We read with great interest the article by Otomo et al, which provided a formula for improved risk assessment in patients with APS by determining the aPL-S (1). Their addition of assays to detect IgG/IgM phosphatidylserine (PS)–dependent antiprothrombin antibodies to the recently recommended international aPL classification criteria (2) increased the predictive value of the aPL-S for thrombotic events. Thus, as discussed in the accompanying editorial by Andreoli and Tincani (3), aPL profiling, as opposed to investigating just a single aPL, provides an innovative way of understanding the occurrence of multiple aPL in APS and its implication for the development of the clinical phenotype of APS. We completely concur with Otomo and colleagues for several reasons. Given the poor standardization of single aPL testing (2), new technical approaches to aPL profiling have been reported recently, which elucidate the possibility of aPL profiling for the diagnosis of and outcome prediction in APS (4). In order to ensure the quality of routine laboratory measurements, along with time and cost efficiency, multiplex aPL analysis might represent a solution for these challenges. Line immunoassay (LIA) uses a different solid phase and is an alternative to enzyme-linked immunosorbent assay in the simultaneous assessment of multiple aPL.
To assess the association between multiple aPL specificities and the clinical phenotype of APS, we longitudinally collected 223 serum samples from 45 patients with APS (3 patients with pregnancy morbidity, 32 patients with venous thrombotic events, and 10 patients with arterial thrombosis) over a period of up to 10 years. Serum samples were tested by LIA for various aPL, i.e., IgG and IgM anti-PS, antiphosphatidylinositol (anti-PI), aCL, and anti-β2GPI (5) (Table 1). We found that IgM anti-PI, anti-PS, aCL, and anti-β2GPI were significantly more prevalent in followup samples from APS patients with arterial thrombosis as compared to the remaining APS patients (P < 0.001). In contrast, levels of IgG anti-PS and anti-β2GPI showed a significantly higher prevalence in APS patients with pregnancy morbidity compared to the remaining APS patients (P < 0.001). The prevalence of IgM anti-PS, aCL, and anti-β2GPI was significantly diminished in this group (P < 0.02). The detection of at least 1 IgG aPL by LIA was also significantly more prevalent in the subgroup of APS patients with pregnancy morbidity (P < 0.05), and the prevalence of at least 1 IgM aPL was significantly reduced (P < 0.01). In contrast, APS patients with arterial thrombosis were characterized by a higher co-occurrence of ≥1 IgM aPL along with a higher frequency of multiple aPL overall as compared with other APS patients (P < 0.0001). This indicates a more striking underlying immune response against phospholipid structures or corresponding cofactors in these patients, consistent with the conclusion that activation of the immune system is different in patients who experience arterial thrombosis as a manifestation of APS versus patients who experience venous thrombotic events and pregnancy morbidity.
|APS with arterial thrombosis (n = 57)||APS with venous thrombotic events (n = 146)||APS with pregnancy morbidity (n = 20)|
|IgG||29 (50.9)||77 (52.7)||18 (90.0)|
|IgM||38 (66.7)||38 (26.0)||0 (0.0)|
|IgG||14 (24.6)||26 (17.8)||1 (5.0)|
|IgM||16 (28.1)||2 (1.4)||1 (5.0)|
|IgG||31 (54.4)||86 (58.9)||16 (80.0)|
|IgM||45 (78.9)||67 (45.9)||2 (10.0)|
|IgG||31 (54.4)||75 (51.4)||19 (95.0)|
|IgM||35 (61.4)||62 (42.5)||4 (20.0)|
|Multiple IgG aPL|
|0||23 (40.4)||58 (39.7)||0 (0.0)|
|1||5 (8.8)||8 (5.5)||2 (10.0)|
|2||1 (1.8)||9 (6.2)||3 (15.0)|
|3||14 (24.6)||46 (31.5)||14 (70.0)|
|4||14 (24.6)||25 (17.1)||1 (5.0)|
|Multiple IgM aPL|
|0||9 (15.8)||70 (47.9)||16 (80.0)|
|1||8 (14.0)||21 (14.4)||1 (5.0)|
|2||7 (12.3)||19 (13.0)||3 (15.0)|
|3||20 (35.1)||34 (23.3)||0 (0.0)|
|4||13 (22.8)||2 (1.4)||0 (0.0)|
Thus, apart from risk assessment, detection of multiple aPL may assist in the differentiation of clinical phenotypes in APS patients during the course of disease and may provide additional data together with the risk prediction proposed by Otomo et al. IgM aPL occur more frequently in APS with arterial thrombosis, which suggests that they play a distinct immunopathogenic role in this condition and are a candidate parameter for phenotype stratification. Overall, aPL profiling within certain subsets of APS patients warrants further investigation and holds the promise of further improving patient care.