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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Objective

We undertook a prospective cohort study to ascertain the risk factors for the development of squamous intraepithelial lesions (SIL) in patients with systemic lupus erythematosus (SLE).

Methods

One hundred thirty-seven SLE patients with a normal Papanicolaou (Pap) smear at baseline were evaluated at 6-month intervals for up to 3 years. At each visit, a Pap smear, human papillomavirus (HPV) DNA test, and clinical assessment were performed.

Results

Among the 137 patients, there were 12 incident cases (8.8%) of SIL over a median followup duration of 30.7 months (interquartile range 25.5–31.7). Among the 30 patients with HPV infection detectable by DNA testing at baseline, 9 (30%) developed SIL. The independent risk factors for the incident SIL in this group of SLE patients included the use of cyclophosphamide (CYC) ever (odds ratio [OR] 5.6, 95% confidence interval [95% CI] 1.1–29.3; P = 0.041) and persistent high-risk HPV infection (OR 26.9, 95% CI 3.2–222.3; P = 0.002). The use of baseline HPV testing has a higher sensitivity than abnormal cytology (defined as atypical squamous cells of undetermined significance; 47.7% versus 33.3%) in predicting the development of SIL.

Conclusion

Independent risk factors associated with the development of SIL in SLE patients included persistent high-risk HPV infection and the use of CYC. Low-risk patients who receive negative test results on both cervical cytology screening and HPV DNA testing may not need to be rescreened within 3 years.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Many studies have indicated a causal relationship between genital human papillomavirus (HPV) infection and cervical cancer (1). Once infected by HPV, the cervical epithelium may undergo a stepwise progression from preinvasive lesions that can be detected by screening and cured with complete excision to frank malignancy. Low-grade squamous intraepithelial lesions (SIL) are characterized by koilocytotic atypia, nuclear enlargement, hyperchromasia, and perinuclear cytoplasmic clearing. Most low-grade SIL and some high-grade SIL undergo spontaneous regression within 6 to 12 months due to host cell immune response (2, 3). However, there is no way to prospectively differentiate among lesions that are destined to regress, persist, or progress to carcinoma.

The prevalence of an abnormal Papanicolaou (Pap) smear was significantly increased in patients with systemic lupus erythematosus (SLE) compared with healthy controls (4–7). The risk factors for SIL from cross-sectional studies included an increased prevalence of high-risk HPV (7, 8) and multiple HPV infections in SLE patients compared with controls (7). In particular, a higher prevalence of HPV-16 infection was observed in SLE patients than in community subjects (8). SLE patients with a high HPV-16 viral load more frequently had SIL than those with a low HPV-16 viral load (8).

In patients with SLE, the association between cervical diseases and intravenous (IV) cyclophosphamide (CYC) was found in some (9, 10) but not all studies (7, 8). Only one prospective study reported that IV CYC and prednisolone therapy was associated with the development of cervical intraepithelial neoplasia (CIN) (11). However, other host and environmental factors, especially HPV typing, were not examined.

The aims of this study were to 1) ascertain the incidence of SIL in SLE patients and 2) assess the association between social, demographic, gynecologic, lifestyle, and clinical parameters; the use of immunosuppressants; and HPV infection and the development of SIL in SLE.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

One hundred fifty consecutive patients attending the lupus clinic at The Prince of Wales Hospital of The Chinese University of Hong Kong who fulfilled the 1997 American College of Rheumatology (ACR) revised criteria for the classification of SLE (12) were recruited for this prospective cohort study. Details of the study have been described elsewhere (13). Briefly, patients were eligible for the study if they were married or sexually active. Patients who were pregnant were excluded. None of these patients had received the HPV vaccine. All of the patients were invited to come back for reassessment every 6 months for a total of 3 years. The first study visit included a structured interview with a standardized questionnaire covering demographics, medical and reproductive history, sexual activity and history of sexually transmitted infections, hormone use, medical history, and tobacco and alcohol use. At the first and subsequent visits, a followup questionnaire, clinical assessment and blood collection for determination of disease activity, gynecologic examination for the collection of specimens for a Pap test, and HPV testing were performed. Medication history for the past 10 years was retrieved from case notes and was recorded at baseline and each subsequent visit. All of the women with an abnormal Pap smear were referred for gynecologic followup (Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). The Ethics Committee of The Chinese University of Hong Kong approved this study, and all of the patients provided written informed consent.

