Non-criteria Manifestations Research Articles

Clinical significance of interferon status in patients with systemic lupus erythematosus. Preliminary data

Background. Studies of systemic lupus erythematosus (SLE) pathogenesis have identified two major families of mediators: type I interferon (IFN-I) and autoantibodies to nucleic acids and their proteins, as the main factors contributing to the development of the disease. Against a background of genetic predisposition, a trigger stimulus, possibly microbial, induces the production of IFN-I, autoantibodies or, more likely, both, leading to inflammation. The interaction of cells of the innate and adaptive immune system are involved in the autoimmune response with the development of a variety of clinical manifestations of SLE.The aim of our study was to describe clinical and immunological characteristics of systemic lupus erythematosus depending on interferon gene signature (IFNGS).Material and methods This observational retrospective-prospective study included 76 patients (86% women, median aged 33 [25; 43] years (median [interquartile range 25%; 75%]), with a definite diagnosis of SLE (SLICC (Systemic Lupus International Collaborating Clinics), 2012) attending a routine visit at our Clinic between February 2021 and June 2024. Baseline demographics, disease characteristic, organ system involvement/damage were analysed descriptively according to SLE Disease Activity Index 2000 (SLEDAI-2K), SLICC Damage Index (SDI) and IFNGS status (high/low). IFN status was assessed by the expression of IFN-inducible genes (MX1, RSAD2, EPSTI1) using real-time polymerase chain reaction. IFNGS was calculated as the average expression value of three selected genes. In patients, IFNGS was considered high when the average value of gene expression exceeded the average value of gene expression in donors. The control group consisted of 20 healthy donors comparable in sex and age with the SLE patients.Results. The median disease duration was 2.3 [0.2; 11.0] years, SLEDAI-2K – 7 [4; 11], SDI – 0 [0; 2]. IFNGS-high was detected in 72% of SLE patients. IFNGS-high patients were younger at the time of inclusion (31 [25; 41] and 40 [32; 49] years, respectively), had less frequent remission of SLE (SLEDAI-2K=0) (2% and 19%, respectively), and higher concentrations of anti-dsDNA (219.8 [120.3; 729.3] and 131.0 [46.6; 265.9] IU/ml, respectively; normal <100 IU/ml), ANF titer ≥1/1280 (84% and 52%, respectively), lower absolute count of blood leukocytes (4.2 [3.2; 5.6] and 6.6 [4.2; 8.8]×109/L, respectively) and lymphocytes (1.3 [0.8; 1.8] and 2.0 [1.2; 3.2]×109/L, respectively; p<0,05 in all cases). Of the criterion and non-criteria manifestations of SLE the greater proportions of IFNGS-high versus IFNGS-low patients had haematological (56% and 29%, respectively), primarily leukopenia (53% and 24%, respectively) and dermal (31% and 19, respectively %) involvement (p<0,05 in all cases).Conclusions. Elevated type I IFN signalling is a marker of a certain type of SLE patients – young age with predominant skin, haematological and immunological disorders. No association with standard therapy and the expression level of certain IFNGS was found.

The 2023 ACR/EULAR Classification Criteria for Antiphospholipid Syndrome: Implications for the Inclusion of Participants in Research vs Diagnosis in Clinical Practice

