Lupus

Antiphospholipid antibody syndrome (APS) is an autoimmune disease that affects women in childbearing age. In recent years, great improvements were achieved in the management of pregnancies in these women. Prematurity could be an issue in these pregnancies, mainly due to the direct pathogenic effect of antiphospholipid antibodies (aPL) on the placental surface. Maternal IgG aPL can cross the placenta and theoretically interact with the growing fetus; it could reach the fetal brain because of the incompleteness of the fetal blood-brain barrier: whether this can have an effect on brain development is still debated. Neonatal thrombosis episodes have been described in children positive for aPL, not always associated with maternal antibody positivity, suggesting the hypothesis of a possible aPL de novo synthesis in fetus and neonates.

A keyword-based literature search was conducted. We also described a case of neonatal catastrophic antiphospholipid syndrome (CAPS).

Offspring of patients with APS are generally healthy but the occurrence of neonatal thrombosis or minor neurological disorders were reported.

The limited number of the available data on this sensitive issue supports the need for further studies. Clinical follow-up of children of mothers with APS seems to be important to exclude, in the neonatal period, the occurrence of aPL associated pathological events such as thrombosis, and in the long-term, impairment in learning skills or behavioral problems.

Lupus fundus abnormalities are a sight-threatening complication of systemic lupus erythematosus (SLE) and its pathogenesis remains to be studied. The aim of this study was to assess the clinical characteristics associated with the presence of anti-recoverin antibodies in patients with SLE, especially those with fundus abnormalities.

Seventy-six participants were enrolled, including 21 patients with fundus abnormalities (fundus group), 30 patients without fundus abnormalities (non-fundus group) and 25 healthy individuals. Serum anti-recoverin antibody levels were measured using enzyme-linked immunosorbent assay, and clinical and laboratory data were obtained from medical records.

Compared with the non-fundus group, the fundus group had a higher incidence of hematuria (p < 0.05). The Systemic Erythematosus Disease Activity Index (SLEDAI) score in the fundus group was significantly higher than the non-fundus group (21.48 ± 8.06 versus 10.80 ± 5.74, p < 0.001). The levels of serum anti-recoverin antibodies in the fundus group were significantly higher than the non-fundus group (p = 0.029) or the healthy control group (p = 0.011). Anti-recoverin-negative and -positive patients differed on a number of clinical parameters, including incidence of fever, rash, antinuclear antibody, anti-dsDNA antibody, erythrocyte sedimentation rate, immunoglobulin G, complement C3 and complement C4. The average SLEDAI score of anti-recoverin-positive patients was significantly higher than anti-recoverin-negative patients (17.73 ± 8.11 versus 12.56 ± 8.37, p < 0.05).

Anti-recoverin antibodies were related to higher disease activities in SLE, especially those with fundus abnormalities, suggesting that anti-recoverin antibodies may play an important role in the pathogenesis of fundus abnormalities in SLE.

This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients.

The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients.

A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors.

Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches.

Caffeine, one of the most widely consumed products in the world, seems to interact with multiple components of the immune system by acting as a non-specific phosphodiesterase inhibitor. In vitro dose-dependent treatment with caffeine down-regulates mRNA levels of key inflammation-related genes in peripheral blood mononuclear cells. So far, no robust data are available about the possible contribution of caffeine in systemic lupus erythematosus (SLE). The aim of this study was to evaluate the impact of caffeine consumption on SLE-related disease phenotype and activity, in terms of clinimetric assessment and cytokine serum levels.

We performed a cross-sectional study, enrolling consecutive patients and reporting their clinical and laboratory data. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K). Caffeine intake was evaluated by a 7-day food frequency questionnaire, including all the main sources of caffeine. As previously reported, patients were divided into four groups according to the daily caffeine intake: <29.1 mg/day (group 1), 29.2–153.7 mg/day (group 2), 153.8–376.5 mg/day (group 3) and >376.6 mg/day (group 4). At the end of questionnaire filling, blood samples were collected from each patient to assess cytokine levels. These were assessed by using a panel by Bio-Plex assays to measure the levels of IL-6, IL-10, IL-17, IL-27, IFNγ, IFNα and BLyS.

We enrolled 89 consecutive SLE patients. We observed a negative correlation between caffeine consumption and disease activity, measured with SLEDAI-2K. A significantly higher prevalence of lupus nephritis, neuropsychiatric involvement, haematological manifestations, hypocomplementaemia and anti-dsDNA positivity was observed in patients with a low intake of caffeine. Furthermore, patients with a low intake of caffeine were more frequently treated with glucocorticoids. Regarding cytokine analysis, a negative correlation between daily caffeine consumption and serum level of IFNγ was found (p = 0.03, r = –0.2); furthermore, patients with a high intake of caffeine showed lower serum levels of IFNα (p = 0.02), IL-17 (p = 0.01) and IL-6 (p = 0.003).

