Use of Immunomodulating Drugs and Risk of Cutaneous Melanoma: A Nationwide Nested Case-Control Study

Figures & data

Table 1 Characteristics of Cases and Controls in the Study Sample

Characteristics		Cases (n=12,106) No. (%)	Controls (n=118,564) No. (%)
Sex
Men		5988 (49.5)	58,309 (49.2)
Women		6118 (50.5)	60,255 (50.8)
Age at diagnosis/index date, years
<50		3163 (26.1)	30,348 (25.6)
50–69		5616 (46.4)	55,279 (46.6)
≥70		3327 (27.5)	32,937 (27.8)
Residential ambient UVR^a exposure
Lowest (northern Norway)		717 (5.9)	11,906 (10.0)
Medium (central/western Norway)		1725 (14.3)	19,445 (16.4)
Highest (southern/eastern Norway)		9664 (79.8)	87,213 (73.6)
Parity (women only)
No children		1864 (30.5)	18,994 (31.5)
1–3 children		3895 (63.7)	36,942 (61.3)
>3 children		359 (5.8)	4319 (7.2)
Tumor site
Head/neck		1315 (10.9)	–
Trunk		5661 (46.8)	–
Upper limb		1559 (12.9)	–
Lower limb		2869 (23.7)	–
Other		52 (0.4)	–
Unspecified		650 (5.3)	–
Histological subtype
Superficial spreading melanoma		6656 (55.0)	–
Nodular melanoma		2079 (17.2)	–
Other		3371 (27.8)	–
Clinical stage
Local disease		9833 (81.2)	–
Regional metastasis		573 (4.7)	–
Distant metastasis		635 (5.2)	–
Unspecified		1065 (8.8)	–
Use of immunomodulating drugs ^b
Overall use by number of prescriptions
≤1		11,029 (91.1)	107,998 (91.1)
2–7		647 (5.3)	6791 (5.7)
≥8		430 (3.6)	3775 (3.2)
Use by number of prescriptions of each drug type
≤1		11,029 (91.1)	107,998 (91.1)
I. Immunosuppressants (L04)^c
2–7		14 (0.1)	190 (0.1)
≥8		40 (0.3)	343 (0.3)
II. Corticosteroids (H02)^d
2–7		612 (5.0)	6392 (5.4)
≥8		201 (1.7)	2123 (1.8)
Use by cumulative dose (DDD^e)
0		10,283 (84.9)	100,488 (84.8)
I. Immunosuppressants overall (L04)^c
1–365		11 (0.1)	197 (0.2)
366–1100		23 (0.2)	189 (0.2)
1101–1800		13 (0.1)	89 (0.1)
1801–2900		6 (0.05)	96 (0.1)
≥2901		6 (0.05)	39 (0.0)
II. Corticosteroids overall (H02)^d
1–365		1353 (11.2)	13,793 (11.6)
366–1100		137 (1.1)	1580 (1.3)
1101–1800		43 (0.4)	342 (0.3)
1801–2900		17 (0.1)	164 (0.1)
≥2901		4 (0.05)	69 (0.0)
Ever use of other drugs
Antidepressant drugs (N06A)^f		1870 (15.4)	20,243 (17.1)
Cardiovascular drugs (C1–10)^g		5840 (48.2)	56,263 (47.5)
Other drugs^h		5450 (45.0)	52,964 (44.7)

Notes: ^aUltraviolet radiation; ^bDoes not show number of individuals dispensed both immunosuppressant and corticosteroid prescriptions (mixed use); ^cUsers of immunosuppressants only; ^dUsers of corticosteroids only; ^eDefined daily dose; ^fUse of antidepressants, but not cardiovascular drugs; ^gUse of cardiovascular drugs, but not antidepressants; ^hUse of all other drugs other than antidepressant or cardiovascular drugs.

