Undiagnosed Systemic Lupus Erythematosus in a Cohort of Infertile Women

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1 AJRI 2004; 51: Copyright Ó Blackwell Munksgaard, 2004 American Journal of Reproductive Immunology ISSN Undiagnosed Systemic Lupus Erythematosus in a Cohort of Infertile Women Geva E, Lerner-Geva L, Burke M, Vardinon N, Lessing JB, Amit A. Undiagnosed systemic lupus erythematosus in a cohort of infertile women. AJRI 2004; 51: Ó Blackwell Munksgaard, 2004 PROBLEM: Systemic lupus erythematosous (SLE) is a chronic disease with a broad spectrum of clinical and immunological manifestations, therefore, this condition may be frequently misdiagnosed. The current study was conducted to determine the prevalence of undiagnosed SLE among a cohort of infertile women. METHOD OF STUDY: Screening was performed using sequential (two stage) testing, which included a self-completed questionnaire followed by an antinuclear antibody (ANA) test. The Liang screening questionnaire was distributed to 143 consecutive infertile patients, aged years (mean, years), who were receiving in-vitro fertilization (IVF) treatment. Patients who completed the questionnaire with three or more positive, were sent for ANA testing; those who tested positive ( 1:40) were referred to the Clinical Immunology Unit for anti-double-stranded DNA (dsdna) antibody test and clinical assessment. RESULTS: A total of 136 women (95.1%) completed the questionnaire. Thirteen patients (9.6%) answered yes to three or more questions. Of these, five patients (3.7%) were ANA-positive and two (1.5%) had undiagnosed SLE. CONCLUSIONS: A 1.5% prevalence of undiagnosed SLE was found in our cohort of infertile women. Additional investigations should be performed as to the role of SLE screening in infertile female population; a high-risk group with regard to ovulation induction treatments. Eli Geva 1,2, Liat Lerner-Geva 2,3, Michael Burke 2,4, Nurit Vardinon 4, Joseph B. Lessing 1,2, Ami Amit 1,2 1 The IVF Unit, Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv; 2 Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 3 Women and Children's Health Research Unit, Gertner Institute for Epidemiology and Health Policy Research, Chaim Sheba Medical Center, Tel Hashomer, Israel; 4 Clinical Immunology Unit, Tel Aviv Sourasky Medical Center, Tel Aviv Key words: Infertility, ovulation induction, reproduction, screening, systemic lupus erythematosous Address reprint requests to Eli Geva, IVF Unit, Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. eli.geva@weizmann.ac.il Submitted August 11, 2003; revised January 27, 2004; accepted February 5, INTRODUCTION Systemic lupus erythematosous (SLE) is a chronic, inflammatory, autoimmune disease characterized by the production of non-organ-specific autoantibodies, and a broad spectrum of clinical and immunological manifestations. 1 Severe clinical manifestations include lupus nephritis, neurologic involvement, thrombosis, and arthritis. However, some symptoms may be mild and, therefore, may be misdiagnosed. Systemic lupus erythematosus predominantly affects women of reproductive age. Prevalence of the disease has been reported to be 1/1000 of the general population, with a female to male ratio of 10:1, increasing to 15:1 during the reproductive years. 2 4 Sex hormones may play different roles in the pathogenesis of autoimmune disease. It has been postulated that oestrogens are associated with the development and exacerbation of SLE, whereas androgens ameliorate the condition. 3 8 Infertility has been suggested as a possible manifestation of autoimmune conditions. 9 This concept was supported by the recognition of abnormal autoantibody levels in a group of clinically healthy women who presented with various forms of reproductive failure. 9,10 Infertility in patients with SLE is usually unaltered by the disease 11 or unexplained. 12,13 However, certain factors may contribute to reduce fertility rate in some patients. Menstrual irregularities with anovulatory cycles may occur during episodes of active