Antiphospholipid syndrome (APS) was first described in patients with systemic lupus erythematosus in 1983, and the primary version in 1989. Multiple clinical manifestations have been associated with antiphospholipid antibodies (aPL) including venous and arterial thromboses, transient ischemic attack (TIA), obstetric complications, thrombocytopenia, hemolytic anemia, livedo reticularis, transverse myelitis, cognitive dysfunction, cutaneous ulcers, Libman-Sacks endocarditis, and a peculiar type of nephropathy. Antiphospholipid antibodies include lupus anticoagulant (LAC), anticardiolipin antibodies (aCL) IgG and IgM, and anti‑beta‑2‑glycoprotein antibodies (aβ2GPI) IgG and IgM. Other antibodies such as anti-prothrombin and anti-prothrombin/phosphatidylserine have been proposed as biomarkers of APS, particularly in cases where the standard antibodies are negative, but they are not officially accepted. Since 1999, the original Sapporo Criteria and its revised 2006 version have been used for the classification of patients in research studies and for the diagnosis of patients with APS. Despite the broad spectrum of clinical manifestations and serological markers considered by physicians as part of the APS, the original and revised versions of Sapporo Criteria include only venous, arterial and microvascular thrombotic events and specific obstetric events among the clinical manifestations, and aCL IgG and IgM antibodies, aβ2GPI-I antibodies IgG and IgM or lupus anticoagulant as the serological markers. Consequently, APS was diagnosed as obstetric and/or thrombotic syndrome, not considering other non-criteria manifestations associated to aPL antibodies. The major limitation of these criteria is that they do not reflect the systemic nature of APS. Due to the importance of classification criteria in research, the ACR and EULAR assumed the responsibility of encouraging the development and validation of new and improved classification criteria for various rheumatic diseases, including APS, based on the current standards of measurement.

Clinical and Serological Findings of Patients with Antiphospholipid Syndrome in Mashhad, Iran, from 2008 to 2018: A Retrospective, Descriptive, Cross-sectional Study.

Antiphospholipid syndrome (APS) is among the autoimmune disorders caused by antiphospholipid antibodies, which provoke blood clots (thrombosis) in arteries and veins. It can also cause such complications as severe preeclampsia, miscarriage, premature birth, and stillbirth in pregnant women. We investigated the clinical and serological characteristics of antiphospholipid syndrome patients. This retrospective cross-sectional study was performed on those with persistently positive antiphospholipid syndrome. Data were extracted from medical records from the hospital information system(HIS) of rheumatology, neurology, cardiology, gynecology, general, and hematology wards of Ghaem Hospital and private rheumatology clinics of Mashhad, which were surveyed for 10 years (2008-2018). Of the 284 patients, 85.6% were female. The most common adverse outcome of pregnancy was miscarriage (68.1%). Non-criteria manifestations, including arthralgia and arthritis, were observed in 37.7% and 33.1% of the patients, respectively. Moreover, deep vein thrombosis (DVT) and cerebrovascular accident (CVA) (13%), organ gangrene (7.4%), and pulmonary thromboendarterectomy (PTE) and transient ischemic attack (TIA) (4.6%) were the most common thrombotic events in antiphospholipid syndrome patients. Deep vein thrombosis was seen in 70.3% of females (P=.005), and subclavian thrombosis was seen in 66.7% of males (P < .001). The risk of DVT in the presence of anti-cardiolipin Ab IgG positive was increased 2.7 times (CI: 95%, 1.2-5.7; P=.007), and it was increased 2.4 times in the presence of anti-β-2 glycoprotein 1 Ab IgG positive (CI: 95%, 1-5.8; P=.033) and 4.2 times in the presence of lupus anticoagulant Ab positive (CI: 95%, 1.9-9.1; P < .001). In patients with anti-β-2 glycoprotein 1 Ab IgG positive, the risk of placental dysfunction increased 4.3 times (CI: 95%, 0.9-20.3; P=.04). This study's results found that this APS syndrome is mainly seen in women with a mean age of 38, and the most common symptoms associated with it are DVT, CVA, and abortion. Anti-β-2 Glycoprotein 1 Ab IgM and Anti-Cardiolipin Ab IgM were the most common positive antibodies in the patients.

Autoantibodies against complement proteins in patients with antiphospholipid syndrome: Prevalence and clinical associations.

Seventy-seven patients with antiphospholipid syndrome were tested for autoantibodies against C1q, C3, FB, FH, and C4bp. Fifty-seven patients had at least one anti-complement antibody. IgM anti-FH positivity was associated with thrombosis when anti-C3 and anti-FB were, negatively or positively, associated with various noncriteria manifestations of antiphospholipid syndrome.

