Hydroxychloroquine and risk of development of cancers: a nationwide population-based cohort study

Figures & data

Figure 1 Flow chart for subject selection process.

Notes: From 2000 to 2013, 7,662 patients diagnosed with RA, SLE, psoriasis, Sjögren’s syndrome, scleroderma, or polymyositis were identified in the NHIRD. A total of 6,541 patients were eligible for subsequent analysis after exclusion. After propensity score matching, 1,993 subjects were assigned to each group. A total of 1,112 patients were excluded: 1) 189 patients for incomplete demographics, 2) 160 patients for being an age of <18 or >100 years, 3) 194 patients for having a previous cancer, and 4) 578 patients for having a follow-up period of ≤1 year.
Abbreviations: HCQ, hydroxychloroquine; NHIRD, National Health Insurance Research Database.

Table 1 Demographics and clinical characteristics of the study population

Characteristic	Before propensity score-matched data			After propensity score-matched data
	HCQ =0 (N=3,133)	HCQ =1 (N=3,408)	P-value	HCQ =0 (N=1,993)	HCQ =1 (N=1,993)	P-value
Age (years)	49.77±14.96	50.16±15.34	0.293	50.95±13.66	50.96±13.69	0.983
Gender, male, n (%)	900 (28.73)	604 (17.72)	<0.001	312 (15.65)	312 (15.65)	1.000
Autoimmune diseases, n (%)
Rheumatoid arthritis	1,370 (43.73)	1,565 (45.92)		1,098 (55.09)	1,098 (55.09)	1.000
Systemic lupus erythematosus	242 (7.72)	612 (17.96)		159 (7.98)	159 (7.98)
Sjögren’s syndrome	1,008 (32.17)	1,162 (34.1)		720 (36.13)	720 (36.13)
Psoriasis	428 (13.66)	15 (0.44)		7 (0.35)	7 (0.35)
Scleroderma	51 (1.63)	36 (1.06)		8 (0.4)	8 (0.4)
Polymyositis	34 (1.09)	18 (0.53)		1 (0.05)	1 (0.05)
Geographic location, n (%)
Northern Taiwan	1,494 (47.69)	1,463 (42.93)	<0.001	931 (46.71)	919 (46.11)	0.796
Central Taiwan	856 (27.32)	971 (28.49)		543 (27.25)	558 (28)
Southern Taiwan	723 (23.08)	911 (26.73)		470 (23.58)	475 (23.83)
Eastern Taiwan and Islands	60 (1.92)	63 (1.85)		49 (2.46)	41 (2.06)
Clinic visit frequency	28.82±18.69	31.92±17.29	<0.001
Monthly income, NTD	18,972.97±16,411.45	17,407.22±14,733.16	<0.001	17,580.58±14,579.27	18,301.88±15,124.61	0.125
Comorbidities
CCIS	1.33±1.49	1.34±1.53	0.741	1.35±1.47	1.32±1.5	0.639
Hypertension, n (%)	716 (22.85)	802 (23.53)	0.516	453 (22.73)	453 (22.73)	1.000
Hyperlipidemia, n (%)	449 (14.33)	444 (13.03)	0.125	284 (14.25)	276 (13.85)	0.715
Diabetes mellitus, n (%)	273 (8.71)	274 (8.04)	0.325	164 (8.23)	175 (8.78)	0.532
CAD, n (%)	281 (8.97)	293 (8.6)	0.596	161 (8.08)	165 (8.28)	0.817
CHF, n (%)	76(2.43)	96 (2.82)	0.323	45 (2.26)	48 (2.41)	0.753
Stroke, n (%)	156 (4.98)	172 (5.05)	0.900	92 (4.62)	90 (4.52)	0.879
COPD, n (%)	364 (11.62)	420 (12.32)	0.380	229 (11.49)	217 (10.89)	0.547
Alcohol-related disease, n (%)	21 (0.67)	21 (0.62)	0.784	10 (0.5)	11 (0.55)	0.827
Long-term medications, n (%)
Antidiabetic drugs	236 (7.53)	247 (7.25)	0.660	130 (6.52)	142 (7.12)	0.451
Antihypertensive drugs	923 (29.46)	1,121 (32.89)	0.003	557 (27.95)	544 (27.3)	0.645
ACEIs/ARBs	475 (15.16)	573 (16.81)	0.069	261 (13.1)	276 (13.85)	0.487
Diuretics	281 (8.97)	372 (10.92)	0.009	162 (8.13)	160 (8.03)	0.907
NSAIDs	465 (14.84)	627 (18.4)	<0.001	291 (14.6)	297 (14.9)	0.789
Analgesic drugs other than NSAIDs	497 (15.86)	691 (20.28)	<0.001	285 (14.3)	300 (15.05)	0.502
Glucocorticoids	477 (15.23)	1,105(32.42)	<0.001	262 (13.15)	273 (13.7)	0.609
TNF-α inhibitors	117 (3.73)	196 (5.75)	<0.001	63 (3.16)	82 (4.11)	0.108
Other immunosuppressants	362 (11.55)	523 (15.35)	<0.001	108 (5.42)	164 (8.23)	<0.001
Propensity score	0.49±0.1	0.55±0.12	<0.001	0.5±0.09	0.5±0.09	0.874
cDDD of HCQ within 1 year	0±0	111.13±86.75	<0.001	0±0	99.83±83.73	<0.001
Outcome, n (%)
Cancer	135 (4.31)	123 (3.61)		93 (4.67)	77 (3.86)
Death	184 (5.87)	200 (5.87)		111 (5.57)	113 (5.67)
Follow-up time (years)	7.64±3.7	6.75±3.73	<0.001	7.82±3.68	6.7±3.73	<0.001

