Cohort characteristics
The analysis cohort included 385 patients from the HeRBT registry that fulfilled two criteria, (a) they had at least 5 years follow-up and (b) they exhibited persistent low or moderate disease. This cohort was selected out of the 1466 RA patients included in the registry until May 2013, after excluding 763 patients due to < 5 years follow-up, 166 patients having missing longitudinal DAS28-data > 50%, 142 exhibiting persistent high inflammatory burden and 10 patients not exhibiting any persistent disease activity level. This was a cohort mostly with established RA (mean disease duration 9.2 years), 70 patients had disease duration < 2 years and the mean monitoring duration was 7.5 years (Table 1). Patients were treated with an average of 2.34 (± 1.13) csDMARDs prior to first bDMARD, while 279 (72%) were on combination with methotrexate. At the end of 5 years, 208 (54%) patients received a second and 99 (26%) received a third sequential bDMARD.
Table 1
Baseline characteristics of patient cohort and the different persistent disease activity groups. §
Variable Name | Cohort (n = 385) | RemissionLow pRLDA (n = 90) | Moderate pMDA (n = 295) | lower-Moderate plMDA (n = 133) | higher-Moderate phMDA (n = 162) |
Females a, b | 293 (76%) | 52 (58%) | 241 (82%) | 102 (78%) | 139 (86%) |
Age (years) a, b | 56.35 ± 13 | 51.96 ± 13 | 57.69 ± 12 | 55.11 ± 12.31 | 59.81 ± 11.59 |
RA Duration (years) | 9.2 ± 8.6 | 9.57 ± 10 | 9.1 ± 8.12 | 8.71 ± 7.71 | 9.43 ± 8.45 |
RA Duration < 2 years | 70 (18%) | 22(24%) | 48 (16%) | 20 (15%) | 28 (17%) |
Seropositive* (n = 217) | 100 (46%) | 15 (47%) | 85 (46%) | 37 (51%) | 48 (43%) |
TJC28* (n = 316) a, b | 10.53 ± 6.5 | 7.93 ± 6.3 | 11.14 ± 6.4 | 9.61 ± 5.56 | 12.39 ± 6.74 |
SJC28* (n = 316) a, b | 8.99 ± 6.24 | 6.17 ± 6.1 | 9.66 ± 6.1 | 8.14 ± 5.55 | 10.89 ± 6.26 |
ESR* mm/s (n = 256) | 38.62 ± 24 | 35.37 ± 23 | 39.4 ± 24 | 37.86 ± 23.42 | 40.63 ± 25.02 |
CRP* mg/dl (n = 227) a | 2.57 ± 6 | 4.07 ± 12 | 2.22 ± 3.15 | 2.31 ± 3.32 | 2.15 ± 3.02 |
DAS28 (Imputed) b | 5.7 ± 0.99 | 4.92 ± 1 | 5.94 ± 0.86 | 5.62 ± 0.74 | 6.02 ± 0.86 |
CDAI* (n = 296) b | 33 ± 12.19 | 26.06 ± 12 | 34.6 ± 12 | 30.86 ± 10.05 | 37.62 ± 12.13 |
SDAI* (n = 261) b | 35.34 ± 13 | 29.99 ± 17 | 36.64 ± 12 | 32.66 ± 10.44 | 39.63 ± 12.18 |
Physician VAS G.* (n = 298) a, b | 69.5 ± 14.8 | 62.92 ± 16 | 71.13 ± 14 | 67.57 ± 15.12 | 73.97 ± 12.7 |
Patient VAS G.* (n = 315) b | 66.11 ± 19 | 59.43 ± 25 | 67.69 ± 17 | 63.74 ± 17.82 | 70.93 ± 15.54 |
Patient VAS Pain* (n = 302) | 67.41 ± 17 | 62.93 ± 25 | 68.5 ± 17.2 | 66.26 ± 18.57 | 70.38 ± 15.87 |
HAQ (Imputed) a, b | 0.84 ± 0.44 | 0.63 ± 0.4 | 0.9 ± 0.5 | 0.77 ± 0.43 | 1 ± 0.45 |
Euroqol* (n = 82) | 0.34 ± 0.38 | 0.36 ± 0.4 | 0.34 ± 0.39 | 0.4 ± 0.34 | 0.26 ± 0.43 |
Previous csDMARDs | 2.34 ± 1.13 | 2.11 ± 0.9 | 2.41 ± 1.18 | 2.34 ± 1.25 | 2.46 ± 1.11 |
Ongoing csDMARDs | 1.15 ± 0.57 | 1.15 ± 0.6 | 1.15 ± 0.6 | 1.1 ± 0.63 | 1.19 ± 0.53 |
Monotherapy b | 32 (8%) | 7 (8%) | 25 (9%) | 16 (12%) | 9 (6%) |
Methotrexate | 279 (73%) | 62 (69%) | 217 (74%) | 97 (73%) | 120 (74%) |
