Vol.23 No.2

Original Article

Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs

Authors

Masayoshi Harigai1,2,3 , Akito Takamura1,3 , Tatsuya Atsumi1,4 , Makoto Dohi1,5 , Shintaro Hirata1,6 , Hideto Kameda1,7 , Hayato Nagasawa1,8 , Yohei Seto1,9 , Takao Koike10 , Nobuyuki Miyasaka11,3

  • The Ad Hoc Committee for the Safety of Biological DMARDs, Japan College of Rheumatology, 1-1-24 Toranomon, Minato-ku, Tokyo, 105-0001, Japan
  • Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
  • Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku,Tokyo, Japan
  • Department of Internal Medicine II, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
  • Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  • The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Fukuoka, Japan
  • Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Faculty of Medicine, Keio University, Tokyo, Japan
  • Department of Rheumatology/Clinical Immunology, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan
  • Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan
  • Sapporo Medical Center NTT EC, Chuo-ku, Sapporo, Hokkaido, Japan
  • Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan
Received:

16 January 2012

Accepted:

19 April 2012

Published online:

17 May 2012

Full Text

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Abstract

Objective The associations between elevated levels of serum Krebs von den Lungen-6 (KL-6) and treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) inhibitors were investigated in five Japanese clinical trials.
Methods Percentages and incidence rates were calculated for elevated serum KL-6 levels. Adverse events associated with elevated levels of serum KL-6 were investigated.
Results In RISING, a clinical trial for infliximab, 15.6 % of the enrolled patients met criterion B (KL-6 ≥500 U/ml and >1.5-fold increase over the baseline value) by week 54. In HIKARI, 7.8 % of the certolizumab pegol (CZP) group and 0 % of the placebo group met criterion B during the double-blind (DB) period (p = 0.003). In J-RAPID, 8.4 % of the methotrexate (MTX) + CZP and 3.9 % of the MTX + placebo groups met criterion B during the DB period. In GO-MONO, 1.8 % of the golimumab (GLM) and 1.3 % of the placebo groups met criterion B during the DB period. In GO-FORTH, 7.1 % of the MTX + GLM and 0 % of the MTX + placebo groups met criteron B during the DB period (p = 0.017). No adverse events accompanied the elevation of serum KL-6 levels in 95.7 % of these patients.
Conclusion Serum KL-6 levels may increase during anti-TNF therapy without significant clinical events. In these patients, continuing treatment with TNF inhibitors under careful observation is a reasonable option.

Key words

Biological disease modifying antirheumatic drug  KL-6 - Rheumatoid arthritis - Interstitial pneumonia - Pneumocystis jirovecii pneumonia