Lower genital tract infections in young female juvenile idiopathic arthritis patients

Abstract

Background:

To evaluate human papillomavirus (HPV), Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections in juvenile idiopathic arthritis (JIA) patients.

Methods:

After exclusion, 33 female adolescent and young JIA patients (ILAR criteria) and 28 healthy controls were selected for this study. Demographic data, gynecological, sexual function, cervical cytology and histological abnormalities were evaluated. JIA clinical/laboratorial parameters and treatment were also assessed. HPV-DNA, CT-DNA and NG-DNA testing in cervical specimens were performed by Hybrid Capture 2 assays.

Results:

The mean current age was similar in JIA patients and controls (23.3 ± 6.24 vs. 26.1 ± 6.03 years, p = 0.09). The frequencies of sexual intercourse (76% vs. 89%, p = 0.201) and abnormal cervical cytology (24% vs. 11%, p = 0.201) were similar in JIA compared to controls. The higher frequency of HPV infection in JIA patients than controls (30% vs. 11%, p = 0.155) did not reach statistical significance. CT (0% vs. 7%, p = 0.207) and NG infections (0% vs. 4%, p = 0.459) were also alike in both groups. Further evaluation of JIA patients with abnormal and normal cervical cytology showed that the former group had a higher frequency of HPV infection (87% vs. 12%, p = 0.0002) with a low frequency of HPV vaccination (0% vs. 8%, p = 1.0). No differences were evidenced between these two JIA groups regarding demographic data, sexual function and clinical/laboratorial parameters. The frequencies of methotrexate (p =0.206) and biological agent use (p =0.238) were similar in both JIA groups.

Conclusions:

To our knowledge, this was the first study to assess lower genital infections in JIA patients allowing the identification of HPV as main cause of cervical dysplasia. Methotrexate and biological agents do not seem to increase risk of lower genital tract infections in JIA patients.

Keywords:
Human papillomavirus; Chlamydia trachomatis; Neisseria gonorrhoeae; Infection; Juvenile idiopathic arthritis

Introduction

Juvenile idiopathic arthritis (JIA) includes a heterogeneous group of diseases characterized by chronic arthritis [¹–³]. This painful and disable disease occurs mainly in females during the adolescence and young adulthood. Patients may have a precocious sexual activity with a possibility of sexually transmitted infections (STI) [⁴].

Others and we have previously demonstrated that lower genital tract infections, such as human papillomavirus (HPV) and Chlamydia trachomatis (CT) [⁵–⁸] are relevant issues in sexually active adults with rheumatoid arthritis (RA). There are, however, no studies assessing these infections and Neisseria gonorrhoeae (NG) in female adolescent and young adults with JIA.

Therefore, the objective of the present study was to evaluate these STI infections in JIA patients. The possible associations among these infections with demographic data, sexual function, disease parameters and treatment were also analyzed.

Methods

A cross-section study was conducted from September 2014 to June 2016 and all 110 female JIA patients, aged between 15 and 40 years, were invited. JIA patients fulfilled the International League of Associations for Rheumatology (ILAR) classification criteria [⁹] and were followed at two services: Pediatric Rheumatology Unit and Rheumatology Division of our tertiary university hospital.

The exclusion criteria were other chronic diseases (n = 10), current gestation or lactation (n = 3) and refusal to participate in this study (n = 64). Thus, after the exclusion of 77 patients, 33 post-pubertal JIA patients were studied. The healthy age-matched control group included 28 community post-pubertal females adolescents or young adults, between 15 and 40 years of age, selected consecutively using the same exclusion criteria. The Local Ethics Committee of our tertiary service approved the study and an informed consent was obtained from all participants or their legal guardian. Treatments in JIA patients with abnormal and normal cervical cytology were included in Table 1.

