Solid extraintestinal malignancies in patients with inflammatory bowel disease

Table 5 Studies on skin cancer in patients with inflammatory bowel disease

Ref.	Type of study	Country	Patients	Follow up time	Results	Limitations
Armstrong et al[89], 2010	Nested case control	United Kingdom	16663 IBD patients; 392 developed Ca vs 1914 IBD controls	6.4 yr	NMSC with AZA use (OR 0.99, CI: 0.35-2.81)	AZA users were included but not 6MP
Long et al[167], 2010	Retrospective cohort; nested case control	United States	53377 IBD patients vs 160037 non-IBD; 742 IBD NMSC cases vs 2968 IBD controls	1.32 yr	NMSC (IRR, 1.64; 95%CI: 1.51-1.78), NMSC recent TP use (OR, 3.56; 95%CI: 2.81-4.50), recent biologics in CD (OR, 2.07; 95%CI: 1.28-3.33), persistent TP use (OR, 4.27; 95%CI: 3.08-5.92), persistent biologic use in CD (OR, 2.18; 95%CI: 1.07-4.46)	Patients aged < 64 yr, no exposure dose, short follow-up
Singh et al[168], 2011	Retrospective cohort; case control	Canada	9618 IBD patients vs 91378 non-IBD; 237 IBD NMSC cases vs 948 IBD controls	11.7 yr	BCC (HR, 1.20; 95%CI: 1.03-1.40). TP use SCC (HR, 5.40; 95%CI: 2.00-14.56) BCC (HR, 1.12; CI 0.68-1.85). Case-control: TP use SCC (OR, 20.52; 95%CI: 2.42-173.81), BCC (OR: 2.07; 95%CI: 1.10-3.87)	Do not include use of IMMs before 1995
Peyrin-Biroulet et al[171], 2011	Prospective observational cohort study (CESAME)	France	19486 IBD patients	2.55 yr	NMSC (SIR 2.89, 95%CI: 1.98-4.08) MSC (SIR 0.64, 95%CI: 0.17-1.63). NMSC: ongoing TP use (HR, 5.9; 95%CI: 2.1-16.4; P = 0.0006), past TP use (HR, 3.9; 95%CI: 1.3-12.1; P = 0.02), age per 1-yr increase (HR, 1.08; 95%CI: 1.05-1.11; P < 0.0001)	Younger patients
van Schaik et al[175], 2011	Retrospective cohort	Holland	2887 IBD patients	6.46 yr	NMSC AZA use (HR 0.85, 95%CI: 0.51-1.41)	Small study sample size
Long et al[169], 2012	Retrospective cohort; nested case-control	United States	108579 IBD vs 434 233 non-IBD controls; 209 MSC cases vs 823 IBD non-MSC controls, 3288 NMSC cases vs 12945 IBD non-NMSC controls	2 yr	MSC (HR, 1.15; 95%CI: 0.97-1.36) NMSC (HR, 1.34; 95%CI: 1.28-1.40). MSC anti-TNF (OR, 1.88; 95%CI: 1.08-3.29), long-term vs non-long-term use (OR 3.93, 95%CI: 1.82-8.50), no association with TP or 5-ASA. NMSC any TP use (OR, 1.85; 95%CI: 1.66-2.05), anti-TNF (OR, 1.14; 95%CI: 0.95-1.36), combination treatment (OR, 3.89; 95%CI: 2.33-6.46)	Study population aged < 64 yr, no dose information about treatments, short mean follow-up
Peyrin-Biroulet et al[176], 2012	Prospective observational cohort study (CESAME)	France	19486 IBD patients	2.55 yr	MSC previously TP treated (SIR: 0; 95%CI: 0-3.11), current TP users (SIR: 1.09; 95%CI: 0.13-3.94)	Younger patient population
Abbas et al[177], 2014	Retrospective cohort; nested case control	United States	14527 patients; 421 NMSC and 45 MSC cases	8.1 yr	NMSC current AZA use (HR 2.1, 95%CI: 1.6-2.6), previous AZA use (HR 0.7, 95%CI: 0.5-1.0). MSC current AZA use (HR 1.5, 95%CI: 0.6-3.4), previous AZA use (HR 0.5, 95%CI: 90.1-1.8)	Patient population limited to VA health care system (older, white, male)
