Secondary amenorrhea in a cohort of Egyptian systemic lupus erythematosus patients

The Egyptian Rheumatologist xxx (xxxx) xxx

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Secondary amenorrhea in a cohort of Egyptian systemic lupus erythematosus patients Nesreen Sobhy a,⇑, Marwa H. Niazy a, Ibrahem Siam b a b

Rheumatology and Rehabilitation Department, Faculty of Medicine, Cairo University, Egypt Internal Medicine Department, National Research Center, Cairo, Egypt

a r t i c l e

i n f o

Article history: Received 23 April 2019 Accepted 5 May 2019 Available online xxxx Keywords: Systemic lupus erythematosus Secondary amenorrhea Egyptian Disease duration Anti ds-DNA

a b s t r a c t Aim of the work: To detect the frequency of secondary amenorrhea in a cohort of Egyptian systemic lupus erythematosus (SLE) patients and to identify potentially related key-players. Patients and methods: The medical records of 140 adult SLE patients above 18 and less than 40 years were revised regarding clinical characteristics, immunological features and medications received. The SLE disease activity index (SLEDAI) and damage index (SLICC-DI) were recorded. Patients were divided into two groups: patients who developed secondary amenorrhea and those having normal menstrual cycles. Results: The mean age of the patients was 26.8 ± 5.7 years, the median disease duration was 3.5 years. The patients had renal involvement in 69.3%, neuropsychiatric in 23.6% and cardiac in 37.9%. Cyclophosphamide (CYC) was received by 52.1% and steroids by 139 patients. Secondary amenorrhea was found in 44 patients (31.4%); 36 (81.8%) of them were 32 years old. Patients with secondary amenorrhea had a higher frequency of positive anti-double stranded deoxyribonucleic acid (ds-DNA) antibodies (75% vs 50%; p = 0.04) and a shorter disease duration (median 2 years vs 4.5 years; p = 0.005). Lupus nephritis, renal failure, neuropsychiatric manifestations, cardiac involvement and receiving CYC and high-dose steroids tended to be more frequent in those with secondary amenorrhea compared to those without. The median SLICC-DI was higher in those with amenorrhea compared to those without (p = 0.2) Conclusion: Cyclophosphamide is not the only key-player for the development of secondary amenorrhea in SLE; other factors as the shorter disease duration, presence of autoantibodies and major organ involvements may be implicated. Ó 2019 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease with diverse clinical manifestations [1], affecting mainly women in childbearing age [2]. This makes reproductive health an important issue for those patients [3]. Menopause occurs naturally in women at about 50 years of age. There is a plenty of data concerning the relationship of early menopause to rheumatic diseases, especially systemic lupus erythematosus [4]. Several factors in SLE patients were involved in impaired reproductive function and results in premature ovarian failure (POF). POF is a disorder defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity before the age of 40 years [3,5]. The prevalence of POF in SLE was reported to be higher than

Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ⇑ Corresponding author. E-mail addresses: [email protected], [email protected] (N. Sobhy).

in the general population, possibly due to the direct impact of the disease itself on the functions of the hypothalamic pituitary ovarian axis which is affected by chronic inflammatory state. Also, ovarian involvement in the form of autoimmune oophoritis may result in reduction in ovarian reserve [6]. Some immunosuppressive drugs administered by lupus patients have been accused in the development of POF. Cyclophosphamide (CYC) and glucocorticoids were particularly involved [7– 10]. Treatment with cyclophosphamide has been accused in the majority of POF cases. The rate of development of POF in SLE patients treated with CYC was variable, and it has been reported to range from 11% to 54% in different studies [11–14], Comorbid conditions are frequently encountered in lupus patients, such as end-stage renal disease and autoimmune hypothyroidism, such condition may contribute to reduced fertility by impairing ovulation [3]. In addition to infertility and its psychological sequelae, POF may result in major health problems on the life of SLE patients, such as increased risks for cardiovascular disease and osteoporosis [6,15]. In a previous study on Egyptian SLE patients, thyroid

https://doi.org/10.1016/j.ejr.2019.05.001 1110-1164/Ó 2019 Egyptian Society of Rheumatic Diseases. Publishing services provided by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: N. Sobhy, M. H. Niazy and I. Siam, Secondary amenorrhea in a cohort of Egyptian systemic lupus erythematosus patients, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2019.05.001

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N. Sobhy et al. / The Egyptian Rheumatologist xxx (xxxx) xxx

dysfunction was frequent and associated with an increased cardiovascular risk [16]. The present study aimed to identify the frequency of secondary amenorrhea in a cohort of SLE patients, and to compare patients with secondary amenorrhea to those without, to identify factors which may associated with increased frequency of secondary amenorrhea.