Table 2 Rate Ratios (RRs) with 95% Confidence Intervals (CIs) for Number of Prescriptions of Immunomodulating Drugs and Melanoma Risk

Number of Prescriptions	No. Case/Controls	RR (95% CI)^a
Immunosuppressants overall (L04)^b
≤1	11,858/116,663	1.00 (reference)
2–7	63/637	0.98 (0.75, 1.28)
≥8	185/1264	1.50 (1.27, 1.77)
OTR^c drugs (L04AA06/10/18, L04AD01/02)^d
≤1	12,069/118,363	1.00 (reference)
2–7	6/50	1.11 (0.47, 2.61)
≥8	31/151	2.02 (1.35, 3.03)
Methotrexate (L04AX03)^e
≤1	11,950/117,270	1.00 (reference)
2–3^f	22/267	0.79 (0.51, 1.22)
≥4^f	134/1027	1.27 (1.04, 1.55)
Other drugs with immunosuppressant actions (L04AA13/21/24/27/31, L04AB01/02/04/05/06, L04AC03/05, L04AX01/02/05)^g
≤1	12,002/117,736	1.00 (reference)
2–7	27/249	1.00 (0.66, 1.50)
≥8	77/579	1.19 (0.91, 1.54)
Systemic corticosteroids (H02)^h
≤1	11,101/108,721	1.00 (reference)
2–7	691/6917	0.96 (0.88, 1.04)
≥8	314/2926	0.98 (0.86, 1.11)

Notes: ^aEstimated RRs with 95% CIs, due to risk-set sampling of controls, adjusted for sex and birth year (by design) and ever use of other drugs and residential ambient ultraviolet radiation exposure; ^bAdditionally adjusted for number of systemic corticosteroid prescriptions; ^cOrgan transplant recipient; ^dAdditionally adjusted for number of non-organ transplant immunosuppressants and systemic corticosteroid prescriptions; ^eAdditionally adjusted for number of non-methotrexate immunosuppressants and systemic corticosteroid prescriptions; ^fMethotrexate prescription categories compensate for comparatively longer duration of use; ^gAdditionally adjusted for number of organ transplant and methotrexate immunosuppressant and systemic corticosteroid prescriptions; ^hAdditionally adjusted for number of immunosuppressant prescriptions.

Table 3 Rate Ratios (RRs) with 95% Confidence Intervals (CIs) for Cumulative Defined Daily Dose (DDD) of Immunomodulating Prescription Drugs and Melanoma Risk

Cumulative Dose, DDD	No. Case/Controls	RR (95% CI)^a
Immunosuppressants overall (L04)^b
0	11,837/116,436	1.14 (0.86, 1.50)
1–365	56/635	1 (Reference)
366–1100	92/657	1.61 (1.13, 2.29)
1101–1800	52/344	1.75 (1.17, 2.61)
1801–2900	38/297	1.45 (0.94, 2.25)
≥2901	31/195	1.75 (1.09, 2.80)
OTR^c drugs (L04AA06/10/18, L04AD01/02)^d
0	12,067/118,352	0.79 (0.41, 1.55)
1–365	10/74	1 (Reference)
366–1800	12/71	1.36 (0.55, 3.37)
≥1801	17/67	1.81 (0.76, 4.30)
Methotrexate (L04AX03)^e
0	11,927/117,072	1.07 (0.78, 1.46)
1–365	45/472	1 (Reference)
366–1800	104/801	1.37 (0.94, 1.98)
≥1801	30/219	1.47 (0.89, 2.40)
Other drugs with immunosuppressant actions (L04AA13/21/24/27/31, L04AB01/02/04/05/06, L04AC03/05, L04AX01/02/05)^f
0	11,994/117,628	1.11 (0.77, 1.60)
1–365	34/343	1 (Reference)
366–1800	59/426	1.34 (0.85, 2.09)
≥1801	19/167	1.07 (0.59, 1.95)
Systemic corticosteroids (H02)^g
0	10,342/101,098	1.04 (0.98, 1.11)
1–365	1445/14,450	1 (Reference)
366–1100	203/2080	0.95 (0.81, 1.11)
1101–1800	69/569	1.11 (0.85, 1.45)
1801–2900	36/268	1.21 (0.85, 1.74)
≥2901	16/99	1.54 (0.90, 2.63)

