Immune thrombocytopenia and pregnancy: an exposed/nonexposed cohort study.

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

Clinical presentation, course, and prognosis of patients with mixed connective tissue disease: A multicenter retrospective cohort.

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.

ANCA-associated scleritis: impact of ANCA on presentation, response to therapy and outcome.

OBJECTIVES: To describe the characteristics, treatment and outcome of isolated ANCA-associated scleritis at diagnosis compared with idiopathic scleritis with negative ANCA tests. METHODS: This retrospective multicentre case-control study was performed within the French Vasculitis Study Group (FVSG) network and in three French tertiary ophthalmologic centres. Data from patients with scleritis without any systemic manifestation and with positive ANCA results were compared with those of a control group of patients with idiopathic scleritis with negative ANCA tests. RESULTS: A total of 120 patients, including 38 patients with ANCA-associated scleritis and 82 control patients, diagnosed between January 2007 and April 2022 were included. The median follow-up was 28 months (IQR 10-60). The median age at diagnosis was 48 years (IQR 33-60) and 75% were females. Scleromalacia was more frequent in ANCA-positive patients (P = 0.027) and 54% had associated ophthalmologic manifestations, without significant differences. ANCA-associated scleritis more frequently required systemic medications, including glucocorticoids (76% vs 34%; P < 0.001), and rituximab (P = 0.03) and had a lower remission rate after the first- and second-line treatment. Systemic ANCA-associated vasculitis (AAV) occurred in 30.7% of patients with PR3- or MPO-ANCA, after a median interval of 30 months (IQR 16.3-44). Increased CRP >5 mg/l at diagnosis was the only significant risk factor of progression to systemic AAV [adjusted hazard ratio 5.85 (95% CI 1.10, 31.01), P = 0.038]. CONCLUSION: Isolated ANCA-associated scleritis is mostly anterior scleritis with a higher risk of scleromalacia than ANCA-negative idiopathic scleritis and is more often difficult to treat. One-third of patients with PR3- or MPO-ANCA scleritis progressed to systemic AAV.

Hydroxychloroquine levels in pregnancy and materno-fetal outcomes in Systemic Lupus Erythematosus patients.

OBJECTIVES: Data about hydroxychloroquine (HCQ) levels during pregnancy are sparse. We assessed HCQ whole blood levels at first trimester of pregnancy as a potential predictor of maternal and obstetric/fetal outcomes in patients with systemic lupus erythematosus (SLE). METHODS: We included pregnant SLE patients enrolled in the prospective GR2 study receiving HCQ, with at least one available first-trimester whole-blood HCQ assay. We evaluated several cut-offs for HCQ whole blood levels, including ≤200 ng/ml for severe non-adherence. Primary outcomes were maternal flares during the second and third trimesters of pregnancy, and adverse pregnancy outcomes (APOs: fetal/neonatal death, placental insufficiency with preterm delivery, and small-for-gestational-age neonates). RESULTS: We included 174 patients (median age: 32.1 years, IQR 28.8-35.2). Thirty (17.2%) patients had flares, 4 (2.3%) being severe. APOs occurred in 28 patients (16.1%). There were no significant differences in APOs by HCQ level for either those with subtherapeutic HCQ levels (≤500 ng/ml vs >500 ng/ml: 23.5% vs 14.3%, p = 0.19) or those with non-adherent HCQ levels (≤200 ng/ml vs >200 ng/ml: 20.0% vs 15.7%, p = 0.71). Similarly, the overall rate of maternal flares did not differ significantly by HCQ level cut-off, but patients with subtherapeutic (HCQ ≤500 ng/ml: 8.8% vs 0.7%, p = 0.02) and non-adherent HCQ levels (≤200 ng/ml: 13.3% vs 1.3%, p = 0.04) had significantly more severe flares. CONCLUSION: In this large prospective study of pregnant SLE patients, first-trimester subtherapeutic (≤500 ng/ml) and severe non-adherent (≤200 ng/ml) HCQ levels were associated with severe maternal flares, but not with APOs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02450396.

