Initiation of a biologic disease-modifying anti-rheumatic drug (DMARD) in women with rheumatoid arthritis (RA) was linked to a numerically, but not statistically, significant increase in the risk of high-grade cervical dysplasia or cervical cancer compared with non-biologic DMARD, according to research published in Arthritis and Rheumatology.

Daniel H Solomon, MD, MPH, and colleagues, of Brigham and Women’s Hospital in Boston, MA, conducted a US population-based cohort study of 22,267 pairs of propensity score (PS)-matched female patients undergoing RA therapy with either a biologic or non-biologic DMARD.

Patients were identified from the US Medicaid and 2 commercial insurance databases (WellPoint, from 2001 to 2008 and United HealthCare from 2003 to 2012) between 2000 and 2012. A validated, claims-based algorithm was used to identify cases of high-grade cervical dysplasia or cervical cancer. Patients undergoing treatment with a biologic DMARD were matched 1:1 to patients undergoing treatment with a non-biologic DMARD in an effort to control for potential confounders.


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The primary outcome of interest was either high-grade cervical dysplasia or cervical cancer. The researchers also assessed the number of gynecologic procedures performed, related to either condition—a Pap smear, colposcopy, cervical biopsy, or cervical excision surgery—during the follow-up period.

Dr Solomon and colleagues found that more than 92% of the biologic DMARDs initiated were tumor necrosis factor (TNF) inhibitors. The table below breaks  down the various biologic DMARDs used within each cohort by percentage.

Table. Percentage Breakdown of Biologic DMARD Therapy at Index Date

Medicaid Cohort Commercial Insurance Cohort

Biologic DMARD

 %

Biologic DMARD

%
Etanercept
47% Etanercept  41%
Methotrexate  40% Methotrexate  40%
hydroxychloroquine  14% hydroxychloroquine  15%
Leflunomide  10% Leflunomide  8%
Sulfasalazine  6% Sulfasalazine  4%

Within the Medicaid cohort, the mean ± SD duration of active treatment was 2 ± 2.1 years for biologic DMARDs vs 1.5±1.8 years for nonbiologic DMARDs, compared to 1.7±1.6 vs 1.1±0.7 years in the commercial insurance cohort for biologic vs nonbiologic DMARDs, respectively.

Incidence rate of high-grade cervical dysplasia per 1000 person years in Medicaid cohort patients was 1.59 with biologic DMARD vs 1.21 with nonbiologic DMARD.

Incidence rates of cervical dysplasia or cancer in the commercial insurance cohort were similar but lower. PS-matched hazard ratios [HR] were 1.25 (95% confidence interval [CI] 0.78-2.01) and 1.63 (95% CI 0.62-4.27) in the Medicaid and commercial insurance biologic DMARD groups, respectively.

Pooled HR was 1.32 (95% CI 0.86-2.01)for biologic DMARD imitators. Dr Solomon and colleagues determined that cervical dysplasia-related rates of gynecologic  procedures were similar in both the biologic and nonbiologic DMARD groups in both cohorts; pooled relative risk was 0.96 (95% CI 0.91-1.02). 

Summary and Clinical Applicability

Pooled data from large insurance databases in the US found an overall incidence rate of high-grade cervical dysplasia or cervical cancer across the entire study cohort was 1.20 per 1000 person-years; overall risk was 1.3 times higher in women with RA who started biologic DMARD therapy, with or without a nonbiologic DMARD, compared to those who started therapy with a nonbiologic DMARD only.

“While the risk of high-grade cervical dysplasia or cervical cancer may be moderately increased in women with RA, the absolute risk we observed was small,” noted Dr Solomon. “With improvement in the numbers of people in the general population, including RA patients, receiving the HPV vaccine, the absolute risk of high-grade cervical dysplasia or cervical cancer should further decrease.”

“If this occurs, it may not be cost-effective to consider a more aggressive cervical cancer screening or HPV vaccination strategy for patients with RA than for the general population,” he concluded. 

Limitations and Disclosures

  • Misclassification bias is a possibility, due to the use of a claims-based algorithm to identify eligible patients with RA

  • Residual RA disease-specific confounders, including disease severity and duration, and  behavioral risk factors could not be completely accounted for with the PS-matched methodolog

  • Within the Medicaid cohort, 63% of patients starting biologic DMARD treatment and 59% within the commercial insurance cohort were treated with methotrexate at baseline or on the index date; as such, the researchers could not determine the risk  of high-grade cervical dysplasia or cervical cancer associated with the use of biologic DMARD alone

Drs Kim and Solomon have received research support through grants to Brigham and Women’s Hospital from Pfizer, AstraZeneca, Genentech, and Lilly. Dr Solomon received additional research support from Amgen and the Consortium of Rheumatology Researchers of North America (CORRONA) and has served in unpaid roles in studies funded by Pfizer. Dr Schneeweiss has received consulting fees from World Health Information Science Consultants (WHISCON) and Aetion, and owns stock in Aetion. 

Reference

Kim SC, Schneeweiss S, Liu J, et al. Biologic disease-modifying antirheumatic drugs and risk of high-grade cervical dysplasia and c0ervical cancer in rheumatoid arthritis. A cohort study. Arthritis Rheumatol. 2016;68(9):2106-2113. doi: 10.1002/art.39689

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