Kliničke manifestacije udružene sa prisustvom antifosfolipidnih antitela

Antiphospholipid antibodies (aPL antibodies) are a heterogeneous group of autoantibodies that target anionic phospholipids or phospholipid-binding proteins. They can be associated with numerous clinical manifestations in almost all areas of clinical medicine, but antiphospholipid syndrome (APS) is the most precisely defined entity. The most common clinical manifestations of aPL are thrombosis in any part of the circulation, as well as pregnancy complications in the form of miscarriage or premature birth due to preeclampsia, eclampsia, or placental insufficiency. According to the modified Sapporo classification of 2006, thrombosis and/or pregnancy complications represent the clinical criteria for diagnosing APS. However, in approximately a quarter of patients with APS, additional clinical manifestations are present, which are not accepted as criteria for APS. Interestingly, these manifestations can be associated with aPL antibodies even in the absence of thrombosis or pregnancy morbidity, i.e., without the presence of the criteria for definitive APS. Recognizing non-criteria manifestations is highly significant because it can draw attention to the possible presence of aPL antibodies and indicate the presence of APS or the risk of its occurrence. The latest classification was published in 2023 by the American College of Rheumatology/European Alliance of Rheumatology Associations (ACR/EULAR). It expanded the list of clinical criteria for the recognition of antiphospholipid syndrome. This classification demonstrates higher specificity but lesser sensitivity in recognizing APS than earlier criteria. At present, the application of the ACR/EULAR criteria is primarily intended for research purposes, i.e., selecting study subjects, rather than for diagnosing APS in everyday clinical practice.

Pattern of disease expression in SLE patients with antiphospholipid antibodies: data from Indian Systemic Lupus Erythematosus Inception cohort (INSPIRE).

Antiphospholipid antibodies (APLA) are present in one-third of systemic lupus erythematosus (SLE) patients, and they are associated with both criteria and non-criteria manifestations. We studied the prevalence, clinical associations, and impact on mortality of APLA in SLE patients from India. Among the Indian SLE inception cohort (INSPIRE), patients who had data on all five routinely performed APLAs [lupus anticoagulant (LA), IgG and IgM anticardiolipin antibody (aCL) and anti-β2-glycoprotein I(β2GPI)] at enrolment were selected. Patients were divided into four categories based on the presence/absence of APLA associated manifestations and presence/absence of the APLA viz SLE-APS, SLE-APLA, SLE: events but no APLA, and SLE: no events, no APLA (reference group). 1035 SLE patients at least 1 APLA antibody was detected in 372 (35.9%). LA was present in 206 (19.9%), aCL in 126 (12.2%) and β2-GPI in 178 (17.2%). There were 88 thrombotic events in 83 patients (8.0%); 73 (82.9%) being arterial; APLA positivity was present in 37 (44.6%) [AOR 1.70 (1.054, 2.76)]. SLE-APS patients were younger and had higher mortality [AOR 4.11 (1.51, 11.3)], neuropsychiatric and hematologic disease. SLE-APLA also had a higher mortality rate [AOR 2.94 (1.06, 8.22)] than the reference group. The mortality was highest in the subset of patients with thrombotic events in the presence of APLA [AOR 7.67 (1.25, 46.9)]. The mere presence of APLA also conferred higher mortality even in the absence of thrombotic events [AOR 3.51 (1.43, 8.63)]. Hematologic manifestations (36.1%) were the most common non-criteria-manifestation. One-third of SLE patients have APLA and its presence is associated with non-criteria hematologic manifestations, arterial thrombosis and higher mortality rate.

The meaning of non-criteria clinical manifestations in a real-life primary antiphospholipid syndrome cohort.

