Review
Inflammation-targeted therapies and cancer

https://doi.org/10.1016/j.jbspin.2021.105176Get rights and content

Highlights

  • Data are reassuring regarding the overall risk of cancer with TNF inhibitors (TNFi).

  • The risk of lymphoma does not seem to be increased with TNFi.

  • There is probably an increased risk of non-melanoma skin cancer (NMSC) associated with TNFi, as with other immunosuppressants.

  • There is no signal for an increased risk of cancer with other biological DMARDs, but additional data are needed.

  • A recent post-marketing surveillance study found out an increased risk of malignancies for tofacitinib compared with TNFi; additional data are therefore urgently needed to confirm or not these results.

Abstract

Objective

To review and analyze the current knowledge on the risk of malignancy associated with inflammation-targeted therapies in rheumatic diseases.

Methods

We performed a non-systematic literature review on PubMEd MEDLINE by screening randomized controlled trials, meta-analyses, reviews, and observational studies focusing on malignancies and inflammation-targeted therapies including TNF inhibitors, other biologics and JAK inhibitors in rheumatic diseases.

Results

Data from literature are reassuring regarding the overall risk of incident and recurrent cancer with TNF inhibitors. The risk of lymphoma is more difficult to analyze and data are controversial; however, in most of the studies, this risk does not seem to be significanlty increased. By contrast, there is probably an increased risk of non-melanoma skin cancer associated with TNF inhibitors, as with other immunosuppressants. There is no signal for an increased risk of malignancies with other biological DMARDs, but additional data are needed. A recent post-marketing surveillance study found out an increased risk of malignancies for tofacitinib compared with TNFi; additional data are, therefore, urgently needed to confirm or not these results.

Conclusion

Data are presently reassuring regarding the overall risk of cancer, whatever the inflammation-targeted treatment. However, additional data are needed for non-TNF biologics and JAK-inhibitors.

Introduction

The occurrence of cancer in patients with a rheumatic condition always rises several questions, particularly regarding the cause of the cancer, and the relative role of the underlying disease or its treatments. Epidemiologic factors may explain the occurrence of cancer in patients with rheumatic diseases. First, age of onset of some rheumatic diseases, such as rheumatoid arthritis (RA), matches the peak of cancer incidence in the general population. Additionally, some cancers may be associated with factors, which are also risk factors of rheumatic diseases: it is for example the case for smoking, which is an established risk factor of both RA and lung cancer.

Nevertheless, some rheumatic diseases seem to be associated with an increased risk of cancer; thus, the association between active RA, Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and B-cell lymphoma is now well established [1]. To a lesser extent, an increased risk of lymphoma is also suspected in psoriatic arthritis (PsA) [2]. Among solid cancers, some studies found an increased risk of lung cancer in patients with systemic sclerosis (SSc) or dermatomyositis/polymyositis (DM/PM) compared with the general population [3], and an increased risk of ovary cancer in patients with SS and DM/PM [3]. On the contrary, a decreased risk of breast and colorectal cancer is observed in RA [4]. Interestingly, no association has been established to date between ankylosing spondylitis (AS) and solid or hematologic malignancies [2].

The role of rheumatic disease treatments, so called, disease modifying anti-rheumatic drug (DMARD), in the occurrence of cancer has also been discussed during the last decades. In the late 1990s, cases of EBV-induced lymphoma occurring in RA patients treated with methotrexate (MTX) have been reported [5]; however, except in two Japanese studies [6], [7], this relationship has not been confirmed in more recent studies [8]. An increased risk of cancer is also known with azathioprine, ciclosporin or cyclophosphamide [9]. Also, with emergence of inflammation-targeted therapies, acting on the immune system, such as biological DMARDs, and more recently targeted synthetic DMARDs, this question has become even more crucial.

Nevertheless, the respective role of the underlying disease and its treatments remains difficult to analyze. Indeed, inflammation-targeted therapies are frequently prescribed in patients with the more severe diseases, who have the most increased risk of inflammation-related malignancies.

Therefore, this review aims to analyze the current knowledge on the risk of malignancy associated with inflammation-targeted treatments in rheumatic diseases, but also to provide some elements to better appraise it and highlight some methodological issues to be kept in mind when evaluating the association between rheumatic diseases, treatments, and the risk of cancer.

Section snippets

Cancer risk assessment methods in rheumatic diseases

Some methodological aspects must be considered when analyzing the risk of cancer in the context of inflammation-targeted treatments.

First, the study design must be appropriate; this point may seem trivial, but it is not easy to implement. Indeed, the occurrence of a treatment-induced cancer is a severe but relatively rare event and may occur years after the treatment exposure or after years of treatments exposures. Thus, randomized controlled trials (RCT), which provide the stronger level of

TNF inhibitors and the risk of cancer

TNFi are the most ancient biologics and consequently, the most studied to date. These treatments are prescribed in rheumatic diseases such as RA, AS and PsA, but also in other conditions such as cutaneous psoriasis and inflammatory bowel diseases (IBD). Infliximab, adalimumab, certolizumab and golimumab, are monoclonal antibodies directed against TNF, whereas etanercept is a fusion protein of human p75 soluble TNF receptor and human IgG 1. The relationship between these biologics and cancer has

Other biologics and the risk of cancer

Fewer data on cancer risk are available for other biologics. Main findings are summarized in Table 6. Studies regarding these treatments often suffer from lack of power, given that they have been marketed later than TNFi and that less patients are undergoing these therapies.

JAK-inhibitors and the risk of cancer

JAK-inhibitors are small molecules which emerged during the last years as a new option of treatment for RA, IBD, psoriasis or AS. These molecules are: tofacitinib (anti-JAK1 and 3), baricitinib (anti-JAK1 and 2), filgotinib and upadacitinib (anti-JAK1). Particular concerns about the risk of malignancy in patients treated with tofacitinib have been raised, given that this molecule inhibits signal transduction of several cytokines, such as type I and type II interferons, and may decrease the

Conclusion

The risk of cancer associated with inflammation-targeted treatments has been largely studied, particularly for TNFi. The data currently available are generally reassuring, except perhaps for an increased risk of non-melanoma skin cancer with TNFi and abatacept. The risk of cancer recurrence with biologics also appears to be low, whatever the molecule. Thus, rituximab and tocilizumab may be used safely in patients with a history of cancer, and the use of other biologics should be discussed on a

Disclosure of interest

The authors declare that they have no competing interest.

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