Antiphospholipid antibody syndrome (APS) is characterized by the presence of thrombosis and obstetric pathology.
ObjectiveTo analyze the diagnostic validity of the APS classification criteria published in 2023 by the American College of Rheumatology (ACR) together with the European Alliance of Associations for Rheumatology (EULAR) and to compare them with the 2006 Sydney criteria in pregnant women with suspected APS.
Material and methodsRetrospective observational cohort study based on the follow-up of 754 pregnancies by the Autoimmune Diseases Unit of the Miguel Servet University Hospital in Zaragoza. The diagnosis of its specialist doctors was considered to be gold-standard. Sensitivity, specificity, positive and negative predictive values, and area under the curve (AUC) were calculated for the Sydney and ACR/ELAR criteria, with a value of P < .05.
ResultsThe 2023 ACR/EULAR classification criteria had a sensitivity of 17.47% (AUC 0.583) compared to 74.70% (AUC 0.871) for the Sydney criteria.
DiscussionThe new ACR/EULAR 2023 criteria are more complex due to the incorporation of new evidence in antiphospholipid syndrome; However, in terms of results, we found a clearly lower sensitivity in the new criteria in agreement with the findings of other studies.
ConclusionsThe diagnosis of APS continues to be a challenge, due to its multifactorial nature, high prevalence of thrombosis and pregnancy morbidity in the population, broad range of antiphospholipid antibody and the absence of a gold-standard. The results of our study suggest a worse diagnostic performance of the ACR/EULAR criteria compared to the Sydney criteria for the classification of obstetric APS, so further studies are needed to confirm these findings.
El síndrome antifosfolipídico (SAF) se caracteriza por la presencia de trombosis y patología obstétrica. Para su clasificación, se precisa cumplir criterios clínicos y serológicos, no siempre presentes en todos los pacientes.
ObjetivosAnalizar la validez diagnóstica de los criterios clasificatorios de SAF publicados en 2023 por la American College of Rheumatology (ACR) junto a la European Alliance of Associations for Rheumatology (EULAR) y comparar con los criterios de Sídney de 2006 en gestantes de nuestra unidad con sospecha de SAF.
Material y métodosEstudio observacional retrospectivo de cohortes basado en el seguimiento de 754 gestaciones por la Unidad de Enfermedades Autoinmunes del Servicio de Medicina Interna del Hospital Universitario Miguel Servet de Zaragoza, desde enero de 2007 hasta diciembre de 2022. Se recogieron variables demográficas, inmunológicas y obstétricas de cada gestación. Se consideró como gold-standard el diagnóstico de sus médicos especialistas. Se calculó la sensibilidad, la especificidad, loas valores predictivos positivo y negativo y el área bajo la curva (AUC), para los criterios de Sídney y ACR/EULAR, considerando significativo un valor de P < ,05.
ResultadosLos criterios de clasificación ACR/EULAR de 2023 presentaron una sensibilidad del 17,47% (AUC 0,583), frente a un 74,70% (AUC 0,871) de los criterios de Sídney.
DiscusiónLos nuevos criterios ACR/EULAR 2023 son más complejos, por la incorporación de nuevas evidencias en el síndrome antifosfolipídico; sin embargo, en cuanto a resultados encontramos una sensibilidad claramente inferior en los nuevos criterios, en concordancia con los hallazgos de otros estudios.
ConclusionesEl diagnóstico del SAF continúa siendo un desafío, debido a su naturaleza multifactorial, alta prevalencia de trombosis y morbilidad obstétrica en la población, heterogeneidad de los AAF y ausencia de un gold standard. Los resultados de nuestro estudio sugieren un peor rendimiento diagnóstico de los criterios ACR/EULAR comparados con los criterios de Sídney para la clasificación de SAF obstétrico, por lo que son necesarios más estudios para confirmar estos hallazgos.
Antiphospholipid syndrome (APS) is considered the most common autoimmune acquired thrombophilia, and mainly affects women of childbearing age. It is characterized by the appearance of recurrent thrombosis and obstetric morbidity.
