Abstract
Objective
Recent research showed an increased risk of high-grade cervical dysplasia and cervical cancer associated with rheumatoid arthritis (RA). We examined whether this risk was associated with biologic disease-modifying antirheumatic drug (DMARD) versus non-biologics.
Methods
We identified RA patients starting either a biologic or a non-biologic DMARD in the US Medicaid and commercial insurance databases (2000–2012). We identified high-grade cervical dysplasia or cervical cancer with a validated claims-based algorithm and assessed utilization of gynecologic procedures. To control for potential confounders, biologic DMARD initiators were 1:1 matched to non-biologic DMARD initiators on the propensity score (PS). Hazard ratios (HR) and rate ratios (RR) from the PS-matched Medicaid and commercial cohorts were pooled by an inverse variance-weighted, fixed-effects model.
Results
We included 14,729 pairs of biologic and non-biologic DMARD initiators from Medicaid and 7,538 pairs from the commercial cohort. During 73,388 person-years of active treatment with either biologic or non-biologic DMARDs, 95 cases of high-grade cervical dysplasia or cervical cancer occurred in the 2 cohorts. The HR of high-grade cervical dysplasia or cervical cancer associated with biologic DMARD was 1.25 (95%CI 0.78–2.01) in Medicaid and 1.63 (95%CI 0.62–1.89) in the commercial cohort with the pooled HR of 1.32 (95%CI 0.86–2.01). The rate of gynecologic procedures involving the uterine cervix was not different between the two groups (pooled RR 0.96, 95%CI 0.90–1.02).
Conclusion
Among women with RA, initiation of biologic DMARDs was associated with a numerically, but not statistically significant, increase in the risk of high-grade cervical dysplasia or cervical cancer versus non-biologics.
Keywords: cervical dysplasia, rheumatoid arthritis, biologic therapy
INTRODUCTION
Cervical cancer caused by human papillomavirus (HPV) is a highly preventable cancer with the widely available screening test, Papanicolaou (Pap) test. It is uncommon in western countries, but it still contributes nearly 8% of all cancers in women worldwide.[1] HPV is currently the most common cause of both incident and prevalent sexually transmitted infections in the U.S. and other developed countries.[2] In 90% of cases, it is asymptomatic and resolves spontaneously within 2 years. However, persistent infection with HPV is a risk factor for high-grade cervical dysplasia [i.e., cervical intraepithelial neoplasia (CIN) 2 or 3] and cervical cancer.[3] Other risk factors for cervical cancer include older age, carcinogenic HPV genotypes, coexisting infections, immunosuppression, and inflammation.[3 4]
Increased risks of HPV infection and cervical dysplasia have been reported in patients with systemic inflammatory disease including rheumatoid arthritis (RA), lupus and inflammatory bowel disease.[5–10] It has been hypothesized that viral reactivation from a latent state and/or impaired innate and cellular immune responses in patients with immunocompromised conditions or immunosuppressive treatment such as biologic or non-biologic disease-modifying antirheumatic drugs (DMARDs) would reduce clearance of HPV infection and thus lead to persistent HPV infection.[11–14] Large U.S. and Swedish population-based cohort studies report a 1.3–1.5 times increased risk of high-grade cervical dysplasia in women with RA compared to non-RA, [15 16] whereas a meta-analysis of 15 observational studies found no consistently increased risk of cervical cancer in RA patients with the pooled standardized incidence ratio of 0.87 (95% CI 0.72–1.05) relative to the general population.[17]
There is a cohort study based on the British Society for Rheumatology Biologics Register reporting no new or recurrent female genital cancers among women treated with tumor necrosis factor inhibitors (TNFi) with pre-existing carcinoma in situ of the cervix. Nonetheless, little is known whether treatment with biologic and/or non-biologic DMARDs for RA alters the risk of persistent HPV infection. Since biologic DMARDs including TNFi have more potent effects in controlling inflammation and immunosuppression compared to non-biologic DMARDs for RA, we conducted a cohort study with several aims: 1) to assess the risk of high-grade cervical dysplasia or cervical cancer associated with new use of biologic DMARD versus non-biologic DMARDs only for RA, and 2) to examine the utilization rate of cervical dysplasia-related gynecologic procedures in biologic DMARD initiators versus non-biologic DMARD initiators in several large U.S. population-based cohorts. We hypothesized that the risk of high-grade cervical dysplasia or cervical cancer and the use of cervical dysplasia-related gynecologic procedures would be higher in patients initiating a biologic DMARD than those initiating a non-biologic DMARD.
