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Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial.

Levitsky A, Erlandsson MC, van Vollenhoven RF, Bokarewa MI - BMC Med (2015)

Bottom Line: Antirheumatic treatment resulted in an overall decrease of serum survivin levels.A decrease of survivin levels during treatment is associated with better clinical responses.For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy.

View Article: PubMed Central - PubMed

Affiliation: Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), Karolinska Institutet, D1:00, Karolinska University Hospital, 17176, Stockholm, Sweden. adrian.levitsky@ki.se.

ABSTRACT

Background: The identification of biomarkers that predict optimal and individual choices of treatment for patients with rheumatoid arthritis gains increasing attention. The purpose of this study was to investigate if the proto-oncogene survivin might aid in treatment decisions in early rheumatoid arthritis.

Methods: Serum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, 3, 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 3 months, and 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).

Results: Antirheumatic treatment resulted in an overall decrease of serum survivin levels. 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).

Discussion: We demonstrate for the first time that survivin is a valuable serologic marker that can distinguish drug-specific clinical responses in early rheumatoid arthritis through the pragmatic clinical setting of the care-based SWEFOT trial. Although treatment response cannot solely be attributable to survivin status, per protocol sensitivity analyses confirmed the superior effect of triple therapy on survivin-positive patients.

Conclusions: Survivin-positive patients have poor outcomes if treated with MTX monotherapy. A decrease of survivin levels during treatment is associated with better clinical responses. For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy.

Trial registration: WHO database at the Karolinska University Hospital: CT20080004 ; ClinicalTrials.gov: NCT00764725, registered 1 October 2008.

No MeSH data available.


Related in: MedlinePlus

Prevalence of active disease among survivin-positive or survivin-negative patients in the SWEFOT trial. The prevalence of active disease (disease activity score, DAS28 > 3.2) among patients who were survivin-positive or survivin-negative at baseline is presented for the groups treated with methotrexate (MTX) monotherapy and the groups randomized to triple therapy (TT) or to anti-TNF therapy. Comparisons were done by Pearson’s χ2 or Fisher’s exact tests, and odds-based estimates (odds ratio, OR) and 95 % confidence intervals (CI) are indicated. Two patients with no available DAS28 at 3 months were excluded from the analysis
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Fig4: Prevalence of active disease among survivin-positive or survivin-negative patients in the SWEFOT trial. The prevalence of active disease (disease activity score, DAS28 > 3.2) among patients who were survivin-positive or survivin-negative at baseline is presented for the groups treated with methotrexate (MTX) monotherapy and the groups randomized to triple therapy (TT) or to anti-TNF therapy. Comparisons were done by Pearson’s χ2 or Fisher’s exact tests, and odds-based estimates (odds ratio, OR) and 95 % confidence intervals (CI) are indicated. Two patients with no available DAS28 at 3 months were excluded from the analysis

Mentions: At 24 months, better clinical outcomes were found among the survivin (+) patients at baseline ((+/+) and (+/−), n = 14 + 19) randomized to TT compared to the survivin (+) patients (n = 16 + 13) randomized to anti-TNF. The TT-treated survivin (+) patients attained a significantly lower DAS28 (2.37 (1.79, 3.27) versus 3.50 (2.05, 4.63), P = 0.020), and the estimated risk of active disease activity (DAS28 > 3.2) was higher among the anti-TNF-treated survivin (+) patients (55 % versus 28 %; OR 3.15 (95 % CI 1.09–9.10), P = 0.037) (Fig. 4). Consequently, the prevalence of DAS28 < 3.2 among the TT-treated survivin (+) patients was similar to MTX responders (72 % and 75 %, respectively). Analogously, TT-treated survivin (+/+) patients (n = 14) had a lower pain-VAS compared to anti-TNF-treated survivin (+/+) patients (n = 16) (14.0 (3.75, 23.0) versus 33.0 (15.0, 66.0), P = 0.038), and the survivin (+/−) patients treated with anti-TNF had a high frequency of active disease compared to the TT-treated subgroup (62 % versus 26 %, P = 0.046). Survivin (−/−) patients showed similar responses to TT and anti-TNF treatment and reached comparable DAS28, HAQ, pain-VAS, and PtGA-VAS outcomes (Fig. 3b,c). The proportion of patients with DAS > 3.2 among MTX responders and survivin (−) at baseline ((−/−) and (−/+), n = 51 + 1) was always lower when compared to survivin (−) MTX non-responders (n = 83 + 13) (Fig. 4). The survivin (−/+) patients treated with TT and anti-TNF had similar outcomes.Fig. 4


Serum survivin predicts responses to treatment in active rheumatoid arthritis: a post hoc analysis from the SWEFOT trial.

