There is an unmet need for accurate and user-friendly definitions of systemic lupus erythematosus (SLE) disease activity and remission. We aimed to derive and validate the SLE Disease Activity Score ...(SLE-DAS) definitions for disease activity categories and clinical remission state.
Derivation was conducted at Padova Lupus Clinic (Italy). Validation was prospectively performed at Cochin Lupus Clinic (France) and by post hoc analysis of BLISS-76 trial. At each clinic, an expert classified patients in three categories: remission, mild or moderate/severe activity. The SLE-DAS cut-offs were derived using the receiver operating characteristic curve analysis in Padova cohort; its performance was assessed against expert classification in Cochin cohort and British Isles Lupus Assessment Group (BILAG) index in BLISS-76. Gold standard for clinical remission state was the fulfilment of Definition Of Remission In SLE. A Boolean and an index-based definitions of remission were sustained by chi-square automatic interaction detection algorithm. An SLE-DAS online calculator was developed and tested.
We included 1190 patients with SLE: 221 in the derivation cohort and 969 in the validation cohorts (150 from Cochin; 819 from BLISS-76). Derived cut-offs were: remission, SLE-DAS ≤2.08; mild activity, 2.08<SLE-DAS≤7.64; moderate/severe activity, SLE-DAS >7.64. Regarding validation in Cochin cohort, sensitivity and specificity are above 90%, 82% and 95% for remission, mild and moderate/severe activity, respectively. The SLE-DAS Boolean-based and index-based remission showed sensitivity of 100% and specificity above 97%.
The SLE-DAS is an accurate and easy-to-use tool for defining SLE clinical remission state and disease activity categories, validated against expert assessment and BILAG.
•About 40% of women with systemic vasculitis were treated by immunosuppressive drugs during pregnancy.•The number of patients treated with non-recommended immunosuppressant during pregnancy gradually ...decreased before pregnancy.•Proportion of systemic vasculitis flare did not increase significantly during pregnancy.
Systemic vasculitis (SV) rarely affects women of childbearing age and only small series have been reported to date in pregnant patients. The discovery of an unplanned pregnancy can be an urgent cause for modifying treatments. This study aimed to describe immunosuppressive drugs use before, during and after pregnancy in women with SV.
We conducted a cohort study using the French nationwide claims database. We included all women with SV being pregnant between 2013 and 2018. Exposure of interest was defined as exposure to oral systemic or injectable immunosuppressive drug identified using out-hospital reimbursement data and in-hospital reimbursement for expensive drugs.
Of 3,246,454 pregnancies, 649 pregnancies were observed in 606 women with SV. Immunosuppressant and glucocorticoids use decreased before pregnancy and then increased after pregnancy (48.4%, 40.7%, 50.4%, respectively before, during, after). Prevalence of glucocorticoids use was broadly stable during pregnancy from 27.9% to 27.6% and 23.7% in the 1st, 2nd and 3rd trimesters, respectively, with a daily dose of about 5 mg. The number of patients treated with non-recommended immunosuppressant during pregnancy gradually decreased before pregnancy and then increased after delivery, whereas proportion of systemic vasculitis flare, estimated from the glucocorticoids daily dose, did not increase significantly during pregnancy.
Immunosuppressants and glucocorticoids use decreased before pregnancy and remained stable throughout, suggesting a vasculitis control during this period. Our findings support the importance of pre-conceptional consultations to review medications, and switch not-recommended and teratogenic medications to drugs considered being safe during pregnancy.
Antiphospholipid antibodies positivity (aPL) is considered as a risk factor for adverse pregnancy outcome (APO). The aim of this study was to determine the risk factors for APO in patients with ...confirmed aPL positivity, isolated (aPL carriers) or associated with a definite primary antiphospholipid syndrome (PAPS).
The clinical and laboratory features of 283 pregnancies occurring between 2000 and 2014 in 200 women were collected in three institutions.
The rate of live birth was 87.9% and APO was observed in 50 cases (17.7%). Multivariate analysis showed that the independent variables related to APO were the concomitant diagnosis of an organ-specific autoimmune disease (
= 0.012, odds ratio (OR) 3.29, confidence interval (CI) 95% 1.29-8.38) and the presence of low complement levels during the first trimester (
= 0.02, OR 2.3, CI 95% 1.17-9.15). No statistical differences were found in APO occurrence among patients treated with low-dose aspirin (LDA) versus those treated with LDA plus heparin (LMWH), but LDA + LMWH was more frequently administered in patients with triple aPL positivity (
= 0.001, OR 3.21, CI 95% 1.48-7.11) and with PAPS (
< 0.001, OR 8.08, CI 95% 4.3-15.4). Based on clinical history, the patients were divided into four groups: obstetric, thrombotic, non-criteria antiphospholipid syndrome (clinical non-criteria), and aPL carriers. APOs were more frequent in the thrombotic group (24%). Seven patients had a thrombotic event during pregnancy or puerperium (2.4%).
Maternal and fetal complications were observed in some aPL-positive patients despite their efficient management according to the current recommendations. A higher risk of APO was observed in patients with a previous thrombosis and/or more complex autoimmune phenotype.
•Pneumococcal vaccination with the 7-valent PnCj vaccine is safe.•There was no clear superiority of the PnCj-PPS group over the placebo-PPS group.•More than 40% of patients failed to mount memory ...immune responses at week 52.•New vaccines and/or innovative schedule designs are warranted.
Invasive pneumococcal disease and respiratory tract infections are both frequent and severe in patients with systemic lupus erythematosus (SLE). This study aimed to compare the immunological efficacy and safety of pneumococcal vaccination with the 23-valent polysaccharide (PPS) vaccine alone to a sequential immunization with the 7-valent pneumococcal conjugate (PnCj) vaccine followed by PPS in patients with SLE and stable diseaase.
Multicenter randomized placebo-controlled double-blind trial: PPS vaccine alone (placebo-PPS group) or PnCj vaccine followed by PPS vaccine (PnCj-PPS group) 24weeks later. The primary endpoint was the rate of responders at week 28 to at least 5 of the 7 serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) shared by both PPS and PnCj. Pneumococcal IgG antibodies’ opsonophagocytic activity (OPA) were also assessed.
Twenty-five patients in the placebo-PPS group and 17 in the PnCj-PPS group were included in a modified intention-to-treat analysis. The primary endpoint was reached in 72% (18/25) in the placebo-PPS and 76% (13/17) in the PnCj-PPS group (p=0.75). There was no difference in the rates of responders with OPA. At week 52, 13/18 (72%) patients in the placebo-PPS group and 10/13 (77%) patients in the PnCj-PPS group (p=0.77) that met the primary endpoint at week 28 were still responders to ≥5/7 serotypes shared by both PPS and PnCj vaccines. Nine SLE flares were reported in 6 patients (4 in the placebo-PPS and 2 in the PnCj-PPS groups respectively, p=0.70).
Sequential administration of PnCj vaccine followed by PPS vaccine is safe and shows short-term immunological efficacy in patients with SLE but was not superior to the PPS vaccine alone.
Trial registration:www.clinicaltrials.gov, NCT NCT00611663
Abstract
Objectives
Onset of primary SS is usually between 40 and 60 years of age, with severe systemic complications in 15% of cases. We sought to determine whether early-onset disease is related to ...a specific phenotype and if it is predictive of a poor outcome.
Methods
Biological and clinical data from 393 patients recruited in the ASSESS cohort, a French multicentre prospective cohort, were compared according to age at diagnosis.
Results
Fifty-five patients had early-onset disease, defined as age ⩽35 years at diagnosis, and presented a significantly higher frequency of salivary gland enlargement (47.2% vs 33.3%, P = 0.045), adenopathy (25.5% vs 11.8%, P = 0.006), purpura (23.6% vs 9.2%, P = 0.002) and renal involvement (16.4% vs 4.4%, P = 0.003). They had a higher frequency of hypergammaglobulinaemia (60.8% vs 26.6%, P < 0.001), RF positivity (41.5% vs 20.2%, P < 0.001), low C3 level (18.9% vs 9.1%, P = 0.032), low C4 level (54.7% vs 40.2%, P = 0.048) and autoantibodies 84.6% with anti-SSA vs 54.4% (P < 0.001) and 57.7% with anti-SSB vs 29.7% (P < 0.001). The change in ESSDAI scores between baseline and the 5-year follow-up was significantly different (P = 0.005) with a trend for worsening in the early-onset group (0.72, P = 0.27) and a significant improvement in the later onset group (−1.27, P < 0.0001).
Conclusion
Early-onset primary SS is associated with a specific phenotype defined by clinical and biological features known to be predictive factors of severe systemic disease. Interestingly, we showed a different evolution of the ESSDAI score depending on the age at disease onset, patients with early-onset disease tending to worsen over time.
An interferon signature is involved in the pathogenesis of primary Sjögren syndrome (pSS), but whether the signature is type 1 or type 2 remains controversial. Mouse models and genetic studies ...suggest the involvement of TH1 and type 2 interferon pathways. Likewise, polymorphisms of the IL-12A gene (IL12A), which encodes for IL-12p35, have been associated with pSS. The IL-12p35 subunit is shared by 2 heterodimers: IL-12 and IL-35.
We sought to confirm genetic association of the IL12A polymorphism and pSS and elucidate involvement of the IL-12/IL-35 balance in patients with pSS by using functional studies.
The genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French control subjects. Functional studies were performed on sorted monocytes, irrespective of whether they were stimulated. IL12A mRNA expression and IL-12 and IL-35 protein levels were assessed by using quantitative RT-PCR and ELISA and a multiplex kit for IL-35 and IL-12, respectively.
We confirmed association of the IL12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in patients with pSS carrying the risk allele (P = .016). Serum levels of IL-12p70 were greater in patients than control subjects (P = .0001), especially in patients with more active disease (P = .05); conversely, IL-35 levels were decreased in patients (P = .0001), especially in patients with more active disease (P = .05). In blood cellular subsets both IL12p35 and EBV-induced gene protein 3 (EBI3) mRNAs were detected only in B cells, with a trend toward a lower level among patients with pSS.