Anti-TNF b | 350 (90%) | 88 (98%) | 262 (89%) | 124 (93%) | 138 (85%) |
Prednisolone | 184 (48%) | 44 (49%) | 140 (48%) | 71 (53%) | 69 (43%) |
Results presented as counts n (%) or mean (± sd). * Missing data > 5%. a Group pRLDA is significantly different from pMDA (Wilcoxon rank-sum test p < 0.05). b Group plMDA is significantly different from phMDA (Wilcoxon rank-sum test p < 0.05). § TJC28 = Tender Joint Count 28; SJC28 = Swollen Joint Count 28; ESR = erythrocyte sedimentation rate; CRP = C reactive protein; DAS28 = Disease Activity Score 28 ESR4; CDAI = Clinical Disease Activity Index; SDAI = Simplified Disease Activity Index; VAS = Visual Analogue Scale 100; Physician VAS G.=Physician VAS Global; Patient VAS G.=Patient VAS Global; HAQ = Health Assessment Questionnaire; csDMARDs = Conventional Synthetic Disease-modifying Antirheumatic Drugs; Anti-TNF = TNFα inhibitors. |
Persistent disease activity groups characteristics
A total 90 (23%) and 295 (77%) patients were categorized in the pRLDA and pMDA groups, respectively. Patients in the pMDA group were further categorized in subgroups plMDA and phMDA including 133 (45%) and 162 (55%) patients, respectively (Table 1). Patients in the pMDA group were older (58 ± 12 vs 52 ± 13 years; p < 0.0019 Bonferroni corrected) and more frequently females (82% vs 58%, p < 0.0019) as compared to pRLDA. At inclusion, patient disease activity (mean DAS28 4.9 ± 1.0 vs 5.9 ± 0.9, p < 0.0019) and functionality (mean HAQ 0.63 ± 0.4 vs 0.9 ± 0.5, p < 0.0019) were higher in pMDA than pRLDA respectively. Analysis within the pMDA group showed that patients in the plMDA subgroup were younger (p = 0.0005) with lower baseline disease activity (mean DAS28 5.6 ± 0.7 vs 6.0 ± 0.9, p < 0.0001) than phMDA patients. A representation of the DAS28 course for each patient in the pRLDA and pMDA groups is provided in Fig. 1 while Fig. 2 presents the 5-year disease activity course (average DAS28 in the 8 TT intervals) of groups pRLDA and pMDA and subgroups plMDA and phMDA, showing clear distinct disease activity trajectories.
pMDA group was associated with worse 5-year functionality than pRLDA
One of the main aims of this study was to investigate whether patients on pMDA have adverse long-term prognosis compared to patients on lower chronic inflammatory burden. The 5-years functionality (HAQ) trajectories (average DAS28 in the 8 TT intervals) of the pRLDA and pMDA groups are presented in Fig. 3, showing a clear distinct trajectory for each group. In multivariable mixed-effect regression analysis (Table 2), the pMDA group was associated with worse 5-year functionality trajectory than the pRLDA group (+ 0.28 higher HAQ trajectory in pMDA, 95% CI + 0.18 to + 0.39, p < 0.0001). Analysis was adjusted for possible confounding effects on gender, age and disease duration. Interestingly, the 5-year functionality was also significantly worse in females than males (+ 0.13 higher HAQ trajectory in females, 95% CI + 0.04 to + 0.23, p = 0.008) and in older patients (+ 0.009 higher HAQ trajectory per 1-year, 95% CI + 0.006 to + 0.012, p < 0.0001).
