Uncovering genetic causes of hypophosphatemia.

BACKGROUND: Chronic hypophosphatemia can result from a variety of acquired disorders, such as malnutrition, intestinal malabsorption, hyperparathyroidism, vitamin D deficiency, excess alcohol intake, some drugs, or organ transplantation. Genetic disorders can be a cause of persistent hypophosphatemia, although they are less recognized. We aimed to better understand the prevalence of genetic hypophosphatemia in the population. METHODS: By combining retrospective and prospective strategies, we searched the laboratory database of 815,828 phosphorus analyses and included patients 17-55 years old with low serum phosphorus. We reviewed the charts of 1287 outpatients with at least 1 phosphorus result ≤2.2 mg/dL. After ruling out clear secondary causes, 109 patients underwent further clinical and analytical studies. Among them, we confirmed hypophosphatemia in 39 patients. After excluding other evident secondary causes, such as primary hyperparathyroidism and vitamin D deficiency, we performed a molecular analysis in 42 patients by sequencing the exonic and flanking intronic regions of a panel of genes related to rickets or hypophosphatemia (CLCN5, CYP27B1, dentin matrix acidic phosphoprotein 1, ENPP1, FAM20C, FGFR1, FGF23, GNAS, PHEX, SLC34A3, and VDR). RESULTS: We identified 14 index patients with hypophosphatemia and variants in genes related to phosphate metabolism. The phenotype of most patients was mild, but two patients with X-linked hypophosphatemia (XLH) due to novel PHEX mutations had marked skeletal abnormalities. CONCLUSION: Genetic causes should be considered in children, but also in adult patients with hypophosphatemia of unknown origin. Our data are consistent with the conception that XLH is the most common cause of genetic hypophosphatemia with an overt musculoskeletal phenotype.

Non-Criteria Obstetric Antiphospholipid Syndrome: How Different Is from Sidney Criteria? A Single-Center Study.

This study aims to compare the demographic characteristics, clinical features, serology, and fetal-maternal outcomes between women with obstetric antiphospholipid syndrome (APS) and those with non-criteria (NC)-APS and seronegative (SN)-APS. Two-hundred and sixty-three women with APS obstetric morbidity ever pregnant were included. Of those, 66 met the APS classification criteria, 140 were NC-APS, and 57 were SN-APS. Patients with other autoimmune diseases were excluded. Adverse pregnancy outcomes (APO) included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. The mean age of the study group was 33.6 ± 5.3 years, and patients were followed up for 129.5 ± 81.9 months. In the NC-APS group, 31 (22.1%) did not fulfill clinical and serological criteria (Subgroup A), 49 (35%) did meet clinical but not serologic criteria (Subgroup B), and 60 (42.9%) fulfilled the serologic criteria but not the clinical ones (Subgroup C). The cardiovascular risk burden was higher in the APS group, due to a higher proportion of smoking. Patients with criteria APS received more intensive treatment than patients in the other study groups. The addition of standard of care (SoC) treatment significantly improved live birth and decreased APO in all groups. Significant clinical differences were observed between the study groups. However, when treated with SoC, fetal-maternal outcomes were similar, with a significant improvement in live births and a decrease in APO. Risk stratification in patients with obstetric morbidity associated with APS can help individualize their treatment.

Pain and health-related quality of life in patients with hypophosphatasemia with and without ALPL gene mutations.

Background: Low serum alkaline phosphatase levels are the hallmark of hypophosphatasia, a disorder due to pathogenic variants of the ALPL gene. However, some patients do not carry ALPL variants and the cause of low alkaline phosphatase remains unknown. We aimed to determine health-related quality of life in adults with low alkaline phosphatase and explore the differences between patients with and without ALPL mutations. Methods: We studied 35 adult patients with persistently low alkaline phosphatase unrelated to secondary acquired causes who had ALPL sequenced, and 35 controls of similar age. Three questionnaires about body pain (Brief Pain Inventory, BPI), physical disability (Health Assessment Questionnaire Disability Index, HAQ-DI), and health-related quality of life (36-item Short-Form Health Survey, SF-36) were delivered by telephone interviews. Results: The mean BPI intensity and interference scores were higher in the patient group (p=0.04 and 0.004, respectively). All domains of the HAQ instrument tended to score better in the control group, with significant differences in the "reach" score (p=0.037) and the overall mean score (0.23 vs 0.09; p=0.029). Patients scored worse than controls in several SF-36 dimensions (Role physical, p=0.039; Bodily pain p=0.046; Role emotional, p=0.025). Patients with and without pathogenic variants scored similarly across all tests, without between-group significant differences. Conclusions: Patients with persistently low levels of alkaline phosphatase have significantly worse scores in body pain and other health-related quality of life dimensions, without differences between patients with and without pathogenic variants identified in ALPL gene. This is consistent with the latter ones carrying mutations in regulatory regions.