Our findings emphasize involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 levels were associated with low disease activity, in contrast with serum IL-12p70 levels, which were associated with more active disease.
To analyze the clinical and immunological characteristics at enrollment in a large prospective cohort of patients with primary Sjögren's syndrome (pSS) and to investigate the association between ...serum BAFF, beta2-microglobulin and free light chains of immunoglobulins and systemic disease activity at enrollment.
Three hundred and ninety five patients with pSS according to American-European Consensus Criteria were included from fifteen centers of Rheumatology and Internal Medicine in the "Assessment of Systemic Signs and Evolution of Sjögren's Syndrome" (ASSESS) 5-year prospective cohort. At enrollment, serum markers were assessed as well as activity of the disease measured with the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI).
Patient median age was 58 (25(th)-75(th): 51-67) and median disease duration was 5 (2-9) years. Median ESSDAI at enrollment was 2 (0-7) with 30.9% of patients having features of systemic involvement. Patients with elevated BAFF, beta2-microglobulin and kappa, lambda FLCS had higher ESSDAI scores at enrollment (4 2-11 vs 2 0-7, P = 0.03; 4 1-11 vs 2 0-7, P< 0.0001); 4 2-10 vs 2 0-6.6, P< 0.0001 and 4 2-8.2 vs 2 0-7.0, P = 0.02, respectively). In multivariate analysis, increased beta2-microglobulin, kappa and lambda FLCs were associated with a higher ESSDAI score. Median BAFF and beta2-microglobulin were higher in the 16 patients with history of lymphoma (1173.3(873.1-3665.5) vs 898.9 (715.9-1187.2) pg/ml, P = 0.01 and 2.6 (2.2-2.9) vs 2.1 (1.8-2.6) mg/l, P = 0.04, respectively).
In pSS, higher levels of beta2-microglobulin and free light chains of immunoglobulins are associated with increased systemic disease activity.
Objectives
The objective of this study is to better characterize the features and outcomes of a large population of patients with mixed connective tissue disease (MCTD).
Methods
We performed an ...observational retrospective multicenter cohort study in France. Patients who fulfilled at least one diagnostic criterion set for MCTD and none of the criteria for other differentiated CTD (dCTD) were included.
Results
Three hundred and thirty patients (88% females, median interquartile range age of 35 years 26–45) were included. The diagnostic criteria of Sharp or Kasukawa were met by 97.3% and 93.3% of patients, respectively. None met other classification criteria without fulfilling Sharp or Kasukawa criteria. After a median follow‐up of 8 (3–14) years, 149 (45.2%) patients achieved remission, 92 (27.9%) had interstitial lung disease, 25 (7.6%) had pulmonary hypertension, and 18 (5.6%) died. Eighty‐five (25.8%) patients progressed to a dCTD, mainly systemic sclerosis (15.8%) or systemic lupus erythematosus (10.6%). Median duration between diagnosis and progression to a dCTD was 5 (2–11) years. The presence at MCTD diagnosis of an abnormal pattern on nailfold capillaroscopy (odds ratio OR = 2.44, 95% confidence interval 95%CI 1.11–5.58) and parotid swelling (OR = 3.86, 95%CI 1.31–11.4) were statistically associated with progression to a dCTD. Patients who did not progress to a dCTD were more likely to achieve remission at the last follow‐up (51.8% vs. 25.9%).
Conclusions
This study shows that MCTD is a distinct entity that can be classified using either Kasukawa or Sharp criteria, and that only 25.8% of patients progress to a dCTD during follow‐up.
Objective
This study was undertaken to characterize kidney and urine antibody‐secreting cells (ASCs) from patients with active lupus nephritis, before and after induction therapy.
Methods
We included ...patients with biopsy‐proven active lupus nephritis and performed anti‐CD138 staining of kidney biopsy samples to visualize ASCs. We performed single‐cell gene expression profiling on sorted ASCs from fresh biopsy samples using multiplex reverse transcriptase–polymerase chain reaction. We used a gene set that allowed for the study of ASC maturation from plasmablasts to long‐lived plasma cells. We quantified urine ASCs from untreated patients with lupus nephritis at diagnosis and after 6 months of prospective follow‐up during induction therapy.
Results
The number of kidney CD138+ ASCs in 46 untreated patients with lupus nephritis was correlated with a low estimated glomerular filtration rate and with tubulointerstitial damage. Most kidney ASCs from 3 untreated patients had a plasmablast molecular signature; in contrast, in 4 patients with refractory lupus nephritis, the kidney ASCs were mainly long‐lived plasma cells, representing an ASC transcriptional profile similar to that in the bone marrow of 2 healthy donors. Some urine ASCs with a plasmablast signature were detected in patients with untreated active lupus nephritis. The presence of urine ASCs at 6 months was associated with treatment failure.
Conclusion
Our results suggest potential for ASC‐directed therapy in refractory lupus nephritis.
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