Levitsky A, Erlandsson MC, van Vollenhoven RF, Bokarewa MI - BMC Med (2015)

Prevalence of active disease among survivin-positive or survivin-negative patients in the SWEFOT trial. The prevalence of active disease (disease activity score, DAS28 > 3.2) among patients who were survivin-positive or survivin-negative at baseline is presented for the groups treated with methotrexate (MTX) monotherapy and the groups randomized to triple therapy (TT) or to anti-TNF therapy. Comparisons were done by Pearson’s χ2 or Fisher’s exact tests, and odds-based estimates (odds ratio, OR) and 95 % confidence intervals (CI) are indicated. Two patients with no available DAS28 at 3 months were excluded from the analysis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4589197&req=5

Fig4: Prevalence of active disease among survivin-positive or survivin-negative patients in the SWEFOT trial. The prevalence of active disease (disease activity score, DAS28 > 3.2) among patients who were survivin-positive or survivin-negative at baseline is presented for the groups treated with methotrexate (MTX) monotherapy and the groups randomized to triple therapy (TT) or to anti-TNF therapy. Comparisons were done by Pearson’s χ2 or Fisher’s exact tests, and odds-based estimates (odds ratio, OR) and 95 % confidence intervals (CI) are indicated. Two patients with no available DAS28 at 3 months were excluded from the analysis
Mentions: At 24 months, better clinical outcomes were found among the survivin (+) patients at baseline ((+/+) and (+/−), n = 14 + 19) randomized to TT compared to the survivin (+) patients (n = 16 + 13) randomized to anti-TNF. The TT-treated survivin (+) patients attained a significantly lower DAS28 (2.37 (1.79, 3.27) versus 3.50 (2.05, 4.63), P = 0.020), and the estimated risk of active disease activity (DAS28 > 3.2) was higher among the anti-TNF-treated survivin (+) patients (55 % versus 28 %; OR 3.15 (95 % CI 1.09–9.10), P = 0.037) (Fig. 4). Consequently, the prevalence of DAS28 < 3.2 among the TT-treated survivin (+) patients was similar to MTX responders (72 % and 75 %, respectively). Analogously, TT-treated survivin (+/+) patients (n = 14) had a lower pain-VAS compared to anti-TNF-treated survivin (+/+) patients (n = 16) (14.0 (3.75, 23.0) versus 33.0 (15.0, 66.0), P = 0.038), and the survivin (+/−) patients treated with anti-TNF had a high frequency of active disease compared to the TT-treated subgroup (62 % versus 26 %, P = 0.046). Survivin (−/−) patients showed similar responses to TT and anti-TNF treatment and reached comparable DAS28, HAQ, pain-VAS, and PtGA-VAS outcomes (Fig. 3b,c). The proportion of patients with DAS > 3.2 among MTX responders and survivin (−) at baseline ((−/−) and (−/+), n = 51 + 1) was always lower when compared to survivin (−) MTX non-responders (n = 83 + 13) (Fig. 4). The survivin (−/+) patients treated with TT and anti-TNF had similar outcomes.Fig. 4

Bottom Line: Antirheumatic treatment resulted in an overall decrease of serum survivin levels.A decrease of survivin levels during treatment is associated with better clinical responses.For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy.

View Article: PubMed Central - PubMed

Affiliation: Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), Karolinska Institutet, D1:00, Karolinska University Hospital, 17176, Stockholm, Sweden. adrian.levitsky@ki.se.

ABSTRACT

Background: The identification of biomarkers that predict optimal and individual choices of treatment for patients with rheumatoid arthritis gains increasing attention. The purpose of this study was to investigate if the proto-oncogene survivin might aid in treatment decisions in early rheumatoid arthritis.

Methods: Serum survivin levels were measured in 302 patients who completed the Swedish pharmacotherapy (SWEFOT) trial at baseline, 3, 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 3 months, and 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).

Results: Antirheumatic treatment resulted in an overall decrease of serum survivin levels. 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).

Discussion: We demonstrate for the first time that survivin is a valuable serologic marker that can distinguish drug-specific clinical responses in early rheumatoid arthritis through the pragmatic clinical setting of the care-based SWEFOT trial. Although treatment response cannot solely be attributable to survivin status, per protocol sensitivity analyses confirmed the superior effect of triple therapy on survivin-positive patients.

Conclusions: Survivin-positive patients have poor outcomes if treated with MTX monotherapy. A decrease of survivin levels during treatment is associated with better clinical responses. For survivin-positive patients who fail MTX, triple therapy is associated with better outcomes than anti-TNF therapy.

Trial registration: WHO database at the Karolinska University Hospital: CT20080004 ; ClinicalTrials.gov: NCT00764725, registered 1 October 2008.

No MeSH data available.


Related in: MedlinePlus