Table 4.

Adjunctive treatment.

Pathophysiology	Evidence for clinical use
Vitamin D
Protect against thrombosis through: -Inhibition of angiogenic factors in endothelial cells -Immunomodulatory effects on inflammatory activity so reducing endothelial damage -Inhibition of tissue factor expression and TLR-4 inhibition which blocks the signalling pathway of adapter protein MyDD88 in inflammatory cells, preventing synthesis of type 1 interferons	-APS patients reported to have significantly lower vitamin D levels compared to normal controls -The thrombotic APS patients had a significantly lower levels of vitamin D than those with obstetric APS -Vitamin D deficiency identified in 50% of APS cohort compared with 30% in controls -Thrombosis was noted in 77% of primary APS patients with vitamin D deficiency compared with 53% in those without vitamin D deficiency
Hydroxychloroquinea
HCQ has immunomodulatory and antithrombotic effects mediated through: -Inhibition of platelet aggregation by preventing the over expression of GPIIbIIIa on the membrane of aPL activated platelets -It may also reduce binding of β2GP1 to the phospholipid bilayer of the target cell	-A systematic review found thrombotic events were prevented if antimalarials were taken consistently -A prospective, non-randomised study of 40 primary on HCQ + standard-intensity warfarin vs. VKA alone showed no recurrent thrombotic event in the HCQ cohort vs. 6 in those not receiving HCQ over 3 years
Statins
Fluvastatin and simvastatin can prevent aβ2GP1-antibodies inducing endothelial cell adhesive properties via NF-κB binding to DNA which plays a central role in inflammation	Elevated levels of VEGF, soluble TF and TNF-α were identified in APS patients and that fluvastatin was able to significantly reduce those markers in the majority of treated patients

Abbreviations: APS, antiphospholipid syndrome; β2GP1, βeta-2 glycoprotein-1; GPIIbIIIa, glycoprotein IIaIIIb; HCQ, hydroxychloroquine; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TF, tissue factor; TLR, toll-like receptor; MyDD88, differentiation primary response gene 88; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor; VKA, vitamin K antagonist(s).

For further details, see refs: [[94], [95], [96], [97], [98], [99], [100], [101], [102], [103]]

^aHydroxychloroquine is standard treatment in patients with SLE if no contraindications.