Treatment with low-dose prednisone in refractory obstetric antiphospholipid syndrome: A retrospective cohort study and meta-analysis.

BACKGROUND: Glucocorticoids have been suggested as a potential therapy in refractory obstetric antiphospholipid syndrome (oAPS). Our aims were to describe a cohort of patients with oAPS treated with low-dose glucocorticoids and to perform a systematic review and meta-analysis evaluating the effects of additional glucocorticoids on the pregnancy outcomes in oAPS patients. METHODS: Retrospective study that included 11 women diagnosed with primary antiphospholipid syndrome. The meta-analysis was conducted by fitting random effects models and was checked for heterogeneity. RESULTS: All women had suffered from early pregnancy losses and two also had a history of fetal deaths. We studied 47 pregnancies that resulted in 32 abortions (68.1%) and 3 fetal deaths (6.4%). Twenty-six pregnancies were under treatment, mainly LDA and LMWH. Low-dose glucocorticoids were indicated in 13 pregnancies (always in association with LDA and LMWH). There was a decrease in pregnancy loss in those patients treated with LDA and LMWH. Treatment with glucocorticoids significantly increased the rate of successful pregnancy (38.5% abortions in treated vs 85.3% abortions in non-treated pregnancies; p=0.003). After multivariate GEE analysis, only glucocorticoids remained inversely associated with pregnancy loss (OR=0.157, (CI 0.025-0.968, p=0.046)). The meta-analysis showed that glucocorticoids tended to improve the frequency of successful pregnancy (OR= 0.509 (0.252-1.028), p=0.06). Three cases of gestational diabetes and one of preeclampsia were observed in our cohort. The meta-analysis, which mostly included studies using high-dose steroids, showed that glucocorticoids increased not only the frequency of preeclampsia and gestational diabetes, but also the rate of pre-term birth. CONCLUSIONS: The efficacy of low-dose glucocorticoids in addition to the standard therapy in patients with refractory oAPS should be confirmed in well-designed clinical trials. However, high doses of steroids significantly increase the frequency of maternal and fetal morbidities, making their use strongly inadvisable.

Pregnancy and systemic lupus erythematosus in Spain: Has anything changed in the 21st century?

OBJECTIVE: To analyse a cohort of pregnant patients with systemic lupus erythematosus and compare the outcomes of both the disease and pregnancy with the results of previous studies conducted in the same geographical area. PATIENTS AND METHODS: Retrospective cohort study of 37 women with systemic lupus erythematosus (64 pregnancies) followed in a multidisciplinary unit. Comparative study with similar Spanish studies identified after literature search. RESULTS: Our cohort was characterized by an older age and by the presence of non-Caucasian patients. Although we found no clinical differences, from the serological point of view our cohort presented a higher frequency of antiphospholipid antibodies. Patients included in this study were treated more frequently with antimalarials and low-dose aspirin. Systemic lupus erythematosus flare frequency was very similar between the different studies, and we did not identify clear predictors for them. Although the rate of live births was similar among studies, the obstetric outcome of our series was better with a very low rate of preeclampsia, preterm birth and low birth weight newborn. The only predictor of adverse obstetric event was age. CONCLUSIONS: Although changes in the therapeutic attitude and planning of pregnancy in recent years have not had a direct impact on the rate of systemic lupus erythematosus flares during pregnancy, they have meant an improvement in the obstetric results. The introduction of new variables independent of the disease such as age at conception, socio-cultural origin, or the availability of multidisciplinary units should be considered in the results of future studies.

Risk Factors for the Development of the Disease in Antiphospholipid Antibodies Carriers: A Long-term Follow-up Study.