METHODS
Data Source
We conducted a cohort study using the claims data from a US government-sponsored health plan, Medicaid (2000–2010), and two commercial health plans, Wellpoint (2001–2008) and United HealthCare (2003–2012). Medicaid is a joint federal and state program that helps low-income individuals and families for the costs associated with medical and long-term custodial care. We used claims data from the Medicaid Analytical eXtract (MAX) files for enrollees in all 50 states and Washington, DC. The two commercial health plans insure primarily working adults and their family members across the US. These databases have been described in details elsewhere.[15] The quality of these claims data on inpatient and outpatient diagnoses, procedures, health care utilization and drug dispensing is known to be high.[18] Patient informed consent was not required as all the study databases were de-identified. The study protocol was approved by the Institutional Review Board of Partners HealthCare.
Study Cohort
Among patients aged 18 years or older, we selected women with RA based on ≥2 International Classification of Diseases, Ninth Revision (ICD-9) code 714.x on two separate visits that are separated by ≥7 days. Of these, we identified new users of two mutually exclusive DMARD groups:[19] 1) a biologic DMARD with and without non-biologic DMARDs; and 2) non-biologic DMARDs only. Biologic DMARDs included abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, Infliximab, rituximab, and tocilizumab. Non-biologic DMARDs included methotrexate, hydroxychloroquine, leflunomide, azathioprine, cyclophosphamide, cyclosporine, D-penicillamine, gold, and sulfasalazine.
The start of the follow-up period (i.e., index date) was defined as the date of first biologic or non-biologic DMARD dispensing after ≥365 days of continuous enrollment in the health plan. Biologic DMARD initiators were required to be naive to any of biologic DMARDs in the 365 days prior to the index date, but could have been treated with non-biologic DMARDs in the past, or currently. Non-biologic DMARD initiators were required to be naive to any biologic or non-biologic DMARD in the 365 days prior to the index date. All persons in the study cohort were required to have had two diagnoses and at least one filled prescription for a DMARD at the index date. The positive predictive value of this claims-based algorithm for RA was 86% in a prior study using similar claims data.[20]
We excluded patients with history of hysterectomy, organ or bone marrow transplantation, HIV/AIDS, or malignancy, receipt of chemotherapy, and nursing home residents in the 365-day period prior to the index date. Patients were allowed to contribute only one exposure period in the study cohort.
Follow-up started from the index date and continued through to the first of any of the following censoring events: discontinuation of biologic DMARDs for the biologic DMARD group, discontinuation of all non-biologic DMARDs or adding or switching to a biologic DMARD for the non-biologic DMARD group, development of the outcome, disenrollment from the health plan, end of study database, or death.
Outcome Definition
The primary outcome of interest was high-grade cervical dysplasia or cervical cancer based on ≥2 ICD-9 and ≥1 procedure code for relevant gynecologic procedures or treatment within 30 days after the ICD-9 code date.[15 21] This claims-based algorithm had a positive predictive value ≥81% using cytologic or pathologic diagnosis of CIN 2 or worse as the gold standard.[21] In addition, we assessed number of gynecologic procedures related to cervical dysplasia including Pap test, colposcopy, cervical biopsy, and cervical excision surgery listed in Supplementary Table 1 during the follow-up time.
Covariates
We assessed variables potentially associated with RA severity, risk of HPV infection or cervical cancer based on the data from the 12-months prior to the index date. These variables were age, risk factors for HPV infection, comorbidities, RA-related medications such as systemic immunosuppressive drugs and steroids, other medications, and markers of health care use intensity (see Table 1). To further assess potential differences in comorbidities between the two groups, we used a comorbidity score that combined 20 conditions in the Charlson and Elixhauser measures based on ICD-9 codes.[22] This comorbidity score is a validated summative score and ranges from −2 to 26. Using a previously validated claims-based algorithm with the positive predictive value>89%,[23] we also identified women who were likely to be sexually active at baseline.
