Dear Editor,

We read with interest the meta-analysis of registries and prospective observational studies conducted by Mariette and colleagues on the risk of malignancies in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) antagonists. (1) Their meta-analysis highlights the complexity surrounding this important clinical issue, when TNF antagonists are considered for patients with RA with a malignancy or a prior history of malignancy. Their meta-analysis revealed that although TNF antagonists did not increase the risk of all-site malignancies, including lymphomas, they did increase the risk of skin cancer, particularly non-melanoma skin cancer (NMSC) with a pooled odds ratio (OR) of 1.45 (95% confidence intervals [CI] 1.17-1.76) based on four prior studies which showed ORs ranging from 1.20 to 1.83. Another recent meta-analysis of randomized controlled trials (RCTs) on the same topic showed similar results with a relative risk (RR) for NMSC of 2.02 (95% CI 1.11-3.95). (2)

We would like to point out that our own retrospective cohort study of 20,648 patients with RA assembled from the Department of Veterans Affairs (VA) national administrative databases in the United States demonstrated remarkably similar results to those of Mariette et al with a hazards ratio (HR) of 1.42 (95% CI 1.24-1.63) for an increased risk of NMSC, despite the inherent limitations associated with a retrospective cohort study. (3)

Thus based on evidence available to date, use of TNF antagonists in patients with RA appears to increase the risk of NMSC. This may be especially true for older patients, males, those on chronic steroids and non-steroidal anti-inflammatory drugs (NSAIDs), and those with a history of prior malignancies, as shown in our study. (3) Rheumatologists should be vigilant about such a risk when using these biologic agents in RA.

References

1. Mariette X, Matucci-Cerinic M, Pavelka K, et al. Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis. Ann Rheum Dis 2011 Nov;70(11):1895-904. Epub 2011 Sep 1

2. Askling J, Fahrbach K, Nordstrom B, et al. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta- analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf 2011;20(2):119-30. doi: 10.1002/pds.2046. Epub 2010 Dec 7.

3. Amari W, Zeringue AL, McDonald JR, et al. Risk of non-melanoma skin cancer in a national cohort of veterans with rheumatoid arthritis. Rheumatology (Oxford) 2011;50(8):1431-9. Epub 2011 Mar 16. Conflict of Interest: none

Conflict of Interest:

None declared

Dear Editor,

We read with much interest the published article entitled 'Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis' by Mariette et al [1]. Beyond any doubt, autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus and psoriatic arthritis are associated with higher incidence of malignancy[2.3,4]. The exact pathophysiology involved is not well understood but inflammatory cells have been proven to produce tumor- associated antigens [5].Besides, the gold standard of therapy in RA i.e. methotrexate is reported to increase the risk of developing malignancies such as lymphoma [6]. Thus, the development of malignancy in this setting appears to be multifactorial. Both the disease and its treatment increase malignant potential. The investigators stated that the risk of developing recurrence or a new primary cancer in patients with previous malignancies were similar in both the DMARD-treated patients and TNFi-treated patients but there was no comparison made between the two groups for subjects without previous history of malignancies.To a certain extent, this information may potentially influence the clinicians' decision of switching over to TNFi after weighing the risks and benefits.

Considering that the inclusion criteria considered patients with RA, PsA and ankylosing spondylitis, we feel that Table 1 under indication, should state the specific disease entity for all publications. The phrase 'rheumatic disease' is too general. Other rheumatic diseases such as systemic lupus erythematosus, takayasu arteriis and dermatomyositis have specific indications for TNFi especially in refractory cases. The investigators could have clarified the indication with the respective authors.

To date, there are many different types of TNFi prescribed worldwide such as Infliximab, Etanercept and Adalimumab. In this meta-analysis, it would have been interesting and beneficial if the investigators had studied the breakdown incidence of malignancy with each individual TNFi.

With reference to Table 2 on the rates of malignancies in TNFi patients, the information on the incidence rate per 1000 patients should have been subdivided into the 1st year of treatment with TNFi, 2nd year and subsequent years. It is vital for clinicians to identify when the incidence peaks in order to be more vigilant during follow-up.

We applaud the quality of the work and thank the editor for publishing such informative articles.

References

1. Mariette X, Matucci-Cerinic M, Pavelka K, et al. Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis. Ann Rheum Dis doi:10.1136/ard.2010.149419.

2. Husni ME, Mease PJ. Managing comorbid disease in patients with psoriatic arthritis. Cur Rheumatol Rep 2010;12:281-7.

3. Bernatsky S, Ramsey-Goldman R, Foulkes WD, et al. Breast, ovarian, and endometrial malignancies in systemic lupus erythematosus: a meta-analysis. Br J Cancer 2011;104:1478-81.

4. Chen YJ, Chang YT, Wang CB, et al. The risk of cancer in patients with rheumatoid arthritis: A nationwide cohort study in Taiwan. Arthritis Rheum 2011;63:352-8.

5. Szekanecz E, Andras C, Sandor Z, et al. Malignancies and soluble tumor antigens in rheumatic diseases. Autoimmun Rev 2006;6:42-7.

6. Matsui Y, Miura Y, Sugino N, et al. Methotrexate-associated lymphoplasmacytic lymphoma complicated with type 2 cryoglobulinemia. Int J Haematol 2011;93:253-6.

Conflict of Interest:

None declared