In this report we demonstrated the impact of caffeine on SLE disease activity status, as confirmed by the inverse correlation between its intake and both SLEDAI-2K values and cytokine levels. Moreover, patients with a low caffeine consumption seem to have a more severe disease phenotype.

To describe clinical effectiveness of belimumab for systemic lupus erythematosus (SLE) in real-world practice in Argentina.

This retrospective, observational study analysed medical record data of patients with SLE treated with belimumab in 15 centres in Argentina. Primary endpoint: overall clinical response (assessed on a scale similar to the 6-point Physician Global Assessment) at months 6, 12, 18 and 24, all versus index (belimumab initiation). Secondary endpoints: improvement in disease activity (SELENA-SLEDAI), SLE manifestations, and corticosteroid dose change.

Records for 81 patients (91% female) were analysed. Clinical improvements were reported for 95%, 95%, 98% and 100% patients at 6, 12, 18, and 24 months post index, respectively. Mean SELENA-SLEDAI score decreased from 11.21 at index to 4.76, 3.77, 3.86 and 2.17 at 6, 12, 18, and 24 months post index, respectively. Number of flares decreased from 1.05 at index to 0.21, 0.09, 0.22 and 0.30 at 6, 12, 18, and 24 months post index, respectively. Mean corticosteroid dose was 14.59 mg/day at index, and 6.45, 5.18, 5.17 and 4.78 mg/day at 6, 12, 18, and 24 months post index, respectively.

Real-world patients with SLE treated with belimumab in Argentina demonstrated clinical improvements and reductions in corticosteroid dose.

Identifying factors predicting adverse pregnancy outcomes involving systemic lupus erythematosus (SLE) is a research priority. The aims of this study were to investigate (a) the maternal and fetal outcomes of pregnant lupus patients and the factors associated with adverse pregnancy outcomes, and (b) the effect of pregnancy on lupus disease activity of these patients.

This was an ambi-directional study collecting information from five multi-specialist referral centres across the state of Karnataka, India over 5 years (2013–2018). Clinical details of pregnancies and outcomes that were temporally associated with lupus disease were recorded using a structured pro forma. The Safety of Estrogen in SLE National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) was used to assess lupus activity during the 6 months prior to pregnancy and the intra- and post-partum periods. Modifications suggested in the SLE Pregnancy Disease Activity Index were considered while scoring.

A total of 121 pregnancies in 80 SLE patients with a mean age of 27.1 (±4.5) years and with a mean disease duration of 4.6 (±4.1) years were reviewed. Largely patients were in clinical remission (109/121; 90.1%). Antiphospholipid antibody positivity was seen in 45/121 (37.2%) patients. A history of lupus nephritis was noted in 29/121 (24%) patients. Maternal complications (32%) were mainly due to hypertensive disorders of pregnancy (HDP; 19/121; 15.7%). Adverse fetal outcomes (58%) were mainly in the form of spontaneous first-trimester abortions (21/121; 16%), stillbirth (14/121; 11.6%) and prematurity (24/121; 20%). HDP is strongly associated with stillbirth and prematurity and is independent of active lupus. Disease activity was associated with a three-fold increased risk of adverse fetal outcome in univariate analysis. The risk of major flare during pregnancy is low (4.1%) when conception occurs during stable disease. Hydroxychloroquine (HCQ) use was associated with reduced risk of flare (p = 0.001) in patients in remission at the time of conception.

The risk of major flare during pregnancy is low when conception happens during stable disease. HCQ use was associated with reduced risk of flare in patients in remission at the time of conception. HDP was strongly associated with stillbirth and prematurity and are independent of active lupus in our cohort.

Fibromyalgia (FM) is prevalent but often under-recognized in patients with systemic lupus erythematosus (SLE). Patient-reported outcomes (PROs) from the Multi-Dimensional Health Assessment Questionnaire (MDHAQ) can identify co-morbid FM in patients with rheumatic diseases. The present study examined the utility of the MDHAQ in recognizing FM in patients with SLE during routine consultations.