Table 1
Treatments in juvenile idiopathic arthritis (JIA) patients with abnormal and normal cervical cytology

Variables			Abnormal cervical cytology (n = 8)	Normal cervical cytology (n = 25)	p
Treatment
	Prednisone, current use		2 (25)	4 (16)	0.616
		Current dose, mg/day	6.3 (5-7.5)	5 (5-9)	0.800
		Cumulative dose, grams	2 (0-137.7)	10 (0-61.2)	0.785
	Methotrexate, current use		1 (12)	11 (44)	0.206
		Current dose, mg/week	15 (15-15)	20 (10-25)	0.383
		Cumulative dose, grams	1.7 (0-16.7)	6.3 (0.3-20.5)	0.034
	Biologic agents, current or previous use		3 (37)	16 (64)	0.238
		Etanercept	1 (12)	6(24)	0.652
		Adalimumab	0 (0)	2 (8)	1.000
		Golimumab	0 (0)	1 (4)	1.000
		Certolizumab	0 (0)	1 (4)	1.000
		Infliximab	1 (12)	0 (0)	0.242
		Tocilizumab	1 (12)	4(16)	1.000
		Abatacept	0 (0)	2 (8)	1.000

• Values expressed as n (%) or median (minimum - maximum value)

Demographic data

The demographic data included current age, disease duration and ethnicity. Socioeconomic class according to Brazilian classification were divided in five categories: upper, upper-middle, middle, lower-middle and lower socioeconomic classes [¹⁰].

Sexual function and gynecological evaluation

The presence of vaginal discharge and sexual function (age of first sexual intercourse, number of sexual activity in the last month, number of sexual activity in the last year, number of sexual partners in the last month and number of sexual partners in the last year) were registered based on recollection [⁶]. A systematic clinical examination of the genitalia was performed by the same expert gynecologist at study entry and includes evaluation of vulva, hymen, vagina and cervix [¹¹]. Previous quadrivalent HPV vaccination was also assessed.

Determination of HPV, CT and NG infections

All exams were carried out in patients and healthy controls and were blinded to JIA disease parameters. HPV DNA testing was performed using Hybrid Capture 2 (HC2 high-risk; Digene Corporation, Gaithersburg, MD, USA) by DNA of oncogenic group of probes. These probes were chosen to detect 13 high-risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). CT DNA testing and NG testing were performed using Hybrid Capture 2 (HC2 CT-ID DNA; Digene Corporation, Gaithersburg, MD, USA). These HPV, CT and NG tests were performed following strictly the manufacturer's instructions and the results were presented as the ratio of the relative light units, which was considered positive when a relative light unit was greater than 1.0.

Cervical cytology and histological evaluations

The Pap smears were collected from virgin adolescents with Cytobrush^®, the brush was inserted in the band of vaginal ostium and gently rotated 90° to 180°, and immediately rolled over the slide. In sexually active patients, the cervicovaginal cytology was collected with Cytobrush^® and spatula Ayre, after insertion of the speculum [¹¹]. The cervix was visualized and the spatula Ayre was inserted in the ostium and rotated 360° under gentle pressure, after inserting the Cytobrush^® for two thirds in the endocervical canal and rotated 90° to 180°. The material of the Cytobrush^® was rolled over the slide and the material on the spatula Ayre was spread on a thin layer in one movement over the middle third of the slide. After the fixation by immersion in 95% ethanol, the specimens were immediately transported to the laboratory [⁶]. All Pap smears were evaluated by the same cytopathologist blinded to gynecology examination in our University Hospital. They were performed according to the Bethesda Classification System in: 1) negative for intraepithelial lesions of malignancy with or without organisms (Trichomonas vaginalis, Candida spp, bacterial vaginosis, Actinomyces spp, herpes simplex virus), 2) other nonneoplastic findings (including inflammatory changes) and 3) epithelial cell abnormalities atypical [atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL) encompassing HPV/mild dysplasia/cervical intraepithelial neoplasia (CIN) 1, high-grade squamous intraepithelial lesion (HSIL) encompassing moderate and severe dysplasia, carcinoma in situ, CIN 1 and CIN 2] [¹²]. Colposcopically guided biopsies were obtained of the most severe visible lesions. Specimen slides were reviewed by a pathologist who had no knowledge of the other clinical or laboratorial data [¹³].

Clinical and laboratorial parameters

The following JIA parameters were systematically assessed: number of active and limited joints, patient and physician global assessment of arthritis activity measured in a 10 cm horizontal visual analogy scale (VAS), erythrocyte sedimentation rate (ESR) by modified Westergren and C-reactive protein (CPR) by nephelometric method.

