Supplemental file
Criteria for dose adjustments, discontinuation of MTX and start of cyclosporin as a consequence of adverse events included:
-Criteria for liver toxicity were based on guidelines for monitoring of liver toxicity(23).
-Number of leucocytes between 2.5 and 3.5 109/l, number of thrombocytes between 100 and 150 109/l, mouth ulcers, or a 25% decrease in creatinine clearance and occurrence of oral ulcers were considered causes for withholding MTX until these values returned to normal or oral ulcers disappeared.
-Leucocytes count of ≤2.5 109/l, thrombocyte count of ≤100 109/l, or pneumonitis were considered reasons for discontinuation of MTX and start of cyclosporin.
-Subcutaneous administration of MTX was considered following severe nausea or dyspepsia.
-Possible adaptations in MTX therapy in case of anaemia were made by the rheumatologist.
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Table S1. Overview of number of patients with an adverse event and frequency of adverse events corrected for total number of evaluated visits.
I-group / C-groupNumber (%) of patients with an adverse event / Number of adverse events / evaluations (%) / Mild / Severity adverse event #
Moderate / Severe / Number (%) of patients with an adverse event / Number of adverse events / evaluations (%) / Mild / Severity adverse event #
Moderate / Severe
Gastro-intestinal (symptoms) / 99(66.4) / 576/3191 (18.1) / 75(53.6) / 215/1132(19.0)
Nausea / 76(51.0) / 309/3191(9.7) / 81(68) / 33(27) / 6(5) / 47(33.6) / 108/1132(9.5) / 27(64) / 12(29) / 3(7)
Vomiting / 14(9.4) / 18/3191(0.6) / 4(67) / 2(33) / 0(0) / 6(4.3) / 9/1132(0.8) / 2(50) / 1(25) / 1(25)
Anorexia / 4(2.7) / 5/3191(0.2) / 2(40) / 3(60) / 0(0) / 1(0.7) / 2/1132(0.2)
Stomach ache / 35(23.5) / 79/3191(2.5) / 13(46) / 11(40) / 4(14) / 13(9.3) / 18/1132(1.6) / 4(67) / 2(33) / 0(0)
Diarrhoea / 21(14.1) / 41/3191(1.3) / 11(48) / 9(39) / 3(13) / 17(12.1) / 30/1132(2.7) / 9(69) / 42(31) / 0(0)
Other / 53(35.6) / 124/3191(3.9) / 14(61) / 8(35) / 1(4) / 32(22.9) / 48/1132(4.2) / 16(70) / 7(30) / 0(0)
Gastro-intestinal (findings) / 3(2.0) / 7/3191(0.2) / 1(0.7) / 2/1132(0.2)
Oesophagitis / 1(0.7) / 5/3191(0.2) / 1(50) / 1(50) / 0(0) / 1(0.7) / 2/1132(0.2) / 0(0) / 1(100) / 0(0)
Gastritis / 0 / 0
Gastric ulcers / 0 / 0
Duodenal ulcers / 0 / 0
Colitis / 0 / 0
Other / 2(1.3) / 2/3191(0.1) / 1(100) / 0(0) / 0(0) / 0
Mucocutaneous / 80(53.7) / 373/3191(11.7) / 56(40.0) / 161/1132(14.2)
Nodulosis / 4(2.7) / 4/1391(0.1) / 0(0) / 1(100) / 0(0) / 2(1.4) / 2/1132(0.2) / 1(100) / 0(0) / 0(0)
Stomatitis / 12(8.1) / 18/3191(0.6) / 7(78) / 1(11) / 1(11) / 8(5.7) / 9/1132(0.8) / 2(50) / 1(25) / 1(25)
Oral ulcers / 41(27.5) / 85/3191(2.7) / 31(83) / 5(14) / 1(3) / 25(17.9) / 49/1132(4.3) / 10(62) / 6(38) / 0(0)
Itching / 23(15.4) / 42/3191 (1.3) / 12(86) / 2(14) / 0(0) / 19(13.6) / 25/1132(2.2) / 4(67) / 1(33) / 0(0)
