Abstract
Objective
To determine rates of cervical cancer screening and associated abnormal results in women with systemic lupus erythematosus (SLE).
Methods
We identified women with an initial diagnosis of SLE in the MarketScan Commercial Claims and Encounters Database from 2001 to 2014. Cervical cancer screening rates and associated diagnostic claims within 3 years of initial claim were determined. Multivariable logistic regression was performed to evaluate the association of screening with lupus treatment. A matched logistic regression analysis was conducted to compare screening rates to those in age-matched women without connective tissue disease.
Results
We included 4,316 women with SLE. Screening rates were higher in SLE women than in general controls (73.4% vs. 58.5%, p < 0.001). Factors associated with decreased screening included: recent time (odds ratio [OR] 0.70, 95% CI 0.55 – 0.89) (2012–2014 compared to 2001–2005); age ≥61 years (OR 0.27, 95% CI 0.18 – 0.39); comorbidity score of ≥2 (OR 0.71, 95% CI 0.6 – 0.83); corticosteroid use (OR 0.77, 95% CI 0.61 – 0.97); and use of immunosuppressants (OR 0.80, 95% CI 0.69 to 0.94). Abnormal pathology claims were more common in women with SLE than in general controls (12.3% vs. 9.8%, P < 0.001).
Conclusions
Though higher than the general cohort, over 25% of the patients with SLE were not screened and screening rates seem to be decreasing over time. Patients with SLE are at higher risk of abnormal cervical screening test results than controls, supporting the need for regular screening.
Keywords: Systemic lupus erythematosus, cervical cancer, human papilloma virus, screening
INTRODUCTION:
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is more prevalent in women, and carries an increased risk for both viral illnesses and malignancies.1–6 This is thought to be related to inherent abnormalities in the innate and adaptive immune systems along with chronic immunosuppression. Women with SLE have an increased risk of cervical cancer, a disease caused primarily by the human papilloma virus (HPV).1,4,5,7–9 Several studies have shown that immunosuppressive therapies, especially cyclophosphamide and corticosteroids, are also associated with an increased risk of cervical cancer.8–10 This increased risk is recognized by the American Society of Colposcopy and Cervical Pathology (ASCCP). In 2019 the ASCCP recommended more frequent cervical cancer screening in women with SLE, than in the general population, similar to what is recommended for HIV-infected patients.11 These recommendations are: (a) perform annual cervical cytology, and if 3 consecutive cytology results are normal, perform cytology every 3 years; and (b) if baseline co-testing for HPV is negative with normal cytology, screening can be performed every 3 years.
There is a paucity of knowledge in patterns of cervical cancer screening and determinants associated with cervical cancer screening in women with SLE. Our objectives were to determine in a large national claims database the proportion of women with SLE that underwent cervical cancer screening within three years of their initial lupus diagnosis claim, and to determine whether screening rates were associated with immunosuppressive therapy. Screening in patients with SLE was compared to screening in women without connective tissue diseases, and in women with diabetes, as age-matched controls. We also examined the frequency of abnormal cervical pathology claims in women with SLE compared to controls.
SIGNIFICANCE & INNOVATIONS
Screening for cervical cancer in women with systemic lupus erythematosus has declined over time, and approximately 25% of women were not screened within 3 years of diagnosis.
Women with lupus were less likely to be screened when receiving immunosuppressant therapies.
Women with lupus had a higher rate of abnormal cervical screening results than controls.
MATERIALS AND METHODS
We performed a retrospective cohort study analyzing claims of female beneficiaries, from the commercial Truven Health Analytics MarketScan Commercial Claims and Encounters Research database.12 This database consists of medical (inpatient and outpatient) and prescription claims for millions of individuals that have employer-sponsored private health insurance, and also includes their spouses and dependents. MarketScan does not include patients that are on Medicaid, uninsured, or other less common private insurance plans. We initially identified women who had any lupus (International Classification of Diseases (ICD) version 9 diagnosis code 710.0 or ICD version10 diagnosis code M32.xx but not M32.0) claims between January 1, 2000 and December 31, 2016 for cohort selection. Inclusion criteria for our final cohort of women with lupus were:
Age between 21 and 64 years old at the first lupus claim
At least three lupus claims within two years, with the first and last lupus claims more than 90 days apart, between 2001 and 2014. Data was available up to 2016, and we included patients with first lupus claims up to 2014 to ensure follow-up of at least two years after the first lupus claim.
