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Patients with rheumatoid arthritis (RA) are more frequent chronic carriers of high-risk human papilloma virus (HPV) strains compared with the background population—an important risk factor for developing cervical cancer—and patients with RA have an increased risk of high-grade cervical dysplasia (CD) and cervical cancer.1–3 Little is known about the safety of biological disease-modifying antirheumatic drug (bDMARD) treatment in arthritis patients with a history of premalignant lesions.
We aimed to investigate how often female patients with inflammatory arthritis (RA, ankylosing spondylitis, psoriatic arthritis or other) and a history of premalignant lesions of the uterine cervix developed cervical cancer or another HPV-associated cancer according to ever versus never exposure to bDMARDs.
The nationwide Danish DANBIO Registry started in 2000 and covers >90% of adults with rheumatological disease treated with bDMARDs in routine care.4 Since 2005, patients not treated with bDMARDs have also been registered. We linked 15 238 female patients identified in DANBIO from 2000 to 2011 with the Danish Cancer Registry (DCR).5 ,6 Among these, 1333 patients were excluded due to cancers occurring before DANBIO entry (184 HPV associated, 4 progression of CD to cervical cancer and 1145 other cancers). Among the remaining, we identified 806 arthritis patients with a history of mild, moderate, severe or unspecified CD or carcinoma in situ (CIS) of the cervix (from 1978 to 2011 International Classification of Diseases (ICD)-10 codes: N87 and D06. Before 1978 modified ICD-7 codes)6 prior to DANBIO entry. The median time from CD or CIS to DANBIO entry was 17.7 years (IQR 9.0–25.4), see table 1.
Of the 806 patients, 208 started bDMARD treatment at DANBIO entry while 479 had never received bDMARDs. Of the latter 479 patients, 119 later switched to bDMARD. None of the patients received bDMARD treatment prior to DANBIO entry. A large proportion of the cohort, mainly patients with RA, received conventional synthetic DMARDs (csDMARDs).
Follow-up was from DANBIO entry date until date of diagnosis of cervical cancer, other HPV-associated cancer (anal, oropharyngeal, vaginal, vulvar, squamous cell skin cancer),7 ,8 other cancer, emigration, death or end of 2011, whichever occurred first. Those who started bDMARD treatment after DANBIO entry contributed person-years to never bDMARD until they received bDMARD and to ever bDMARD thereafter.
None of the 806 women experienced malignant progression to cervical cancer and none were diagnosed with another HPV-related cancer after DANBIO entry, neither among ever or never bDMARD treated.
Our finding is in line with a smaller British study, which investigated the occurrence of incident female genital cancers among patients with RA with a history of CIS of the cervix and treated with either csDMARD or tumour necrosis factor inhibitor (TNFi).9 In addition, data from a US study support the finding of no additional risk of CD/CIS of the cervix with bDMARD treatment in patients with RA.10
The strengths of the current study include high coverage of bDMARD exposure in DANBIO. Furthermore, diagnostic information from the DCR is of high validity due to thorough quality control procedures.5 ,6 The main limitations of our study were the relatively low number of patients considering the rarity of the events investigated as well as the short follow-up period. Thus, we had insufficient power to exclude an excess risk. Also, we did not take into account potential treatment of the cervical lesion in the time from diagnosis of CD to DANBIO registration.
In conclusion, we found no HPV-related cancers after bDMARD treatment in women with a history of precancerous lesions of the uterine cervix. However, more patients and longer follow-up are required to assess the risk associated with the use of bDMARDs.
Contributors LD conceived the study. LD, LM and RC designed the study. LD and LM acquired the data. RC performed the analysis. All authors contributed to the interpretation of data. RC drafted the manuscript and all authors revised the article critically for intellectual content and final approval of the article to be published. LD is the guarantor for the study.
Funding The Danish Rheumatism Association and Danish Cancer Society.
Competing interests None.
Ethics approval The project is entirely register based, and the patients have not been contacted. Therefore, no approval by the ethics committees was needed according to the Danish law. Approval by the Danish Data Protection Board Agency was obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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