Table 1.
Baseline characteristics of the study cohort in 12 months prior to the index date: propensity score-matched
| Database | Medicaid | Commercial | ||
|---|---|---|---|---|
| Biologic DMARDs | Non-biologic DMARDs | Biologic DMARDs | Non-biologic DMARDs | |
| N | 14,729 | 14,729 | 7,538 | 7,538 |
| Percentage or mean ± SD | ||||
| Age, years | 46.4 ± 11.9 | 46.4 ± 11.9 | 50.2 ± 12.5 | 50.0 ± 12.9 |
| HPV infection-associated factors | ||||
| Sexually active | 52 | 50 | 61 | 60 |
| Oral contraceptives | 6 | 6 | 10 | 10 |
| Non-oral contraceptives | 2 | 2 | 1 | 1 |
| Smoking | 13 | 13 | 9 | 9 |
| Sexually transmitted diseases | 5 | 5 | 4 | 4 |
| Substance abuse | 1 | 1 | 1 | 1 |
| Alcoholism | 0.5 | 0.4 | 0.4 | 0.4 |
| Receipt of HPV vaccine | 0.3 | 0.3 | 1 | 1 |
| Comorbidities | ||||
| Comorbidity score a | 0.6 ± 1.3 | 0.6 ± 1.3 | 0.4 ± 1.1 | 0.4 ± 1.2 |
| Diabetes | 21 | 21 | 12 | 12 |
| Chronic kidney disease | 3 | 2 | 2 | 2 |
| Liver disease | 8 | 8 | 5 | 5 |
| Prior abnormal Pap test | 3 | 3 | 4 | 3 |
| Medications | ||||
| Recent use of systemic steroids | 46 | 45 | 40 | 39 |
| Cumulative steroid dose, mg b | 1,185.9 ± 8,539.7 | 974.4 ± 11,273.4 | 685.1 ± 1,115.1 | 673.2 ± 1,401.5 |
| Health care utilization | ||||
| No. of total physician visits | 11.7 ± 8.9 | 12.1 ± 9.9 | 11.6 ± 7.9 | 11.7 ± 7.7 |
| No. of gynecology visits | n/a | n/a | 0.8 ± 2.0 | 0.8 ± 2.3 |
| No. of emergency room visits | 1.2 ± 2.6 | 1.3 ± 2.5 | 0.6 ± 2.7 | 0.5 ± 2.5 |
| No. of prescription drugs | 16.8 ± 9.0 | 17.1 ± 9.7 | 11.7 ± 7.1 | 11.9 ± 7.3 |
| Acute hospitalizations | 21 | 20 | 17 | 17 |
| Preventive medical services | ||||
| Pap test | 26 | 26 | 40 | 40 |
| HPV DNA test | 3 | 3 | 6 | 6 |
| Mammogram | 26 | 26 | 39 | 39 |
| Fecal occult blood test | 6 | 5 | 12 | 11 |
| Serum cholesterol test | 37 | 36 | 40 | 38 |
| Sigmoidoscopy/colonoscopy | 7 | 7 | 8 | 9 |
HPV: human papillomavirus, Pap: Papanicolaou
The range of combined comorbidity score is −2 to 26.
Cumulative steroid dose equivalent to prednisone was calculated over the 365-day baseline period.
Statistical Analyses
We compared the baseline characteristics of the two treatment groups in Medicaid and the commercial health plans separately. Propensity score (PS) matching was used to control for potential confounders between the biologic and non-biologic DMARD groups.[24] The PS was defined as the predicted probability of a patient starting a biologic DMARD versus a non-biologic DMARD drug given patient characteristics at baseline. To estimate the PS, we used multivariable logistic regression that included over 40 baseline covariates (listed in Table 1) and the index calendar year. Due to the anticipated differences between the Medicaid and commercial insurance populations, we estimated the PS separately for each data source. We then used nearest neighbor matching within a caliper of 0.05 on the PS with a fixed ratio of 1:1 in the Medicaid and commercial insurance separately.[25 26]
For the primary analysis, incidence rates of high-grade cervical dysplasia or cervical cancer were calculated with 95% confidence intervals (CIs) in the PS matched cohorts. Cox proportional hazard models estimated the hazard ratio (HR) of high-grade cervical dysplasia or cervical cancer associated with initiation of biologic DMARD vs. non-biologic DMARD in the PS matched groups. The proportional hazards assumption was assessed by testing the significance of the interaction term between exposure and follow-up time and was not violated in any models.[27]
For the secondary analysis, rates of receiving cervical dysplasia-related gynecologic procedures in the biologic DMARD group were compared to those in the non-biologic DMARD group. HRs and RRs from the PS-matched commercial health plan and Medicaid cohorts were then pooled by an inverse variance-weighted, fixed-effects model.[28] All analyses were completed using SAS 9.3 and STATA 14.
