Background Survivin is a known inhibitor of apoptosis and a regulator of cell division. In rheumatoid arthritis (RA), survivin has been shown to be involved in joint destruction. Here, we investigated survivin in early RA patients from the SWEFOT trial who were administered methotrexate (MTX) monotherapy for 3 months. Non-responders (DAS28 at 3 months >3.2) were randomized to triple therapy (MTX + sulfasalazine + hydroxychloroquine, group A) or anti-TNF (infliximab + MTX, group B).
Methods Serum survivin levels were measured using ELISA with samples from 294 patients. Values >0.45 ng/mL were considered positive. Independent Samples t-tests and nonparametric Mann-Whitney U tests were performed where applicable.
Results Out of 294 patients, 112 (38%) were positive for survivin at BL. The survivin (+) patients were more often male (30% vs. 22%, p=0.036) and RF (+) (80% vs. 58%, p<0.001), and had higher mean BL ESR (42.6 vs. 37.5, p=0.018), whereas other parameters of disease activity were similar.
Out of the 112 survivin (+) patients at BL, 37 (33%) converted to (−) by 3 months. These patients had greater improvements in disease activity compared to (+) and significantly greater reductions in tender joint count (TJC) and ESR (8.4 vs. 3.9, 30.9 vs. 19.0, respectively; p<0.050). Out of 182 survivin (−) patients at BL, 14 (8%) converted to (+) and had significantly less DAS28 reduction than those who remained (−) (1.1 vs. 1.7, p=0.043).
Among MTX responders, the (+/−) converters (n=11) had significantly greater reductions in DAS28 and patient's global VAS than those who remained (+) (n=28) (3.5 vs. 2.5, 46.6 vs. 23.2, respectively; p<0.010). Among MTX non-responders, significant reductions were observed among the (+/−) converters (n=26) for TJC, swollen joint count (SJC), and ESR compared to those who remained (+) (n=47) (8.8 vs. 3.3, 9.4 vs. 4.3, 35.4 vs. 22.9, respectively; p<0.05). In comparison to those who remained (−) (n=108), the converters had significantly greater reductions in TJC, SJC, ESR, and CRP (8.8 vs. 4.0, 9.4 vs. 3.9, 32.5 vs. 12.3, 35.4 vs. 13.8, respectively; p<0.010). Converters from (−/+) were few, which precluded analysis.
Likewise, in the MTX non-responders, disease activity was improved more for (+/−) converters in the randomized group, A, compared to those who remained (+) or (−). Among these patients, those whose survivin status converted from (+) to (−) from 3 to 12 months (n=12) had numerically greater improvements, and a significantly greater reduction in patient's global VAS than those who remained (+) (n=15) (17.3 vs. −2.9 [an increase], p=0.024). Converters (+/−) among the randomized group, B (n=7), on the other hand, had numerically worse changes for most parameters compared to those who remained (+) (n=16).
Conclusions Serum survivin is positive in about one third of patients with early RA and correlates with male gender, RF-positivity, and higher ESR. Survivin seroconversion (+/−) upon MTX is not uncommon and is associated with clinical improvements. Survivin conversion from (+/−) led to greater improvements for patients on triple therapy compared to non-converters. This finding was not observed among patients treated with anti-TNF.
Disclosure of Interest : A. Levitsky: None declared, M. Erlandsson: None declared, M. Bokarewa: None declared, R. van Vollenhoven Grant/research support: AbbVie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex
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