The natural history of antiphospholipid antibodies (aPL) carriers is not well-established. The objectives of the present study were (a) to study the probability of developing clinical criteria of antiphospholipid syndrome (APS), (b) to identify potential risk factors for developing thrombosis and/or obstetric complications, (c) to study the association between the antibody profile and development of APS, and (d) to determine the efficacy of primary prophylaxis. We retrospectively analyzed 138 subjects with positive aPL who did not fulfill clinical criteria for APS. The mean follow-up time was 138 ± 63.0 months. Thirteen patients (9.4%) developed thrombosis after an average period of 73.0 ± 48.0 months. Independent risk factors for thrombosis were smoking, hypertension, thrombocytopenia, and triple aPL positivity. Low-dose acetyl salicylic acid did not prevent thrombotic events. A total of 28 obstetric complications were detected in 92 pregnancies. During the follow-up, only two women developed obstetric APS. Prophylactic treatment in pregnant women was associated with a better outcome in the prevention of early abortions. The thrombosis rate in patients with positive aPL who do not meet diagnostic criteria for APS is 0.82/100 patients-year. Smoking, hypertension, thrombocytopenia, and the aPL profile are independent risk factors for the development of thrombosis in aPL carriers. Although the incidence of obstetric complications in this population is high (31.6%), only a few of them meet APS criteria. In these women, prophylactic treatment might be effective in preventing early abortions.

Does Adjusted Global Antiphospholipid Syndrome Score (aGAPSS) Predict the Obstetric Outcome in Antiphospholipid Antibody Carriers? A Single-Center Study.

The adjusted Global Antiphospholipid Syndrome (APS) Score (aGAPSS) is a tool proposed to quantify the risk for antiphospholipid antibody (aPL)-related clinical manifestations. However, aGAPSS has been validated mainly for thrombotic events and studies on APS-related obstetric manifestations are scarce. Furthermore, the majority of them included patients with positive aPL and different autoimmune diseases. Here, we assess the utility of aGAPSS to predict the response to treatment in aPL carriers without other autoimmune disorders. One-hundred and thirty-seven women with aPL ever pregnant were included. Sixty-five meet the APS classification criteria, 61 had APS-related obstetric manifestations, and 11 were asymptomatic carriers. The patients' aGAPSS risk was grouped as low (< 6, N = 73), medium (6-11, N = 40), and high risk (≥ 12, N = 24). Since vascular risk factors included in the aGAPSS were infrequent in this population (< 10%), the aGAPSS score was mainly determined by the aPL profile. Overall, the live birth rate was 75%, and 37.2% of the patients had at least one adverse pregnancy outcome (APO). When considering patients according to the aGAPSS (high, medium, and low risk), no significant differences were found for pregnancy loss (29.2%, 25%, and 21.9%) or APO (33.3%, 47.5%, and 32.9%). In the present study, including aPL carriers without other autoimmune diseases, aGAPSS is not a valuable tool to identify patients at risk for obstetric complications despite treatment. In these patients with gestational desire, in addition to the aPL profile, other pregnancy-specific factors, such as age or previous obstetric history, should be considered.

Mild Hypophosphatemia-Associated Conditions in Children: The Need for a Comprehensive Approach.

To better understand the causes of hypophosphatemia in children, we evaluated all serum phosphate tests performed in a tertiary hospital with unexpected but persistent temporary or isolated hypophosphatemia over an 18 year period. We collected 29,279 phosphate tests from 21,398 patients, of which 268 (1.2%) had at least one result showing hypophosphatemia. We found that endocrinopathies (n = 60), tumors (n = 10), and vitamin D deficiency (n = 3) were the medical conditions most commonly associated with mild hypophosphatemia, but in many patients the cause was unclear. Among patients with endocrinopathies, those with diabetes mellitus were found to have lower mean serum phosphate levels (mean 3.4 mg/dL) than those with short stature (3.7 mg/dL) or thyroid disorders (3.7 mg/dL). In addition, we found a correlation between glycemia and phosphatemia in patients with diabetes. However, despite the potential relevance of monitoring phosphate homeostasis and the underlying etiologic mechanisms, renal phosphate losses were estimated in less than 5% of patients with hypophosphatemia. In the pediatric age group, malignancies, hypovitaminosis D, and endocrine disorders, mostly diabetes, were the most common causes of hypophosphatemia. This real-world study also shows that hypophosphatemia is frequently neglected and inadequately evaluated by pediatricians, which emphasizes the need for more education and awareness about this condition to prevent its potentially deleterious consequences.

Do all antiphospholipid antibodies confer the same risk for major organ involvement in systemic lupus erythematosus patients?