RESULTS
Cohort Selection
There were over 400,000 patients with at least 2 diagnoses for RA and at least 1 year of continuous enrollment in Medicaid and the commercial health plans. After applying our inclusion and exclusion criteria, the final study cohort included 14,729 PS-matched pairs of biologic and non-biologic DMARD initiators from Medicaid and 7,538 PS-matched pairs of biologic and non-biologic DMARD initiators from the commercial health plans (see Figure 1).
Figure 1. Cohort Selection Flow.
The final study cohort includes 14,729 propensity score-matched pairs of biologic and non-biologic DMARD initiators in Medicaid and 7,538 propensity score-matched pairs of biologic and non-biologic DMARD initiators in the commercial health plans.
Patient Characteristics
Baseline characteristics of the PS-matched groups in Medicaid and the commercial health plans are presented in Table 1. The mean (SD) age was 46 (12) years for the Medicaid cohort and 50 (13) years for the commercial. Within the individual data sources, patients’ age, risk factors for HPV infection, comorbidities, medication use and health care use intensity were similar between the biologic and non-biologic DMARD initiators. Over 92% of biologic DMARD initiators were for TNFi. Etanercept was the most frequently used TNFi (47% in Medicaid and 41% in the commercial health plans). In Medicaid, 40% of biologic DMARD initiators were on methotrexate, 14% were on hydroxychloroquine, 10% were on leflunomide and 6% were on sulfasalazine at the index date. In the commercial health plans, similarly, 40% of biologic DMARD initiators were on methotrexate, 15% on hydroxychloroquine, 8% on leflunomide, and 4% on sulfasalazine at the index date. Patients in Medicaid were younger, had less use of oral contraceptives, more comorbidities including smoking, more emergency room visits and acute hospitalization, and greater number of prescription drugs but less use of preventive medical services including Pap test than patients in the commercial health plans.
Risk of High-grade Cervical Dysplasia or Cervical Cancer
In Medicaid, the mean (SD) duration of active treatment was 2.0 (2.1) years for biologic DMARDs and 1.5 (1.8) years for non-biologic DMARDs. In the commercial health plans, the mean (SD) duration of active treatment was 1.7 (1.6) years for biologic DMARDs and 1.1 (0.7) years for non-biologic DMARDs. The IR of high-grade cervical dysplasia or cervical cancer per 1,000 person-years was 1.59 in biologic DMARD initiators and 1.21 in non-biologics in Medicaid. The IR of high-grade cervical dysplasia or cervical cancer was similar but lower in the commercial health plan cohort (Table 2). The PS–matched hazard ratio of high-grade cervical dysplasia or cervical cancer was 1.25 (95% CI 0.78–2.01) in biologic DMARD initiators in Medicaid and 1.63 (95% CI 0.62–4.27) for biologic DMARD initiators in the commercial, compared to non-biologics. The pooled HR was 1.32 (95% CI 0.86–2.01) for biologic DMARD initiators.
Table 2.
Risk of high-grade cervical dysplasia or cervical cancer associated with initiation of biologic versus non-biologic DMARDs: propensity score matched
| Database | Biologic DMARD | Non-biologic DMARD | ||||||
|---|---|---|---|---|---|---|---|---|
| Event | Person- years (PY) |
IR * (95% CI) |
Hazard ratio (95% CI) |
Event | Person- years (PY) |
IR * (95% CI) |
Hazard ratio (95% CI) |
|
|
Medicaid (n=14,729 pairs) |
48 | 30,149 | 1.59 (1.20–2.11) |
1.25 (0.78-2.01) |
27 | 22,252 | 1.21 (0.83–1.76) |
Ref |
|
Commercial (n=7,538 pairs) |
14 | 12,452 | 1.12 (0.66–1.89) |
1.63 (0.62–4.27) |
6 | 8,536 | 0.70 (0.31–1.56) |
Ref |
| Pooled | 1.32 (0.86–2.01) |
Ref | ||||||
IR is per 1,000 person-years.