We aimed to evaluate the prevalence of non-criteria clinical features in patients with primary antiphospholipid syndrome (APS), and to assess their relationship to thrombosis and damage. We retrospectively included 177 primary APS patients, and/or patients who only achieved the serological Sydney criteria but had thrombocytopenia and/or haemolytic anaemia. We registered demographics, serology, treatment, thrombotic/obstetric manifestations and non-criteria clinical manifestations (cutaneous, haematologic, renal, heart valve disease, and neurological). We scored the DIAPS and a modified SLICC index. We used logistic regression and reported OR with 95% CI. 78% were women with a median follow-up of 6.7 years. Thrombosis was found in 74% of patients, 29.3% had obstetric features, and 64% had non-criteria clinical manifestations. The frequency of the non-criteria clinical manifestation was: haematologic 40.1%, cutaneous 20.9%, neurologic 18%, cardiac 5% and renal 4.5%. Non-criteria features were associated with LA (OR 2.3, 95% 1.03-5.1) and prednisone use (OR 8.2, 95% CI 1.7-39.3). A DIAPS score ≥1 was associated with thrombosis (OR 53.1, 95% CI 17.8-15.2), prednisone use (OR 0.27, CI 95% 0.09-0.83) and neurological involvement (OR 6.4, 95% CI 1.05-39.8); whereas a modified SLICC ≥ 1 with thrombosis (OR 10.2; IC 95% 4.43-26.1), neurological involvement (OR 6.4, 95%CI 1.05-39.8), obstetric features (OR 0.32 CI 95% 0.12-0,81) and cutaneous features (OR 5.3, CI 95% 1.4-19), especially livedo reticularis (OR 5.45; IC 95% 1.49-19.8). Non-criteria clinical manifestations are common and associated with LA. Among them, neurologic involvement and the presence of livedo were associated with damage accrual.

Efficacy of telitacicept in patients with lupus‐ and antiphospholipid syndrome‐associated refractory thrombocytopenia

AbstractIntroductionThrombocytopenia, a common noncriteria manifestation of antiphospholipid syndrome (APS), is severe in approximately one‐third of patients with APS. However, there are no guidelines for treating such thrombocytopenia. B‐cell‐targeting therapy may be an option in refractory cases; however, its efficacy has not been firmly established. Here, we report on two patients with refractory antiphospholipid antibodies (aPLs)‐associated thrombocytopenia treated with telitacicept.Case DescriptionCase 1, a 39‐year‐old woman, presented with systemic lupus erythematosus (SLE) and APS with diffuse alveolar hemorrhage, persistent thrombocytopenia, and recurrent miscarriages. The thrombocytopenia had been refractory to multiple lines of treatments, the most recent being mycophenolate mofetil and prednisone (5 mg/day). After receiving telitacicept (160 mg/week) for 3 months, she had presented with decreased titers of aPLs and a slight increase in platelet counts (14 × 109 to 35 × 109/L). Case 2, a 51‐year‐old woman, presented with SLE and APS with refractory thrombocytopenia. She had been diagnosed with pulmonary tuberculosis 4.5 years ago and received antituberculosis therapy for 2 years. She had also undergone pulmonary lobectomy 4 years ago for lung adenocarcinoma. Her thrombocytopenia relapsed (lowest 14 × 109/L) when prednisone was tapered to &lt;10 mg/day. After adding telitacicept (160 mg/week) to cyclosporin A (150 mg/day) and hydroxychloroquine (400 mg/day) for 5 months, aPLs decreased and platelet counts increased (78 × 109 to 183 × 109/L), enabling halving of her dose of prednisone from 15 to 7.5 mg/day. Neither patient had any adverse effects.ConclusionTelitacicept can safely reduce aPLs titers and improve refractory thrombocytopenia in patients with secondary APS. Randomized‐controlled trials to assess its effectiveness are urgently required.

Haematological and other manifestations in the presence of antiphospholipid antibodies in a multicentric paediatric cohort.