Patients with SLE completed an MDHAQ. FM status was determined by the validated 2016 revision of the ACR 2010/2011 preliminary FM criteria. Individual PROs from the MDHAQ and composite Fibromyalgia Assessment Tool (FAST) indices of the discriminatory PROs were compared between patients with and without FM using Student’s unpaired t-test and receiver operating characteristic curve analysis to determine the area under the curve (AUC). The physician’s clinical impression of FM was recorded, and the SLE Disease Activity Index was used to assess disease activity.

Of 88 patients with SLE, 23 (26%) satisfied the 2016 FM criteria. The FAST3 composite measure of two out of three of pain (≥6/10), joint count (≥16/48) and symptom checklist (≥16/60) correctly classified 89% of patients (AUC=0.90, kappa=0.71). Physician diagnosis demonstrated moderate agreement with the 2016 FM criteria (kappa=0.43) but missed 43% of patients with FM. In the presence of active disease, the FAST3 correctly classified 91% of patients.

Co-morbid FM is prevalent in SLE yet often underdiagnosed by physicians. The simple FAST3 index of the MDHAQ provides an easy-to-use self-reported tool to improve identification of FM in patients with SLE.

IgA antiphospholipid antibodies (aPL) are prevalent in systemic lupus erythematosus (SLE) patients of African American, Afro-Caribbean and South African origin. Nevertheless, data from North Africa are lacking, and most studies use manufacturer-suggested cut-offs based on Caucasian controls. Therefore, we compared aPL isotypes in Sudanese and Swedish SLE patients using nation-based cut-offs.

Consecutive SLE patients and age- and sex-matched controls from Sudan (N = 115/106) and Sweden (N = 340/318) were included. All patients fulfilled the 1982 American College of Rheumatology SLE classification criteria. Antiphospholipid syndrome–related events were obtained from patients’ records. IgA/G/M anticardiolipin and anti-β₂ glycoprotein I (β₂GPI) were analysed with two independent assays. IgA anti-β₂GPI domain 1 (D1) was also investigated. Manufacturers’ cut-offs and the 95th and 99th percentile cut-offs based on national controls were used.

Sudanese patients and controls had higher levels and were more often positive for IgA aPL than Swedes when using manufacturers’ cut-offs. In contrast, using national cut-offs, the increase in IgA aPL among Sudanese patients was lost. Occurrence of IgA anti-D1 did not differ between the countries. Venous thromboses were less common among Sudanese patients and did not associate with aPL. No clinical associations were observed with IgA anti-β₂GPI in Sudanese patients. Thromboses in Swedes were associated with IgG/M aPL. Fetal loss was associated with aPL in both cohorts.

IgA anti-β₂GPI prevalence was higher among Sudanese compared to Swedish patients when manufacturers’ cut-offs were used. This situation was reversed when applying national cut-offs. Anti-D1 was not increased in Sudanese patients. Previous studies on populations of African origin, which demonstrate a high prevalence of IgA aPL positivity, should be re-evaluated using a similar cut-off approach.

To determine the prevalence of subclinical synovitis in Lupus patients without peripheral joint symptoms, in those with arthralgias without arthritis and those with episodic arthritis but without radiological structural damage.

We conducted a multicentre cross-sectional study. Patients with lupus from those three categories were recruited to take part in a greyscale ultrasound scan performed by an expert blinded rheumatologist. Data from a historical control group from a previous study was also included for comparisons. Images were assessed separately in order to determine the presence and level of synovitis following Eular recommendations.

Ninety-six patients (88.5% female) with an average age of 40 ± 6.2 years old, were included. SLICC/ACR score was 0.6 ± 0.3 in the group without joint symptoms (group 0), 0.8 ± 0.3 in the group with arthralgias (group I) and 1.1 ± 0.4 in the group with episodic arthritis. The global prevalence of subclinical synovitis was 38.5%. In group 0, that prevalence was 30%. The time since onset of symptoms of patients with subclinical synovitis was longer than the rest of the patients (9.4 ± 2.2 vs 6.5 ± 4.0 years, P < 0.001). No other remarkable association was founded with clinical features of the disease.

This is the first study focused on subclinical synovitis in patients with lupus. Other previous studies had included patients with different levels of arthropathy. Subclinical synovitis does exist in lupus patients in over a third of patients. Its meaning remains unclear and must be a topic of further studies.

Subclinical myocardial dysfunction has been reported to occur early in systemic lupus erythematous (SLE). The study aim was to search for biomarkers of subclinical myocardial dysfunction which may correlate with disease activity in SLE patients.