The propensity score model includes age, sex, calendar year, comorbidities, HPV vaccine, being sexually active, STD, other comorbidities, medication use including oral contraceptives and steroids, Pap test, HPV DNA test, and other health care utilization factors.
Rates of cervical dysplasia-related gynecologic procedures were similar in the non-biologic and biologic DMARD groups in Medicaid and the commercial health plan (Table 3) with the pooled RR of 0.96 (95% CI 0.90–1.02).
Table 3.
Rate ratio of any gynecologic procedures associated with initiation of biologic versus non-biologic DMARDs: propensity score matched
|
Database |
Biologic DMARD | Non-biologic DMARD | ||||||
|---|---|---|---|---|---|---|---|---|
| Event | Person- years (PY) |
IR * (95% CI) |
Rate ratio (95% CI) |
Event | Person- years (PY) |
IR * (95% CI) |
Rate ratio (95% CI) |
|
|
Medicaid (n=14,729 pairs) |
1,512 | 11,132 | 135.8 (129.1–142.8) |
0.99 (0.90–1.09) |
961 | 7,001 | 137.3 (128.9–146.2) |
Ref |
|
Commercial (n=7,538 pairs) |
2,399 | 12,473 | 192.3 (184.8–200.2) |
0.94 (0.86–1.02) |
161 | 8,541 | 188.6 (179.6–198.1) |
Ref |
| Pooled | 0.96 (0.90–1.02) |
Ref | ||||||
IR is per 1,000 person-years.
The propensity score model includes age, sex, calendar year, comorbidities, HPV vaccine, being sexually active, STD, other comorbidities, medication use including oral contraceptives and steroids, Pap test, HPV DNA test, and other health care utilization factors.
DISCUSSION
This large U.S. population-based cohort study found that the overall incidence rate of high-grade cervical dysplasia or cervical cancer in the entire study was 1.30 per 1,000 person-years and the risk of high-grade cervical dysplasia and cervical cancer was 1.3 times greater, with a wide confidence interval overlapping the null, in women with RA after initiating a biologic DMARD with and without non-biologic DMARDs compared to non-biologics only. Our findings are similar to those in a Swedish cohort study which showed that the risk of developing CIN 3 was 1.3 times greater in biologics-naive RA patients versus the general population.[16] This potentially increased risk of high-grade cervical dysplasia or cervical cancer associated with use of biologics can be explained by that the cytokines blocked by biologic DMARDs such as TNF-α play a critical role in defense against viral infection.[29] However, unlike what we hypothesized, utilization of gynecologic procedures related to cervical dysplasia was similar between biologic and non-biologic DMARD initiators.
