Anti-Biopharmaceutical Immunization: Prediction and analysis of clinical relevance to minimize the risk of immunization in Rheumatoid arthritis patients

The introduction of biopharmaceuticals (BP) has been a critical step forward in
care for RA and 9 BP are now licensed for the treatment of RA. In spite of this
progress, failure of response to BP is frequent and in most of the registries,
less than 50 % of patients are still on drug at 5 years. These failures may be
primary failures or secondary failures. The fact is that the low level of
response becomes insufficient compared to the expectations. One of the main
potential causes of these failures of BP therapy response is the development of
ADAb in some patients. ADAb may decrease the efficacy of BPs by neutralizing
them or modifying their clearance and they may be associated with BP-specific
hypersensitivity reactions. The prediction, prevention and cure of anti-drug
(AD) immunization are thus major goals in BP development.
In addition, many factors (patient-, disease- or product-related) may influence
the potential risk of BP immunogenicity. Therefore, the immunogenic potential
of BPs can only be definitively assessed in human studies. Furthermore,
emphasis has been placed on optimizing assays designed to detect ADAb response.
This prospective study (ABI-RA-P01) will assess the occurrence of ADAb using
standardized and validated assay(s) and also cellular, genetic and molecular
parameters in RA patients treated with adalimumab, etanercept, infliximab,
tocilizumab and rituximab, to address the mechanism of immunogenicity.
Patient-related factors that might predispose an individual to an immune
response will be taken into account: underlying disease, genetic background,
immune status, including immunomodulating therapy and dosing schedule.
Thus, novel approaches to characterize anti-drug lymphocytes responses will be
tested in patient materials (DNA, RNA, serum, PBMC).

PRIMARY OBJECTIVE
• To find early bio-markers within 3 months of the treatment with
biopharmaceuticals (BP) able to predict immunization against BP within the
first year of treatment.

SECONDARY OBJECTIVES
• To analyze the correlation between immunization to BP and hypersensitivity
reactions and loss of response
• To analyze the correlation between immunization to BP and BP blood levels
• To analyze the correlation between BP levels and hypersensitivity reactions
and loss of response
• To identify molecular and cellular biomarkers associated with the development
of ADAb at any time of treatment
• To find predictive bio-markers before initiation of the treatment BP able to
predict immunization against BP within the first year of treatment
• To be able to associate an immunological signature to patients with ADAb

This is an exploratory multicenter, prospective cohort study in patients with
RA. The study will be performed within approximately 25 to 50 centres in 4
countries, including 18 centres in France.
There will be 6 fixed study visits. The visits will be done according to
standard clinical practice with additional blood sampling.

Duration of study participation for each patient
• Screening : From 1 to 4 weeks
• Sampling period(s) : it will be the same for the 4 studied BPs
- M-5 to D0 (Screening)
- M0/W0/D0 (Baseline)
- M1/W4 ± 2W
- M3/W12 ± 2W
- M6/W26 ± 2W
- M12/W52 ± 4W
• End-of-study : At W52 after all the scheduled study procedures (e.g. blood
sampling) and after agreement by the investigator or sub-investigator
• Total study duration: 52 weeks

Since the BP therapy will be prescribed by the Treating Physician this study is
not an intervention trail. Therefore, the pre-screening of patients for
administration of BP therapy and safety follow-up will be done according to
national guidelines for BP*s. This will be the responsibility of the Treating
Physician.
The procedures of this study are;
1) gathering clinical data
2) drawing of blood for further analysis
Blood drawing has a relatively low risk of adverse reactions.
Due to the fact that this study is accompanied with a small risk of adverse
reactions we do not expect serious adverse reactions to occur.