Coverage for at least 12 months before the date of the first lupus claim with no lupus claims during that same period. This criterion was set to capture as many incident cases, assuming that most patients with prevalent lupus would have at least one annual visit with a documented lupus claim.
At least 90 days of supply of one or more of the following antimalarial drugs between three months before and two years after the first lupus claim: hydroxychloroquine, chloroquine, or quinacrine.
Coverage for at least two years after the first lupus claim.
We excluded women who had:
i) A claim for antimalarial drugs between three to 12 months before the first lupus claim in order to increase likelihood of recent disease onset.
ii) Two or more claims of 710.3 / M33.xx (dermatomyositis), 710.1 / M34.xx (systemic sclerosis), or 714.0 / M05.xx / M06.xx (rheumatoid arthritis) within one year before and two years after the first lupus claim.
v) any claim for hysterectomy (see Supplementary Table 1, available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24414/abstract) before the first lupus claim, or follow-up.
Outcome
We identified cervical cancer screening using diagnosis or procedure codes for Papanicolaou (Pap) smears and HPV testing (see Supplementary Table 1, available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24414/abstract) within one year before and two years after the first lupus claim. We included the year prior to lupus diagnosis as we assumed that if screening had been recently performed it would be appropriate not to repeat it.
Codes were selected after review of various publications related to cervical cancer screening.13–15
Among women who had cervical cancer screening, results were categorized as abnormal if there were associated codes of abnormal cervical pathology as defined by the Healthcare Common Procedure Coding System (HSPCS) codes (see Supplementary Table 1, available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24414/abstract) between the year before and two years after the first lupus claim.
Covariates
From the claims file, we included year of first lupus claim (2001–2014), age at first lupus claim (21–30, 31–40, 41–50, 51–60, 61–64); Deyo’s modification of Charlson’s comorbidity score (0–1, 2+) 16; insurance type including preferred provider organization (PPO), health maintenance organization (HMO), or other; and region of residence (northeast, north central, south, west, and unknown). From the prescription file we identified women who had claims for corticosteroids between one year prior and two years after the first lupus claim by using both prescription files and Healthcare Common Procedure Coding System J-codes. The corticosteroids included were betamethasone, cortisone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone. Administration routes considered were oral, intramuscular (IM), subcutaneous, and intravenous (IV) (see Supplementary Table 2, available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24414/abstract). Patients were categorized into two groups according to the duration of corticosteroid therapy: 0–89 days; and 90 or more days. We also identified therapy with immunosuppressive and biologic agents including rituximab, belimumab, azathioprine, methotrexate, leflunomide, cyclophosphamide, mycophenolate, cyclosporine, and tacrolimus, using claims with prescription data and HCPCS J-codes (see Supplementary Table 2, available at http://onlinelibrary.wiley.com/doi/10.1002/acr.24414/abstract). We included oral, intravenous (IV) (hospital and outpatient administered), subcutaneous (subQ) and intramuscular (IM) administration routes. Dosage intervals and mode of administration were used to established duration of treatment, grouped into: 0–89 days and no IV administration, and 90 or more days or IV administration. For oral drugs, we only included patients who had been dispensed 60 tablets over 90 days.
Matched Controls
We matched SLE cases by date of birth with two control cohorts: (1) women without connective tissue disease and not on antimalarial drugs (general controls); (2) women without connective tissue disease and not on antimalarial drugs and with at least two diabetes claims 7 or more days apart (diabetes mellitus cohort). The codes are shown in Supplementary Table 1, available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24414/abstract. We included a diabetes control cohort to evaluate screening practices in patients with a chronic non-rheumatologic disease.
For these two control cohorts, the inclusion criteria were coverage for at least three years in the database between 2001 and 2015 and ages between 21 and 63. Cases were randomly matched with controls with a maximum of a 1:20 ratio. The inception follow-up date for the controls was the date of first lupus claim for their matched case.
Statistical analysis
Descriptive statistics (means, medians and frequencies) were calculated. We compared sociodemographic and clinical characteristics between groups using Chi-square tests and trend tests when appropriate. Multivariable logistic regression was performed to evaluate the association between baseline characteristics and cervical cancer screening in women with SLE, forcing all variables into the model. Results were expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs).