To identify the variables associated with the development of haematological manifestations in the presence of antiphospholipid antibodies (aPLs) in a paediatric cohort. We conducted a multicentric retrospective cohort study of children under the age of 18 years. One hundred and thirty-four children were included; 12.2% had at least one thrombotic event (TE) and 67% at least one non-criterion manifestation. Of them, 90% did not develop any TE. Haematological manifestations were the most frequent (42%), followed by neurological (19.8%), cutaneous (17.6%), cardiac (16.8%) and renal (1.5%) manifestations. In those children with haematological disorders, the aPLs positivity rate was: 67.3% LA, 65.6% aβ2GPI, 60% aCL, 45.5% single, 23.6% double and 30.9% triple. A univariate analysis showed that children with IgM aCL+, IgM aβ2GPI+, triple positivity and with a SLE diagnosis had a significantly higher frequency of haematological manifestations (p<0.05). Finally, a stepwise regression analysis identified IgG aβ2GPI positivity [OR 2.91, 95% CI (1.26-6.74), p=0.013], SLE [OR 2.67, 95% CI (1.13-6.3), p=0.026] and LA positivity [OR 2.53, 95% CI (1.08-5.94), p=0.033] as independent risk factors for the development of haematological manifestations. Non-criteria manifestations and among them haematological disorders, are the most frequent events in the presence of aPLs and/or LA in our paediatric cohort. Children with SLE, LA and/or IgG aβ2GPI positivity showed a higher risk of haematological manifestations.

Identifying high-risk profile in primary antiphospholipid syndrome through cluster analysis: French multicentric cohort study

IntroductionAntiphospholipid syndrome (APS) is an autoimmune disease characterised by thrombosis (arterial, venous or small vessel) or obstetrical events and persistent antiphospholipid antibodies (aPL), according to the Sydney classification criteria. Many...

OA04 Paediatric APS - children are not just small adults

OA04 Paediatric APS - children are not just small adults

Rapidly evolving necrotic skin lesions of the face

Rapidly evolving necrotic skin lesions of the face

Analysis of Serbian Primary Antiphospholipid Syndrome Patients Confirmed a Strong Association Between Livedo Reticularis and Arterial Thrombosis: A National Cross-Sectional Cohort Study.

Antiphospholipid syndrome (APS) is characterized by antiphospholipid antibodies (aPLs) associated with thrombosis (arterial and/or venous) and/or obstetrical manifestations. However, various manifestations, which are considered to be noncriteria manifestations, are frequently found in APS. The purpose of this study was to evaluate whether noncriteria manifestations may be found more frequently in subjects with thrombotic and/or obstetrical APS ("criteria" manifestations) in a population of patients with primary APS (PAPS). This study presents the results from our national cohort. This is a cross-sectional study of 360 PAPS patients. Data regarding the presence of thrombocytopenia, livedo reticularis, chorea, and valvulopathy were analyzed. The aPL analysis included the detection of anticardiolipin antibodies (aCLs: immunoglobulin G [IgG]/IgM), anti-β 2 glycoprotein I (IgG/IgM), and lupus anticoagulant positivity. In our cohort, livedo reticularis was significantly related to arterial thromboses in the same way as valvular manifestations (valvular vegetations and valvular thickening and dysfunction not related to age) ( p = 0.0001, p = 0.013, respectively). Age was strongly related to all the noncriteria manifestations analyzed. Thrombocytopenia was significantly related to β 2 glycoprotein I IgG and lupus anticoagulant positivity ( p = 0.043, p = 0.030, respectively), as well as to double and triple aPL positivity ( p = 0.041, p = 0.013 respectively). Moreover, in a multivariate model, livedo reticularis was strongly and independently related to arterial thrombosis in our cohort (odds ratio, 2.010; confidence interval, 1.229-3.288; p = 0.005). This cross-sectional analysis of a large cohort of Serbian PAPS patients confirmed a strong relationship between livedo reticularis and arterial thrombosis, suggesting a more cautious approach regarding the presence of noncriteria manifestations, especially livedo reticularis, in APS.

