E064 The relationship between lipid profile changes and inflammation across the Phase 3 sarilumab rheumatoid arthritis (RA) development programme
Bibliographic record
Abstract
Background: Serum lipids may be reduced in the setting of chronic inflammation associated with active RA, and they may increase following an effective response to RA therapy, which may be associated with decreased cardiovascular risk, an effect known as the lipid paradox. Sarilumab, an IL-6R blocker approved for the treatment of RA, showed superiority to placebo and adalimumab in RA Phase 3 trials. In this post hoc analysis, we investigated the relationship between lipid levels and markers of inflammation in these trials. Methods: Fasting total (TC), high- (HDL-C) and low-density lipoprotein cholesterol (LDL-C), triglycerides, lipoprotein (a) (Lp(a)), and apolipoproteins (Apo) A and B were evaluated in two placebo-controlled studies of sarilumab (150 mg and 200 mg q2w) +csDMARDs in patients with inadequate response (IR) to methotrexate (MOBILITY; NCT01061736) or IR/intolerance to tumour necrosis factor inhibitors (TARGET; NCT01709578) and in a monotherapy study of sarilumab vs adalimumab (MONARCH; NCT02332590). Spearman and Pearson correlations compared relationships between lipid levels and inflammatory markers (C-reactive protein [CRP] and serum amyloid A [SAA, MOBILITY only]). Results: Safety profile of sarilumab has been previously reported; there was no increased risk of major adverse cardiac events with sarilumab. In 52-week MOBILITY and 24-week TARGET, both sarilumab doses led to increases in TC, HDL-C, LDL-C, and triglyceride levels vs placebo (as early as Week 2), and these increases were maintained. In MONARCH, compared to adalimumab, sarilumab treatment led to a greater increase from baseline in TC (16.3 vs 1.4 mg/dL), HDL-C (1.4 vs -0.2), LDL-C (10.5 vs 0.5), and triglycerides (26.6 vs 5.7) and a greater decrease in Lp(a) (-41% vs -2.8%). Changes from baseline in TC/HDL-C ratio for sarilumab 200 mg vs placebo were 0.41 vs 0.01 (MOBILITY Week 52), 0.32 vs -0.06 (TARGET Week 24) and for sarilumab vs adalimumab were 0.22 vs 0.02 (MONARCH Week 24). Sarilumab reduced CRP and SAA (MOBILITY) vs placebo and adalimumab. Negative Spearman correlations (nominal P < 0.001 or P < 0.0001) between decreases from baseline in CRP and increases in lipid levels were seen with adalimumab (data not shown) and with sarilumab 200 mg for TC (-0.26 [MOBILITY Week 52] and -0.33 [TARGET Week 24]), HDL-C (-0.26 TARGET Week 24), LDL-C (-0.21 [MOBILITY Week 24] and -0.25 [TARGET Week 24]), and triglycerides (-0.21 [MOBILITY Week 52]). Conclusion: Sarilumab treatment resulted in increases in lipid parameters vs placebo or adalimumab and reductions in Lp(a). This was seen relatively quickly and stabilised after 4 weeks. Lipid elevation was associated with a reduction in inflammatory markers and was consistent with IL-6 blockade. Disclosures: C. Charles-Schoeman: Consultancies; Regeneron-Sanofi, Pfizer, Octapharma, Amgen, and Gilead. Grants/research support; Bristol-Myers Squibb, AbbVie, Octapharma, and Pfizer. G. St John: Corporate appointments; Regeneron Pharmaceuticals, Inc. Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. H. Leher: Corporate appointments; Regeneron Pharmaceuticals, Inc. Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. T. Kimura: Corporate appointments; Regeneron Pharmaceuticals, Inc. Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. H. van Hoogstraten: Corporate appointments; Sanofi Genzyme. Shareholder/stock ownership; Sanofi Genzyme. M. Nurmohamed: Honoraria; AbbVie, Pfizer, Merck, Roche, BMS, UCB, Sanofi, Eli Lilly, Celgene, and Janssen. Grants/research support; AbbVie, Pfizer, Merck, Roche, BMS, UCB, Sanofi, Eli Lilly, Celgene, and Janssen. M.A. González-Gay: Consultancies; AbbVie, Roche, Sanofi, Eli Lilly, and Novartis. Grants/research support; AbbVie, Roche, Sanofi, Eli Lilly, and Novartis. E. Wilson: Corporate appointments; Sanofi Genzyme. Shareholder/stock ownership; Sanofi Genzyme. E.C. Keystone: Consultancies; AbbVie, Amgen, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Celltrion, Crescendo Bioscience, F. Hoffmann-La Roche Inc, Genentech Inc, Gilead, Janssen Inc, Lilly Pharmaceuticals, Merck, P. Honoraria; Amgen, AbbVie, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Pfizer Pharmaceuticals, Sanofi Genzyme, and UCB. Grants/research support; AbbVie, Amgen, Bristol-Myers Squibb, F. Hoffmann-La Roche Inc, Gilead, Janssen Inc, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, and Sanofi-Aventis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.008 | 0.009 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.016 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".