The immunogenicity of ReFacto AF (moroctocog alfa AF-CC) in previously untreated patients with haemophilia A in the United Kingdom.

INTRODUCTION: Factor VIII inhibitor development is currently the most serious complication of the treatment of haemophilia A. Differences in manufacturing and the molecular structure of brands of recombinant factor VIII have led to speculation that concentrates may differ in immunogenicity. This has led to a regulatory focus on the immunogenicity of factor VIII concentrates both before and after licensure. AIM: To investigate the immunogenicity of ReFacto AF post licensure in a real-world setting in previously untreated patients (PUPs) treated exclusively with this product until at least 50 exposure days (EDs). METHODS: The United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) National Haemophilia Database (NHD) identified a consecutive cohort of patients with severe haemophilia A (<0.01 IU/L) whose first treatment was with ReFacto AF, monitored time to inhibitor development and described associated risk factors. RESULTS: One hundred and three boys reached 50 EDs within the study period, of whom 35 developed an inhibitor (P(t ≤ 50) = 0.33, [95% CI: 0.25-0.43]), of which 15 (P(t ≤ 50) = 0.16, [95% CI: 0.10-0.25]) were high titre. Inhibitors arose after a median (interquartile range) 11 (7-16) EDs. Inhibitors were significantly associated with high-risk mutations and non-significantly associated with non-white ethnicity. Inhibitors were negatively associated with a family history of haemophilia A. High-titre inhibitors were significantly associated with a family history of inhibitors. CONCLUSION: Inhibitor incidence in a single country population of ReFacto AF PUPs was similar to that previously described. Low- and high-titre inhibitors were detected after a similar number of EDs, contrasting with previous data, probably reflecting standardized inhibitor monitoring within the United Kingdom.

The incidence of factor VIII inhibitors in severe haemophilia A following a major switch from full-length to B-domain-deleted factor VIII: a prospective cohort comparison.

Although it has been suggested that switching of factor VIII (FVIII) products may increase inhibitor formation this is disputed. Half of UK patients changed rFVIII brands because of national contracting in 2010, presenting an opportunity to compare inhibitor incidence of switchers with non-switchers. Centres were requested to test all the patients for inhibitors prior to the switching date and 6-monthly thereafter. Positive and negative inhibitor test data were also collected to analyse for testing bias. A total of 1198 patients with severe haemophilia A and treated with Advate, Kogenate/Helixate or Refacto AF preswitch were included in the analysis, of whom 516 switched to Refacto-AF and 682 did not switch products. Five new inhibitors were reported amongst previously treated patients (>50 exposure days) with a median titre at the time of detection of 1.25 BU mL(-1) (IQR 0.7-23.05). One inhibitor occurred in a non-switcher using Kogenate, an incidence of 1.5 per 1000 treatment-years (95% CI 0.2-10.5). Four inhibitors arose in patients who had switched from Kogenate (two) or Advate (two) to ReFacto-AF, an incidence of 7.8 per 1000 treatment-years (95% CI 2.9-20.8). These incidence rates did not differ significantly from one another (incidence rate ratio 5.3 (95% CI 0.5-260.3) or from the historical rate of 6.05 inhibitors/1000 treatment-years (95% CI 5.18-7.06). Only one inhibitor (non-switcher) persisted. Non-switchers were significantly older (P = 0.03), and used significantly less FVIII per year (P = 0.005) prior to switching. Following switching, factor usage increased similarly (P = 0.53) in both groups. Switching from FLRFVIII to Refacto-AF (BDDRFVIII) was not associated with an increased inhibitor development.

Systemic lupus erythematosus (SLE) and hair treatment: a large community based case-control study.

OBJECTIVE: To investigate the association of hair treatment, including permanent and non-permanent dyes, bleach, highlights and lowlights on the development of systemic lupus erythematosus (SLE). METHODS: 150 SLE patients and 300 controls from Nottingham, UK were interviewed in a case-control study. Controls were matched to cases for gender and year of birth. All patients met at least four of the American Rheumatology Association criteria for SLE. Controls were randomly selected from the Nottingham Family Health Services Authority register. Information was collected via an interview-administered questionnaire concerning demographic variables and hair treatment. RESULTS: For hair treatment no significant associations were observed between ever using permanent colouring, non-permanent colouring, bleach or lowlights, and disease. Nevertheless a significant association (OR 0.55, 95% CI 0.31-0.95) was observed between 'ever having' used highlights and disease with cases having used highlights less frequently than their healthy counterparts. No significant differences were observed in duration of usage of hair bleach, permanent colouring, non-permanent colouring, highlights and lowlights between cases and controls. CONCLUSIONS: Hair treatment or duration of hair treatment usage is not significant in the aetiology of SLE. Although patients with SLE were less likely in this study to have highlights than controls, for all other hair treatments no differences were observed.

