Uterine fibroids are the most common gynecological disorder, classically requiring surgery when symptomatic. Although attempts at finding a nonsurgical cure date back to centuries, it is only around the middle of the last century that serious attempts at a medical treatment were carried out. Initially, both progestins and estrogen–progestin combinations have been utilized, although proof of their usefulness is lacking. A major step forward was achieved when peptide analogs of the GnRH were introduced, first those with superagonist properties and subsequently those acting as antagonists. Initially, the latter produced side effects preventing their routine utilization; eventually, this problem was overcome following the synthesis of cetrorelix. Because both types of analogs produce hypoestrogenism, their use is limited to a maximum of 6 months and, for this reason, today they are utilized as an adjuvant treatment before surgery with overall good results. Over the last decade, new, nonpeptidic, orally active GnRH-receptor blockers have also been synthesized. One of them, Elagolix, is in the early stages of testing in women with fibroids. Another fundamental development has been the utilization of the so-called selective progesterone receptor modulators, sometimes referred to as “antiprogestins”. The first such compound to be applied to the long-term treatment of fibroids was Mifepristone; today, this compound is mostly used outside of Western Countries, where the substance of choice is Ulipristal acetate. Large clinical trials have proven the effectiveness of Ulipristal in the long-term medical therapy of fibroids, although some caution must be exercised because of the rare occurrence of liver complications. All selective progesterone receptor modulators produce unique endometrial changes that are today considered benign, reversible, and without negative consequences. In conclusion, long-term medical treatment of fibroids seems possible today, especially in premenopausal women.

The risk-benefit profile of any pharmacologic agent must be evaluated against risks connected with the events to be avoided. This is especially true in the case of hormonal contraception, not intended to combat a disease. Over the six decades during which their use has progressively expanded, the risk-benefit profile of combined oral contraceptives (COC) has substantially changed, with new combinations, dosages and mode of administration appearing on the market. Area covered: In a series of articles, recent information on the complex issue of COC risks and benefits will be reviewed in the hope of providing an updated picture. The present article reviews metabolic changes occurring during use of modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), often compared to classic compounds, such as levonorgestrel. Three categories of metabolic effects in healthy women are detailed: on carbohydrates, lipid and bone mineral content. Expert commentary: Overall, the picture is reassuring: the new generations of progestins are basically devoid of androgenic, estrogenic or glucocorticoid related side-effects. This should result in an improved safety profile, although past history teaches us that that large comparative and surveillance studies are required before firm conclusions can be drawn. At any rate, available evidence indicates that metabolic effects of third and fourth generation progestins, especially when they are combined with natural estrogens, are minimal and, if used in healthy women, should not cause concern.

Ulipristal acetate (UPA) is now recommended as first choice hormonal emergency contraception (EC), due to its higher efficacy and similar safety compared to Levonorgestrel – EC. Even though all trials demonstrated that the first mechanism of action is inhibition of ovulation, some authors still postulate that a post fertilization effect is also possible, raising the alert on medication and fostering the ethical debate. A Medline database search was performed in order to find recent articles related to UPA’s effects on ovulation, on fallopian tube and on endometrium. We also analyzed the effects on sperm function and pregnancy. All studies conclude that UPA is effective in inhibition of ovulation even when administered shortly before LH peak. The effects on fallopian tube are unclear: according to some authors UPA inhibits ciliar beat through an agonistic effect on progesterone receptors, according to others it antagonizes the progesterone-induced ciliar beat decrease. Concerning the action on endometrium and on embryo implantation most of the studies concluded that low dose UPA used for EC has no significant effect on the decrease of endometrial thickness and on embryo’s attachment, but these results are still matter of debate. Finally recent evidence suggests that UPA modulates human sperm functions while it has no effect on established pregnancy. To date the majority of the evidence concurs in excluding a post-fertilization effect of UPA, even though more studies are needed to clarify its mechanism of action.

The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture. The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel. Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed. Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn. At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range.

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An exact profile of women requesting EC can help women in their choice of permanent contraception, and help clinicians in counselling women on appropriate contraception.