Complications of obstetric APS consist in early pregnancy losses, which are the most frequent complication, and are observed in the majority of women with obstetric APS (approximately 54%) included in the European Registry on Obstetric Antiphospholipid Syndrome[1]. Other later complications include preeclampsia, placental insufficiency, and even fetal death as a consequence of placental dysfunction. With proper management, more than 70% of pregnant women with APS will achieve a successful pregnancy [2].
APS can be primary or associated with another underlying autoimmune disease, mainly systemic lupus erythematosus (SLE), where it appears in up to 30%–40% of these patients.
The first description of the disease dates back to the 80s as a syndrome associated with SLE due to the presence of antiphospholipid antibodies (APA). The first classification criteria, known as the Sapporo criteria, were not established until 1999. In 2006, after the discovery of new APAs, the Sydney criteria were proposed [3], based on 2 fundamental aspects: clinical and analytical, with the existence of at least one of the criteria from each group being mandatory for the definitive diagnosis of APS. They include the anti-β2-glycoprotein I (anti-β2-GPI) as diagnostic of the disease and in the obstetric setting with the addition of preeclampsia, eclampsia and placental insufficiency [3,4].
Clinical criteria include 2 sections, vascular thrombosis and obstetric morbidity, and on the other hand, laboratory criteria, shown in Table 1.
2006 Sydney Classification Criteria for antiphospholipid syndrome.
| 2006 Sydney Classification Criteria for APS |
|---|
| Clinical criteria |
| 1. Vascular thrombosis: one or more episodes of arterial, venous, or small vessel thrombosis |
| 2. Pregnancy-associated morbidity: |
| a. One or more idiopathic deaths of a morphologically normal fetus of 10 or more weeks of gestation |
| b. One or more preterm deliveries of a morphologically normal neonate before the 34th week of gestation due to eclampsia or preeclampsia, or recognizable features of placental insufficiency |
| c. Three or more consecutive spontaneous abortions before the 10th week of gestation, without alterations in maternal uterine anatomy or hormonal changes, excluding chromosomal abnormalities of the progenitors |
| Laboratory criteria |
| 1. Presence of lupus anticoagulant (LA) in blood, on 2 or more occasions at least 12 weeks apart |
| 2. Anticardiolipin antibodies (aCL) of IgG and/or IgM isotype in blood, present in medium or high titers, on 2 occasions at least 12 weeks apart |
| 3. Anti-β2-glycoprotein I (anti-β2-GPI) antibodies of IgG and/or IgM class in blood, present on 2 occasions at least 12 weeks apart |
APS: Antiphospholipid syndrome.
As for the best characterized APAs, we find 3 types: anticardiolipin antibodies (IgG or IgM), anti-β2-GPI IgG or IgM, and lupus anticoagulant (LA). These antibodies must appear positive in 2 determinations, 12 weeks apart, in order to have diagnostic value [4]. Other antibodies, which are not part of the classification criteria for APS, are also known: antiprothrombin, antiphosphatidylserine and antiphosphatidylethanolamine, among others [3,4].
Sometimes, APA positivity may be found during the evaluation of another SAD, early pregnancy loss, a prolonged activated partial thromboplastin time, or a false-positive result in a syphilis test, without compatible clinical symptoms, which conditions the diagnosis to the professional judgment of the clinician who evaluates it [5].
Not only are there manifestations derived from the prothrombotic state, but we also find other non-criteria manifestations [6].
Regarding the classification of patients with suspected APS, we differentiate 3 main groups: Seropositive APS with compatible clinical features, seronegative APS with compatible clinical features, non-criteria APS, which are those who do not meet classification criteria, but possess clinical/serological features, distinguishing 3 subgroups: subgroup A (suggestive clinical manifestations and inconclusive serology), subgroup B (classificatory clinical manifestations with inconclusive serology) and subgroup C (inconclusive clinical manifestations, positive serology) [7].
Given the need for classification criteria that include the heterogeneity of the clinical spectrum of APS, two entities, such as the ACR and the EULAR, have developed new criteria using a rigorous scientific method. The methodology consisted, firstly, of generating a pool of items by reviewing the literature and evidence to date; secondly, they reduced these items, selecting those with high sensitivity, specificity, reliability and feasibility, then they ordered them into domains (6 clinical criteria and 2 laboratory criteria), and finally they were validated [8] (Appendix Bannex 1 of the supplementary material. ACR/EULAR criteria).