Clinical characteristics and prognosis of patients with antiphospholipid antibodies based on cluster analysis: an 8-year cohort study

BackgroundAntiphospholipid syndrome (APS) is an autoimmune disease characterized by persistent antiphospholipid antibodies (aPLs) positivity with a wide manifestation spectrum. A risk stratification is needed for management guidance and prognosis assessment. We aimed to identify phenotypes among aPL-positive patients and assess the prognosis of each phenotype.MethodsThis was a single-center, prospective cohort study of aPL-positive patients presented to Peking Union Medical College Hospital from 2012 to 2020. Demographic characteristics, aPL-related manifestations, cardiovascular risk factors, and antibodies profiles were recorded. The primary endpoint was defined as a combination of newly onset thrombosis, major bleeding events, non-criteria manifestations, and all-cause death. Hierarchical cluster analysis and Kaplan-Meier survival analysis were performed.ResultsFour clusters among 383 patients (70.2% female; mean age 37.7 years) were identified. Cluster 1 (n = 138): patients with systemic lupus erythematosus (SLE) and non-criteria manifestations; cluster 2 (n = 112): patients with multiple cardiovascular risk factors; cluster 3 (n = 83): female patients with obstetric morbidity; cluster 4 (n = 50): patients with isolated lupus anticoagulant (LA) positivity.Non-criteria manifestations were found aggregated with SLE from cluster analysis of variables. Cluster 3 showed the best outcome, while cluster 2 suffered highest frenquency of newly onset arterial thrombosis.ConclusionsWe identified 4 clinical phenotypes of aPL-positive patients. Non-criteria manifestations may indicate underlying SLE, for which immunosuppressive therapy besides anticoagulation may be necessary. Patients with isolated LA positivity suffered similar risks with secondary APS and patients with multiple cardiovascular risk factors. Attention should be paid to male patients, and the screening of cardiovascular risk factors should never be ignored.

Clinical and prognostic significance of antinuclear antibodies in primary antiphospholipid syndrome: A multicenter retrospective study.

Clinical and prognostic significance of antinuclear antibodies in primary antiphospholipid syndrome: A multicenter retrospective study.

Pediatric antiphospholipid syndrome: clinical features and therapeutic interventions in a single center retrospective case series

Background/purposePediatric antiphospholipid syndrome (APS) is a thromboinflammatory disease characterized by the presence of circulating antiphospholipid antibodies and either thrombotic events or pregnancy morbidity. The objective of this study was to review a large institution’s experience to better understand the characteristics of children with APS.MethodsWe conducted a retrospective review of pediatric APS at a tertiary referral center. The electronic medical record system was queried from 2000 through 2019, and 21 cases were included based on meeting the revised Sapporo Classification criteria by age 18 or younger. Comparisons between primary and secondary APS patients were made with two-tailed t-tests.ResultsTwenty-one patients were included with a median age at diagnosis of 16 years and median follow-up of 5.8 years. Secondary APS was slightly more common than primary APS (11 vs. 10 cases) and was primarily diagnosed in the context of systemic lupus erythematosus. Two thirds of patients (67%) also had “non-criteria” manifestations of APS including thrombocytopenia, autoimmune hemolytic anemia, and livedo reticularis/racemosa. Almost half of patients (43%) had recurrent thrombosis, typically when patients were subtherapeutic or non-adherent with anticoagulation. Damage Index in Patients with Thrombotic APS (DIAPS) scores indicated a chronic burden of disease in both primary and secondary APS patients.ConclusionThis case series of pediatric APS provides important context regarding disease phenotypes displayed by children with APS. High prevalence of non-criteria clinical manifestations highlights the need to consider these characteristics when developing pediatric-specific classification criteria and when considering this relatively rare diagnosis in pediatric practice.