Cervical cancer is preventable through widely available and recommended screening with a regular Pap test with and without HPV DNA testing in sexually active women, and HPV vaccines for adolescents and young adults. In this study, 26% of women in Medicaid and 40% in the commercial health plans had a Pap test in the year prior. The baseline use of HPV vaccine in the study cohort was very uncommon (≤1% seen in Table 1) because the majority of women were middle-aged and the study period included the years before the HPV vaccines were introduced. In addition, a recent cohort study noted that the uptake of HPV vaccine was low in both patients aged 9–26 years with and without systemic inflammatory disease.[30] 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. With improvement in the uptake of HPV vaccine in the general population including RA patients, the absolute risk of high-grade cervical dysplasia or cervical cancer should further decrease;[31] if this comes to pass, it may not be cost-effective to consider a more aggressive cervical cancer screening or HPV vaccination strategy for patients with RA than the general population. Prior studies reported that patients with RA received a similar or slightly higher rate of cancer screening tests.[16 32] Nevertheless, it is important to encourage RA patients to keep up with the current practice guidelines with regard to HPV vaccination and cervical cancer screening.[33 34]
The strengths of this study include the large size and generalizability as it is based on three large public and commercial insurance databases in the U.S. Detailed longitudinal information on patients’ drug use in pharmacy claims data linked to medical claims is also a strength of this study. Furthermore, we used rigorous pharmacoepidemiologic approach including the new user design, use of active comparator and PS matching methods to perform appropriate statistical control for confounders and to minimize confounding by indication and immortal time bias.[35]
Several limitations of this study are worth mentioning. First, because we used a claims-based algorithm to identify eligible RA patients, a misclassification bias is possibility. However, the claims-based algorithm that combined both ICD-9 codes and DMARD prescription data was shown to have a high positive predictive value (86%) in a prior study using Medicare claims data.[20] Second, even with the PS matching method that controlled for over 30 covariates simultaneously, this study may still be subject to residual confounding by RA duration, RA severity, race, ethnicity, socioeconomic status, behavioral risk factors (e.g., substance abuse, smoking, alcoholism), and long-term gynecologic history (e.g., parity) of the patients. Third, as the primary outcome was rare, this study including over 44,000 DMARD initiators may be still underpowered to detect a significant difference between the two DMARD groups. Fourth, because we relied on the claims data, there is a potential for outcome misclassification which could cause bias toward the null. There is also a potential for incomplete ascertainment of patient comorbidities (e.g., sexually transmitted disease). Fifth, this study is unable to determine the effect of long-term biologic DMARD use because of the relatively short follow-up time. The short follow-up time is partially explained by that, on average, patients are enrolled in a commercial health plan for 2 to 3 years in the U.S. Sixth, in our present study, 63% of biologic DMARD initiators in Medicaid and 59% in the commercial health plans were also treated with methotrexate at baseline or on the index date. Thus, our study cannot determine the risk of high-grade cervical dysplasia or cervical cancer associated with biologic DMARD alone. Lastly, we applied the exclusion criteria using the data during the 365-day period prior to the index date. This period may not be long enough to capture all the excluded conditions.
In conclusion, among women with RA, initiation of biologic DMARDs appeared to be associated with an increased risk, but with a wide confidence interval overlapping the null, of high-grade cervical dysplasia or cervical cancer compared to initiation of non-biologics only. The absolute risk of high-grade cervical dysplasia or cervical cancer was low in both treatment groups. Since cervical cancer is preventable and may be slightly more common in women using biologic DMARDs, it remains important to have continuous efforts to maintain both patients’ and physicians’ awareness of the importance of HPV vaccination and cervical cancer screening.
Supplementary Material
Acknowledgments
This study was funded by the NIH grant K23 AR059677.
Kim was supported by the NIH grant K23 AR059677. Kim has received research grants to the Brigham and Women’s Hospital from Pfizer, Astra Zeneca, Lilly and Genentech.
Katz receives support from several NIH grants including P60 AR047782.
Karlson is supported by NIH AR052403, AR047782, and AR049880.
Schneeweiss is Principal Investigator of the Harvard-Brigham Drug Safety and Risk Management Research Center funded by FDA. His work is partially funded by grants/contracts from PCORI, FDA, and NHLBI. Schneeweiss is consultant to WHISCON, LLC and to Aetion, Inc. of which he also owns shares. He has received research grants to the Brigham and Women’s Hospital from Novartis, Genentech, and Boehringer-Ingelheim.
Solomon is supported by the NIH grants K24 AR055989, P60 AR047782 and R01 AR056215. Solomon has received research grants to the Brigham and Women’s Hospital from CORRONA, Astra Zeneca, Amgen, Genentech, Pfizer, and Lilly. He serves in unpaid roles on studies sponsored by Pfizer.
Kim receives research support from Pfizer, Astra Zeneca, Genentech and Lilly.
Solomon receives research support from Amgen, Lilly, Pfizer, Astra Zeneca, Genentech and CORRONA.
Footnotes
Disclosures
Liu and Feldman have nothing to disclose.
Authors’ contributions: All authors conceived and designed the study, interpreted the data, and critically revised the manuscript for important intellectual content. SCK drafted the paper. SCK has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Competing interests
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare:
Katz, Liu, Karlson, and Feldman have nothing to disclose for financial support or conflict of interest.
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