They establish as entry criteria the presence of one or more documented clinical criteria and at least one positive APA test. Subsequently, they establish 2 domains, the clinical and the laboratory domains, in which they assign a series of scores based on their relevance. It is important to point out that any manifestation that can be explained by another underlying disease will not be considered as positive.
A condition is classified as APS for research purposes, if at least 3 or more points of clinical domains and 3 or more points of laboratory domains are met. In addition, risk stratification for macrovascular and microvascular events, pregnancy morbidity, and thrombocytopenia is assessed.
In the laboratory aspect, antibody titers are quantified and the subtypes are differentiated, obtaining 2 levels (moderate and high) [8].
Regarding the clinical domain, we find 6 subsections: venous thromboembolism and arterial thrombosis (Appendix Bannex 1-D1,2 of the supplementary material and Appendix Bannex 2 of the supplementary material); microvascular involvement (Appendix Bannex 1-D3 of the supplementary material); obstetric involvement (Appendix Bannex 1-D4 of the supplementary material); heart valve disease (Appendix Bannex 1-D5 of the supplementary material); hematological involvement (Appendix Bannex 1-D6 of the supplementary material).
With respect to the laboratory domain, it distinguishes and weights the positivity for a single, 2 or 3 APAs. We find 2 sub-sections: LA positive in one determination or persistent and, on the other hand, positive anticardiolipin (aCL)/anti-β2-GPI, separating the IgG and IgM isotypes and according to high or moderate titer of one or both, giving them different levels of risk (Appendix Bannex 1-D7,8 of the supplementary material).
Objectives- •
To assess the ability of the new classification criteria developed by ACR/EULAR for the diagnosis of antiphospholipid syndrome.
- •
To compare the APS status of the pregnant women in our unit with the Sydney classification criteria with respect to those of ACR/EULAR.
Retrospective observational historical cohort study, based on the follow-up of 826 pregnancies in the Autoimmune Diseases Unit of the Internal Medicine Service of the Miguel Servet University Hospital in Zaragoza. The follow-up was carried out from January 1, 2007 to December 31, 2022. The study was authorized by the Ethics and Clinical Research Committee of Aragon.
Inclusion criteriaPregnant women with clinical features suggestive of SAD or with a positive APA determination (826 pregnancies).
Exclusion criteriaDifficulty or impossibility to follow-up by the unit, incomplete data or pending results; with a final study population of 754 pregnancies.
The variables studied are collected during the face-to-face visit with the patient or through her electronic medical record (EMR).
Variables studiedDeliveries, abortions, previous thrombosis, gestational age at delivery, fetal status at birth, antiphospholipid antibodies (LA, aCL, anti-β2-GPI); preeclampsia, eclampsia or HELLP syndrome during pregnancy.
Outcome variablesThe Sydney 2006 and the ACR/EULAR 2023 classification criteria.
Statistical analysisQuantitative variables were described by frequency, mean, standard deviation, minimum and maximum values; and qualitative variables were described by percentages.
Sensitivity (S), specificity (E), positive and negative predictive value (PPV and NPV) were used for the evaluation techniques of the diagnostic tests; ROC curves were used to compare the validity of diagnostic tests. Significant differences were considered with P < .05.
Microsoft Access® 2007, from Microsoft Redmond, Washington, USA, was used for data collection. The SPSS® Statistics for Windows, v.25.0. data editor IBM Corp, Armonk, NY, USA was used for their analysis.
ResultsRegarding the sociodemographic characteristics of the study population, the mean age of the pregnant women was 35.16 ± 4.95 years, with an average duration of pregnancy of 34.06 ± 10.89 weeks (mean ± standard deviation).
In the clinical classification we will be able to differentiate pregnancies according to their APA profile, establishing 6 categories, as can be seen in Table 2.