Comparison of patients with isolated cutaneous lupus erythematosus versus systemic lupus erythematosus with cutaneous lupus erythematosus as the sole clinical feature: A monocentric study of 149 patients.

BACKGROUND: Cutaneous lupus erythematosus (CLE) may present as an isolated entity or be classified as Systemic lupus erythematosus (SLE) by the presence of laboratory abnormalities, including cytopenia, low complement levels, and/or autoantibodies (CLE with laboratory SLE). OBJECTIVE: To compare isolated CLE and CLE with laboratory SLE and to validate an existing 3-item score with age < 25 years (1 point), phototypes V to VI (1 point), antinuclear antibodies ≥ 1:320 (5 points) to predict the risk of progression from CLE to severe SLE (sSLE). METHODS: Monocentric cohort study including consecutive patients with CLE. CLE with laboratory SLE was defined by 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for SLE score of ≥10 points at baseline with CLE as the sole clinical feature. RESULTS: Of the 149 patients with CLE, 20 had CLE with laboratory SLE. The median follow-up duration was 11.3 years (IQR: 5.1-20.5). Ten patients (7%) had sSLE developed. In survival analysis, the risk of progression to sSLE was higher among CLE with laboratory SLE (hazard ratio = 6.69; 95% CI: 1.93-23.14, P < .001) compared to isolated CLE. In both groups, none of the patients with a risk score ≤ 2 had sSLE developed. LIMITATIONS: Monocentric study with a limited number of patients. CONCLUSIONS: CLE with laboratory patients with SLE have a higher risk of progression to sSLE than isolated CLE.

Chronic interstitial lung disease associated with systemic lupus erythematosus: A multicentric study of 89 cases.

BACKGROUND AND OBJECTIVE: Chronic interstitial lung disease (ILD) occurs rarely with systemic lupus erythematosus (SLE) as compared with other connective tissue diseases. This multicentric retrospective study of patients with SLE-ILD from the OrphaLung and French SLE networks during 2005-2020 aimed to describe the characteristics of patients with SLE-ILD and analyse factors associated with prognosis. METHODS: We analysed data for 89 patients with SLE-ILD (82 women, 92.1%) (median age at SLE diagnosis: 35 years [interquartile range 27-47]). All patients met the 2019 EULAR/ACR criteria for the diagnosis of SLE. RESULTS: Forty two (47.2%) patients were positive for anti-ribonuclear protein antibodies and 45 (50.6%) for anti SSA/Ro antibodies. A total of 58 (65.2%) patients had another connective tissue disease: Sjögren's syndrome (n = 33, 37.1%), systemic sclerosis (n = 14, 15.7%), inflammatory myopathy (n = 6, 6.7%), or rheumatoid arthritis (n = 6, 6.7%). ILD was diagnosed along with SLE in 25 (28.1%) patients and at a median of 6 (0-14) years after the SLE diagnosis. The most frequent CT pattern was suggestive of non-specific interstitial pneumonia (n = 41, 46.0%) with or without superimposed organizing pneumonia. After a median follow-up of 86.5 [39.5-161.2] months, 18 (20.2%) patients had died and 6 (6.7%) underwent lung transplantation. The median 5-year and 10-year transplantation-free survival were 96% (92-100) and 87% (78-97). In total, 44 (49.4%) patients showed ILD progression. Cutaneous manifestations and Raynaud's phenomenon were associated with better survival. Only forced vital capacity was significantly associated with survival and ILD progression. CONCLUSION: ILD is a rare manifestation of SLE with good overall prognosis but with possible risk of ILD progression. Patients with SLE-ILD frequently have another connective tissue disease.

Glomerular diseases in pregnancy: pragmatic recommendations for clinical management.

