Session Information
Title: Systemic Lupus Erythematosus - Clinical Aspects: Non-biologic Disease-modifying Antirheumatic Drugs
Session Type: Abstract Submissions (ACR)
Background/Purpose: The BOLD study was designed to test the discriminatory capacity and safety of a trial design eliminating background immune suppressants (IS) in SLE patients (pts) with active, non-organ threatening disease.
Methods: 103 active pts (SLEDAI >/= 6 and/or >/= 2 BILAG B or 1 A) were evaluated at baseline (BV) for effects of IS on immunologic variables, then 41 pts entered a prospective phase with depomedrol injections to improve disease, withdrawal of background IS, and serial biomarker samples until flare. Designation of improving visits (IV) and flare visits (FV) were weighted by clinical opinion and confirmed by BV vs IV: universal decreases in SLEDAI, BILAG, PGA, CLASI, and joint counts (all p<0.0001), IV vs FV: universal increases (all p<0.0013).
Results: The regimen was well tolerated. Of 48 adverse events only one was serious (bleeding ulcer) and resolved. 40/41 pts flared within 24 weeks. All flares improved within 6 weeks with treatment. Median (95% CI) Days to flare (DTF) was 56 (40-76). This was influenced by baseline disease activity and amount of steroid given. BILAG >/= 17 DTF 40 (29-72) vs BILAG < 17 DTF 71 (43-91) (log rank p= 0.043), depomedrol /= 17 DTF 38 (22-76) vs depomedrol >/= 320mg + BILAG < 17 DTF 91 (40-107). Baseline (withdrawn) IS had no impact on DTF. 47% of pts had elevated type I interferon signature (IFN HI) defined by a novel 11 gene panel we have reported (1). 38% of Caucasians were IFN HI vs 50% Asians, 69% Native Americans and 65% African Americans (Cauc vs others: p=0.012). IFN HI pts were more likely to have antibodies to dsDNA (p=0.001) SSA/Ro (p=0.0007) RNP (p=0.0001) and Sm (p=0.01), had higher circulating BLyS (p=0.00018) and IL23 (p=0.02) but not increased CR3 membrane expression. The table below illustrates potential differences between IFN HI and LOW pts in the impact of different IS on fold expression of non-IFN RNA [e.g. Increase (INCR) or Decrease (DECR), blank cells indicate no differences.
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Mechanistic Impact of Background Treatments Commonly Allowed in Lupus Trials Evaluated By Underlying IFN Signature: Fold Increase or Decrease in RNA Expression |
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All Pts (n=103) vs healthy controls |
Pts on AZA vs Pts on no IS |
Pts on MMF vs Pts on no IS |
Pts on MTX vs Pts on no IS |
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Gene product |
IFN HI |
IFN LOW |
IFN HI |
IFN LOW |
IFN HI |
IFN LOW |
IFN HI |
IFN LOW |
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BLyS/TNFSF13B (p value) |
INCR 2.43 (0.0001) |
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INCR 1.36(0.018) |
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IL23A (p value) |
DECR 1.29 (0.04) |
DECR 1.24 (0.09) |
INCR 1.57(0.029) |
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CR3/ITGAM (p value) |
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DECR 1.27 |
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DECR 1.69(0.006) |
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LGALS3BP (p value) |
INCR 2.93 (0.0001) |
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DECR 2.77(0.0009) |
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IgE Recptr (p value) |
DECR 2.13(0.0001) |
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INCR 1.95 (0.053) |
INCR 2.28(0.02) |
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INCR 2.20(0.051) |
INCR 3.43(0.0008) |
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This exploratory, biomarker analysis was not corrected for multiple comparisons.
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Conclusion: The BOLD treatment regimen is safe in pts without organ threatening disease and confirms the feasibility of an efficient trial design, ensuring low placebo response rates after brief baseline steroid intervention. This allows consideration of immediate rescue treatment at time of non-response without obfuscating the endpoint, and solves the problem of conventional trials requiring year-long stability of ineffective IS. Less background IS may also decrease infection risk. All outcome measures (BILAG, SLEDAI, PGA, CLASI) performed robustly in this simplified protocol, consistent with clinician-determined improvement and flare. With improved understanding of individual treatment effects on immune targets in key patient subsets, IS might be more strategically selected for studies of sicker pts and withdrawn entirely for stable pts, improving the discriminatory capacity of lupus trials while illuminating the optimal use of medications in clinic.
(1) Hill et al EULAR 2013 FRI0003
Disclosure:
J. T. Merrill,
Pfizer Inc,
5;
F. W. Immermann,
Pfizer Inc,
3;
T. Zhou,
Bristol Myers Squibb,
3,
Pfizer Inc,
3;
M. O’Toole,
Pfizer Inc,
3;
M. Whitley,
Pfizer Inc,
3;
A. A. Hill,
Pfizer Inc,
3,
Pfizer Inc,
1;
Y. Zhang,
Pfizer Inc,
3;
D. von Schack,
Pfizer Inc,
3;
P. S. Reddy,
Pfizer Inc,
3;
J. L. Masferrer,
Pfizer Inc,
3;
S. Kamp,
None;
J. M. Guthridge,
None;
A. Thanou,
None;
P. Wu,
Pfizer Inc,
3;
T. Paradis,
Pfizer Inc,
3;
W. M. Mounts,
Pfizer Inc,
3;
J. A. James,
Pfizer Inc,
5;
S. T. Sridharan,
Pfizer Inc,
3.
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