This is a prospective, controlled, cross-sectional study of 57 consecutive patients with SLE and 18 controls. Serum samples were obtained to determine serum soluble ST2 (sST2), CXCL-10 and high-sensitivity troponin (hs-troponin) levels. All participants underwent an echocardiographic tissue Doppler study.

sST2, CXCL-10 and hs-troponin levels were higher in patients with higher SLE disease activity (SLEDAI). sST2 and CXCL-10 levels were higher in patients with more disease damage as measured by the SLE damage index. Measures of diastolic dysfunction, as assessed by echocardiographic tissue Doppler negatively correlated with log CXCL-10: including E/A; E/e′_lateral and E/e′_septal, while E/e′ positively correlated with CXCL-10. Diastolic dysfunction parameters also correlated with log sST2 levels, a negative correlation was seen with E/e′_lateral and a positive correlation was seen with E/e′. Systolic dysfunction parameters positively correlated with hs-troponin: LVED, LVES, IVS, LVMASS and LVMASS index. In a multivariate analysis, sST2 and CXCL-10 were found to be significantly different in SLE vs. healthy controls, independent of each other and independent of cardiovascular risk factors.

Soluble ST2 and CXCL-10 are markers of disease activity and accrued damage in SLE and may serve as sensitive biomarkers for detection of subclinical diastolic dysfunction, independent of traditional cardiovascular risk factors.

To investigate the effect of cosmetic camouflage in health-related quality of life (HRQoL) in women with systemic lupus erythematosus (SLE) and permanent facial skin damage.

This is a randomized controlled clinical trial (Universal Trial Number: U1111-1210-2554e) with SLE women from outpatients using ACR/1997 and/or SLICC/2012 criteria, aged over 18 years old, with modified SLEDAI 2k < 4 and permanent facial skin damage, recruited in two tertiary centers to use cosmetic camouflage (n = 36) or no intervention (n = 20). Endpoints were score variations in SLE Quality of Life (SLEQoL) (total and each domain), Dermatology Life Quality Index (DLQI), Rosenberg self-esteem scale and Hospital Anxiety and Depression Scale (HADS), after daily use of cosmetic camouflage for 12 +/−2 weeks (Phase I), “as needed” use of cosmetic camouflage for another 12 +/−2 weeks (Phase II), and during total follow up (24 +/−2 weeks). Univariate and multivariate linear regressions were conducted by protocol analysis.

Both groups were similar at baseline regarding age, disease duration, socio-demographic, clinical, laboratory and treatment characteristics. The comparison of score variations between intervention and control groups showed an independent HRQoL improvement in total SLEQoL score after using cosmetic camouflage in Phase I [β −27.56 (CI 95% −47.86 to −7.27) p = 0.009] and total follow up [β −28.04 (CI 95% −48.65 to −7.44) p = 0.09], specifically in mood, self-image and physical functioning domains. Also, there was an improvement in DLQI scores during Phase I [β −7.65 (CI 95% −12.31 to −3.00) p = 0.002] and total follow up [β −8.97(CI95% −12.99 to −4.94) p < 0.001). Scores for depression [β −1.92 (CI 95% −3.67 to −0.16) p = 0.033], anxiety [β −2.87 (CI 95% −5.67 to −0.07] p = 0.045] and self-esteem [β 2.79 (CI 95% 0.13 to 5.46) p = 0.041] improved considering the total follow up. No significant changes occurred in the control group scores.

The use of cosmetic camouflage improved the HRQoL in female SLE patients with permanent facial skin damage.

Many studies in adult patients with systemic lupus erythematosus (SLE) have demonstrated that myocardial dysfunction was significantly associated with enhanced disease activity. However, similar studies in paediatric patients with SLE are limited. The aim of this study was to evaluate the role of speckle tracking echocardiography (STE) to detect left ventricular dysfunction in children with active and inactive SLE.

This prospective case–control study was carried out on 50 children with SLE. Thirty healthy age- and sex-matched children comprised the control group. The patients were further subdivided into two subgroups: active SLE and inactive SLE. Laboratory investigations undertaken included complete blood count, renal function, C3, C4, ANA, anti-dsDNA and serum N-terminal pro-B type natriuretic peptide. Echocardiographic examinations were performed on all children and included conventional echocardiography, tissue Doppler imaging (TDI) and two- and three-dimensional STE.

There was no statistically significant difference in N-terminal pro B natriuretic peptide between the studied groups. The myocardial performance index by TDI was statistically significantly higher in SLE patients compared to controls. STE parameters were statistically significantly lower in SLE patients compared to controls. There was no correlation between STE parameters and disease activity.

STE could be a promising technique in the early detection of subclinical left ventricular dysfunction in children with SLE.