Abbreviations: CAD, coronary artery disease; cDDD, cumulative defined daily dose; CHF, congestive heart failure; HCQ, hydroxychloroquine.

Figure 2 Kaplan–Meier curves for cumulative incidence of cancer, HCQ nonuser and user.

Note: No significant different cumulative incidence of cancer between HCQ user and nonuser.
Abbreviation: HCQ, hydroxychloroquine.

Figure 3 Kaplan–Meier curves for cumulative incidence of cancer with various cDDDs of HCQ.

Note: The incidence of cancer was not significantly increased in larger cDDD of HCQ group.
Abbreviations: cDDDs, cumulative defined daily doses; HCQ, hydroxychloroquine.

Figure 4 Kaplan–Meier curves for cumulative incidence of cancer with various prescribed daily dose of HCQ.

Note: Prescribed daily dose did not affect the incidence of cancer significantly.
Abbreviation: HCQ, hydroxychloroquine.

Table 2 Incidences and hazard ratios of cancer in hydroxychloroquine users compared with nonusers

Cohorts	Before matched data						After matched data
	Events (n/N)	Incidencea	aHRb (95% CI)	P-value	aHRb (95% CI)	P-value	Events (n/N)	Incidence	cHRb (95% CI)	P-value	aHRb (95% CI)	P-value
Hydroxychloroquine use
Nonusers	135/3,133	5.64 (4.69–6.59)	1		1		93/1,993	5.97 (4.75–7.18)	1		1
User	123/3,408	5.35 (4.40–6.30)	0.97 (0.76–1.24)	0.807	0.901 (0.70–1.16)	0.420	77/1,993	5.77 (4.48–7.05)	1.015 (0.75–1.37)	0.921	1.027 (0.76–1.39)	0.863
cDDD
0	135/3,133	5.64 (4.69–6.59)	1		1		93/1,993	5.97 (4.75–7.18)	1		1
1–142	84/2,256	5.58 (4.39–6.78)	1.016 (0.77–1.33)	0.909	0.944 (0.72–1.25)	0.686	56/1,432	5.87 (4.33–7.41)	1.038 (0.74–1.45)	0.824	1.077 (0.77–1.5)	0.661
>142	39/1,152	4.91 (3.37–6.45)	0.895 (0.63–1.28)	0.540	0.819 (0.56–1.19)	0.294	21/561	5.50 (3.15–7.86)	0.981 (0.61–1.57)	0.937	0.933 (0.58–1.50)	0.774
P for trend				0.959		0.912				0.995		0.934
Prescribed daily dose
0 mg	135/3,133	5.64 (4.69–6.59)	1		1		93/1,993		1		1
≤200 mg	29/935	4.87 (3.1–6.65)	0.905 (0.61–1.35)	0.624	0.876 (0.59–1.31)	0.521	21/591		1.031 (0.64–1.65)	0.898	1.088 (0.68–1.75)	0.728
≤400 mg	49/1,494	4.87 (3.51–6.23)	0.888 (0.64–1.23)	0.476	0.826 (0.59–1.16)	0.265	33/839		1.050 (0.71–1.56)	0.811	1.051 (0.71–1.57)	0.805
>400 mg	45/979	6.45 (4.57–8.34)	1.167 (0.83–1.63)	0.369	1.044 (0.74–1.47)	0.808	23/563		0.997 (0.63–1.57)	0.991	0.986 (0.63–1.55)	0.951
P for trend				0.739		0.760				0.952		0.975