To compare cases and controls we performed matched logistic regression including all baseline characteristics as covariates. We included group (case versus control) as the primary independent variable, and adjusted for year of claim groups (2001–2005, 2006–2007, 2008–2009, 2010–2011, 2012–2014), age groups (21–30, 31–40, 41–50, 51–60, 61–64), comorbidity score (0–1, 2+), and insurance type. We tested interactions between group (case or control) and covariates. All analyses were conducted using SAS, version, 9.3. This study was exempt by our Institutional Review Board, as it only used de-identified claims data.
RESULTS
We included a total of 4,316 women with SLE (Figure 1). Median age at first lupus claim was 45 years. Of these, 3,165 (73.4%, 95% CI 72.0% - 74.6%) underwent cervical cancer screening within the three-year window of the first lupus claim (one year prior to and two years after the claim). Table 1 summarizes the baseline characteristics in patients with and without cervical cancer screening. Older patients, those with more comorbidities, and those receiving corticosteroids or immunosuppressants were less likely to undergo cervical cancer screening than their counterparts. The temporal trend of cervical cancer screening decreased over time from 75.6% in 2004 to 69.9% in 2015 (trend test = 0.003.)
Figure 1.
Flow chart of cohort selection
Table 1.
Patient Characteristics at First Claim According to Cervical Cancer Screening Utilization*
| Characteristics | Total N (N = 4,316) N (Column %) |
No Screening (N = 1,151) N (Row %) |
Screening (N = 3,165) N (Row %) |
P† (Chi-square) | P (Trend) |
|---|---|---|---|---|---|
|
| |||||
| Year of first lupus claim | |||||
| 2001–2005 | 507 (11.7) | 122 (24.1) | 385 (75.9) | 0.019 | 0.003 |
| 2006–2009 | 1,013 (23.5) | 252 (24.9) | 761 (75.1) | ||
| 2010–2011 | 1,293 (30) | 334 (25.8) | 959 (74.2) | ||
| 2012–2014 | 1,503 (34.8) | 443 (29.5) | 1,060 (70.5) | ||
| Age at first lupus claim (years) | |||||
| Median | 45 | 50 | 43 | ||
| 21–30 | 490 (11.4) | 74 (15.1) | 416 (84.9) | <0.001 | <0.001 |
| 31–40 | 1,081 (25) | 198 (18.3) | 883 (81.7) | ||
| 41–50 | 1,290 (29.9) | 334 (25.9) | 956 (74.1) | ||
| 51–60 | 1,237 (28.7) | 458 (37) | 779 (63) | ||
| 61–64 | 218 (5.1) | 87 (39.9) | 131 (60.1) | ||
| Deyo comorbidity | |||||
| 0–1 | 3,418 (79.2) | 836 (24.5) | 2,582 (75.5) | <0.001 | - |
| 2+ | 898 (20.8) | 315 (35.1) | 583 (64.9) | ||
| Insurance | |||||
| PPO | 2,514 (58.2) | 651 (25.9) | 1,863 (74.1) | 0.32 | - |
| HMO | 712 (16.5) | 186 (26.1) | 526 (73.9) | ||
| Other | 993 (23) | 287 (28.9) | 706 (71.1) | ||
| Unknown | 97 (2.2) | 27 (27.8) | 70 (72.2) | ||
| Corticosteroids (days) | |||||
| 0–89 days | 529 (12.3) | 112 (21.2) | 417 (78.8) | 0.002 | - |
| ≥90 days | 3,787 (87.7) | 1,039 (27.4) | 2,748 (72.6) | ||
| Biologic medications and other immunosuppressive agents* (days supply or IV) | |||||
| 0–89 days, no IV | 3,250 (75.3) | 829 (25.5) | 2,421 (74.5) | 0.003 | - |
| ≥90 days or IV | 1,066 (24.7) | 322 (30.2) | 744 (69.8) | ||
| Biologic medications (days supply or IV) | |||||
| 0–89 days, no IV | 4,201 (97.3) | 1,114 (26.5) | 3,087 (73.5) | 0.18 | - |
| ≥90 days or IV | 115 (2.7) | 37 (32.2) | 78 (67.8) | ||
| Other immunosuppressive agents (days supply or IV) | |||||
| 0–89 days, no IV | 3,300 (76.5) | 847 (25.7) | 2,453 (74.3) | 0.007 | - |
| ≥90 days or IV | 1,016 (23.5) | 304 (29.9) | 712 (70.1) | ||
Values are the number (%) unless indicated otherwise.
HMO = health maintenance organization; IV = intravenous; PPO = preferred provider organization.