OBJECTIVES: We aimed to investigate the association between the different antiphospholipid antibodies (aPL) and both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) manifestations. METHODS: Patients from the RELESSER registry, a Spanish retrospective, cross-sectional, forty-five hospital registry of adult SLE patients, were included. RESULTS: Out of a total of 3,658 SLE patients, 1372 were aPL positive (555 of them fulfilled criteria for APS). All aPL types showed a negative association with cutaneous SLE manifestations. Lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) were both associated with haematological, ophthalmological and neuropsychiatric manifestations. IgG isotypes were associated with a higher risk of lupus manifestations compared with IgM. We found that the risk of neuropsychiatric and ophthalmological manifestations significantly increased with a higher number of positive aPL whereas the risk of cutaneous symptoms showed a negative correlation. All types of aPL, and more strongly LA, were associated with non-criteria antiphospholipid syndrome (APS) manifestations such as thrombocytopenia and haemolytic anaemia. Moreover, LA and aCL (particularly IgG isotype) were also associated with Libman-Sacks endocarditis and cognitive impairment. This association was stronger with more than one positive aPL. All types of aPL were also associated with classic APS manifestations, although LA, IgG isotypes, and patients with more than one aPL displayed a higher risk. CONCLUSIONS: There is a hierarchy for aPL and the risk of APS and SLE manifestations. aCL, and especially LA, confer a higher risk for major organ involvement in SLE. IgG isotypes seem to have a more important role. The load of aPL confer a higher risk for APS and certain SLE manifestations.

Pregnancy and Systemic Lupus Erythematosus in Spain: Has Anything Changed in the 21st Century? / Embarazo y lupus eritematoso sistémico en España: ¿ha cambiado algo en el siglo xxi?

OBJECTIVE: To analyse a cohort of pregnant patients with systemic lupus erythematosus and compare the outcomes of both the disease and pregnancy with the results of previous studies conducted in the same geographical area. PATIENTS AND METHODS: Retrospective cohort study of 37 women with systemic lupus erythematosus (64 pregnancies) followed in a multidisciplinary unit. Comparative study with similar Spanish studies identified after literature search. RESULTS: Our cohort was characterized by an older age and by the presence of non-Caucasian patients. Although we found no clinical differences, from the serological point of view our cohort presented a higher frequency of antiphospholipid antibodies. Patients included in this study were treated more frequently with antimalarials and low-dose aspirin. Systemic lupus erythematosus flare frequency was very similar between the different studies, and we did not identify clear predictors for them. Although the rate of live births was similar among studies, the obstetric outcome of our series was better with a very low rate of preeclampsia, preterm birth and low birth weight newborn. The only predictor of adverse obstetric event was age. CONCLUSIONS: Although changes in the therapeutic attitude and planning of pregnancy in recent years have not had a direct impact on the rate of systemic lupus erythematosus flares during pregnancy, they have meant an improvement in the obstetric results. The introduction of new variables independent of the disease such as age at conception, socio-cultural origin, or the availability of multidisciplinary units should be considered in the results of future studies.

Antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE) implies a more severe disease with more damage accrual and higher mortality.

INTRODUCTION: Antiphospholipid antibodies (aPL) have been associated with organ damage and certain features in systemic lupus erythematosus(SLE) patients. Our aim was to investigate the differences between SLE patients according to the presence of aPL and/or clinical antiphospholipid syndrome (APS). MATERIALS AND METHODS: Patients from the RELESSER-T registry were included. RELESSER-T is a Spanish multicenter, hospital-based, retrospective, SLE registry. RESULTS: We included 2398 SLE patients, 1372 of whom were positive for aPL. Overall 1026 patients were classified as SLE, 555 as SLE-APS and817 as SLE-aPL. Regarding cardiovascular risk factors, SLE-APS patients had higher rates of hypertension, dyslipidemia and diabetes than those with SLE-aPL and SLE (p < 0.001). SLE-APS patients showed higher rates of neuropsychiatric, cardiac, pulmonary, renal and ophthalmological manifestations than the other groups (p < 0.001). SLE-APS patients presented greater damage accrual with higher SLICC values (1.9 ± 2.2 in SLE-APS, 0.9 ± 1.4 in SLE-aPL and 1.1 ± 1.6 in SLE, p < 0.001) and more severe disease as defined by the Katz index (3 ± 1.8 in SLE-APS, 2.7 ± 1.7 in SLE-aPL and 2.6 ± 1.6 in SLE, p < 0.001). SLE-APS patients showed higher mortality rates (p < 0.001). CONCLUSIONS: SLE-APS patients exhibited more severe clinical profiles with higher frequencies of major organ involvement, greater damage accrual and higher mortality than SLE-aPL and SLE patients.

