Systemic lupus erythematosus is associated with an increased frequency of spontaneous preterm births:systematic review and meta-analysis

Objective: Preterm birth is one of the most frequent complications of pregnancy in women with systemic lupus erythematosus. The high indicated preterm birth proportion due to hypertensive disorders of pregnancy and/or fetal growth restriction is well known, and preventive measures and screening for early detection are performed. The risk of spontaneous preterm birth is less well recognized. This study aimed to determine the proportions of spontaneous and indicated preterm birth in pregnancies of women with systemic lupus erythematosus. Data Sources: A systematic literature search using Pubmed, Embase, Web of Science, and Google Scholar was performed in June 2021. Study Eligibility Criteria: Studies in pregnant women with systemic lupus erythematosus reporting spontaneous and indicated preterm birth rates were selected. Original research articles published from 1995 to June 2021 were included. Methods: Quality and risk of bias of the included studies were assessed using the Newcastle–Ottawa quality assessment scale. To estimate the pooled event rates and 95% confidence intervals, meta-analysis of single proportions with a random-effects model was performed. Results: We included 21 articles, containing data of 8157 pregnancies in women with systemic lupus erythematosus. On average, 31% (95% prediction interval, 0.14–0.50) of the pregnancies resulted in preterm birth, including 14% (95% prediction interval, 0.04–0.27) spontaneous and 16% (95% prediction interval, 0.03–0.35) indicated preterm birth. Conclusion: In pregnant women with systemic lupus erythematosus, spontaneous and indicated preterm birth proportions are high. This information should be applied in (prepregnancy) counseling and management in pregnancy. The knowledge obtained by this meta-analysis paves the way for further research of associated risk factors and development of interventions to reduce spontaneous preterm birth in systemic lupus erythematosus pregnancies.</p

Bone Disease in Connective Tissue Disease/Systemic Lupus Erythematosus

This article reviews recent advances in the research of the mechanisms of bone loss, as well as clinical features, economic impact and therapeutic implications of osteoporosis and fractures in patients with systemic lupus erythematosus (SLE) as an illustration of bone disease in a complex systemic autoimmune connective tissue disease. Recent studies demonstrated an increased incidence of osteoporosis and peripheral and vertebral fractures in patients with SLE. The aetiology of bone loss in SLE is multifactorial, including clinical osteoporosis risk factors, systemic inflammation, serological factors, metabolic factors, hormonal factors, possibly genetic factors and medication-induced adverse effects. The incidence of symptomatic fractures in patients with SLE is increased 1.2–4.7-fold and age, disease duration, glucocorticoid use, previous cyclophosphamide use, seizures and a prior cerebrovascular event have been identified as important risk factors. Moreover, a high prevalence of morphometric vertebral fractures was demonstrated, while one in three of these patients has normal bone density, which finding points to the multifactorial aetiology of fractures in SLE. The clinical consequences and economic burden of osteoporosis and fractures as glucocorticoid treatment-related adverse events and the high frequency of glucocorticoid therapy underline the importance of reducing glucocorticoid treatment and prescribing steroid-sparing agents. No data on fall risk and its determinants and the relationship with the occurrence of fractures in patients with SLE are currently available. Fall risk might be increased in lupus patients for several reasons. In addition, the recently reported high prevalence (20%) of frailty in SLE patients may contribute to the increased fracture incidence. Therefore, the relationships between fall risk, frailty and fracture occurrence in SLE might be interesting subjects for future studies

Both prolonged remission and Lupus Low Disease Activity State are associated with reduced damage accrual in systemic lupus erythematosus