2 INFERTILITY AND UNDIAGNOSED SLE / 337 disease and lupus nephritis with chronic renal failure. 5,14 Non-steroidal anti-inflammatory drugs (NSAIDs), high dose of corticoid treatment and cyclophosphamides affect ovulation and the gametes. 5,15,16 The pathobiology of early pregnancy loss in SLE patients has been associated mainly with implantation failure. 9,17 Currently, with improved treatment of SLE, more women may seek infertility therapy. However, some recent reports published data regarding the risk of lupus exacerbation and fatal cases, associated with controlled ovarian hyperstimulation and high oestrogen levels. 12,13,18 21 As most patients with SLE are diagnosed during their childbearing years, some may suffer from infertility and may be receiving treatment with ovulation induction drugs. Since early diagnosis and treatment of SLE may prevent severe morbidity and even mortality in these patients, we performed a preliminary study to evaluate the prevalence of previously undiagnosed disease in a cohort of infertile woman. TABLE I. Patients characteristics (n ¼ 143) PatientsÕ age (years) (m S.D.) (range 24 42) Duration of infertility (years) (m SD) (range 1 20) Number of patients who gave 21 (14.7%) (range 0 2) birth before IVF treatment Number of patients who had a 55 (38.5%) (range 0 7) miscarriage before IVF treatment Number of patients who had an IUFD 4 (2.8%) (range 0 2) Type of infertility Primary 82 (57.3%) Secondary 54 (37.8%) Cause of infertility Mechanical factor 32 (22.4%) Male factor 49 (32.2%) Unexplained 44 (30.8%) Combined 11 (7.7%) Mean number of IVF (range 0 12) cycles/patient (m S.D.) m S.D., mean standard deviation; IVF, in-vitro fertilization; IUFD, intrauterine fetal death. TABLE II. The Liang screening questionnaire 24 (n ¼ 136) Number of patients who answered positively (%) Have you ever had painful swollen 15 (11.0) joints for more than 3 months? Do your fingers ever change color, become 12 (8.8) numb or uncomfortable in the cold? Have you ever had mouth ulcers 4 (2.9) for more than two weeks? Have you ever been told that you have low 22 (16.2) blood count (anemia, low white cell count, or low platelet count)? Have you ever had an obvious or prominent 7 (5.1) rash on your cheeks for more than a month? Do you develop a distinct rash in the 10 (7.4) sun (not just sunburn)? Has it ever been painful to take a deep 2 (1.5) breath for more than just a few days? Have you ever been told you have 3 (2.2) protein in your urine? Do you find a lot of hair on your pillow on waking? 26 (19.1) Have you ever had a seizure, convulsion, or fit? 2 (1.5) AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY VOL. 51, 2004

3 338 / GEVA ET AL. MATERIAL AND METHODS Study Population During the period October 1996 and April 1998, all 143 new infertile patients, aged years (mean, years) that were undergoing treatment in our in-vitro fertilization (IVF) program were recruited (Table I). Screening was performed using sequential (two stage) design. 22 Prior to the medical interview, each patient was asked to complete the screening questionnaire, based on the 1982 revised criteria for the classification of SLE, according to the American Rheumatism Association Diagnosis and Therapeutic Criteria Committee. 23 The screening questionnaire includes 10 items and takes between 3 and 5 min to complete (the Liang screening questionnaire 24 ) (Table II). Patients who responded positively to three or more questions were tested for antinuclear antibody (ANA). The patients who tested positive (ANA titer of 1:40 or more) were referred to the Clinical Immunology Unit, Tel Aviv Sourasky Medical Center for clinical assessment as n = 136 (95.1%) Completed the questionnaire n = 143 Study population n = 7 (4.9%) Did not complete the questionnaire well as an anti-double-stranded DNA (dsdna) antibody test. Laboratory Evaluation Fluorescent ANA was determined by indirect immunofluorescence, using heparin two-cell line substrate (Kallestad, Austin, TX, USA). 20 Anti-dsDNA antibodies were detected using a radioimmunoassay technique (Farr test). 25 RESULTS Of the 143 infertile patients attending our IVF program, 136 women (95.1%) completed the questionnaire (Table I). Eighty-three patients (61.0%) answered negatively to all 10 questions, 18 patients (13.2%) answered yes on one question, and 22 patients (16.2%) answered ÔyesÕ to two questions (Table II) (Fig. 1). Thirteen patients (9.6%) answered positively to three or more questions and were invited to undergo a blood test for ANA. All 13 agreed and five (3.7%) were found to be ANA-positive. These five patients were referred to the Clinical Immunology Unit for consultation as well as anti-dsdna antibody test. Two of these, Israeli-born Jewish Caucasians (one Ashkenazi and one Sepharadic), had definite clinical features suggestive of SLE, that had not been previously diagnosed (Table III). Neither was found to have serious renal or neurological disease, nor had been previously hospitalized. In one patient, the lupus symptoms were sufficient to require steroids and NSAID therapy. The identification of SLE in the two undiagnosed patients in our study may suggest a prevalence of 1.5% of undiagnosed SLE in a cohort of infertile women, aged years. DISCUSSION n = 13 (9.6%) 3 positive n = 5 (3.7%) ANA positive n = 2 (1.5%) Undiagnosed SLE Fig. 1. The study profile. n = 22 (16.2%) 2 positive n = 8 (5.9%) ANA negative n = 3 (2.2%) Negative to SLE n = 18 (13.2%) 1 positive answer n = 83 (61.0%) No positive The annual incidence of SLE in the USA and Europe has been estimated to be 2 8/100,000, and estimated prevalence ranges between 20 and 60 cases/100,000. More than 85% of SLE patients are females, with the highest incidence occurring in the premenopausal years. 2,3,24,26,27 The results of our pilot study indicate a prevalence of 1.5% SLE in a cohort of infertile women. This is higher than the prevalence rate for diagnosed SLE among females of this age group using the same methodology. 2,3,24,26,27 Liang 24 through telephone questionnaires, reported a prevalence of 704/100,000 in the USA with wide confidence intervals (CI) (95% CI, ). Hochberg et al. 28 suggested that the prevalence of SLE in the USA may be up to three to 10-fold greater than previously estimated: 124 cases per 100,000 (95% CI,