Alopecia / 17(11.4) / 79/3191(2.5) / 26(65) / 14(35) / 0(0) / 15(10.7) / 28/1132(2.5) / 8(73) / 3(27) / 0(0)
Hypertrichosis / 3(2.0) / 9/3191(0.3) / 2(67) / 1(33) / 0(0) / 1(0.7) / 1/1132(0.1) / 0(0) / 1(100) / 0(0)
Gum hyperplasia / 13(8.7) / 28/3191(0.9) / 8(62) / 5(38) / 0(0) / 3(2.1) / 3/1132(0.3) / 2(100) / 0(0) / 0(0)
Other / 47(31.5) / 108/3191(3.4) / 13(56) / 8(35) / 2(9) / 24(17.1) / 44/1132(3.9) / 5(56) / 2(22) / 2(22)
CNS / 88(59.1) / 453/3191(14.2) / 54(38.6) / 169/1132(14.9)
Headache / 44(29.5) / 117/3191(3.7) / 18(57) / 11(34) / 3(9) / 17(12.1) / 31/1132(2.7) / 10(91) / 1(9) / 0(0)
Dizziness / 36(24.2) / 85/3191(2.7) / 18(69) / 7(27) / 1(4) / 24(17.1) / 49/1132(4.3) / 12(67) / 6(33) / 0(0)
Disordered mood / 19(12.8) / 42/3191(1.3) / 5(50) / 5(50) / 0(0) / 11(7.9) / 23/1132(2.0) / 2(33) / 4(67) / 0(0)
Blurred vision / 17(11.4) / 40/3191(1.3) / 5(83) / 1(17) / 0(0) / 9(6.4) / 16/1132(1.4) / 0(0) / 2(100) / 0(0)
Dry eyes / 17(11.4) / 51/3191(1.6) / 11(58) / 5(26) / 3(16) / 6(4.3) / 6/1132(0.5) / 2(100) / 0(0) / 0(0)
Lost hearing / 4(2.7) / 5/3191(0.2) / 4(2.9) / 5/1132(0.4) / 1(50) / 1(50) / 0(0)
Other / 52(34.9) / 113/3191(3.5) / 16(44) / 19(51) / 2(5) / 22(15.7) / 39/1132 (3.5) / 7(59) / 4(33) / 1(8)
Table S1. Overview of number of patients with an adverse event and frequency of adverse events corrected for total number of evaluated visits.
I-group / C-groupNumber (%) of patients with an adverse event / Number of adverse events / evaluations (%) / Mild / Severity adverse event #
Moderate / Severe / Number (%) of patients with an adverse event / Number of adverse events / evaluations (%) / Mild / Severity adverse event #
Moderate / Severe
Hepatic / 82 (55.0) / 550/3191(17.2) / 49(35.0) / 163/1132(14.4)
ALT:
Number of patients having:
-only a value 1-2 times of upper cut-off normal range
-having at least one visit with 2-3 times upper cut-off normal range
-having at least one visit with >3 times upper cut-off normal range / 70(47.0)
41
15
14 / 335/3128(10.7) / 40(29.0)
32
5
3 / 102/1107(9.2)
AST:
Number of patients having:
-only a value 1-2 times upper cut-off normal range
-having at least one visit with 2-3 times upper cut-off normal range
-having at least one visit with >3 times upper cut-off normal range / 63(42.3)
48
15
0 / 208/2996(6.9) / 30(21.4)
23
6
1 / 61/1049(5.8)
Alkaline phosphatase / 2(1.3) / 2/3191(0.06) / 0
gamma-GGT / 3(2.0) / 5/3191(0.2) / 0
Other / 0 / 0
Renal / 58(38.9) / 326/3191(10.2) / 62(44.3) / 178/1132(15.7)
Proteinuria / 0 / 0
Elevated serum creatinine / 19(12.8) / 32/2935(1.1) / 23(16.4) / 23/1066(2.2)
Hypertension / 44(29.5) / 287/2391(12.0) / 43(30.7) / 155/904(17.2)
Increased potassium / 1(0.7) / 1/3191(0.03) / 0
Increased uric acid / 0 / 0 / 0
Other / 3(2.0) / 6/3191(0.2) / 0 / 0
Table S1. Overview of number of patients with an adverse event and frequency of adverse events corrected for total number of evaluated visits.
