Acquired Immunodeficiency in ANCA Associated Vasculitis
Acquired Immunodeficiency in ANCA Associated Vasculitis
This study will address the following hypothesis: Rituximab therapy leads to an acquired
 immune deficiency, as demonstrated by impaired vaccine responses, in AAV patients.

 Aims:

 1. To investigate whether rituximab leads to immune deficiency in patients with AAV when
 compared to both disease and healthy controls.

 2. To investigate whether the degree of immune deficiency is associated with the degree of
 B cell depletion.

 3. To investigate whether T-independent vaccine responses are more severely affected than
 T-dependent vaccine responses after rituximab and whether a conjugated vaccine will
 overcome this postulated deficit in T independent vaccine responses.
Inclusion Criteria:

 To be included in the trial all participants must:

 -  Have given written informed consent to participate

 -  Be aged 40 years and over

 For patients in Group 1 only (rituximab treated):

 -  Have a diagnosis of AAV [granulomatosis with polyangiitis (GPA) or microscopic
 polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (eGPA)]

 -  Have current or historical PR3/MPO ANCA positivity by ELISA or histological
 confirmation of AAV

 -  Have received ≥ 2g rituximab

 -  Have received their last dose of rituximab at least 12 months prior to enrolment

 -  Be in stable remission with a prednisolone dose of ≤ 5mg/day

 For patients in Group 2 only (disease controls who have never received rituximab):

 -  Have a diagnosis of AAV (GPA, MPA or eGPA)

 -  Have current or historical PR3/MPO ANCA positivity by ELISA or histological
 confirmation of AAV

 -  Have received cyclophosphamide (oral or IV) as initial induction therapy

 -  Be on stable immunosuppression for the 6 months preceding screening including
 prednisolone ≤ 5mg/day AND either azathioprine, methotrexate or mycophenolate mofetil
 (at stable or tapering dose)

 For healthy controls:

 • Healthy individuals aged 40 years and over

 Exclusion Criteria:

 The presence of any of the following will preclude participant inclusion:

 -  Age < 40 years

 -  History of severe allergic or anaphylactic reactions to pneumococcal vaccinations

 -  Pneumococcal vaccination within 5 years prior to screening

 -  Females who are pregnant, plan to become pregnant, or breast feeding

 -  Medical, psychiatric, cognitive or other conditions that, in the investigator's
 opinion, compromise the patient's ability to understand the patient information, give
 informed consent, comply with the trial protocol, or to complete the study.

 -  History of malignancy within the past five years or any evidence of persistent
 malignancy, except fully excised basal cell or squamous cell carcinomas of the skin,
 or cervical carcinoma in situ which has been treated or excised in a curative
 procedure.

 -  Replacement immunoglobulin (IVIg) administered intravenously or subcutaneously in the
 12 weeks prior to screening visit.

 For patients in Groups 1 and 2 only (AAV patients):

 -  Presence of another multisystem autoimmune rheumatic disease

 -  The prior receipt of more than 36g of cumulative cyclophosphamide ever (either IV or
 oral)

 For patients in group 1 only (rituximab group)

 • The receipt of any immune suppressing agent (azathioprine, methotrexate or mycophenolate
 mofetil) after rituximab

 For patients in Group 2 only (disease controls):

 -  A relapse of AAV within the 6 months prior to screening which has necessitated an
 increase in prednisolone or azathioprine, methotrexate or MMF dose.

 -  Previous rituximab therapy at any time

 For healthy controls:

 -  Any history of any autoimmune condition

 -  Any history of use of immune suppressing medication, including > 4 weeks of oral
 glucocorticoids, within the 5 years prior to screening.