Association between use of disease-modifying antirheumatic drugs and diabetes in patients with ankylosing spondylitis, rheumatoid arthritis, or psoriasis/psoriatic arthritis: a nationwide, population-based cohort study of 84,989 patients

Figures & data

Table 1 Characteristics of Taiwanese patients with AS, RA, or PS/PSA who initiated therapy with a DMARD from 1999 to 2011

Variable	DMARD therapy				P-value
	Anti-TNFa (n=6,824)	CSAa (n=2,940)	HCQa (n=27,783)	Referencea (n=44,635)
Age at initiation of DMARDs (years)	49.2 (14.9)	43.6 (15.7)	50.3 (15.5)	38.2 (14.7)	<0.001
Sex
Female	4,553 (66.7%)	1,313 (44.7%)	20,058 (72.2%)	13,200 (29.6%)	<0.001
Male	2,271 (33.3%)	1,627 (55.3%)	7,725 (27.8%)	31,435 (70.4%)
Disease group
AS	1,126 (16.5%)	204 (6.9%)	4,384 (15.8%)	30,473 (68.3%)	<0.001
RA	4,975 (72.9%)	874 (29.7%)	21,530 (77.5%)	3,148 (7.1%)
PS/PSA	723 (10.6%)	1,862 (63.3%)	1,869 (6.7%)	11,014 (24.7%)
Disease duration
≤5 years	2,606 (38.2%)	1,756 (59.7%)	24,735 (89.0%)	35,343 (79.2%)	<0.001
>5–10 years	2,593 (38.0%)	788 (26.8%)	2,396 (8.6%)	6,033 (13.5%)
>10 years	1,625 (23.8%)	396 (13.5%)	652 (2.3%)	3,259 (7.3%)
Pretreatment CCI score
0	1,131 (16.6%)	1,618 (55.0%)	10,525 (37.9%)	33,628 (75.3%)	<0.001
1	3,428 (50.2%)	734 (25.0%)	10,822 (39.0%)	7,082 (15.9%)
2–4	1,998 (29.3%)	460 (15.6%)	5,467 (19.7%)	3,015 (6.8%)
≥5	267 (3.9%)	128 (4.4%)	969 (3.5%)	910 (2.0%)
Pretreatment prednisolone doseb
None	1,536 (22.5%)	1,245 (42.3%)	10,098 (36.3%)	30,631 (68.6%)	<0.001
≤1 mg/day	535 (7.8%)	785 (26.7%)	12,279 (44.2%)	10,592 (23.7%)
>1 mg/day	4,753 (69.7%)	910 (31.0%)	5,406 (19.5%)	3,412 (7.6%)
MTX used
Total	4,884 (71.6%)	2,111 (71.8%)	15,029 (54.1%)	13,893 (31.1%)	<0.001
AS	212 (4.3%)	55 (2.6%)	890 (5.9%)	3,159 (22.7%)	<0.001
RA	4,272 (87.5%)	560 (26.5%)	13,440 (89.4%)	1,945 (14.0%)
PS/PSA	400 (8.2%)	1,496 (70.9%)	699 (4.7%)	8,789 (63.3%)

Notes:

a Based on the DMARD medication use, the patients were categorized into 4 mutually exclusive groups: (1) anti-TNF: TNF inhibitors with or without other DMARDs; (2) CSA: without TNF inhibitors or HCQ; (3) HCQ: without TNF inhibitors or CSA; (4) reference: nonbiologic DMARDs without TNF inhibitors, CSA, or HCQ.

b Daily average-equivalent dose in the 1 year before the index date.

Abbreviations: AS, ankylosing spondylitis; RA, rheumatoid arthritis; PS/PSA, psoriasis/psoriatic arthritis; DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor; CSA, cyclosporine; HCQ, hydroxychloroquine; CCI, Charlson comorbidity index; MTX, methotrexate.

Table 2 Incidence of DM in patients who used different DMARDs

	DMARD therapy
	Anti-TNFa (n=6,824)	CSAa (n=2,940)	HCQa (n=27,783)	Referencea (n=44,635)
Sum of person-years	43,964.5	13,258.9	39,458.5	105,835. 9
New diagnoses of DM	127.0	138.0	1,073.0	1,137.0
Incidence (per 1,000 person-years)	2.9	10.4	27.2	10.7

Notes:

a Based on the DMARD medication use, the patients were categorized into 4 mutually exclusive groups: (1) anti-TNF: TNF inhibitors with or without other DMARDs; (2) CSA without TNF inhibitors or HCQ; (3) HCQ without TNF inhibitors or CSA; (4) reference: other nonbiologic DMARDs without TNF inhibitors, CSA, or HCQ.

