Risk Factors Associated with Methotrexate Intolerance in Rheumatoid Arthritis Patients

Figures & data

Table 1 Baseline Demographic Information of Participants and Bivariate Analysis of Difference Between Methotrexate Tolerant and Methotrexate Intolerant Groups

Baseline Characteristic	Total	Tolerant	Intolerant	P-value
	(n = 117)	(n = 62)	(n = 55)
Age, mean (SD)	50.8 (12.7)	52.9 (13.7)	48.5 (11.2)	0.257
Gender, n (%)
Female	101 (86.3)	49 (79.0)	52 (94.5)	0.015*
Marital status, n (%)
Unmarried	32 (27.4)	20 (32.3)	12 (21.8)	0.206
Married	85 (72.6)	42 (67.7)	43 (78.2)
Living, n (%)
In Riyadh	95 (81.2)	48 (77.4)	47 (85.5)	0.267
Education, n (%)
Higher level of education	30 (25.6)	16 (25.8)	14 (25.5)	0.965
Lower level of education	87 (74.4)	46 (74.2)	41 (74.5)
Smoking, n (%)
Non-smoker	112 (95.7)	58 (93.5)	54 (98.2)	0.369
Other medications, n (%)
No	14 (12.0)	5 (8.1)	9 (16.4)	0.254
Yes	103 (88.0)	57 (91.9)	46 (83.6)

Note: *Significant according to a significance level of P ≤0.05.

Abbreviation: SD, standard deviation.

Table 2 Baseline Methotrexate Related Information of Participants and Bivariate Analysis of Difference Between Methotrexate Tolerant and Methotrexate Intolerant Groups

Baseline Characteristic	Total	Tolerant	Intolerant	P-value
	(n = 117)	(n = 62)	(n = 55)
Methotrexate dose (milligram/week), mean (SD)	15.2 (3.82)	15.0 (3.8)	15.5 (3.9)	0.525
Route of administration, n (%)
Oral	89 (76.1)	45 (72.6)	44 (80.0)	0.348
Subcutaneous	28 (23.9)	17 (27.4)	11 (20.0)
Time of administration, n (%)
Morning	32 (27.4)	18 (29.0)	14 (25.5)	0.665
Evening	85 (72.6)	44 (71.0)	41 (74.5)
Methotrexate in relation to meals, n (%)
Before	6 (5.1)	3 (4.8)	3 (5.5)	0.851
Between	17 (14.5)	8 (12.9)	9 (16.4)
After	94 (80.3)	51(82.3)	43(78.2)

Abbreviation: SD, standard deviation.

Table 3 Rheumatoid Arthritis Related Information of Participants and Bivariate Analysis of Difference Between Methotrexate Tolerant and Methotrexate Intolerant Groups

Baseline Characteristic	Total	Tolerant	Intolerant	P-value
	(n = 117)	(n = 62)	(n = 55)
Methotrexate Intolerance Severity Score (MISS), mean (SD)	6.3 (5.5)	2.2(1.8)	10.9 (4.6)	<0.001*
Rheumatoid arthritis duration, mean (SD)	6.6 (5.7)	6.5 (5.8)	6.8 (5.6)	0.736
Rheumatoid factor (International Unit/milliliters), n (%)
Negative	8 (6.8)	3 (4.8)	5 (9.1)	0.472
Positive	109 (93.2)	59 (95.2)	50 (90.0)
Anti-cyclic citrullinated peptide (unit/milliliter), n (%)
Negative	2 (1.7)	1 (1.6)	1 (1.8)	1.000
Positive	115 (98.3)	61 (98.4)	54 (98.2)
Seropositive/Seronegative, n (%)
Seropositive	116 (99.1)	62 (100.0)	54 (98.2)	0.470
Seronegative	1 (0.9)	0 (0)	1 (1.8)
Pain using 100 visual analogue scale, median (IQR)	50.0(50.0–70.0)	47.3(47.3–50.0)	50.0(50.0–70.0)	0.010*
Patient global assessment, median (IQR)	59.1 (59.1–70.0)	50.0(50.0–59.1)	60.0 (59.1–80.0)	0.004*
Provider global assessment, median (IQR)	48.0 (48.0–100.0)	48.0 (48.0–100.0)	48.0 (48.0–80.0)	0.934
Erythrocyte sedimentation rate (millimeter/hour), mean (SD)	23.0 (16.5)	22.4(13.7)	23.7(19.3)	0.663
C-reactive protein (milligram/Liter), mean (SD)	26.7 (88.7)	20.0(13.6)	34.2(128.7)	0.390
Disease Activity Score With 28-Joint Counts (DAS28), median (IQR)	3.6 (3.6–4.1)	3.6 (3.6–5.2)	3.6 (3.6–4.4)	0.013*
Simplified Disease Activity Index (SDAI), median (IQR)	17.0 (17.0–20.7)	17.0 (17.0–19.8)	17.0 (17.0–25.2)	0.435
Clinical Disease Activity Index (CDAI), median (IQR)	13.4 (13.4–17.0)	13.4 (13.4–17.0)	13.4 (13.4–20.0)	0.655
Disease Activity Score With 28-Joint Counts (DAS28), n (%)
Remission	12 (10.3)	7 (58.3)	5 (41.7)	0.292
Low	11 (9.4)	8 (72.7)	3 (27.3)
Moderate	82 (70.1)	43 (52.4)	39 (47.6)
High	12 (10.3)	4 (33.3)	8 (66.7)
Clinical Disease Activity Index (CDAI), n (%)
Remission	3 (2.6)	3 (100.0)	0 (0.0)	0.225
Low	22 (18.8)	12 (54.5)	10 (45.5)
Moderate	85 (72.6)	45 (52.9)	40 (47.1)
High	7 (6.0)	2 (28.6)	5 (71.4)
Simplified Disease Activity Index (SDAI), n (%)
Remission	1 (0.9)	1 (100.0)	0 (0.0)	0.231
Low	10 (8.5)	6 (60.0)	4 (40.0)
Moderate	100 (85.5)	54 (54.0)	46 (46.0)
High	6 (5.1)	1 (16.7)	5 (83.3)