OBJECTIVES: To identify predictors of organ damage and specifically the relationship between prolonged disease remission or low disease activity and damage accrual in a longitudinal cohort of SLE patients. METHODS: Data were prospectively assessed including the occurrence of minor/major flares. Once a year remission and Lupus Low Disease Activity State (LLDAS) were determined retrospectively. A prediction model for damage accrual during follow-up was constructed with backward logistic regression analyses. Secondly, odds ratios (ORs) for damage accrual (SLICC damage index increase of ⩾ 1 during follow-up) were calculated for patients with or without prolonged remission during 5 years, and with or without LLDAS in ⩾ 50% of observations. RESULTS: Data from 183 patients with a median follow-up duration of 5.0 years were analysed. The most significant predictors for damage accrual were: occurrence of ⩾ 1 major flare, mean daily prednisone dose during follow-up and nephrological manifestations at baseline. Prolonged remission was present in 32.5% (38/117) and LLDAS in ⩾ 50% of observations in 64.5% (118/183) of patients. Both the presence of prolonged remission during 5 years and LLDAS in ⩾ 50% of observations were associated with a reduced risk of damage accrual (OR = 0.20, 95% CI: 0.07, 0.53, P = 0.001 and OR = 0.52, 95% CI: 0.28, 0.99, P = 0.046, respectively). CONCLUSION: This cohort study shows that prolonged remission and LLDAS were associated with an improved outcome, as determined by yearly assessments. In order to improve the outcome in SLE patients, future studies should investigate whether these targets can be reached actively with therapeutic strategies

Prevalence of malnutrition and validation of bioelectrical impedance analysis for the assessment of body composition in patients with systemic sclerosis

Objectives. The aims were to assess the prevalence of malnutrition and to validate bioelectrical impedance analysis (BIA) against whole-body DXA for the assessment of body composition in patients with SSc. Methods. Malnutrition was defined as BMI10% in combination with a fat-free mass index (FFMI)70 years). Body composition was assessed in 72 patients with whole-body DXA (Hologic, Discovery A) and BIA (Bodystat Quadscan 400). The manufacturer's equation and the Geneva equation were used to estimate FFM and fat mass. The agreement between BIA and whole-body DXA was assessed with Bland-Altman analysis and intraclass correlation coefficient. Results. Malnutrition was found in 8.3% (n = 6) and low FFMI in 20.8% (n = 15) of patients. The mean difference in FFM between BIA and DXA applying the Geneva equation was 0.02 (S.D. 2.4) kg, intraclass correlation coefficient 0.97 (95% CI: 0.95, 0.98). Limits of agreement were ±4.6 kg. The manufacturer's equation was less adequate to predict FFM. Conclusion. This study shows a relatively low prevalence of malnutrition in comparison with other studies, but a high prevalence of low FFMI, underlining the necessity of measuring body composition in SSc patients with a standardized and validated method. A good validity of BIA in determining FFM was found at a group level, while at an individual level the FFM may vary by 4.6 kg

Deficiency of functional mannose-binding lectin is not associated with infections in patients with systemic lupus erythematosus

Infection imposes a serious burden on patients with systemic lupus erythematosus (SLE). The increased infection rate in SLE patients has been attributed in part to defects of immune defence. Recently, the lectin pathway of complement activation has also been suggested to play a role in the occurrence of infections in SLE. In previous studies, SLE patients homozygous for mannose-binding lectin (MBL) variant alleles were at an increased risk of acquiring serious infections in comparison with patients who were heterozygous or homozygous for the normal allele. This association suggests a correlation between functional MBL level and occurrence of infections in SLE patients. We therefore investigated the biological activity of MBL and its relationship with the occurrence of infections in patients with SLE. Demographic and clinical data were collected in 103 patients with SLE. Functional MBL serum levels and MBL-induced C4 deposition were measured by enzyme-linked immunosorbent assay using mannan as coat and an MBL- or C4b-specific monoclonal antibody. The complete MBL-dependent pathway activity was determined by using an assay that measures the complete MBL pathway activity in serum, starting with binding of MBL to mannan, and was detected with a specific monoclonal antibody against C5b-9. Charts were systematically reviewed to obtain information on documented infections since diagnosis of SLE. Major infections were defined as infections requiring hospital admission and intravenous administration of antibiotics. In total, 115 infections since diagnosis of lupus, including 42 major infections, were documented in the 103 SLE patients (mean age 41 ± 13 years, mean disease duration 7 ± 4 years). The percentage of SLE patients with severe MBL deficiency was similar to that in 100 healthy controls: 13% versus 14%, respectively. Although deposition of C4 to mannan and MBL pathway activity were reduced in 21% and 43% of 103 SLE patients, respectively, neither functional MBL serum levels nor MBL pathway activity was associated with infections or major infections in regression analyses. In conclusion, SLE patients frequently suffer from infections, but deficiency of functional MBL does not confer additional risk

Hydroxychloroquine treatment in European patients with lupus erythematosus: Dosing, retinopathy screening and adherence