Abbreviations: DM, diabetes mellitus; DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor; CSA, cyclosporine; HCQ, hydroxychloroquine.

Figure 1 Cumulative incidence of DM with patients classified into 4 DMARD groups (A) and 5 DMARD groups (B). (A) The cumulative incidence of DM in the CSA group was significantly higher than that in the other 3 groups (vs anti-TNF: P=0.014; vs HCQ: P=0.022; vs other nonbiologic DMARDs: P=0.013). (B) The cumulative incidence of DM was similar in the CSA group and the group that used anti-TNF without HCQ, and significantly lower in the other 3 groups (anti-TNF + HCQ, HCQ, other DMARDs); the cumulative incidence of DM in the anti-TNF + HCQ group was significantly lower than in the other 4 groups (vs anti-TNF without HCQ: P<0.001; vs CSA: P<0.001; vs HCQ: P=0.015; vs other DMARDs: P=0.031).

Abbreviations: DM, diabetes mellitus; DMARD, disease-modifying antirheumatic drug; CSA, cyclosporine; TNF, tumor necrosis factor; HCQ, hydroxychloroquine.

Table 3 Univariate (crude HR) and multivariate (adjusted HR) analysis of factors associated with DM

Variable	Crude HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
Age	1.04 (1.04, 1.04)	<0.001*	1.03 (1.03, 1.04)	<0.001*
Sex (male to female)	0.90 (0.83, 0.97)	0.008*	1.05 (0.96, 1.15)	0.299
Disease group
AS	Reference		Reference
RA	1.99 (1.81, 2.20)	<0.001*	1.90 (1.61, 2.25)	<0.001*
PS/PSA	3.50 (3.13, 3.91)	<0.001*	3.09 (2.63, 3.62)	<0.001*
Disease duration
≤5 years	Reference		Reference
>5–10 years	1.45 (1.28, 1.64)	<0.001*	0.82 (0.71, 0.94)	0.004*
>10 years	1.22 (0.92, 1.63)	0.168	0.51 (0.38, 0.69)	<0.001*
Pretreatment CCI
0	Reference		Reference
1	1.15 (1.04, 1.26)	0.005*	1.04 (0.94, 1.15)	0.459
2–4	1.87 (1.68, 2.08)	<0.001*	1.28 (1.13, 1.44)	<0.001*
≥5	1.96 (1.56, 2.47)	<0.001*	1.36 (1.08, 1.72)	0.010*
Pretreatment prednisolone dosea
None	Reference		Reference
≤1 mg/day	1.36 (1.25, 1.48)	<0.001*	1.35 (1.22, 1.48)	<0.001*
>1 mg/day	1.47 (1.32, 1.64)	<0.001*	1.45 (1.27, 1.65)	<0.001*
DMARD group	Reference		Reference
Anti-TNF (CSA/HCQ: −/−)	1.64 (1.29, 2.10)	<0.001*	1.18 (0.89, 1.56)	0.244
Anti-TNF (CSA/HCQ: +/−)	0.98 (0.44, 2.18)	0.957	0.72 (0.32, 1.62)	0.428
Anti-TNF (CSA/HCQ: −/+)	0.73 (0.54, 1.01)	0.056	0.44 (0.31, 0.63)	<0.001*
Anti-TNF (CSA/HCQ: +/+)	0.84 (0.47, 1.48)	0.541	0.65 (0.36, 1.17)	0.152
CSA	1.66 (1.39, 1.98)	<0.001*	0.90 (0.75, 1.08)	0.256
HCQ	1.12 (1.03, 1.21)	0.011*	0.57 (0.50, 0.65)	<0.001*
Prednisolone	0.81 (0.74, 0.89)	<0.001*	0.67 (0.60, 0.74)	<0.001*
MTX	0.95 (0.88, 1.03)	0.230	0.58 (0.53, 0.64)	<0.001*
SSZ	0.42 (0.38, 0.45)	<0.001*	0.65 (0.59, 0.71)	<0.001*
LEF	0.60 (0.50, 0.71)	<0.001*	0.62 (0.51, 0.74)	<0.001*
AZA	0.99 (0.83, 1.18)	0.929	0.96 (0.81, 1.15)	0.694

Notes: Reference for DMARD group: other nonbiologic DMARDs without TNF inhibitors, CSA, or HCQ.

a Daily average-equivalent dose in the 1 year before the index date.

* P<0.05 indicates a significant association with DM.

