Title

 

Authors

S. Mantarro¹, M. Tuccori^2,3, C. Scollo¹, S. Montagnani¹, G. Giustarini¹, M. Moschini^2,4, F. Lapi^2,4, A. Testi^2,5, E. Ruggiero^2,6, A. Vannacci^2,4, L. Sottosanti⁷, A. Mugelli^2,4, F. Ferrazin⁷, C. Blandizzi^1,2

1 Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa
2 Tuscan Regional Centre for Pharmacovigilance,
3 Unit of Pharmacology, University Hospital of Pisa
4 Department of Preclinical and Clinical Pharmacology, University of Florence
5 Pharmaceutical Unit, Regional Health System, Local Healthof Pisa
6 Pharmaceutical Unit, University Hospital of Pisa
7 Italian Drug Agency (Agenzia Italiana del Farmaco, AIFA), Rome 

 

Abstract

Tumor necrosis factor alpha (TNF-α) is a cytokine playing a major role in the surveillance of malignancies by regulation ofcell-immunity-mediated killing of tumor cells. TNF-α is also involved in the pathogenesis of several rheumatologic diseases, and drugs inhibiting TNF-α have gained large employment in the treatment of rheumatologic disorders. The possible role of anti-TNF-αdrugs in tumorigenesis is currently debated, since several rheumatologic diseases are themselves associated with an increased risk of malignancy, and rheumatologic patients often report a history of immunosuppression. An increased frequency of skin tumours (basal cell carcinoma and malignant melanoma) has been hypothesized for anti-TNF-α drugs (Chakraverty, 2005, Askling et al., 2011). The objective of this study is to investigate possible “alarm signals” of skin cancers associated with anti-TNF-α drugs.The present analysis was performed on spontaneous reports of adverse drug reactions (ADRs) received by the Italian Drug Agency (AIFA; January 2000 - March 2011), integrated with ADR reports recorded by the Interregional Group of Pharmacovigilance (GIF; 1988-2006). Associations between drugs and skin cancers were assessed by means of ADR proportional reporting ratio (PRR), as a measure of disproportionality. Cases were defined as reports including at least one ADR codified as “malignant melanoma” or “basal cell carcinoma” by the WHOART preferred term. Non-cases comprised all remaining reports. Index reports included ADRs associated with etanercept, infliximab, adalimumab, certolizumab pegol or golimumab, while all ADR reports not involving index drugs were used as controls. PRR was calculated only for index drugs with at least 2 cases in the whole database.According to selection criteria, 116,142 reports were included in the analysis. Anti-TNF-α drugs were indicated as suspected drugs in ADR reports as follows: 693 reports for infliximab, 432 reports for etanercept, 277 reports for adalimumab, 3 reports for certolizumab pegol and 1 report for golimumab. The very low number of ADR reports recorded for certolizumab pegol and golimumab depends on their recent marketing in Italy (< 1 year). Anti-TNF-α drugs were considered as suspected in 9 cases of malignant melanoma (infliximab: 1 case, PRR: not assessed; etanercept: 4 cases, PRR: 76.2 [95%CI: 25.4-228.5]; adalimumab: 4 cases, PRR: 170.4 [50.6-531.3]) and 7 cases of basal cell carcinoma (infliximab: 1 case, PRR: not assessed; etanercept: 4 cases, PRR: 228.5 [95%CI: 61.6-847.9]; adalimumab: 2 cases, PRR: 133.9 [95%CI: 28-641]). Patients who experienced malignant melanoma were 5 males and 4 females; the median age was 51.6 years [range: 30-68 years] and the median time to event onset was 36.7months [range: 16-63 months]. Patients with basal cell carcinomawere 3 males and 4 females; the median age was 61 years [range: 37-73 years] and the median time to event onset was 24.9months [range: 5 days-72 months].In our database, the estimation of PRR suggests a significant risk of malignant melanoma and basal cell carcinoma reporting for both etanercept and adalimumab. Although the present analysis is limited by the small number of reports and the elevated PRR values depend on the rarity of drug-associated skin cancer in the database, our findings are in line with previous literature reports. Since the mechanisms underlying these ADRs are likely to depend on TNF-α blockade, it is reasonable to suggest skin cancers as rare class effects associated with anti-TNF-α treatments.

References
Chakraverty EF, et al. J Rheumatol. 2005;32:2130-5
Askiling J, et al.,Pharmacoepidemiol Drug Saf .2011;20:119-30