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ANTI-DSDNA ANTIBODIES AND EXACERBATION OF RENAL DISEASE IN
PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS FROM 2 RANDOMIZED
CONTROLLED TRIALS [RCTS] WITH LJP 394
M. D. Linnik, J. Z. Hu, K. R. Heilbrunn, F. L. Hurley
Background: Anti-dsDNA antibodies (anti-dsDNA Abs) are diagnostic
for systemic lupus erythematosus (SLE) and increases are prognostic
for SLE flares. The current analyses examined the relationship
between changes in anti-dsDNA Abs levels and SLE renal flares
using data from two large randomized placebo-controlled trials
(RCTs) where anti-dsDNA Ab levels were selectively reduced following
treatment with LJP 394.
Methods: Databases from a Phase 2/3 and Phase 3 RCT were
used as the basis for a retrospective evaluation of the relationship
between change from baseline in anti-dsDNA Abs levels and risk
of renal flare. The analysis populations from the Phase 2/3 and
Phase 3 RCTs included 189 and 298 SLE patients, respectively,
with a history of renal disease, anti-dsDNA Abs levels ≥15 IU/mL
at baseline by Farr assay and high-affinity antibodies to the
LJP 394 epitope at baseline. Anti-dsDNA Ab levels, serum chemistry
and urinalysis were evaluated at least monthly and SLE-related
renal flares were documented according to prespecified changes
from baseline in serum creatinine, proteinuria or hematuria. A
Cox proportional hazard regression model with time-dependent covariate
was used to evaluate the relationship between change from baseline
in log 10anti-dsDNA Abs and risk of renal flare.
Results: Treatment with LJP 394 was associated with statistically
significant decreases from baseline in anti-dsDNA Abs levels compared
with placebo (p<0.0001 for both RCTs) and an increased frequency
of pts with sustained reductions in anti-dsDNA Ab levels (Ž 10%
reduction in Ž 2/3 of all observed anti-dsDNA Ab values; levels
following initiation of high-dose corticosteroids and/or cyclophosphamide
were imputed to <10% reductions) with LJP 394 treatment compared
with placebo (58.7% and 55.2% vs. 13.4% and 26.8% for LJP 394
and PBO in Phase 2/3 and Phase 3 RCTs, respectively). The pathogenicity
of elevated anti-dsDNA Ab levels was supported by changes in anti-dsDNA
levels that were inversely correlated with C3 levels (p<0.001
for both RCTs). Cox proportional hazard regression models established
that changes from baseline in log 10 anti-dsDNA Ab levels were
associated with risk of renal flare in both Phase 2/3 and Phase
3 RCTs with estimated hazard ratios of 11.1 (95% CI: 2.8 to 44.8;
nominal p=0.0007) and 12.5 (95% CI: 3.8 to 41.1; nominal p<0.0001)
for a one-log change in anti-dsDNA, respectively. The majority
of renal flares were observed in patients who did not meet criteria
for sustained reduction in anti-dsDNA Ab levels: 93% (26/28) in
Phase 2/3 RCT and 88% (36/41) in Phase 3 RCT.
Conclusion: Data from two large RCTs in SLE patients with
elevated anti-dsDNA Abs levels at baseline and a history of renal
disease demonstrated an inverse relationship between anti-dsDNA
Abs levels and C3, support the hypothesis that increases in anti-dsDNA
increase the risk of renal flare and indicate that reductions
in anti-dsDNA Abs are associated with a reduced risk of renal
flare.
Presented at the
Annual European Congress of Rheumatology "EULAR 2004"
Berlin, Germany
June 9 –12, 2004
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