Abbreviations: HR, hazard ratio; DM, diabetes mellitus; CI, confidence interval; AS, ankylosing spondylitis; RA, rheumatoid arthritis; PS/PSA, psoriasis/psoriatic arthritis; CCI, Charlson comorbidity index; DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor; CSA, cyclosporine; HCQ, hydroxychloroquine; MTX, methotrexate; SSZ, sulfasalazine; LEF, leflunomide; AZA, azathioprine.

Table 4 Multivariable analysis of risk factors for DM with stratification by disease duration

Variable	Duration ≤5 years (n=64,440)		Duration >5–10 years (n=11,810)		Duration >10 years (n=5,932)
	Adjusted HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
Age	1.04 (1.03, 1.04)	<0.001*	1.03 (1.02, 1.04)	<0.001*	1.02 (1.00, 1.04)	0.109
Sex (male to female)	1.07 (0.97, 1.18)	0.196	0.96 (0.73, 1.24)	0.732	0.91 (0.47, 1.73)	0.763
Disease group
AS	Reference		Reference		Reference
RA	1.82 (1.52, 2.18)	<0.001*	2.79 (1.51, 5.17)	0.001*	0.83 (0.23, 2.97)	0.773
PS/PSA	2.90 (2.43, 3.44)	<0.001*	4.96 (2.93, 8.43)	<0.001*	0.82 (0.32, 2.14)	0.686
Pretreatment CCI
0	Reference		Reference		Reference
1	1.04 (0.93, 1.17)	0.445	0.88 (0.63, 1.23)	0.470	2.55 (1.26, 5.17)	0.009*
2–4	1.24 (1.09, 1.41)	0.001*	1.39 (0.99, 1.95)	0.060	2.26 (0.96, 5.34)	0.063
≥5	1.41 (1.09, 1.82)	0.009*	1.15 (0.62, 2.14)	0.656	1.66 (0.37, 7.40)	0.506
Pretreatment prednisolone dose a
None	Reference		Reference		Reference
≤1 mg/day	1.35 (1.22, 1.50)	<0.001*	1.28 (0.95, 1.73)	0.101	1.48 (0.73, 2.99)	0.281
>1 mg/day	1.44 (1.25, 1.66)	<0.001*	1.61 (1.12, 2.32)	0.009*	1.21 (0.52, 2.80)	0.658
DMARD group	Reference		Reference		Reference
Anti-TNF (CSA/HCQ: −/−)	0.87 (0.53, 1.41)	0.568	1.10 (0.64, 1.90)	0.719	0.68 (0.30, 1.55)	0.356
Anti-TNF (CSA/HCQ: +/−)	1.20 (0.44, 3.26)	0.715	0.44 (0.10, 1.86)	0.261	NA
Anti-TNF (CSA/HCQ: −/+)	0.41 (0.26, 0.67)	<0.001*	0.42 (0.22, 0.78)	0.006*	0.20 (0.04, 1.11)	0.066
Anti-TNF (CSA/HCQ: +/+)	1.15 (0.60, 2.20)	0.675	0.17 (0.04, 0.75)	0.019*	NA	0.984
CSA	0.92 (0.75, 1.14)	0.440	0.79 (0.52, 1.21)	0.277	0.31 (0.07, 1.34)	0.117
HCQ	0.57 (0.50, 0.66)	<0.001*	0.51 (0.34, 0.77)	0.001*	0.12 (0.03, 0.56)	0.007*
Prednisolone	0.66 (0.58, 0.74)	<0.001*	0.63 (0.48, 0.84)	0.001*	1.33 (0.69, 2.59)	0.394
MTX	0.61 (0.55, 0.67)	<0.001*	0.47 (0.35, 0.63)	<0.001*	0.34 (0.17, 0.67)	0.002*
SSZ	0.61 (0.55, 0.67)	<0.001*	0.97 (0.75, 1.24)	0.792	0.57 (0.29, 1.10)	0.094
LEF	0.58 (0.47, 0.71)	<0.001*	0.71 (0.47, 1.08)	0.109	0.74 (0.27, 2.01)	0.560
AZA	1.01 (0.83, 1.22)	0.934	0.65 (0.36, 1.19)	0.162	1.07 (0.31, 3.71)	0.911

Notes: Reference for DMARD group: other nonbiologic DMARDs without TNF inhibitors, CSA, or HCQ. NA indicates HR not available due to no new cases of DM.

a Daily average-equivalent dose within 1 year before the index date.

* Significant association with DM.

