Evaluation of sexual dysfunction and its predictive factors in female and male patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a common disabling joint disease affecting both males and females. Sexual dysfunction (SD) is a common association with RA. The aim of this work was to study the prevalence and predictors of sexual dysfunction in male and female patients with rheumatoid arthritis. The mean age of female patients was 32.1 years and 39.7 years for males. The prevalence of sexual dysfunction was higher in RA female patients than controls, 62.1% versus 41.2% respectively (P ≤ 0.05). The prevalence of global sexual dysfunction was higher in RA male patients than controls, 63.8% versus 47.5% respectively (P ≤ 0.05). Predictors of sexual dysfunction in female RA patients were the number of children, BMI, disease duration, DAS score, HADs-D score, HAQ score, VAS score, joint deformity, and the number of drugs. Predictors of sexual dysfunction in male RA patients were age, disease duration, DAS score, HAQ score, VAS score, and the number of drugs. SD is prevalent in RA patients. Disease activity, pain, depression, and disturbed quality of life affect nearly all domains of sexual functions in female and male patients.

discomfort which leads also to sexual problems [2,7,8]. Sexual problems that were described to be affected in RA were dyspareunia, decrease in sexual desire and sexual arousal, difficulty in reaching an orgasm, or being unable to reach an orgasm [9,10].
Several researchers studied the prevalence of SD in RA patients. Female sexual dysfunction (FSD) was prevalent in Egyptian women with RA, cardiovascular disease was a risk factor [7], older age, hypercholesterolemia, hypertension, diabetes mellitus, and high disease activity increase the sexual dysfunction risk in Egyptian females [11]. Pain, fatigue, and morning stiffness were the main determinant factors in Tunisian females with RA [12]. Male sexual dysfunction was also commonly prevalent in Egyptian males suffering from RA [7]. Predictors of sexual dysfunction were quality of life, depression, disease activity, and low testosterone levels [13]. As well as Indian men suffering from RA, sexual dysfunction was a common complaint. Pain, stiffness of joints, functional limitations, fatigue, depression, drug therapy, and altered body image were the major determinant factors [14].
SD in RA patients was found to be related to some predictors like disease activity (DAS 28 score), quality of life (HAQ score), disease duration, joint deformity, depression, mood disorders, and the number of drugs [15,16].
The current work aimed at discovering the prevalence of sexual dysfunctions in RA patients, to find out gender differences, commonly affected sexual domains, and clinical predictors of sexual dysfunctions in female and male RA patients. Identification of these sexual dysfunctions in RA patients helps to understand the actual disease effect on sexual functions of the affected patient that helps in turn to early management of those dysfunctions, which leads to more improvement of psychosocial aspects, interpersonal relations, and response to treatment.

Methods
This study was carried out as a cross-sectional casecontrol study on 342 patients suffering from RA attending rheumatology, physical medicine and rehabilitation, orthopedic surgery, andrology outpatient clinics, and rheumatology clinics in health insurance complex during the period from October 2019 to July 2020. Patients included in the study had been diagnosed as RA according to the criteria of the American College of Rheumatology/European League against Rheumatism (ACR/ EULAR 2010) [17].
The study included 248 female and 94 male patients who accepted to participate in the study, were randomly chosen according to the planned eligibility criteria.

Inclusion criteria:
Premenopausal married female patients aged  years and married males aged 18-60 years with a confirmed diagnosis of RA at least 2 years before participation in the study and with a regular stable sexual relationship in the last 6 months with a normal partner. Exclusion criteria included pregnant and menopausal women, females with sex hormones abnormalities, females with gynecological or urological problems, partner sexual dysfunction, irregular sexual relationship, patients receiving antidepressants, tranquilizers, or hormonal treatment in the last 3 months before the study, and patients with chronic debilitating diseases affecting sexual functions (diabetes mellitus, cardiovascular diseases, chronic renal disease, chronic liver disease, malignancy, etc...).
We recruited 102 sexually active age-matched premenopausal females and 80 sexually active age-matched males as a control group. The control group was randomly chosen from normal volunteers or patients attending the hospital for complaints rather than RA, sexual dysfunctions, or general medical diseases affecting sexual functions and with an available normal partner.
All patients and controls were subjected to: Medical history: All patients recruited in the study were subjected to full history taking including personal history, rheumatologic history, drug history, sexual history, general medical and surgical history, and gynecological history for female participants.

