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The Pharmacogenomic Association of Fcγ Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Author information

Cartin-Ceba R1, Indrakanti D2, Specks U1, Stone JH3, Hoffman GS4, Kallenberg CG5, Langford CA4, Merkel PA6, Spiera RF7, Monach PA8, St Clair EW9, Seo P10, Tchao NK11, Ytterberg SR1, Brunetta PG12, Song H2, Birmingham D2, Rovin BH2; RAVE-Immune Tolerance Network Research Group. Arthritis Rheumatol. 2017 Jan;69(1):169-175. doi: 10.1002/art.39822.

Abstract

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1 Mayo Clinic and Foundation, Rochester, Minnesota, and Scottsdale, Arizona.

2 Ohio State University, Columbus.

3 Massachusetts General Hospital, Boston.

4 Cleveland Clinic, Cleveland, Ohio.

5 University of Groningen, Groningen, The Netherlands.

6 University of Pennsylvania, Philadelphia.

7 Hospital for Special Surgery, New York, New York.

8 Boston University School of Medicine, Boston, Massachusetts.

9 Duke University Medical Center, Durham, North Carolina.

10 Johns Hopkins University, Baltimore, Maryland.

11 Immune Tolerance Network, San Francisco, California.

12 Genentech, South San Francisco, California.

Abstract

OBJECTIVE:

The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcγ receptors (FcγR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively. METHODS:

Functional SNPs for FcγR (FcγRIIa 519G>A, FcγRIIb 695T>C, FcγRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests. RESULTS:

No significant associations were identified between complete remission and any FcγR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcγRIIa and complete remission (P = 0.01). The 519AA genotype predicted complete remission (P = 0.006) and a shorter time to complete remission (P < 0.001). CONCLUSION:

The finding that the homozygous FcγRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcγRIIa may be broadly involved in disease pathogenesis and response to therapy.