P value by chi-square test.
Biologic medications included rituximab (IV) and belimumab (IV or subcutaneous). Other immunosuppressive agents included azathioprine, cyclophosphamide, cyclosporine, leflunomide, methotrexate, mycophenolate, and tacrolimus.
We conducted a multivariate logistic regression model to evaluate the association of screening in SLE patients with covariates (Table 2). The following factors were associated with decreased cervical cancer screening: year of first lupus claim, 2012–2014 vs. 2001–2005 (OR 0.70, 95% CI 0.55 – 0.89, P < 0.001); older age, 61–64 vs. 21–30 years (OR 0.27, 95% CI 0.18 – 0.39, P < 0.001); comorbidity score of 2+ vs. 0–1 (OR 0.71, 95% CI 0.6 – 0.83, P < 0.001); use of corticosteroids for more than 90 days versus use of 0–89 days (OR 0.77, 95% CI 0.61 – 0.97, P = 0.026); and use of biologic or other immunosuppressant drugs (OR 0.80, 95% CI 0.69 – 0.94, P = 0.008). Insurance type was not associated with different screening rates.
Table 2.
Multivariable Logistic Regression for Cervical Cancer Screening in Women with SLE*
| Variable | Odds Ratio | 95% CI | P |
|---|---|---|---|
|
| |||
| Year of first lupus claim | |||
| 2001–2005 | 1 | ||
| 2006–2009 | 0.94 | 0.73 to 1.22 | 0.65 |
| 2010–2011 | 0.85 | 0.66 to 1.09 | 0.20 |
| 2012–2014 | 0.70 | 0.55 to 0.89 | 0.003 |
| Age at first lupus claim (years) | |||
| 21–30 | 1 | ||
| 31–40 | 0.75 | 0.56 to 1.01 | 0.06 |
| 41–50 | 0.49 | 0.37 to 0.64 | <0.001 |
| 51–60 | 0.29 | 0.22 to 0.39 | <0.001 |
| 61–64 | 0.27 | 0.18 to 0.39 | <0.001 |
| Deyo comorbidity | |||
| 0–1 | 1 | ||
| 2+ | 0.71 | 0.6 to 0.83 | <0.001 |
| Insurance | |||
| PPO | 1 | ||
| HMO | 0.90 | 0.74 to 1.1 | 0.31 |
| Other | 0.86 | 0.73 to 1.02 | 0.09 |
| Unknown | 0.84 | 0.52 to 1.34 | 0.46 |
| Corticosteroids (days) | |||
| 0–89 days | 1 | ||
| ≥90 days | 0.77 | 0.61 to 0.97 | 0.026 |
| Biologic medications, other immunosuppressive agents (days supply or IV) † | |||
| 0–89 days, no IV | 1 | ||
| ≥90 days or IV | 0.80 | 0.69 to 0.94 | 0.008 |
| Region | |||
| Northeast | 1 | ||
| North central | 0.72 | 0.56 to 0.92 | 0.01 |
| South | 0.77 | 0.61 to 0.96 | 0.02 |
| West | 0.69 | 0.54 to 0.9 | 0.005 |
95% CI = 95% confidence interval; HMO = health maintenance organization; IV = intravenous; PPO = preferred provider organization; SLE = systemic lupus erythematosus.
Biologic medications included rituximab (IV) and belimumab (IV or subcutaneous). Other immunosuppressive agents included azathioprine, cyclophosphamide, cyclosporine, leflunomide, methotrexate, mycophenolate, and tacrolimus.
The general control cohort included 82,723 women. Results of the multivariable conditional logistic regression are shown in Table 3. Women with SLE were more likely to undergo cervical cancer screening than the general controls (OR 2.2, 95% CI 2.03 to 2.36, P < 0.001), after adjusting for covariates. The following factors were associated with decreased cervical cancer screening across the entire group: more recent years (OR 0.49, 95% CI 0.47 to 0.52, P < 0.001); older ages, most notably 61–64 (OR 0.38, 95% CI 0.35 to 0.42, P < 0.0001); increased comorbidities (OR 0.74, 95% CI 0.67 to 0.82); HMO insurance (OR 0.93, 95% CI 0.89 to 0.97, P < 0.001), and region, mostly notably West (OR 0.55, 95% CI 0.53 to 0.58, P < 0.001). A significant interaction between group (case or control) and year of claim was observed. For SLE women the screening rates were stable around 74% - 76% from 2001 to 2011, and decreased to 70.5% in 2012–2014. For women in the general control cohort, the screening rate decrease was larger, from 69% in 2001–2005 to 59% in 2006–2009, to 56.5% in 2010–2011, and to 53% in 2012–2014. No significant interactions were observed for the other covariates. Similar findings were found when comparing the SLE and diabetes cohorts, with exception of insurance. Models with full covariates are included in Supplementary Table 3, available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24414/abstract.