Notes: ^aEstimated RRs with 95% CIs, due to risk-set sampling of controls, adjusted for sex and birth year (by design) and ever use of other drugs and residential ambient ultraviolet radiation exposure; ^bAdditionally adjusted for cumulative corticosteroid dose; ^cOrgan transplant recipient; ^dAdditionally adjusted for cumulative dose of non-organ transplant immunosuppressants and systemic corticosteroids; ^eAdditionally adjusted for cumulative dose of non-methotrexate immunosuppressants and systemic corticosteroids; ^fAdditionally adjusted for cumulative dose of organ transplant immunosuppressants, methotrexate and systemic corticosteroids; ^gAdditionally adjusted for cumulative dose of immunosuppressants.

Table 4 Rate Ratios (RRs) with 95% Confidence Intervals (CIs) for Melanoma Risk for 2–7 and ≥8 vs ≤1 Prescription of Immunosuppressants and Systemic Corticosteroids, Stratified by Sex, Age at Diagnosis/Index Date and Residential Ambient Ultraviolet Radiation (UVR) Exposure

Variables	2–7 and ≥8 Prescriptions vs ≤1 Prescription
	Immunosuppressants (L04)	Systemic Corticosteroids (H02)
	RR (95% CI)^a	RR (95% CI)^b
Sex^c
Men
≤1	1.00	1.00
2–7	1.25 (0.87, 1.80)	0.93 (0.82, 1.05)
≥8	1.36 (1.05, 1.77)	0.80 (0.65, 0.98)
Women
≤1	1.00	1.00
2–7	0.79 (0.54, 1.16)	0.98 (0.88, 1.09)
≥8	1.60 (1.29, 1.98)	1.12 (0.95, 1.31)
Pinteraction^f	0.068	0.018
Age at diagnosis/index date^d, years
<50
≤1	1.00	1.00
2–7	0.89 (0.46, 1.72)	1.04 (0.86, 1.24)
≥8	1.16 (0.74, 1.82)	1.15 (0.77, 1.73)
50–69
≤1	1.00	1.00
2–7	1.18 (0.83, 1.69)	0.91 (0.81, 1.04)
≥8	1.47 (1.17, 1.85)	0.98 (0.80, 1.20)
>70
≤1	1.00	1.00
2–7	0.76 (0.46, 1.26)	0.97 (0.85, 1.11)
≥8	1.72 (1.29, 2.29)	0.94 (0.79, 1.13)
Pinteraction^f	0.174	0.405
Residential ambient UVR exposure^e
Low (northern Norway)
≤1	1.00	1.00
2–7	0.14 (0.02, 1.23)	0.84 (0.46, 1.53)
≥8	0.77 (0.27, 2.18)	1.30 (0.60, 2.84)
Medium (central/western Norway)
≤1	1.00	1.00
2–7	1.14 (0.44, 2.90)	0.90 (0.68, 1.19)
≥8	2.36 (1.26, 4.45)	0.47 (0.27, 0.81)
Highest (southern/eastern Norway)
≤1	1.00	1.00
2–7	1.02 (0.76, 1.37)	0.95 (0.87, 1.04)
≥8	1.52 (1.26, 1.85)	1.01 (0.87, 1.16)
Pinteraction^f	0.105	0.064

Notes: ^aEstimated RRs with 95% CIs, due to risk-set sampling of controls, adjusted for number of corticosteroid prescriptions; ^bAdjusted for number of immunosuppressant prescriptions; ^cAdjusted for age (by design), ever use of other drugs and residential ambient UVR exposure; ^dAdjusted for sex (by design) ever use of other drugs and residential ambient UVR; ^eAdjusted for sex and age (by design) and ever use of other drugs; ^fInteraction is analyzed on a multiplicative scale.

