The efficacy and safety of rituximab in a chart review study of 15 patients with systemic lupus erythematosus.

In contrast to randomised clinical trials, open-label studies have suggested that B cell depletion by a course of rituximab is associated with a significant clinical benefit. Our aim was to assess the safety and efficacy of rituximab in 15 refractory lupus patients, particularly those with more than one course of therapy. Disease activity was measured by the classic British Isles Lupus Assessment Group (BILAG) index, anti-DNA antibodies and complement levels. We assessed immunoglobulin levels, functional antibodies and serious adverse events. The mean patient age ± SD was 37.9 ± 7.2 years and mean disease duration was 8.5 ± 3.3 years; 46% were Afro-Caribbean, 27% South Asian, 20% Caucasian and 7% others. Twelve patients responded by 6 months; six avoided major flare for >1 year. Complete absence of disease activity (BILAG D/E) lasted for 5.5 (SD 3.8) months and 4.8 (SD 3.6) months after the first (n = 15) and second (n = 9) rituximab course, respectively. The mean 6-month reduction in daily prednisolone was 10.4 (SD 11.4) mg/day and 10.7 (SD 9.3) mg/day from baseline after the first and second course, respectively. Patients with low C3/C4 normalised their C3 by 6 months. Most patients with raised anti-dsDNA normalised after rituximab courses. Serious adverse events only occurred after more than four courses of rituximab. Rituximab was safe and efficacious for treating patients with refractory systemic lupus erythematosus (SLE) and was associated with significant steroid reduction, but more than four courses of rituximab was associated with an increased risk of serious infection in two patients.

Bilateral retinal vasculitis in a patient with systemic lupus erythematosus and its remission with rituximab therapy.

Severe retinal vasculitis is a rare, but potentially blinding, complication of patients with systemic lupus erythematosus (SLE). We describe here the first reported case of treating severe bilateral SLE-associated retinal vasculitis with the anti-CD20 monoclonal antibody rituximab, a drug which has established its role in rheumatoid arthritis and has shown promise in case series for the treatment of severe SLE that is unresponsive to other therapies. This case suggests that rituximab-induced B-cell depletion may provide an important new therapeutic option for refractory cases of this devastating ocular complication.

Effects of rituximab on resistant SLE disease including lung involvement.

We present a retrospective review of 11 patients with refractory systemic lupus erythematosus (SLE) treated with rituximab after failing corticosteroids and at least one other immunosuppressive drug. We measured clinical response using the Classic British Isles Lupus Assessment Group (BILAG) index, serum complement and reduction in maintenance prednisolone dose. B cells were measured using flow cytometry, and lung function testing was used to assess severe pulmonary disease (three patients). The median patient age was 42 years (range, 25-64) with median disease duration 6 years (range, 2-12). In all, 10 of 11 patients responded initially, with median global BILAG reduction of 7.5 at 6 months (P = 0.007), with loss of all A and B scores by 7 months. Rituximab treatment was associated with normalisation of complement (C3 P = 0.008, C4 P = 0.018) and reduction in steroid requirement, median reduction 15 mg/day (P = 0.036). In 9 of 10 patients who responded, all other immunosuppressants were stopped. There was no significant difference in anti-dsDNA antibody titres in these responders, but they were negative or had low titres at baseline. B-cell depletion continued for median 4 months (range, 2-9), and disease flare occurred at a median 6.6 months (range, 1.5-23) and was preceded by B-cell recovery in all but two patients. Rituximab was beneficial in refractory SLE including severe neurological and cardiorespiratory disease by inducing disease remission, allowing withdrawal of other agents and reduction in steroid requirement. Rituximab appeared to stabilise and possibly improve progressive lung disease.

Beliefs about medicines in patients with rheumatoid arthritis and systemic lupus erythematosus: a comparison between patients of South Asian and White British origin.

OBJECTIVE: To assess whether patients with RA and SLE who are of South Asian origin have different beliefs about medicines in general, and about DMARDs in particular, compared with patients of White British/Irish origin. METHODS: One hundred patients of South Asian origin (50 RA; 50 SLE) and 100 patients of White British/Irish origin (50 RA; 50 SLE) were recruited. Demographic and disease-related details and responses to the Beliefs about Medicines Questionnaire (BMQ), the SF-36 and the HAQ were collected. RESULTS: Patients of South Asian origin had significantly higher General Overuse (GO), General Harm (GH) and Specific Concern (SC) scores compared with patients of White British/Irish origin. Forward stepwise multivariable regression analysis showed that ethnic origin was an independent predictor of the GO, GH and SC scores with patients of South Asian origin having higher scores in these three scales of the BMQ. CONCLUSION: RA and SLE patients of South Asian origin have very high levels of concern about DMARDs and are generally worried about prescribed medicines. This may have an impact on adherence in this group of patients and further work is needed to understand the reasons underlying these beliefs.