Table 3.
Cervical Cancer Screening in Cases and Controls after Multivariable Adjustment*
| Variable | N | Screening rate (%) | Odds Ratio† | 95% CI | P |
|---|---|---|---|---|---|
|
| |||||
| General Control | 82,723 | 58.5 | 1 | ||
| Lupus | 4,316 | 73.3 | 2.19 | 2.03 to 2.36 | <0.001 |
|
| |||||
| Diabetes Control | 81,830 | 56.2 | 1 | ||
| Lupus | 4,092 | 73.3 | 2.44 | 2.27 to 2.63 | <0.001 |
95% CI = 95% confidence interval; OR = odds ratio.
Multivariable conditional logistic regression models were adjusted for year of first lupus claim, age at first lupus claim, comorbidity, insurance, employee relation, and region.
We also examined changes in screening strategies over time, with statistically significant increases in Pap and HPV co-testing for all three cohorts (Table 4.) For the lupus cohort changes in screening rates over time according to age are shown in Appendix Figures 1A and 2A, available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24414/abstract. Overall declines in any testing were observed in more recent years for all age groups. Increases in co-testing were observed for all age groups.
Table 4.
Types of Cervical Screening Methods in Cases and Controls over Time*
| Screening Method | |||||
|---|---|---|---|---|---|
|
| |||||
| Cohort | Year of screening | Pap + HPV N (%) |
Pap only N (%) |
HPV only N (%) |
P |
|
| |||||
| Lupus | 2000–2005 | 38 (9) | 386 (91) | 0 (0) | <0.001 |
| 2006–2007 | 73 (32.4) | 152 (67.6) | 0 (0) | ||
| 2008–2009 | 249 (39) | 387 (60.7) | 2 (0.3) | ||
| 2010–2011 | 406 (45) | 496 (55) | 0 (0) | ||
| 2012–2014 | 495 (55) | 398 (44.2) | 7 (0.8) | ||
| 2015–2016 | 41 (53.9) | 35 (46.1) | 0 (0) | ||
| General control | 2000–2005 | 435 (7.4) | 5,440 (92.5) | 8 (0.1) | <0.001 |
| 2006–2007 | 1115 (23.5) | 3,625 (76.3) | 10 (0.2) | ||
| 2008–2009 | 5,774 (30) | 13,408 (69.7) | 64 (0.3) | ||
| 2010–2011 | 3,462 (34.5) | 6,503 (64.8) | 63 (0.6) | ||
| 2012–2014 | 4,350 (46.1) | 5,037 (53.4) | 50 (0.5) | ||
| 2015–2016 | 657 (50.1) | 631 (48.1) | 23 (1.8) | ||
| Diabetes control | 2000–2005 | 370 (6.5) | 5,351 (93.5) | 5 (0.1) | <0.001 |
| 2006–2007 | 970 (22.5) | 3,326 (77.1) | 19 (0.4) | ||
| 2008–2009 | 6,014 (29.2) | 14,494 (70.4) | 72 (0.3) | ||
| 2010–2011 | 3,057 (33.8) | 5,947 (65.8) | 37 (0.4) | ||
| 2012–2014 | 4,256 (47.2) | 4,717 (52.3) | 44 (0.5) | ||
| 2015–2016 | 451 (49.2) | 455 (49.6) | 11 (1.2) | ||
Values are the number (%) unless indicated otherwise.
Table 5 shows the prevalence of abnormal cervical pathology results claims in all three cohorts. Women with SLE had more abnormal claims (12.3%) than the general (9.8%) or diabetic (9.0%) controls (p < 0.001). Among women with lupus, 14.6% of those who received immunosuppressant agents with or without corticosteroids had abnormal results, compared to 11.5% of those who received corticosteroids only, and 12.7% of those who did not receive either of the above during follow-up (p=0.09)( see Supplementary Table 4, available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24414/abstract).
