Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis

Xavier Mariette; Marco Matucci-Cerinic; Karel Pavelka; Peter Taylor; Ronald van Vollenhoven; Rebecca Heatley; Claire Walsh; Richard Lawson; Alan Reynolds; Paul Emery

doi:10.1136/ard.2010.149419

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Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis

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Updated meta-analysis of non-melanoma skin cancer rates reported from prospective observational studies in patients treated with tumour necrosis factor inhibitors
Xavier Mariette
Published on: 23 August 2012
Non-melanoma skin cancer risk in patients with rheumatoid arthritis on tumor necrosis factor inhibitors
PRABHA RANGANATHAN
Published on: 10 November 2011
Association of malignancies with tumour necrosis factor inhibitors: real facts
Srijit Das
Published on: 2 October 2011

Published on: 23 August 2012
Updated meta-analysis of non-melanoma skin cancer rates reported from prospective observational studies in patients treated with tumour necrosis factor inhibitors
- Xavier Mariette, Rheumatologist
- Other Contributors:
  Alan Reynolds, Paul Emery
Dear Editor,
Dear Editor,
We recently published a meta-analysis of malignancy rates reported from prospective observational studies in patients treated with tumour necrosis factor inhibitors (TNF-I). [1] Whilst there was no increase in the rates of all-site malignancy or lymphoma, there was an increased risk of non-melanoma skin cancer (NMSC) (1.45, 95% CI 1.15 to 1.76).
The skin cancer analysis incl...
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Dear Editor,
Dear Editor,
We recently published a meta-analysis of malignancy rates reported from prospective observational studies in patients treated with tumour necrosis factor inhibitors (TNF-I). [1] Whilst there was no increase in the rates of all-site malignancy or lymphoma, there was an increased risk of non-melanoma skin cancer (NMSC) (1.45, 95% CI 1.15 to 1.76).
The skin cancer analysis included data from an abstract from the British Society for Rheumatology Biologics Register (BSRBR) [2] that has since been published as a full paper with different estimates [3}. In the BSRBR abstract, the adjusted hazard ratio (HR) in comparison to a control cohort of patients treated with disease-modifying antirheumatic drugs (DMARD), without a prior NMSC, was 1.7 (95% CI 0.9, 3.4). [2] The updated analysis provided separate estimates for basal cell carcinoma (HR 0.95 [95% CI 0.53 to 1.71]) and squamous cell carcinoma (HR 1.16 [95% CI 0.35, 3.84]). [3]
Since the updated results were substantially lower than the value reported in the BSRBR abstract, we revised our analysis to include the updated data, to investigate whether our original conclusions regarding the increased risk of skin cancer could be sustained.
In our revised analysis, the pooled risk estimate for NMSC in patients treated with TNF-I was 1.33 (95% CI 1.06, 1.60).
Therefore, the revised analysis is consistent with our original conclusion that treatment with TNF-I increases the risk of NMSC; although, the lower confidence interval bound is only just above 1.0. These revised results are still aligned with a meta-analysis of randomised controlled trials across indications; although, here the increased risk of NMSC was 2 -fold (RR 2.02, 95% CI 1.11 to 3.95). [4]
Direct random effects meta-analyses were conducted in a frequentist framework using Stata version 11. The level of heterogeneity was determined using the I2 statistic
References
1. Mariette X, Matucci-Cerenic M, Pavelka K, et al. Malignancies associated with TNF inhibitors in registries and prospective observational studies: A systematic review and meta-analysis. Ann Rheum Dis. 2011;70:1895-1904.
2. Mercer LK, Galloway JB, Lunt M, et al. The Influence of Anti-TNF Therapy Upon Incidence of Non-Melanoma Skin Cancer (NMSC) in Patients with Rheumatoid Arthritis (RA): Results From the BSR Biologics Register (BSRBR) Arthritis Rheum. 2009;60(Suppl 10):2062
3. Mercer LK, Green AC, Galloway JB, et al. The influence of anti-TNF therapy upon incidence of keratinocyte skin cancer in patients with rheumatoid arthritis: longitudinal results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2012;71:869-874
4. 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;20:119-30 .
5. Askling J, ARTIS study group. Anti-TNF therapy and risk of skin cancer, data from the Swedish ARTIS registry 1998-2006. Ann Rheum Dis. 2009;68:(Suppl 3) 423
6. Greenberg J, Strand V, Keystone E, et al. TNF Inhibitors (TNF-I) and Risk of Malignancy in 8,072 RA Patients Followed Over 15,495 Patient Years. American College of Rheumatology Annual Meeting. 2007;Abstract 282
7. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum. 2007;56:2886-2895.
Conflict of Interest:
XM has received research grants or honoraria from Bristol Myers Squibb, GSK, Pfizer and Roche AR was an employee of Wyeth Europa and had held shares in Wyeth and currently has Pfizer share options and has undertaken consultancy work for UCB Pharma and Pfizer PE has received research grants or honoraria from Bristol Myers Squibb, GSK, Pfizer and Roche This work was undertaken without external funding
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Conflict of Interest:
None declared.
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Published on: 10 November 2011
Non-melanoma skin cancer risk in patients with rheumatoid arthritis on tumor necrosis factor inhibitors
- PRABHA RANGANATHAN, Associate Professor of Medicine
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...
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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
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Conflict of Interest:
None declared.
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Published on: 2 October 2011
Association of malignancies with tumour necrosis factor inhibitors: real facts
- Srijit Das, Lecturer
- Other Contributors:
  Sakthiswary Rajalingham
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 maligna...
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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
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Conflict of Interest:
None declared.
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