Notes: Model was adjusted for age, gender, type of autoimmune diseases, and propensity score.

a Per 1,000 person-years.

b All analyses incorporated in regard to death as competing risks.

Abbreviations: aHR, adjusted hazard ratio; cDDD, cumulative defined daily dose; cHR, crude hazard ratio.

Table 3 Results of subgroup analysis for cancer incidence of HCQ users and nonusers stratified by various confounders

Subgroup	Overall patients						Propensity score-matched data
	HCQ nonuser		HCQ user		aHR (95% CI)	P-value	HCQ nonuser		HCQ user		aHR (95% CI)	P-value	PInt
	Events (n/N)	Incidence	Events (n/N)	Incidence			Events (n/N)	Incidence	Events (n/N)	Incidence
Age (years)
<50	35/1,534	2.78 (1.86–3.7)	42/1,633	3.49 (2.44–4.55)	1.06 (0.65–1.72)	0.814	26/891	3.5 (2.15 to 4.84)	29/889	4.50 (2.86 to 6.14)	1.366 (0.8–2.32)	0.250	0.266
50–64	52/1,071	6.59 (4.8–8.38)	36/1,118	5.02 (3.38–6.66)	0.82 (0.53–1.27)	0.376	40/767	6.88 (4.75 to 9.02)	28/762	5.76 (3.63 to 7.9)	0.910 (0.56–1.48)	0.704
≥65	48/528	13.82 (9.91–17.73)	45/657	11.87 (8.4–15.34)	0.833 (0.55–1.27)	0.391	27/335	11.54 (7.18 to 15.89)	20/342	9.74 (5.47 to 14.01)	0.893 (0.50–1.60)	0.702
Gender
Female	93/2,233	5.34 (4.26–6.43)	95/2,804	4.99 (3.98–5.99)	0.921 (0.68–1.24)	0.589	79/1,681	5.98 (4.66 to 7.29)	66/1,681	5.88 (4.46 to 7.30)	1.057 (0.76–1.47)	0.740	0.694
Male	42/900	6.42 (4.48–8.36)	28/604	7.1 (4.47–9.73)	0.845 (0.51–1.39)	0.507	14/312	5.91 (2.82 to 9.01)	11/312	5.16 (2.11 to 8.20)	0.908 (0.41–2.01)	0.812
Comorbidity
No	56/1,835	3.87 (2.85–4.88)	54/2,035	3.79 (2.78–4.81)	0.924 (0.63–1.37)	0.694	40/1,161	4.32 (2.98 to 5.66)	40/1,215	4.78 (3.3 to 6.27)	1.172 (0.76–1.82)	0.479	0.447
Yes	79/1,298	8.34 (6.5–10.18)	69/1,373	7.88 (6.02–9.74)	0.885 (0.63–1.24)	0.475	53/832	8.38 (6.12 to 10.63)	37/778	7.41 (5.02 to 9.80)	0.927 (0.61–1.41)	0.725
Autoimmune diseases
Rheumatoid arthritis	69/1,370	6.32 (4.83–7.81)	60/1,565	5.49 (4.1–6.88)	0.872 (0.61–1.24)	0.442	54/1,098	6.05 (4.44 to 7.66)	46/1,098	5.98 (4.25 to 7.70)	1.068 (0.72–1.58)	0.743	0.902
Systemic lupus erythematosus	9/242	4.47 (1.55–7.39)	19/612	4.27 (2.35–6.19)	0.629 (0.27–1.46)	0.282	9/159	6.71 (2.33 to 11.1)	7/159	6.06 (1.57 to 10.56)	0.899 (0.33–2.44)	0.835
Sjögren’s syndrome	41/1,008	5.64 (3.92–7.37)	40/1,162	5.55 (3.83–7.27)	0.905 (0.57–1.42)	0.667	29/720	5.59 (3.56 to 7.63)	23/720	5.24 (3.1 to 7.38)	1.010 (0.58–1.75)	0.973
Others	16/513	4.27 (2.18–6.36)	4/69	9.91 (0.2–19.62)	2.176 (0.59–7.98)	0.241	1/16	7.32 (−7.03 to 21.68)	1/16	8.58 (−8.24 to 25.41)	1.261 (0.08–20.56)	0.871

Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; HCQ, hydroxychloroquine.

Table 4 Risk of solid cancer and hematological cancer

Cancer	Event in patients without HCQ user	Event in patients with HCQ user	cHR (95% CI)	P-value	aHR (95% CI)	P-value
Hematological malignancy	1	1	1.07 (0.07–17.17)	0.962	0.953 (0.05–16.52)	0.9737
Solid cancer	134	122	0.969 (0.76–1.24)	0.8029	0.9 (0.7–1.16)	0.4172
Head and neck	6	10	1.497 (0.53–4.2)	0.4431	1.718 (0.57–5.18)	0.3363
Esophagus	2	0	–		–
Stomach	4	10	2.442 (0.78–7.67)	0.1261	1.858 (0.58–5.98)	0.2984
Small intestine	0	1	–		–
Colon	16	16	1.076 (0.54–2.15)	0.8361	0.925 (0.45–1.89)	0.8299
Liver	16	16	1.059 (0.53–2.12)	0.8711	1.167 (0.57–2.4)	0.6752
Pancreas	2	0	–		–
Lung	14	15	1.128 (0.54–2.34)	0.7457	1.019 (0.48–2.16)	0.9616
Skin	0	1	–		–
Female breast	31	26	0.791 (0.47–1.33)	0.3792	0.75 (0.43–1.3)	0.3025
Uterus	10	10	0.951 (0.4–2.29)	0.9112	0.741 (0.3–1.84)	0.5189
Prostate	7	2	0.551 (0.12–2.5)	0.4395	0.438 (0.09–2.1)	0.3019
Bladder	6	5	0.883 (0.27–2.89)	0.8369	0.941 (0.28–3.2)	0.9217
Kidney	8	3	0.446 (0.12–1.64)	0.224	0.484 (0.13–1.86)	0.2915
Brain	1	0	–		–
Thyroid	4	5	1.313 (0.35–4.89)	0.6844	1.532 (0.39–5.95)	0.5377

Abbreviations: aHR, adjusted hazard ratio; cHR, crude hazard ratio; CI, confidence interval; HCQ, hydroxychloroquine.

Table 5 Results of sensitivity analyses

	Overall patients		Propensity score-matched data
	aHR (95% CI)	P-value	aHR (95% CI)	P-value
Multivariate model adjusted for covariate in Table 1
Nonusers	1		1
Users	0.903 (0.7–1.17)	0.435	1.034 (0.76–1.4)	0.729
Hydroxychloroquine use at intervals 90 days after first disease diagnosis
Nonusers	1		1
Users	0.929 (0.72–1.2)	0.569	0.946 (0.69–1.3)	0.729
Hydroxychloroquine use at intervals 150 days after first disease diagnosis
Nonusers	1		1
Users	0.918 (0.71–1.18)	0.5119	0.962 (0.7–1.31)	0.806
Hydroxychloroquine use at intervals 180 days after first disease diagnosis
Nonusers	1		1
Users	0.940 (0.73–1.21)	0.6328	1.038 (0.76–1.42)	0.815
As treat model
Nonusers	1		1
Users	0.931 (0.68–1.27)	0.649	1.042 (0.7–1.54)	0.8387
Patients who were followed up for >7 years
Nonusers	1		1
Users	0.94 (0.59–1.5)	0.7956	1.024 (0.62–1.69)	0.9259
Patients who were followed up for >10 years
Nonusers	1		1
Users	1.109 (0.48–2.59)	0.8104	1.127 (0.47–2.68)	0.7861
After removal of patients with other immunosuppressants
Nonusers	1		1
Users	0.892 (0.68–1.17)	0.404	0.992 (0.72–1.36)	0.9581

Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval.