Predicting Radiographic Progression in Early RA
Predicting Radiographic Progression in Early RA
A total of 235 patients had complete radiographic, clinical and serological data for evaluation in this study ('study cohort'). Demographic and clinical data at baseline for these patients were similar to those for the overall SWEFOT trial population ( Table 1 ). Overall, the patients in the study cohort had a mean symptom duration of 6.1 months from diagnosis and moderate to high disease activity, as expected in an early-onset RA population.
Following 3 months of MTX therapy, 78 (33%) of the 235 patients in the study cohort responded to treatment and continued to receive MTX monotherapy per protocol and 157 (67%) did not respond and were randomised to receive triple DMARD therapy (group A) or MTX with infliximab (group B; table 2 ).
RRP, defined as ΔSHS>5 from baseline to 1 year, was observed for 43 of the 235 patients in the study cohort.
Among baseline parameters, MBDA, ESR and CRP values were significantly higher in patients with RP versus those without (p<0.001, p=0.001 and p=0.018 respectively; Table 1 ). Mean changes in SHS from baseline to 1 year were 2.1 and 3.6 for the responder and non-responder groups, respectively and 13% of the responder group had RRP (ΔSHS>5), compared with 21% in the non-responder group. Other thresholds including ΔSHS>0 and ΔSHS>3 were also tested (see online supplementary table S1 http://ard.bmj.com/content/74/6/1102/suppl/DC1).
The discriminative capacity of the baseline MBDA score, CRP, DAS28 and ESR for RP is illustrated by cumulative probability plots of ΔSHS from baseline to 1 year (figure 1 and see online supplementary figures S1 and S2 http://ard.bmj.com/content/74/6/1102/suppl/DC1). The curve for the high MBDA group was markedly different from curves for the low or moderate MBDA groups (figure 1A). By contrast, curves for the three baseline CRP groups, two DAS28 groups and three ESR groups were more similar, with RRP being relatively frequent in all categories of these baseline measures (figure 1B–D, respectively). Mean ΔSHS values and frequencies of progression for other thresholds of ΔSHS followed the same trends across categories of MBDA score as observed for ΔSHS>5 (Table 2).
(Enlarge Image)
Figure 1.
Probability plots of radiographic progression at year 1 for high, moderate and low disease activity patient (N=235) grouped according to baseline MBDA (A), CRP (B), DAS28 (C) and ESR (D). Each black circle represents a patient with low disease activity, red triangle—moderate disease activity and blue square—high disease activity. Horizontal dashed line represents ΔSHS=5 from baseline to 1 year, above which the change is considered as rapid radiographic progression (ΔSHS>5). DAS28, disease activity score; ESR, erythrocyte sedimentation rate; MBDA, multi-biomarker disease activity; SHS, Sharp–van der Heijde score.
As illustrated in figure 2, none of the patients had low DAS28-ESR or DAS28-CRP at baseline (because of the trial inclusion criteria), but among those with moderate DAS28-ESR/CRP and low/moderate CRP, approximately 15% developed RP during 1 year (figure 2A–C, respectively). While all patients with low MBDA score had low CRP and no RP, a high MBDA score was observed in 59% (42/71) of patients with low CRP and all rapid progression associated with low CRP (n=10) occurred in the high MBDA subgroup (figure 2C). Thus, almost all patients with RP (42 of 43 cases) belonged to the high MBDA group (n=201) and represented 21% of that group versus only one case of progression (3.4%) among patients with moderate (n=29, p=0.021), and none among patients with low MBDA score (figure 2D).
(Enlarge Image)
Figure 2.
Cross tabulation of all analysed patients (N=235) and subset (n=43) with rapid radiographic progression (ΔSHS>5) over 1 year, by baseline disease activity measures. The denominator in each cell represents the number of patients cross classified by baseline MBDA score and DAS28-ESR (A), baseline MBDA score and DAS28-CRP (B) and baseline MBDA score and CRP (C) disease activity scores. The numerator in each cell represents the number of patients with radiographic progression at 1 year. (D) Radiographic progression for MBDA low, moderate and high score groups (%). Radiographic progression at 1 year is defined by increase in SHS>5 compared with baseline. CRP, C-reactive protein; DAS28-CRP, disease activity score based on C-reactive protein; DAS28-ESR, disease activity score based on erythrocyte sedimentation rate; MBDA, multi-biomarker disease activity; SHS, Sharp–van der Heijde score.
