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

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 factoranti-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.
Conclusion. 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.