Impaired endothelial function in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) patients suffer from excess cardiac deaths due to accelerated atherosclerosis. Endothelial dysfunction is a marker of early atherosclerosis. We tested the hypothesis that SLE patients have impaired endothelial function and assessed the relationship between endothelial function and clinical outcome over the subsequent five years. Thirty-six female SLE patients were compared with 22 healthy age and sex matched controls. Endothelial dependent vasodilatation (EDD) was assessed at the brachial artery in response to shear stress. Endothelium-independent dilatation induced by glyceryl trinitrate was also measured. Patients were followed for up to five years and the development of damage in the cardiovascular and other systems recorded. SLE patients showed significantly impaired endothelial function (median EDD 5.6%, IQR 3.1-7.2%) compared with healthy controls (median EDD 8.0%, IQR 6.3-9.3%; P = 0.001). Endothelium independent dilatation did not differ between the two groups. Endothelial function was significantly worse in postmenopausal compared with premenopausal women (median EDD 6.6%, IQR 3.9-7.8% versus 3.1%, IQR 2.6-5.1%; P = 0.016). Total cholesterol was inversely correlated with endothelial function in SLE patients (Spearman correlation r = -0.422, P = 0.025). There was no relationship between endothelial function and the development of damage in any organ system, including the cardiovascular system during patient follow-up. Patients with SLE have impaired endothelial Lupus (2007) 16, 84-88.

Changes in plasma lipids and markers of oxidative stress in normal pregnancy and pregnancies complicated by diabetes.

The purpose of the present study was to determine changes in plasma lipids and markers of oxidative stress longitudinally in pregnancy complicated by diabetes compared with non-diabetic pregnancy. This was carried out by following a group of normal pregnant women (n=17) and groups of pregnant women with Type I diabetes (n=19), Type II diabetes (n=12) and gestational diabetes mellitus (n=12) throughout pregnancy, with sampling carried out at the end of each trimester. Serum total cholesterol and triacylglycerols (triglycerides) were determined using standard colorimetric techniques and low-density lipoprotein (LDL) subfraction profile by disc PAGE. Total antioxidant capacity (TAC) was determined by enhanced chemiluminescence and lipid hydroperoxides by the ferrous oxidation of Xylenol Orange method. Total cholesterol and triacylglycerols increased significantly throughout pregnancy in all groups, but there were no significant differences between normal and diabetic women with respect to either. The LDL score was significantly higher (P<0.001) in diabetic women compared with normal women at each point throughout pregnancy, although there were no significant differences between the diabetic groups. There was evidence of greater oxidative stress in diabetic compared with normal women throughout. Corrected TAC was significantly lower (P<0.001) in all diabetic women throughout pregnancy. In addition, lipid hydroperoxides were higher in all diabetic compared with normal women, particularly so in those with Type II diabetes (P<0.05). These changes may have important implications for diabetic women during pregnancy, as an elevated risk of pre-eclampsia is thought to reflect an oxidative stress-related mechanism. In addition, these changes may have important implications for the development of atherosclerosis and the long-term cardiovascular health of women with diabetes.

Oxidative stress and normal pregnancy.

OBJECTIVE: To determine whether, in normal pregnancies, there is evidence of oxidative stress that is related to the lipid changes observed in pregnancy. DESIGN: Longitudinal study of healthy women having a normal pregnancy. Samples were obtained towards the end of each trimester and after 8 weeks postpartum. PATIENTS: Seventeen healthy women during a normal singleton pregnancy were compared with 12 healthy, non-pregnant women. MEASUREMENTS: Oxidative stress was determined by measuring total antioxidant capacity (TAC), uric acid and lipid hydroperoxides (LHP). Lipid status was evaluated by measuring total and high-density lipoprotein cholesterol, triglycerides and low-density lipoprotein (LDL) subfractions. RESULTS: Pregnancy was associated with decreased TAC and uric acid in the first trimester, which gradually increased during pregnancy, reaching normal values during the postpartum period. LHP significantly increased towards the end of pregnancy. The changes observed in LHP were significantly correlated with increases in LDL subfraction profile. CONCLUSIONS: Late pregnancy was associated with the formation of susceptible, oxidisable particles (high LDL score) and an increase in oxidative damage. These biochemical changes may be relevant for the long-term cardiovascular health of women, especially those of high parity or those who are at high risk for cardiovascular disease (e.g. women with diabetes).

The cardioprotective role of beta-blockers in patients with diabetes mellitus.

This paper reviews the role of beta-blockers in the prevention of cardiovascular morbidity and mortality in patients with diabetes mellitus. There is good evidence from randomized controlled trials that beta-blockers, in particular the lipophilic agents, substantially reduce cardiovascular mortality and morbidity. However, hitherto beta-blockers have been underused in diabetic patients, perhaps because of perceived risks of beta-blocker therapy. Reappraisal of the evidence suggests that the traditional reluctance to use beta-blockers in this group is based on fears of adverse effects that are largely unfounded.

Quality of diagnostic services for cancer: a comparison of open access and conventional outpatient clinics.

OBJECTIVE AND STUDY DESIGN: To assess quality of a quick and early diagnosis route (QED) by determining effectiveness and cost-effectiveness of five clinics compared with three conventional outpatient clinics. Prospective economic evaluation. Six-month cohort of all referrals (November 1996-April 1997). SUBJECTS: All referrals for suspected cancers of: upper gastro-intestinal tract; urinary tract, prostate and testis; skin. EFFECTIVENESS: Median days saved between GP referral and date of: diagnostic appointment; consultant decision; intervention. RESULTS: GP referral to diagnostic appointment: QED was effective (median days) for all clinics. Diagnostic appointment to consultant decision: QED was effective for testicular and haematuria clinics. Consultant decision to intervention: QED was effective for haematuria, testicular and melanoma clinics. COST-EFFECTIVENESS: Extra (incremental) NHS cost per patient diagnosed. RESULTS: Less than 5 Pounds per day saved between GP referral and diagnostic appointment for: endoscopy; haematuria; prostate; testicular; melanoma. Less than 3 Pounds per day saved between GP referral and consultant decision for: testicular; haematuria. Less than 3 Pounds per day saved between GP referral and intervention for: endoscopy; haematuria; testicular; melanoma. CONCLUSION: A "quick and early" diagnostic route provides a higher quality service through improved effectiveness and cost-effectiveness compared to conventional outpatients.

McArdle's disease: molecular genetics and metabolic consequences of the phenotype.

McArdle's disease is defined as a lack of functional muscle glycogen phosphorylase. Analysis of the myophosphorylase gene has demonstrated substantial heterogeneity in the mutations that cause the disease, but in almost all individuals, the molecular phenotype is the absence of the protein in skeletal muscle. Muscle glycogen phosphorylase is a major repository of vitamin B6 in the body, accounting for at least 80% of the total body pool. In McArdle's patients, this pool is therefore missing, introducing the possibility that vitamin B6 metabolism might be altered in these individuals. Preliminary data have shown that McArdle's patients show signs of a subclinical vitamin B6 deficiency, and that oral vitamin B6 supplementation can improve vitamin B6 status and enhance fatigue resistance in muscle.

Historical perspective: a framework for interpreting pathobiological ideas on human muscle fatigue.

The flow of ideas on the causes of human muscle fatigue appear to have been established in the literature during the last century. Critical analysis had to await innovative experimental designs or techniques. Progress has come particularly from the recognition of inconsistencies, particularly in clinical conditions in which there are alterations in the supply of energy or contractile function. While there is a continuing search for a unique cause of fatigue, much evidence points to there being different causes according to the type of muscular activity or clinical condition. "Nature's experiments" (patients exhibiting isolated defects of function or metabolism) offer unique opportunities for understanding the relative importance of particular levels of metabolic organization or physiological control. Theories of limiting biochemical processes and the Ca- kinetic basis of electromechanical coupling defects are both essentially "single-cell" models of fatigue. Functional requirements appear to determine the diversity of structure and organization of motor units. This would suggest that a "muscle cell population" approach would take into account the consequences of disease altering the number, type of functioning fibers or intrinsic strength of individual fibers. A graphical model is offered to allow a possible interpretation of the cause of fatigue in different forms of exercise and clinical conditions.