title: The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers.
abstract: OBJECTIVE
  To investigate the polymorphisms in the promoter region of the B lymphocyte stimulator (BLyS) gene as markers of response to rituximab (RTX) in rheumatoid arthritis (RA).
  
  
  METHODS
  The study was first conducted in 152 Italian RA patients and then replicated in an additional 117 RA patients (73 Italian, 44 British). The European League Against Rheumatism response criteria were used to evaluate the response rate at months 4 and 6 after the first cycle of RTX, by means of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; patients were classified according to the best response shown between months 4 and 6. BLyS promoter polymorphisms were analyzed by polymerase chain reaction followed by the analysis of the restriction fragments, BLyS promoter haplotypes were analyzed using the expectation-maximization algorithm, and BLyS serum levels were analyzed using enzyme-linked immunosorbent assay. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs).
  
  
  RESULTS
  The TTTT BLyS promoter haplotype appeared to be significantly associated with response to RTX only in the subset of seropositive patients (those positive for rheumatoid factor and/or anti-cyclic citrullinated peptide). The replication study confirmed that this association was limited to seropositive RA patients in whom treatment with anti-tumor necrosis factor (anti-TNF) agents had previously failed. In the whole series of seropositive patients in whom anti-TNF agents had previously failed, patients carrying the TTTT BLyS promoter haplotype were more prevalent in good responders (18 of 43 [41.9%]) than in moderate responders (20 of 83 [24.1%]) or in nonresponders (1 of 21 [4.8%]) (for good responders versus nonresponders, OR 14.4 [95% CI 1.77-117.39], P=0.0028). Furthermore, multivariate analysis selected the TTTT BLyS promoter haplotype as an independent marker of good response to RTX (for good responders versus nonresponders, OR 16.2 [95% CI 1.7-152.5], P=0.01; for good responders versus moderate responders and nonresponders combined, OR 3.1 [95% CI 1.2-7.8], P=0.02). The relationship between BLyS polymorphisms and BLyS serum levels remained unclear.
  
  
  CONCLUSIONS
  BLyS promoter genotyping may be suitable for identifying seropositive RA patients who may have a good response to RTX after anti-TNF agents have failed.
authors.affiliation: DSMB, Azienda Ospedaliero Universitaria of Udine, Udine, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Fabris
authors.forename: Luca
authors.initials: L
authors.lastname: Quartuccio
authors.forename: Ed
authors.initials: E
authors.lastname: Vital
authors.forename: Elena
authors.initials: E
authors.lastname: Pontarini
authors.forename: Sara
authors.initials: S
authors.lastname: Salvin
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fabro
authors.forename: Alen
authors.initials: A
authors.lastname: Zabotti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Benucci
authors.forename: Mariangela
authors.initials: M
authors.lastname: Manfredi
authors.forename: Viviana
authors.initials: V
authors.lastname: Ravagnani
authors.forename: Domenico
authors.initials: D
authors.lastname: Biasi
authors.forename: Fabiola
authors.initials: F
authors.lastname: Atzeni
authors.forename: Piercarlo
authors.initials: P
authors.lastname: Sarzi-Puttini
authors.forename: Pia
authors.initials: P
authors.lastname: Morassi
authors.forename: Fabio
authors.initials: F
authors.lastname: Fischetti
authors.forename: Laura
authors.initials: L
authors.lastname: Bazzicchi
authors.forename: Marta
authors.initials: M
authors.lastname: Saracco
authors.forename: Raffaele
authors.initials: R
authors.lastname: Pellerito
authors.forename: Marco
authors.initials: M
authors.lastname: Cimmino
authors.forename: Valeria
authors.initials: V
authors.lastname: Carraro
authors.forename: Angelo
authors.initials: A
authors.lastname: Semeraro
authors.forename: Franco
authors.initials: F
authors.lastname: Schiavon
authors.forename: Roberto
authors.initials: R
authors.lastname: Caporali
authors.forename: Roberto
authors.initials: R
authors.lastname: Bortolotti
authors.forename: Marcello
authors.initials: M
authors.lastname: Govoni
authors.forename: Federico
authors.initials: F
authors.lastname: Fogolari
authors.forename: Elio
authors.initials: E
authors.lastname: Tonutti
authors.forename: Stefano
authors.initials: S
authors.lastname: Bombardieri
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Vita
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D053264:B-Cell Activating Factor / Q000235:genetics*; D001799:Blood Sedimentation; D015331:Cohort Studies; D004351:Drug Resistance / Q000235:genetics; D004739:England; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012189:Retrospective Studies; D000069283:Rituximab; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D053264:B-Cell Activating Factor; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab