Serious adverse events—Missing in action: Comment on the article by Kremer et al


Serious Adverse Events—Missing in Action: Comment on the Article by kremer et al

To the Editor:

In a recent article, Kremer and colleagues reported the results of a phase IIb dose-ranging study of tofacitinib used in combination with methotrexate (MTX) in the treatment of patients with active rheumatoid arthritis who had an inadequate response to methotrexate alone (Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib [CP-690,550] versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum 2012;64:970–81). According to the authors, this 24-week trial was a rich source of data on the efficacy and safety of the treatment. In fact, detailed descriptions concerning efficacy, clinical adverse events (AEs), and laboratory AEs are prominent features of the report. Unfortunately, the 21 serious AEs occurring in 4.1% of patients are only mentioned in passing. Slightly more information was provided in the supplementary materials (, which include a table that shows the number of serious AEs occurring by dose but does not mention the type of event.

One key safety aspect of investigational drug studies involves reporting of all serious AEs. In addition to clinical and laboratory events, serious AEs provide a critical perspective on overall safety. What were the serious AEs that occurred in patients receiving tofacitinib and MTX? Did they involve malignancy or opportunistic infection? Was there any relationship between event type and dose? Were other medical conditions thought to be involved? All of these questions could have been answered with a more complete accounting, preferably in the body of the article.

Tofacitinib represents a new approach to treating chronic inflammatory disease. As such, it could have utility for a variety of indications across several disciplines. Because it is difficult to anticipate which data will be important to any given specialty, the level of disclosure becomes more important.

Perhaps the safety data generated in this trial could be revisited by the authors in a more comprehensive way. I am confident that rheumatologists and other medical professionals would appreciate knowing much more about the safety profile of tofacitinib.


Dr. Leonardi has received consulting fees, speaking fees, and/or honoraria from Centocor, Pfizer, and Eli Lilly (less than $10,000 each) and from Abbott and Amgen (more than $10,000 each). He has served as an investigator for Abbott, Allergan, Altana, Alza, Amgen, Astellas, Celgene, Centocor, Genentech, Bristol-Myers Squibb, Eli Lilly, Ferndale, Fujisawa, Galderma, GlaxoSmithKline, Incyte, Pfizer, Sirtris, Stiefel, Novo Nordisk, Vasculas Biogenics, CombinatoRx, 3M Pharmaceuticals, Medicis, Maruho, Protein Design Labs, Perrigo Israel Pharmaceutical, Schering-Plough, Serono, Symbio, RTL, Novartis, Vitae, and Wyeth.

Craig L. Leonardi MD*, * Central Dermatology, St. Louis, MO.