee, Scotland, UK. · Scand J Rheumatol. · Pubmed #16393764 No free full text.

Abstract: OBJECTIVES: Previous work has shown that the human platelet antigen (HPA) 1b polymorphism of platelet glycoprotein IIIa (GPIIIa) is implicated in the development of ischaemic vascular disease. HPA1b positive platelets have a lower threshold for activation and may exert a greater thrombotic tendency than those without the 1b allele. However, platelets heterozygous for the polymorphism are also more sensitive to aspirin than those homozygous for the 1b allele, which have a similar sensitivity to those without the 1b allele. A flow cytometric method has become available to identify this polymorphism. The aim of our study was to evaluate the use of this assay in patients with rheumatoid arthritis (RA) and to determine the incidence of the 1b allele in these patients. We also compared platelet aggregation and platelet/white blood cell interaction in patients with or without this polymorphism. METHODS: We enrolled 99 patients and measured platelet aggregation in whole blood and platelet-rich plasma (prp), platelet/white blood cell interaction and C-reactive protein (CRP). RESULTS: Thirty-four of the 99 patients were unsuitable for analysis because their baseline expression of GPIIIa was outwith the normal range, making the results outwith the limits of the flow cytometric method. The incidence of the 1b allele in the patients was 29%, with incidence being higher in females, although this failed to reach statistical significance. The number of circulating platelet aggregates and adenosine diphosphate (ADP)-induced aggregation in prp was significantly higher in those patients with the 1b allele. CONCLUSIONS: This method may be of use as an initial screening test.

Alkaabi JK, Ho M, Levison R, Pullar T, Belch JJ. · University Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. · Rheumatology (Oxford). · Pubmed #12595625 links to  free full text

Abstract: OBJECTIVE: To measure the extent of subclinical atherosclerosis in patients with rheumatoid arthritis (RA) compared with controls, and to evaluate any potential vascular risk factors. METHODS: Forty RA patients were compared with an age- and sex-matched control group. Non-invasive vascular tests, i.e. carotid duplex scanning [measuring common carotid artery intima-media thickness (IMT)], ankle-brachial blood pressure index (ABPI) and QT dispersion on ECG (QTD), were performed. Traditional risk factors such as high blood pressure, blood sugar, lipids and steroid usage were assessed. RESULTS: The average IMT (S.E.) in RA patients was 0.73 (0.03) mm, compared with 0.62 (0.03) mm in the control group (P=0.01, Mann-Whitney). Ten out of 40 RA patients (25%) had an ABPI < 1.0 compared with 1/40 (2.5%) in the control group (P=0.007, Fisher's). QTD was higher in RA patients; mean (S.E.) 55 (2.70) ms compared with 40 (2.50) ms in the control group (P < 0.001, t-test). There were no significant differences in the prevalence of high blood pressure, diabetes or lipid profiles. However, patients on steroids had a higher mean QTD (S.E.): 63.5 (4) compared with 48 (2.7) ms in those patients who had not received long-term steroids (P=0.003, t-test). CONCLUSION: RA patients have an increased risk of subclinical vascular disease as was shown by a higher prevalence of carotid disease, peripheral arterial disease and increased QTD. Among traditional risk factors we found a history of steroid usage to be one of the potential risk factors.

McLaren M, Alkaabi J, Connacher M, Belch JJ, Valenete E. · Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. · Rheumatol Int. · Pubmed #12215862 No free full text.

Abstract: Rheumatoid arthritis (RA) is associated with premature mortality, with approximately 50% of deaths being due to cardiovascular disease. It has been shown that the increased incidence of cardiovascular disease is independent of traditional risk factors. Previous studies have shown an increased risk of coronary heart disease with increased levels of activated factor XII (FXIIa). The aim of this study was to investigate levels of FXIIa in patients with RA. We studied 32 patients with RA and 30 age- and sex-matched control subjects. We found FXIIa levels significantly increased in the patient group, with 56% of the patients and 6.7% of controls having levels greater than or equal to 2 ng/ml. A previous study has shown that individuals with levels of 2 ng/ml or more have an increased risk of coronary heart disease. Measurement of FXIIa could perhaps help to identify an 'at risk' group of patients, allowing early intervention therapy.