Background
Methods
Patients and study design
Cohort, n = 152
| ||||
---|---|---|---|---|
Variables
|
Frequency n (%)
a
|
OR (95%-CI)
|
p-value
| |
Demographics
| ||||
Female | 92 (60.5) | 1.34 (0.64-2.82) | 0.432 | |
Age at disease onset | >8 years | 80 (52.6) | 0.68 (0.34-1.36) | 0.271 |
Age at MTX start*
| >12 years | 72 (47.4) | 0.54 (0.27-1.07) | 0.073 |
Disease duration at MTX start | >0.5 years | 103 (67.8) | 0.79 (0.37-1.70) | 0.535 |
JIA category
*b
| ||||
Oligoarticular (persistent/extended) | 62 (40.8) | Reference | 0.094 | |
Polyarticular (RF negative/positive) | 64 (42.1) | 1.91 (0.86-4.24) | ||
Other (systemic/psoriatic/enthesitis) | 26 (17.1) | 0.78 (0.27-2.31) | ||
Disease characteristics
| ||||
ANA*b,c
| Positive | 84 (55.3) | 1.98 (0.97-4.07) | 0.057 |
RF
c
| Positive | 16 (10.5) | 1.52 (0.62-3.72) | 0.352 |
HLA-B27
c
| Positive | 11 (7.2) | 0.78 (0.29-2.12) | 0.510 |
Uveitis | Present | 21 (13.8) | 1.44 (0.55-3.78) | 0.455 |
Disease activity
| ||||
CHAQ disability score
c
| ≤0.250 | 36 (23.7) | Reference | 0.395 |
0.250-1.875 | 88 (57.9) | 0.61 (0.24-1.55) | ||
>1.875 | 15 (9.9) | 0.72 (0.18-2.80) | ||
Parent/patient assessment of pain*b,c
| ≤3 cm | 58 (38.2) | Reference | 0.086 |
3-6 cm | 36 (23.7) | 2.19 (0.84-5.67) | ||
>6 cm | 42 (27.6) | 0.78 (0.30-2.02) | ||
Parent/patient global assessment
c
| >2.5 cm | 90 (59.2) | 0.79 (0.36-1.72) | 0.494 |
Active joints*
| >2 | 92 (60.5) | 2.00 (0.91-4.41) | 0.070 |
Limited joints*
| >1 | 108 (71.1) | 2.02 (0.92-4.46) | 0.072 |
PGA
d
| ≤2 cm | 50 (32.9) | Reference | 0.496 |
2-5 cm | 86 (56.6) | 1.35 (0.53-3.47) | ||
>5 cm | 16 (10.5) | 0.87 (0.21-3.60) | ||
ESR
c
| >15 mm/hr | 74 (48.7) | 1.46 (0.66-3.25) | 0.341 |
CRP
c
| >10 mg/L | 49 (32.2) | 0.83 (0.40-1.74) | 0.544 |
JADAS-27*b,c
| ≤5 | 16 (10.5) | Reference | 0.048 |
5-15 | 59 (38.8) | 0.40 (0.11-1.40) | ||
>15 | 52 (34.2) | 0.93 (0.25-3.44) | ||
Biochemical variables
c
| ||||
Haemoglobin | >7.5 mmol/L | 78 (51.3) | 1.18 (0.60-2.32) | 0.620 |
Leucocytes | >7 × 109/L | 96 (63.2) | 1.21 (0.59-2.47) | 0.606 |
Thrombocytes*b
| >350 × 109/L | 74 (48.7) | 1.61 (0.82-3.16) | 0.161 |
AST | >17 IU/L | 96 (63.2) | 1.08 (0.50-2.36) | 0.635 |
ALT*b
| >12 IU/L | 101 (66.4) | 0.41 (0.19-0.88) | 0.019 |
Creatinine*b
| >50 μmol/L | 56 (36.8) | 0.51 (0.24-1.08) | 0.069 |
Medication
| ||||
MTX dose, median (IQR) | mg/m2/week | 9.9 (9.0-11.2) | NA | |
MTX route | oral | 148 (97.4) | NA | |
MTX restarted | 31 (20.4) | 1.22 (0.48-3.11) | 0.554 | |
Folic acid | 150 (98.7) | NA | ||
Anti-emetics | 5 (3.3) | NA | ||
NSAID | 120 (78.9) | 0.93 (0.38-2.28) | 0.655 | |
Single nucleotide polymorphisms
c
| ||||
MTHFR rs1801133 C > T | TT | 15 (9.9) | 0.60 (0.21-1.69) | 0.322 |
MTHFR rs1801131 A > C | CC/AC | 79 (52.0) | 1.65 (0.76-3.62) | 0.201 |
MTRR rs1801394 A > G*
| GG/AG | 117 (77.0) | 0.53 (0.24-1.20) | 0.123 |
RFC/SLC19A1 rs1051266 C > T*
| TT | 17 (11.2) | 1.77 (0.74-4.25) | 0.194 |
ITPA rs1127354 C > A | AA/CA | 15 (9.9) | 0.62 (0.22-1.74) | 0.350 |
AMPD1 rs17602729 G > A | AA/GA | 41 (27.0) | 1.46 (0.70-3.05) | 0.304 |
ATIC rs2372536 C > G | GG/CG | 93 (61.2) | 0.84 (0.39-1.83) | 0.614 |
ADA22 rs73598374 C > T | TT/CT | 13 (8.6) | NA | |
ADORA2A rs5751876 C > T | TT | 28 (18.4) | 1.54 (0.65-3.64) | 0.319 |
MDR-1/ABCB1 rs 128503 G > A*
| AA | 32 (21.1) | 1.73 (0.75-3.98) | 0.190 |
MDR-1/ABCB1 rs1045642 G > A | AA | 44 (28.9) | 1.40 (0.65-3.01) | 0.376 |
