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Objectives: To systematically review risk of sustained amenorrhea with intravenous (IV) cyclophosphamide in autoimmune rheumatic disease (ARD), and evaluate efficacy of gonadotropin-releasing hormone agonists (GnRHa) to reduce this risk.Methods: Systematic search for papers reporting incidence of sustained amenorrhea ≥12 months in ARD following: IV cyclophosphamide; or GnRHa and IV cyclophosphamide compared to IV cyclophosphamide alone.Results: From 31 articles and 1388 patients (mean age 27.7 years) sustained amenorrhea occurred in 273 patients (19.7%). Of 56 patients (mean age range 23.9-25.6 years) receiving GnRHa and IV cyclophosphamide, and 37 controls (mean age range 25-30.1 years) given IV cyclophosphamide only, sustained amenorrhea occurred in 2/56 (3.6%) patients treated with GnRHa, compared to 15/37 (40.5%) controls. Pooled odds ratio of sustained amenorrhea with GnRHa and cyclophosphamide versus cyclophosphamide alone was 0.054 (95% CI 0.0115-0.2576 p 5 g. GnRHa reduced this risk and should be considered with IV cyclophosphamide in women of childbearing age with ARD.

Background Premature ovarian insufficiency (POI) is a side effect of intravenous cyclophosphamide (i.v.CYC), which is the treatment of choice for many severe manifestations of autoimmune rheumatic disease (ARD) (1). The risk of POI post-CYC appears to be dependent on cumulative dose and patient age but has not been precisely quantified. Gonadotropin Releasing Hormone Analogues (GnRHa) may reduce this risk (2). Studies however, on GnRHa and CYC use in ARD patients have been limited in size and/or by combined analysis with patients receiving CYC for malignancies. Objectives In order to more precisely categorise the risk of POI in ARD patients, and determine whether GnRHa are effective in reducing this risk, we performed a systematic review to assess the risk of sustained amenorrhoea with i.v.CYC in ARD and a meta-analysis of the efficacy of GnRHa in reducing this risk. Methods Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses principles, we searched English language papers using Pubmed, MEDLINE, EMBASE and the Cochrane Library to April 2018. We included all studies that reported the incidence of sustained amenorrhoea (defined as at least 12 months of amenorrhoea) during i.v.CYC treatment in patients with ARD; and those that assessed sustained amenorrhoea in patients receiving GnRHa and i.v.CYC, compared to controls receiving i.v.CYC alone. Results 1099 articles were identified and their titles and abstracts screened, following which 81 papers were selected for full text review. 31 studies were then identified that addressed the risk of sustained amenorrhoea with i.v.CYC in n=1382 patients with ARD. The majority of these patients had systemic lupus erythematosus (1326 out of 1382 patients, 96.0%). The mean age was 24.9 (range 13-36.1) years. Sustained amenorrhoea occurred in 269 patients (19.5%, range 0-54% depending on age and cumulative cyclophosphamide dose). The rate of sustained amenorrhoea significantly positively correlated with increasing cumulative cyclophosphamide dose, and occurred in patients with a mean age ranging from 13-36.1 years at mean cumulative doses ranging from 1-20.1g. A further 3 studies assessed ARD patients given i.v.CYC +/- GnRHa, including 56 patients (mean age range 23.9-25.6 years) receiving GnRHa and i.v.CYC, and 37 controls (mean age range 25-29.4 years) given i.v.CYC only. Sustained amenorrhoea occurred in 2/56 (3.6%) patients treated with GnRHa, compared to 15/37 (40.5%) of controls. The pooled odds ratio of sustained amenorrhoea with GnRHa and i.v.CYC compared to i.v.CYC alone was 0.0543 (95%CI 0.0115-0.2576, p=0.0002). The number needed to treat was 2.7 (95%CI 2.0-4.4) and the absolute risk reduction was 37.0% (95%CI 35.6-38.4%). Conclusion Although the risk of POI with i.v.CYC was associated with increasing age, it was observed across all age groups and from cumulative doses of 1g or more. GnRHa markedly reduced this risk in ARD, and therefore should be considered for concomitant use with i.v.CYC in all women of child-bearing age with ARD. References [1] Marder W, Fisseha S, Ganser MA, Somers EC. Ovarian damage during chemotherapy in autoimmune diseases broad health implications beyond fertility. Clin Med Insights Reprod Health 2012;6:9-18. [2] Marder W, McCune WJ, Wang L, Wing JJ, Fisseha S, McConnell DS, et al. Adjunctive GnRH-a treatment attenuates depletion of ovarian reserve associated with cyclophosphamide therapy in premenopausal SLE patients. Gynecol Endocrinol2012;28(8):624-7. Acknowledgement Arthritis Australia Disclosure of Interests Shi-Nan Luong: None declared, Anthony Isaacs: None declared, Fang En Sin : None declared, Ian Giles Consultant for: UCB, Speakers bureau: UCB