Antiphospholipid autoantibody detection is important in all patients with systemic autoimmune diseases

doi:10.1016/j.jaut.2020.102524

Journal of Autoimmunity

Volume 115, December 2020, 102524

https://doi.org/10.1016/j.jaut.2020.102524 Get rights and content

Highlights

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aPL detection characterizes all patients with Systemic Autoimmune Diseases (SADs).
•
aPL profile, clinical and biological manifestations in SADs.
•
In case of multiple positivity, the risk for thrombosis and miscarriage is increased.
•
The critical role of complement consumption is associated with aPL.

Abstract

Antiphospholipid (aPL) autoantibodies are uncommon in systemic autoimmune diseases (SADs). However, the European PRECISESADS study provides the opportunity to better characterize this rare association. The study was composed of 1818 patients with SADs including 453 with systemic lupus erythematosus (SLE), 359 with rheumatoid arthritis (RA), 385 with systemic sclerosis (SSc), 367 with Sjögren's syndrome (SjS), 94 with mixed connective tissue disease (MCTD), and 160 with undifferentiated connective tissue disease (UCTD). Assays used for aPL determination include the lupus anticoagulant (LAC) analysis using the dilute Russell's viper venom time (dRVVT) assay plus anti-cardiolipin (aCL) and anti-aβ2GPI autoantibodies of IgG and IgM isotype. Information regarding clinical and biological characteristics of SAD patients was available. Among SAD patients, the prevalence of aPL differs significantly between two groups: SLE (57.6%) and non-SLE SADs (13.7%, p < 10⁻⁴). Next, association between aPL plus thrombosis and miscarriage were observed in both SLE and non-SLE patients. Thrombosis was best predicted in SLE patients by dRVVT (OR = 6.1; IC95:3.5–10.3) and miscarriage by aCL±β2GPI IgG (OR = 2.5; IC95:1.2–5.2); while in non-SLE SADs the best predictors were aCL±β2GPI IgG for thrombosis (OR = 6.6; IC95:2.4–18.4) and aCL±β2GPI IgM for miscarriage (OR = 2.9; IC95:1.2–6.8). In the case of multiple positivity of aPL, the risk for thrombosis and miscarriage was increased. Central nervous system involvement characterized the SLE patients, in contrast to pulmonary and skin fibrosis, valve lesions, hypertension, elevated creatinemia, C4 fraction reduction, platelet reduction and inflammation that characterized the non-SLE SAD patients. Anti-PL determination remains important in SADs patients and should not be restricted to only SLE patients.

Introduction

Two forms of antiphospholipid syndromes exist, primary antiphospholipid syndrome (APS-I) in half of cases, and secondary APS (APS-II) when associated with another systemic autoimmune disease (SAD) [1]. In both cases, the persistent detection (>12 weeks) of antiphospholipid (aPL) autoantibodies is predominantly associated with arterial/venous thrombosis and/or pregnancy morbidity. The aPL spectrum includes the presence of lupus anticoagulant (LAC) and/or anti-cardiolipin (aCL) autoantibodies in association with anti-β2 glycoprotein-I (aβ2GPI) autoantibodies of IgG and IgM isotypes [2,3]. The main pathogenic target for aPL has been characterized and is located within the N-terminal domain (Domain I) of β2GPI, a PL binding glycoprotein [4].

With an aPL prevalence ranging between 1% and 5% in the general population, the risk of thrombosis and/or pregnancy morbidity (mainly miscarriage) due to aPL remains scarce with 40–50 cases of thrombosis per 100,000 persons corresponding to an incidence of 5 new cases per 100,000 persons per year. Such risk significantly increases in those patients with SADs as observed in aPL positive SLE patients with a risk of thrombosis estimated at 50–70% during 20 years of follow-up [5]. Accordingly, we took advantage of the PRECISESADS study to better characterize the risk factors associated with aPL positivity not only in SLE patients but also in non-SLE SAD patients.

Section snippets

Study design and subjects

A total of 1818 individuals with SADs were included in the observational, European multicentric, PRECISESADS study between 2015 and 2018 (Table 1). The study encompassed 453 patients with systemic lupus erythematosus (SLE), 359 with rheumatoid arthritis (RA), 385 with systemic sclerosis (SSc), 367 with Sjögren's syndrome (SjS), 94 with mixed connective tissue disease (MCTD), and 160 with undifferentiated connective tissue disease (UCTD). Diagnostic criteria used for patient inclusion followed

aCL, aβ2GPI and dRVVT prevalence in systemic autoimmune diseases

In order to estimate the prevalence of aPL in SADs, we took advantage of the PRECISESADS study composed of 592 HCs and 1818 patients with SADs (SLE, RA, SSc, SjS, MCTD and UCTD). Gender and sex-based differences were reported between HC and SADs (Table 1). Regarding the presence of aPL Abs in SADs, a higher prevalence was reported in the SAD group for dRVVT (p < 10⁻⁴), aCL IgG (p < 10⁻⁴), aβ2GPI IgG (p < 10⁻⁴), while this was not significant for aCL and aβ2GPI IgM. For statistical purposes, the

Discussion

In this study, performed with a European multi-center study of 1818 patients with SADs, we observed: (i) that aPL detection characterizes patients with SAD; (ii) that aPL positivity is less frequent in non-SLE SADs such as SjS, RA, SSc, MCTD and UCTD than in SLE (13.7% versus 57.6%); (iii) that dRVVT and aCL ± aβ2GPI IgG Abs perform similarly for association with thrombosis and at medium/high level with miscarriage in SAD, while aCL ± aβ2GPI IgM Abs detection was associated with miscarriage in

Authorship contribution statement

AM, PLM, EB, and YR: Formal analysis and writing original draft; EB, GP, SN, HG: Investigation; MAR, JF: Project administration; and MAR: Funding acquisition.

Funding

This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (PRECISESADS, grant n. 115565) including in-kind contributions from the EFPIA members involved.

Declaration of competing interest

All authors declare that they have no conflict of interest.

Acknowledgements

The work described has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115565, the resources for which are composed of a financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in-kind contribution. We thank all the members of PRECISESADS Consortium and INSERM U1227 for their effort in the sample recruitment,

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¹: Have contributed equally to this work.

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Antiphospholipid autoantibody detection is important in all patients with systemic autoimmune diseases

Highlights

Abstract

Introduction

Section snippets

Study design and subjects

aCL, aβ2GPI and dRVVT prevalence in systemic autoimmune diseases

Discussion

Authorship contribution statement

Funding

Declaration of competing interest

Acknowledgements

Blood Rev.

J. Autoimmun.

J. Thromb. Haemostasis

J. Thromb. Haemostasis

Clin. Immunol.

J. Autoimmun.

Autoimmun. Rev.

Pathology

Blood

J. Thromb. Haemostasis

Blood

Autoimmun. Rev.

Antiphospholipid syndrome

Nat Rev Dis Primers

Pathogenesis of antiphospholipid syndrome: understanding the antibodies

Nat. Rev. Rheumatol.

The epidemiology of antiphospholipid syndrome: a population-based study

Arthritis Rheum.

Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus

Arthritis Rheum.

Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League against Rheumatism collaborative initiative

Ann. Rheum. Dis.

Classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative

Ann. Rheum. Dis.

Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group

Ann. Rheum. Dis.

Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients

J. Rheumatol.

Criteria for the classification of early systemic sclerosis

J. Rheumatol.

Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients

Arthritis Rheum.

The active immunological profile in patients with primary Sjogren's syndrome is restricted to typically encountered autoantibodies

Clin. Exp. Rheumatol.