Table 5:
Cervical Abnormalities by Method of Screening*
| Screening Method | Lupus cases | General control | P* (vs. lupus) † | Diabetes control | P* (vs. lupus) † |
|---|---|---|---|---|---|
|
| |||||
| Pap only, N | 1854 | 34,644 | 0.10 | 34,290 | 0.006 |
| Abnormal results, N (%) | 104 (5.6) | 1,648 (4.8) | 1,464 (4.3) | ||
|
| |||||
| HPV only, N | 9 | 218 | 1.0 | 188 | 0.60 |
| Abnormal results, N (%) | 0 (0) | 21 (9.6) | 21 (11.2) | ||
|
| |||||
| Pap + HPV | 1,302 | 15,793 | 0.34 | 15,118 | 0.05 |
| Abnormal results, N (%) | 286 (22.0) | 3,294 (20.9) | 2,979 (19.7) | ||
|
| |||||
| All regardless of screening method, N | 3,165 | 50,655 | <0.001 | 49,596 | <0.001 |
| Abnormal results, N (%) | 390 (12.3) | 4,963 (9.8) | 4,464 (9.0) | ||
Values are the number (%) unless indicated otherwise.
HPV = human papillomavirus; Pap = Papanicolaou.
P value by chi-square test or Fisher’s exact test when appropriate.
DISCUSSION
To our knowledge, this is the first study to determine patterns of cervical cancer screening in the United States in women with SLE, while considering concomitant immunosuppressive therapy. Our results indicate that while most patients with SLE undergo cervical cancer screening within three years of their first lupus claim, over a quarter were not screened. Screening rates were nevertheless higher than those observed in the general and diabetes control cohorts, possibly suggesting awareness by patients and/or providers of increased risk for cervical cancer. Previous studies conducted in Italy and Sweden showed similar rates of cervical cancer screening in women with SLE compared to controls. These rates were lower than those observed in our study, 55% in Sweden and 66% in Italy. 9,17 Our cohort, as well as those in the European studies in countries with universal healthcare, had access to health insurance so this was not a barrier. Our study did not include uninsured patients which have been shown to have decreased rates of cervical cancer screening.18,19 Many women with lupus in the United States are from minority ethnic groups, especially African-American and Hispanic, and frequently uninsured or underinsured, so conceivably cervical screening rates are much lower in these populations.
Overall cervical cancer screening rates in women with SLE decreased over time, from 76% in 2001–2005, to 70% in 2012–2014. The reasons for this decline are unclear, but it was also observed in the general population. A study by Watson et al. also using MarketScan in the general population reported a similar decline over time, which was more marked in women aged 18 to 29 and women aged 40 and older.13 This may be secondary to increased time periods between screening as recommended by more recent guidelines – albeit this should not apply to newly diagnosed SLE patients if using screening guidelines as recommended by the ASCCP. Co-testing with Pap smears and HPV testing increased over time, which is consistent with HPV testing becoming more widely available throughout more recent years. We found that being older, having more comorbidities, longer duration of corticosteroid and/or immunosuppressant therapy were associated with decreased cervical cancer screening. Older age, and comorbidities have also been associated with decreased screening for cervical cancer in the general population.13,20
We suspect that patients on longer duration of corticosteroids or on immunosuppressants have increased disease activity which may contribute to less utilization of other healthcare services which could include cervical cancer screening. This finding is concerning as multiple studies have demonstrated an association between HPV infection and/or abnormal cervical cancer screening results in women with SLE receiving corticosteroids or immunosuppressants, most commonly cyclophosphamide.7–9,21–24 More data is needed to determine the effect of chronic steroid use and various different immunosuppressants and biologics on HPV, but this patient population should especially be considered for cervical cancer screening in clinical practice as they are likely at a higher risk of developing cervical cancer. One prospective study in Italy in 2011 interviewed 140 consecutive SLE patients to determine cervical cancer screening habits.17 It was found that 66% of SLE patients underwent appropriate cervical cancer screening and there was no difference in abnormalities in cervical cancer screening between patients on immunosuppressants or other disease-related variables. It is important to note that the study was not powered to detect a difference in patient characteristics associated with cervical cancer screening. A recent publication evaluated factors associated with cervical cancer screening adherence in patients with systemic sclerosis.25 This study also found that older patients were less likely to undergo routine screening; comorbidities, use of corticosteroids or immunosuppressants, and secular trends were not examined.