BackgroundRisk-stratification is key in a heterogeneous disease like systemic sclerosis (SSc). Until now, SSc patients are stratified according to the extent of skin involvement into limited cutaneous, diffuse cutaneous and sine scleroderma subtypes. However, this classification remains inaccurate to capture disease heterogeneity. Autoantibodies are found in more than 90% of the patients and can be detected before onset of the disease. Among them, three predominant and specific antibodies are used: anti-centromere, anti-Scl70 and RNA polymerase III antibodies.ObjectivesTo compare the performances of stratification into LeRoy’s cutaneous subtypes versus autoantibody status in SSc versus combination of cutaneous subtypes and autoantibodies status.MethodsPatients from the EUSTAR database were classified either as (i) limited cutaneous, diffuse cutaneous or sine scleroderma (based on the recording made by the treating physician) or (ii) according to autoantibodies with the following subclassifications: (1) no specific autoantibodies, (2) isolated ANA, (3) anti-centromere antibodies, (4) anti-Scl70 antibodies and (5) anti-RNA polymerase III antibodies or (iii) according to combination of cutaneous subset and auto-antibodies. The respective performance of each model to predict overall survival (OS), progression-free survival (PFS), disease progression and different organ involvements was assessed and the three models were compared by the area under the receiver operating characteristic curve (AUC 95%CI) and the net reclassification improvement (NRI). Missing data were imputed through multiple imputation using chain equations.ResultsIn all, 10’711 patients were included: 84.6% females, mean age: 54.4±13.8 years, mean disease duration: 7.9±8.2 years. In the prospective analysis (n= 6’467 to 7’829 according to the outcome), after a mean follow-up of 56 months and a mean of three visits per patient, we did not identify any difference in AUC between the cutaneous-based model and the antibody-based model for prediction of OS and disease progression. However, the NRI showed a significant improvement in prediction of OS (0.57 [0.46-0.71] vs. 0.29 [0.19-0.39]) and disease progression (0.36 [0.29-0.46] vs. 0.21 [0.14-0.28]) at 4 years using the antibody-based model. Regarding prediction of each organ involvement in longitudinal analyses, the antibody-based model showed better performance than the cutaneous-one for renal crisis (AUC: 0.719 [0.696-0.742] vs. 0.664 [0.643-0.685]), with the highest association observed with anti-RNA polymerase III (OR: 7.47 [1.63-34.24], p= 0.010). Similarly, the antibody-based model was better than the cutaneous model in predicting lung fibrosis (AUC 0.719 [0.715-724] vs. 0.653 [0.647-0.659]) and restrictive lung fibrosis (AUC 0.759 [0.749-0.766] vs. 0.711 [0.701-0.721]) which were both associated with anti-Scl70 antibodies (OR: 9.29 [8.17-10.55] and 7.92 [5.37-11.69], respectively, p<0.0001 for both). Although there was no difference in the AUC to predict digital ulcers, NRI showed an improvement using the antibody-based model (0.31 [0.29-0.33] vs. 0.24 [0.22-0.26]) with the highest association with anti-Scl70 antibodies (OR: 3.57 [2.68-4.75], p<0.0001). The two models had similar performances in assessing occurrence of intestinal involvement, heart dysfunction or elevated sPAP. Combining both antibody status and cutaneous subtype did not improve the performance of our models. In the exploratory analysis, there was no change using modified Rodnan skin score to define cutaneous form.ConclusionAuto-antibody status outperforms the common cutaneous subsetting to risk-stratify SSc patients in the EUSTAR cohort. This easily performed subclassification using autoantibodies specific status can be used by the clinicians to risk-stratify their patients and to adapt disease monitoring in routine practice.Disclosure of InterestsMuriel Elhai Speakers bureau: BMS outside of the submitted work, Marouane Boubaya: None declared, Nanthara Sritharan: None declared, Alexandra Balbir-Gurman: None declared, Elise Siegert: None declared, Eric Hachulla: None declared, Jeska de Vries-Bouwstra: None declared, Gabriela Riemekasten: None declared, Jörg H.W. Distler: None declared, Douglas Veale: None declared, Edoardo Rosato: None declared, Francesco Del Galdo: None declared, Fabian A Mendoza: None declared, Daniel Furst Consultant of: Abbvie, Novartis, Pfizer, R-Pharm, Grant/research support from: Emerald, Kadmon, PICORI, Pfizer,Prometheus, Talaris, Mitsubishi, Carlos De la Puente Bujidos: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli: None declared, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim, Coralie Bloch-Queyrat: None declared, Yannick Allanore Consultant of: Actelion, Bayer, BMS, Boehringer-Ingelheim, Inventiva, Roche, Sanofi-Aventis, Grant/research support from: Actelion, Bayer, BMS, Boehringer-Ingelheim, Inventiva, Roche, Sanofi-Aventis

A variety of infections has been recognized as an important cause of morbidity and mortality in patients with nephrotic syndrome, and membranous nephropathy is a common cause of this in the elderly. The reasons for infection risk are due to oedema complications, urinary loss of factor B and D of the alternative complement pathway, cellular immunity, granulocyte chemotaxis, hypogammaglobulinemia with serum IgG levels below 600 mg/dL, and secondary effects of immunosuppressive therapy. Many different prophylactic interventions have been used for reducing the risks of infection in these patients but recommendations for routine use are still lacking. We report two membranous nephropathy cases in the elderly in which Intravenous immunoglobulin were useful in long-term infectious prophylaxis, showing safety in renal function. During immunosuppressant therapy in membranous nephropathy, intravenous immunoglobulin without sucrose are a safe therapeutic option as prophylaxis in those patients with nephrotic syndrome and IgG levels below 600 mg/dL. The long-term goal of infection prevention in these patients is to reduce mortality, prolong survival and improve quality of life.