I-group / C-groupNumber (%) of patients with an adverse event / Number of adverse events / evaluations (%) / Mild / Severity adverse event #
Moderate / Severe / Number (%) of patients with an adverse event / Number of adverse events / evaluations (%) / Mild / Severity adverse event #
Moderate / Severe
Haematological / 38(25.5) / 178/3191(5.6) / 15(10.7) / 38/1132(3.4)
Anaemia / 19(12.8) / 41/3140(1.3) / 10(7.1) / 18/1113(1.6)
Leucopenia / 4(2.7) / 5/3122(0.2) / 3(2.1) / 8/1110(0.7)
Thrombocytopenia / 14(9.4) / 120/3102(3.9) / 5(3.6) / 8/1109(0.7)
Pancytopenia / 1(0.7) / 1/3102(0.03) / 3(2.1) / 3/1109(0.3)
Other / 4(2.7) / 11/3102(0.4) / 1(0.7) / 1/1109(0.1)
Lung (symptoms) / 21(14.1) / 44/3191(1.4) / 19(13.6) / 33/1132(2.9)
Cough / 15(10.1) / 30/3191(0.9) / 7(54) / 6(46) / 0(0) / 12(8.6) / 19/1132(1.7) / 2(40) / 2(40) / 1(20)
Dyspnoea / 8(5.4) / 11/3191(0.3) / 2(50) / 1(25) / 1(25) / 1(0.7) / 2/1132(0.2) / 1(100) / 0(0) / 0(0)
Chest pain / 1(0.7) / 1/3191(0.03) / 0
Other / 2(1.3) / 2/3191(0.06) / 10(7.1) / 12/1132(1.1) / 2(67) / 1(33) / 0(0)
Lung (findings) / 4(2.7) / 4/3191(0.1) / 3(2.1) / 3/1132(0.3)
Pneumonitis or pneumonia / 0 / 0
Other / 4(2.7) / 4/3191(0.1) / 3(2.1) / 3/1132(0.3)
General / 40(26.9) / 73/3191(2.3) / 21(15.0) / 31/1132(2.7)
Fever / 5(3.4) / 6/3191(0.2) / 2(67) / 1(33) / 0(0) / 3(2.1) / 3/1132(0.3) / 1(50) / 0(0) / 1(50)
Weight loss / 1(0.7) / 1/3191(0.2) / 2(1.4) / 4/1132(0.4) / 1(100) / 0(0) / 0(0)
Fatigue / 34(22.8) / 60/3191(1.9) / 7(41) / 9(53) / 1(6) / 14(10.0) / 22/1132(1.9) / 2(50) / 2(50) / 0(0)
Other / 5(3.4) / 6/3191(0.2) / 2(1.4) / 2/1132(0.2) / 2(100) / 0(0) / 0(0)
Post dosing reactions / 19(12.8) / 42/3191(1.3) / 8(5.7) / 17/1132(1.5)
Arthralgia / 9(6.0) / 17/3191(0.5) / 7(70) / 1(10) / 2(20) / 5(3.6) / 6/1132(0.5) / 0(0) / 2(100) / 0(0)
Stiffness / 10(6.7) / 14/3191(0.4) / 3(42) / 2(29) / 2(29) / 6(4.3) / 9/1132(0.8) / 1(33) / 2(67) / 0(0)
Other / 10(6.7) / 11/3191(0.3) / 1(33) / 1(33) / 1(33) / 2(1.4) / 2/1132(0.2) / 2(100) / 0(0) / 0(0)
Other / 19(12.8) / 34/3191(1.1) / 6(4.3) / 6/1132(0.5)
Other / 19(12.8) / 28/3191(0.9) / 5(42) / 6(50) / 1(8) / 6(4.3) / 6/1132(0.5) / 2(100) / 0(0) / 0(0)
Cardiovascular / 4(2.7) / 6/3191(0.2) / 2(100) / 0(0) / 0(0) / 0
# Severity of adverse event according to rheumatologist. Since the rheumatologist could optionally describe the severity of an adverse event, the sum of the three codings for severity (i.e. mild, moderate, severe) is less than the total number of reported adverse events.