Clinical examination:
All patients were subjected to general examination for chronic diseases and local rheumatologic examinations for the number of swollen and tender joints, deformities, and functional disabilities.
Disease Activity Assessment (DAS28 score): To assess the activity of RA in studied patients we used the DAS28-ESR (erythrocyte sedimentation rate) score. This was done by counting the number of swollen and tender joints (out of the 28), measurement of the (ESR) or C reactive protein (CRP), and global assessment of health fulfilled by the patient (marked from 0 to 10 indicating a range from very bad to very good). These results had been used then by specific formula to produce the overall disease activity score. A DAS28 score of fewer than 2.6 means remission, 2.6 to 3.2 means mild disease activity, 3.2-5.1 means moderate disease activity, and a score greater than 5.1 implies severe disease activity [18]. Quality of life assessment: A validated Arabic version of the Health Assessment Questionnaire (HAQ) Disability Index (DI) [19] was used to assess the quality of life and functional status for patients with RA. The HAQ-DI consists of 20 items and the score was categorized according to the severity of disability into mild to moderate (HAQ score of 0-1.0), moderate to severe (1.1-2.0), and severe to very severe (2.1-3.0) [20].
Visual analogue scale (VAS): VAS was used to assess arthritis-related pain on a 15cm-long horizontal linear scale, which was labeled from zero (no pain) at the left anchor point to 100 (severe pain) at the right anchor point. Patients either recorded a percentage to describe their pain or placed a vertical mark on the VAS scale. The higher the number on the scale, the more the arthritis pain [21].

Assessment of psychological status:
The Arabic version of the Hospital Anxiety and Depression Scale (HADS): The HADS included anxiety (HADS-A) and depression (HADS-D) subscales, and each subscale had seven items. The Arabic version of HADS was used to assess the psychological well-being of the participants [22]. Each item was rated from 0 to 3. The total score for depression and anxiety between 0 and 7 means normal person, a score between 8 &10 means Borderline abnormal person, and from 11 to 21 means abnormal person [23].
Female sexual function assessment: All-female patients and controls were subjected to the validated Arabic version of the Female Sexual Function Index (ArFSFI). The ArFSFI is a 19-item scale grouped into six domains that had been used to assess the sexual functions in female participants during the past four weeks [24]. Each item was scored on a scale of 0 to 5. Each domain score was calculated by summing up the scores of that domain's questions and multiplying the obtained number by a multiplier factor of that domain. Participants were categorized into either sexually functional or sexually dysfunctional considering the cutoff score of 26.55. The cutoff scores in a particular domain were as follows: less than 4.28, less than 5.08, less than 5.45, less than 5.05, less than 5.04, and less than 5.51 in the desire, arousal, lubrication, orgasm, satisfaction, and pain domains, respectively [25].
Male sexual function assessment: The validated Arabic version of the International Index of Erectile Function (IIEF-15) was used to assess sexual functions in male patients and controls. It consists of 15 questions covering the main sexual domains of male, which were erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Six questions about erectile function, two about orgasmic function, two about sexual drive, three about intercourse satisfaction, and two about overall satisfaction [26]. The maximum total IIEF score is 75 and the minimum IIEF score is 5, with higher scores indicating greater sexual function. The Erectile function domain consists of 5 questions; each question has a value ranging from 0 to 5, adding the sum score of these 5 questions to the score of question 15 results in an IIEF5 score (= 30) which expresses the status of erectile function in males. A score more than 26 indicated normal erectile functions, 22 to 25 indicated mild dysfunction, 17 to 21 indicated moderate dysfunction, 11 to 16 indicated severe moderated dysfunction, and less than 10 indicated severe dysfunction [27].

Laboratory investigations:
All male and female patients who participated were subjected to laboratory measurement of rheumatoid factor, CBC, ESR, CRP, RBS, liver, and kidney function tests. Serum total testosterone, free testosterone, and sex hormone-binding globulin were measured in all male patients and controls to exclude androgen deficiencies that could affect sexual functions.

Ethics approval and consent to participate:
This study was approved by the Institutional Review Board and the Ethics Committee. All participants signed an informed written consent form included study aims, objectives, and applications at the beginning of the study.