Current and previous treatment

Use of non-steroidal anti-inflammatory drugs, corticosteroids, disease-modifying antirheumatic drugs -DMARDs (methotrexate, leflunomide, sulfasalazine and hydroxichloroquine) and biological agents (etanercept, adalimumab, abatacept and tocilizumab) were systematically assessed.

Statistical analysis

The results for the continuous variables were presented by median (minimum and maximum values) or mean ± standard deviation (SD), and for categorical variables presented as frequency (percentage). The scores that had normal and abnormal distributions were compared by Student's t-test and Mann-Whitney test, respectively. The differences of categorical variables were calculated by Fisher's exact test. The adopted significance level in all analyses was set at 5%.

Results

The mean current age was similar in JIA patients and healthy controls (23.3 ± 6.24 vs. 26.1 ± 6.03 years, p = 0.09). No differences in Caucasians and in upper middle and lower middle socio-economic classes were observed in both groups (p > 0.05). The mean of JIA duration was 15.0 ± 7.3 years (Table 2).

Table 2
Demographic data, sexual function, gynecological evaluation, Pap smears, genital infections and HPV vaccination in juvenile idiopathic arthritis (JIA) patients and healthy controls

Variables			JIA (n = 33)	Controls (n = 28)	p
Demographic data
	Current age, years		23.3 ± 6.24	26.1 ± 6.03	0.090
	Disease duration, years		15 ± 7.3	–	–
	Caucasian		20 (61)	23 (82)	0.092
	Upper-middle and lower-middle SE classes		32 (97)	23 (79)	0.085
Sexual function and gynecological evaluation
	Vaginal discharge		10 (30)	5(18)	0.378
	Sexual intercourse		25 (76)	25 (89)	0.201
	First sexual activity age, years		18 (14-30)	17 (10-24)	0.196
	Sexual intercourse in last month		19 (57)	19 (68)	0.439
	Sexual intercourse in last month, number		2 (0-15)	4 (0-30)	0.231
	Sexual intercourse in last year		23 (70)	21 (75)	0.767
	Sexual intercourse in last year, number		20 (0-180)	48 (0-360)	0.167
	Sexual partner in last month, number		1 (0-1)	1 (0-2)	0.148
	Sexual partner in last year, number		1 (0-2)	1 (0-5)	0.184
Pap smears and genital infections
	Abnormal cervical cytology		8(24)	3 (11)	0.201
		Inflammation	25 (76)	25 (89)	0.201
		ASCUS	3 (9)	0 (0)	0.243
		LSIL	5 (15)	3(11)	0.715
		HSIL	0 (0)	0 (0)	1.000
		Gardnerella vaginalis	4(12)	1 (4)	0.367
		Candida sp.	0 (0)	1 (4)	0.459
		Trichomonas vaginallis	0 (0)	0 (0)	1.000
	Hybrid capture detection
		Chlamydia trachomatis	0 (0)	2 (7)	0.207
		Neisseria gonorrhoeae	0 (0)	1 (4)	0.459
		Human papillomavirus (HPV)	10 (30)	3(11)	0.115
	Previous quadrivalent HPV vaccination		2 (6)	6(21)	0.127

• Values expressed as n (%), median (minimum - maximum value) or mean ± standard deviation
• SE socio-economic, ASCUS atypical squamous cells of undetermined significance, LSIL low-grade squamous intraepithelial lesion, HSIL high-grade squamous intraepithelial lesion

The frequencies of sexual intercourses (76% vs. 89%, p = 0.201), vaginal discharge (30% vs. 18%, p = 0.378) and abnormal cervical cytology (24% vs. 11%, p = 0.201) were similar in JIA patients compared to healthy controls. No differences were evidenced in sexual intercourse and sexual partner in both groups (Table 2). Group sex was not reported by any JIA patients and healthy controls.