Table 2
Multivariable mixed-effect regression associated group pMDA with worse 5-year functionality (HAQ) trajectory than pRLDA group. §
HAQ Multivariable Analysis† | Coefficient‡ | 95% CI | p-value |
Group pMDA (vs pRLDA) | + 0.28 | + 0.18 to + 0.39 | p < 0.0001* |
Gender Female (vs Male) | + 0.13 | + 0.04 to + 0.23 | p = 0.008* |
Age (per year) | + 0.009 | + 0.006 to + 0.012 | p < 0.0001* |
Disease Duration (per year) | + 0.004 | -0.001 to + 0.009 | p = 0.092 |
Time 3–9 Months (vs baseline) | -0.203 | -0.279 to -0.126 | p < 0.0001* |
Time 9–15 Months (vs baseline) | -0.289 | -0.366 to -0.212 | p < 0.0001* |
Time 15–21 Months (vs baseline) | -0.288 | -0.364 to -0.213 | p < 0.0001* |
Time 21–27 Months (vs baseline) | -0.285 | -0.362 to -0.208 | p < 0.0001* |
Time 27–33 Months (vs baseline) | -0.347 | -0.432 to -0.261 | p < 0.0001* |
Time 33–42 Months (vs baseline) | -0.326 | -0.399 to -0.254 | p < 0.0001* |
Time 42–54 Months (vs baseline) | -0.323 | -0.396 to -0.251 | p < 0.0001* |
Time 54–60 Months (vs baseline) | -0.375 | -0.448 to -0.303 | p < 0.0001* |
* Variable is associated significantly with patients’ 5-year functionality (HAQ) course (p < 0.05 significance threshold). ‡ Regression coefficient that represents increase (+) or decrease (-) in 5-year functionality (HAQ) course associated with the variable (category membership for categorical variable or unit increase for continuous variable). † Efficiency of multivariable analysis: RMSE (Root mean square error) = 0.352, R2 (R-squared) = 0.573. § Terms: pRLDA = Persistent Remission/Low Disease Activity Group; pMDA = Persistent Moderate Disease Activity Group. |
At 5 years, although both groups had improved functionality as compared to baseline (HAQ decrease from baseline: -0.375 HAQ, 95% CI -0.448 to -0.303, p < 0.0001), pMDA group had worse functionality than pRLDA (HAQ 0.3 ± 0.31 vs 0.55 ± 0.47, p < 0.001). Notably, most of the improvement occurred within the first 12 months of treatment (HAQ decrease from baseline in first 12 months: -0.289, 95% CI -0.366 to -0.212, p < 0.0001), showing minimal additional improvement thereafter (12th up-to 60th month).
Subgroup phMDA was associated with worse 5-year functionality than plMDA
Clinical heterogeneity has been reported for the MDA group of patients on csDMARDs while limited data are available concerning bDMARDs. We assessed whether our cohort of RA patients on bDMARDs having persistent moderate disease activity represents a heterogenous group. For this, we compared lower and higher pMDA subgroups, the plMDA and phMDA, respectively. The 5-year functionality trajectories (average HAQ in the 8 TT intervals) of the patients classified in plMDA and phMDA subgroups are presented in Fig. 3, revealing a clear distinct trajectory for each subgroup. In multivariable mixed-effect regression analysis (Table 3), the phMDA subgroup was associated with worse 5-year functionality trajectory than plMDA subgroup (+ 0.26 higher HAQ trajectory in pMDA, 95% CI + 0.17 to + 0.36, p < 0.0001). Analysis was adjusted for possible confounding effects on gender, age and disease duration. The 5-year functionality was also significantly worse in females than males (p = 0.04) and in older patients (p < 0.0001). At 5 years, group phMDA had worse functionality status than plMDA (HAQ 0.41 ± 0.38 vs 0.66 ± 0.52 respectively, p < 0.001), although both groups were associated with improved functionality as compared to baseline (HAQ decrease from baseline: -0.38 HAQ, 95% CI -0.463 to -0.297, p < 0.0001). The differentiation of 5-year functionality between subgroups plMDA and phMDA indicates heterogeneity within the pMDA group.
Table 3
Multivariable mixed-effect regression associated subgroup phMDA with worse 5-year functionality (HAQ) trajectory than plMDA subgroup. §
HAQ Multivariable Analysis† | Coefficient‡ | 95% CI | p-value |
Group phMDA (vs plMDA) | + 0.26 | + 0.17 to + 0.36 | p < 0.0001* |
Gender Female (vs Male) | + 0.12 | + 0.01 to + 0.24 | p = 0.04* |
Age (per year) | + 0.009 | + 0.005 to + 0.013 | p < 0.0001* |
Disease Duration (per year) | + 0.002 | -0.004 to + 0.007 | p = 0.543 |
Time 3–9 Months (vs baseline) | -0.200 | -0.287 to -0.114 | p < 0.0001* |
Time 9–15 Months (vs baseline) | -0.285 | -0.373 to -0.196 | p < 0.0001* |
Time 15–21 Months (vs baseline) | -0.291 | -0.378 to -0.204 | p < 0.0001* |
Time 21–27 Months (vs baseline) | -0.279 | -0.369 to -0.190 | p < 0.0001* |
Time 27–33 Months (vs baseline) | -0.342 | -0.444 to -0.240 | p < 0.0001* |
Time 33–42 Months (vs baseline) | -0.308 | -0.392 to -0.225 | p < 0.0001* |
Time 42–54 Months (vs baseline) | -0.313 | -0.396 to -0.231 | p < 0.0001* |
Time 54–60 Months (vs baseline) | -0.380 | -0.463 to -0.297 | p < 0.0001* |
* Variable is associated significantly with patients’ 5-year functionality (HAQ) course (p < 0.05 significance threshold). ‡ Regression coefficient that represents increase (+) or decrease (-) in 5-year functionality (HAQ) course associated with the variable (category membership for categorical variable or unit increase for continuous variable). † Efficiency of multivariable analysis: RMSE (Root mean square error) = 0.366, R2 (R-squared) = 0.538. § Terms: plMDA = Persistent Lower-Moderate Disease Activity Group; phMDA = Persistent Higher-Moderate Disease Activity Group. |
Patient (sub)groups are associated with different serious adverse events occurrence
We also assessed SAEs occurrence during the course of the follow-up to estimate for any differences in the long-term outcome between distinct patients groups. The 5-year cumulative SAEs trajectories of pRLDA and pMDA groups as well as of the plMDA and phMDA subgroups are presented in Fig. 4, showing a clear distinct trajectory for each group and subgroup respectively. At 5 years, pMDA group had higher occurrence of SAEs than pRLDA group (0.2 ± 0.48 in pRLDA vs 0.5 ± 0.96 in pMDA, p = 0.006). In addition, the phMDA subgroup had also higher occurrence of SAEs than the phMDA subgroup (0.32 ± 0.6 in vs 0.64 ± 1.16 respectively, p = 0.038). The differentiation between subgroups plMDA and phMDA in serious adverse events occurrence, further supports the heterogeneity within the pMDA group.
