Non-Hodgkin's lymphoma and nonsteroidal anti-inflammatory drugs: a confounding problem?

Abstract

The International Journal of Cancer article by Cerhan et al.1 fuels the controversy over the association between non-Hodgkin's lymphoma (NHL) and use of nonsteroidal anti-inflammatory drugs (NSAIDs). After examination of a prospective cohort of postmenopausal women in Iowa, the authors suggest that NSAIDs increase the risk of NHL independent of a history of rheumatoid arthritis (RA). However, before indicting NSAIDs as a risk factor for NHL, one must carefully consider study limitations and findings. No data were collected on many of the known risk factors for NHL that are likely confounded with NSAID use; no data were collected on NSAID exposure by type, strength and duration of intake, and perhaps most notably, there was a complete absence of any dose response in the observed patterns of NHL risk with frequency of NSAID use. Of particular importance is that exposure to NSAIDs is potentially confounded with inflammation, treatment and immunosuppression in not just RA but a myriad of other immunosuppressive autoimmune disorders and medications that have been etiologically linked to NHL development. Such potential confounders with NSAID use in subjects without RA include chronic viral infections (hepatitis C virus, Epstein-Barr virus and human immunodeficiency virus) and several other autoimmune disorders (systemic lupus erythematosus, Sjörgen's syndrome, Felty's syndrome, Graves' disease, Reiter's syndrome, Hashimoto's thyroiditis, autoimmune hemolytic anemia, celiac disease, etc.) as well as multiple cytotoxic and immunosuppressive drugs used to treat these conditions.2, 3, 4, 5, 6, 7, 8, 9, 10 Without adjustment for important confounders, the interpretation of relative risk estimates may be fallacious. Dose response is a critical indicator of causation in epidemiologic investigations.11 The elevated risk estimates observed by Cerhan et al.1 for subjects with reported sporadic NSAID use and the total absence of a dose response are not consistent with causality. Interestingly, Holly et al.,12 who limited their study to women and heterosexual men, found that NSAIDs decrease the risk of NHL. They suggested that these compounds reduce the activation of macrophages and the proliferation of B lymphocytes (the cell of origin in the majority of NHLs). This is consistent with molecular studies that show that inflammatory stimuli activate macrophages, neutrophils and T lymphocytes that result in overexpression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE-2).13 In particular, PGE-2 has been found to be a potent regulator of B-lymphocyte function by promoting immunoglobulin class switching to IgE.14 Baecklund et al.15 and Tennis et al.16 found that when they stratified arthritic patients by disease severity and use of immunosuppressive drugs, the occurrence of NHL was attributable to inflammation and effects of cytotoxic compounds but not to NSAIDs. In my view, epidemiologic investigations that are designed to collect appropriate data and correct for immunosuppressive and inflammatory conditions as well as the intake of immunosuppressive and cytotoxic drugs will be needed to clarify the true nature of the association between NSAIDs and NHL. Yours sincerely, Randall E. Harris