Antiphospholipid status of the pregnant women.
| Description | Frequency | Percentage | |
|---|---|---|---|
| APA+ | Pregnant women with positive APAs without clinical manifestations of APS | 153 | 20.3 |
| NEGATIVE | Negative APA pregnant women without clinical manifestations | 176 | 23.34 |
| SNAPS | Seronegative APS (clinical manifestations suggestive of APS, APA-negative) | 63 | 8.35 |
| OAPS | Obstetric APS (obstetric clinical manifestations and meets APA criteria) | 122 | 16.2 |
| OMAPS | APS-associated obstetric morbidity (obstetric clinical findings and APA that does not meet criteria) | 196 | 26.0 |
| TAPS | Thrombotic APS (Positive APAs with thrombotic clinical manifestations) | 44 | 5.8 |
| Total | 754 | 100 |
APA: antiphospholipid antibodies; APS: antiphospholipid syndrome.
As for the serological status of the pregnant women, LA was positive (278 cases, 36.87%), and anticardiolipin antibodies (aCL) were positive: IgG 183 cases, 24.27% and IgM 116 cases, 15.38%, and in a smaller percentage anti-β2-GPI antibodies: IgG 66 cases, 8.75% and IgM 38 cases, 5.04%.
84.62% (638 cases) of the pregnancies ended with a live newborn, however, obstetric manifestations were recorded: abortion rate 11.01% (83 cases), fetal loss between weeks 10th and 22nd of gestation 14 cases (1.86%), 2 ectopic pregnancies, a voluntary interruption of pregnancy and a stillbirth. The most frequent gestational vascular complication was intrauterine growth retardation (IUGR) with 12% and preeclampsia with 7%.
According to the Sydney criteria, we identified 2 groups that meet the criteria: clinical APS 278 cases (36.87%) and analytical APS 263 cases (34.88%). On the other hand, 476 and 491 that do not meet the criteria (63.13 and 65.12%, respectively), for a total of 127 cases of positive APS.
Regarding the ACR/EULAR criteria, a total of 486 pregnancies without related clinical manifestations were clinically ruled out, and a total of 82 cases were obtained according to the ACR/EULAR criteria (Fig. 1).
From the analytical point of view, we obtained a total of 245 cases with a score higher than 3 points (Fig. 2).
Therefore, 34 positive cases were recorded based on clinical and analytical criteria.
The APS classification, as determined by the specialist doctors responsible for the follow-up of the pregnant women, was considered as the gold standard.
The corresponding 2 × 2 tables were then created to compare the validity of both criteria (Tables 3 and 4).
In the following comparative table (Table 5) it can be seen that the sensitivity of the ACR/EULAR 2023 criteria was 17.47% compared to 74.70% in the Sydney 2006 criteria. In the field of specificity, both criteria are very specific, and in terms of PPV and NPV, superior results are observed in the Sydney criteria.
Comparison of parameters and validity of Sydney 2006 and 2023 ACR/EULAR criteria vs. Gold Standard (specialists).
| ACR/EULAR 2023 | Sydney 2006 | |
|---|---|---|
| S | 17.47% | 74.70% |
| 95% CI: 12.02%−24.12% | 95% CI: 67.38%−81.12% | |
| E | 99.15% | 99.49% |
| 95% CI: 98.03%−99.72% | 95% CI: 98.52%−99.89% | |
| PPV | 85.29% | 97.64% |
| 95% CI: 68.94%−95.05% | 95% CI: 93.25%−99.51% | |
| NPV | 80.97% | 93.30% |
| 95% CI: 77.91%–83.78% | 95% CI: 91,05%–95,13% |
E: specificity; S: sensitivity; NPV: negative predictive value; PPV: positive predictive value.
In the ROC curve graph (Fig. 3), an area under the curve of 0.871 (95% CI: 0.831−0.911) was determined in the case of the Sydney criteria and of 0.583 (95% CI: 0.530−0.636) in the ACR/EULAR criteria.
Discussion
The purpose of this study was to apply the new ACR/EULAR 2023 classification criteria for APS in our sample of pregnant women with suspected APS, categorized according to their serological profile, and to compare the validity of the new criteria against those used up to this point [3,9,10].
While the diagnostic criteria are based on clinical findings and complementary tests to guide risk-based treatment approach, classification criteria aim to establish a more homogeneous group for research purposes [11].