According to hybrid capture detections, CT (0% vs. 7%, p = 0.207) and NG infections (0% vs. 4%, p = 0.459) were also similar in JIA patients and healthy controls. The frequency of HPV infection was higher in JIA patients than in controls, however without statistical significance (30% vs. 11%, p = 0.155). Previous quadrivalent HPV vaccination was similar in both groups (6% vs. 21%, p = 0.127) (Table 2). None of them had condylomata acuminata.

Further evaluation of JIA patients with abnormal and normal cervical cytology showed that the former group had a higher frequency of HPV infection (87% vs. 12%, p = 0.0002). No differences were evidenced between two groups regarding demographic data, gynecologic history, sexual function, previous quadrivalent HPV vaccination and JIA clinical and laboratorial parameters (p > 0.05; Table 3). The frequencies of current methotrexate (12% vs. 44%, p = 0.206) and biological agent use (37% vs. 64%, p = 0.238) were similar in JIA patients with abnormal and normal cervical cytology.

Table 3
Demographic data, sexual function, gynecological evaluation, Pap smears, genital infections and HPV vaccination and disease parameters in juvenile idiopathic arthritis (JIA) patients with abnormal and normal cervical cytology

Variables		Abnormal cervical cytology (n = 8)	Normal cervical cytology (n = 25)	p
Demographic data
	Current age, years	26.2 ± 6.3	23.5 ± 6.3	0.730
	Disease duration, years	13.5 ± 6.6	15.9 ± 7.5	0.427
	Caucasian	4(50)	16 (64)	0.681
	Upper middle and lower middle SE class	8 (100)	24 (96)	1.000
Sexual function and gynecological evaluation
	Vaginal discharge	4 (50)	6 (24)	0.205
	Sexual activity	7 (87)	18 (72)	0.649
	First sexual activity age, years	19.5 (15-22)	17 (14-30)	0.779
	Sexual intercourse in last month	4 (50)	15 (60)	0.695
	Sexual intercourse in last month, number	1 (0-12)	2.5 (0-15)	0.85
	Sexual intercourse in last year	6 (75)	17 (68)	1.000
	Sexual intercourse in last year, number	12 (0-144)	20 (0-180)	0.813
	Sexual partner in last month, number	1 (0-1)	1 (0-1)	0.849
	Sexual partner in last year, number	1 (0-1)	1 (0-2)	0.776
Urogenital infections
	Gardnerella vaginalis	1 (12)	3 (12)	1.000
	Candida sp.	0 (0)	0 (0)	1.000
	Trichomonas vaginallis	0 (0)	0 (0)	1.000
Hybrid capture detection
	Chlamydia trachomatis	0 (0)	0 (0)	1.000
	Neisseria gonorrhoeae	0 (0)	0 (0)	1.000
	Human Papillomavirus (HPV)	7 (87)	3 (12)	0.0002
Previous quadrivalent HPV vaccination		0 (0)	2 (8)	1.000
JIA clinical and laboratory parameters
	JADAS 71 (0-101)	0	2 (0-5)	NA
	DAS28 (0-7)	4.5 (1.36-2.66)	5.0 (1.05-5.21)	0.674
	Number of active joints	0 (0-3)	1 (0-12)	0.514
	Number of limited joints	1.5 (0-43)	5 (0-39)	0.425
	Patient global VAS (0-10)	1.5 (0-8)	2 (0-9)	0.705
	Physician global VAS (0-10)	0 (0-2)	1 (0-5)	0.344
	ESR, mm/1st hour	12.8 ± 5.4	9.7 ± 6.9	0.268
	CRP, mg/L	3.7 (0.4-77)	1.8 (0.2-14)	0.257

• Values expressed as n (%), median (minimum - maximum value) or mean ± standard deviation
• SE socio-economic, JADAS71 Juvenile Arthritis Disease Activity Score, DAS28 Disease Activity Score 28-Joint Counts, NA not applicable, VAS visual analog scale, CRP C-reactive protein (normal range method: < 5 mg/L), ESR erythrocyte sedimentation rate

Discussion

To our knowledge, this was the first study to assess lower genital infections in JIA patients allowing the identification of HPV as main cause of cervical dysplasia in this disease.