Statistical analysis of the data
Data were managed using IBM Statistical Package of Social Sciences (SPSS) version 25. Descriptive statistics were presented as (mean ± standard deviation) for quantitative variables and as (%) for qualitative variables. For relations between qualitative variables, a chi-square test was used. The significance value was P ≤ 0.05.

Results
This study was carried out on 342 patients (248 premenopausal females and 94 males) with RA of more than 2 years duration and 182 age-matched control subjects (102 females and 80 males).
Sociodemographic characteristics of studied female patients revealed that mean age was 32.1 ± 8.3 years, mean duration of marriage was 7.8 ± 6.4 years, 41.9% of them were not working, the mean number of children was 2.3 ± 1.8, 10.5 % were smokers, and mean BMI was 27.1 ± 4.5. In male patients, mean age was 39.7 ± 11.9 years, mean duration of marriage was 11.0 ± 10.0 years, 21.3% of them were not working, the mean number of children was 2.6 ± 1.8, 53.2% were smokers, and mean BMI was 25.6 ± 4.7. There was a significant difference between female and male patients regarding age, age of partner, occupation, age of the youngest child, smoking, BMI, and frequency of sexual activity. Sociodemographic characteristics of the control subjects were quite matched to studied subjects in most of the variables (Table 1).
RA characteristics in the studied group revealed that disease duration in female and male patients was 7.5 ± 5.3 years versus 10 ± 6.7 years respectively (P ≤ 0.05). DAS score was higher insignificantly in females than males 5.5 ± 8.2 versus 4.1 ± 1.9 respectively but the severity of DAS was statistically significant. Mean HADs A score was higher in females than males, 4.1 ± 3.2 versus 3.3 ± 2.1 respectively (P>0.05). Mean HADs D score was higher significantly also in females than males, 8.9 ± 5.8 versus 7.1 ± 4.9 respectively. The mean HAQ score was also higher but insignificantly in female than male patients 1.3 ± 1 versus 1.2 ± 1.1 respectively. VAS score mean was higher significantly in female patients than male patients, 44.4 ± 23.6 versus 36.7 ± 25.9 respectively. Joint deformity and number of drugs had no statistically significant difference between females and males ( Table 2).
Prevalence of SD was significantly higher in RA female patients than controls 62.1% versus 41.2% respectively, while the mean sexual function score was higher in normal females than RA females 26.5 ± 6.7 versus 20.9 ± 9.7 respectively (P ≤ 0.05). Regarding affected sexual domains, there was a significantly statistical difference between female patients and controls regarding desire, arousal, orgasm, and satisfaction ( Table 3).
Prevalence of erectile dysfunction and global sexual dysfunction was significantly higher in RA male patients than controls 66% versus 42.5% for erectile dysfunction and 63.8% versus 47.5% for global sexual dysfunction respectively. Mean erectile function and mean total sexual function (IIEF-15) scores were higher in normal males than males with rheumatoid arthritis, 23.7 ± 6.8 versus 17.5 ± 7.7 respectively for erectile function score (P ≤ 0.05) and 46.5 ± 16.3 versus 57.8 ± 15.8 respectively for total sexual function score (P ≤ 0.05). There was a significantly statistical difference between male patients and controls regarding erectile function, intercourse satisfaction, and overall satisfaction while the mean serum level of sex hormones (SHBG, total testosterone, and free testosterone) in male patients and controls was insignificantly different ( Table 4).
Correlation between mean total sexual function scores in female and male RA patients and means of different predictors revealed that in female patients, number of children, BMI, mean disease duration, mean DAS score, mean HADs D score, mean HAQ score, and mean VAS score were the main predictors while in male patients, age, age of partners, frequency of sexual act, DAS score, and HAQ score were the main predictors (Table 6).