The new 2023 ACR/EULAR criteria add complexity due to the incorporation of new evidence in APS [12], however, our study indicates a clearly lower sensitivity in the new criteria, in line with the findings in an Asian cohort [13], which suggests that these criteria have less validity compared to the Sydney criteria.
The diagnosis of APS) continues to be a great challenge due to its multifactorial nature, the high prevalence of thrombosis and obstetric morbidity in the population, and the heterogeneity of the APAs. It should be noted that the new criteria give less weight to IgM antibodies. Regarding the thrombotic risk of aCL and anti-β2-GPI IgM antibodies, compared to IgG antibodies, according to literature reviews, the IgG isotype was most significantly correlated with thrombotic events [14] and IgM positivity was associated with obstetric morbidity [15], which may explain the performance disparity in the tests, and therefore, the fact that it affects the classification of obstetric APS. The absence of a gold standard to effectively evaluate new tools for its diagnosis [8,12]. The presence of obstetric symptoms or APA positivity was common in our sample; however, we only obtained a total of 34 ACR/EULAR positive cases. The classification criteria can guide the assessment of positive APA, in order to avoid overdiagnosis.
Regarding the limitations of the study, it is a single-center, retrospective study of the historical cohort type. Furthermore, since there is no gold standard for the diagnosis of obstetric APS, the diagnostic impression of the specialist physicians of the SAD unit of the internal medicine service was used.
We consider that these criteria should be reviewed in greater depth through comparative studies, especially at the obstetric level, since aspects that are classificatory according to the Sydney criteria (three consecutive miscarriages and fetal loss), in those of ACR/EULAR, other manifestations are required to meet the clinical criteria. This means that a large group of pregnant women do not meet classification criteria and their therapeutic management may be different.
Therefore, the new criteria should be open to further refinement as experience is gained with their use and more is learned about the underlying biology of this disease, which would encourage the development of new diagnostic and therapeutic tools [10].
Conclusions- 1
The diagnosis of APS is a complex process given the heterogeneity of the disease, both clinical and serological, which makes it difficult, unlike the classification that aims to homogenize patients with APS for research.
- 2
The 2023 APS classification criteria proposed by the ACR/EULAR
- 3
have shown lower diagnostic validity results in our sample, highlighting a lower sensitivity compared to the Sydney 2006 criteria, which is consistent with other studies.
- 4
The gold standard in terms of diagnosis and treatment is the expert's opinion, so the risk-benefit of starting treatment should be assessed, since it has been seen that women who do not meet the classification criteria for APS also benefit from its treatment.
- •
Laura Vela Valle: Methodology, writing and revision of the work.
- •
Jorge Perbech Larraz: Database, data analysis, graphs and tables.
- •
Margarita Míriam Lesta Colmenero: Literature review.
- •
María Patricia Solana Hidalgo: Writing of the results.
- •
Borja del Carmelo Gracia Tello: Methodology (study design)).
- •
Mercedes Pilar Pérez Conesa and Luis Sáez Comet: Conceptualization of the work (objectives and hypotheses).
Patients whose data belong to the database had previously signed an informed consent given in the UEAS consultations of the HUMS (Appendix Bannex 1 of supplementary material).
The researcher has not had access to data that could identify the patients, but worked from a database with previously anonymized patients.
Since this is an observational and retrospective study, the pharmacological treatment of the patients has not been influenced in any way.
In addition, the project has the approval of the Clinical Research Ethics Committee of Aragon (CEICA) (Appendix Bannex 2 of the supplementary material), which considered that the study was carried out in accordance with the requirements of Royal Decree 957/2020 of 3 November, which regulates observational studies with medicinal products for human use; and that the suitability requirements were met; as well as that the use of the data is appropriate because it has permission and the appropriate means for its use; issuing a favorable opinion in favor of the study.
Declaration of Generative AI and AI-assisted technologies in the writing processNo artificial intelligence has been used in the study.
FundingThere was no funding of any kind, either public or private, for the study.
The authors of the article declare that they do not have any conflict of interest that could influence the objectivity of the work.
The following is Supplementary data to this article:
