Background/Purpose: In SLE, homocysteine has been shown to be a potentially modifiable, independent risk factor for stroke and thrombotic events. All previous epidemiological studies used total plasma homocysteine as a disease marker, but it remains unclear whether plasma or intracellular homocysteine is causing detrimental effects. Folic acid (0.5 mg/day) supplementation does lower homocysteine in plasma as expected, but homocysteine and all its metabolites in white bloods cells remain unaffected (1). We hypothesized that intracellular homocysteine and homocysteine metabolite levels in patients with SLE are disproportionately elevated compared to the levels seen in healthy subjects and that intracellular homocysteine and homocysteine metabolite levels are independently associated with coronary plaque in SLE.

Methods: A liquid chromatography coupled to tandem mass spectrometry absolute quantification assay was used for the determination of 6 analytes in both plasma and PBMCs: homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), methionine (Met), cystathionine (Cysta), and 5-methyltetrahydrofolate (5m-THF). We then compared intracellular (PBMC) and extracellular (plasma) homocysteine and homocysteine metabolite (SAM, SAH, Met, Cysta, 5m-THF) concentrations in 10 patients who met ACR or SLICC classification criteria for SLE and in 10 age, sex, and ethnicity matched controls. Subjects with a history of diabetes mellitus, cardiovascular disease, hypertension, alcohol consumption in excess of 3 units per day, anemia, renal insufficiency (serum creatinine >1.5mg/dl), and pregnancy were excluded. All SLE patients had two coronary CT angiography (CCTA) studies (follow up mean=3.77 years, SD=0.94 years) as screening for occult coronary atherosclerotic disease in asymptomatic individuals. Fisher’s t-test was used to analyze the differences between homocysteine and homocysteine metabolite levels in SLE and controls. The correlation between metabolite levels and coronary plaque volumes was analyzed using Pearson correlation.

Results: Plasma from SLE patients had higher levels of homocysteine (P< 0.0001), SAH (P< 0.05), SAM (P< 0.001), and lower levels of Met (P< 0.05) and Cysta (P< 0.001) compared to controls. PBMC intracellular concentrations from SLE patients had higher levels of Cysta (p< 0.05), SAH (p< 0.05), SAM (p< 0.001) and lower levels of 5m-THF (p< 0.001). Plasma SAH showed a positive correlation to the total coronary plaque, calcified plaque, and noncalcified plaque measured by CCTA (p< 0.05).

Conclusion: Intracellular concentrations of homocysteine metabolites were significantly different between SLE patients and controls, despite similar intracellular homocysteine levels. Plasma S-adenosylhomocysteine was positively correlated to total coronary plaque, calcified plaque, and noncalcified plaque. Further studies are needed to clarify the importance of intracellular homocysteine metabolites as cardiovascular risk factors in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/intracellular-homocysteine-and-homocysteine-metabolites-in-systemic-lupus-erythematosus-sle/