An open-label pilot study on the effects of trivalent inactivated influenza vaccination (Influvac®) in rheumatoid arthritis patients treated with rituximab

Rituximab (anti-CD20) is a promising new drug in the treatment of rheumatoid
arthritis (RA) patients. After treatment peripheral B cell depletion occurs
rapidly and sustains for 6-9 months. Therefore dampened humoral and/or cellular
immune responses in RA patients might be expected, although increased infection
rates have not been shown in relation to treatment with rituximab.

Because patients on immunosuppressive drugs are at increased risk for
complicated influenza, national guidelines advice to immunize these patients
annually for influenza. To our knowledge, no studies have been published on
efficacy of vaccination against influenza virus with the currently used subunit
vaccines in RA-patients treated with rituximab.

In this pilot study patients treated with a single course of rituximab or
treated with multiple courses of rituximab, matched RA controls treated with
methotrexate and healthy controls will be included in order to answer the
following questions:
1. Is vaccination with trivalent inactivated influenza vaccine in RA patients
treated with rituximab useful; do these patients elicit adequate humoral and
cellular T-cell responses after influenza vaccination?
2. Are effects of single or multiple courses of rituximab long lasting; is the
response to influenza vaccination after B cell repopulation affected?

In this open-label pilot study humoral and T-cell responses will be determined
by several proven methods (respectively Hemagglutionation Inhibition test
(HAI), IFN-gamma and IL-4 Enzyme Linked Immunospotting (ELISPOT), Intracellular
Cytokine Staining and Fluorescence-activated cell sorting (ICC & FACS) and
assessment of proliferation of CD4 and CD8 T cells using CFSE dye dilution and
analysis by Flow Cytometry). in patients treated with single or multiple doses
of rituximab. These test will be performed on blood drawn before and at two
time points following vaccination with influenza virus subunit vaccine for the
season 2007-2008, and compared with the responses in RA-controls treated with
montherapy methotrexate and with healthy controls. A number of 30 patients on
rituximab, 20 RA-controls on methotrexate and 20 matched healthy controls will
be included.

Burden for patients/patients efforts:
- the drawing of extra bloodsamples, 180 ml (3 times 60 ml) more than the usual
amount to be drawn
- an extra time investment during hospital visits, estimed to be in total 45
minutes
- extra hospital visits, 2 or 3 in total

Risks:
- the only additional risk will consist of the extra bloodsamples that are
drawn for determing parameters of humoral and cellular immunity after influenza
vaccination.

NB: The influenza vaccination is part of the standard treatment in this
patientgroup, the healthy controls will receive influenza vaccination
voluntarily as participators of the Influenza Vaccination Programme of Health
Care Workers (HCWs) in the University Medical Center Groningen