We examined the use of different screening strategies and frequency of abnormal results. We found that compared to both diabetic and general controls, women with SLE were more likely to have abnormal screening claims (12.3% vs. 9.8% in general controls). These results provide further evidence to prior studies reporting that women with SLE have an increased risk of both abnormal cervical cancer screening results and cervical cancer.1,4,5,7,9 Our study however, attempted to include primarily patients with newly diagnosed SLE (no claims in year prior to inception), and abnormal screening results could have been present prior to the onset of SLE. Differences between patients and controls before disease onset could be secondary to socioeconomic or other unmeasured environmental cofounders (such as smoking) between these groups of women, or to abnormalities in the innate immune system that may occur prior to symptom onset in patients with SLE. Prospective longitudinal studies are needed to further explore these findings.
The strengths of this study include a large national community-based sample of 4,316 women with SLE, matched with 82,723 general controls and long follow-up with the ability to study trends over time. In order to select a valid, well-specified cohort, we required that all women have several claims for lupus, be treated with antimalarials, and have no prior lupus diagnosis claims for a year to enhance capture of incident cases. However, we cannot completely rule out misclassification of lupus diagnosis. We were also able to examine treatment on the basis of prescription and drug administration claims. All women were required to have two years of continuous coverage for follow-up after the initial claim. We chose two separate control groups, one of women without connective tissue diseases, and the other including women with diabetes to control for the potential effects of screening utilization of having a chronic disease that is non-rheumatic.
As for all claims-based studies, there are certain limitations inherent to this design. The MarketScan database is comprised of insurance claims from private health insurers, large employers, and some government programs. As such, the data presented may not be generalizable to the population of women with SLE at large, especially those uninsured or under-insured. There are limitations when utilizing ICD codes in administrative data studies. There may be information not reported (such as prior hysterectomy) that may have accounted for some patients not being screened. However, procedure codes are usually very reliable to establish utilization rates and Pap smears and HPV testing are interventions that are typically billed. Most of the misclassification related to claims codes relate to diagnosis of conditions, and for this reason, we required at least three claims with a lupus diagnostic code and treatment with hydroxychloroquine during follow-up, to ensure high specificity in case definition. As a result, we may have missed patients with mild disease who may have not been prescribed antimalarials. A major potential source of misclassification could be the determination of abnormal cervical findings, as these results are based on professional coding. We did find an increased frequency of abnormal results in women with SLE compared to controls, but these results cannot be considered as true prevalence rates, as many patients were not screened and there are practice-based variations in diagnostic coding among healthcare providers. However, an increased risk for abnormal cervical screening results, and in the incidence of cervical cancer has been documented by others.1,4,5,7–9
In conclusion, our data indicates that although more women with SLE undergo cervical cancer screening than controls, a large proportion, over 25%, do not undergo cervical cancer screening within three years of their first lupus claim. We identified older age, increased comorbidities, and longer duration of corticosteroids and immunosuppressant therapy to be associated with decreased screening. These subgroups of SLE women are likely to have the highest rates of cervical dysplasia and cancer, emphasizing the importance of adherence to guidelines for cervical cancer screening in this population. Future studies to identify barriers in cervical cancer screening and to increase adherence to guidelines are warranted. Finally, our results also provide evidence for prior findings suggesting that women with SLE carry an increased risk of abnormal cervical cancer screening results.
Supplementary Material
Acknowledgements
This study was supported in part by the NCI P30 CA016672, and by the Duncan Family Institute. SG is supported by the CPRIT Grant RP160674 and Komen SAC150061
Supported by the National Cancer Institute (P30-CA-016672) and by the Duncan Family Institute. Dr. Giordano’s work was supported by the Cancer Prevention and Research Institute of Texas (grant RP160674) and by Komen (SAC150061).
Dr. Hwang has received a research grant from Merck. Dr. Suarez-Almazor has received consulting fees from Pfizer, AbbVie, Eli Lilly and Company, Agile Therapeutics, AMAG Pharmaceuticals, Gilead, and Avenue Therapeutics (less than $10,000 each). No other disclosures relevant to this article were reported.
Footnotes
Conflicts of interest:
Jessica P. Hwang – research grant from Merck.
Maria E. Suarez-Almazor – Past member on advisory boards for Pfizer, AbbVie, Eli Lilly, Agile Therapeutics, AMAG Pharmaceuticals, Gilead, Avenue Therapeutics, all unrelated to the topic of this paper. All activities have ended
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