The SMILE Study — Safety of Methotrexate in Combination with Leflunomide in Rheumatoid Arthritis

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Figure 1.
An homunculus was developed to assist determination of joint scores.
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Figure 2.
Neutropenia (neutrophils < 2.0 × 10⁹/l) and abnormal transaminases (ALT/AST > 1.0 times upper limit of normal) across the treatment groups. MTX: methotrexate; LEF: leflunomide; ALT: alanine aminotransferase; AST: aspartate aminotransferase.
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Figure 3.
Cessation because of adverse reactions; other: cessation was reported with no record of adverse reaction. MTX: methotrexate; LEF: leflunomide.

Table 1.

Characteristics of the RA cohort.

Characteristic	MTX Monotherapy	LEF Monotherapy	MTX + LEF	Neither^*
N (%)	1552 (52.2)	217 (7.3)	415 (13.9)	791 (26.6)
Sex, %
Female	72.7	75.9	72.7	76.7
Male	27.3	24.1	27.3	23.3
Mean age, yrs (SD)	63.0 (13.8)	63.0 (12.8)	60.0 (12.8)	62.0 (13.7)
DAS28 available, n (%)	892 (57)	100 (46)	228 (54)	235 (29)
DAS28, mean (SD)	2.9 (1.2)	3.2 (1.2)	3.3 (1.4)	2.8 (1.3)
Other medications
Prednisone, %	34.0	37.3	39.3	22.9
Prednisone daily dose, mean (SD)	6.8 (6.2)	5.4 (2.6)	6.5 (4.0)	7.4 (5.9)
NSAID	19.4	14.7	19.5	15.5
Comorbidities, %
Viral hepatitis	0.1	0.5	0.0	0.3
Other liver disease	0.5	3.7	0.5	1.1
Diabetes	4.6	4.6	4.1	4.4
Steatohepatitis	0.2	0.9	0.0	0.3
Blood disorders	2.3	1.8	2.9	4.3
Infectious diseases	0.8	0.0	1.9	1.0

↵* Nonbiologic disease-modifying antirheumatic drug other than MTX and LEF. MTX: methotrexate; LEF: leflunomide; DAS: Disease Activity Score; NSAID: nonsteroidal antiinflammatory drug.

Table 2.

Therapy cessation because of adverse reactions.

	MTX	MTX in MTX + LEF	LEF	LEF in MTX + LEF	MTX + LEF
Total cessations, n	71	49	31	71	6
Because of adverse reaction, n (%)	25 (35)	37 (76)	17 (55)	28 (39)	4 (67)
Hepatic	2 (8)	4 (11)	1 (6)	2 (7)	0
Hematologic	3 (12)	1 (3)	0	1 (4)	2 (50)
Solid malignancy	2 (8)	0	0	0	0
Other^*	18 (72)	32 (65)	16 (52)	25 (35)	2 (50)
Because of other, n (%)	46 (65)	12 (24)	14 (45)	43 (61)	2 (33)

↵* Cessation was reported without record of adverse reaction. MTX: methotrexate; LEF: leflunomide.

Table 3.

Patients with reported pulmonary abnormalities.

Patient	Adverse Event Recorded	Supporting Investigations	Severity Grade^*	Causality^** MTX or LEF
1	Pleural effusion	CT, PFT	4	Unrelated
2	Interstitial lung disease	CT, PFT	2	LEF unrelated, MTX possible
3	Fibrosing alveolitis	CT, PFT	2	Unrelated
4	Pulmonary infiltrate	CT, PFT, bronchoscopy, biopsy	3	MTX probable, LEF unrelated
5	Interstitial lung disease	CT	3	LEF unrelated, MTX possible
6	Fibrosing alveolitis	None	3	LEF unrelated, MTX unlikely
7	Pneumonia	CT	2	MTX possible, LEF unrelated
8	Interstitial lung disease	CT	2	Unrelated

↵* According to the Common Terminology Criteria for Adverse Events⁷.
↵** Relationship to study drug. CT: computed tomography; PFT: pulmonary function tests; MTX: methotrexate; LEF: leflunomide.