Association of a multibiomarker disease activity score at multiple time-points with radiographic progression in rheumatoid arthritis: results from the SWEFOT trial.

OBJECTIVES: In rheumatoid arthritis (RA), predictive biomarkers for subsequent radiographic progression (RP) could improve therapeutic choices for individual patients. We previously showed that the multibiomarker disease activity (MBDA) score in patients with newly diagnosed RA identified patients at risk for RP. We evaluated the MBDA score at multiple time-points as a predictor of RP during 2 years of follow-up. METHODS: A subset of patients with RA (N=220) from the Swedish Farmacotherapy (SWEFOT) trial were analysed for MBDA score, disease activity score of 28 joints (DAS28), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) at baseline (BL), month 3 and year 1, for predicting RP based on modified Sharp/van der Heijde scores at BL, year 1 and year 2. RESULTS: Patients with persistently low MBDA (<30) scores or those with a decrease from moderate (30-44) to low MBDA scores, did not develop RP during 2 years of follow-up. The highest risk for RP during 2 years of follow-up (42%) was observed among patients with persistently high (>44) MBDA scores. Among methotrexate non-responders with a high MBDA score at BL or month 3, significantly more of those who received triple therapy had RP at year 2 compared with those who received antitumour necrosis factor therapy. CONCLUSIONS: Measuring the MBDA score both before and during treatment in RA was useful for the assessment of individual patient risk for RP during 2 years of follow-up. In comparison with low CRP, ESR or DAS28, a low MBDA score at any time-point was associated with numerically lower proportions of RP. TRIAL REGISTRATION NUMBER: NCT00764725.

Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial.

OBJECTIVES: Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. METHODS: Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. RESULTS: Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.05, 95% CI 1.02 to 1.08) and dichotomised variable (high versus low/moderate, OR=3.86, 95% CI 1.04 to 14.26). CONCLUSIONS: In patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP. TRIAL REGISTRATION NUMBER: WHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725.

Increasing chemotherapy dose density and intensity: phase I trials in non-small cell lung cancer and non-Hodgkin's lymphoma.

Dose densification and dose escalation of cytotoxic chemotherapy may be important in improving the cure rates of chemotherapy-responsive cancers. We conducted two phase I studies, in non-small cell lung cancer (NSCLC) and in lymphoma, to explore the possibility of intensifying chemotherapy by compressing the delivery of and escalating the dose of standard combination chemotherapy. One study used etoposide and cisplatin chemotherapy in patients with unresectable stage III or IV NSCLC, intensifying chemotherapy by reducing the cycle length. The second study used cyclophosphamide, doxorubicin, vincristine, and prednisone, CHOP chemotherapy, in the treatment of stage II-IV intermediate or immunoblastic high-grade lymphoma, intensifying chemotherapy first by reducing the cycle length and then by escalating the dosages of cyclophosphamide and doxorubicin. Filgrastim support was used during dose intensification. Fifty-five patients with NSCLC and 49 with non-Hodgkin's lymphoma (NHL) were enrolled and treated in successive cohorts. At standard dosages and intervals of chemotherapy, filgrastim support resulted in incidences of grade 3 and 4 neutropenia that were between 62% and 77% lower than those in the no-filgrastim control; the mean duration of neutropenia was, likewise, more than 80% lower. Absolute neutrophil counts were >/=2 x 10(9)/l at day 14 in virtually 100% of patients receiving filgrastim. In the NSCLC trial, etoposide and cisplatin were intensified by >50%, and in the lymphoma trial, cyclophosphamide was intensified by 270% and doxorubicin was intensified by 87%. Chemotherapy reductions or delays for neutropenia were rare in the groups receiving filgrastim; but at higher chemotherapy intensities, dose-limiting thrombocytopenia was encountered. We conclude that the delivery of myelosuppressive chemotherapy in both a dose-intense and a dose-dense manner is feasible with filgrastim support.