Background Use of hydroxychloroquine (HCQ) is common in patients with lupus erythematosus. Long-term use (ie, ≥5 years) and high-dose HCQ (ie, >5 mg/kg/day) are both risk factors for developing HCQ retinopathy. Advances in our understanding of HCQ retinopathy have led to changes in the recommendations for HCQ dosing and retinopathy screening. The latest EULAR guidelines for the management of SLE recommend a maximum HCQ dose of 5 mg/kg/day and ophthalmological screening at baseline and annually after 5 years of HCQ treatment. Objectives This study aimed to assess whether the EULAR guidelines are affecting HCQ prescription patterns and screening frequencies in Europe. Furthermore, we inventoried adherence to HCQ. Results The online questionnaire was completed by 2936 patients with systemic, cutaneous or juvenile lupus from 33 countries. The majority were female (86.5%) and diagnosed with SLE (81.2%). Among those taking HCQ, the median HCQ dose reported was 4.26 mg/kg/day. More than one-third of respondents (36.8%) exceeded the recommended maximal HCQ dose of 5 mg/kg/day. Baseline ophthalmological screening had been done in 857 out of 1017 respondents diagnosed in the past 10 years (84.3%). Of patients using HCQ ≥5 years, 69.2% reported yearly retinopathy screening. Lastly, 17.3% of patients reported that they skipped HCQ once a week or more often. Conclusion The results of our study demonstrate that higher than recommended dosages of HCQ are prescribed to more than one-third of patients with lupus in Europe. Recent recommendations regarding screening for retinopathy are incompletely implemented

Anti-hinge antibodies recognize IgG subclass- and protease-restricted neoepitopes

Anti-hinge Abs (AHAs) target neoepitopes exposed after proteolytic cleavage of IgG. In this study, we explored the diversity of protease- and IgG subclass-restricted AHAs and their potential as immunological markers in healthy donors (HDs) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). AHA reactivity against IgG-degrading enzyme of Streptococcus pyogenes (IdeS)- or pepsin-generated F(ab′)2 fragments of all four human IgG subclasses was determined. AHA reactivity against one or more out of eight F(ab′)2 targets was found in 68% (68 of 100) of HDs, 69% (68 of 99) of SLE patients, and 81% (79 of 97) of RA patients. Specific recognition of hinge epitopes was dependent on IgG subclass and protease used to create the F(ab′)2 targets, as confirmed by inhibition experiments with F(ab′)2 fragments and hinge peptides. Reactivity against IdeS-generated F(ab′)2 targets was found most frequently, whereas reactivity against pepsin-generated F(ab′)2 targets better discriminated between RA and HDs or SLE, with significantly higher AHA levels against IgG1/3/4. In contrast, AHA levels against pepsin-cleaved IgG2 were comparable. No reactivity against IdeS-generated IgG2-F(ab′)2s was detected. The most discriminatory AHA reactivity in RA was against pepsin-cleaved IgG4, with a 35% prevalence, ≥5.8-fold higher than in HDs/SLE, and significantly higher levels (p < 0.0001). Cross-reactivity for F(ab′)2s generated from different IgG subclasses was only observed for subclasses having homologous F(ab′)2 C termini (IgG1/3/4). For IgG2, two pepsin cleavage sites were identified; anti-hinge reactivity was restricted to only one of these. In conclusion, AHAs specifically recognize IgG subclass- and protease-restricted hinge neoepitopes. Their protease-restricted specificity suggests that different AHA responses developed under distinct inflammatory or infectious conditions and may be markers of, and participants in, such processes

Maternal and Perinatal Outcome in Women with Systemic Lupus Erythematosus: A Retrospective Bicenter Cohort Study

Objective. To investigate disease activity around and during pregnancy and pregnancy outcome in women with systemic lupus erythematosus (SLE) considering antiphospholipid antibody status. Moreover, differences between first and consecutive pregnancies were examined. Methods. Pregnancies > 16 weeks gestation of SLE patients receiving joint care from rheumatologists and gynecologists in two tertiary centers in the Netherlands between 2000 and 2015 were included. Disease activity, flare rate, and pregnancy outcomes and complications were assessed. Results. Ninety-six women (84% Caucasian) with 144 pregnancies were included. The median SLE(P)DAI score was 2 before, during, and after pregnancy. Flare rates were 6.3%, 20.1%, and 15.3%, respectively. Severe hypertensive disorder of pregnancy, intrauterine fetal death, preterm birth, and small-for-gestational age infants occurred in 18.1%, 4.1%, 32.7%, and 14.8%, respectively. Complication rates were similar in the first and consecutive pregnancies. Half of the women did not experience any pregnancy complication whereas 42.7% developed a complication during all pregnancies. Mean number of pregnancies was 2.4 and live births 1.7. Conclusion. In this SLE population with low disease activity, pregnancy complications were present irrespective of antiphospholipid antibody status. Furthermore, there were no differences in complication rates between the first and consecutive pregnancies as seen in healthy mothers. This information is useful for patient counseling

Erratum: Maternal and Perinatal Outcome in Women with Systemic Lupus Erythematosus: A Retrospective Bicenter Cohort Study(Journal of Immunology Research (2017) 2017 (8245879) DOI: 10.1155/2017/8245879)

In the article titled "Maternal and Perinatal Outcome in Women with Systemic Lupus Erythematosus: A Retrospective Bicenter Cohort Study"[1], the authors identified some discrepancies in the data following its publication. There are very small changes in incidence of HELLP syndrome (N = 5 instead of N = 7), preeclampsia (N = 22 instead of 24), and mild hypertensive disorder (N = 19 instead of 21), which showed no significant difference in the preeclampsia group. The incidence of preeclampsia < 34 weeks, eclampsia, and HELLP syndrome were too low to conduct the generalized estimating equations (GEE) analysis; therefore, a new p value cannot be produced. Due to the very small differences, we believe that our conclusions are not changed. As already described on page 6 of the article: "In our cohort, we only found an association with APS and HELLP. However, considering the low numbers of HELLP in the paper by Moroni et al. (2 out of 71 pregnancies = 2:6%) and our study (7 out of 144 pregnancies = 4:9%), we do not venture to interpret these findings."The corrected Table 3 is shown below. Additionally, in Section 3.3.2, the sentence "Of all preterm births (<37 weeks), 44.2% occurred spontaneously, and in the others, labour was induced. Main indications for preterm induction of labour (<37 weeks) were HD (54.1%) and IUFD (12.5%)."should be corrected to "Of all preterm births (<37 weeks), 61.9% occurred spontaneously. Main indications for preterm induction of labor (<37 weeks) were HD (30.8%) and IUGR (23.1%). IUFD as reason for preterm induction of labor occurred once (7.7%)."Also, the email address of the corresponding author should be changed to "[email protected]."The authors confirm that this does not affect the results and conclusions of the article, and the editorial board agrees to the publication of a corrigendum.(Table Presented)

Similar efficacy and safety of initial COBRA-light and COBRA therapy in rheumatoid arthritis: 4-year results from the COBRA-light trial

Objective. To assess the efficacy and safety of initial COBRA-light vs COBRA therapy in RA patients after a 4-year follow-up period. Methods. In the COBRA-light trial, 162 consecutive patients with recent-onset RA were randomized to either COBRA-light (prednisolone and MTX) or COBRA therapy (prednisolone, MTX and SSZ) for 1 year. After 1 year, treatment was continued without protocol, and adjusted by the treating physician according to clinical judgement, preferably with a treat-to-target strategy. Four years after trial initiation, all patients were invited to participate in the COBRA-light extension study, in which patients were interviewed and physically examined, patient reported outcomes were assessed, radiographs were made and clinical records were examined for comorbidities and medication use. Results. In the extension study, 149 out of 162 (92%) original trial patients participated: 72 COBRA-light and 77 COBRA patients. Initial COBRA-light and COBRA therapy showed similar effect on disease activity, physical functioning, radiological outcome and Boolean remission over the 4-year follow-up period. In addition, both treatment groups showed similar survival and major comorbidities, although the power to detect differences was limited. Besides protocolled differences in prednisolone, MTX and SSZ use, the use of other synthetic and biologic DMARDs and intra-articular and intramuscular glucocorticoid injections was similar in both treatment groups over the 4-year period. Conclusion. Early RA patients initially treated with COBRA-light or COBRA therapy had similar efficacy and safety outcomes over a 4-year follow-up period