gms | German Medical Science

With the licensing of the first anti-TNF therapies for rheumatoid arthritis (RA) in 2000 biologics registers were set up in several European countries to monitor their long-term safety and effectiveness.

First results of biologics registers were reported in 2003 from BIOBADASER (Spain). They observed a significantly increased incidence of tuberculosis in patients treated with infliximab. This finding lead to the development of guidelines for Tb prevention, which were shown to be successful.

Since 2005 several investigations of the overall infection risk were published showing an increased risk of serious infections under treatment with anti-TNFs which seemed to decline over time. Analysis from the German RABBIT register showed that this decline is both a result of losing patients at higher risk but also clinical improvement. With taking time-varying changes and cohort effects into account it was possible to develop a risk calculator which allows rheumatologists to calculate the risk for serious infections for every patient at any point in time based on their individual risk profile.

Disease activity was found to be a main risk factor for myocardial infarction and stroke in RA patients. In RABBIT every 5 mm/h elevation of the ESR increases the risk for a myocardial infarction by 20% [95%CI 1,1–1,3]. Similarly, the risk for the development of a stroke is increased by 60% with every unit in the compound measure of disease activity (DAS28, range 0–10).

High disease activity is also associated with increased mortality. Patients with high disease activity (DAS28>5.1) in more than 80% of the observation had, compared to those with low disease activity (DAS28<3.2) a shortened life expectancy of 10 years. Intake of glucocorticoids of ≥15 mg/d increases mortality risk by the factor 3,6. Patients treated with anti-TNF or Rituximab had a significantly lower mortality risk than patients under non-biologic DMARDs, even if the control of disease activity was taken into account.

Although the analysis of observational cohorts has limitations, e.g. confounding by indication or channelling bias, data from biologics registers are important to complement our knowledge from clinical trials. They provide valuable information about drug safety and effectiveness when new agents are used to treat patients in everyday care. Two-thirds of these patients are not comparable with those investigated in RCTs because of their age, comorbidities, or poor functional status. Furthermore, we have learned to consider time-varying risks during safety analyses and to be careful in choosing the methods with which we analyse the data.