Table 1 The clinical features, immunological profile, medications received, disease activity and damage in systemic lupus erythematosus patients. Parameter

SLE patients (n = 140)

Clinical features

Constitutional Mucocutaneous Arthritis Neuropsychiatric Serositis Pulmonary Cardiac Renal Renal failure Gastrointestinal Hematological

87 (62.1) 68 (48.6) 75 (53.6) 33 (23.6) 76 (50) 84 (60) 53 (37.9) 97 (69.3) 20 (14.30 7 (5) 137 (97.9)

Immune profile

ANA positivity Positive anti ds DNA Consumed C3 Consumed C4 Positive ACL IgG Positive ACL IgM Positive LAC

100 (100) 78 (55.7) 92 (65.7) 67 (47.9) 20 (14.3) 25 (17.9) 28 (20)

Drugs

Antimalarial Azathioprine Cyclophosphamide Mycophenolate mofetil Steroids

122 (87.1) 94 (67.1) 73 (52.1) 20 (14.3) 139 (99.3) 5 (4–8) 1 (0–2)

2. Patients and methods This retrospective study included 140 adult SLE female patients fulfilling Systemic Lupus International Collaborating Clinics (SLICC) classification criteria [17]. They were attending Rheumatology and Rehabilitation Department, Cairo University Hospitals during the last four months of 2017. Their medical records were revised for the demographic data, clinical features, immune profile and the medications received. Disease activity was assessed by the SLE disease activity index (SLEDAI) [18] and damage index scored by the SLICC-DI [19]. Secondary amenorrhea was defined as the lack of menstrual cycles for at least 12 months due to unknown reasons (excluding hysterectomy) [11] within the menstruating age group. Patients were divided into two groups, according to the presence or absence of secondary amenorrhea and both groups were compared. Low dose steroid was considered if 7.5 mg/day, moderate if >7.5 but 30 mg/day and high if >30 mg/day [20]. SLE patients <18 years or >40 years, patients with missing data and those with amenorrhea prior to disease onset were excluded from this study. The study was performed in accordance with the Declaration of Helsinki and was revised and ethically approved by the Scientific Research Committee of the Rheumatology Department, Cairo University (5-SRC-RCU2019). An informed consent was obtained from the subjects. 3. Statistical analysis Data were processed and analyzed using the computer program SPSS (Statistical Package for the Social Science Program) version 16 for windows (SPSS Inc., Chicago, Illinois, USA). For normally distributed quantitative variables mean and standard deviation were used. The median and percentiles were used to describe non parametric data, while frequency and percentages described qualitative variables. Chi square (X2) test was performed and Fisher exact test was used when appropriate. Student t test was used to estimate differences between parametric quantitative variables. Mann Whitney was used when indicated. Stepwise logistic regression was performed. P value was considered significant at < 0.05. 4. Results The mean age of the patients was 26.8 ± 5.7 years (18– 40 years), the median disease duration was 3.5 years (2–7 years). The clinical characteristics, immunological profile, SLEDAI, SLICC DI and medications received are listed in Table 1. Among the patients 44 (31.4%) had secondary amenorrhea, 36 (81.8%) of them were 32 years of age. Comparison of patients with secondary amenorrhea to those without are shown in table 2. Anti ds DNA was found to be an independent factor for secondary amenorrhea (p = 0.045). 5. Discussion Secondary amenorrhea was found in almost a third of the patients in the current study. This is in line with the secondary amenorrhea prevalence range of (27–54%), that was previously

SLEDAI SLICC DI

SLE: systemic lupus erythematosus; ANA: antinuclear antibody; anti ds DNA: anti double stranded deoxy ribonucleic acid; C: complement; ACL Ig: anticardiolipin immunoglobulin; LAC: lupus anticoagulant, SLEDAI: SLE disease activity index; SLICC DI: Systemic Lupus International Collaborating Clinics damage index. Results are presented as number (%) or median (range).

reported by many authors in SLE patients, especially those with history of CYC intake [3,14,21]. Several factors have been accused to play a pivotal role in POF and occurrence of secondary amenorrhea in SLE patients, of which the use of CYC is considered to be the most important [14,22–24]. However the effect of CYC depends on the cumulative dose received, and the age of the patients; sustained amenorrhea may be unavoidable in women aged 32 years or older and receiving CYC [13,14]. In addition to CYC other factors have been considered to be a possible risk for sustained amenorrhea in SLE as, other medications used as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, especially long term use may impair ovulation. [8–10]. Disease activity, autoimmune oophoritis which may occur even in mild disease have been also involved [6,25] as well as associated autoimmune diseases such as autoimmune hypothyroidism which may be found in relation to SLE [3]. Furthermore, Ma et al. [26] stated that SLE patients not receiving alkylating therapy may suffer from impaired ovarian reserve, and the authors considered the disease itself as a risk factor for impaired ovarian function. On the other hand, co-treatment with gonadotropin-releasing hormone agonists or the use of oral contraception may persevere ovarian function in young women receiving CYC [13,14,25,27–31]. Although in the current study, most of the clinical features of SLE as renal, cardiac, neurological and hematological manifestations were more frequent in those with amenorrhea, difference between the two groups did not reach statistical significance. Notably, a higher frequency of patients with amenorrhea tended to be on a higher steroid dose and had administered CYC. Among clinical, laboratory characteristics and medications used, only positivity of anti ds-DNA was found to be remarkably higher in patients with secondary amenorrhea. Anti ds-DNA was considered as a marker for poor prognosis in SLE [32]. However, anti ds-DNA can’t be accused alone as a cause for secondary amenorrhea in the current study. It is suggested that amenorrhea in SLE patients,

