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Effect of Mycophenolate on the White Disclosures for Michelle Petri, MD MPH Blood Cell Count and the Frequency of • Clinical Trials Infection in Systemic Lupus – HGS/GSK – Medimmune Erythematosus – Pfizer – TEVA – Anthera – UCB Ananta Subedi M.D. • Consultant Hong Fang M.D. M.S. – Genentech – Lilly Michelle Petri M.D. M.P.H. – Merck Serono

Johns Hopkins University School of Medicine

Leukopenia, Lymphopenia and Neutropenia Leukopenia Occurs in 4 to 36% of Transplant Are All Frequent in SLE Patients on Mycophenolate Mofetil

# of Study Leukopenia (%) Lymphopenia (%) Neutropenia (%) Patients No of Patients with Study Patients Transplant Rivero et al, 1978 158 18 75 ND leukopenia (%) on MMF Isenberg et al, 1982 30 37 57 6 Nossent et al, 1991 126 ND 19.8 47 Fischer et al, 2000 31 Liver 6.5

Ng et al, 2005 91 27 62 ND Hao et al, 2008 63 Liver 36

Vila et al, 2006 591 ND 64.6 ND Becker et al, 2008 297 Liver 10.4 Dias et al, 2009 124 36.3 67 40.3 El-Agroudy et al , 2009 25 Kidney 4 (At least 1 visit) Herlenius et al, 2010 13 Liver 11 Dias et al, 2009 124 12.9 41 4.8 (Persistent) Boudjema et al, 2011 95 Liver 29 Castillo-Martinez et al, 85 ND ND 8 2011

Leukopenia in SLE Patients on Mycophenolate Infection is One of the Most Frequent Adverse Events in May be Less Than Transplant Patients SLE Patients on MMF

SLE patients Infection Study with leukopenia (%) Study # of PTS Frequency (%) Chan et al, 2000 0 Chan et al, 2000 21 19 Ginzler et al, 2005 1.2 Weixin et al, 2002 23 17.3 Ong et al, 2005 37 Ong et al, 2005 26 23.1 Houssiau et al, 2010 3.7 Ginzler et al, 2005 83 45.8 Wang et al, 2007 9 11.1 Weng et al, 2010 2.9 Appel et al, 2009 184 68.5

El-Shafey et al, 2010 17 El-Shafey et al, 2010 24 50 Radhakrishnan et al, 2010 0 Dooley et al, 2011 115 79.1 Dooley et al, 2011 0 Li et al, 2012 20 40

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MMF is Associated with More Infections than Other Infection Risk of Mycophenolate Mofetil Immunosuppressive Drugs in SLE in Lupus Nephritis

Placebo Ocrelizumab 52-week double-blind Long-term continuation period (years 1–4), all placebo-controlled period Belimumab-treated patients * 400 mg 1,000 mg (year 1) (n=125) (n=126) (n=127) Placebo Belimumab Year 1 Year 2 Year 3 Year 4 (n= 113) (n=336) (n= 424) (n= 339) (n= 274) (n= 248) Patients with infections (%) 56.0 68.3 59.1 Patients receiving background ELNT Non MMF immunosuppressant 44.4 61.7 39.6 regimen* (%) Overall infection , % 68.9 71.8 75.6 82.6 73.0 79.7 Serious and severe Patients receiving background MMF (%) 62.5 72.2 70.9 2.7 4.2 11 6.4 2.1 8.1 infection , %

MMF Patients with serious infections (%) 14.4 21.4 15.0 Overall infection, % 99.1 83.0 93.7 77.5 74.2 90.0 ELNT regimen (%) 11.1 10.6 10.4 Serious and severe 12.4 14.9 13.1 7 13.2 2.8 MMF (%) 16.3 27.8 19.0 infection, %

* Expressed as AEs/100 patient-years * ELNT: Euro-Lupus Nephritis Trial regimen (CYC/AZA) Merrill, J T et al. Arth Rheum 64:3364-73, 2012 Mysler et al. Arth Rheum 65: 2368-79, 2013

Objectives Methods

We analyzed the effect of • Patients: Patients on mycophenolate mofetil mycophenolate mofetil on: within the Hopkins Lupus Cohort were included in the study 1. White blood cell count 2. Rate of infection since starting • Definition of infection: mycophenolate – Bacterial or viral – Diagnosed on the basis of the clinical judgment of the treating physician – Recorded at every visit

Methods Methods

• SLE patients served as their own control • Statistical analysis was performed using (before and after mycophenolate the paired t-test. mofetil). • The P-value was adjusted (for ethnicity • The white blood cell count and rate of and prednisone dose) by using the infection on the day mycophenolate was generalized estimating equation. started were compared with the white blood cell count and rate of infection at the next visit.

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Demographics The WBC is Not Reduced by MMF Ethnicity

African-American 47% Before During Patient Group Mycophenoalate Mycophenolate P-value Caucasian 43% mofetil mofetil Other ethnicities 10% All patients (n=300) 6.65±3.34 7.02±3.28 0.075 African-American (n=140) 6.30±2.94 6.53±3.23 0.40 Gender Caucasian (n=130) 7.15±3.84 7.36±3.15 0.44 Baseline WBC 2.49±0.46 4.83±2.66 0.0007 Female 87% <3,000/mm3 (n=26) Male 13%

African-American Ethnicity Reduced the WBC Mycophenolate Increased and Prednisone Increased It Only Bacterial Infections

Effect on white Before After Variable P-value Adjusted blood cell count Variable mycophenolate mycophenolate p-value* Ethnicity mofetil (%) mofetil (%) Infection (Viral African-American vs. 14 18 0.087 -0.91±0.33 0.0049 or bacterial) Caucasian Viral infection 10 10 0.17 Other ethnicity vs. Bacterial -0.52±0.51 0.31 5 9 0.032 Caucasians infection

Prednisone (per mg/dl) 0.07±0.01 <0.0001 *p-value adjusted for prednisone dose. Mycophenonate mofetil 0.20±0.18 0.28 (before vs. after)

Conclusion Conclusion

• We found overall a slight increase in • There was a statistically significant the white blood cell count with increase in the frequency of bacterial mycophenolate mofetil use. infection in SLE patients on • In SLE patients with baseline mycophenolate mofetil. leukopenia (white blood cell count less • There was no difference in the 3 than 3,000/mm ), there was a frequency of viral infection. statistically significant increase in the white blood cell count.

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Conclusions Limitations of the study • Improvement in the white • The Hopkins Lupus Cohort visits blood count on MMF was still were outpatient visits, but associated with an increase in ascertainment of infection included any during a hospitalization. bacterial infection. • Lymphocyte or neutrophil counts were not recorded in the database.

Supported by a Grant from

The Institute for Clinical and Translational Research Clinical Research Units

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