Primary antiphospholipid syndrome in pediatrics: beyond thrombosis. Report of 32 cases and review of the evidence

ObjectiveDescribe the frequency of thrombotic and non-thrombotic clinical manifestations, laboratory, treatment and prognosis in patients with pediatric primary antiphospholipid syndrome.Material and methodsA retrospective study was carried out in patients with a diagnosis of primary antiphospholipid antibody syndrome, under 16 years of age, under follow-up by the pediatric rheumatology service of the General Hospital, National Medical Center, La Raza, from January 2013 to December 2020. The antiphospholipid syndrome was defined when it met the laboratory criteria of the Sidney criteria and the presence of thrombosis or non-criteria manifestations of the disease (hematological, neurological, cutaneous, renal, cardiac or pulmonary). Demographic, clinical, laboratory, treatment, and prognosis data were collected.ResultsWe report 32 patients, 21 female (65%) and 11 male (35%), mean age 11.75 years, evolution time 16 weeks. Thrombosis 9 patients (28%), 1 arterial and 8 venous. Non-thrombotic manifestations; Hematologic: thrombocytopenia 22 patients (69%), autoimmune hemolytic anemia 13 (40%), Fisher-Evans syndrome 6 (19%), lupus anticoagulant with hypoprothrombinemia syndrome 2 (6%). Dermatological: livedo reticularis 20 (62%), skin ulcers 2 (6%), Raynaud's phenomenon 8 (25%). Neurological: epilepsy 1 (3%), migraine 3 (9%), chorea 1 (3%) and cognitive impairment 3 (9%). Renal in 4 (13%). Laboratory: prolonged aPTT 30 (93%), lupus anticoagulant 32 (100%), positive IgG anticardiolipin 20 (62%), positive IgM anticardiolipin 19 (60%). AntiB2GPI was performed in only 3 patients, being positive in all. Treatment: anticoagulation in patients with thrombosis, antiplatelet in 23 (72%), steroid 30 (94%), immunosuppressant 30 (94%) and rituximab 4 (12.5%). No deaths were reported.ConclusionsThe clinical characteristics of patients with pediatric primary antiphospholipid syndrome differ from those presented in adults, since non-thrombotic manifestations are more frequent in children, for which classification criteria that include these manifestations are necessary for a better characterization of the disease in pediatric population.

Non-criteria manifestations in the presence of antiphospholipid antibodies in a paediatric cohort.

To identify the variables associated with the development of non-criteria manifestations in the presence of antiphospholipid antibodies (aPLs) in a paediatric cohort. Multicentric historical cohort study of children under the age of 18 years to determine thrombotic events (TEs) and non-criteria manifestations in the presence of aPL. Eighty-two children were included; 8.5% had at least one TE and 69.5% at least one non-criteria manifestation. Of them, 96.5% did not associate TEs. Haematological manifestations were the most frequent (43.65%), followed by cutaneous (22%), neurological (15.9%) and cardiac (4.9%) events. The most frequent aPLs were: 77.8% LA; 42.7% aCL and 41.5% aβ2GP. The positivity rate was: 64.6% simple, 18.3% double and 17.1% triple. ANA positivity was 68.1%. A bivariate analysis revealed that children with IgM aCL+, IgM aβ2GP+, ANA+, an SLE diagnosis or the absence of TEs had a significantly higher percentage of non-criteria manifestations (P&lt;0.05). The logistic regression showed family history of autoimmune diseases [odds ratio (OR) 4.26, 95% CI: 0.8, 22.2, P=0.086] and the absence of TEs (OR 17.18, 95% CI: 1.2, 244.6, P=0.03) as independent risk factors of developing non-criteria manifestations. An SLE diagnosis, aPL profile and ANA+ were not identified. Non-criteria manifestations were more frequent than TEs. A positive family history of autoimmune diseases and the absence of TEs were associated with a higher risk of developing non-criteria manifestations. Therefore, their inclusion as APS classification criteria should be considered in order to get an improved prognosis in the paediatric population.