SLE activity and damage.

The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (14) and the Systemic Lupus International Collaborating Clinics/ACR Damage Index (15) were used to indicate disease activity and damage, respectively.

HPV sampling procedure and identification.

The method of cervical sample collection, detection, and identification of HPVs has been described elsewhere (16). Briefly, a cervical sample was collected with a Cervex brush (Rovers Medical Devices) from each woman for routine liquid-based cytologic examination. After cytologic examination, the remaining sample was used for HPV DNA detection. DNA was extracted as described elsewhere (17). HPV DNA detection was performed by the PGMY polymerase chain reaction (PCR) targeting the consensus region of the HPVL1 gene. Briefly, 5 μL of the extracted DNA was amplified in a 50-μL reaction mix containing 0.2 mM of deoxynucleoside triphosphate and an equimolar mixture of PGMY09 and PGMY11 primers at a final concentration of 0.06 μM, according to a previous protocol with minor modifications (18). All of the PCRs were done under conditions to minimize contamination. A negative control containing all of the PCR reagents except DNA template was added after every fifth specimen to monitor for contamination. A positive control consisting of ∼50 copies of the full-length HPV-16 genome was included in each PCR run to monitor for sensitivity. Serial dilutions of recombinant plasmids containing the entire genome of HPV-6, -11, -16, and -18 were used to estimate the analytic sensitivity of the PCR. The amplification reactions allowed for consistent and reproducible detection of ≥50 copies of these HPV genomes.

Samples that tested positive for HPV DNA were subjected to HPV typing using the Linear Array HPV Genotyping Test, which can detect 37 HPV types. For the purpose of analysis in this study, HPV-16, -18, -26, -31, -33, -35, -39, -45, -51, -52, -53, -56, -58, -59, -66, -68, -73, and -82 were grouped as high risk (including those with probable high risk); and HPV-6, -11, -34, -40, -42, -44, -54, -61, -62, -67, -69, -70, -71, -72, -81, -82, -83, -84, and -89 were grouped as low risk (including those with unknown risk) (19, 20).

Definition of HPV infection and cervical diseases.

Incident HPV infection or cytologic abnormality (atypical squamous cells of undetermined significance [ASCUS] or SIL) was defined as an HPV genotype or cytologic abnormality not identified on a previous visit. Persistent infection or cytologic abnormality was defined as the detection of the same type of HPV or cytologic abnormality at two or more subsequent examinations (≥6 months apart). Based on the definition of Winer and colleagues (21), if a woman tested positive, negative, and then positive for the same HPV type over 3 consecutive visits, the infection was considered to be persistent with an intercurrent false-negative result. Multiple infections were defined as >1 HPV type detected in one or more visits. For the purpose of study analysis, subjects were grouped to the worst category, i.e., subjects with both ASCUS and SIL were counted as SIL.

Statistical analysis.

Results are expressed as the mean ± SD for normally distributed data. Non–normally distributed data are expressed as the median (interquartile range [IQR]). The incidence of SIL was defined as the number of newly detected SIL divided by the total number of followup visits per woman-year. Baseline risk factors for SIL included a variety of sociodemographic, lifestyle, reproductive, and gynecologic variables; disease-related variables; and the use of immunosuppressants. The association between baseline clinical, demographic, and lifestyle variables; the use of immunosuppressants in the 10 years prior to study entry; baseline HPV typing results; persistent high-risk HPV infection; and the development of SIL was examined by univariate analysis using the chi-square test for categorical variable. For continuous variables, Student's t-test and Mann-Whitney U tests were used, where appropriate. All of the risk factors identified in the univariate analysis with P values less than 0.05 will be put into binary logistic regression analysis using “SIL ever” as the dependent variable (method:enter). The Statistical Package for the Social Sciences, version 13.0 (SPSS), was used for the analyses.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Baseline social, demographic, and clinical characteristics.

The baseline characteristics of this cohort have been reported elsewhere (13). Briefly, the cohort was composed of 150 SLE patients. The mean ± SD age was 41 ± 9 years (range 23–63), 55 (36.7%) were postmenopausal, and 114 (76%) were married. Only 3 women (2%) were current tobacco smokers and 19 (12.7%) were current alcohol drinkers at baseline. The mean disease duration was 8.6 years (range 4.6–14.4).

At baseline, 9 (6.0%) of 150 patients were found to have SIL (7 had low-grade SIL and 2 had high-grade SIL). Four other women with a normal Pap smear at baseline did not have a second Pap smear. These 13 patients were excluded from the analysis. Seven patients with ASCUS at baseline were included in the subsequent analysis. One hundred thirty-seven women (91.3%) with at least 2 Pap smears done were included in the analysis for the incidence of SIL. The total followup duration was 3,783 patient-months, and the median followup duration was 30.7 months (IQR 25.5–31.7). There were a total of 689 visits. The median number of visits was 5 (IQR 4–5) per patient and the duration between 2 consecutive visits was 7.5 months (IQR 6.4–8.0, range 5.8–16.3).

Pap smear findings.

Of the 137 patients, cytologic abnormality was found in 26 (19.0%). Twenty-two (16.1%) developed at least one episode of ASCUS (15 patients with ASCUS only) and 12 (8.8%) developed at least one episode of low-grade SIL. None of the patients had high-grade SIL. The risk of developing ASCUS and low-grade SIL in this cohort was 5.8 and 3.4 per 1,000 patient-months, respectively.

Colposcopy findings.

According to the guideline listed in Supplementary Appendix A (available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658), a colposcopy was performed in 16 (11.7%) of 137 patients. The indications for colposcopy included SIL (12 patients), persistent ASCUS during 2 consecutive Pap smears (3 patients), and atypical glandular cells (1 patient). CIN 2 or 3 was identified at colposcopy in 3 (2.2%) of 137 patients, with a cumulative incidence of 0.79 per 1,000 patient-months. None of the patients referred for persistent ASCUS were diagnosed to have CIN 2 or 3 on colposcopy. The prevalence of CIN 2 or 3 identified at colposcopy was 3 (25%) of 12 in patients with low-grade SIL (Table 1).

Table 1. Colposcopy findings according to Papanicolaou smear results*
Indication for colposcopyNormalHPVCIN 1CIN 2CIN 3Cervicitis
  • *

    Values are the number of patients. HPV = human papillomavirus; CIN = cervical intraepithelial neoplasia; ASCUS = atypical squamous cells of undetermined significance; SIL = squamous intraepithelial lesions; AGC = atypical glandular cells.

Persistent ASCUS (n = 6)141000
Low-grade SIL (n = 17)355121
AGC (n = 1)010000
Total no. of colposcopies performed (n = 24)4106121
Total no. of patients (n = 16)075121

Risk factors for SIL in SLE.

Univariate analysis showed that the development of SIL was associated with previous treatment of cervical lesions (Table 2), as was the use of azathioprine and CYC ever in the past 10 years, a higher cumulative CYC dose, and a longer duration receiving CYC (Table 3). Other demographic, lifestyle, and clinical parameters and the use of other immunosuppressants were not associated with the development of SIL (Tables 2 and 3).

Table 2. Association between baseline sociodemographic variables, disease parameters, and the development of SIL in patients with systemic lupus erythematosus*
 No SIL (n = 125)SIL (n = 12)P
  • *

    Values are the number of patients unless otherwise indicated. SIL = squamous intraepithelial lesions; SLEDAI = Systemic Lupus Erythematosus Disease Activity Index; IQR = interquartile range; SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index.

  • Previous treatment for cervical lesion was significantly associated with the development of SIL.

Age, mean ± SD years41 ± 843 ± 70.453
Menopause  0.225
 Yes (n = 55)487 
 No (n = 81)765 
Married  1.0
 Yes (n = 122)11111 
 No (n = 12)111 
High school or lower  0.215
 Yes (n = 111)9912 
 No (n = 22)220 
Low income  0.345
 Yes (n = 40)355 
 No (n = 93)867 
Current smoker  1.0
 Yes (n = 6)60 
 No (n = 131)11912 
Alcohol use  0.683
 Yes (n = 18)162 
 No (n = 107)9710 
Age ≤18 years at first sexual intercourse  0.274
 Yes (n = 26)224 
 No (n = 111)1038 
Lifetime sexual partners ≥3  0.246
 Yes (n = 10)82 
 No (n = 115)10510 
Oral contraceptives ever  1.0
 Yes (n = 35)323 
 No (n = 90)819 
Condom use by male partner  1.0
 Yes (n = 92)839 
 No (n = 33)303 
Parity >1  0.762
 Yes (n = 50)455 
 No (n = 84)777 
Treatment for cervical lesion  0.046
 Yes (n = 4)22 
 No (n = 121)11110 
Current vaginal discharge  0.613
 Yes (n = 13)130 
 No (n = 112)10012 
Bleeding after intercourse  1.0
 Yes (n = 10)91 
 No (n = 115)10411 
Sexually transmitted disease  0.461
 Yes (n = 6)51 
 No (n = 119)10811 
Disease duration, mean ± SD years10.4 ± 6.99.0 ± 6.50.493
SLEDAI at baseline, median (IQR)2.0 (0–4.0)0 (0–3.0)0.208
SDI ≥1 at baseline  0.3
 Yes (n = 36)315 
 No (n = 101)947 
Table 3. The association between the use of immunosuppressants in the past 10 years and the development of incident SIL in systemic lupus erythematosus*
 No SIL (n = 125)SIL (n = 12)P
  • *

    Values are the number (percentage) unless otherwise indicated. SIL = squamous intraepithelial lesions; IQR = interquartile range; CYC = cyclophosphamide; IV = intravenous.

  • The use of CYC and azathioprine ever in the past 10 years, a longer duration receiving CYC, and a higher cumulative CYC dose were associated with the development of SIL.

Prednisolone ever104 (83.2)11 (91.6)0.690
 At baseline97 (77.6)12 (100)0.126
 Duration, mean ± SD years4.1 ± 3.24.2 ± 2.80.907
 Cumulative dose, median (IQR) gm7.1 (1.6–11.5)10.2 (7.5–13.7)0.131
CYC (oral or IV) ever (n = 59)26 (20.8)7 (58.3)0.008
 At baseline (n = 5)3 (2.4)2 (16.7)0.061
 Duration, median (IQR) years0 (0–0)0.2 (0–0.7)0.001
 Cumulative dose, median (IQR) gm0 (0–0)1.0 (0–1.0)0.004
Azathioprine ever (n = 80)70 (56.0)10 (83.3)0.009
 At baseline (n = 41)35 (28.0)6 (50.0)0.183
 Duration, median (IQR) years0 (0–2.6)1.3 (0.4–3.8)0.055
 Cumulative dose, median (IQR) gm0 (0–47)24 (4–82)0.055
Hydroxychloroquine ever (n = 87)79 (63.2)8 (66.7)1.0
 At baseline (n = 76)69 (55.2)7 (58.3)0.835
 Duration, median (IQR) years1.6 (0–4.3)1.5 (0–4.0)0.838
 Cumulative dose, median (IQR) gm80 (9–279)145 (0–307)0.717

Details of the natural history of HPV infection in this cohort have been published elsewhere (13). Briefly, the cumulative prevalence of any HPV and high-risk HPV infection was 30 (21.9%) of 137 and 24 (17.5%) of 137, respectively (Table 4). In patients with SIL, the most common high-risk HPV types identified included HPV-18, -51, and -52 (n = 3); HPV-45 and -58 (n = 2); followed by HPV-16, -53, -66, and -82 (n = 1). Among the patients with any HPV, multiple HPV, and high-risk HPV infection detectable by DNA testing at baseline, 5 (38.5%) of 13, 3 (50%) of 6, and 5 (45.5%) of 11 patients developed SIL over the period of 3 years, respectively (Table 4). Univariate analysis revealed that any HPV infection (at baseline, incident infection, and ever), multiple HPV infection (at baseline, during any subsequent visit, and ever), high-risk HPV infection (at baseline and ever), persistent HPV infection (since baseline, at any subsequent visits, or ever), and persistent high-risk HPV infection (Table 4) were associated with the development of SIL over a period of 3 years.

