Survivin Predicts Rheumatoid Arthritis Treatment Response

For the first time, it’s been demonstrated that the proto-oncogene survivin can distinguish drug-specific clinical responses in early rheumatoid arthritis (RA), according to new study in BMC Medicine.

Survivin is a biomarker of cancer and known to be critical for the process of antigen presentation. But how and why it is released by the body isn’t yet known, and until now it hasn’t been studied as a possible predictor of pharmacologic effectiveness in RA — alongside female sex, age, and smoking status. According to the researchers, “Marked individual heterogeneity with respect to specific genetic and environmental load, autoantibody production, and cellular, cytokine and gene expression profiles of the inflamed synovia strongly suggests that a more personalized choice of antirheumatic treatment would yield considerably better results [in RA treatment].”

Methotrexate (MTX) monotherapy is generally first-line treatment, but it can be more effective for some patients when combined with glucocorticoids, other conventional antirheumatic drugs anti-tumor necrosis factor (anti-TNF) agents. For patients who fail initial MTX therapy, several reasonable options are available.

The Swedish pharmacotherapy (SWEFOT) trial was a standard care-based study in which all patients initially received open-label MTX monotherapy followed by randomized treatment with either triple therapy (MTX+ sulfasalazine (SSZ) and hydroxychloroquine (HCQ) or MTX + anti-TNF (in this case, infliximab) in the patients who failed to achieve low disease activity on MTX. The trial showed that anti-TNF was initially clinically superior to TT after 12 months, but the difference between the treatment arms leveled-off after 24 months.

The current study measured serum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, three, 12, and 24 months. Survivin levels > 0.45 ng/mL were considered positive. Based on the survivin status, core set outcomes measuring disease activity, functional disability, as well as global health and pain were evaluated after methotrexate (MTX) monotherapy at three months, as well as at 12 and 24 months of follow-up. Treatment of non-responders was randomly intensified with either a combination of disease-modifying antirheumatic drugs (triple therapy: MTX, sulfasalazine, and hydroxychloroquine) or by adding antibodies against tumor necrosis factor (anti-TNF).

Survivin-positive patients at baseline who initially responded to MTX had a higher risk of disease re-activation (OR 3.21 (95 % CI 1.12—9.24), P = 0.032) and failed to improve in their functional disability (P = 0.018) if having continued on MTX monotherapy compared to survivin-negative patients. Ever-smokers who were survivin-positive were less likely to respond to MTX than those who were survivin-negative (OR 1.91 (1.01—3.62), P = 0.045). In survivin-positive patients, triple therapy led to better improvements in disease activity than did MTX + anti-TNF. At 24 months, survivin-positive patients randomized to anti-TNF had a higher risk of active disease than those randomized to triple therapy (OR 3.15 (1.09—9.10), P = 0.037).

“Our results confirm that patients survivin-positive at baseline can have poor long-term outcomes,” the study authors observed. “Patients who remain positive by three months, despite initially responding by [disease activity score 28] DAS28, are recognized by a risk for later disease reactivation and possess early functional disability that deteriorates even further over 24 months. These findings support the previously reported association between radiographic damage and a considerable gain in HAQ over time despite clinical remission.”