Table 1.
Prevalence, univariable ORs (95%-CI) and p-values for potential predictors of MTX intolerance at MTX start
| 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 |
| RFc | Positive | 16 (10.5) | 1.52 (0.62-3.72) | 0.352 |
| HLA-B27c | 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 scorec | ≤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 assessmentc | >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 |
| PGAd | ≤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) | ||
| ESRc | >15 mm/hr | 74 (48.7) | 1.46 (0.66-3.25) | 0.341 |
| CRPc | >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 |
Abbreviations: ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, asparagine aminotransferase; CHAQ, childhood health assessment questionnaire; CI, confidence interval; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HLA, human leucocyte antigen; IQR, interquartile range; IU, international units; JADAS, juvenile arthritis disease activity score; JIA, juvenile idiopathic arthritis; MICE, multivariate imputation by chained equations; MTX, methotrexate; NSAID, non-steroidal anti-inflammatory drug; OR, odds ratio; PGA, physician global assessment; RF, rheumatoid factor.
*Variables associated with the outcome at p < 0.20 in the univariable logistic regression analysis. Variables with observed frequencies of <5 in the cross-tabulation with the outcome were excluded from the univariable logistic analysis: MTX route, use of folic acid, use of anti-emetics and ADA22 rs73598374.
aFrequencies are based on observed data, not imputed data.
bJIA category, ANA, parent/patient assessment of pain, JADAS-27, thrombocytes, ALT and creatinine were included in the multivariable logistic regression analysis.
cMICE was used to impute missing values in the following variables (percentage of missing values): HLA-B27 (60.5), RF (19.1), JADAS-27 (16.4), CRP (15.8), parent/patient global assessment (11.8), RFC/SLC19A1 rs1051266 (11.8), creatinine (11.2), parent/patient assessment of pain (10.5), CHAQ disability score (8.6), MDR-1/ABCB1 rs2032582 (8.6), ALT (7.9), AST (7.2), ESR (5.3), GGH rs3758149 (4.6), MRP-2/ABCC2 rs717620 (3.9), MRP-4/ABCC4 rs868853 (3.9), MRP-5/ABCC5 rs2139560 (3.9), GGH rs10106587 (3.9), MTHFR rs1801131 (3.3), ATIC rs2372536 (3.3), ADORA2A rs5751876 (3.3), MRP-1/ABCC1 rs3784862 (3.3), MRP-2/ABCC2 rs4148396 (3.3), MRP-3/ABCC3 rs4793665 (3.3), BCRP/ABCG2 rs13120400 (3.3), PCFT/SLC46A1 rs2239907 (3.3), MTHFR rs1801133 (2.6), MTRR rs1801394 (2.6), ITPA rs1127354 (2.6), AMPD1 rs17602729 (2.6), ADA22 rs73598374 (2.6), MDR-1/ABCB1 rs1128503 and rs1045642 (2.6), MRP-1/ABCC1 rs35592 (2.6), MRP-3/ABCC3 rs3785911 (2.6), MRP-4/ABCC4 rs2274407 (2.6), BCRP/ABCG2 rs2231142 (2.6), FPGS rs4451422 (2.6), thrombocytes (2.0), ANA (2.0), hemoglobin (1.3), leucocytes (1.3).
dPGA was determined retrospectively by an experienced physician (SJV) in 20 visits (13.2%).