Table 4. Association between HPV status and the development of SIL in systemic lupus erythematosus*
 No SIL (n = 125)SIL (n = 12)P
  • *

    Values are the number of patients. HPV = human papillomavirus; SIL = squamous intraepithelial lesions.

Any HPV infection   
 At baseline (n = 13)850.002
  No (n = 124)1177 
 Ever (n = 30)2010< 0.001
  No (n = 107)1052 
Incident infections (n = 24)168< 0.001
  No (n = 113)1094 
Multiple HPV infection   
 At baseline (n = 6)330.009
  No (n = 131)1229 
 Ever (n = 19)1270.001
  No (n = 118)1135 
 At any subsequent visit (n = 16)1060.001
  No (n = 121)1156 
High-risk HPV infection   
 At baseline (n = 11)650.001
  No (n = 126)1197 
 Ever (n = 24)159< 0.001
  No (n = 113)1103 
Persistent HPV infection   
 At baseline (n = 5)230.005
  No (n = 132)1239 
 Ever (n = 14)86< 0.001
  No (n = 123)1176 
 At any subsequent visit (n = 9)630.032
  No (n = 128)1199 
 High-risk HPV (n = 10)46< 0.001
  No (n = 127)1216 

In order to address whether HPV typing results at baseline (any HPV, high-risk HPV, and multiple HPV infection) and persistent high-risk HPV infection are independent predictors for the development of low-grade SIL, all of these variables and potential explanatory variables were identified in the univariate analysis, including previous treatment of cervical lesions; the use of azathioprine and CYC ever in the past 10 years, cumulative CYC dose, and duration receiving CYC were analyzed using regression analysis. The independent risk factors for the incident SIL in this group of SLE patients included the use of CYC ever (odds ratio [OR] 5.6, 95% confidence interval [95% CI] 1.1–29.3; P = 0.041) and persistent high-risk HPV infection (OR 26.9, 95% CI 3.2–222.3; P = 0.002).

Four (2.9%) of the 137 patients had previous cervical lesions, including 3 patients with CIN 1 diagnosed 8, 3, and 2 years prior to baseline, and 1 patient with CIN 2 to 3 diagnosed 3 years prior to baseline. Although these lesions can regress spontaneously, this population may be different from those without a history of cervical pathology. Therefore, the analysis was repeated, excluding these patients with a prior history of cervical lesions. The independent risk factors for the incident SIL in this group of SLE patients were similar to the analysis that included patients with a prior history of cervical lesions, the use of CYC ever (OR 9.3, 95% CI 1.4–62.5; P = 0.022), and persistent high-risk HPV infection (OR 31.5, 95% CI 3.4–295.8; P = 0.003) (Table 5).

Table 5. Independent risk factors associated with the development of squamous intraepithelial lesions*
 POdds ratio95% CI
  • *

    95% CI = 95% confidence interval; HPV = human papillomavirus.

Including patients with previous history of cervical lesions (n = 137)   
 Persistent high-risk HPV infection0.00226.93.2–222.3
 Use of cyclophosphamide ever0.0415.61.1–29.3
Excluding patients with previous history of cervical lesions (n = 133)   
 Persistent high-risk HPV infection0.00331.53.4–295.8
 Use of cyclophosphamide ever0.0229.31.4–62.5

HPV and cervical cytology for screening for low-grade SIL.

The performance of HPV and cervical cytology at baseline for screening for low-grade SIL over the period of 3 years, either alone or in combination, is summarized in Table 6. In this cohort, the use of baseline HPV testing has a higher sensitivity than abnormal cytology (defined as ASCUS; 47.7% versus 33.3%) in predicting the development of SIL. Combining HPV testing and cytology at baseline only increased the sensitivity of HPV testing alone from 47.7% to 50.0%. However, repeat cytology in 6 months has the highest sensitivity and relatively high specificity (58.3% and 96.8%, respectively) in predicting the development of SIL.

