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ACR, EULAR Roll Out Updated Antiphospholipid Syndrome Criteria

Richard Mark Kirkner

November 22, 2022

PHILADELPHIA — A draft update of criteria for classifying antiphospholipid syndrome (APS) incorporates a much broader
spectrum of disease signs and symptoms, such as kidney disease and more variables for pregnancy, and meets a higher level
of specificity than the existing Sapporo criteria, although at the expense of lower sensitivity.

Members of the ACR/EULAR core planning group, (left to right) Dr Doruk Erkan, Dr Medha Barbhaiya, and Dr Stéphane Zuily,
presented updated APS criteria at ACR 2022.

Three members of the core planning group that wrote the update, jointly commissioned by the American College of
Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR), reviewed the proposed criteria at
the annual meeting of the ACR.

If ACR and EULAR adopt the new criteria, it would be an update to the Sapporo classification criteria for APS, which was last
updated in 2006. The pending criteria consist of the following eight domains encompassing clinical findings and laboratory test
results:

Macrovascular — venous thromboembolism (VTE) with and without high VTE risk profile.

Macrovascular — arterial thrombosis with and without a high cardiovascular disease risk profile.

Microvascular — additional categories for kidney disease, pulmonary embolism, and other conditions for both suspected
and established APS.

Obstetric — expanded definitions to account for the absence or presence of preeclampsia or premature birth with or
without fetal death.

Cardiac valve — accounts for thickening and vegetation.

Hematologic — includes thrombocytopenia (defined as the lowest platelet count, 20-130 x 109/L).

Antiphospholipid (aPL) test — coagulation-based functional assay, assigning greater weight to persistent over one-time
positive test results.

aPL test by solid-phase assay — includes anticardiolipin enzyme-linked immunosorbent assay (aCL ELISA), and
aCL/anti-beta 2 glycoprotein-I (aCL/anti-beta 2 GPI) tests, with greater weight assigned for moderate-to-high positive
results depending on isotype, whether immunoglobulin G or M.

Changes From Sapporo Criteria

The existing Sapporo criteria include two clinical categories, vascular thrombosis and pregnancy morbidity; and three laboratory
categories, positive lupus anticoagulant, medium or high antibody titers, and high aCL/anti-beta 2 GPI measured by ELISA. All
of these are included in the draft criteria under two domains.

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"These novel clinical features will help us better stratify patients according to the risk factor profile," Stéphane Zuily, MD, PhD, a
vascular specialist and European co-principal investigator of the planning group, said in explaining the proposed updated
domains.

"We well-defined the microvascular domain items further than the aPL nephropathy; we redefined pregnancy morbidities; we
added cardiac valve disease and thrombocytopenia; and, through gathering novel laboratory features, we were able to quantify
single, double, and triple aPL positivity based on different domains and weights," said Zuily, professor of medicine at Lorraine
University in Nancy, France.

Also noteworthy is the separation of aCL/anti-beta 2 GPI testing by IgG and IgM isotypes. "And we were also able to identify
different thresholds in terms of aPL positivity," Zuily said.

Rationale and Methodology

Planning group member Medha Barbhaiya, MD, MPH, an attending physician at the Hospital for Special Surgery and assistant
professor at Weill Cornell Medicine in New York, explained the rationale for the update. "The existing criteria were drafted in
1999 and updated in 2006 and require one clinical criterion, either vascular thrombosis event or pregnancy morbidity along with
antiphospholipid antibodies," she said.

Those 16-year-old criteria also ignored heterogeneous manifestations such as heart valve disease or thrombocytopenia, failed
to stratify thrombotic events as risk factors, and used an outdated definition of pregnancy morbidity related to APS, she said.

"These findings helped to support our rationale for new criteria development, along with the fact that over the last 1 to 2 decades
there have been important advancements in the methodology of classification criteria development," she said. ACR and EULAR
both endorsed the new methodology for developing the classification criteria, Barbhaiya added.

That methodology involved multidisciplinary international panels of experts and data-driven efforts, with the goal of identifying
patients with a high likelihood of APS for research purposes. The planning group collected 568 cases from 29 international
centers, dividing them into two validation cohorts of 284 cases each.

How Classification Criteria Work

Doruk Erkan, MD, MPH, coprincipal investigator representing the United States on the planning group, an attending physician at
the Hospital for Special Surgery in New York, and a professor at Weill Cornell Medicine in New York, explained how the
classification system works. "If you have a patient that you are considering for APS classification, the story starts with entry
criteria, which are one documented clinical criterion plus a positive aPL [antiphospholipid] test within 3 years of observation of
the clinical criteria," he said.

Once the entry criteria for APS are met, there are the clinical and laboratory domains. Erkan explained that weighted point
values are assigned to individual categories under each domain. For example, in the macrovascular VTE domain, VTE with a
high VTE risk profile is worth 1 point, but VTE without a high VTE risk profile is worth 3 points.

"APS classification will be achieved with at least three points from clinical domains and at least three points from the laboratory
domains," he said.

The planning group conducted a sensitivity and specificity analysis of the draft classification system using the two validation
cohorts. "Our goal was very high specificity to improve the homogeneity in APS research, and we achieved this in both cohorts
with 99% specificity," Erkan said. That compares to sensitivity of 91% and 86% of the Sapporo criteria in the validation cohorts.

"Our sensitivity was 83% and 84% capturing a broad spectrum of patients assessed with APS suspicion," he added, vs. 100%
and 99% with the Sapporo criteria.

These criteria are not absolute and are structured to permit future modifications, Erkan said. "When this work is completed,
another chapter will start," he said. "If a case doesn't meet APS classification criteria, the case may still be uncertain or
equivocal rather than not APS. Uncertain or controversial cases should be studied separately to guide future updates of the new
criteria."

Comment: Why These Updates Are Needed

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Dr April Jorge

April Jorge, MD, a rheumatologist at Massachusetts General Hospital in Boston and moderator of the session on the draft APS
criteria, explained why these updated criteria are needed. "It's very important to get the updated criteria because, as the
speakers mentioned, the prior Sapporo criteria were limited to just large-vessel venous thrombosis or pregnancy complications,
and so that makes it difficult to study the disease in other manifestations, such as kidney manifestations, if they're not part of the
criteria."

She added, "I think there was a need for clear classification criteria that was thought to be highly specific for the disease so that
future studies can be done in this population."

Jorge called the 99% specificity described in the analysis "impressive" and "promising."

Barbhaiya and Zuily have no relevant disclosures. Erkan disclosed relationships with Aurinia, Eli Lilly, Exagen, and
GlaxoSmithKline. Jorge has no relevant disclosures.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

Credit:

Lead image: iStock/Getty Images

Image 1: Richard Mark Kirkner/MDedge News

Image 2: Harvard Medical School

© 2022  Frontline Medical Communications Inc.

Cite this: ACR, EULAR Roll Out Updated Antiphospholipid Syndrome Criteria - Medscape - Nov 22, 2022.

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