Notes: *Significant according to a significance level of P ≤ 0.05. Bold formatting indicates p value.

Abbreviations: SD, standard deviation; IQR, interquartile range.

Table 4 Binary Logistic Regression Analysis to Determine Factors Associated with Methotrexate Intolerance Among the Study Population Adjusted by Age, Gender, and Disease Duration

Factors	Adjusted Odds Ratio	95% Confidence Interval	P-value
Gender
Male (Ref.)
Female	6.724	[1.420, 31.843]	0.016*
Age (years)	0.975	[0.945, 1.006]	0.115
Rheumatoid arthritis duration	1.005	[0.938, 1.077]	0.889
Education
Lower level (Ref.)
Higher level	0.819	[0.312, 2.150]	0.685
Marital status
Unmarried (Ref.)
Married	2.549	[1.037, 6.270]	0.042*
Living
In Riyadh (Ref.)
Outside Riyadh	0.614	[0.219, 1.727]	0.356
Smoking
No (Ref.)
Yes	0.677	[0.044, 10.447]	0.780
Methotrexate dose	1.041	[0.942, 1.152]	0.430
Route of administration
Oral (Ref.)
Subcutaneous	0.591	[0.235, 1.488]	0.265
Time of administration
Morning (Ref.)
Evening	1.191	[0.500, 2.838]	0.693
Methotrexate in relation to meals
Before (Ref.)
Between	0.835	[0.103, 6.787]	0.866
After	0.643	[0.099, 4.179]	0.644
Rheumatoid factor
No (Ref.)
Yes	0.502	[0.101, 2.498]	0.400
Anti-cyclic citrullinated peptide
No (Ref.)
Yes	1.688	[0.096, 29.817]	0.721
Traditional disease-modifying antirheumatic drugs
No (Ref.)
Yes	0.695	[0.299, 1.615]	0.398
Biologics
No (Ref.)
Yes	1.640	[0.707, 3.805]	0.250
Other medications
No (Ref.)
Yes	0.548	[0.163, 1.835]	0.329
Erythrocyte sedimentation rate	1.003	[0.980, 1.026]	0.819
C-Reactive protein	1.002	[0.995, 1.009]	0.512
Disease Activity Score With 28-Joint Counts (DAS28)
Remission (Ref.)
Low	0.985	[0.143, 6.778]	0.988
Moderate	1.539	[0.421, 5.630]	0.514
High	2.770	[0.500, 15.335]	0.243
Disease Activity Score With 28-Joint Counts (DAS28)	1.612	[1.032, 2.517]	0.036*
Clinical Disease Activity Index (CDAI)	1.059	[0.991, 1.132]	0.090
Simplified Disease Activity Index (SDAI)	1.071	[0.988, 1.161]	0.098
Patient global assessment (PtGA)	1.023	[1.007, 1.040]	0.005*
Provider global assessment (PrGA)	0.998	[0.983, 1.013]	0.757
Pain using 100 visual analogue scale	1.018	[1.003, 1.033]	0.020*

Notes: *Significant according to a significance level of P ≤ 0.05. Bold formatting indicates p value.

Figure 1 Radar chart of Methotrexate Intolerance Severity Score (MISS) and related components.

Table 5 Model of Linear Regression to Determine Factors Affecting Methotrexate Intolerance Severity Score (MISS), Adjusted to Age, Gender, and Rheumatoid Arthritis Duration

Factors	Unstandardized B	Standard Error	Standardized Coefficients Beta	t	CI	P-value
CDAI	1.657	0.894	0.172	1.854	[−0.115, 3.429]	0.067
SDAI	1.975	1.212	0.150	1.630	[−0.427, 4.377]	0.106
DAS28	1.193	0.666	0.166	1.791	[−0.128, 2.514]	0.076
Pain^¥	0.046	0.018	0.241	2.545	[0.010, 0.082]	0.012*
PtGA	0.056	0.018	0.278	3.090	[0.020, 0.091]	0.003*
PrGA	−0.006	0.020	−0.028	−0.277	[−0.045, 0.034]	0.782

Notes: ^¥Using 100 Visual Analogue Scale. *Significant according to a significance level of P ≤ 0.05, bold formatting indicates p value.

Abbreviations: CI, confidence interval; CDAI, Clinical Disease Activity Index; SDAI, Simplified Disease Activity Index; DAS28, Disease Activity Score with 28-Joint Counts; PtGA, patient global assessment; PrGA, provider global assessment.