Background/Purpose:

Several inducers of angiogenesis have been shown to play a central role in rheumatoid arthritis (RA) pathogenesis: VEGF (Vascular Endothelial Growth Factor), EMMPRIN (Extracellular Matrix Metalloproteinase Inducer), a transmembrane immunoglobulin which stimulates secretion of MMPs (Matrix Metalloproteinases); and NGAL (Neutrophil Gelatinase-Associated Lipocalin), a pro-inflammatory adipokine which binds MMP9 and inhibits its degradation, but which has also anti-inflammatory properties. IL-6 blockade by Tocilizumab (TCZ) , an effective treatment for RA ,may inhibit angiogenesis.

Aim: To explore the effect of TCZ treatment on serum levels of the above pro-angiogenic factors in RA patients compare to healthy controls (HC).

Methods:

Clinical data and blood samples were collected from 40 active RA patients and 40 age and sex-matched HC. Serum levels were analyzed for high sensitivity C-Reactive Protein (hsCRP), VEGF, EMMPRIN, MMP-9 and NGAL by Enzyme-Linked Immunosorbent Assay (ELISA) before initiation of TCZ treatment and 4 months following treatment in the RA group compare to HC. Student’s t-test was used for analysis of EMMPRIN, MMP-9, and NGAL levels and Mann-Whitney Test and Pearson Chi-square Test were used for analysis of VEGF levels. Results were considered statistically significant for p values ≤0.05.

Results:

The majority of the patients responded to TCZ treatment and reduced their disease activity scores (DAS) from DAS28 score of 5.45±1.06 to 3.46±1.37 (p<0.0001).The levels of hsCRP was higher in RA patients than in HC and decreased 4 months after initiation of TCZ treatment (3.37±2.0, 0.74±1.36mg/dl, p<0.001). EMMPRIN levels were higher in RA patients than HC (43.55±10.77ng/ml, 34.44±10.00ng/ml respectively, p<0.0002) and were reduced significantly following initiation of treatment (40.01±8.43ng/ml, p<0.006). VEGF levels were very low, and therefore separated into two groups (equal to 0, above 0 pg/ml) , 15% of RA patients had detectable levels as compared to 41% of HC P<0.01 and it did not change significantly following 4 months of treatment. Interestingly, serum NGAL levels were higher in HC than RA patients (91.78±31.44ng/ml, 73.21±20.80ng/ml, respectively p<0.003), and increased in the RA group following TCZ treatment (85.27±28.9ng/ml, p<0.001). Similarly, MMP-9 levels were higher in the serum of HC than RA patients (119.76±45.49ng/ml, 75.85±47.47ng/ml, respectively, p<0.0001) but were not affected by TCZ (75.89±44.91ng/ml, p<0.84).

Conclusion:

Our results demonstrate that IL-6 pathway blockade using TCZ was effective in reducing the serum level of EMMPRIN in RA patients, implying its clinicopathologic role in the disease pathogenesis . Our results suggest that IL-6 blockade did not affect serum VEGF, NGAL and MMP-9 levels, either because they are active at the joint level and not peripherally, or because NGAL may play an anti-inflammatory role in RA, so that IL-6 blockade increased its levels. Future studies may help elucidate the site of action and mechanism of action of the various pro-angiogenic factors in RA pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tocilizumab-effect-on-serum-angiogenic-factors-in-rheumatoid-arthritis-patients/