Our understanding of the various aspects of pregnancy in women with kidney diseases has significantly improved in the last decades. Nevertheless, little is known about specific kidney diseases. Glomerular diseases are not only a frequent cause of chronic kidney disease in young women, but combine many challenges in pregnancy: immunologic diseases, hypertension, proteinuria, and kidney tissue damage. An international working group undertook the review of available current literature and elicited expert opinions on glomerular diseases in pregnancy with the aim to provide pragmatic information for nephrologists according to the present state-of-the-art knowledge. This work also highlights areas of clinical uncertainty and emphasizes the need for further collaborative studies to improve maternal and fetal health.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Cutaneous vasculitis occurring in the setting of systemic lupus erythematosus: a multicentre cohort study.

OBJECTIVES: To describe the clinical and pathological features of biopsy-proven cutaneous vasculitis (CV) associated with SLE, focusing on diagnosis classification and impact on overall SLE activity. METHODS: Retrospective multicentric cohort study including SLE patients with biopsy-proven CV identified by (i) data from pathology departments of three university hospitals and (ii) a national call for cases. SLE was defined according to 1997 revised ACR and/or 2019 ACR/EULAR criteria. CV diagnosis was confirmed histologically and classified by using the dermatological addendum of the Chapel Hill classification. SLE activity and flare severity at the time of CV diagnosis were assessed independently of vasculitis items with the SELENA-SLEDAI and SELENA-SLEDAI Flare Index. RESULTS: Overall, 39 patients were included; 35 (90%) were female. Cutaneous manifestations included mostly palpable purpura (n = 21; 54%) and urticarial lesions (n = 18; 46%); lower limbs were the most common location (n = 33; 85%). Eleven (28%) patients exhibited extracutaneous vasculitis. A higher prevalence of Sjögren's syndrome (51%) was found compared with SLE patients without CV from the French referral centre group (12%, P < 0.0001) and the Swiss SLE Cohort (11%, P < 0.0001). CV was mostly classified as urticarial vasculitis (n = 14, 36%) and cryoglobulinaemia (n = 13, 33%). Only 2 (5%) patients had no other cause than SLE to explain the CV. Sixty-one percent of patients had inactive SLE. CONCLUSION: SLE-related vasculitis seems very rare and other causes of vasculitis should be ruled out before considering this diagnosis. Moreover, in more than half of patients, CV was not associated with another sign of active SLE.

Determination of four homogeneous subgroups of patients with antiphospholipid syndrome: a cluster analysis based on 509 cases.

OBJECTIVE: APS is a heterogeneous disease with different phenotypes. Using an unsupervised hierarchical cluster analysis, we aimed to determine distinct homogeneous phenotypes among APS patients. METHODS: We performed an observational, retrospective study of APS patients enrolled in the French multicentre 'APS and SLE' registry who met the Sydney classification criteria. The clustering process involved an unsupervised multiple correspondence analysis followed by a hierarchical ascendant clustering analysis; it used 27 variables selected to cover a broad range of APS clinical and laboratory manifestations. RESULTS: These analyses included 509 patients, mainly women (77.8%). Mean (s.d.) age at APS diagnosis was 36.2 (14.6) years, and mean follow-up since diagnosis 10.3 (8.5) years. This hierarchical classification cluster analysis yielded four homogeneous groups of patients: cluster 1, mostly with venous thromboembolism without any associated autoimmune disease; cluster 2, older, lowest proportion of women, history of arterial events, and/or with migraines, arterial hypertension, diabetes mellitus, or dyslipidaemia; cluster 3, younger, highest proportion of women, associated SLE or other autoimmune diseases, and a history of venous thromboembolism or pregnancy morbidity; and cluster 4, mainly with a history of catastrophic antiphospholipid syndrome, aPL-associated nephropathy, and pregnancy morbidity, with frequent triple positivity and more deaths (16.7%). CONCLUSIONS: Our study applied an unsupervised clustering method to distinguish four homogeneous APS patient subgroups that were predominantly venous; arterial; associated with SLE or another autoimmune disease; and arterial microthrombotic. Heterogeneous pathophysiological mechanisms may explain these findings.