To determine the prevalence of myocardial injury (MInj) in systemic lupus erythematosus (SLE) according to cardiac magnetic resonance (CMR) criteria. To compare clinical and echocardiographic features of patients with and without MInj and identify predictors of myocardial tissue characteristics according to CMR.

SLE inpatients underwent CMR screening for MInj based on the Lake Louise Criteria (LLC). Tissue characteristics included inflammation (increased T2-weighted signal or early gadolinium enhancement ratio (EGEr)) and necrosis or fibrosis (late gadolinium enhancement (LGE)). Echocardiographic parameters included left (left ventricular ejection fraction (LVEF)) and right ventricular function (tricuspid annular plane systolic excursion (TAPSE)), global longitudinal strain (GLS), wall motion score (WMSi) and left ventricular internal diameter index (LVIDi). Variables were compared with regards to the presence/absence of CMR criteria. Logistic regression identified variables predictive of CMR tissue characteristics.

A hundred and six SLE patients were screened of whom 49 patients were included. Fifty-seven patients were excluded due to intolerance of or contraindication to CMR (27/57 due to renal impairment). Twenty-three patients had CMR evidence of MInj, of which 60.9% was subclinical. Inflammation occurred in 16/23 and necrosis/fibrosis in 12/23 patients. Patients with any evidence of MInj were more frequently anti-dsDNA positive (p = 0.026) and patients fulfilling LLC for myocarditis had higher SLE disease activity (p = 0.022). The LVIDi (p = 0.005), LVEF (p = 0.005) and TAPSE (p = 0.011) were more abnormal in patients with an increased EGEr, whereas WMSi (p = 0.002) and GLS (0.020) were more impaired in patients with LGE. On multivariable logistic regression analyses, TAPSE predicted inflammation (OR: 0.045, p = 0.006, CI: 0.005–0.415) and GLS predicted necrosis/fibrosis (OR: 1.329, p = 0.031, CI: 1.026–1.722). A model including lymphocyte count, TAPSE and LVIDi predicted an increased EGEr on CMR (receiver operating characteristic-curve analyses: area under the curve: 0.901, p < 0.001, sensitivity: 88.9%, specificity: 76.3%).

CMR evidence of MInj frequently occurs in SLE and is often subclinical. The utility of CMR in SLE is limited by a high exclusion rate, mainly due to renal involvement. Models including echocardiographic parameters (TAPSE, LVIDi and GLS) are predictive of CMR myocardial injury. Echocardiography can be used as a cost-effective screening tool with a high negative predictive value, in particular when CMR is contraindicated or unavailable.

The administration of induction immunosuppressive therapy to children with newly diagnosed systemic lupus erythematosus (SLE) and concurrent infections can lead to unfavourable outcomes. This study was conducted to describe characteristics of infections occurring before the initiation of immunosuppressants in hospitalized children with newly diagnosed SLE in underresourced areas.

Medical records of paediatric patients with the diagnosis of SLE, who were admitted to a university-based hospital from 2002 to 2018, were reviewed. Only patients younger than 18 years of age with newly diagnosed SLE were included in the study. The primary outcome was infection before the administration of immunosuppressants. Logistic regression analysis was used to determine factors associated with infection and adjusted odds ratio (OR). The diagnostic accuracy of CRP was assessed.

Infections were confirmed in 52/124 (41.9%) children. Pathogens were identified in 24 (46.2%) patients with bacterial predominance. The most common site was respiratory infections (36.5%). Fever and serosal involvement were more prevalent in patients with infection. Serum CRP levels were significantly higher in patients with infection than in those without infection (median 5.5 mg/L (interquartile range (IQR) 3.6–76.3 mg/L) vs. 3.5 mg/L (IQR 3.0–3.6 mg/L), p = 0.004). When a positive CRP level of >5 mg/L was used, positive CRP was found with a higher prevalence in patients with infection and was independently associated with infection (adjusted odds ratio (OR) = 28.6, 95% confidence interval (CI) 2.3–350.6; p = 0.009). Patients with infection had a longer hospital stay than patients without infection (median 20 days (IQR 13–25 days) vs. 15 days (IQR 9–24 days), p = 0.04). Sensitivity, specificity, positive predictive value and negative predictive value with 95% CI of CRP >5 mg/L were 62.5% (35.4–84.8%), 88.9% (65.3–98.6%), 80.3% (51.0–94.1%) and 76.6% (63.1–86.3%), respectively.

Infections were common among hospitalized children with newly diagnosed SLE. Children with infections had a prolonged course of hospitalization. Positive CRP was associated with a predisposition towards infection. However, the diagnostic accuracy of CRP requires further validation in a larger study.