Background/Purpose

Recent studies have found that a high proportion of female rheumatoid arthritis (RA) patients are chronic carriers of high-risk HPV-strains and that these patients are at increased risk of high-grade cervical dysplasia (CD) and cervical cancer. There are uncertainties regarding the safe use of biological DMARDs (bDMARDs) in arthritis patients with premalignant conditions. The aim of the present study was to investigate the occurrence of premalignant lesions of the uterine cervix progressing to a more malignant stage or developing another HPV associated cancer in female RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients treated with bDMARDs or conventional synthetic DMARDs (csDMARDs). 

Methods In this observational study, we used the nationwide Danish DANBIO Registry covering > 90% of rheumatologic patients treated with bDMARDs in routine care and also patients treated with csDMARDs have been registered since 2006. Patient data from RA, AS and PsA patients registered from 2000-2011 was linked with data from The Danish Cancer Registry. We specifically included patients with a history of mild, moderate and severe cervical dysplasias (CD) or carcinoma in situ (CIS) of the cervix, including both CD/CIS diagnosed before or after DANBIO entry. Patients were followed up for a cancer diagnosis or progression of the premalignant grading of the lesion from the date of diagnosis of CD/CIS of the cervix or first registration in DANBIO, whichever came latest. End of follow-up was date of diagnosis with cervical cancer or other HPV-associated cancer (vulvar, vaginal, anal or oropharyngeal cancer), other cancer diagnosis, death or end of 2011, whichever came first.

Results We identified 905 arthritis patients with a history of CD or CIS. Of these, 806 were diagnosed with CD/CIS prior to DANBIO entry, while the remaining 99 were diagnosed during their time registered in DANBIO. Overall, 356 had ever been exposed to bDMARDs and 673 to csDMARDs of which 124 patients switched from csDMARD to bDMARD therapy and therefore contributed with person-years of observation in both csDMARD and bDMARD groups. The table shows the number of arthritis patients registered in DANBIO with a history of CD/CIS and characteristics of the RA patients. Only 1 of the 356 bDMARD exposed patients experienced malignant progression from CD to CIS of the cervix. None were diagnosed with cervical cancer or any other HPV-related cancer after DMARD treatment initiation during 2740 person years of observation.

Conclusion

Our findings suggest that DMARD – and bDMARD treatment in particular – has limited harmful effects on precancerous lesions of the uterine cervix in female arthritis patients, but more patients and longer follow-up are required to confirm these findings.

Table: Number of arthritis patients in DANBIO with a diagnosis of cervical dysplasia (CD) or carcinoma in situ of the cervix (CIS) and occurrence of malignant progression. Characteristics of RA patients at first registration according to ever biological DMARD (bDMARD) or conventional synthetic DMARD (csDMARD) exposure, respectively.#
			Treatment
			bDMARD*							csDMARD
			Total	CIS			CD	Unspecified§		Total	CIS				CD	Unspecified§
Rheumatologic diagnosis and No. of patients.		All	356	99			211	46		673	170				422	81
		RA	245	77			129	39		499	143				288	68
		AS	22	5			17	0		22	3				19	0
		PsA	49	11			34	4		92	18				65	9
		Other	40	6			31	3		60	6				50	4
Age at start of follow-up, years						52 (18-85)							53 (20-85)
Age at diagnosis, years						43 (3-74)							47 (1-81)
Follow-up time, years						3.3 (0.0-11.3)							1.4 (0.0-8.3)
Person-years of observation						1409							1331
No. of patients
	with progression of CD or CIS					1								0
	developing HPV-associated malignancy ¤					0							0
Characteristics of RA patients at start of follow-up#
No. of IgM RF seropositive  %						75 %						69 %
Disease duration, years						6 (0-48)						4 (0-51)
Proportion with disease duration < 2 years						21 %						25 %
Tender Joint Count  (0-28)						8 (0-27)						4 (0-28)
Swollen Joint Count (0-28)						4 (0-24)						1 (0-28)
CRP, mg/L						9 (0-142)						6 (0-158)
DAS28-CRP						4.4 (0.0-8.2)						2.7 (0.0-7.8)
HAQ						0.9 (0.0-3.3)						0.5 (0.0-3.0)
#Shown are medians (range) unless otherwise indicated. * First biological treatment for RA patients: adalimumab 114 patients; etanercept 77; infliximab 119, golimumab 10 and certolizumab 8. Number of patients treated with other bDAMRDs: 1 Abatacept, 6 Anakinra, 9 Rituximab, 4 Tocilizumab, 6 Other. §A total of 127 patients with precancerous cervical lesions had no specified histopathologic grading in The Danish Cancer Registry. ¤ According to International Agency for Research on Cancer (IARC) monograph on HPV; anal, vulvar, vaginal, oropharyngeal cancers were defined as HPV-associated.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/malignant-progression-of-precancerous-lesions-of-the-uterine-cervix-following-dmard-therapy-in-female-arthritis-patients/