Discussion
The prevalence of sexual disorders in RA patients ranging from 31 to 70%, SD is an underestimated RA comorbidity due to the lack of multidisciplinary approaches [28]. Sexuality clearly constitutes a fundamental element in both personal and social behavior [7].
Sexual dysfunctions are closely related to the symptoms of RA, specifically chronic pain, physical disability, medication side effects, and low self-esteem that ultimately cause reduction of sexual desire and satisfaction [29].
SD in males and females is assessed by validated questionnaires that measure all aspects of sexual health as sexual desire, arousal, orgasm, and satisfaction [30]. The Arabic version of the Female Sexual Function Index (ArFSFI) was assumed to be a reliable, validated, and locally accepted tool to be used in the assessment of FSD in the Egyptian females [24], and the validated 15 item International Index of Erectile Function (IIEF-15) questionnaire had been found to have a high degree of specificity and sensitivity in assessment of sexual dysfunction in Egyptian male population [26].
Gender differences in sexual functions have been investigated in patients with chronic diseases as cardiovascular disease and diabetes [31,32]. Studies have suggested that mental factors affect women's sexual functioning, while mainly physical factors affect men's sexual functioning [33].
In the current work, the prevalence of SD in female patients with RA was 62.1% in comparison to 41.2% in controls with a statistically significant difference between both groups. Mean FSFI was significantly higher in female controls than studied female patients with RA, 26.5 ± 6.7 versus 20.9 ± 9.7 respectively (P ≤ 0.05). Sexual desire, arousal, orgasm, satisfaction, and pain scores were significantly affected in females with RA in comparison to controls, while lubrication score was not significantly affected. Statistically significant correlation between sexual function index score and BMI, mean disease duration, mean DAS score, mean HADs D score, mean HAQ score, mean VAS score, joint deformity, and the number of drugs were also had been found.
These results were in harmony with several similar studies, Yilmaz and colleagues in 2019, which studied sexual functions in 95 females with (RA) in comparison to 108 normal controls. They reported that 70% of females with RA assessed by FSFI score had SD and all subscales of FSFI were affected, they found a strong  negative correlation between total female sexual function score and DAS-28 score, there was a moderate negative correlation between total female sexual function score and HAQ, BDI, VAS scores, age, and morning stiffness and lastly, there was a weak negative correlation between total female sexual function score and BMI in females with RA [34]. In the same line, FSD was found in 64 of 140 Egyptian women (45.7%) with RA in an Egyptian study by El Miedany et al. [7]. Coskun and colleagues studied the relation between SD and RA on 32 females and 20 controls and reported that all sexual domains of FSFI including desire, arousal, lubrication, orgasm, and satisfaction were lower in the RA group than controls except for pain which was higher in controls than the RA group [8]. Khnaba et al. studied the prevalence of FSD on 60 Moroccan females with RA in comparison to normal controls, they found that the prevalence of FSD was 71.9% versus 54% in patients versus controls respectively (P < 0.05) and the total FSFI score was significantly higher in controls than patients with RA (23.05 ± 7.91 versus 18.29 ± 9.09) respectively (P = 0.016). Desire, arousal, orgasm, and satisfaction were significantly affected in patients than controls while pain and lubrication were not significantly affected; VAS, HAD, and quality of life assessed by SF36 scores were the determinant factors of sexual dysfunction. Pain and depression were the main independent factors affecting sexual function [6]. Saad et al. studied sexual functions in Tunisian females with RA versus controls on 71 females with a diagnosis of RA according to the (ACR/EULAR) 2010 Criteria and 71 normal females. They found that FSD prevalence was 49% and 23.9% in patients versus controls respectively (P ≤ 0.05). There was also a statistically significant difference between patients and controls according to FSFI score (24 ± 6.7 versus 27.05 ± 5.34 respectively; P ≤ 0.05). A statistically significant difference between patients and controls regarding sexual desire, arousal, and satisfaction was also reported. However, insignificant differences were found for pain, lubrication, and orgasm. A significant association was found between SD and pain, tender joint counts, DAS28 ESR, fatigue, and functional disability. No association was found between SD and treatment [35].
In the current study, prevalence of SD in male patients with RA according to the IELF-15 score was 66% and 42.5% in male patients and control subjects respectively (P ≤ 0.05) as well as the prevalence of erectile dysfunction in male patients with RA according to  score was 63.8% versus 47.5% in control subjects (P ≤ 0.05). The mean total sexual function (IIEF-15) score was 46.5 ± 16.3 in males with RA versus 57.8 ± 15.8 in control subjects (P ≤ 0.05). The mean erectile function score (IIEF-5) was 23.7 ± 6.8 in controls versus 17.5 ± 7.7 in patients (P ≤ 0.05). This denotes that RA affects sexual functioning in affected males both on the level of erectile function and total sexual function aspects. Predictors of SD in male RA patients were mean disease duration; mean DAS28 score, mean HAQ score, and the number of drugs with a significant positive relationship.   In the same line, Ghareeb and colleagues in 2021 studied 60 males aged 18-45 years in a crosssectional Egyptian study in comparison to normal controls. They found that there was a highly statistically significant difference between patients and controls regarding all sexual functions domains and the total IEEF score (mean score 42.73 ± 25.65 in the case group vs. 61.2 ± 14.41 in the control group) They reported that sexual dysfunction was significantly related to depression, quality of life, disease activity, and free and total testosterone levels [13].
Nasr and El-Shafey compared serum androgen levels and erectile dysfunctions in 24 male patients with RA versus 18 healthy controls; they found that the occurrence of erectile dysfunction was prevalent more in RA patients (45.8%) than controls (11.1%). The Sexual Health Inventory for Men (SHIM) means was significantly higher in the control group than the patient's group. The SHIM score was significantly correlated to CRP, ESR, and DAS-28 in male RA patients [37]. We are in harmony in this study with an Egyptian study by El Miedany et al in 2012 who studied sexual dysfunction in 91 men with RA, they reported that SD was found in 49 out of 91 (53.8%) RA male patients (mean age 51.4 ± 9.4 years). Using the IIEF, a statistically significant correlation between SD and several factors that are usually present in RA patients was reported. These factors were; age, pain, tender joint count, disease activity, fatigue, cardiovascular disease, and psychological status. Interestingly, the intramuscular steroid injections number, but not the oral intake of prednisone, was correlated with more SD [7].
A newly published cross-sectional study by Madhukar et al. investigated sexual dysfunctions in 50 men with RA; the mean age was 42.28 years and the mean duration of the disease was 7 years. They reported that 40 patients had some kind of sexual dysfunction. In 35 out of 40 dysfunctional patients, pain or stiffness of joints, functional limitations, fatigue, and chronic medications were the cause of their sexual dysfunction [14].
Similarly, the prevalence of SD was assessed by Gaber et al. on 29 male patients with RA. The mean age was 45.2 ± 12.1 years and the mean duration of RA was 8.2 ± 7.6 years. They reported that the mean DAS28 score was 3.5, indicating moderate disease activity. SD was found in 48.3% of patients versus 33.3% of controls (P > 0.05). All SD parameters were significantly higher in RA patients compared to controls. Risk factors suggested by authors were DM, hypertension, hypercholesterolemia, old age, and high DAS28 and HAQ scores [11].