Table 5 Rate Ratios (RRs) with 95% Confidence Intervals (CIs) for 2–7 and ≥8 vs ≤1 Prescription of Immunosuppressants and Systemic Corticosteroids, and Melanoma Risk, Stratified by Tumor Site, Histological Subtype, and Clinical Stage at Diagnosis

	2–7 and ≥8 Prescriptions vs ≤1 Prescription
	Immunosuppressants (L04)	Systemic Corticosteroids (H02)
	RR (95% CI)^a	RR (95% CI)^b
Tumor site (cases/controls)
Head/neck (1315/12,842)
≤1	1.00	1.00
2–7	1.71 (0.90, 3.22)	0.98 (0.78, 1.24)
≥8	2.22 (1.45, 3.40)	1.17 (0.87, 1.57)
Trunk (5661/55,107)
≤1	1.00	1.00
2–7	1.24 (0.86, 1.79)	0.95 (0.84, 1.07)
≥8	1.67 (1.30, 2.13)	0.92 (0.75, 1.12)
Upper limb (1559/15,197)
≤1	1.00	1.00
2–7	0.31 (0.10, 0.98)	0.95 (0.76, 1.19)
≥8	1.51 (0.96, 2.36)	1.08 (0.78, 1.50)
Lower limb (2869/28,005)
≤1	1.00	1.00
2–7	0.72 (0.40, 1.31)	0.93 (0.78, 1.10)
≥8	1.01 (0.70, 1.47)	0.96 (0.73, 1.27)
Other (52/511)
≤1	1.00	1.00
2–7	1.04*-8 (0, NA)	1.04 (0.29, 3.68)
≥8	2.27 (0.21, 25.09)	0.37 (0.04, 3.00)
Unspecified (650/6357)
≤1	1.00	1.00
2–7	0.96 (0.29, 3.21)	1.08 (0.77, 1.51)
≥8	1.04 (0.43, 2.49)	0.68 (0.36, 1.28)
Pheterogeneity	0.112	0.507
Histological subtype (cases/controls)
SSM^c (6656/64,826)
≤1	1.00	1.00
2–7	0.90 (0.62, 1.31)	0.97 (0.87, 1.08)
≥8	1.41 (1.12, 1.76)	0.99 (0.83, 1.19)
NM^d (2079/20,330)
≤1	1.00	1.00
2–7	1.02 (0.56, 1.87)	0.92 (0.75, 1.12)
≥8	1.56 (1.06, 2.31)	1.10 (0.83, 1.45)
Other^e (3371/32,863)
≤1	1.00	1.00
2–7	1.11 (0.69, 1.78)	0.96 (0.82, 1.12)
≥8	1.67 (1.21, 2.30)	0.86 (0.68, 1.10)
Pheterogeneity	0.676	0.417
Clinical stage (cases/controls)
Local disease (9833/95,842)
≤1	1.00	1.00
2–7	0.88 (0.65, 1.19)	0.95 (0.87, 1.04)
≥8	1.50 (1.26, 1.79)	1.03 (0.90, 1.18)
Regional metastasis (573/5610)
≤1	1.00	1.00
2–7	0.94 (0.28, 3.12)	0.92 (0.64, 1.33)
≥8	2.17 (1.04, 4.54)	0.73 (0.41, 1.31)
Distant metastasis (635/6216)
≤1	1.00	1.00
2–7	1.27 (0.43, 3.73)	1.01 (0.71, 1.43)
≥8	1.39 (0.60, 3.20)	0.87 (0.49, 1.54)
Unspecified (1065/10,351)
≤1	1.00	1.00
2–7	1.99 (0.95, 4.15)	1.11 (0.81, 1.54)
≥8	0.48 (0.12, 2.03)	0.58 (0.30, 1.13)
Pheterogeneity	0.338	0.260

Notes: ^aEstimated RRs with 95% CIs, due to risk-set sampling of controls, adjusted for sex and age (by design), number of corticosteroid prescriptions, ever use of other drugs, and residential ambient ultraviolet radiation exposure; ^bAdjusted for sex and age (by design), number of immunosuppressant prescriptions, ever use of other drugs, and residential ambient ultraviolet radiation exposure; ^cSuperficial spreading melanoma; ^dNodular melanoma; ^eIncludes all other histological types.