Table 6. Performance of HPV and cervical cytology for screening for low-grade squamous intraepithelial lesions in systemic lupus erythematosus over a period of 3 years*
Screening strategyPPVNPVSensitivitySpecificity
  • *

    Values are the percentage. HPV = human papillomavirus; PPV = positive predictive value; NPV = negative predictive value; ASCUS = atypical squamous cells of undetermined significance.

ASCUS at baseline57.193.833.397.6
High-risk HPV infection at baseline45.594.441.795.2
Any HPV infection at baseline38.594.447.793.6
ASCUS or any HPV at baseline37.595.050.092.0
ASCUS or high-risk HPV at baseline42.895.150.093.6
ASCUS at baseline or second visit63.696.058.396.8

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

To our knowledge, this is the largest prospective study assessing most of the potential risk factors, including HPV typing, for the development of SIL in a cohort of patients with SLE. Cytologic abnormality developed in 19.0% of patients over a period of 3 years, including ASCUS in 16.1% and low-grade SIL in 8.8% of the patients. Persistent high-risk HPV infection and the use of CYC were independent risk factors for the development of SIL in SLE.

Ognenovski et al (11) reported a 9.8% cumulative incidence of CIN in a group of 61 SLE patients (mean age 33 years) over a period of 3 years, which is very similar to our group (8.8%) of older patients (mean age 41 years). Compared to one of the largest and most generalizable studies (22), the standardized incidence ratio for CIN in lupus was 3.08 (95% CI 1.13–6.70) (11), which represents a significantly elevated incidence of CIN in the lupus cohort compared to the general population in the US.

Moscicki et al conducted a prospective cohort study in a group of young healthy females (mean age at study entry 19.7 years) from the US with HPV infection at baseline or in followup, and low-grade SIL developed in 15% of the cohort at 36 months (23). In comparison, the prevalence of HPV-positive patients who developed SIL was increased 2-fold (10 [33%] of 30) in this group of older lupus patients (mean age at study entry 41 years). One obvious reason may be related to the older age of our lupus patients. Studies on the natural history of cervical HPV infection in young females showed that most incident infections were transient, lasting <6 months (24, 25). However, in older females with less frequent rates of sexual activity, HPV DNA detection more often reflects a persistent infection (25). Persistent high-risk HPV infection was associated with an OR of 26.9 for the development of low-grade SIL (95% CI 3.2–222.3) in this lupus cohort. Similarly, women who tested positive for a high or probable high-risk HPV at enrollment and after approximately 1 year (range 9–21 months; positive/positive) had a 3-year cumulative incidence of CIN 2+ of 17.0% (95% CI 12.1–22.0%). Those who tested negative/positive (3.4%, range 0.1–6.8%), positive/negative (1.2%, range −0.2% to 2.5%), and negative/negative (0.5%, range 0.1–0.9%) were at a significantly lower risk (26). This is of great importance, since we have demonstrated that almost half (47.8%) of the incident high-risk HPV infections in our lupus patients persisted for more than 6 months (13). A future prospective study with a larger sample size followed for a longer period of time is warranted to study the risk of developing high-grade CIN in the lupus patients with persistent high-risk HPV.

The use of CYC during the past 10 years was associated with an increased risk of developing SIL in this group of lupus patients, similar to the results from other previous studies (9–11). Ognenovski et al demonstrated that patients who had received CYC had a significantly high risk of developing CIN compared to patients receiving prednisolone alone (11). In addition, a 13% increase in the risk of progression from normal to CIN was observed for each year of IV CYC administered (11). Another report found that in women currently receiving azathioprine, or who had a history of receiving azathioprine, 50% had cervical atypia compared with 11% of controls (6). In our study, prior use of azathioprine was associated with the development of SIL only in the univariate analysis. In contrast, Nath et al noticed that patients with normal smears were more likely to be receiving hydroxychloroquine (8). This could potentially reflect the disease severity, since azathioprine and CYC are usually given to patients with major organ involvement, whereas hydroxychloroquine is usually given to patients with mild disease. A higher cumulative dose of CYC and a longer duration receiving CYC for the past 10 years were associated with the development of SIL only in the univariate analysis. Whether there is a dose-dependent effect of CYC and other immunosuppressants on the risk of SIL in SLE could not be ascertained in this study. A future prospective study with a larger sample size and a longer followup duration would be required to formally assess the risk of SIL and the use of immunosuppressants.