Severe Libman-Sacks endocarditis complicating antiphospholipid syndrome: a retrospective analysis of 23 operated cases.

OBJECTIVE: Data on severe heart valve disease (HVD), including Libman-Sacks endocarditis, associated with SLE and/or APS requiring valvular surgery are scarce. We thus conducted a retrospective study, aimed at describing and clarifying clinical, laboratory, echocardiographic, histopathological and evolutional features of SLE and/or APS patients with severe associated-HVD. METHODS: An observational retrospective multicentric analysis of 23 adults with SLE and/or APS and HVD between 1996 and 2019 and available histopathological report evaluating long-term follow-up. RESULTS: Twenty-three individuals (20 females, median age 37 [range 17-76] years) were included. All had APS (thrombotic in 22, with an arterial phenotype in 15 and with catastrophic APS [CAPS] in six), and 11 (47%) had SLE. Systemic underlying disease had been diagnosed prior to HVD in 12 (52%). In 10 patients (43%), HVD was complicated by cerebral stroke prior to surgery. Twenty patients (87%) had only one pathological valve, the mitral valve in 18 patients (78%). Valvular thickening (n = 19) and valvular regurgitation (n = 19) were the most frequently reported lesions. Fifteen (62%) patients underwent mechanical valve replacement, six (26%) conservative valve repair (five were later re-operated after a median time of 1 [0-4] year), and two (9%) underwent biological valve replacement. Nine patients (39%) presented early-onset post-operative complications, including three CAPS immediately after surgery and one death. After surgery, 18 patients (78%) had normal postoperative valvular function, but almost half of the patients (43%) had post-operative neurological sequelae (median follow-up of 6 [2-20] years). CONCLUSION: Severe HVD leading to surgery was strongly associated with thrombotic APS, especially arterial phenotypes. Half of the reported patients presented cerebral stroke complicating the HVD. Valvular surgery carried a significant risk of CAPS.

Azathioprine-induced vanishing bile duct syndrome: The value of early thiopurine metabolism assessment.

About 15% to 28% of patients treated with thiopurines experienced adverse drug reactions, such as haematological and hepatic toxicities. Some of these related to the polymorphic activity of the thiopurine S-methyltransferase (TPMT), the key detoxifying enzyme of thiopurine metabolism. We report here a case of thiopurine-induced ductopenia with a comprehensive pharmacological analysis on thiopurine metabolism. A 34-year-old woman, with a medical history of severe systemic lupus erythematosus with recent introduction of azathioprine therapy, presented with mild fluctuating transaminase blood levels consistent with a hepatocellular pattern, which evolved to a cholestatic pattern over the next weeks. A blood thiopurine metabolite assay revealed low 6-thioguanine nucleotides (6-TGN) level and a dramatically increased 6-methylmercaptopurine ribonucleotides (6-MMPN) level, together with an unfavourable [6-MMPN:6-TGN] metabolite ratio and a high TPMT activity. After a total of about 6 months of thiopurine therapy, a transjugular liver biopsy revealed a ductopenia, and azathioprine discontinuation led to further clinical improvement. In line with previous reports from the literature, our case supports the fact that ductopenia is a rare adverse drug reaction of azathioprine. The mechanism of reaction is unknown but may involve high 6-MMPN blood level, due to unusual thiopurine metabolism (switched metabolism). Early therapeutic drug monitoring with measurement of 6-TGN and 6-MMPN blood levels may help physicians to identify patients at risk of similar duct injury.

Risk factors of progression from discoid lupus to severe systemic lupus erythematosus: a registry-based cohort study of 164 patients.