Limitations
The small number of patients, shyness, and harassment of patients especially females when sexual issues were discussed, due to religious and cultural restrictions towards sex in Egypt; this could affect the reliability of data obtained from patients. Assessment of partner's sexual functions was not applicable in most of the instances which might make a bias in the diagnosis of the patient's SD as it could be secondary to partner dysfunction not from dysfunction in the patient himself, and finally, an assessment of erectile function in males was dependent only on the IIEF-5 questionnaire which might give a false diagnosis; it had been better to use the intracavernosal injection test or penile duplex as a reliable method for diagnosis erectile dysfunction in those patients.

Conclusions
Rheumatoid arthritis is a prevalent inflammatory joint disabling disease affecting both males and females. Sexual dysfunction is a common association with RA. Sexual dysfunction is highly prevalent in females (62.1%) and males (63.8%) with RA than control subjects. Predictors of sexual dysfunction in RA female patients were the number of children, BMI, disease duration, DAS score, HADs-D score, HAQ score, VAS score, joint deformity, and the number of drugs. Predictors of sexual dysfunction in male RA patients were age, disease duration, DAS score, HAQ score, and the number of drugs. We recommend that rheumatologists and orthopedicians should be aware of sexual dysfunctions associated with RA in females and males. Sexual function assessment should be considered an essential part of the clinical assessment of RA patients. Early diagnosis of sexual dysfunction and early referral to specialists leads to more improvement of patient psychological aspects and quality of life. On the other hand, to manage sexual dysfunction in RA patients appropriately, disease activity, joint pain and deformity, depression, and the number of drugs should be controlled.