The suggestion, therefore, is that novel dosing regimens of FVIII may be associated with greater long-term arthropathy than current widely used schedules. The ‘danger theory’ suggests that the immune system can discriminate between ‘self’ and ‘non-self’, but can also detect whether or not antigens are potentially dangerous CHIR-99021 chemical structure . In this context, FVIII inhibitor development during prophylaxis in haemophiliac patients has been extensively discussed, and it has been suggested
that FVIII prophylaxis may protect against inhibitor development by reducing bleeding frequency, inflammation and ‘danger’ [10,11]. In the multicentre Concerted Action on Neutralising Antibodies in severe haemophiLia A (CANAL) study, the likelihood of inhibitor development was 60% lower for regular prophylaxis
compared with on-demand treatment [relative check details risk 0.4; 95% confidence interval (CI): 0.2, 0.8] . Moreover, in a case-control comparison of patients with inhibitors versus controls without inhibitors, Santagostino et al.  documented that age at first FVIII infusion (cases 11 days; controls 13 days) had no significant influence on inhibitor development; also, patients who received FVIII as prophylaxis rather than as on-demand therapy had an 80% lower risk of inhibitor development (adjusted odds ratio 0.2; 95% CI: 0.06, 0.9). Although these findings appear to convincingly define that FVIII prophylaxis significantly protects 上海皓元 against inhibitor development, it should be remembered that these studies have some major flaws. Nevertheless, compelling evidence comes from a small study of a new prophylaxis schedule (the Bremen regimen) compared with standard joint-protection prophylaxis (40–50 IU kg−1 3 times per week, which started after a median of 30 FVIII on-demand EDs) . Basically, the Bremen regimen
starts with a low dose of FVIII before the first bleed over the first 20-50 EDs to try to induce tolerance to FVIII and minimise inhibitor development by averting immunological danger signals; subsequently, the regimen is intensified. Importantly, over 175 EDs, inhibitors manifested in only 1 of 26 patients treated with the Bremen schedule compared with 14 of 30 patients given standard prophylaxis (3.8% vs. 46.7%; P = 0.0003) . These intriguing results of an almost complete lack of inhibitor development during FVIII prophylaxis now warrant confirmation in larger-scale trials. Overall, excellent long-term outcomes can be achieved by starting an appropriate schedule of FVIII prophylaxis at an early age in patients with haemophilia, as for example is now common practice in Malmö. Clearly, such early commencement of suitable FVIII prophylaxis can substantially improve survival, markedly reduce bleeding-related morbidity, and considerably improve patient well-being and quality of life. The most serious problem in haemophilia A patients is inhibitor development.