Non-criteria manifestations in primary antiphospholipid syndrome: a French multicenter retrospective cohort study

BackgroundFrom this retrospective study, we aimed to (1) describe the prevalence and characteristics of non-criteria features in primary antiphospholipid syndrome (p-APS) and (2) determine their prognostic value.MethodsThis retrospective French multicenter cohort study included all patients diagnosed with p-APS (Sydney criteria) between January 2012 and January 2019. We used Kaplan-Meier and adjusted Cox proportional hazards models to compare the incidence of relapse in p-APS with and without non-criteria manifestations.ResultsOne hundred and seventy-nine patients with p-APS were included during the study time, with a median age of 52.50 years [39.0; 65.25] and mainly women (n = 112; 62.6%). Among them, forty-three patients (24.0%) presented at least one non-criteria manifestation during the follow-up: autoimmune cytopenias (n = 17; 39.5%), Libman Sachs endocarditis (n = 5; 11.6%), APS nephropathy (n = 4; 9.3%), livedo reticularis (n = 8; 18.6%), and neurological manifestations (n = 12; 27.9%). In comparison to p-APS without any non-criteria manifestations (n = 136), p-APS with non-criteria features had more arterial thrombosis (n = 24; 55.8% vs n = 48; 35.3%; p = 0.027) and more frequent pre-eclampsia (n = 6; 14.3% vs n = 4; 3.1%; p = 0.02). The prevalence of triple positivity was significantly increased in patients with non-criteria features (n = 20; 47.6% vs n = 25; 19.8%; p = 0.001). Patients with p-APS and non-criteria manifestations (n = 43) received significantly more additional therapies combined with vitamin K antagonists and/or antiaggregants. Catastrophic APS (CAPS) tended to be more frequent in p-APS with non-criteria features (n = 2; 5.1% vs none; p = 0.074).The p-APS with non-criteria manifestations had significantly increased rates of relapse (n = 20; 58.8% vs 33; 33.7%; p = 0.018) in bivariate analysis, but in survival analyses, the hazard ratio (HR) of relapse was not significantly different between the two groups (HR at 1.34 [0.67; 2.68]; p = 0.40).ConclusionsThe presence of non-criteria features is important to consider, as they are associated with particular clinical and laboratory profiles, increased risk of relapse, and need for additional therapies. Prospective studies are necessary to better stratify the prognosis and the management of p-APS.

Characteristics of Patients With Antiphospholipid Antibody Positivity in the APS ACTION International Clinical Database and Repository.

To describe the baseline characteristics of patients with positivity for antiphospholipid antibodies (aPLs) who were enrolled in an international registry, the Antiphospholipid Syndrome (APS) Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository, overall and by clinical and laboratory subtypes. The APS ACTION registry includes adults who persistently had positivity for aPLs. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS only, obstetric APS only, and both thrombotic APS/obstetric APS). We assessed baseline characteristics of patients tested for the presence of three aPLs (lupus anticoagulant [LAC] test, anticardiolipin antibody [aCL], and anti-β2 -glycoprotein I [anti-β2 GPI]) antibodies by aPL profiles (LAC only, single, double, and triple aPL positivity). The 804 aPL-positive patients assessed in the present study had a mean age of 45 ± 13 years, were 74% female, and 68% White; additionally, 36% had other systemic autoimmune diseases. Of these 804 aPL-positive patients, 80% were classified as having APS (with 55% having thrombotic APS, 9% obstetric APS, and 15% thrombotic APS/obstetric APS). In the overall cohort, 71% had vascular thrombosis, 50% with a history of pregnancy had obstetric morbidity, and 56% had experienced at least one non-criteria manifestation. Among those with three aPLs tested (n=660), 42% were triple aPL-positive. While single-, double-, and triple aPL-positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup, which consisted of aCLs or anti-β2 GPI only. Our study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter international cohort. Within single aPL positivity, LAC may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification.