Table 3: Proportions of patients who experienced increases in liver enzymes during RA .

% of ≤6 months>6 monthsClinical sequelae
ALT or AST > 3 × ULNALT or AST > 3 × ULN

Conventional synthetic DMARDs

Methotrexate3.6% [60] >2 × ULN: 12.9% [57]
25% [56]
3.7% of patients discontinued due to liver toxicity [57] 
4.2% discontinued by 2 years due to liver toxicity [56]

Leflunomide>5 × ULN: 3.0% [82]1.5%6.4% [30, 56]Due to grade 2 hepatotoxicity, 1 patient (1%) was withdrawn from LEF treatment and 1 patient (1%) continued LEF at a reduced dose [82].
1.6% of patients discontinued by 2 years [56]

LEF + MTX6.8% [83]3.8% for LEF + MTX; 
(0.8% for MTX + placebo) [30] 
17% [83]
Four patients (4.5%) were withdrawn from treatment due to persistent elevation of plasma liver enzyme level

Sulfasalazine4% [84]N/AN/A

Biologic

Adalimumab3.5% [85]  
<1% (w/MTX) [62]
<1% (w/MTX) [62]N/A

Infliximab>5 × ULN: <1%≥3 × ULN: 5%  N/A

EtanerceptGrades 2–4: 0% [86]Grades 2–4: 0% [86]N/A

GolimumabAny ALT or AST elevation: 
0% (monotherapy); 
4.4%6.3% (w/MTX) [58]
N/AN/A

Tocilizumab3.4%6.5% [31, 87]11% (TCZ + MTX); 
2%-3% (MTX → TCZ) [88] 
10.8% [27]
There were no serious liver function disorders during TCZ treatment [89].
Seven patients (1.1%) prematurely discontinued due to elevated liver aminotransferases (with concomitant MTX) [87]

AnakinraN/APatients with elevated liver enzymes: <1% [90]N/A

Targeted small-molecule DMARD

Tofacitinib1.1%1.6% (w/MTX) [91]
≤1.0% [92]
<1% [91]
3.2% (w/MTX) [62]
N/A

ALT, alanine aminotransferase; AST, aspartate aminotransferase; DMARD, disease-modifying antirheumatic drug; LEF, leflunomide; MTX, methotrexate; N/A, not available; RA, rheumatoid arthritis; TCZ, tocilizumab; ULN, upper limit of normal. ALT and AST levels, grade 3 was >5 to 10 × ULN and grade 4 was >10 × ULN. are the proportions of patients with ALT or AST ≥ 3 × ULN except where noted. data were available for rituximab, certolizumab, or abatacept. of these patients were also taking methotrexate or nonsteroidal anti-inflammatory drugs. medical letter (personal communication), data on file.