Granulomatosis with polyangiitis with isolated orbital involvement in children: a case report successfully treated with Rituximab and review of literature.

We report the case of a 15-year old girl who presented with a non-tender right upper eyelid swelling. Magnetic resonance confirmed the presence of an enlargement of the orbicular muscle with moderate contrast enhancement. Biopsy revealed the presence of necrotizing granulomatous vasculitis. Further studies ruled out systemic involvement. Thus, she was diagnosed with isolated granulomatosis with polyangiitis (GPA). Treatment with steroids and methotrexate was started. Due to the persistence of the lesion, rituximab (RTX) was added with excellent clinical and radiological response. This is, to the best of our knowledge, the first case of isolated orbital GPA treated with RTX in a pediatric patient.

Kawasaki disease in Spanish paediatric population and synoptic weather types: an observational study.

Kawasaki disease (KD) is a vasculitis of unelucidated pathogenesis that usually occurs in paediatric patients. In this study we analyse the temporal pattern and geographical distribution of the disease in Spain, and its relationship with atmospheric circulation patterns. We performed a retrospective study in which we collected all hospital admissions due to KD in the country between 2005 and 2015 and explored their relationship with demographic and geographical characteristics. Moreover, we calculated daily surface atmospheric patterns over Spain to study the relationship between weather types (WT) and KD Admissions. The average admission rate for KD in the paediatric population was 3.90 per 100,000, with a male to female ratio of 1.56:1. The highest rate of admissions was found in the 0-4-year-old group, with an incidence of 11.7 cases per 100,000. Admissions followed an annual cyclic pattern with a peak of incidence in January (p = 0.022) and a nadir in September. There was an upwards trend in the number of KD admissions in male sex during the study period (p = 0.004). However, there were marked geographical differences in the incidence rate. Finally, the analysis of the relationship between the WT and the number of admissions by KD revealed no statistically significant association. KD admissions follow a peculiar seasonal and spatial distribution, that suggest the involvement of environmental factors in the disease; however, the absence of an association with WT should be interpreted with caution and regional studies should be done to explore this relationship.

Epigenetics of Skeletal Diseases.

PURPOSE OF REVIEW: Epigenetic mechanisms modify gene activity in a stable manner without altering DNA sequence. They participate in the adaptation to the environment, as well as in the pathogenesis of common complex disorders. We provide an overview of the role of epigenetic mechanisms in bone biology and pathology. RECENT FINDINGS: Extensive evidence supports the involvement of epigenetic mechanisms (DNA methylation, post-translational modifications of histone tails, and non-coding RNAs) in the differentiation of bone cells and mechanotransduction. A variety of epigenetic abnormalities have been described in patients with osteoporosis, osteoarthritis, and skeletal cancers, but their actual pathogenetic roles are still unclear. A few drugs targeting epigenetic marks have been approved for neoplastic disorders, and many more are being actively investigated. Advances in the field of epigenetics underscore the complex interactions between genetic and environmental factors as determinants of osteoporosis and other common disorders. Likewise, they help to explain the mechanisms by which prenatal and post-natal external factors, from nutrition to psychological stress, impact our body and influence the risk of later disease.

Peripheral B-Cell Subset Distribution in Primary Antiphospholipid Syndrome.

BACKGROUND: B-cell differentiation and B-cell tolerance checkpoints may be different in antiphospholipid syndrome (APS) from systemic lupus erythematosus (SLE) and can help to understand differences between them. Our aim was to define alterations of B-cell subsets in patients with primary APS (pAPS) and to compare them with SLE patients and healthy controls (HC). METHODS: Cross-sectional study including three study groups: 37 patients with pAPS, 11 SLE patients, and 21 age- and gender-matched HC. We determined the frequencies of different B-cell subsets in peripheral blood naïve and memory compartments. In addition, we measured serum B cell-activating factor (BAFF) levels and circulating pro-inflammatory cytokines, such as IL-6, by commercial ELISA and CBA, respectively. RESULTS: Patients with pAPS showed a lower percentage of immature and naïve B cells than patients with SLE (p = 0.013 and p = 0.010, respectively) and a higher percentage of non-switched memory B cells than patients with SLE (p = 0.001). No differences either in the percentage of switched memory cells or plasma cells were found among the different groups. Serum BAFF levels were higher in SLE patients than in healthy controls and pAPS patients (p = 0.001 and p = 0.017, respectively). A significant increase in the serum BAFF levels was also observed in pAPS patients compared to HC (p = 0.047). Circulating IL-6 levels were higher in SLE and pAPS patients than HC (p = 0.036 and p = 0.048, respectively). A positive correlation was found between serum BAFF and IL-6 levels in patients with SLE but not in pAPS (p = 0.011). CONCLUSIONS: Our characterization of peripheral blood B-cell phenotypes in pAPS demonstrates different frequencies of circulating B cells at different stages of differentiation. These differences in the naïve B-cell repertoire could explain the higher number and variety of autoantibodies in SLE patients in comparison to pAPS patients, especially in those with obstetric complications.