BACKGROUND: No study has assessed the risk factors of progression from discoid lupus erythematosus (DLE) to severe systemic lupus erythematosus (sSLE) (defined as requiring hospitalization and specific treatment). OBJECTIVE: To identify the risks factors of and generate a predicting score for progression to sSLE among patients with isolated DLE or associated with systemic lupus erythematosus with mild biological abnormalities. METHODS: In this registry-based cohort study, multivariable analysis was performed using risk factors identified from literature and pruned by backward selection to identify relevant variables. The number of points was weighted proportionally to the odds ratio (OR). RESULTS: We included 30 patients with DLE who developed sSLE and 134 patients who did not. In multivariable analysis, among 12 selected variables, an age of <25 years at the time of DLE diagnosis (OR, 2.8; 95% CI, 1.1-7.0; 1 point), phototype V to VI (OR, 2.7; 95% CI, 1.1-7.0; 1 point), and antinuclear antibody titers of ≥1:320 (OR, 15; 95% CI, 3.3-67.3; 5 points) were selected to generate the score. Among the 54 patients with a score of 0 at baseline, none progressed to sSLE, whereas a score of ≥6 was associated with a risk of approximately 40%. LIMITATIONS: Retrospective design. CONCLUSION: In our cohort, an age of <25 years at the time of DLE diagnosis, phototype V to VI, and antinuclear antibody titers of ≥1:320 were risk factors for developing sSLE.

Pregnancy and neonatal outcomes in women with axial spondyloarthritis: pooled data analysis from the European Network of Pregnancy Registries in Rheumatology (EuNeP).

OBJECTIVE: To investigate outcome and course of pregnancies in women with axial spondyloarthritis (axSpA) in a pooled data analysis of pregnancy registries in rheumatology. METHODS: Prospectively followed women with axSpA, fulfilling ASAS classification criteria and for whom a pregnancy outcome was reported, were eligible for the analysis. Anonymised data of four registries was pooled. Rates of adverse pregnancy outcomes were calculated. Systemic inflammation, disease activity and treatment patterns with tumour necrosis factor inhibitor (TNFi) before, during and after pregnancy were analysed. RESULTS: In a total of 332 pregnancies from 304 axSpA women, 98.8% of the pregnancies resulted in live birth. Mean maternal age was 31 years and disease duration 5 years. Most of these patients received pre-conception counselling (78.4%). Before pregnancy, 53% received TNFi treatment, 27.5% in first and 21.4% in third trimester. Pregnancy and neonatal outcomes were favourable with rates of 2.2% for pre-eclampsia, 4.9% for preterm birth, 3.1% for low birth weight and 9.5% for small for gestational age. Neonates were delivered by caesarean section in 27.7% of pregnancies, of which 47.4% were emergencies. Pooled mean CRP was 4 mg/L before conception peaking in the second trimester at 9.4 mg/L. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was below 4 at all time-points. CONCLUSIONS: Pooled rates of most outcomes were better than what had been reported in the literature and within expected rates of those reported for the general population. Pre-conception counselling, planned pregnancies and a tight management in expert centres applying a tailored treatment approach may have contributed to the favourable pregnancy outcomes.

Weaning of maintenance immunosuppressive therapy in lupus nephritis (WIN-Lupus): results of a multicentre randomised controlled trial.

OBJECTIVES: Lupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE). Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST, to target remission and avoid relapses. The optimal duration of maintenance IST is unknown. The WIN-Lupus trial tested whether IST discontinuation after 2‒3 years was non-inferior to IST continuation for two more years in proliferative LN. METHODS: WIN-Lupus was an investigator-initiated multicentre randomised controlled trial. Patients receiving maintenance IST with azathioprine or mycophenolate mofetil for 2-3 years, and hydroxychloroquine, were randomised (1:1) into two groups: (1) IST continuation and (2) IST discontinuation. The primary endpoint was the relapse rate of proliferative LN at 24 months. Main secondary endpoints were the rate of severe SLE flares, survival without renal relapse or severe flare, adverse events. RESULTS: Between 2011 and 2016, 96 patients (out of 200 planned) were randomised in WIN-Lupus: IST continuation group (n=48), IST discontinuation group (n=48). Relapse of proliferative LN occurred in 5/40 (12.5%) patients with IST continuation and in 12/44 (27.3%) patients with IST discontinuation (difference 14.8% (95% CI -1.9 to 31.5)). Non-inferiority was not demonstrated for relapse rate; time to relapse did not differ between the groups. Severe SLE flares (renal or extrarenal) were less frequent in patients with IST continuation (5/40 vs 14/44 patients; p=0.035). Adverse events did not differ between the groups. CONCLUSIONS: Non-inferiority of maintenance IST discontinuation after 2‒3 years was not demonstrated for renal relapse. IST discontinuation was associated with a higher risk of severe SLE flares. TRIAL REGISTRATION NUMBER: NCT01284725.

Definition of low disease activity state based on the SLE-DAS: derivation and validation in a multicentre real-life cohort.

OBJECTIVES: To derive and validate a definition of low disease activity (LDA) for SLE based on the SLE Disease Activity Score (SLE-DAS), in a real-life multicentre cohort of SLE patients. METHODS: Derivation was conducted using data from a monocentric cohort of SLE (Portugal), and validation was performed in a multicentre cohort (Italy, France and Spain). The Lupus Low Disease Activity State (LLDAS) was used as comparator. We applied receiver operating characteristics curve analysis against the LLDAS to determine the cut-off of SLE-DAS for LDA using bootstrap methodology. In a second step, we tested a definition of SLE-DAS LDA that included: (i) the statistically derived SLE-DAS upper threshold for LDA and (ii) prednisone dose ≤7.5 mg/day. In the multicentre validation cohort, we assessed the classification performance of this SLE-DAS LDA definition. RESULTS: We included 774 patients, 300 in the derivation and 474 in the validation cohort. In the derivation cohort, the optimal cut-off to identify patients in LLDAS was SLE-DAS ≤2.48, presenting an area under the curve of 0.965 (95% CI 0.935, 0.994). When applied to the multicentre validation cohort, the SLE-DAS LDA definition showed a sensitivity of 97.1% and a specificity of 97.7% for LLDAS and an almost perfect agreement (Cohen's Kappa = 0.933; P < 0.001). McNemar's test found no significant differences between the two definitions (P = 0.092). CONCLUSION: The SLE-DAS LDA is a validated, accurate and easy-to-use definition for classifying SLE patients in LDA state.

Evaluation of lupus anticoagulant, damage, and remission as predictors of pregnancy complications in systemic lupus erythematosus: the French GR2 study.

OBJECTIVES: The specific roles of remission status, lupus low disease activity state (LLDAS), and damage accrual on the prognosis of pregnancies in women with SLE are unknown. We analysed their impact on maternal flares and adverse pregnancy outcomes (APOs). METHODS: We evaluated all women (≥18 years) with SLE enrolled in the prospective GR2 study with an ongoing singleton pregnancy at 12 weeks (one pregnancy/woman). Several sets of criteria were used to define remission, disease activity and damage. APOs included: foetal/neonatal death, placental insufficiency with preterm delivery and small-for-gestational-age birth weight. First trimester maternal and disease features were tested as predictors of maternal flares and APOs. RESULTS: The study included 238 women (98.3% on hydroxychloroquine (HCQ)) with 230 live births. Thirty-five (14.7%) patients had at least one flare during the second/third trimester. At least one APOs occurred in 34 (14.3%) women. Hypocomplementemia in the first trimester was the only factor associated with maternal flares later in pregnancy (P=0.02), while several factors were associated with APOs. In the logistic regression models, damage by SLICC-Damage Index [odds ratio (OR) 1.8, 95% CI: 1.1, 2.9 for model 1 and OR 1.7, 95% CI: 1.1, 2.8 for model 2] and lupus anticoagulant (LA, OR 4.2, 95% CI: 1.8, 9.7 for model 1; OR 3.7, 95% CI: 1.6, 8.7 for model 2) were significantly associated with APOs. CONCLUSION: LA and damage at conception were predictors of APOs, and hypocomplementemia in the first trimester was associated with maternal flares later in pregnancy in this cohort of pregnant patients mostly with well-controlled SLE treated with HCQ. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02450396.