The accuracy of the baseline MBDA score to predict RP at year 1 was assessed by calculating measures of sensitivity and specificity (see online supplementary table S2 and text S1 http://ard.bmj.com/content/74/6/1102/suppl/DC1). Additionally, the relationship between RP and baseline MBDA score was further examined in the subgroup of patients with high baseline scores (>44) (see online supplementary figures S3 and S4 http://ard.bmj.com/content/74/6/1102/suppl/DC1).
Univariate analyses of the radiographic subgroup (n=235) demonstrated significant associations with RRP, defined as ΔSHS>5 units in 1 year, for baseline MBDA score (the odds of RP increased by 5% for each 1-unit increase in the MBDA score: OR=1.05, p<0.001) and baseline CRP (OR=1.10, p=0.018) but not for baseline DAS28-ESR (OR = 1.31, p=0.107) or DAS28-CRP (OR = 1.22, p=0.237) (Table 3). Further analyses of the high MBDA subset also confirmed that odds for RP is doubled in patients whose MBDA score is above 65 compared with those whose MBDA score is >44–65 (see online supplementary figure S4 http://ard.bmj.com/content/74/6/1102/suppl/DC1).
In bivariate analyses that adjusted the MBDA scores for 11 different clinical variables and for sex, one at a time, the baseline MBDA score was always an independent predictor of RRP (OR values: 1.04–1.06, p values: 0.021 to <0.001).
Furthermore, MBDA score as a continuous variable was a strong independent predictor of RRP after 1 year (OR=1.05, p<0.001; Table 3), using a multivariate logistic regression model with adjustment for all significant baseline predictors from univariate analyses (sex, symptom duration, current smoking status, erosions, Health Assessment Questionnaire score), as in our recent publication. When dichotomised into high MBDA score versus not, the adjusted OR for RRP after 1 year was 3.86 (p=0.04).
Results
Description of the Study Cohort
A total of 235 patients had complete radiographic, clinical and serological data for evaluation in this study ('study cohort'). Demographic and clinical data at baseline for these patients were similar to those for the overall SWEFOT trial population ( Table 1 ). Overall, the patients in the study cohort had a mean symptom duration of 6.1 months from diagnosis and moderate to high disease activity, as expected in an early-onset RA population.
Following 3 months of MTX therapy, 78 (33%) of the 235 patients in the study cohort responded to treatment and continued to receive MTX monotherapy per protocol and 157 (67%) did not respond and were randomised to receive triple DMARD therapy (group A) or MTX with infliximab (group B; table 2 ).
RRP, defined as ΔSHS>5 from baseline to 1 year, was observed for 43 of the 235 patients in the study cohort.
Baseline Characteristics and RP
Among baseline parameters, MBDA, ESR and CRP values were significantly higher in patients with RP versus those without (p<0.001, p=0.001 and p=0.018 respectively; Table 1 ). Mean changes in SHS from baseline to 1 year were 2.1 and 3.6 for the responder and non-responder groups, respectively and 13% of the responder group had RRP (ΔSHS>5), compared with 21% in the non-responder group. Other thresholds including ΔSHS>0 and ΔSHS>3 were also tested (see online supplementary table S1 http://ard.bmj.com/content/74/6/1102/suppl/DC1).
Relationship Between RP and Baseline Level of MBDA Score, CRP, ESR or DAS28
The discriminative capacity of the baseline MBDA score, CRP, DAS28 and ESR for RP is illustrated by cumulative probability plots of ΔSHS from baseline to 1 year (figure 1 and see online supplementary figures S1 and S2 http://ard.bmj.com/content/74/6/1102/suppl/DC1). The curve for the high MBDA group was markedly different from curves for the low or moderate MBDA groups (figure 1A). By contrast, curves for the three baseline CRP groups, two DAS28 groups and three ESR groups were more similar, with RRP being relatively frequent in all categories of these baseline measures (figure 1B–D, respectively). Mean ΔSHS values and frequencies of progression for other thresholds of ΔSHS followed the same trends across categories of MBDA score as observed for ΔSHS>5 (Table 2).
