IgG and IgM Anti-Phosphatidylserine/Prothrombin Complex Antibody Detection May Improve Classification Accuracy of Systemic Lupus Erythematosus and Antiphospholipid Antibody Syndrome

Abstract

Objective: Antiphospholipid antibody (aPL) syndrome (APS) classification requires a thrombotic event and detection of lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), or anti-β₂-glycoprotein I (anti-β₂GPI) antibodies on two occasions ≥12 weeks apart. Here, we investigated the utility of anti-phosphatidylserine/prothrombin complex (anti-PS/PT) aPL in patients with APS with and without concurrent systemic lupus erythematosus (SLE) with the aim to improve disease disease classification and clinical care.

Methods: A total of 1,286 patients were tested for presence of IgA, IgG, and IgM anti-phosphatidylserine/prothrombin complex (anti-PS/PT) antibodies along with IgA, IgM, and IgG anti-β₂GPI and aCL and LAC assays, including hexagonal phase phospholipid neutralization assay (HPPNA), dilute Russell's viper venom time (dRVVT), and platelet neutralization procedures (PNP). Statistical analyses were performed with the chi-square test using Bonferroni correction for multiple comparisons.

Results: A total of 324 patients with SLE, 88 patients with APS, and 54 patients with concurrent SLE and APS had simultaneous testing for IgA, IgG, and IgM anti-PS/PT, aCL, and anti-β₂GPI antibodies and HPPNA, dRVVT, and PNP LAC assays. IgM anti-PS/PT antibody was sensitive for discriminating patients with SLE (P = 0.0024), APS (P < 0.0001), and SLE and APS from those without either diagnosis (P < 0.0001). IgG anti-PS/PT antibody discriminated patients with APS (P < 0.0001) and SLE and APS from those without either diagnosis (P < 0.0001). Among 46 patients with SLE lacking aCL, anti-β₂GPI aPL, LAC, or any clinical manifestation of APS, 35 patients only had IgM anti-PS/PT antibodies, whereas 11 different patients only had IgG anti-PS/PT antibodies.

Conclusion: These results demonstrate a significant utility of IgM and IgG anti-PS/PT antibody testing for more precise classification of SLE and more sensitive diagnosis and timely treatment of patients with relevant thrombotic clinical manifestations.

Figure 1

A 27‐year‐old African American woman with SLE and catastrophic APS involving mitral valve vegetation consistent with Libman‐Sacks endocarditis, right eye vision loss due to right cerebral hemispheric stroke, and class V lupus nephritis. (A) Echocardiogram shows thickened mitral valve leaflets with moderate to severe mitral regurgitation (red arrow). There were definitive regular small mobile echodensities seen on the anterior and posterior leaflet tips consistent with her history of Libman‐Sacks endocarditis. (B) Brain MRI diffusion‐weighted sequences show small areas of increased intensity signal on the trace diffusion‐weighted sequences involving the left to precentral and postcentral gyri. With exception of one focus of true restricted diffusion, the remainder of the cortical‐based findings could represent either a subacute or old ischemic event. (C) Brain MRI following intravenous contrast administration. There is no evidence of abnormal parenchymal or meningeal enhancement. Incidentally seen is a small developmental venous anomaly in the left thalamus. (D) MR angiogram shows patent superior sagittal and straight sinuses, bilateral internal cerebral veins, and right transverse and sigmoid sinuses. The left transverse and sigmoid sinuses are not visualized. This may be due to development of chronic thrombosis. (E) CT scan shows near complete occlusion of the proximal superior division of the left middle cerebral artery, with contrast filling in the branches distal to the occlusion. (F) Renal biopsy shows class V membranous lupus nephritis with focal acute tubular epithelial injury, 5% global glomerulosclerosis (4 of 83 glomeruli in all specimens) and 5% interstitial fibrosis with tubular atrophy. (G) Electron microscopy was consistent with membranous lupus nephritis. (H) Immune fluorescence staining shows capillary granular staining for IgG, IgA, C1q, C3, and κ and λ light chains. APS, antiphospholipid syndrome; CT, computed tomography; MR, magnetic resonance; MRI, magnetic resonance imaging; SLE, systemic lupus erythematosus.

Figure 2

A 60‐year‐old White man with APS characterized by positive 1:80 titer speckled ANA, positive RF level of 174 U/mL, negative anti‐CCP, right‐sided facial droop with numbness and slurred speech, binocular diplopia with persistent headaches and nausea, and a one‐time vomiting episode. Head CT scan showed chronic left vertebral artery occlusion. MRI of the orbits showed right optic perineuritis. CTA of the chest revealed a right‐sided pulmonary embolism, and the patient was started on therapeutic heparin. Hypercoagulable workup was ordered and was unremarkable with a negative aPL panel, except for a positive IgM antiphosphatidylserine level of 50 U/mL. He was discharged and started on rivaroxaban. Three months after discharge, he complained of arthralgia of the shoulders, knees, and ankles, with prolonged morning stiffness. A repeat aPL panel showed a persistently positive IgM antiphosphatidylserine level of 52 U/mL. He was presumed to have APS and was started on hydroxychloroquine 200 mg twice a day and switched from rivaroxaban to warfarin. (A) CTA of the head shows chronic left vertebral artery occlusion. (B) CTA of the head shows chronic left vertebral artery occlusion. (C) MRI of the orbits shows right optic perineuritis. (D and E) CTA of the chest shows a right‐sided pulmonary embolism. ANA, antinuclear antibody; anti‐CCP, anti–cyclic citrullinated peptide; aPL, anti‐phospholipid antibodies; APS, antiphospholipid syndrome; CT, computed tomography; CTA, computed tomography angiogram; MRI, magnetic resonance imaging; RF, rheumatoid factor.

Figure 3

Demyelinating brain disease in a 55‐year‐old White woman. Magnetic resonance imaging of the brain shows scattered white matter lesions.

Figure 4

Venous sinus thrombosis in a 47‐year‐old White woman. Computed tomography angiogram of the head shows dural venous sinus thrombosis in the (A) straight sinus, (B) left transverse sinus, and (C) left sigmoid sinus.