Thirty-eight percent of patients with a positive HPV DNA test at baseline developed SIL in our cohort compared with 15% reported in other literature (23). In this cohort, the use of baseline HPV testing has a higher sensitivity than abnormal cytology (defined as ASCUS; 47.7% versus 33.3%) in predicting the development of SIL. The high sensitivity of HPV DNA testing for screening has been repeatedly demonstrated in the general population (27–30). When cervical cytology and HPV DNA testing are used together, low-risk women can be screened less frequently. Current guidelines from the US (31) recommend that any low-risk woman age 30 years or older who receives negative test results on both cervical cytology screening and HPV DNA testing should be rescreened no sooner than 3 years later. Our results also support this recommendation, since no lupus patients who belonged to this category developed any high-grade CIN or cancer over a period of 3 years.

One of the greatest challenges in developing cancer screening guidelines is devising strategies that maximize screening benefits and minimize screening harms. In this lupus cohort, repeating cytology testing twice in the first year also increased the sensitivity in predicting the subsequent development of SIL from 33.5% to 58.3% over a period of 3 years. Nonetheless, this strategy would incur an extra visit for all of the patients with negative cytology results at baseline. In the current study, colposcopy was performed for 16 (11.7%) of 137 patients with cytologic abnormality. If high-risk HPV testing was used as the initial screening test, then 24 (17.5%) of 137 would require colposcopy. In this study, if HPV testing was combined with cytology, then 13 (9.5%) more patients would require colposcopy. On the other hand, patients with negative cytology and HPV testing may not require followup until 3 years later. We propose to offer HPV testing in addition to Pap smear screening to newly diagnosed sexually active SLE patients, and then at a regular interval of approximately every 3 years to identify patients who are at an increased risk for SIL. HPV-positive patients should either receive cytology followup every 6 months or an early colposcopy examination. Nonetheless, the optimal screening strategy in patients with SLE would need to be elucidated in future research.

The main limitation of this study is the lack of a healthy control group for comparison. Whether the incidence and the risk factors for the development of SIL in SLE patients is different from the controls would need to be addressed in future studies. Moreover, approximately 10% of the more sensitive items (history of sexually transmitted diseases, age of first sexual intercourse, lifetime sexual partners) are missing. This could potentially lead to false-negative associations. Further research is also needed to understand the incidence and risk factors for SIL in other lupus populations with different ethnic and socioeconomic backgrounds. Previous studies have speculated that disease activity may be as or more important than disease therapy in increasing the risk for lymphoma in rheumatoid arthritis and SLE (32, 33). Unfortunately, we did not have data on the disease activity since the diagnosis of SLE. It would be of interest for a future study to include a measure such as average mean SLEDAI since disease onset is a potential predictor of incident SIL.

In SLE patients with HPV infection, those who were treated with CYC, had persistent high-risk HPV infection, and had previous treatment for cervical lesions are at an increased risk of developing SIL over a period of 3 years. Low-risk patients who receive negative test results on both cervical cytology screening and HPV DNA testing may not need to be rescreened within 3 years. We propose to offer HPV testing in addition to Pap smear testing to newly diagnosed sexually active SLE patients, and then at a regular interval of approximately every 3 years to identify patients who are at an increased risk for SIL. HPV-positive patients should either receive cytology followup every 6 months or an early colposcopy examination. Future studies should address the efficacy and safety of HPV vaccination in this group of immunosuppressed patients.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Tam had 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.

Study conception and design. Tam, Chan, Ho, Li.

Acquisition of data. Tam, Chan, Yu, Yim, Tak-Hong Cheung, Jo L. K. Cheung.

Analysis and interpretation of data. Tam, Wong.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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ACR_20367_sm_appendix.doc63KSupplementary Data

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