Abbreviations: DM, diabetes mellitus; HR, hazard ratio; CI, confidence interval; AS, ankylosing spondylitis; RA, rheumatoid arthritis; PS/PSA, psoriasis/psoriatic arthritis; CCI, Charlson comorbidity index; DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor; CSA, cyclosporine; HCQ, hydroxychloroquine; NA, not available; MTX, methotrexate; SSZ, sulfasalazine; LEF, leflunomide; AZA, azathioprine.

Table 5 Multivariable analysis of factors associated with DM with stratification by type of disease

Variable	AS (n=36,187)		RA (n=30,527)		PS/PSA (n=15,468)
	Adjusted HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
Age	1.06 (1.05, 1.06)	<0.001*	1.03 (1.03, 1.03)	<0.001*	1.03 (1.02, 1.03)	<0.001*
Sex (male to female)	1.33 (1.07, 1.64)	0.009*	1.04 (0.91, 1.19)	0.581	0.99 (0.84, 1.17)	0.911
Disease duration
≤5 years	Reference		Reference		Reference
>5–10 years	0.76 (0.49, 1.20)	0.243	0.87 (0.68, 1.11)	0.266	0.78 (0.65, 0.94)	0.008*
>10 years	1.68 (0.72, 3.94)	0.228	0.66 (0.32, 1.35)	0.257	0.33 (0.22, 0.50)	<0.001*
Pretreatment CCI
0	Reference		Reference		Reference
1	1.05 (0.83, 1.33)	0.682	0.92 (0.80, 1.06)	0.262	1.10 (0.88, 1.37)	0.398
2–4	1.60 (1.21, 2.11)	<0.001*	1.13 (0.96, 1.32)	0.144	1.16 (0.90, 1.49)	0.265
≥5	1.48 (0.88, 2.51)	0.141	1.19 (0.87, 1.64)	0.280	1.30 (0.82, 2.06)	0.260
Pretreatment prednisolone dose a
None	Reference		Reference		Reference
≤1 mg/day	1.35 (1.11, 1.64)	0.003*	1.44 (1.25, 1.66)	<0.001*	1.26 (1.05, 1.51)	0.012*
>1 mg/day	1.31 (0.99, 1.73)	0.062	1.57 (1.31, 1.90)	<0.001*	1.50 (1.15, 1.95)	0.003*
DMARD group	Reference		Reference		Reference
Anti-TNF (CSA/HCQ: −/−)	0.95 (0.44, 2.04)	0.897	0.90 (0.62, 1.32)	0.592	1.39 (0.66, 2.93)	0.379
Anti-TNF (CSA/HCQ: +/−)	NA		0.83 (0.36, 1.92)	0.666	NA
Anti-TNF (CSA/HCQ: −/+)	NA		0.39 (0.27, 0.58)	<0.001*	0.44 (0.06, 3.16)	0.412
Anti-TNF (CSA/HCQ: +/+)	NA		0.58 (0.31, 1.08)	0.086	NA
CSA	1.11 (0.40, 3.06)	0.844	0.92 (0.60, 1.43)	0.719	0.81 (0.66, 1.01)	0.059
HCQ	0.54 (0.39, 0.75)	<0.001*	0.51 (0.43, 0.61)	<0.001*	0.43 (0.32, 0.59)	<0.001*
Prednisolone	0.70 (0.58, 0.84)	<0.001*	0.62 (0.51, 0.75)	<0.001*	0.64 (0.54, 0.77)	<0.001*
MTX	0.83 (0.66, 1.05)	0.127	0.59 (0.52, 0.67)	<0.001*	0.35 (0.28, 0.43)	<0.001*
SSZ	0.35 (0.25, 0.47)	<0.001*	0.69 (0.61, 0.78)	<0.001*	0.63 (0.53, 0.76)	<0.001*
LEF	1.53 (0.72, 3.25)	0.273	0.59 (0.48, 0.73)	<0.001*	0.58 (0.39, 0.88)	0.010*
AZA	1.04 (0.64, 1.68)	0.877	1.05 (0.83, 1.33)	0.677	0.60 (0.42, 0.87)	0.007*

Notes: Reference for DMARD group: other nonbiologic DMARDs without TNF inhibitors, CSA, or HCQ. NA indicates HR not available due to no new cases of DM.

a Daily average-equivalent dose within 1 year before the index date.

* Significant association with DM.

Abbreviations: DM, diabetes mellitus; AS, ankylosing spondylitis; RA, rheumatoid arthritis; PS/PSA, psoriasis/psoriatic arthritis; HR, hazard ratio; CI, confidence interval; CCI, Charlson comorbidity index; DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor; CSA, cyclosporine; HCQ, hydroxychloroquine; NA, not available; MTX, methotrexate; SSZ, sulfasalazine; LEF, leflunomide; AZA, azathioprine.