The strength of the present study was the systematic assessment of HPV, CT and NG infections in JIA patients and healthy controls with comparable age and sexual function. The use of hybrid capture test for HPV including the oncogenic group of probes is an additional advantage due to its high sensitivity and specificity [¹³, ¹⁴].

HPV infection identified in young JIA patients was subclinical, mild and significantly associated with cervical abnormalities and no evidence of cervical cancer. Contrasting with the reported increased risk of cervical dysplasia and persistent HPV infection in adults with RA [⁵, ⁶, ¹⁵] and anogenital warts due to condyloma acuminatum in young systemic lupus erythematosus patients [¹¹, ¹⁶]. In Sjögren syndrome, a disease with mean age of onset usually in the 4th to 5th decade, a very low prevalence of HPV infection was evidenced [¹⁷].

CT and NG infections are rare in sexually active Chilean adolescents and young adults [¹⁸] and adult RA patients [⁶]. Likewise, we have not observed these STI in JIA or health control groups.

A high rate of serious infections, including tuberculosis, herpes zoster and systemic mycosis, were reported in JIA patients under biologic therapy and methotrexate in a real-life setting [¹⁹]. On the contrary, anti-TNF does not seem to increase short-term risk of exacerbation and/or progression genital infections (HPV and CT) in RA patients [⁶]. Further prospective studies are necessary to determine if JIA patients with HPV will develop cervical cancer, and therefore a rigorous surveillance is recommended for this group of patients.

Only 6% of our JIA patients received previous HPV vaccination, in spite of prompt indication by our service for all adolescent and young JIA patients. In fact, HPV vaccines are efficacious and safe in patients with autoimmune diseases, including systemic lupus erythematosus and JIA, and systematic use should be reinforced for all patients in clinical practice [²⁰, ²¹].

In addition, methotrexate and biological agents do not seem to increase the risk of lower genital tract infections in JIA patients.

Conclusions

This study further reinforces the importance of vaccination in adolescent with chronic arthritis. It also showed a low frequency of STIs in spite of immunosuppressive and biological agents exposure. We further demonstrated that cervical dysplasia in JIA patients was highly associated with HPV, reinforcing the need of close observation and HPV immunization during childhood.

Abbreviations
• ASCUS  Atypical squamous cells of undetermined significance
• CIN  Cervical intraepithelial neoplasia
• CPR  C-reactive protein
• CT   Chlamydia trachomatis
• DMARDs  Disease-modifying antirheumatic drugs
• DNA  Deoxyribonucleic acid
• ESR  Erythrocyte sedimentation rate
• HPV  Human papillomavirus
• HSIL  High-grade squamous intraepithelial lesion
• ILAR  International League of Associations for Rheumatology
• JIA  Juvenile idiopathic arthritis
• LSIL  Low-grade squamous intraepithelial lesion
• NG   Neisseria gonorrhoeae
• RA  Rheumatoid arthritis
• SD  Standard deviation
• STI  Sexually transmitted infections
• VAS  Visual analogy scale

Acknowledgements

Not applicable.

• Funding
  This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 301805/2013-0 to RMRP, 305068/2014-8 to EB and 303422/2015-7 to CAS), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2014/14806-0 to CAS; 2015/037564 to CAS), Federico Foundation (to RMRP, EB and CAS) and by Núcleo de Apoio à Pesquisa “Saúde da Criança e do Adolescente” da USP (NAP-CriAd) to CAS.
• Availability of data and materials
  Not applicable.
• Ethics approval and consent to participate
  This study was approved by our Ethics Committee. The Local Ethics Committee of our tertiary service (CAPPesq - Comissão de Pesquisa e Ética do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo) approved the study and an informed consent was obtained from all participants or their legal guardian. The Local Ethics Committee of our tertiary service (CAPPesq - Comissão de Pesquisa e Ética do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo) approved the study and an informed consent was obtained from all participants or their legal guardian.
• Consent for publication
  All JIA patients and healthy controls signed the consent for publication.
• Publisher's Note
  Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Publication Dates

• Publication in this collection
  05 Dec 2019
• Date of issue
  2019

History

• Received
  01 Aug 2019
• Accepted
  24 Oct 2019
• Published
  15 Nov 2019