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J-C. Gris et al.
was not the one currently perceived as being the most thrombogenic (i.e., aβ2GP1-G). Chronic cell activation, engagement of cell signaling pathways, modulation of cell autophagy and apoptosis, and induction of an uncon- trolled inflammatory cascade are new hypotheses regard- ing aPL antibody-related pathogenesis, which may play a role in this association.17,26 There is increasing evidence to suggest that patients with systemic lupus erythematosus have a slightly higher overall risk of malignancy but the underlying mechanisms remain speculative.27 Finally, cur- rently unidentified factors, more frequently present in patients with autoimmune diseases, may be the real cul- prits, for example DNA-damaging autoantibodies,28 as well as key inflammatory chemokines and cytokines.29
Our study has various limitations. The first drawback of this study is that it was performed in a single center. Multicenter replication studies should be carried out to confirm its results. Second, the investigators were not
Table 3. Hazard ratios for an incident cancer according to the type of antiphospholipid antibody present at inclusion.
aHR* 95%CI P
Table 4. Analysis of incident cancers according to exposure to antiphos- pholipid antibodies during the follow-up.
aOR* 95%CI P
Age at inclusion, per year 1.28
ELA 1.08 EaCL-G 1.01
EaCL-M 1.04 Eaβ2GP1-G 0.99
Eaβ2GP1-M 1.00
1.14-1.43
1.02-1.13
<0.0001
0.0061
Figure 2. Cancer-free survival in the three groups of women in the NOH-APS study. APS: antiphos- pholipid syndrome.
0.96-1.06 0.79
0.98-1.10 0.22
0.93-1.04 0.59
0.95-1.05 0.94
For a given antiphospholipid antibody, exposure (E) is defined as the sum of all the annual positivities throughout the duration of the follow-up. aOR: adjusted odds ratio; 95% CI: 95% confidence interval; aβ2GP1-G: anti-β2GP1 IgG isotype; aβ2GP1-M: anti- β2GP1 IgM isotype; ELA: exposure to lupus anticoagulant; EaCL-G: anticardiolipin IgG isotype; EaCL-M: anticardiolipin IgM isotype; Eaβ2GP1-G: anti-β2GP1 IgG isotype; Eaβ2GP1-M: anti- β2GP1 IgM isotype. *For each of the five E parameters: adjustment on the four others, and on age at inclusion.
Table 5. Analysis of incident cancers according to intensity of exposure to antiphospholipid antibodies during the follow-up.
aOR* 95%CI P
Age at inclusion, per year 1.28
IELA 1.04 IEaCL-G 0.99
IEaCL-M 1.03 IEaβ2GP1-G 0.99 IEaβ2GP1-M 1.01
1.14-1.43
1.01-1.07
0.98-1.01 0.57
<0.0001
0.0059
Age at inclusion, per year 1.29
Positive aPL antibody:
LA 2.61 aCL-G 0.99 aCL-M 1.17 aβ2GP1-G 0.67 aβ2GP1-M 0.85
1.15-1.45
1.09-6.24 0.44-2.19 0.46-2.95 0.26-1.75 0.38-1.94
<0.0001
0.0312 0.97 0.75 0.41 0.70
1.01-1.07
0.0288
0.96-1.01 0.23
0.97-1.06 0.59
aHR: adjusted hazard ratio; 95% CI: 95% confidence interval; aPL antiphospholipid; LA: lupus anticoagulant; aCL-G: anticardiolipin IgG isotype; aCL-M: anticardiolipin IgM iso- type; aβ2GP1-G: anti-β2GP1 IgG isotype; aβ2GP1-M: anti-β2GP1 IgM isotype. *For each of the five aPL antibodies, adjustment on the four others, and for age at inclusion.
Foragivenantiphospholipidantibody,theintensityofexposure(IE)isdefinedasthe sum of all the antibody titers of annual positivities throughout the duration of the fol- low-up. aOR: adjusted odds ratio; 95% CI: 95% confidence interval; IELA: intensity of exposure to lupus anticoagulant; IEaCL-G: intensiy of exposure to anticardiolipin IgG iso- type; IEaCL-M: intensity of exposure to anticardiolipin IgM isotype; IEaβ2GP1-G: intensity of exposure to anti-β2GP1 IgG isotype; IEaβ2GP1-M: intensity of exposure to anti-β2GP1 IgM isotype.*For each of the five IE:adjustment on the four others,and on age at inclusion.
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haematologica | 2020; 105(2)