Clonal haematopoiesis of indeterminate potential and cardiovascular events in systemic lupus erythematosus (HEMATOPLUS study).

OBJECTIVE: The detection of somatic mutations among the genes of myeloid cells in asymptomatic patients-defining clonal haematopoiesis of indeterminate potential (CHIP)-is associated with a predisposition to cardiovascular events (CVEs) in the general population. We aimed to determine whether CHIP was associated with CVEs in SLE patients. METHODS: The study is an ancillary study of the randomized, double-blind, placebo-controlled, multicentre PLUS trial conducted from June 2007 through August 2010 at 37 centres in France, involving 573 SLE patients. The search for somatic mutations by high-throughput sequencing of 53 genes involved in clonal haematopoiesis was performed on genomic DNA collected at PLUS inclusion. CHIP prevalence was assessed in SLE and in a retrospective cohort of 479 patients free of haematological malignancy. The primary outcome was an incident CVE in SLE. RESULTS: Screening for CHIP was performed in 438 SLE patients [38 (29-47) years, 91.8% female]. Overall, 63 somatic mutations were identified in 47 patients, defining a CHIP prevalence of 10.7% in SLE. Most SLE patients (78.7%) carried a single mutation. Most variants (62.5%) were located in the DNMT3A gene. CHIP frequency was related to age and to age at SLE diagnosis, and was associated with a lower frequency of aPLs. CHIP occurred >20 years earlier (P < 0.00001) in SLE than in controls. The detection of CHIP at inclusion was not found to be associated with occurrence of CVEs during follow-up [HR = 0.42 (0.06-3.21), P = 0.406]. CONCLUSION: The prevalence of CHIP is relatively high in SLE for a given age, but was not found to be associated with incident CVEs. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05146414.

Splenectomy for primary immune thrombocytopenia revisited in the era of thrombopoietin receptor agonists: New insights for an old treatment.

Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval of thrombopoietin receptor agonists (TPO-RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO-RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicenter retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO-RAs and/or rituximab before the splenectomy. The median follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow-up, for an overall sustained response of 65.4%, similar to that observed in the pre-TPO-RA era. Among patients who received at least one TPO-RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO-RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO-RAs that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re-challenged with TPO-RAs.

Gender differences in primary antiphospholipid syndrome with vascular manifestations in 433 patients from four European centres.

OBJECTIVES: Gender can influence incidence and clinical course of autoimmune diseases (ADs). Antiphospholipid syndrome (APS) is a rare AD characterised by thromboses and/or pregnancy morbidities and antiphospholipid antibodies (aPL) positivity. Our aim is to conduct a gender-oriented analysis of primary thrombotic APS (t-APS). METHODS: Consecutive patients diagnosed with primary t-APS, followed from 1967 to 2019 in four European Centres, were enrolled. RESULTS: The cohort included 296 women and 137 men. Median age at onset [31 (24-46) vs. 41 (29-53) years, p<0.001] was lower in females. In women, venous thromboses were more frequent while, among males, arterial events prevailed. During follow-up, 14% of patients suffered at least two relapses and this occurred especially among males (22% vs. 10%, p=0.001). No gender differences were found in the aPL profile (33% single, 24% double and 43% triple aPL positivity). Most patients had concomitant risk factors (RFs) for thrombosis: established cardiovascular RFs were represented especially among men while estrogenic exposure was the main RF in women. CONCLUSIONS: Women presented mostly with venous thromboses at a younger age, while men with arterial events, later in life and suffered more recurrent events. This different frequency of arterial and venous thromboses could be attributed mainly to the presence of additional RFs rather than to biological gender-specific issues. However, some RFs are exclusive or more represented in one gender rather than the other, so assessing the link of causality between gender and manifestations of t-APS remains difficult.