MDR-1/ABCB1 rs2032582 C > A/T | AA/TT | 24 (15.8) | 1.51 (0.63-3.64) | 0.344 |
MRP-1/ABCC1 rs35592 T > C | CC/TC | 52 (34.2) | 0.79 (0.39-1.57) | 0.494 |
MRP-1/ABCC1 rs3784862 A > G | GG/AG | 73 (48.0) | 0.97 (0.50-1.91) | 0.824 |
MRP-2/ABCC2 rs4148396 C > T | TT | 18 (11.8) | 1.57 (0.60-4.08) | 0.349 |
MRP-2/ABCC2 rs717620 C > T | TT/CT | 44 (28.9) | 0.82 (0.37-1.82) | 0.626 |
MRP-3/ABCC3 rs4793665 T > C | CC/TC | 92 (60.5) | 0.73 (0.36-1.49) | 0.381 |
MRP-3/ABCC3 rs3785911 A > C*
| CC/AC | 78 (51.3) | 1.67 (0.84-3.32) | 0.136 |
MRP-4/ABCC4 rs868853 T > C | CC/TC | 22 (14.5) | 0.88 (0.35-2.18) | 0.734 |
MRP-4/ABCC4 rs2274407 C > A | AA/CA | 20 (13.2) | 1.33 (0.48-3.73) | 0.514 |
MRP-5/ABCC5 rs2139560 G > A | AA/GA | 92 (60.5) | 1.31 (0.64-2.68) | 0.450 |
BCRP/ABCG2 rs13120400 T > C | CC/TC | 63 (41.4) | 0.77 (0.38-1.59) | 0.470 |
BCRP/ABCG2 rs2231142 G > T | TT/GT | 30 (19.7) | 0.96 (0.42-2.20) | 0.744 |
FPGS rs4451422 A > C | CC/AC | 102 (67.1) | 1.37 (0.63-2.94) | 0.417 |
GGH rs10106587 A > C | CC/AC | 73 (48.0) | 1.20 (0.59-2.46) | 0.508 |
GGH rs3758149 G > A | AA/GA | 77 (50.7) | 1.20 (0.57-2.55) | 0.602 |
PCFT/SLC46A1 rs2239907 C > T | TT/CT | 104 (68.4) | 1.49 (0.69-3.23) | 0.306 |
Development of MTX intolerance over time and patient selection
Time point
|
N
|
Intolerance, n(%)
a
|
---|---|---|
3 months | 140
b
| 22 (15.7) |
6 months | 137
b
| 33 (24.1) |
12 months | 129
b
| 30 (23.3) |
First treatment year | 142 | 59 (41.5) |
6 or 12 months
d
| 152
c
| 51 (33.6) |
Potential clinical and genetic predictors
Statistical analysis
Prediction model construction
Prediction model validation and risk score computation
Results
Baseline characteristics of the prediction model cohort
Clinical prediction model
Predictors
|
OR (95%-CI)
|
p-value
|
β
a
|
Score
b
| |
---|---|---|---|---|---|
JIA category | |||||
Oligoarticular (persistent/extended) | Reference | 0 | |||
Polyarticular (RF negative/positive) | 4.99 (1.36-18.34) | 0.016 | 0.914 | 5 | |
Other (systemic/psoriatic/enthesitis) | 0.93 (0.16-5.49) | 0.935 | −0.042 | 0 | |
ANA | Positive | 1.98 (0.83-4.68) | 0.122 | 0.387 | 2 |
Parent/patient assessment of pain | ≤3 cm | Reference | 0 | ||
3-6 cm | 2.06 (0.72-5.89) | 0.175 | 0.412 | 2 | |
>6 cm | 0.60 (0.17-2.07) | 0.421 | −0.288 | −1 | |
JADAS-27 | ≤5 | Reference | 0 | ||
5-15 | 0.35 (0.08-1.56) | 0.168 | −0.599 | −3 | |
>15 | 0.77 (0.14-4.32) | 0.766 | −0.150 | −1 | |
Thrombocytes | >350 × 109/L | 1.27 (0.49-3.27) | 0.621 | 0.136 | 1 |
ALT | >12 IU/L | 0.39 (0.16-0.96) | 0.040 | −0.534 | −3 |
Creatinine | >50 μmol/L | 1.37 (0.33-5.67) | 0.665 | 0.179 | 1 |
Interaction term creatinine: JIA category | |||||
>50 μmol/L & polyarticular arthritis | 0.17 (0.02-1.35) | 0.093 | −1.022 | −5 | |
>50 μmol/L & other JIA category | 0.82 (0.07-9.74) | 0.878 | −0.110 | −1 | |
Constant | −0.039 | 7 | |||
C-statistic | 77.5% | ||||
C-statistic (optimism-corrected by bootstrap) | 66.7% | ||||
Hosmer-Lemeshow test (p-value) | 0.705 |
Clinical-genetic prediction model
Prediction model validation
Risk score
Cut-off
|
Sensitivity (%)
|
Specificity (%)
|
PPV (%)
|
NPV (%)
|
Accuracy (%)
|
---|---|---|---|---|---|
≥4 | 93.4 | 29.9 | 50.3 | 85.7 | 57.3 |
≥5 | 87.8 | 46.1 | 55.3 | 83.3 | 64.1 |
≥6 | 82.0 | 56.1 | 58.7 | 80.4 | 67.3 |
≥7 | 69.2 | 69.9 | 63.6 | 74.9 | 69.6 |
≥8 | 58.7 | 80.3 | 69.4 | 71.9 | 71.0 |
≥9 | 46.0 | 86.8 | 72.6 | 67.9 | 69.2 |