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Extended report
Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein
  1. Stacy P Ardoin1,
  2. Laura Eve Schanberg2,
  3. Christy I Sandborg3,
  4. Huiman X Barnhart2,
  5. Greg W Evans4,
  6. Eric Yow2,
  7. Kelly L Mieszkalski2,
  8. Norman T Ilowite5,
  9. Anne Eberhard6,
  10. Lisa F Imundo7,
  11. Yuki Kimura8,
  12. Deborah Levy9,
  13. Emily von Scheven10,
  14. Earl Silverman9,
  15. Suzanne L Bowyer11,
  16. L Punaro12,
  17. Nora G Singer13,
  18. David D Sherry14,
  19. Deborah K McCurdy15,
  20. Marissa Klein-Gitelman16,
  21. Carol Wallace17,
  22. Richard M Silver18,
  23. Linda Wagner-Weiner19,
  24. Gloria C Higgins1,
  25. Hermine I Brunner20,
  26. Lawrence Jung21,
  27. Jennifer B Soep22,
  28. Ann M Reed23,
  29. Susan D Thompson20,
  30. for the APPLE investigators
  1. 1Department of Medicine, Nationwide Children's Hospital, Ohio State University, Columbus, Ohio, USA
  2. 2Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, Durham, North Carolina, USA
  3. 3Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, USA
  4. 4Departments of Biostatistical Sciences and Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  5. 5Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA
  6. 6Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York, USA
  7. 7Department of Pediatrics, Columbia University Medical Center, New York, New York, USA
  8. 8Department of Pediatrics, Joseph M. Sanzari Children's Hospital at Hackensack University Medical Center, Hackensack, New Jersey, USA
  9. 9Department of Rheumatology, Toronto Hospital for Sick Children, Toronto, Ontario, Canada
  10. 10Department of Pediatrics, University of California at San Francisco, San Francisco, California, USA
  11. 11Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA (deceased)
  12. 12Department of Rheumatology, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA
  13. 13Department of Medicine, University Hospitals/Case Medical Center, Cleveland, Ohio, USA
  14. 14Department of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  15. 15Division of Pediatric Rheumatology, University of California Los Angeles School of Medicine, Los Angeles, California, USA
  16. 16Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  17. 17Department of Pediatric Rheumatology, Seattle Children's Hospital, Seattle, Washington, USA
  18. 18Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
  19. 19Department of Pediatrics, University of Chicago, Chicago, Illinois, USA
  20. 20Department of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  21. 21Department of Rheumatology, Children's National Medical Center, Washington, DC, USA
  22. 22Department of Rheumatology, The Children's Hospital, Denver, Colorado, USA
  23. 23Department of Rheumatology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Stacy P Ardoin, Departments of Pediatrics and Medicine, Ohio State University and Nationwide Children's Hospital, S2056 480 Medical Center Drive, Columbus, Ohio 43210, USA; stacy.ardoin{at}osumc.edu

Abstract

Objective Participants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy.

Methods Subgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score ≥4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models.

Results Significant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures.

Conclusions Pubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy.

ClinicalTrials.gov identifier: NCT00065806.

  • Atherosclerosis
  • Systemic Lupus Erythematosus
  • Autoimmune Diseases

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