4 INFERTILITY AND UNDIAGNOSED SLE / ) in women aged 18 years and above. In Taiwan, Chou et al. 29 found one case of undiagnosed SLE through questionnaires distributed to 1836 people in the community population and 2000 students at a girlsõ college. The prevalence rate in this study was 55/100,000 (95% CI, 2 303). Through a mailed questionnaire to 3500 women aged years randomly selected from a general practice list in the area of Birmingham, UK, Johnson et al. 27 reported that the prevalence of SLE is 200/100,000 (95% CI, ), whereas the prevalence of undiagnosed SLE in this age group was 86/100,000 (95% CI, ). Thus, a substantial number of undiagnosed cases exist, and further work needs to focus on the prevalence in TABLE III. Profile of two patients with undiagnosed systemic lupus erythematosus Patient 1 Patient 2 Age (years) Ethnicity Ashkenazi Sepharadic Infertility profile Duration of infertility 3 2 (years) Type of infertility Primary Secondary Cause of infertility Unexplained Male Delivery ) 1 Miscarriage ) ) Other disease ) ) Treated with gonadotropins Yes No prior to IVF Number of IVF cycles 0 3 Clinical symptoms Photosensitivity ) ) Oral ulcers ) + Sicca ) ) Alopecia ) ) Raynaud s syndrome ) ) Arthritis + ) Anemia + ) Malar ÔButterflyÕ rash + + Pleuritis ) + Proteinuria ) ) Myalgia + ) Migraine ) ) Laboratory evaluation ANA >1:100 >1:100 Anti-dsDNA Treatment following diagnosis Steroids + NSAIDs Observation IVF, in-vitro fertilisation; ANA, antinuclear antibody; dsdna, antidouble-stranded DNA; NSAID, non-steroidal anti-inflammatory drugs. different ethnic groups and the benefits of early diagnosis and treatment. 27 We identified two cases (1.5%) of undiagnosed SLE in a cohort of 136 infertile women. Although the study population was small, this preliminary study raises three important issues: (1) the high prevalence of SLE in our cohort may suggest an increased frequency of the disease in infertile women compared to the general population; (2) sex hormones have been considered to play a role in SLE, that predominantly affects premenopausal women. Flares are more common in the second half of the menstrual cycle, during pregnancy and the postpartum period, and are exacerbated by oestrogens (e.g. oral contraceptives and hormone replacement therapy). 3 5 The infertile women in our study have been treated by ovulation induction with gonadotropins and IVF therapy, which produce elevated oestrogen levels (five to 20-fold higher than normal). Moreover, some recently published case reports and articles point to an association between ovulation induction and exacerbation of SLE, and even mortality. 12,13,18 21 Our preliminary study may raise the question of whether infertile females should be screened for SLE before ovulation induction, or IVF treatment (one patient was accepted for IVF because of male infertility). A larger study that would confirm our results may provide the answer; (3) in this cohort of infertile women, early diagnosis of previously undiagnosed SLE may prevent deterioration to severe disease, which would be much more difficult and expensive to treat. In conclusion, this is the first study that screened infertile women for undiagnosed SLE. Screening for SLE in infertile females may be beneficial, since early diagnosis may prevent exacerbation of the disease, and prevent severe and even fatal events. Larger studies are needed to confirm the higher prevalence of SLE in infertile woman. REFERENCES 1. Cevera R, Khamashta M, Font J, Hughes G: Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. Medicine 1993; 72: Lawrence RC, Hochberk MC, Kelsey JL, McDuffie FC, Medlsger A Jr, Felts WR, Shulman LE: Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol 1989; 16: Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Parks CP, Gilkeson GS: Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. Arthritis Rheum 1998; 41: Lahita RG: The role of sex hormones in systemic lupus erythematosus. Curr Opin Rheumatol 1999; 11: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY VOL. 51, 2004

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