McKenna et al[178], 2014	Database inquiry (AE- (FAERS)	United States	315 skin Ca	NA	PRR, increased odds of MSC and NMSC for anti-TNF (P = 0.035 and 0.03, respectively) and combination treatment (P < 0.001 and P < 0.001)	AE database (reporting bias) skewed towards CD
Kopylov et al[179], 2015	Nested case control	Canada	19582 patients; (MSC 102 vs IBD Controls 1014) (NMSC 474 IBD vs Controls 4684)	No reported mean	NMSC: TP treatment ≥ 3 yr (OR 1.41; 95%CI: 1.11-1.79), TP treatment ≥ 5 yr (OR: 2.07; 95%CI: 1.36-3.7), combination treatment (OR: 3.11; 95%CI: 1.33-7.27). After stopping TP, OR: 1.04 (0.69-1.55). IMMs-anti-TNF were not associated with MSC	Younger, employed patients are underrepresented, not mentioned disease severity
Scott et al[180], 2016	Retrospective cohort	United States	2788 IBD patients	2.24 yr	Second NMSC with short-term TP treatment (HR 1.53, 95%CI: 0.87-2.70), with > 1 yr of TP therapy (HR 1.49, 95%CI: 0.98-2.27)	Older patient population
Nissen et al[181], 2017	2 Retrospective case-control studies	The Netherlands	304 IBD patients with MSC, 1800 IBD controls, 8177 MSC non-IBD controls		MSC: UC (pancolitis OR 3.09; 95%CI: 1.670-5.727), CD (ileocolonic disease: OR 1.98; 95%CI: 1.009-3.882). Corticosteroids (OR 1.41-3.72), anti-TNF UC (OR 0.15-0.88), CD (0.27-0.92). (only attributed to the in situ MSC). Survival with anti-TNF (HR 0.32; 95%CI: 0.08-1.27) and TP (HR 0.72; 95%CI: 0.37-1.31). Survival after MSC diagnosis anti-TNF (HR 0.16, 95%CI: 0.02-1.21) and TP (HR 0.55, 95%CI: 0.25-1.23)	Medication of patients after 1990 was included. Not informed about skin type, number of sun burns
Clowry et al[182], 2017	Retrospective cohort	Ireland	2053 patients with IBD	9.8 yr	NMSC under IMMs SIR 1.8 (95%CI: 1.0-2.7), TP exposure (OR: 5.26, 95%CI: 2.15-12.93, P < 0.001), TP and/or anti-TNF (OR: 6.45, 95%CI: 2.69-15.95, P <0.001)	Small sample size, hospital database mostly severe IBD
Khan et al[183], 2020	Retrospective cohort	United States	54919 patients with IBD; VAHS 518 patients with BCC	5.71 yr	Repeated BCC occurrences, compared with 5-ASA, under active TP use (HR 1.65, 95%CI: 1.24-2.19, P = 0.0005), 6 mo after TP discontinuation (HR 1.22, 95%CI: 0.86-1.74, P = 0.26), for anti-TNF use (HR 1.27, 95%CI: 0.84-1.90, P = 0.26), for combination treatment (HR 1.37, 95%CI: 0.90-2.08, P = 0.14)	Study population mostly males. Prescriptions outside VAHS not included

IBD: Inflammatory bowel disease; Ca: Cancer; NMSC: Non-melanoma skin cancer; AZA: Azathioprine; OR: Odds ratio; CI: Confidence interval; 6MP: 6-Mercaptopurine; IRR: Incidence rate ratio; TP: Thiopurine; CD: Crohn’s disease; BCC: Basal cell cancer ; SCC: Squamous cell carcinoma; HR: Hazard ratio; IMMs: Immunomodulators; MSC: Melanoma skin cancer; SIR: Standardized incidence ratio; anti-TNF: Anti-tumor necrosis factor; NA: Not applicable; PRR: Projection pursuit regression; AE: Adverse events; 5-ASA: 5-Aminosalicylic acid; VAHS: Veterans affairs healthcare system.