Vitamin D and antiphospholipid syndrome: A retrospective cohort study and meta-analysis.

OBJECTIVES: (a) To determine serum 25-OH vitamin D (vitD) levels in primary antiphospholipid syndrome (APS) and to compare them with patients with positive antiphospholipid serology who do not meet clinical criteria for APS, and with healthy controls. (b) To analyze the association of vitD levels with both the clinical manifestations and the immunological profile of patients with primary APS. (c) To perform a meta-analysis evaluating potential differences in serum vitD levels between APS and controls as well as the frequency of vitD deficiency in APS patients. METHODS: Retrospective study including 74 patients with primary APS, 54 with positive antiphospholipid (aPL) serology not meeting clinical criteria for APS, and 215 healthy controls. We considered 30 and 10ng/ml as the thresholds for vitD insufficiency and deficiency, respectively. Meta-analysis included four case-control studies (325 primary APS patients and 507 controls) and was conducted by fitting random effects models and checked for heterogeneity. RESULTS: Median serum vitD levels were similar in the three groups: 21ng/ml in primary APS, 25ng/ml in the aPL-positive group, and 21ng/ml in controls (p = 0.115). However, we found differences in the PTH levels, being 40.4 ± 24.9pg/ml in APS, 34.1 ± 18.2pg/ml in aPL serology, and 23.4 ±12.6pg/ml in healthy controls (p < 0.001). Regarding vitD deficiency, we found significant differences across the groups: 16.2% in APS, 11.1% in patients with positive serology, and 3.7% in controls (p = 0.001). There was a trend for the presence of thrombotic events in patients with vitD deficiency (38.9% vs 19.1%, p = 0.071). The meta-analysis confirmed that the combined mean difference in serum vitD levels between APS and controls was -3.605 (p < 0.001) and that APS patients had an increased frequency of vitD deficiency, with an OR = 3.06 (95% CI: 2.12-4.43, p < 0.001). CONCLUSIONS: APS patients show higher frequency of vitD deficiency than the healthy individuals. The meta-analysis study, including three cohorts and ours, suggests that APS patients have significantly lower serum vitD levels and higher frequency of vitD deficiency than controls.

Serological evolution in women with positive antiphospholipid antibodies.

OBJECTIVES: To explore the clinical and serological course of fertile women with positive antiphospholipid (aPL), and the factors and therapeutic implications associated with aPL negativization. METHODS: Retrospective study including 105 women with a positive aPL serology between 1995 and 2013 attending the obstetric autoimmune pathology clinic of a tertiary facility. Patients were classified into the following 3 groups: patients with primary antiphospholipid syndrome (pAPS, 49), patients with a positive serology for aPL, not meeting clinical criteria (42), and patients with systemic lupus erythematosus and a positive aPL serology (14). They were also classified according to the serological aPL evolution: persistently negative aPL, transiently positive serology, and persistently positive serology according to established criteria. RESULTS: After a mean follow-up of 114.4 ± 37.2 months, 59% of patients had persistently negative antibodies, while 25.7% of patients presented persistently positive aPL serology. Multivariate analysis confirmed that smoking (OR = 4; 95% CI: 1.45-11.08; p = 0.008) was an independent risk factor for positive persistence. Persistent positivity as well as a higher antibody load was associated with higher risk for further pregnancy morbidity. In 29 patients, with persistently negative serology who were asymptomatic, treatment with low-dose aspirin was discontinued. No clinical events related to APS were reported after treatment withdrawal, during the 40.95 months of follow-up. CONCLUSIONS: A significant proportion of fertile women with aPL antibodies became negative during follow-up. Tobacco use and the number of positive antibodies are associated with persistently positive serology. Patients with persistently positive aPL serology suffer more obstetric complications. Treatment withdrawal might be safe in selected patients.