Please cite this article as: N. Sobhy, M. H. Niazy and I. Siam, Secondary amenorrhea in a cohort of Egyptian systemic lupus erythematosus patients, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2019.05.001

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N. Sobhy et al. / The Egyptian Rheumatologist xxx (xxxx) xxx

Table 2 Comparison between the clinical features, immunological profile, medications received, disease activity and damage in systemic lupus erythematosus patients with and without secondary amenorrhea. Variable

SLE patients (n = 140)

Age (years) Age < 32 years Disease duration (years)

2nd amenorrhea (n = 44)

normal cycle (n = 96)

P

25.7 ± 6.02 36 (81.8) 2 (1–5)

27.3 ± 5.5 70 (72.9) 4.5 (2–7.5)

0.1 0.29 0.005

Clinical features

Constitutional Mucocutaneous Arthritis Renal Renal failure Neuropsychiatric Serositis Pulmonary Cardiac Gastrointestinal Hematological

30 (68.2) 22 (50) 23 (52.3) 32 (72.7) 7 (15.9) 11 (25) 25 (56.8) 26 (59) 21 (47.7) 3 (6.8) 44 (1 0 0)

57 (59.4) 46 (47.9) 52 (54.1) 65 (67.7) 13 (13.5) 22 (22.9) 51 (53.1) 58 (60.4) 32 (33.3) 4 (4.1) 93 (96.9)

0.3 0.8 0.8 0.5 0.7 0.7 0.7 0.9 0.1 0.6 0.5

Immune profile

Positive ANA Positive anti-dsDNA Consumed C3 Consumed C4 Positive ACL IgG Positive ACL IgM Positive LAC

44 (1 0 0) 30 (75) 29 (65.9) 21 (47.7) 9 (20.5) 11 (25) 8 (18.2)

96 48 63 46 11 14 20

(1 0 0) (50) (65.6) (47.9) (11.5) (14.6) (20.8)

– 0.04 0.9 0.9 0.1 0.1 0.7

Medications

Cyclophosphamide Mycophenolate mofetil Antimalarial Azathioprine Steroid dose: Low Moderate High

24 (55) 6 (13.6) 40 (90) 30 (68.2)

49 14 82 64

(51) (14.6) (85.4) (66.7)

0.7 0.8 0.3 0.8

1 (2.3) 16 (36.4) 27 (61.4) 5 (3.5–8.5) 1 (0–2)

8 (8.3) 34 (35.4) 53 (55.2) 5 (4–8) 0 (0–1.5)

0.2

SLEDAI SLICC DI

0.8 0.2

SLE: systemic lupus erythematosus; ANA: antinuclear antibody; anti ds DNA: anti double stranded deoxy ribonucleic acid; C: complement; ACL Ig: anticardiolipin immunoglobulin; LAC: lupus anticoagulant, SLEDAI: SLE disease activity index; SLICC DI: Systemic Lupus International Collaborating Clinics damage index. Results are presented as mean ± SD, number (%) or median (range).

especially in those <32 years, may be multifactorial rather than the known role of CYC per se as has been reported in the development of POF [3,5]. This can explain the lack of significant association of CYC intake and secondary amenorrhea. Moreover, this supports that, although the disease duration was significantly shorter in those with secondary amenorrhea, other factors may be have a potential impact. Not including the cumulative dose of CYC in the current study may be considered a limitation. Also the small sample size of our retrospective cohort is another limitation as it makes the suggested causes accused for secondary amenorrhea, cannot be considered as strong evidence owing to the small sample size. Future longitudinal studies on different age groups and on a large sample with SLE is recommended to further analyze the possible risk factors associated with secondary amenorrhea. In conclusion, secondary amenorrhea in SLE is multifactorial and not related to cyclophosphamide alone. Other factors as the shorter disease duration, presence of autoantibodies and major organ involvements may be implicated.

Conflict of interest None

Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Please cite this article as: N. Sobhy, M. H. Niazy and I. Siam, Secondary amenorrhea in a cohort of Egyptian systemic lupus erythematosus patients, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2019.05.001