Early predictors for classification between pRLDA and pMDA groups
In view of the aforementioned clinically meaningful differences between pRLDA and pMDA patient groups, we developed a predictive model for the early classification of patients using data from patients’ early therapy months (first semester of treatment). Multivariable logistic regression analysis (Table 4) was used adjusting for possible confounding effects of gender, age, disease duration, previous csDMARDs (at baseline). Classification in the pRLDA group (compared to pMLDA group) was associated with male gender (female gender OR 0.38, 95% CI 0.17 to 0.84, p = 0.017), lower baseline disease activity (DAS28 per unit: OR 0.45, 95% CI 0.29 to 0.7, p < 0.001), lower first semester’s average disease activity (DAS28-average per unit: OR 0.19, 95% CI 0.12 to 0.29, p < 0.001) and functionality improvement greater than 0.22 HAQ units in first semester’s compared to baseline (ΔHAQ <-0.22: OR 0.38, 95% CI 0.16 to 0.91, p = 0.029). Performance evaluation of the model in 10-fold cross-validation process yielded 88.3% accuracy, 68% sensitivity, 95% specificity and 91% area under the ROC curve.
Table 4
Multivariable logistic regression analysis to predict classification in pRLDA compared to pMDA group. §
pRLDA Classification | Univariable Analysis | Multivariable Analysis† |
(vs pMDA) | OR | 95% CI | p-value | OR | 95% CI | p-value |
Gender Female (vs Male) | 0.31 | 0.18 to 0.52 | p < 0.001* | 0.38 | 0.17 to 0.84 | p = 0.017* |
Age (per year) | 0.97 | 0.95 to 0.98 | p < 0.001* | 0.98 | 0.96 to 1.02 | p = 0.26 |
Disease Duration (per year) | 1.01 | 0.98 to 1.03 | p = 0.65 | 0.99 | 0.95 to 1.03 | p = 0.68 |
Previous csDMARDs, count < 2 | 1.56 | 0.91 to 2.67 | p = 0.11 | 1.11 | 0.49 to 2.5 | p = 0.8 |
Anti-TNF Baseline | 5.54 | 1.3 to 23.57 | p = 0.02* | 2.9 | 0.51 to 16.55 | p = 0.23 |
DAS28 Baseline (per unit) | 0.27 | 0.2 to 0.38 | p < 0.001* | 0.45 | 0.29 to 0.7 | p < 0.001* |
HAQ Baseline (per unit) | 0.21 | 0.11 to 0.4 | p < 0.001* | 0.53 | 0.2 to 1.38 | p = 0.19 |
DAS28 1st Semester (per unit) | 0.17 | 0.11 to 0.25 | p < 0.001* | 0.19 | 0.12 to 0.29 | p < 0.001* |
ΔHAQ 1st Semester <-0.22 | 0.65 | 0.37 to 1.15 | p = 0.14 | 0.38 | 0.16 to 0.91 | p = 0.029* |
§ Terms: pRLDA = Persistent Remission/Low Disease Activity Group; pMDA = Persistent Moderate Disease Activity Group; cDMARDs = Conventional Synthetic Disease-modifying Antirheumatic Drugs; 1st Semester = Therapy Months 3–9; HAQ = Health Assessment Questionnaire; ΔHAQ = HAQ Difference 1st Semester’s Average from Baseline; ACC = Accuracy; TPR = Sensitivity; TNR = Specificity; AUC = Area Under Receiver-Operating-Characteristic Curve. † Multivariable analysis efficiency (10-fold cross-validation): ACC = 88.3%, TPR = 68%, TNR = 95%, AUC = 91%. * Below significance threshold 0.05. |