(Enlarge Image)
Figure 1.
Probability plots of radiographic progression at year 1 for high, moderate and low disease activity patient (N=235) grouped according to baseline MBDA (A), CRP (B), DAS28 (C) and ESR (D). Each black circle represents a patient with low disease activity, red triangle—moderate disease activity and blue square—high disease activity. Horizontal dashed line represents ΔSHS=5 from baseline to 1 year, above which the change is considered as rapid radiographic progression (ΔSHS>5). DAS28, disease activity score; ESR, erythrocyte sedimentation rate; MBDA, multi-biomarker disease activity; SHS, Sharp–van der Heijde score.
Discordance Between MBDA Scores and Clinical Assessments: Relationship to RP
As illustrated in figure 2, none of the patients had low DAS28-ESR or DAS28-CRP at baseline (because of the trial inclusion criteria), but among those with moderate DAS28-ESR/CRP and low/moderate CRP, approximately 15% developed RP during 1 year (figure 2A–C, respectively). While all patients with low MBDA score had low CRP and no RP, a high MBDA score was observed in 59% (42/71) of patients with low CRP and all rapid progression associated with low CRP (n=10) occurred in the high MBDA subgroup (figure 2C). Thus, almost all patients with RP (42 of 43 cases) belonged to the high MBDA group (n=201) and represented 21% of that group versus only one case of progression (3.4%) among patients with moderate (n=29, p=0.021), and none among patients with low MBDA score (figure 2D).
(Enlarge Image)
Figure 2.
Cross tabulation of all analysed patients (N=235) and subset (n=43) with rapid radiographic progression (ΔSHS>5) over 1 year, by baseline disease activity measures. The denominator in each cell represents the number of patients cross classified by baseline MBDA score and DAS28-ESR (A), baseline MBDA score and DAS28-CRP (B) and baseline MBDA score and CRP (C) disease activity scores. The numerator in each cell represents the number of patients with radiographic progression at 1 year. (D) Radiographic progression for MBDA low, moderate and high score groups (%). Radiographic progression at 1 year is defined by increase in SHS>5 compared with baseline. CRP, C-reactive protein; DAS28-CRP, disease activity score based on C-reactive protein; DAS28-ESR, disease activity score based on erythrocyte sedimentation rate; MBDA, multi-biomarker disease activity; SHS, Sharp–van der Heijde score.
The accuracy of the baseline MBDA score to predict RP at year 1 was assessed by calculating measures of sensitivity and specificity (see online supplementary table S2 and text S1 http://ard.bmj.com/content/74/6/1102/suppl/DC1). Additionally, the relationship between RP and baseline MBDA score was further examined in the subgroup of patients with high baseline scores (>44) (see online supplementary figures S3 and S4 http://ard.bmj.com/content/74/6/1102/suppl/DC1).
Disease Activity at Baseline for Predicting RRP
Univariate analyses of the radiographic subgroup (n=235) demonstrated significant associations with RRP, defined as ΔSHS>5 units in 1 year, for baseline MBDA score (the odds of RP increased by 5% for each 1-unit increase in the MBDA score: OR=1.05, p<0.001) and baseline CRP (OR=1.10, p=0.018) but not for baseline DAS28-ESR (OR = 1.31, p=0.107) or DAS28-CRP (OR = 1.22, p=0.237) (Table 3). Further analyses of the high MBDA subset also confirmed that odds for RP is doubled in patients whose MBDA score is above 65 compared with those whose MBDA score is >44–65 (see online supplementary figure S4 http://ard.bmj.com/content/74/6/1102/suppl/DC1).
In bivariate analyses that adjusted the MBDA scores for 11 different clinical variables and for sex, one at a time, the baseline MBDA score was always an independent predictor of RRP (OR values: 1.04–1.06, p values: 0.021 to <0.001).
Furthermore, MBDA score as a continuous variable was a strong independent predictor of RRP after 1 year (OR=1.05, p<0.001; Table 3), using a multivariate logistic regression model with adjustment for all significant baseline predictors from univariate analyses (sex, symptom duration, current smoking status, erosions, Health Assessment Questionnaire score), as in our recent publication. When dichotomised into high MBDA score versus not, the adjusted OR for RRP after 1 year was 3.86 (p=0.04).