1. Managing Infection Risk in Primary Systemic Vasculitis Patients Dr Matthew Morgan University of Birmingham

2. The Problem  ANCA vasculitis causes lung and kidney damage  Treatment requires long term immunosuppression

3. Patient outcomes - EUVAS trials 535 patients from 4 EUVAS trials recruited 1995-2002

4. What are the risk factors for infection?  Direct drug side effects –Neutropenia –Steroids –Cyclophosphamide –Azathioprine/ Methotrexate/ Mycophenolate  Other factors?  Lymphopenia?  B-cell depletion?  Hypogammaglobunaemia?

5. Birmingham Vasculitis Clinic Experience –89 PSV patients median follow up 5 years (2-22 years) –90% had at least 1 episode infection –57% had severe infection requiring hospital admission and IV antibiotics –Overall infection rate 1.5/patient/year –Severe infections 0.86/patient/year

6. Immunodeficiency is a risk for infection  IgG <5g/L increased risk of  All infections (p=0.03)  Severe infections (p=0.01)

7. Does vaccination improve infection risk?  92 patients in remission –Median age 51 (23-91)  On low dose/no immunosuppression  Received –Prevnar 7 –Menitorix (Hib) –Men A, C, W135, Y  Antibody titres measured at weeks 0, 4, 8 &16  Serum IgG and lymphocyte subsets measured at baseline

8. Represents median Vasculitis patients have low numbers of lymphocytes

9. Immunodeficiency  22% of patients had IgG <6.0 g/dL  Correlates with –CD19 B-cell count (co-efficient 0.3; p=0.002) –CD4 T-Cell count (co-efficient 0.3; p=0.005)  Low IgG correlates with low anti- Pneumococcal and Diphtheria antibodies  Older age correlates with reduced CD19 and CD4 cells

10. Response to Prevnar 7 Serotype Percentage of patients with titre >0.35 P value Week 0 vs week16 BaselineWeek 16 Pn42346<0.001 Pn6b4871<0.001 Pn9v5583<0.001 Pn145574<0.001 Pn18c7091<0.001 Pn19f5976<0.001 Pn23f5080<0.001

11. Reponses to other vaccines Patients with protective antibody titres VaccineBaselineWeek 16 Baseline vs week 16 HIb2426%5563% p<0.001 Men A3033%6271%p=0.001 Men C89%4349%p=0.003 Men W13522%1821%ns Men Y1112%4451%p<0.001

12. Predictors of poor vaccine response  Low immune competence score predicts poor vaccine response (p=0.039)  Low IgG predicts poor vaccine response (p=0.017)  CD4 and CD19 counts do not predict response p=0.039

13. Summary  Infection is a significant problem in systemic vasculitis  Low IgG is associated with increased infection  Most patients respond to vaccination  Low IgG predicts a poor vaccination response

14. Acknowledgements  Profs. Lorraine Harper & Mark Drayson  Drs. Alex Richter, Julia Flint, Mark Cobbold  Wellcome Trust Clinical Research Facility Staff  Clinical Immunology – University of Birmingham