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Table S2. Possible association between baseline data and the risk of increased transaminase enzyme levels during follow-up.
I-group / C-groupOR (95%CI) / P-value / OR (95%CI) / P-value
ALT
Age, years / 1.015 (0.99 to 1.04) / 0.200 / 1.005 (0.98 to 1.03) / 0.672
Gender, female vs male / 1.163 (0.58 to 2.35) / 0.673 / 0.597 (0.28 to 1.29) / 0.190
BMI, kg/m 2 / 1.084 (0.97 to 1.21) / 0.141 / 1.116 (1.00 to 1.25) / 0.051
Swollen joint count, number / 1.038 (0.99 to 1.10) / 0.165 / 1.025 (0.96 to 1.09) / 0.445
Tender joint count, number / 1.019 (0.97 to 1.07) / 0.407 / 1.002 (0.95 to 1.06) / 0.939
VAS pain, mm / 0.996 (0.98 to 1.01) / 0.586 / 0.998 (0.98 to 1.01) / 0.771
VAS general well-being, mm / 1.003 (0.99 to 1.02) / 0.712 / 1.009 (0.99 to 1.03) / 0.346
Functional disability, HAQ / 0.882 (0.51 to 1.15) / 0.653 / 1.208 (0.67 to 2.20) / 0.535
ESR, mm/hr / 1.009 (1.00 to 1.02) / 0.166 / 1.000 (0.99 to 1.02) / 0.957
Creatinine, µmol/L / 0.994 (0.97 to 1.02) / 0.631 / 1.033 (1.00 to 1.07) / 0.038
Creatinine clearance, ml/minutes / 0.997 (0.98 to 1.01) / 0.591 / 1.005 (0.99 to 1.02) / 0.471
AST, U/L / 1.012 (0.97 to 1.06) / 0.576 / 1.039 (0.99 to 1.09) / 0.110
ALT, U/L / 1.031 (1.00 to 1.06) / 0.036 / 1.076 (1.04 to 1.12) / <0.01
Rheumatoid factor status, positive vs negative / 1.196 (0.58 to 2.49) / 0.632 / 1.038 (0.46 to 2.34) / 0.929
AST
Age, years / 1.017 (0.99 to 1.04) / 0.163 / 1.022 (0.99 to 1.05) / 0.124
Gender, female vs male / 1.125 (0.58 to 2.28) / 0.742 / 1.093 (0.47 to 2.57) / 0.838
BMI, kg/m 2 / 1.053 (0.95 to 1.17) / 0.317 / 1.005 (0.89 to 1.13) / 0.930
Swollen joint count, number / 0.990 (0.94 to 1.04) / 0.705 / 0.981 (0.92 to 1.05) / 0.596
Tender joint count, number / 0.984 (0.94 to 1.03) / 0.505 / 0.980 (0.92 to 1.05) / 0.545
VAS pain, mm / 0.999 (0.99 to 1.01) / 0.935 / 0.990 (0.97 to 1.01) / 0.241
VAS general well-being, mm / 1.004 (0.99 to 1.02) / 0.642 / 1.001 (0.98 to 1.02) / 0.943
Functional disability, HAQ / 0.879 (0.51 to 1.53) / 0.647 / 1.004 (0.53 to 1.92) / 0.990
ESR, mm/hr / 1.011 (1.00 to 1.02) / 0.091 / 1.003 (0.99 to 1.02) / 0.732
Creatinine, µmol/L / 1.008 (0.98 to 1.03) / 0.541 / 1.021 (0.99 to 1.05) / 0.204
Creatinine clearance, ml/minutes / 0.993 (0.98 to 1.01) / 0.297 / 0.985 (0.97 to 1.00) / 0.072
AST, U/L / 1.038 (0.99 to 1.08) / 0.090 / 1.068 (1.02 to 1.12) / 0.009
ALT, U/L / 1.002 (0.98 to 1.03) / 0.874 / 1.065 (1.03 to 1.10) / 0.001
Rheumatoid factor status, positive vs negative / 1.906 (0.90 to 4.05) / 0.093 / 0.527 (0.22 to 1.26) / 0.148
OR = adjusted Odds Ratio (adjusted for NSAID use at baseline).
95%CI = 95% confidence interval.
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