Published online January 4, 2006
PEDIATRICS Vol. 117 No. 1 January 2006, pp. 253-254 (doi:10.1542/peds.2005-2312)

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LETTER TO THE EDITOR

Niflumic Acid and Mucocutaneous Reactions

Francesca Menniti-Ippolito, MSc
Giuseppe Traversa, MD
Roberto Da Cas, MSc
National Centre for Epidemiology
Surveillance and Health Promotion
National Institute of Health
00161 Rome, Italy

Roberto Leone, PhD
Department of Medicine and Public Health
University of Verona
37134 Verona, Italy

Achille Caputi, MD
Department of Clinical and Experimental Medicine and Pharmacology
University of Messina
98122 Messina, Italy

To the Editor.—

We read with interest the article by Sturkenboom et al,¹ in which they found that, in comparison with paracetamol and other nonsteroidal antiinflammatory drugs, no increased risk of mucocutaneous events was present among users of niflumic acid. This article followed a previous short report² in which we documented that, in comparison with nonusers, children who had used niflumic acid experienced an increased risk of mucocutaneous events (odds ratio [OR]: 4.9; 95% confidence interval [CI]: 1.9–12.8), whereas the corresponding OR among users of paracetamol was 1.2 (95% CI: 0.6–2.4).

In the discussion section of their article, Sturkenboom et al examine 3 possible reasons for the discrepancies: the choice of the exposure reference group; the fact that ORs were not adjusted by age; and the possibility that "protopathic bias" may have influenced the estimates. The first objection cannot explain the difference in the ORs between niflumic acid and paracetamol, because users of both substances were compared with the same reference group.

We recognize that age may represent a potential confounding factor. In the Naples study, the median age of cases and controls was 41 and 44 months, respectively. Because the OR estimates did not change after adjusting also for age and gender, we did not take these variables into account in the article.

Protopathic bias is a potential threat for most pharmacoepidemiologic studies. Sturkenboom et al will agree that the risk of protopathic bias should be lowest when, like in the Naples study, the question is explicitly addressed at ascertaining the use of drugs preceding the symptoms that led to hospitalization (for both cases and controls). Moreover, in our opinion, it would be unreasonable to explain the difference in the OR estimates of niflumic acid and paracetamol found in the Naples study through a protopathic bias that acted differentially for the 2 drugs.

The possibility remains that our findings on niflumic acid represented a "random high"³ superimposed on an elevated risk among users of nonsteroidal antiinflammatory drugs. However, the possibility should also be considered that the findings presented by Sturkenboom et al represented, at least partially, a false-negative result. In this regard, the absence of risk associated with antibiotic use was unexpected. In their Table 3,¹ the relative risk estimates associated with antibiotic use, in comparison with nonuse, were 0.8 (95% CI: 0.4–1.6) for severe reactions and 1.0 (95% CI: 0.9–1.1) for mild reactions. Is it possible that the large bias toward the null that affected the estimates for antibiotic use also may have acted for the other estimates?

Because the discussion of the study that was summarized by Sturkenboom et al in their article was presented officially at the Pharmacovigilance Committee of the Italian Medicines Agency, this letter is also signed by some experts of that committee.

REFERENCES

1. Sturkenboom M, Nicolosi A, Cantarutti L, et al. Incidence of mucocutaneous reactions in children treated with niflumic acid, other nonsteroidal antiinflammatory drugs, or nonopioid analgesics. Pediatrics. 2005;116 (1). Available at: www.pediatrics.org/cgi/content/full/116/1/e26
2. Menniti-Ippolito F, Sagliocca L, Da Cas R, Saggiomo G, Di Nardo R, Traversa G. Niflumic acid and cutaneous reactions in children. Arch Dis Child. 2001;84 :430 –431
3. Vandenbroucke JP. In defense of case reports and case series. Ann Intern Med. 2001;134 :330 –334

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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Pediatrics 2006 117: 254-255. [Extract] [Full Text]  

This Article Extract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article to a friend Related articles in Pediatrics Similar articles in this journal Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Menniti-Ippolito, F. Articles by Caputi, A. Search for Related Content PubMed Articles by Menniti-Ippolito, F. Articles by Caputi, A. Related Collections Therapeutics & Toxicology Social Bookmarking                         What's this?