Pregnancy outcome and family size in systemic lupus erythematosus: a case-control study.

OBJECTIVE: To establish pregnancy outcomes and family size in a geographically defined population of systemic lupus erythematosus (SLE) patients. METHODS: One hundred and thirty-eight SLE patients (all women satisfying at least four American Rheumatism Association criteria) and 276 age-matched female controls, from the Nottingham area, were interviewed by a single investigator. Demographic details and maternity histories were obtained, and the data collected were analysed statistically to calculate odds ratios (ORs) for risk of fetal loss (through miscarriage, stillbirth and abortion). Family size was also determined in White and non-White cases and controls. RESULTS: Women with SLE are at greater risk of spontaneous fetal loss than their healthy counterparts (OR = 2.21, 95% CI 1.46-3.35, P < 0.01) and they are more likely than controls to have a surgical abortion (OR 2.44, 95%, CI 1.22-4.87, P = 0.01). The excess risk of both of these outcomes exists both before and after diagnosis of SLE. The median number of children in White and non-White families of cases and controls is the same, i.e. two. White women with SLE, however, appear less likely than controls to have more than two children, whereas non-White lupus women tend to retain their propensity to have larger families, i.e. more than two children. CONCLUSIONS: We confirm that lupus women who have, or later develop, SLE are at greater risk of pregnancy loss by spontaneous or surgical means. We have also shown that race, and the inherent differences in social and cultural influences, appears to be an important determinant of ultimate family size; White women with SLE have fewer children than controls, whilst non-White lupus women tend to have larger families.

Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study.

OBJECTIVE: To investigate the effect of smoking on the development of systemic lupus erythematosus (SLE), and the association between alcohol consumption and the disease. METHODS: 450 subjects (150 SLE patients and 300 controls) from Nottingham, UK were interviewed in a case-control study. Controls were matched to cases for age and sex. All patients met at least four of the American Rheumatology Association criteria for SLE. Controls were randomly selected from the Nottingham Family Health Services Authority register. Information was collected by interview administered questionnaire concerning demographic variables, smoking histories, and drinking habits. RESULTS: Analysis of the data by conditional logistic regression revealed current smokers to have a significantly increased risk of development of SLE compared with never smokers (odds ratio (OR) 1.95, 95% confidence intervals (CI) 1.14, 3.31), although ex-smokers were not at increased risk. There was also suggestion of a marked, highly significant negative association between SLE and alcohol consumption, the magnitude of which increased with units consumed. CONCLUSIONS: This study suggests that current smokers are at increased risk of developing SLE compared with non-smokers and ex-smokers. In contrast, alcohol consumption seems to be negatively associated with the disease.

Prostaglandin F2 alpha effects on intraocular pressure negatively correlate with FP-receptor stimulation.

According to the current working classification for prostanoid receptors, the prostaglandin F2 alpha-sensitive receptor (FP-receptor) may be identified by comparing the rank order of activity of prostaglandin F2 alpha (PGF2 alpha) and its analogues. In order to further understand the pharmacology of PGF2 alpha-induced ocular hypotension, the intraocular pressure response to PGF2 alpha and selected analogues was compared with their rank order of activity in typical FP-receptor preparations such as contraction of the cat iris sphincter and affinity for corporal luteal membrane binding sites. The rank order of potency for decreasing intraocular pressure was as follows: PGF2 alpha greater than PGF1 alpha greater than 16-phenoxytetranor PGF2 alpha greater than 17-phenyltrinor PGF2 alpha = fluprostenol (inactive). For cat iris sphincter contraction, the rank order of potency appears to be fluprostenol = 17-phenyltrinor PGF2 alpha greater than 16-phenoxytetranor PGF2 alpha = PGF2 alpha greater than PGF1 alpha. The rank order of potency for PGF2 alpha analogues in decreasing intraocular pressure appears to negatively correlate with the rank order for cat iris sphincter contraction and literature values for corporal luteal membrane binding. It is concluded that the ocular hypotensive effect of PGF2 alpha is not mediated by the FP-receptor.